kenhktsui/code-natural-language-classification-dataset

text stringlengths 2 1.05M	repo_name stringlengths 5 101	path stringlengths 4 991	language stringclasses 3 values	license stringclasses 5 values	size int64 2 1.05M
Cadmium concentrations in human kidneys from the UK. The concentration of cadmium in the cortex and medulla of nearly 1000 kidneys obtained at autopsy was determined by atomic absorption spectrophotometry. Particular care was taken over the analytical procedures to ensure the accuracy and precision of the results; intrakidney variability was examined and found to be small. The frequency distributions of cadmium concentrations were approximately lognormal. There was much variability in cadmium concentrations between individuals, with geometric coefficients of variation for both cortex and medulla of around 100%. Cadmium concentrations varied with age and smoking habits, but not sex. Values were successively higher than those in the previous age-group up to 50-59 years (geometric mean 19 micrograms/g), after which they were successively lower; on average, heavy smokers had cadmium concentrations some 15-20% higher than those in light smokers who in turn had values some 15-20% higher than those in non-smokers. No definite conclusions could be reached on the variation of cadmium concentrations with either cause of death or location, or over time. The present study, the first of its kind in the UK, has provided benchmark data; its results are broadly in line with those from previous but smaller studies in other countries.	null	minipile	NaturalLanguage	mit	null
You can't blame the Cleveland Browns for wanting to get this one right. A franchise that historically hasn't had much luck in the draft, Cleveland is leaving no stone unturned in their quest to draft someone who'll actually be on the roster four years from now. According to CBS Sports, now-departed team president Joe Banner commissioned the study last year, and current management decided to let it play out - the money had already been spent. Jason La Canfora says the study was extremely thorough: "[it evaluated] decades of successful NFL quarterbacks and [took] all sorts of variables into consideration...and ultimately pointed to Teddy Bridgewater having the best success rate of this year's group of quarterbacks." It's hard to find a consensus on Bridgewater - some draft analysts - like our own Tom Downey - agree with the study, while others are far from optimistic about his NFL future. The Browns have the fourth pick in tonight's draft, and we'll find out then if they decided to take the results of their $100,000 study to heart. Our latest mock draft has them going in a slightly different direction, and it's	null	minipile	NaturalLanguage	mit	null
Q: In BroadcastReceiver, getResultCode() always returns -1 for SMS sent and delivered actions Following most people I guess, I am deriving my SMS handling code from http://mobiforge.com/developing/story/sms-messaging-android. I am trying to catch the broadcasts for sent and delivered messages, with this code (for sent messages): appContext.registerReceiver(new BroadcastReceiver() { @Override public void onReceive(Context arg0, Intent arg1) { Log.i("Debug", "My embedded receiver: " + String.valueOf(getResultCode())); } }, new IntentFilter("iam.applications.SmsReceiver.SMS_SENT")); This always results in getResultCode() returning a value of -1, even when the SMS is successfully sent. I don't know of another way to tell whether my SMS was sent or not. I have also subclassed BroadcastReceiver to see if that makes any difference, but it does not. -1 is always returned: @Override public void onReceive(Context context, Intent intent) { String action = intent.getAction(); Log.i("Debug", "Result code in onReceive: " + String.valueOf(getResultCode())); } My creation of the PendingIntent looks like this (snippet from a for-loop for processing parts of long SMS messages): Intent sentIntent = new Intent( "iam.applications.SmsReceiver.SMS_SENT"); sentIntent.putExtra(SmsHandler.PHONE_NUMBER, phoneNumber); sentIntent.putExtra(SmsHandler.MESSAGE, message); sentPIArray.add(PendingIntent.getBroadcast(appContext, (int) Calendar.getInstance().getTimeInMillis(), sentIntent, PendingIntent.FLAG_UPDATE_CURRENT)); A: I'm a big idiot: // Field descriptor #14 I public static final int RESULT_OK = -1;	null	minipile	NaturalLanguage	mit	null
The lived experiences of midwives with spirituality in childbirth: mana from heaven. The purpose of this study was to describe the lived experiences of midwives who experienced the phenomenon of spirituality when they attended births. The research design was descriptive, using a transcendental phenomenological approach reflected in Moustakas' model. Purposive and snowball sampling were used to recruit the sample of 10 certified nurse-midwives. The major findings of this study consisted of 5 theme categories that revealed the essential structure of the midwives' lived experiences of spirituality during childbirth: belief in the existence of a higher power, the essence of spirituality, birth is spiritual, the essence of midwifery, and relationships. The midwives in the study experienced spirituality as an integral and essential component of childbirth. The midwives reported using elements of spirituality as instruments that helped them assist their clients through the process of pregnancy and birth. The midwives also revealed their dependence on spirituality and belief in a higher being who guided their lives and their calling to midwifery.	null	minipile	NaturalLanguage	mit	null
people are angrier at women who claim to hate men than at men who actually hate, rape, kill and abuse women. ok then.	null	minipile	NaturalLanguage	mit	null
WATCH: Lafontaine Tunnel work: "significant" impact on traffic There's another major roadwork project heading your way and that means more traffic problems. Work on the 50-year-old Lafontaine Tunnel will begin after the new Champlain Bridge is up and running, sometime around 2020. That will take about four years and result in traffic disruptions, said junior minister for major transport projects Marie-France Bérard. "Two years will have significant impact on mobility, two years will be partial because we will work (at) night or not where cars or trucks are using (the tunnel)," said Bérard at a news conference updating the project. Bérard said they will introduce mitigation measures before that to try to change motorists' habit and ease traffic congestion, such as increased bus service and more incentive parking at bus, metro and train stations. Jr minister in charge of major transport projects Marie-France Bérard says they hope to change motorists' habits before work begins. #CJADpic.twitter.com/vy7dSqe1p6 Revamping the tunnel will include repaving, modernizing the lighting, ventilation and drainage, redoing the walls and ceiling, and adding an extra layer of fire protection. Officials said it's too early to say whether the work will be around the clock. The newly refurnished tunnel will not have tolls. The project will not be a private-public partnership but rather a formula that will see the company responsible for the design, the construction and the finaincing, making the company accountable not only to the government but to the lenders for the financing of the project. Reports say the project will cost an estimated one billion dollars. As many as 100,000 cars and 15,000 trucks pass through the tunnel every day. Quebec school boards ran a collective $141 million dollar surplus last year, but the president of the Quebec Federation of School Boards says given that the annual school board budget is $11 billion, the surplus is modest.	null	minipile	NaturalLanguage	mit	null
CIVIL SERVICE COMPENSATION SCHEME That this House is concerned by the Government's proposed reforms of the Civil Service Compensation Scheme (CSCS); notes the proposal to drastically cut civil service compensation payments by between 25 and 60 per cent, affecting thousands of civil servants across the UK; is alarmed that these reforms are being brought forward at the same time as hundreds of government offices are closing and departments are facing immense pressure to downsize, putting thousands of civil service jobs at risk; is aware that the then Minister for the Cabinet Office introduced changes to the CSCS in 2010 which he described as fair and sustainable in the long term; further notes that an equality impact assessment on these proposed new reforms has not been carried out; is concerned that cuts to the CSCS may affect older workers, women, those with disabilities and BME civil servants; notes that civil servants across the UK are facing an uncertain future and that additional uncertainty regarding exit payments has had a negative impact on staff morale and health; and therefore calls on the Government to halt its plans to further cut the CSCS and instead invest in the civil service through staff training, decent pay rises and honouring the terms and conditions of all civil servants.	null	minipile	NaturalLanguage	mit	null
Ecotin modulates thrombin activity through exosite-2 interactions. Ecotin is a Escherichia coli-derived protein that has been characterized as a potent inhibitor of serine-proteases. This protein is highly effective against several mammalian enzymes, which includes pancreatic and neutrophil-derived elastases, chymotrypsin, trypsin, factor Xa, and kallikrein. In this work we showed that ecotin binds to human alpha-thrombin via its secondary binding site, and modulates thrombin catalytic activity. Formation of wild type ecotin-alpha-thrombin complex was observed by native PAGE and remarkably, gel filtration chromatography showed an unusual 2:1 ecotin:enzyme stoichiometry. Analysis of the protease inhibitor effects on thrombin biological activities showed that (i) it decreases the inhibition of thrombin by heparin/antithrombin complex (IC50=3.2 microM); (ii) it produces a two-fold increase in the thrombin-induced fibrinogen clotting; and (iii) it inhibits thrombin-induced platelet aggregation (IC50=4.5 microM). Allosteric changes on thrombin structure were then evaluated. Complex formation with ecotin caused a three-fold increase in the rate of thrombin inhibition by BPTI, suggesting a displacement of the enzyme's 60-loop. In addition, ecotin modulated the enzyme's catalytic site, as demonstrated by changes in the fluorescence emission of fluorescein-FPRCK-alpha-thrombin (EC50=3.5 microM). Finally, solid phase competition assays demonstrated that heparin and prothrombin fragment 2 prevents thrombin interaction with ecotin. Altogether, these observations strongly support an ecotin interaction with thrombin anion-binding exosite-2, resulting in modulation of its biological activities. At this point, ecotin might be useful as a new tool for studying thrombin allosteric modulation.	null	minipile	NaturalLanguage	mit	null
86m3/5 - 4722m*2 + 209738m/5 - 36788 = 0. -1082, -17, 1, 5 Let 27t4/2 - 233208t*3 - 622041t*2/2 + 906915t + 1295700 = 0. What is t? -5/3, 2, 17276 Factor 2m3/7 + 74m*2/7 - 12356m/7 + 24400/7. 2(m - 61)(m - 2)(m + 100)/7 Find i, given that -i5/4 + 215i*4/2 + 11703i*3/4 + 17442i*2 = 0. -17, -9, 0, 456 Factor -2m*3/15 + 725896m*2/15 + 1451798m/15 + 145180/3. -2(m - 362950)(m + 1)*2/15 Factor -2d*2/13 + 216020d/13 + 7779312/13. -2(d - 108046)(d + 36)/13 What is f in 3f2/2 + 5320998f - 53210055/2 = 0? -3547337, 5 Factor t*5/2 - 97t*4 + 6561t*3 - 195426t*2 + 4884165t/2 - 8085825. (t - 90)(t - 33)3(t - 5)/2 Factor 2t3 - 436870t*2 - 1747522t + 2184390. 2(t - 218439)(t - 1)(t + 5) Solve -45v*5 - 94965v*4 - 25692470v*3 - 158491270v*2 + 114239075v - 19516805 = 0. -1793, -311, -7, 1/3 Factor 4g2 + 233656g + 467296. 4(g + 2)(g + 58412) Factor o*2/5 - 385438374o/5 + 37140685037940969/5. (o - 192719187)*2/5 Find p such that -2p*3 - 2244312p*2 + 17954592p - 35909248 = 0. -1122164, 4 Find j, given that -j*5/3 + 3029j*4 - 18162j*3 - 18j*2 + 163485j - 245187 = 0. -3, 3, 9081 Factor 464840820d3 + 932092140d*2 + 4824125d + 6250. 5(d + 2)(9642d + 25)2 Factor -3p*2 - 42024p + 1432284. -3(p - 34)(p + 14042) Find y such that -4y2 - 262220y + 2098016 = 0. -65563, 8 Solve 2f2 - 14474f - 19864120 = 0. -1180, 8417 What is u in -u*2/2 - 29657u/2 + 608809 = 0? -29698, 41 Factor -25m2/4 + 95495m/4 + 12513115/2. -5(m - 4066)(5m + 1231)/4 Find n, given that 20n*4 + 7444305n*3 - 13027700n*2 - 39082695n + 33499530 = 0. -372217, -2, 3/4, 3 Factor -2k2 - 1101866k + 52894176. -2(k - 48)(k + 550981) Factor -k*2/9 - 5380k/9 + 430100/3. -(k - 230)(k + 5610)/9 Suppose 2x*5 + 836x*4 - 31448x*3 + 124636x*2 + 2695350x = 0. What is x? -453, -7, 0, 17, 25 Suppose -7i4/3 - 15878i*3/3 + 17583979i*2/3 + 5025290i/3 = 0. What is i? -3083, -2/7, 0, 815 Factor 2w3 + 1188738w*2 + 176640225888w + 883171411240. 2(w + 5)(w + 297182)*2 What is a in 5a*4 - 3770a*3 - 3795a*2 + 15080a + 15100 = 0? -2, -1, 2, 755 Let i*4/4 + 1382519i*3/4 + 159279783570i*2 + 24467392300046800i - 24467551580176000 = 0. Calculate i. -460840, 1 Find g such that 361g4/4 + 3553g*3/4 - 61889g*2/2 + 170816g - 270504 = 0. -26, 68/19, 9 Let -2q3/3 + 2670258q*2 - 2673836813200q - 104280989540000/3 = 0. What is q? -13, 2002700 Determine g, given that -81g4/10 - 16353g*3/5 - 956269g*2/10 + 47347386g - 1697548410 = 0. -258, 505/9 Find a such that 5a3 - 8935a*2 - 1014380a + 2064460 = 0. -109, 2, 1894 Factor -3m2/4 + 77607m/4 + 194848605/2. -3(m - 30174)(m + 4305)/4 Solve 189a3 + 74139a*2 - 264320688a + 75514140 = 0 for a. -1395, 2/7, 9022/9 Factor -3v2 + 35019v - 7525278. -3(v - 11454)(v - 219) Factor 2m3/15 - 64m*2/15 - 274m/5 - 252/5. 2(m - 42)(m + 1)(m + 9)/15 Factor 90h*5 - 585628h*4/9 - 482h*3/3. 2h*3(h - 723)(405h + 1)/9 Factor -2l2/3 + 43802l/3 + 5614308. -2(l - 22279)(l + 378)/3 Factor 142j2/7 + 24700j/7 + 1062528/7. 2(j + 96)(71j + 5534)/7 Suppose -5c*4 + 505c*3 - 9520c*2 - 93100c = 0. Calculate c. -7, 0, 38, 70 Find r such that 361r5 - 26144r*4 - 1294986r*3 + 11182824r*2 + 20026305r + 8213400 = 0. -39, -15/19, 9, 104 Find d such that -2d3/9 - 66362d*2/9 - 3511672d/9 - 3445312/9 = 0. -33128, -52, -1 Factor 4o4 + 2188o*3 + 27816o*2 + 25632o. 4o(o + 1)(o + 12)(o + 534) Determine n so that n*2 + 28304986n + 200293058115049 = 0. -14152493 What is f in 2f2 - 8383980f - 25151958 = 0? -3, 4191993 Suppose -4l3/3 + 12073876l*2/3 - 48295420l/3 - 20123100 = 0. Calculate l. -1, 5, 3018465 Let -3b5 + 23241b*4 - 45486246b*3 + 1838199162b*2 - 23517675543b + 90098001021 = 0. What is b? 7, 17, 3853 Determine q so that -q*4/5 + 12997604q*3/5 - 42234401439972q*2/5 - 33787593938592q + 506813441164992/5 = 0. -6, 2, 6498804 Find a, given that -a*4 - 843a*3 - 232776a*2 - 21135280a = 0. -355, -244, 0 Factor 3y3/2 + 84081y*2/2 - 378486y. 3y(y - 9)(y + 28036)/2 Let -3h*3 - 101301h*2 - 428868048h + 7944735260700 = 0. Calculate h. -20146, 6525 Suppose 3w2 + 1032279w/4 + 258069/4 = 0. Calculate w. -86023, -1/4 Determine p, given that -2p4/5 - 3002798p*3/5 - 1127097977196p*2/5 + 225421397120p + 450840392000 = 0. -750700, -1, 2 Let -40q4 - 136325q*3 - 153320q*2 - 17035q = 0. Calculate q. -3407, -1, -1/8, 0 Let 2i4/15 + 422i*3/15 + 17126i*2/15 + 53118i/5 - 312984/5 = 0. What is i? -161, -27, 4 Let -2g2 - 1523123984g - 289988333829504032 = 0. Calculate g. -380780996 Factor -s*3 + 119s*2 + 39734s + 1116864. -(s - 277)(s + 32)(s + 126) Factor 3i3/5 - 232839i*2/5 + 651861i - 11407053/5. 3(i - 77599)(i - 7)2/5 Factor -j2/4 - 1685j/2 + 3374. -(j - 4)(j + 3374)/4 Determine i so that -3i5/2 - 24i*4 + 4281i*3/2 - 31551i*2 + 160212i - 210912 = 0. -52, 2, 8, 13 Factor -l*2/3 - 489957736l/3 - 60014645766561424/3. -(l + 244978868)*2/3 Find k, given that -2k*5/7 + 2462k*4/7 + 29886k*3/7 - 9450k*2 - 1208196k/7 = 0. -9, 0, 6, 1243 Suppose -1471369s2/7 - 7848110s/7 - 10465225/7 = 0. Calculate s. -3235/1213 Factor d*2/2 + 127800092d + 8166431757604232. (d + 127800092)*2/2 Determine k so that -2k*3/19 - 175288k*2/19 + 1227114k/19 = 0. -87651, 0, 7 Suppose 4o4/3 - 662868o*3 - 6628772o*2 - 61647844o/3 - 19886440 = 0. What is o? -5, -3, -2, 497161 Solve -614m2 + 29646m - 177436 = 0. 7, 12674/307 Factor -4w2 + 1002152w + 1002156. -4(w - 250539)(w + 1) Let t*4/3 - 232t*3 + 109349t*2/3 + 713442t + 3297240 = 0. Calculate t. -9, 284, 430 Determine r so that -2r5 + 52r*4 + 438r*3 - 1728r*2 = 0. -9, 0, 3, 32 What is m in -2m*3/5 + 105054m*2/5 + 9677664m/5 + 222683608/5 = 0? -46, 52619 Determine t so that 2t5/11 - 399624t*4/11 - 3996368t*3/11 - 1307916t*2 - 21580722t/11 - 10790388/11 = 0. -3, -1, 199822 Factor 3f2 + 51047592f + 217154720749872. 3(f + 8507932)2 Let -4h*3 + 2931580h*2 + 4h - 2931580 = 0. Calculate h. -1, 1, 732895 Factor 4c3 - 53728c*2 + 218547540c - 280343939976. 4(c - 7186)(c - 3123)*2 Solve 4g*2/3 - 6177488g + 7155254623152 = 0 for g. 2316558 Factor -5g3 - 2105g*2 - 78470g - 216600. -5(g + 3)(g + 38)(g + 380) Suppose -3x*2/4 + 1902960x - 1207085587200 = 0. What is x? 1268640 Suppose -h*3/4 - 95147h*2/4 + 2284081h/4 - 2188933/4 = 0. Calculate h. -95171, 1, 23 What is b in -129b4/2 - 12516b*3 - 698409b*2/2 + 344985b + 16800 = 0? -160, -35, -2/43, 1 Let 2t3 - 442t*2 - 50464t = 0. Calculate t. -83, 0, 304 Find q such that q*3 - 361q*2 + 719q - 359 = 0. 1, 359 Determine l, given that 97l4/9 + 11090l*3/3 - 33905l*2/9 - 22130l/3 + 688/9 = 0. -344, -1, 1/97, 2 Solve -2y3 - 189088y*2 + 756378y - 567288 = 0 for y. -94548, 1, 3 Let 3a4/4 - 5711a*3/4 + 172283a*2/4 + 61871a/4 - 58063/2 = 0. Calculate a. -1, 2/3, 31, 1873 Factor -3i4 - 13228104i*3 - 14581894619568i*2. -3i*2(i + 2204684)2 Find y, given that -y5/3 + 182y4/3 - 3016y*3 + 62096y*2/3 + 531824y/3 - 414176 = 0. -6, 2, 14, 86 What is q in -3q4 + 28011q*3 + 504903q*2 + 2497569q + 2020680 = 0? -9, -8, -1, 9355 Determine u so that u*4/5 - 6304u*3/5 + 711961u*2/5 - 1398714u/5 = 0. 0, 2, 113, 6189 Find i such that -2i4/9 - 760i*3/3 - 183082i*2/3 - 4174888i/9 + 5843200/3 = 0. -800, -332, -11, 3 Find v, given that -6v4/11 + 522v*3/11 + 134472v*2/11 - 1242360v/11 + 1942752/11 = 0. -118, 2, 7, 196 Solve 5y3 + 7265y*2 + 2374335y - 12053925 = 0. -951, -507, 5 What is o in -17150o5/3 + 102896o*4/3 - 188626o*3/3 + 102856o*2/3 + 8o = 0? -2/8575, 0, 1, 2, 3 Suppose -4m2/3 - 502031686m/3 + 83671948 = 0. What is m? -125507922, 1/2 Determine i so that 3i2/5 + 53862i/5 + 430704/5 = 0. -17946, -8 Let -3z4 + 70320z*3 + 844452z*2 - 4221552z + 4502784 = 0. Calculate z. -16, 2, 23452 Factor 2t2/5 - 3114t/5 - 356096/5. 2(t - 1664)(t + 107)/5 Find d such that -d*2/2 - 125503d/2 - 125501 = 0. -125501, -2 D	null	minipile	NaturalLanguage	mit	null
Kavacham is a Sanskrit word for armour and Stotras are hymns sung in praise and worship. So, together Kavacha Stotras are hymns which are sung to obtain divine protection. Here in Kavacha Sangraha, we present you a collection of various Kavachams- which are the Kavacha Stotras. Usually such hymns are sung to obtain specific protection at specific times in one’s life and then there are other kavacham stotras which are typically sung to obtain general armour of divine’s blessings- to protect oneself from general problems and mishaps in day to day living. There are kavacham which are sung to various divine energies, such as those covered in this app- e.g. Ganesh Kavacham, Gayatri Kavacham, Shiva Kavacham etc. This is a prayer app-tool. You can use the favorites feature to mark the parts you are praying or contemplating and then use the Journal feature to write down any guidance, insight or directives you receive. Then using standard iOS features such as copy-paste, text and email; you can share your insights with others. Please note (check screen shots) that the menu commands, text editor and other app features are in English. The actual Kavacha Sangraha content is presented in Devanagri script with English transliteration.	null	minipile	NaturalLanguage	mit	null
The Comparison of Experiential Avoidance, [corrected] Mindfulness and Rumination in Trauma-Exposed Individuals With and Without Posttraumatic Stress Disorder (PTSD) in an Iranian Sample. The aim of this study was to compare experimental avoidance, mindfulness and rumination in trauma-exposed individuals with and without PTSD in an Iranian sample. The method of the study was retrospective. The statistical population of the study composed of all people under the auspices of Committee on Relief or Martyr Foundation because of exposure to at least one traumatic event in Gilan-Gharb city (Iran) (N=1708). One hundred people, selected randomly by stratified sampling method, responded to Mississippi PTSD scale and the questionnaires of experimental avoidance, mindfulness and rumination individually. Subjects were divided into two groups of with and without PTSD based on Mississippi PTSD scale and structured clinical interview. Multivariate analysis of variance (MANOVA) test was used for analyzing data. Results showed that although the mean scores of the group with PTSD were significantly higher than the group without PTSD in variables of experimental avoidance (P<0/001, F=63/8) and rumination (P<0/001, F=21/34), the mean scores of the group with PTSD were significantly lower than the group without PTSD in the overall score of mindfulness (P<0/05, F=6/64) and variables of observing (P<0/05, F=8/27) and action description (P<0/05, F=9/19). These results show that the experimental avoidance and rumination are as the risk factors and mindfulness as the protective factor PTSD in people faced with trauma.	null	minipile	NaturalLanguage	mit	null
After seizing power in a bloody CIA-backed coup, General Augusto Pinochet ruled Chile with a rod of iron for two decades, during which human rights violations became the norm of Chilean life. Hailing from an upper-middle class background, Pinochet entered the military academy in Santiago at the age of 18, graduating three years later as a second lieutenant. By 1968 he had risen to the rank of brigadier general. In 1970, Salvador Allende, a Marxist, became president of Chile with the backing of the Christian Democrats, and began restructuring Chilean society along socialist lines. In the process he expropriated the US-owned copper-mining companies, alienating the US government and foreign investors. He further annoyed Washington by establishing relations with Cuba and Communist China, which the United States did not recognise at that time. As a result, America imposed tough economic sanctions and the CIA spent millions of dollars destabilising the Allende regime, much of it going into Pinochet’s pockets. By 1972, the Chilean economy had collapsed. With no foreign investment, production had come to a standstill. There were widespread strikes, inflation, food shortages and civil unrest. With the backing of armed forces, Pinochet staged a military coup on 11 September 1973. It was bloody even by Latin American standards. The navy seized the key port of Valparaiso, while the army surrounded the presidential palace in Santiago. Allende refused to step down. When the palace was overrun a few hours later, he was found dead. It appears that he shot himself rather than face inevitable torture and execution. A junta took over and declared marital law. Those who violated the curfew were shot on sight. Pinochet was named president two days later. He broke off relations with Cuba – Nixon had staged his famous rapprochement with China by then – and moved against Allende’s supporters. Some 14 000 would be tried and executed or expelled from the country, while Pinochet claimed he was only trying to ‘restore institutional normality’ of Chile. In June 1974 Pinochet assumed sole power, with the rest of the junta relegated to an advisory role. Under Pinochet’s tyrannical rule, it is estimated that 20 000 people were killed and torture was widespread. While Pinochet continued to maintain tight control over the political opposition, he was rejected by a plebiscite in 1988. He eventually stepped down in 1990 after immunity from prosecution in Chile. He stayed on as army chief of staff. However, during a shopping trip to London in October 1998, he was arrested on a Spanish warrant charging him with murder. He was later accused of torture and human rights violations. For 16 months, he fought his extradition through the British courts, and then in January 2000, Home Secretary Jack Straw decided that he was too ill to stand trial and sent him back to Chile.	null	minipile	NaturalLanguage	mit	null
In a letter to customers, the Apple CEO called the move from the EU “unprecedented” and “harmful.” Cook laid out the case that Apple, which has had operations in Ireland since 1980 and currently employees close to 6,000 people in the country, fully abides by international and local law with the rate of tax that is pays in the European country. “The European Commission has launched an effort to rewrite Apple’s history in Europe, ignore Ireland’s tax laws and upend the international tax system in the process. The opinion issued on August 30th alleges that Ireland gave Apple a special deal on our taxes,” Cook wrote. “This claim has no basis in fact or in law. We never asked for, nor did we receive, any special deals. We now find ourselves in the unusual position of being ordered to retroactively pay additional taxes to a government that says we don’t owe them any more than we’ve already paid,” he added. Cook acknowledged that tax laws for companies that do business globally are challenging. He argued, however, that by paying its taxes “where the value is created,” Apple has done nothing wrong and it is being unfairly targeted by the EU. “Nearly all of our research and development takes place in California, so the vast majority of our profits are taxed in the United States. European companies doing business in the U.S. are taxed according to the same principle. But the Commission is now calling to retroactively change those rules, “Beyond the obvious targeting of Apple, the most profound and harmful effect of this ruling will be on investment and job creation in Europe. Using the Commission’s theory, every company in Ireland and across Europe is suddenly at risk of being subjected to taxes under laws that never existed,” Cook said. Cook explained that Apple supports international tax reform, but it would rather have that debate with impacted countries and their leaders than with the EU. He added that measures should take action going forward, not retroactively as the EU’s directive is. Apple plans to appeal the decision. Cook said he is “confident” that it will prevail.	null	minipile	NaturalLanguage	mit	null
Design and fabrication of computer-generated beam-shaping holograms. For the design of computer-generated holograms reconstructing certain intensity patterns with phase freedom, we use an object-oriented approach. The given intensity pattern is decomposed into elementary objects for which appropriate phase-only hologram functions can be constructed. The total hologram function is found by the subsequent superposition of its constituents, with a relative amplitude and phase weighting for each of them. Thus, the degrees of freedom are dramatically reduced compared with those of sampling approaches. The design algorithm allows us to compensate on the one hand for the intensity and phase distribution of the impinging laser beam and on the other hand for the shape of the hologram aperture. We report on the computer-aided design of such holograms, as well as their fabrication through the use of laser lithography and reactive ion etching. Optical reconstructions are shown.	null	minipile	NaturalLanguage	mit	null
Introduction {#s1} ============ Juvenile Dermatomyositis (JDM) is a systemic immune-mediated disease of childhood. It is the most common idiopathic inflammatory myopathy in children, with an incidence of 2--4/million/year ([@B1]). Although the exact etiology is still elusive, both genetic and environmental factors are thought to play a role in the development of the disease ([@B2]--[@B5]). JDM is characterized by inflammation of skeletal muscles and skin, leading to muscle weakness and a typical skin rash of the face and hands (heliotrope rash and Gottron\'s papules, respectively), which are also used as classification criteria ([@B6], [@B7]). Next to the muscle and skin, other organs can be affected. Vital organ involvement, especially of the lungs, is still the major cause of death in JDM patients ([@B8], [@B9]). Although rare, cardiac involvement and microangiopathy of the intestine, brain and kidneys have been described ([@B10]). Thus, rather than being confined to specific tissues, JDM is a truly systemic disease, which can affect multiple organ systems. Before the introduction of corticosteroids as a treatment option, mortality and morbidity among JDM patients were high, and long-term outcomes were not the primary focus. Since then, mortality rates have dropped from over 30% to 2--3% ([@B11]). With increasing survival, long-term outcomes become an important concern of patients and physicians, as patients\' quality of life and societal participation depend on it. Long-term outcomes are likely dependent on various factors such as disease severity and activity, response to treatment and medication side effects which together determine the cumulative organ and tissue damage. Especially low-grade inflammation and extramuscular manifestations of the disease are difficult to investigate in routine clinical care and may therefore be overlooked. Unrecognized, local inflammation leading to tissue damage and subsequent organ dysfunction may have serious consequences for short-term and long-term outcomes. So far, reliable assessment of disease activity and the type and extent of tissue involvement has been rather challenging. Current clinical tools for assessment of disease activity require active collaboration of patients, which can be difficult for young, unwell children. Detecting low-grade inflammation or differentiating clinically between various causes of muscle impairment is even more challenging. Hence, there is a great need for minimally invasive, objective and reliable diagnostic tools for the assessment and monitoring of (low-grade) disease activity and related organ involvement. Optimally, such tools could guide clinical decision making, facilitate individually tailored treatment regimens, and reduce the risk of over- and under-treatment. In this review we will discuss the types of (extra)muscular tissue involvement that have been described in JDM and their relation to vasculopathic changes, critically assess the available diagnostic and monitoring tools and reflect on the immunopathogenic implications of identified markers. Signs of Systemic Disease Activity in JDM Based on affected Tissues and Organs {#s2} ============================================================================== JDM patients can present with a spectrum of symptoms. Most, but not all patients, have the classic combination of muscle involvement and typical skin rashes. Approximately 1--5% of JDM patients present with amyopathic JDM, but it was estimated that 26% of these patients will eventually progress to classical JDM, which can occur up to years after onset ([@B12]). This indicates that the phenotype can evolve over the course of the disease, possibly also dependent on treatment. True amyopathic JDM however is very rare and mild muscle involvement may be present but missed ([@B13]). Amyopathic JDM generally has a relatively mild disease course with fewer systemic manifestations, less required immunosuppressive treatment and a good prognosis ([@B12], [@B14], [@B15]). (Sub)Cutaneous and Other Extramuscular Symptoms ----------------------------------------------- Cutaneous symptoms can range from the pathognomonic heliotrope rash and Gottron\'s papules, to photosensitive rashes such as malar and truncal erythema, and severe complications such as skin ulceration and dystrophic calcinosis. Calcinosis occurs in 12--47% of patients and can occur in the skin and in subcutaneous, myofascial, or muscle tissue. Most often it is a long-term complication and its presence has been associated with delayed diagnosis and more severe disease with poorer functional outcomes. Effective treatment of calcinosis is still challenging, but aggressive high-dose immunosuppression or, in very severe cases, autologous stem cell transplantation have been shown to be able to reverse calcinosis, suggesting that chronic (low-grade) inflammation may be accountable for calcifications ([@B16]--[@B20]). Cutaneous and oral ulceration affects up to 30% of patients and is thought to result from occlusive endartheropathy of the small vessels ([@B10], [@B21]). Lipodystrophy affects 8--14% of JDM patients and is often associated with hormonal and metabolic changes ([@B10], [@B22]--[@B24]). We suspect that patients with lipodystrophy may therefore have an increased risk of cardiovascular events in the long-term. Limb edema and arthritis are also common, occurring in 11--32 and 23--58% of patients, respectively ([@B10]). Next to the skin and musculoskeletal system, other organ systems can be involved, of which the lung is the most frequently affected. Up to 75% of children with JDM develop respiratory involvement, which may result from a complication of respiratory muscle weakness or immunosuppressive therapy, or from interstitial lung disease (ILD) ([@B25], [@B26]). ILD occurs in 8--19% of juvenile myositis patients and has been described as the major cause of death in JDM ([@B27]--[@B30]). Cardiac involvement may be present subclinically more often than recognized, as even in JDM patients without clinical cardiac dysfunction abnormal ECG and echocardiographic findings are relatively common ([@B31]--[@B33]). Conduction abnormalities and myocarditis have been reported, and systolic and diastolic dysfunction was found after long-term follow-up ([@B34]--[@B37]). Cardiac complications are thought to result from myocarditis and coronary artery disease as well as involvement of the small vessels of the myocardium ([@B38]). Involvement of the gut or neural system are rare complications of JDM and are also thought to result from an underlying small vessel angiopathy or vasculitis ([@B39]--[@B41]). Intestinal consequences of the small vessel angiopathy include ulceration, perforation, hemorrhage, pneumatosis intestinalis and malabsorption ([@B42]--[@B44]). Vasculopathy ------------ The pathologic changes underlying symptoms and tissue damage in the skin, muscles, and vital organs have a common factor: in all the affected tissues typical vasculopathic changes are observed, which include loss of capillaries (capillary dropout), perivascular inflammation, and (occlusive) small vessel angiopathy ([@B21], [@B45]). In a recently reported French JDM cohort of 116 patients, vasculopathy-related complications were the main cause of admission to the intensive care unit, illustrating the severity and relevance of vascular involvement in JDM ([@B46]). These complications include life-threatening disorders like systemic capillary leak syndrome, recently also described in 3 patients with JDM ([@B47]). Deposition of complement, immune complexes and anti-endothelial antibodies is thought to play an important role in endothelial damage and subsequent capillary dropout ([@B48]--[@B54]). Clinically, the severity of vasculopathy and the disease phenotype have also been linked. The presence of prominent vascular injury in muscle biopsies identified a subgroup of patients with more severe clinical presentation and outcomes, including profound muscle weakness, limb edema and gastrointestinal involvement ([@B55]). This suggests that local vasculopathic changes can reflect systemic vasculopathy and the resulting clinical symptoms. Nailfold capillaroscopy, a commonly and easily used indicator of disease activity in clinical practice, is also based on this principle. The pathologic changes observed in nailfold capillaries, such as capillary dropout, branching and dilatation, likely reflect the systemic blood vessel abnormalities. Loss of end row nailfold capillaries is significantly associated with clinical disease activity scores for muscle and skin and can thus be used as a marker of skin and muscle activity. Nailfold capillaroscopy is especially suited as a non-invasive tool to follow up changes in disease activity over time in patients ([@B56]--[@B59]). Taken together, JDM is a truly systemic disease in which not only the muscles and skin are affected, but also vital organs can be involved. The presence of typical vasculopathic changes in the various affected tissues points toward a central role for systemic endothelial dysfunction in the pathogenesis of JDM. Monitoring of Disease Activity and Tissue Involvement {#s3} ===================================================== During clinical follow-up, monitoring of disease activity is crucial to determine the rate of medication tapering or to assess the requirement for intensification of immunosuppressive therapy. Next to clinical evaluation, various tools have been investigated for monitoring of disease activity, among which autoantibodies and other circulating biomarkers, and histopathologic evaluation of muscle biopsies, as well as several imaging techniques. Clinical Assessment ------------------- The primary and most important evaluation of disease activity involves clinical assessment by experienced clinicians and health care professionals. Over the past years, several scoring tools have been devised for internationally standardized evaluation of disease activity ([@B60]). The most commonly used tools are now the childhood myositis assessment scale (CMAS), manual muscle testing of 8 muscle groups (MMT-8), physician\'s and patient\'s global assessment on a visual analog scale (PGA), cutaneous assessment tool (CAT), cutaneous dermatomyositis disease area and severity index (CDASI), disease activity score (DAS), myositis disease activity assessment tool (MDAAT) and childhood health assessment questionnaire (CHAQ) ([@B61]--[@B69]). Combined scoring systems are currently being developed ([@B70]). The Pediatric Rheumatology International Trials Organization (PRINTO) has composed criteria for defining clinically inactive disease ([@B71]). A recent re-evaluation of these PRINTO criteria showed that skin disease may be underestimated as a factor in the assessment of disease activity ([@B72]). Clinical measures of disease activity, however, have limited capacity to detect low-grade inflammation in the tissues which does not cause overt symptoms, but may still contribute to tissue damage in the long term. Moreover, it is challenging to differentiate between various underlying causes of symptoms by clinical assessment. For example, muscle weakness may result from an ongoing inflammatory process, from medication side effects (e.g., steroid myopathy), muscle damage or effects of immobility. Biological assessment of the affected tissues and organs can therefore be helpful or even necessary to aid clinical decision-making concerning medication dose and additional interventions. Biomarkers for Disease Course, Activity, and Tissue Involvement --------------------------------------------------------------- Laboratory investigation of blood is a minimally invasive and time-efficient procedure, especially compared to muscle biopsy and some of the imaging methods. It is therefore particularly suited as a method for serial sampling during clinical follow-up. Laboratory investigation can be used for measurement of autoantibodies and for biomarkers related to disease activity and specific (extra)muscular symptoms. ### Autoantibodies Antibodies found in myositis include myositis-specific autoantibodies (MSA), relatively specific to myositis, and myositis-associated antibodies (MAA), which are observed both in myositis and other connective tissue diseases ([@B6]). In the past years, different disease phenotypes have been linked to the presence of autoantibodies and particularly myositis-specific autoantibodies ([@B16]). The frequencies of autoantibodies in juvenile patients differ substantially from adult DM patients ([@B73]). Anti-TIF1 (p155/140) and anti-NXP2 (p140 or MJ) are the most commonly identified autoantibodies in Caucasian JDM patients (20--35 and 16--23%, respectively) ([@B28], [@B73]--[@B76]). Anti-TIF1 is associated with skin ulceration, photosensitive skin rashes, lipodystrophy, and edema ([@B24], [@B75]--[@B78]), whereas anti-NXP2 is associated with a severe disease course with more profound muscle involvement, calcinosis, gastrointestinal ulceration, joint contractures, and dysphonia ([@B75], [@B77], [@B79], [@B80]). A recently identified myositis specific autoantibody which is especially frequent in the Asian JDM population, is anti-MDA5 (CADM-140) ([@B81]). It is found in 33% of Asian JDM patients, compared to 7% of Caucasian patients ([@B8], [@B82]). Patients with anti-MDA5 have a higher risk of developing ILD than patients without these antibodies. This anti-MDA5 conferred risk is seen in both Asian and Caucasian JDM cohorts, although the risk difference appears to be more pronounced in Asian cohorts ([@B8], [@B83]). Common symptoms in Caucasian patients with anti-MDA5 antibodies include oral and cutaneous ulceration, arthritis, and milder muscle disease with fewer histologic abnormalities and a higher remission rate off medication after 2 years of follow-up ([@B76], [@B82], [@B84], [@B85]). Less frequently identified autoantibodies in the juvenile population include anti-Mi2 (4--10%) and anti-amino-acyl-tRNA synthetase antibodies such as anti-Jo-1 (1--3%) and anti-SAE (\<1%). Anti-SRP and anti-HMG-CoA-reductase (Anti-HMGCR) autoantibodies, both accounting for \<3% of juvenile myositis patients, are associated with a necrotizing type of myopathy with severe muscle weakness ([@B73], [@B76], [@B86], [@B87]). It remains unclear whether each MSA reflects a distinct pathologic process, influencing the type and severity of disease phenotype and tissue involvement. Notably, autoantibodies against Jo-1, TIF1, SRP, and Mi-2 are not only informative at disease onset, but their levels have been found to correlate with disease activity during follow-up in the context of rituximab treatment ([@B88]). This highlights that perhaps autoantibodies should be measured during or soon after the first clinic visit as their levels may decline and become undetectable in remission. A last and different (not myositis-specific) category of autoantibodies identified in JDM comprises autoantibodies against components of endothelial cells, which are thought to contribute to capillary loss. These anti-endothelial cell autoantibodies (AECA) were detected in 76% of JDM patients, as opposed to 30% of control patients ([@B49]). Twenty-two candidate target autoantigens for AECA were identified in JDM plasma, 17 of which were proteins associated with antigen processing and protein trafficking ([@B50]). Identification of autoantibody targets may provide novel insights into the auto-immune process and self-antigens involved in JDM. ### Biomarkers for Systemic Inflammation and Muscle Disease Activity Reliable assessment of disease activity during follow-up can be aided by laboratory markers that represent systemic and/or local inflammation. Especially for detection of low-grade inflammation and for differentiation between various causes of muscle weakness, laboratory investigation can be a helpful or even necessary tool. So far, reliable and validated laboratory markers for disease activity and tissue involvement in JDM are still lacking. A large number of proteins in plasma, serum, and urine as well as circulating immune cell subsets have been investigated as potential biomarkers for (tissue-specific) disease activity in patients with JDM (Tables [1](#T1){ref-type="table"}, [2](#T2){ref-type="table"}). In theory, every biological parameter that can be measured, could serve as a biomarker. To be suited for use in clinical practice however, a biomarker has to meet additional criteria, such as being reliable, robust, relatively stable and easy to measure. In the following paragraphs we highlight all biological markers that have been associated with disease activity in JDM, regardless of their suitability for use in clinical practice, as some of these identified markers may still contribute to the understanding of the immunopathogenesis of JDM. However, it is important to note that due to the rarity of the disease, many of these studies were carried out in small cohorts of \<30 patients (as outlined in Tables [1](#T1){ref-type="table"}, [2](#T2){ref-type="table"}). Insights based on such small numbers have limitations in a heterogeneous disease like JDM. Therefore, validation of identified markers in larger cohorts is crucial before implementation into clinical practice. ###### Biomarkers for disease activity in JDM cohorts. Biomarker Global disease activity Muscle disease activity Other activity measures Patients Material & technique Cohort References -------------------------------------------------------------- ------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------------------------------------- --------------------------------------------------------- ---------------------------------------------------------------------- ---------------------------------------------- -------------------------- Interferon related biomarkers MxA ++++[^\\^](#TN2){ref-type="table-fn"} (DAS, O), +++[^\^](#TN1){ref-type="table-fn"} (DAS, FU) NS (skin DAS) 14 act JDM: 7 untreated, 7 treated PBMC, qRT-PCR USA O\'Connor [@B89] IFNα activity \#\#\#[^\^](#TN1){ref-type="table-fn"} (DAS, off therapy at 36 months) NS (DAS) \#\#\#[^\\^](#TN2){ref-type="table-fn"} (skin DAS, off therapy at 36 months), [^\\^](#TN2){ref-type="table-fn"} (vsHC) 39 JDM and 19 ped HC Serum, Functional reporter assay USA Niewold [@B90] IFN gene score r~p~: NS (DAS) r~p~: NS (DAS) 27 JDM Whole blood, qRT-PCR USA Baechler [@B91] IFN chemokine score r~p~: ++[^\\^](#TN2){ref-type="table-fn"} (DAS) r~p~: ++[^\^](#TN1){ref-type="table-fn"} (DAS) 29 JDM Eotaxin \+[^\\^](#TN2){ref-type="table-fn"} (DAS) NS (DAS) \+[^\\^](#TN2){ref-type="table-fn"} (skin DAS), [^\^](#TN1){ref-type="table-fn"} (vsHC) 54 JDM Serum, Luminex Norway Sanner [@B92] MCP-1 \+ [^\^](#TN1){ref-type="table-fn"} (DAS) NS (DAS) NS (skin DAS), [^\\^](#TN2){ref-type="table-fn"} (vsHC) 54 age+sex matched controls IP-10 NS (DAS) NS (DAS) NS (skin DAS), [^\^](#TN1){ref-type="table-fn"} (vsHC) Median time 16.8 yrs after onset IP-10 +++[^\\\^](#TN3){ref-type="table-fn"} (PGA) \#\#\#[^\\\^](#TN3){ref-type="table-fn"} (CMAS) 2014: 25 JDM (18 act, 19 rem), 14 ped HC, 8 NIMD Plasma and serum, Luminex NL Enders [@B93], [@B94] TNFR2 +++[^\\\^](#TN3){ref-type="table-fn"} (PGA) NS (CMAS) Galectin-9 +++[^\\\^](#TN3){ref-type="table-fn"} (PGA) \#\#[^\\^](#TN2){ref-type="table-fn"} (CMAS) 2015: 3 refractory JDM (pre and post aSCT) Soluble IL-2R [^\\^](#TN2){ref-type="table-fn"} (diagnosis vs. rem) 7 JDM: 7 at diagnosis, 7 in rem Serum, ELISA & HPLC Japan Kobayashi [@B95] Neopterin Higher in act than rem Neopterin +++[^\\\^](#TN3){ref-type="table-fn"} (act), ++++[^\^](#TN1){ref-type="table-fn"} (FU 3 pts) (both with study-specific DAS) 15 JDM (21 samples: 12 act, 9 rem) Serum, radioimmunoassay Italy De Benedetti [@B96] Urine neopterin ++[^\\^](#TN2){ref-type="table-fn"} (PGA) \#\#\#[^\^](#TN1){ref-type="table-fn"} (MMT), \#\#[^\\^](#TN2){ref-type="table-fn"} (CMAS) ++[^\\^](#TN2){ref-type="table-fn"} (skin VAS), ++[^\\^](#TN2){ref-type="table-fn"} (CHAQ), ++[^\\^](#TN2){ref-type="table-fn"} (MRI) 39 JDM, 3 JDM with overlap CTD, 3 JPM Urine and plasma, ELISA, HPLC, gas chromatographic mass spectrometry USA Rider [@B97] Urine quinolonic acid ++[^\\^](#TN2){ref-type="table-fn"} (PGA) \#\#\#[^\^](#TN1){ref-type="table-fn"} (MMT), \#\#[^\\\^](#TN3){ref-type="table-fn"} (CMAS) ++[^\\\^](#TN3){ref-type="table-fn"} (CHAQ), ++[^\\^](#TN2){ref-type="table-fn"} (MRI) Plasma neopterin/quinolonic acid NS (PGA) NS (CMAS, MMT) OTHER MARKERS OF INFLAMMATION MRP8/14 +++[^\\\^](#TN3){ref-type="table-fn"} (PGA) \#\#[^\\^](#TN2){ref-type="table-fn"} (CMAS) NS (CHAQ) 56 JDM Serum, ELISA UK Nistala [@B98] CRP Low during relapse in 4 patients 9 JDM: 4 during relapse and 3 rem Serum UK Haas [@B99] IMMUNE CELL SUBSETS* Changes in %CD19+ cells ++[^\^](#TN1){ref-type="table-fn"} (DAS) PBMC, flow cytometry USA Eisenstein [@B100] T cell subsets NS (DAS) T cell activation (CD25, HLA-DR) NS (DAS) T cell recognition of human Hsp60 Higher in rem than act 22 JDM: 6 new-onset, 6 act, 10 rem PBMC, ^3^H-thymidine assay NL Elst [@B101] Th1 within CXCR5+ CD4 T cells Higher in rem than act[^\\\^](#TN3){ref-type="table-fn"} 45 JDM (52 samples): 26 act, 26 rem, 43 ped HC PBMC, Flow cytometry USA Morita [@B102] Ratio (Th2+Th17)/Th1 in CXCR5+ CD4 T cells Higher in act than rem[^\\\^](#TN3){ref-type="table-fn"} \% Plasmablasts (CD19+CD20--CD27+CD38++) Higher in act than rem[^\\\^](#TN3){ref-type="table-fn"} Change in % CD3+CD69+ T cells ++[^\^](#TN1){ref-type="table-fn"} 24 JDM PBMC, Flow cytometry USA Ernste [@B103] Change in HLA-DR- CD11c+ mDC ++[^\^](#TN1){ref-type="table-fn"} (extra) Change in HLA-DR- CD123+ pDC \#\#[^\^](#TN1){ref-type="table-fn"} \% FOXP3+ Tregs NS (CMAS) 48 JDM: 21 act, 27 rem Muscle biopsies, immunohistochemistry NL Vercoulen [@B104] Defective suppressive function of Tregs In 4/11 active pts vs. 0/9 in remission Flow cytometry, ^3^H-thymidine incorporation RORC [^\^](#TN1){ref-type="table-fn"} [^\^](#TN1){ref-type="table-fn"} NS (extra) 26 JDM new-onset Whole blood, qRT-PCR USA Lopez de Padilla [@B105] IL-17F NS [^\^](#TN1){ref-type="table-fn"} NS (extra) GATA3 NS [^\^](#TN1){ref-type="table-fn"} NS (extra) STAT4 [^\\\^](#TN3){ref-type="table-fn"} [^\\\^](#TN3){ref-type="table-fn"} NS (extra) Changes in STAT6 NS NS [^\^](#TN1){ref-type="table-fn"} (extra) Changes in IL-17D NS NS [^\\^](#TN2){ref-type="table-fn"} (extra) Changes in BCL6 NS NS [^\\^](#TN2){ref-type="table-fn"} (extra) \% Immature transitional B cells +++[^\\\^](#TN3){ref-type="table-fn"} (PGA) 68 JDM (113 samples): 20 pre-treatment, 93 on treatment PBMC, Flow cytometry UK Piper [@B106] Absolute number immature transitional B cells +++[^\\\^](#TN3){ref-type="table-fn"} (PGA) MARKERS RELATED TO ENDOTHELIAL ACTIVATION OR DYSFUNCTION vWF Sens 0.85; Spec 0.45 (for flare) 16 JDM, prospective Serum CA Guzman [@B107] vWF Sens 0.40 (6/15 act had high vWF) NS (muscle strength) NS (skin rash, calcinosis) 15 JDM Serum USA Bloom [@B108] C3d Elevated in 6/7 pts with act 15 JDM: 7 act, 5 mild disease, 3 rem, 15 ped HC Plasma, radioimmuno assayand rocket immuno-elektrophoresis USA Scott [@B109] Fibrinopeptide A [^\^](#TN1){ref-type="table-fn"} (vsHC) Factor VIII-related antigen [^\\^](#TN2){ref-type="table-fn"} (vsHC) MiRNA-10a NS (DAS) NS (DAS) NS (skin DAS) 15 untreated JDM Muscle boipsies, RT-PCR USA Xu [@B110] EPC number NS (DAS) NS (skin DAS) 34 JDM: 6 untreated, 19 act on med, 9 rem PBMC, Flow cytometry USA Xu [@B111] LIPID METABOLISM* HDL NS (PGA) ++[^\^](#TN1){ref-type="table-fn"} (CMAS), NS (MMT) NS (Skin, CHAQ) 16 JDM, 1 JPM Serum USA Coyle [@B112] LDL r~p~: ++[^\^](#TN1){ref-type="table-fn"} (DAS) r~p~: \#\#[^\^](#TN1){ref-type="table-fn"} (CMAS) r~p~: ++[^\\^](#TN2){ref-type="table-fn"} (MYOACT) 25 JDM Serum Brazil Kozu [@B113] Triglycerides All r~p~: +++[^\\^](#TN2){ref-type="table-fn"} (DAS), ++[^\\^](#TN2){ref-type="table-fn"} (MITAX) All r~p~: \#\#[^\\^](#TN2){ref-type="table-fn"} (CMAS), \#\#[^\\^](#TN2){ref-type="table-fn"}(MMT) r~p~: +++[^\\^](#TN2){ref-type="table-fn"} (MYOACT) IL-6 NS \#[^\^](#TN1){ref-type="table-fn"} NS (extra) 26 JDM Whole blood, qRT-PCR USA Olazagasti [@B114] Resistin ++[^\\\^](#TN3){ref-type="table-fn"} ++[^\\\^](#TN3){ref-type="table-fn"} \+[^\^](#TN1){ref-type="table-fn"} (extra) Spearman correlations (r~s~) of biomarkers with global/muscle/skin/extraskeletal VAS are shown unless otherwise specified. +:r~s~ ≥0.2, ++:r~s~ ≥0.4, +++:r~s~ ≥0.6, ++++:r~s~ ≥0.8, \#:r~s~ ≤ −0.2, \#\#:r~s~ ≤ −0.4, \#\#\#:r~s~ ≤ −0.6, \#\#\#\#: r~s~ ≤ −0.8. r~p~: Pearson correlation. Statistical significance: P \< 0.05, P \< 0.01, P \< 0.001, NS, not significant. Sens, sensitivity; Spec, specificity. Abbreviations biomarkers: IFN, interferon; MCP-1, CCL2; IP-10, CXCL10; TNFR2, Tumor necrosis factor receptor 2; IL-2R, Interleukin-2 receptor; MRP8/14, myeloid related protein 8/14 (S100A8/9); CRP, C-reactive protein; Hsp60, heat shock protein 60; Th, T helper; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; Treg, Regulatory T cell; IL, interleukin; vWF, von Willebrand factor; EPC, endothelial progenitor cell; HDL, high density lipoprotein; 25(OH)D, Vitamin D. Abbreviations disease activity: DAS, disease activity score; VAS, visual analog scale; PGA, physician\'s global activity VAS; MyoAct, Myositis disease activity assessment visual analog scales; MITAX, myositis intention to treat activity index; MMT, manual muscle testing; CMAS, childhood myositis assessment scale; vsHC, compared to healthy controls; CHAQ, childhood healthy assessment questionnaire; MRI, magnetic resonance imaging; ANA, anti-nuclear antibody; extra, extraskeletal/extramuscular symptoms. Abbreviations patients: JDM, juvenile dermatomyositis; JPM, juvenile polymyositis; HC, healthy control; ped, pediatric; act, active; rem, remission/asymptomatic/inactive disease; yrs, years; NIMD, non-inflammatory muscle disease; aSCT, autologous stem cell transplantation; CTD, connective tissue disease; O, onset of disease; FU, follow-up. Abbreviations material & technique: ELISA, enzyme-linked immuno sorbent assay; HPLC, high-performance liquid chromatography; PBMC, peripheral blood mononuclear cells; qRT-PCR, quantitative real time polymerase chain reaction. ###### Biomarkers for disease activity in mixed cohorts containing patients with JDM. Biomarker* Global disease activity Muscle disease activity Other activity measures Patients (samples) Material & technique Cohort References ----------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------ -------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------- ---------------------------------------------------- ------------------------- -------------------------- Interferon related biomarkers Type I IFN signature NS 2 JDM, 10 DM, 15 ad HC Whole blood, microarray USA Baechler [@B115] IP-10 NS Serum, Luminex ITAC NS MCP-1 ++[^\^](#TN4){ref-type="table-fn"} MCP-2 +++[^\\^](#TN5){ref-type="table-fn"} IFN gene score ++[^\\^](#TN5){ref-type="table-fn"} ++[^\\^](#TN5){ref-type="table-fn"} (VAS), \#\#[^\\^](#TN5){ref-type="table-fn"} (MMT) ++[^\\^](#TN5){ref-type="table-fn"} (skin), +[^\^](#TN4){ref-type="table-fn"} (extra) 19 JDM, 37 DM, 20 ad HC Whole blood, qRT-PCR USA Bilgic [@B116] IP-10 +++[^\\\\^](#TN7){ref-type="table-fn"} Serum, multiplexed sandwich immunoassay I-TAC +++[^\\\\^](#TN7){ref-type="table-fn"} MCP-1 ++[^\\\^](#TN6){ref-type="table-fn"} MCP-2 ++[^\\\^](#TN6){ref-type="table-fn"} MIP-1α ++[^\\\^](#TN6){ref-type="table-fn"} IL-6 ++[^\\\^](#TN6){ref-type="table-fn"} \+[^\\^](#TN5){ref-type="table-fn"} (VAS), \#\#[^\\^](#TN5){ref-type="table-fn"} (MMT) \+[^\^](#TN4){ref-type="table-fn"} (skin), ++[^\\^](#TN5){ref-type="table-fn"} (extra) IL-10 \+[^\^](#TN4){ref-type="table-fn"} TNFα \+[^\^](#TN4){ref-type="table-fn"} TNFR1 \+[^\^](#TN4){ref-type="table-fn"} MIG, MIP-1β, IL-8 NS Type I IFN chemokine score (Summarization of ITAC, IP-10, MCP-1, and MCP-2) ++[^\^](#TN4){ref-type="table-fn"} (JDM), +++[^\\\\^](#TN7){ref-type="table-fn"} (mixed) ++[^\\\^](#TN6){ref-type="table-fn"} (VAS, mixed), \#\#[^\\^](#TN5){ref-type="table-fn"} (MMT, mixed) \+[^\^](#TN4){ref-type="table-fn"} (skin), ++[^\\^](#TN5){ref-type="table-fn"} (extra) Type I IFN gene score \+[^\^](#TN4){ref-type="table-fn"} ++[^\\^](#TN5){ref-type="table-fn"} NS (extra) 21 JDM (each active and remission sample), 30 DM (each active and remission sample) Whole blood, qRT-PCR USA Reed [@B117] Type I IFN chemokine score ++[^\\\^](#TN6){ref-type="table-fn"} ++[^\\\^](#TN6){ref-type="table-fn"} ++[^\\\^](#TN6){ref-type="table-fn"} (extra) Serum, multiplexed sandwich immunoassay IP-10 ++[^\\\^](#TN6){ref-type="table-fn"} ++[^\\^](#TN5){ref-type="table-fn"} ++[^\\\^](#TN6){ref-type="table-fn"} (extra) ITAC ++[^\\^](#TN5){ref-type="table-fn"} ++[^\\^](#TN5){ref-type="table-fn"} ++[^\\^](#TN5){ref-type="table-fn"} (extra) MCP-1 ++[^\\^](#TN5){ref-type="table-fn"} ++[^\\^](#TN5){ref-type="table-fn"} ++[^\\^](#TN5){ref-type="table-fn"} (extra) MCP-2 NS ++[^\\\^](#TN6){ref-type="table-fn"} NS (extra) IL-6 ++[^\\\^](#TN6){ref-type="table-fn"} ++[^\\\^](#TN6){ref-type="table-fn"} \+[^\^](#TN4){ref-type="table-fn"} (extra) IL-8 \+[^\^](#TN4){ref-type="table-fn"} \+[^\^](#TN4){ref-type="table-fn"} NS (extra) TNFα \+[^\\^](#TN5){ref-type="table-fn"} ++[^\\\^](#TN6){ref-type="table-fn"} \+[^\^](#TN4){ref-type="table-fn"} (extra) OTHER MARKERS OF INFLAMMATION* IL-1Ra High in act than rem ++[^\^](#TN4){ref-type="table-fn"} (CK) [^\\\^](#TN6){ref-type="table-fn"} (vsHC) 2 JDM, 5 DM, 2 caDM, 4 PM, 2 OM, 12 HC Serum, ELISA Switzerland Gabay [@B118] sTNFR75 (sTNFR2) ++[^\^](#TN4){ref-type="table-fn"} (CK) BAFF \+[^\\\^](#TN6){ref-type="table-fn"} (CK, mixed) 49 DM (of which ≥1 JDM), 44 PM, 6 IBM, 30 HC Serum, ELISA Sweden & Czech Republic Krystufkova [@B119] BAFF \+[^\\\^](#TN6){ref-type="table-fn"} (mixed) \+[^\^](#TN4){ref-type="table-fn"} (mixed) \+[^\\\^](#TN6){ref-type="table-fn"} (extra, mixed) 20 JDM, 45 DM, 26 PM, 7 IBM, 21 HC PBMC, qRT-PCR USA Lopez de Padilla [@B120] ΔBAFF (downregulates BAFF activity) ++[^\\\^](#TN6){ref-type="table-fn"} (mixed) \+[^\\^](#TN5){ref-type="table-fn"} (mixed) ++[^\\\^](#TN6){ref-type="table-fn"} (extra, mixed) Anti-Jo1 LMM: ++[^\\\^](#TN6){ref-type="table-fn"} LMM: \#\#[^\\\^](#TN6){ref-type="table-fn"} (MMT), +++[^\\\^](#TN6){ref-type="table-fn"} (ME) LMM: +[^\\^](#TN5){ref-type="table-fn"} (extra), ++[^\\\^](#TN6){ref-type="table-fn"} (HAQ) Refractory pts: 48 JDM, 76 DM, 76 PM (all analyses in mixed cohort) Serum, ELISA & RNA and protein immunoprecipitation USA Aggarwal [@B88] Anti-TIF1γ LMM: ++[^\\^](#TN5){ref-type="table-fn"} LMM: \#\#\#[^\\\^](#TN6){ref-type="table-fn"} (MMT), NS (ME) LMM: +++[^\\\^](#TN6){ref-type="table-fn"} (HAQ), NS (extra) Anti-SRP LMM: NS LMM: NS (MMT), +[^\\^](#TN5){ref-type="table-fn"} (ME) LMM: NS (extra, HAQ) Anti-Mi2 LMM: +++[^\\\^](#TN6){ref-type="table-fn"} LMM: \#\#[^\\\^](#TN6){ref-type="table-fn"} (MMT), ++[^\\^](#TN5){ref-type="table-fn"} (ME) LMM: +[^\^](#TN4){ref-type="table-fn"} (extra), NS (HAQ) IMMUNE CELL SUBSETS \% CD3+ cells Higher in rem than act[^\^](#TN4){ref-type="table-fn"} (DM, not JDM) 14 JDM, 24 DM, 17 ad HC, 9 ped HC PBMC, Flow cytometry Japan Ishida [@B121] \% CD8+ cells Higher in rem than act[^\^](#TN4){ref-type="table-fn"} (DM, not JDM) \% CD20+ cells Higher in act than rem[^\^](#TN4){ref-type="table-fn"} (DM, not JDM) \% CD3+ cells Higher in rem than act[^\^](#TN4){ref-type="table-fn"} (DM) 29 DM act (of which ≥1 JDM), 20 DM rem, 13 PM act, 37 PM rem, 32 ad HC PBMC, Flow cytometry Hungary Aleksza [@B122] \% CD8+ cells Higher in rem than act[^\^](#TN4){ref-type="table-fn"} (DM) \% IFNγ+ of CD4 T cells Higher in rem than act[^\\^](#TN5){ref-type="table-fn"} (DM) \% IFNγ+ of CD8 T cells Higher in rem than act[^\\^](#TN5){ref-type="table-fn"} (DM) \% CD19+ cells Higher in act than rem[^\^](#TN4){ref-type="table-fn"} (DM) \% IL-4+ of CD4+ T cells Higher in act than rem[^\^](#TN4){ref-type="table-fn"} (DM) MARKERS RELATED TO ENDOTHELIAL ACTIVATION OR DYSFUNCTION* sVCAM-1 NS (CK, mixed) NS (skin, mixed) 5 JDM, 27 DM, 4 PM, 25 HC Serum, ELISA Japan Kubo [@B123] sE-selectin [^\^](#TN4){ref-type="table-fn"} (CK, mixed) sICAM Higher in act than rem[^\^](#TN4){ref-type="table-fn"} (mixed) 4 JDM, 2 ped MCTD, 8 ped SLE, 4 ped Vasculitis Serum, ELISA USA Bloom [@B124] sICAM-3, sVCAM-1, sL-selectin, sE-selectin NS (mixed) Spearman correlations (r~s~) of biomarkers with global/muscle/skin/extraskeletal VAS are shown unless otherwise specified. +:r~s~ ≥ 0.2, ++:r~s~ ≥ 0.4, +++:r~s~ ≥ 0.6, ++++:r~s~ ≥ 0.8, \#:r~s~ ≤ −0.2, \#\#:r~s~ ≤ −0.4, \#\#\#:r~s~ ≤ −0.6, \#\#\#\#:r~s~ ≤ −0.8. r:~p~: Pearson correlation, LMM, linear mixed model. Statistical significance: P \< 0.05, P \< 0.01, P \< 0.001, P \< 0.0001, NS, not significant. Abbreviations biomarkers: IFN, interferon; MCP-1, CCL2; MCP-2, CCL8; IP-10, CXCL10; ITAC, CXCL11; MIP-1α, CCL3; IL, interleukin; TNF, Tumor necrosis factor; TNFR1 /2 = TNF receptor 1/2, MIG, CXCL9; MIP-1β, CCL4; IL-1Ra, IL-1 receptor alpha; BAFF, B cell activating factor. Abbreviations disease activity: CK, creatine kinase; ME, muscle enzymes; VAS, visual analog scale; MMT, manual muscle testing; HAQ, health assessment questionnaire; extra, extraskeletal/extramuscular symptoms. Abbreviations patients: JDM juvenile dermatomyositis; JPM, juvenile polymyositis; DM, adult dermatomyositis; caDM, cancer-associated DM; PM, adult polymyositis; OM, overlap myositis; IBM, inclusion body myositis; SPA, spondylartropathy; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; MCTD, mixed connective tissue disease; HC, healthy control; ped, pediatric; ad, adult; act, active; rem, remission/asymptomatic/inactive disease. Abbreviations material & technique: ELISA, enzyme-linked immuno sorbent assay; PBMC, peripheral blood mononuclear cells; qRT-PCR, quantitative real time polymerase chain reaction. #### Currently used laboratory markers The markers that are currently used in clinical practice, AST, ALT, LDH, aldolase and in particular creatine kinase activity (CK), do not correlate as well with disease activity in JDM as in DM ([@B125]--[@B127]). At diagnosis, any one muscle enzyme was only elevated in 80--86% of patients with JDM and CK was found to be elevated in only 61--64% of patients ([@B125], [@B128]). In almost 20% of patients the most abnormal measurement of CK was not elevated above normal values ([@B28]). Low muscle enzymes at first presentation may be associated with delayed diagnosis ([@B129]). During follow-up, CK may underestimate disease activity due to suppressed release by corticosteroids, circulating inhibitors of CK activity, or loss of muscle mass ([@B127], [@B130]--[@B132]). On the other hand, CK and aldolase can be elevated in steroid myopathy and are therefore not reliable as markers for disease activity requiring more potent immunosuppression ([@B133]). However, according to recent consensus guidelines, these muscle enzymes are still regarded as an important monitoring tool ([@B134], [@B135]). #### Markers related to the interferon signature An important group of investigated biomarkers is related to the type 1 interferon (IFN) signature, which has been demonstrated in the peripheral blood and muscle biopsies of JDM patients ([@B136], [@B137]). Activated plasmacytoid dendritic cells (pDC) are generally thought to be the main producers of the type 1 IFNs (IFNα and IFNβ) in JDM. This notion may be challenged by a recent study measuring circulating IFNα with a highly sensitive assay and investigating the cellular source of IFNα in several systemic inflammatory diseases. JDM patients had higher levels of circulating IFNα than patients with systemic lupus erythematosus (SLE), but lower levels than patients with monogenic interferonopathies. However, neither isolated circulating pDC nor other circulating immune cell subsets from JDM patients expressed more IFNα than cells from healthy controls, suggesting that a non-circulating cellular source may be responsible for IFNα production in JDM ([@B138]). Due to the lack of available methods to measure circulating IFNα and IFNβ until recently, the type 1 IFN signature, consisting of genes upregulated in response to IFNα or IFNβ stimulation, was used as a surrogate marker of type 1 IFN levels. The type 1 IFN signature in whole blood of three mixed DM and JDM cohorts correlated weakly to moderately with global disease activity \[spearman r (r~s~) = 0.33--0.44\] and muscle activity (r~s~ = 0.44--0.47), while single IFN signature related serum chemokines MCP-1, IP-10 (CXCL10) and ITAC (CXCL11) had moderate to strong correlations with global (r~s~ = 0.42--0.66), muscle (r~s~ = 0.44--0.50), and extraskeletal disease activity (r~s~ = 0.42--0.55) ([@B115]-- [@B117]). MxA expression in PBMC, also used as a surrogate for the IFN signature, had a very strong correlation with muscle disease activity of JDM patients (r~s~ = 0.80) at disease onset, but not with skin disease activity ([@B89]). IFNα activity measured by a functional reporter assay was also higher in JDM patients than controls ([@B90]). Recently, IP-10, TNF receptor 2 (TNFR2) and galectin-9 were found to strongly correlate with global disease activity (r = 0.60--0.75) in two studies by Enders et al. ([@B93], [@B94]) IP-10, together with MCP-1 and eotaxin, was also higher in 54 JDM patients a median of 17 years after disease onset than matched healthy controls ([@B92]). TNFR2 correlated with CK in a mixed IIM cohort (r~s~ = 0.55) ([@B118]). Galectin-9 was recently identified as a biomarker for the IFN signature in SLE and anti-phospholipid syndrome ([@B139]). IP-10, TNFR2 and galectin-9 are promising biomarkers for disease activity, as they can potently discriminate between active disease and remission even during treatment ([@B93], [@B94]). After stem cell transplantation and concomitant eradication of circulating immune cells, their levels stayed high over several months, which suggests that these proteins are not primarily produced by circulating immune cells, but rather by non-circulating immune or tissue cells, just as IFNα ([@B94], [@B138]). IP-10 and galectin-9 are currently being validated as biomarkers for disease activity in two large international JDM cohorts. One of the best investigated biomarkers so far in JDM is neopterin, a catabolic product of guanosine triphosphate, which was previously shown to be a marker of immune activation that can be induced by stimulation with IFNγ ([@B140]). In the first study identifying serum neopterin as a biomarker for JDM, neopterin levels correlated strongly with muscle strength impairment in 15 JDM patients (r~s~ = 0.68) ([@B96]). Elevated serum neopterin levels at diagnosis compared to remission were confirmed in an independent cohort ([@B95]). In a juvenile myositis validation cohort, plasma neopterin (n = 13), and quinolonic acid (n = 24), however, did not correlate with myositis disease activity measures ([@B97]). Urine neopterin (n = 45) moderately correlated with global (r~s~ = 0.42), muscle (r~s~ = 0.50--0.62) and skin activity (r~s~ = 0.49), and edema on MRI (r~s~ = 0.55). Urine quinolonic acid also correlated with global and muscle activity and edema on MRI (r~s~ = 0.45--0.61) ([@B97]). Despite these efforts of validation, neopterin has not been widely implemented into clinical practice as a biomarker for disease activity in JDM. #### Other inflammatory mediators Next to type 1 IFN-related markers, other inflammatory mediators have been studied as biomarkers for JDM. The innate TLR4 ligand myeloid related protein 8/14 (MRP8/14 or S100A8/9), originally found to be elevated in patients with systemic-onset juvenile idiopathic arthritis (JIA), correlated moderately to strongly with global and muscle disease activity in a large cohort of 56 JDM patients (r~s~ = 0.55--0.65) ([@B98], [@B141]). Another marker adopted from studies in JIA, the soluble IL-2 receptor, was elevated at disease onset compared to remission ([@B95], [@B142]). Serum/plasma levels of the more conventional pro-inflammatory cytokines IL-6, IL-8, and TNFα also moderately correlated with global (r~s~ = 0.19--0.46) and muscle disease activity (r~s~ = 0.35--0.52) in three mixed JDM and DM cohorts ([@B116], [@B117]). Remarkably, CRP levels did not increase during disease flares ([@B99]). BAFF and especially its antagonistic non-cleavable form ΔBAFF, both important for survival and maturation of B cells, moderately correlated with global, muscle and extraskeletal VAS (r~s~ = 0.27--0.54), and CK (r~s~ = 0.37) in two mixed IIM cohorts ([@B119], [@B120]). #### Markers related to vasculopathy and cardiovascular risk Due to the vasculopathic component of JDM, markers related to endothelial activation and dysfunction were explored for their association with disease activity. Von Willebrand factor (vWF) was increased during most periods of active disease in a prospective cohort study, but did not reliably predict disease flares in another study ([@B107], [@B108]). sICAM-1, a marker of endothelial activation, was higher during active disease than remission in a combined cohort of juvenile patients with various systemic autoimmune diseases. VCAM-1, sICAM-3, and L-selectin did not correlate with disease activity, although expression of MiRNA-10a in JDM muscle, which is negatively associated with VCAM-1 expression, showed a correlative trend with muscle and global DAS \[Pearson r (r~p~) = −0.45\] ([@B110], [@B123], [@B124]). C3d and fibrinopeptide A, which are related to vasculopathic changes, were higher in JDM patients with active disease than in remission ([@B109]). Endothelial progenitor cell numbers did not differ between JDM patients and controls and did not correlate with disease activity ([@B111]). In view of the increased cardiovascular risk in JDM patients, the lipid profile has been investigated in relation to disease activity ([@B41]). Serum HDL negatively correlated with muscle activity (r~s~ = −0.54), but not global or skin activity ([@B112]). Triglyceride levels correlated strongly with global disease activity assessed by DAS (r~s~ = 0.61) and LDL was higher in patients with a higher disease activity ([@B113]). Gene expression of the adipokine resistin in PBMC was also upregulated in JDM patients compared to controls and moderately correlated with global and muscle disease activity (r~s~ = 0.51 and r~s~ = 0.50, respectively) ([@B114]). These results indicate that the cardiovascular risk profile is more pronounced in JDM patients with active disease. #### Circulating immune cell subsets as biomarkers for disease activity Among the circulating immune cell subsets, T cells and B cells have been studied most extensively in relation to disease activity in JDM. In two mixed cohorts of JDM and DM patients, the frequency of T cells, and especially CD8+ and IFNγ-producing T cells, was decreased during active disease, while the frequency of B cells and IL-4 producing CD4+ T cells was increased compared to remission ([@B121], [@B122]). This may suggest a shifted balance toward a T helper 2 (Th2) type immune response. In cohorts with only JDM patients, total B cell numbers were also increased compared to controls and changes in B cell frequencies accompanied changes in disease activity (r~s~ = 0.47) ([@B100], [@B106]). Within the B cell compartment, numbers and frequencies of circulating immature transitional B cells correlated strongly with global disease activity (r~s~ = 0.69--0.71). Compared to healthy pediatric controls, these specialized B cells were highly proliferative, had a prominent IFN signature and produced less of their regulatory signature cytokine IL-10 ([@B106]). Plasmablast frequencies were also increased during active disease compared to remission ([@B102]). Several T cell subsets have been studied in JDM. In 26 new-onset JDM patients the blood gene expression of Th17-related genes, such as RORC and IL-17F, Th1-related genes, including STAT4, and Th2-related genes, including GATA3 and STAT6, was studied in relation to disease activity. RORC, IL-17F, STAT4, and GATA3 positively correlated with muscle activity and RORC and STAT4 correlated with global activity. This would suggest that the immune response is not specifically skewed toward a certain T helper response. However, at baseline, JDM patients had higher gene expression of Th17 related cytokines IL-23, IL-17F, IL-6, and IL-21 than DM patients, indicating that the Th17 pathway may play a more prominent role in the pathogenesis of JDM than DM. Changes in BCL6, a transcription factor for follicular helper T cells, correlated negatively with a change in extramuscular activity ([@B105]). Within CXCR5+ follicular helper T cells, the Th1 subset was decreased in active JDM compared to remission and controls, and Th2 and Th17 subsets were increased in JDM compared to controls ([@B102]). Regulatory T cell frequencies in muscle biopsies did not correlate with muscle activity, but suppressive activity of circulating Tregs may be impaired during active disease ([@B104]). Finally, global disease activity correlated moderately with the activation status of circulating T cells assessed by CD69 expression (r~s~ = 0.43), but not with CD25 and HLA-DR expression ([@B100], [@B103]). The expansion and functional alteration of particular B cell and CD4+ T cell subsets, coinciding with changes in disease activity, hints toward the involvement of these cell subsets in the pathogenesis of JDM. In conclusion, many circulating, either soluble or cellular, markers have been studied for their relation with muscle and global disease activity. Correlations with disease activity were only moderate for most markers, and some of these molecules are relatively unstable in blood samples or complicated to measure, rendering them unsuited for use in clinical practice. The highest correlations with disease activity were found for markers related to the IFN signature, the lipid profile, for MRP8/14, and immature transitional B cells. However, most of these biomarkers were identified in small patient cohorts and except for neopterin, so far none have been reproduced or thoroughly validated in independent and large JDM cohorts. Neopterin was investigated in a validation cohort, but its correlation with disease activity could only be confirmed in urine, not in plasma. Galectin-9 and IP-10 are currently being validated in two international cohorts and are promising biomarkers for implementation in clinical practice due to their high sensitivity and stability in serum. ### Biomarkers for Extramuscular Disease Activity Next to markers for global and muscle disease activity, biomarkers for involvement of specific tissues and organs have been investigated. Four studies by Kobayashi et al. have focused on biomarkers for ILD, and specifically the rapid progressive (RP-ILD) and chronic ILD type, in a Japanese JDM cohort. Not only the presence, but also the level of anti-MDA5 was a sensitive and specific marker for ILD, with the highest levels found in patients with RP-ILD ([@B8], [@B143], [@B144]). In addition, BAFF, APRIL, KL-6, and IL-18 levels were higher in patients with RP-ILD compared to chronic ILD and JDM patients without ILD ([@B145]). KL-6 was prognostic for ILD, as it stayed high in patients with persistent damage on HRCT ([@B144]). Biomarkers for cardiac involvement were tested in a Norwegian JDM cohort, a median of 17 years after diagnosis. Eotaxin and MCP-1 were elevated in patients with cardiac dysfunction and correlated moderately to strongly with systolic and diastolic dysfunction especially in patients with persistently active disease (r~s~ = 0.45--0.65) ([@B146]). In the same cohort, a reduced heart rate variability, which is an indicator of cardiac disease, correlated moderately with ESR, hsCRP, and also MCP-1 and eotaxin levels (r~s~ = 0.29--0.47) ([@B147]). Next to the autoantibody NXP2, which is prognostic for the development of calcinosis, phosphorylated matrix Gla protein was shown to be higher in patients with calcinosis than without calcinosis ([@B79], [@B148]). Reduced osteocalcin levels were found to be predictive of reduced bone mass, even before start of steroids ([@B149]). The presence of the TNFα-308A allele is associated with a more severe disease in JDM. However, apparent associations with this allele are likely to reflect the association with ancestral haplotype 8.1 due to linkage disequilibrium and should be interpreted with this in mind ([@B150]). Patients with this genotype are reported to show prolonged symptoms requiring ≥36 months of immunosuppressive therapy, a higher incidence of pathologic calcifications, increased production of TNFα by peripheral blood mononuclear cells in vitro and JDM muscle fibers in vivo, a higher IFNα activity and a higher rate of complications arising from occlusion of capillaries. Vascular occlusion has been linked to higher levels of the anti-angiogenic thrombospondin-1 ([@B90], [@B151]--[@B154]). In summary, a number of potential biomarkers for extramuscular disease activity has been identified, and especially for ILD and cardiac dysfunction the biomarkers seem promising. Validation in independent cohorts will have to confirm their potential as biomarkers for these extramuscular symptoms. Histopathology of Muscle and Skin Biopsies ------------------------------------------ The diagnostic criteria for JDM by Peter and Bohan encompass histopathological findings consistent with DM: "necrosis of myofibers, phagocytosis, regeneration with basophils, large vesicular sarcolemmal nuclei, and prominent nucleoli, atrophy in a perifascicular distribution, variation in fiber size and an inflammatory exudate, often perivascular" ([@B155], [@B156]). For a long time, muscle biopsies were therefore taken as part of routine diagnostic workup. However, with evolving diagnostic options and more specialized trained pediatric rheumatologists muscle biopsies are currently not always considered a necessity for diagnosis ([@B135]). One of the main problems hindering standardized evaluation of muscle biopsies was the lack of an internationally agreed upon scoring tool. An international consensus group of pediatric rheumatologists and pathologists developed such a tool, which encompasses 4 histopathological scoring domains: inflammatory, vascular, muscle fiber and connective tissue changes ([@B157]). The scoring tool has now been validated in an independent cohort consisting of 55 patients and was found to correlate with clinical measures of disease activity, including CMAS, PGA, and MMT-8 (r~s~ = 0.40--0.62) ([@B45]). Muscle biopsy scores may also have prognostic potential: in combination with MSA group, these scores were found to predict the risk of remaining on treatment over time, based on analysis of muscle biopsies from 101 JDM patients ([@B158]). The most common findings in muscle biopsy specimens in JDM compared to healthy individuals or patients with non-inflammatory muscle diseases, are profound upregulation of MHC I expression on muscle fibers, increased expression of integrins and complement and membrane attack complex deposition on capillaries and perimysial large vessels, a type 1 IFN signature and immune cell infiltrates consisting mostly of mature pDC, memory CD4+ T cells, and B cells ([@B48], [@B52], [@B159]--[@B169]). (Figure [1](#F1){ref-type="fig"}) The IFN signature, measured by expression of MxA, correlated with muscle disease activity ([@B166]). In skin biopsies similar features are found, with the additional presence of diffuse mast cell infiltration ([@B164]). ![Histopathological features and biomarkers in JDM. JDM is characterized by vasculopathic changes in the tissues, with loss and dysfunction of endothelial cells, leading to capillary dropout and subsequent atrophy of muscle fibers. The exact chain of events leading to loss of blood vessels and muscle fibers is not known, but it is thought that both overexpression of MHC-I (and MHC-II) on myocytes and endothelial damage are early events in the cascade ([@B159], [@B170]). They result in the first attraction of immune cells to the tissue, probably by a stress response of the myocytes and endothelial cells, leading to a first production of chemoattractants. The immune cell infiltrates, which can be organized in lymphoid structures, consist mostly of CD4+ and CD8+ memory T cells, B cells, mature plasmacytoid dendritic cells (pDC) and monocytes. CD4+ and CD8+ T cells are considered responsible for direct killing of muscle cells. pDC are considered the main producers of type I interferons (IFNs), which explains the IFN-I signature that is found in the muscles of JDM patients. Some typical IFN-inducible chemokines, CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (ITAC), are known for their angiostatic properties. The receptor for these cytokines, CXCR3, is upregulated on endothelial cells in JDM muscle, which may be one of the factors contributing to endothelial dysfunction ([@B137]). Other factors include anti-endothelial circulating antibodies (AECA), complement and membrane attack complex (MAC) deposition on endothelial cells. Endothelial cells in muscle also express high levels of ICAM-1 and VCAM-1, which further enables extravasation of immune cells into the tissues and promotes a positive feedback loop resulting in further tissue damage. Not only immune cells in the tissues, but also circulating immune cells show a type I IFN signature and increased IFNα activity. Various circulating markers reflecting immune activation and endothelial activation or distress are increased during active disease in JDM and can potentially be used as biomarkers for disease activity.](fimmu-09-02951-g0001){#F1} Several studies have suggested associations between histopathological findings in muscle biopsies and disease duration before the biopsy or disease severity at a later time point. Biopsy specimens taken after a short duration of untreated disease (\<2 months), showed higher expression of VCAM-1 (which correlated with higher serum soluble VCAM-1) and expression of genes involved in stress response and protein turnover, whereas biopsies taken after more than 2 months of untreated disease had more pDC infiltration, higher expression of genes involved in the immune response and vascular remodeling and more apoptosis-related markers ([@B171]--[@B173]). Thus, it should be taken into account that histological findings can depend on the disease duration before the biopsy. In addition, these findings may indicate that endothelial activation is an early feature of JDM, which precedes immune cell infiltration and vasculopathy. The degree of vasculopathy and vascular injury (as defined by marked capillary dropout, increased direct immunofluorescent arterial staining and lymphocytic vasculitis, amongst others) was associated with a more severe and chronic disease, with severe or persistent weakness, low remission rates at 12 months requiring additional treatment, subcutaneous edema, and chronic ulcerative disease of the skin and gastrointestinal tract ([@B21], [@B55], [@B165]). The degree of vasculopathy was also correlated with the expression of angiostatic chemokines MIG, IP-10 and ITAC ([@B137]). This indicates that the degree of vascular injury may be one of the most important factors determining long-term disease outcomes and that it is related to the IFN signature. Not only the type of immune cell infiltration, but also the organization of immune cells in the muscle is of significance in JDM. Organization of immune infiltrates in lymphocytic aggregates or lymphoid follicle--like structures with dendritic cells and T cells, as compared to diffuse infiltrates, was associated with a more severe disease course and less response to treatment ([@B174]). MHC I expression, one of the most prominent and early histological features in JDM, did not correlate with clinical features of the disease ([@B159], [@B160], [@B175]). The importance of thorough and standardized assessment of tissue involvement is underlined by the fact that even in cases with amyopathic DM, with normal EMG and MRI findings, the muscle biopsy can show focal endomysial lymphocyte and macrophage aggregates and 90% positivity for HLA class I in the sarcolemma ([@B176]). Unrecognized, low-grade muscle inflammation may be undertreated, resulting in a larger risk of long term damage. However, muscle biopsy is not routinely performed for children with JDM in all centers and therefore in future, biomarkers which are measureable in blood and correlate with biopsy features would represent a major advance. Immunopathogenic Implications: Interferons and Vasculopathy {#s4} =========================================================== From the biological research conducted in JDM so far, it has become clear that IFNs and their signature play an important role in the immunopathogenesis of JDM (Figure [1](#F1){ref-type="fig"}). The IFN signature is detectable in muscle fibers, myogenic precursor cells, endothelial cells, skin and several circulating cell subsets of patients with JDM and could point toward a viral etiology ([@B89], [@B106], [@B167]). Although it has never been demonstrated definitively, several studies suggest that infections may be more common before onset of JDM ([@B177]--[@B180]). Not only are IFNs potent drivers of (auto)inflammation, they may also be anti-angiogenic factors that could directly or indirectly contribute to endothelial damage and loss in JDM: directly by inhibiting angiogenesis and disrupting the vascular network organization and indirectly by inducing several other angiostatic factors such as galectin-9, IP-10, and ITAC ([@B137], [@B181]--[@B186]). In addition, type 1 IFNs inhibit the generation of myotubes and induce atrophy-associated genes in differentiated myotubes. Human skeletal muscle cells can also produce large quantities of IP-10 upon stimulation with IFNγ and TNFα ([@B186], [@B187]). Rather than being produced by circulating immune cells, IFNs are probably mainly produced within inflamed tissues. Satellite cells, active myogenic cells and endothelial cells in JDM muscle strongly express IFNβ ([@B167]). The notion that non-circulating cells within tissues are responsible for IFN production also fits observations by Rodero et al. ([@B138]). In particular within muscle of JDM patients the dysbalance between angiogenic and angiostatic factors can contribute to endothelial loss ([@B137], [@B188]). Endothelial cells in JDM muscle downregulate genes related to vessel development, cell adhesion and migration, which are essential for angiogenesis ([@B167]). Downregulation of these genes is likely a key event in the development of vasculopathy. Next to being a target of the inflammation, the endothelium may also play an active role in the inflammatory process. In biopsies from JDM patients endothelial cells express inflammatory features, such as high levels of adhesion molecules ICAM-1 and VCAM-1, and produce cytokines and chemokines ([@B161]). These can facilitate the attraction and invasion of immune cells into tissues, thereby supporting the inflammatory process and subsequent damage. IP-10 and ITAC were the most highly upregulated genes in endothelial cells from JDM muscle and correlated with the degree of vasculopathy ([@B137], [@B167]). Endothelium-derived IP-10 can even stabilize the interaction between T cells and endothelial cells, thereby possibly contributing to the chronicity of T cell infiltration ([@B189]). Recently, a new function has been ascribed to endothelial cells as "semi-professional" antigen presenting cells, which act as sentinels for antigens, and possibly self-antigens, in tissues and facilitate T cell trafficking into these tissues ([@B190], [@B191]). The high expression of MHC molecules on endothelial cells in JDM muscle may support the notion that this process is involved in JDM ([@B160], [@B175]). Although the exact mechanisms of interaction between immune cells and endothelial cells in JDM are still elusive, they may be more elaborate than so far recognized. Conclusions and Future Perspectives for Biomarker Research {#s5} ========================================================== JDM is a multisystem disease. Not only the skin and skeletal muscles are affected, but also other organ systems and tissues such as the lungs, heart and intestines are frequently (subclinically) involved and may be under-evaluated. Vasculopathy due to loss and dysfunction of endothelial cells as a result of the inflammatory process is thought to underlie the symptoms in most of these organs and tissues. Monitoring of disease activity and damage in all of these affected tissues is important during clinical follow-up, as these are key determinants for the long-term outcomes of patients. Tools for monitoring of tissue activity and damage include histopathological investigation of biopsies, and laboratory testing of blood for specific biomarkers as well as several imaging methods. Each of these methods has their strengths and weaknesses and can be of value for specific diagnostic questions at disease onset or during follow-up, as outlined in the consensus-based recommendations for the management of JDM ([@B135], [@B192]). There is still a need for minimally invasive, but at the same time sensitive and specific diagnostic methods that correlate well with clinical symptoms or reflect low-grade, local inflammation. Tissue-specific biomarkers can therefore be of great value as a monitoring tool. To be able to identify sensitive, robust and reliable biomarkers or develop monitoring tools, it is of key importance to set up well-defined and large prospective patient cohorts, with a thorough longitudinal collection of a standardized clinical dataset assessing disease activity and organ involvement, paired with collection of patient material ([@B193]). Such a dataset is required to ensure a strict definition of active and inactive disease \[e.g., as proposed by Almeida et al. ([@B72])\]. An important consideration for a successful biomarker study is the timing of data and sample collection: depending on the purpose of the biomarker, time points before start of immunosuppressive treatment, before each adjustment of medication, during flares, at paired time points during active and inactive disease or even at regular intervals of max 3--4 months may be crucial to reliably investigate the potency of a biomarker. Next to the "classical" statistical approach, comparing patients with active disease and patients in remission (cross-sectionally or in paired samples), new computational approaches providing analysis methods that can integrate longitudinal data from multiple patients and multiple (bio)markers or scoring tools should be considered. These methods take into account the fluctuating nature of a relapsing-remitting disease such as JDM and are therefore better suited to test the reliability of a tool that will be used for longitudinal follow-up in clinical practice ([@B194], [@B195]). To achieve implementation of a marker or tool into clinical practice, both clinical and technical validation in independent cohorts is of utmost importance. Only few markers prove to be stable, reliable and easy to measure, which are key features for a marker or tool to be suited for implementation into clinical practice. Also the invasiveness of the method should be taken into account. Ideally, a period of experimental implementation can demonstrate the added value and feasibility of a marker or tool in clinical practice. To achieve all this in a large group of JDM patients to ensure sufficient statistical power, international networks with well-established collaborations are fundamental. Eventually, monitoring of disease activity with a reliable tool can be used to guide treatment and thereby facilitate precision medicine, with high dose therapy when indicated but also preventing overtreatment. This may reduce both the duration of active disease and thereby the disease-inflicted damage, and medication side effects, which will benefit the long-term outcomes on various domains, such as muscle weakness, organ damage, cardiopulmonary fitness, and quality of life. Next to facilitating personalized treatment strategies, newly identified biomarkers may also provide insights into the immunopathogenesis of JDM and provide new treatment targets. For instance, new treatment strategies targeting the IFN signature, such as anti-IFN antibodies (sifalimumab) or JAK-inhibition (ruxolitinib) have been shown to reduce the IFN signature in blood and muscle of adult dermatomyositis patients, and may therefore be promising new strategies for patients with JDM ([@B186], [@B196], [@B197]). Several studies discussed in this review suggest a strong link between the IFN signature and vasculopathy; and vasculopathy has been related to disease severity. Targeting the IFN signature may thus benefit vascularization in JDM and thereby improve outcomes. Author Contributions {#s6} ==================== JW collected literature and wrote the manuscript draft. FvW and AvR-K supervised JW, outlined the manuscript focus and revised the manuscript. CD and LW critically revised the manuscript. Conflict of Interest Statement ------------------------------ The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding. JW is funded by the Bas Stichting, the Princess Beatrix Muscle Foundation and Innovatiefonds Zorgverzekeraars. LW and CD are supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital and by grants from Arthritis Research UK (21953), Cure-JM, and The Myositis Association. [^1]: Edited by: Ann Marie Reed, Duke University, United States [^2]: Reviewed by: David A. Hafler, Yale University, United States; Hanna Kim, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), United States [^3]: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology	null	minipile	NaturalLanguage	mit	null
Civilization VI is Turning Into a Competitive Esport I know, Civilization VI being an Esport sounds weird, but bear with me for a moment. Just this past weekend, competitive Esports team Team Liquid announced that they had just recruited their first pro Civ player, and were looking to build a full team of Civ players, with Stephen ‘MrGameTheory’ Takowsky leading them. ‘MrGameTheory is a former world champion Civilization player who achieved the rank of #1 on the Civilization Revolution leader board, Civilization IV international league, and Civilization V international league. He holds the records for most 1v2, 1v3, 1v4, and 1v5 ladder victories in Civilization IV. He is commonly referred to by members of the competitive community as a the “God” or “Legend” of Civilization. Civilization provides the perfect platform for players to showcase their gaming intellect and we feel that Firaxis is on the cusp of bringing the franchise to a competitive esports level. It is inevitable that Civilization will take its place alongside the top esports in the world.’ While I can’t disagree with the comparisons drawn between Civ and chess, I can’t imagine that a competitive game of Civilizavion VI will be very interesting to watch. Still, it should be fun to see how this develops.	null	minipile	NaturalLanguage	mit	null
Western Airways Western Airways was an airline based in Weston-super-Mare, Somerset, England between 1932 and 1978. Before World War II, for a short period it was the world's busiest airline. It survived WWII by using its aircraft engineering expertise. History Origins and development On 26 September 1932, Norman Wallace George Edgar started a twice-daily passenger service between Bristol (Whitchurch) Airport and Cardiff (Splott) Airport – a 20-minute trip in the De Havilland Fox Moth of his company, Norman Edgar & Co. At that time a road journey between Bristol and Cardiff meant either crossing the Severn by the Aust Ferry, or a long detour upstream via Gloucester. Business boomed, and Edgar formed a new company, Norman Edgar (Western Airways) Ltd at Whitchurch, with a larger aircraft, a De Havilland Dragon. New routes were added, across the English Channel to Le Touquet and Paris, and also to Cardiff and Bournemouth (Christchurch), as that airport's first airline service. Further Dragons were added to the fleet, and Edgar decided to look for a new base. In January 1933 Edgar approached the council of Weston-super-Mare to finance the construction of a new airfield. Convinced, the council bought the land and construction started in February 1936. Edgar's company started two new ventures: Western Air Transport whose role was 'to operate airlines', and Airways Union, to 'establish lines of aerial connection'. Airways Union appears to have been a holding company for all of the planned activities. Western Airways was to manage the new airport for a fee that would help to mitigate the landing and per-passenger fees charged by the council to recover its large investment. In May, the new airport was licensed for De Havilland Dragon flights and, to Edgar's dismay, Railway Air Services started flights on two routes the same month, one to Cardiff and Whitchurch, and another via Cardiff and Haldon, Devon, to Plymouth (Roborough) Airport. With the help of good publicity, Edgar soon responded with the Weston to Cardiff 'air ferry', another between Weston and Whitchurch, and a route to Birmingham (Castle Bromwich). By the end of July 1936 the company had relocated to Weston and the fleet had expanded to four Dragons, plus two De Havilland Puss Moths and a Gipsy Moth available for charter and pleasure flights. To Edgar's great relief, Railway Air Services withdrew all its services from Weston on 12 September, leaving his company with no competition. In 1937 the company started Western Airways Aero Club, teaching many pupils to fly. Edgar also gained a contract with the Army for night flying for anti-aircraft practice. This meant equipping Weston Airport with lighting, including floodlights, and a control tower. Many of the company's aircraft were fitted with radios, and operations got under way by the end of April. At first, aircraft engineering and maintenance had been performed by outside contractors in a hangar at Weston. With the growth of activity, it was decided to do this work in-house and in October 1937 an ex British Airways chief engineer, Freddy Jeans, was hired to oversee this work. An Air Training School was started by Western Airways to train engineers to work there. Up to now, despite all its activity, the airline had failed to make a profit. On 10 July 1937, Louis Strange, a director of Straight Corporation, diverted to Weston during the annual air race from London (Heston) to Cardiff (Pengam Moors, which had been renamed from Splott). Seeing all the activity at Weston may have had an influence on the Straight management, who intended to get into the airline business, and in January 1938 the Straight Corporation bought a controlling share in Norman Edgar (Western Airways) Ltd, renaming it Western Airways Ltd. It was then operating the highest frequency of flights of any airline in the world: 58 services a day. At the same time, Western Air Transport was renamed Straghtways Ltd. On 10 August 1938, Norman Edgar left the company in some acrimony after he alleged that some of its pilots were flying while drunk. An unfair dismissal claim ran on into 1940. With airport lighting in place for the Army contract, the airline wanted to start night passenger operations, principally for the Cardiff air ferry route. The Air Ministry demanded further work, mainly the lighting of nearby electricity pylons and the cables between them. All four runways were also lengthened, and once the work at Weston and Pengam Moors had been approved, the first British commercial night service began. The event, on 2 October 1938, was covered live by BBC reporters, and famous aviators Arthur Whitten Brown and Jim Mollison were at Cardiff to meet the incoming Rapide. Routes in 1938 Weston – Cardiff (Pengam Moors Airport) Bristol – Cardiff – Swansea (Jersey Marine Airport) Swansea – Barnstaple – Newquay (Trebelzue airfield) – Penzance Swansea – Weston Weston – Bristol – Birmingham (Castle Bromwich) – Manchester (Barton airport, moving to Ringway) Weston – Le Touquet – Paris (Le Bourget) Routes in 1939 Weston – Cardiff – Swansea: Until 30 April, four times weekly. Weston – Cardiff: Until 4 March, five times daily; 5 March to 15 April, six times daily; 16 to 30 April, seven times daily; 1 to 31 May, twenty-eight times daily; 1 to 30 June, twenty-five times daily; from 1 July, twenty-six times daily. Bristol – Cardiff – Swansea: From 1 May, five times daily. Swansea – Barnstaple: From 8 May, twice daily. Swansea – Barnstaple – Newquay – Penzance: From 8 May, once daily. Weston – Bristol – Birmingham (Elmdon) – Manchester (Ringway): From 17 June, three times daily. To service these routes, a DH.86 Express and two Percival Q.6 airliners were acquired, offering greater capacity and, with the Q6s, greater speed, than the airline's existing fleet. World War II On 3 September 1939, war with Germany was declared and the National Air Communications (NAC) organisation came into action. All British aerodromes and civil transport aircraft were requisitioned and most of the aircraft were flown to RAF bases. Western's DH.86 Express had been parked through lack of spares, but was overhauled and soon converted to an air ambulance. The NAC was persuaded to allow the Weston – Cardiff air shuttle to resume, but it only operated, on an hourly schedule, from 25 November until 30 March 1940. This was the last day of Western Airways' pre-war airline operations, but not the end of the company itself. The maintenance facilities were expanding rapidly with work to repair, maintain and modify a wide range of aircraft, ranging from Miles Magisters to Curtiss Tomahawks, Avro Ansons and Fairey Battles. This work continued until the end of the war, during which time the airfield had been greatly expanded, hard runways laid, and the Bristol Aeroplane Company had established a huge presence at Weston Airport. Post-war diversification Western Airways had done subcontracting work for Bristol, and after the war was producing components for their aircraft, such as for the Type 170 Freighter. It already had a contract for Royal Canadian Air Force Canadair Sabres, and to this was added component work on the Britannia airliner. They also refurbished a wide range of military vehicles, many for export, and Slingsby gliders, which led to them being appointed dealers for Slingsby Sailplanes and Percival Aircraft, a business that lasted into the early 1950s. Another post-war activity was the conversion of military aircraft for civilian use. At first the aircraft were from the old Straight Corporation fleet which had been impressed for war service; these were restored to their old registrations and sold on. A wide range of aircraft types were then worked on, including Avro Tutor, Supermarine Walrus, Percival Petrel (military Q6), Taylorcraft and Miles. Eight Ansons were converted for the corporation's Straight Aviation Training. Two were retained as civilian conversions with seven passenger seats and used for communications and charter work. Other Ansons were converted for other, mainly military, customers. Western Airways' airline operations restarted in July 1946, when the Ministry of Civil Aviation permitted services on the Weston – Cardiff air ferry route. At first Western operated the route alone, but the following year the ministry dictated that it had to be operated in conjunction with Cambrian Airways. Western used its Avro Ansons, while Cambrian used Rapides which they had acquired specially for the route. The service only lasted until the end of the 1949 holiday season, when Western withdrew, Cambrian carrying on for a few weeks, finally stopping on 29 October. Western Airways then again concentrated on its parts manufacturing operations. Starting with orders for components for the Westland Wyvern and De Havilland Vampire, they started on parts for the Bristol 170 Freighter. This soon led to a Freighter production line being created in one of Western Airways' hangars. The first one was rolled out on 28 September 1953, the last on 23 March 1958. In total, 31 were built by Western Airways. With many Freighters used for intense English Channel car ferry operations, stresses on the airframe were high, and Western Airways got considerable business replacing components in the wing's main spar for many years after production finished. More work was obtained for Bristol, the next major project being completion of the Britannia, two of which could just be squeezed into Western's hangar. Again Western Airlines got further repair and parts replacement work from that aircraft. Other work also came in, and during the 1960s work on Concorde and the Rolls Royce RB211 engine was done. However, the company had already started to diversify, and in 1958 a hangar was taken over by a company soon to be called Barber Weston Ltd, whose director, Arthur A Barber, became a director of Western Airways and its holding company, Airways Union. Barber manufactured a range of products including conveyor systems, wheelchairs, vending machines, and prefabricated steel-frame buildings, many of which were bought by the Little Chef restaurant chain. Another subsidiary was created, Straghtaways Ltd, taking its name from the Straight Corporation's pre-war house magazine. On the Weston Airport site it made prams and push-chairs for Mothercare along with chicken cages and electrically heated clothes driers. In the early 1970s, Western Airways had a contract to weld the fuselages of autogyros to be produced for Campbell Aircraft, and were contracted to build the prototype of a new version, the Campbell Cougar. It was completed in 1973 and flight testing went well. However, Campbell's funding ran out and the whole project was abandoned, the Cougar moving to The Helicopter Museum, built on the site of Weston Airport's control tower. Western Airways continued to operate Weston Airport, and serviced and maintained a number of private aircraft. Pleasure flights were still popular, and for a short while in the 1976 season, famous ATA pilot Jackie Moggridge was employed as a pilot. However, during the 1970s the level of activity was declining, and the runway was in need of costly resurfacing. Airways Union decided to relinquish the airport's licence at the end of 1978, and the remaining staff were made redundant. Fleet list (pre-war airline use only) After takeover by the Straight Corporation, aircraft were moved between their different airlines, airport operating companies and flying clubs as the need arose. Therefore aircraft listed here probably didn't spend their entire career with Western before disposal, and some Straight Corporation aircraft not listed here may have operated for Western Airways. References: De Havilland DH.83 Fox Moth G-ABYO Norman Edgar from 5 January 1933 to 16 June 1934 (crashed) De Havilland DH.84 Dragon G-ACAO from 8 July 1938, impressed 2 April 1940 as N9398 G-ACJT from 26 August 1933 to 20 December 1939 (crashed) G-ACLE from 18 May 1939, impressed 2 April 1940 as X9397 G-ACMJ from 1 July 1938, impressed 2 April 1940 as X9396 G-ACPX from 23 July 1938, impressed 2 April 1940 as X9399 G-AECZ from 1 February 1937, impressed 8 May 1940 as AV982 De Havilland DH.86B Express G-AETM from 18 April 1939 to 31 January 1940 De Havilland DH.89 Dragon Rapide G-ACTU from 14 July 1937, impressed 8 June 1940 as AW115 G-ADBV from 31 May 1937, impressed 2 March 1940 as N8511 G-ADDD from 8 July 1937, impressed 4 June 1940 as AW116 G-AFSO (DH.89A) from 21 May 1939, impressed 23 January 1940 as W6457 De Havilland DH.90 Dragonfly G-ADNA from 27 January 1939, impressed 17 April 1940 as X9452 G-AEDH from 25 September 1937, impressed 10 May 1940 as AV987 General Aircraft ST-6 Monospar G-ACGI from 6 November 1936, impressed 6 May 1940 as AV979 Percival Q.6 G-AFIX from April 1939, impressed 2 April 1940 as X9406 G-AFVC from 30 June 1939, impressed 10 May 1940 as AX860 Short S.16 Scion G-ADDV from 22 May 1936, impressed 11 April 1940 as X9456 G-ADDX from 15 May 1936, impressed 3 April 1940 as X9430 Spartan Cruiser II G-ACBM from 28 July 1937 to August 1937 (scrapped} Aircraft production Bristol Type 170 Freighter Mk 31 (1953–1958) F-VNAR Air Vietnam G-APLH Dan-Air ZK-BVM Safe Air Total = 3 Mk 31M (1954–1957) S4408 Royal Pakistan Air Force (RPAF) S4410 RPAF S4413 RPAF S4415 RPAF S4417 RPAF S4419 RPAF S4421 RPAF S4422 RPAF S4424 RPAF S4426 RPAF S4427 RPAF S4429 RPAF S4430 RPAF S4432 RPAF S4433 RPAF S4435 RPAF S4437 RPAF S4438 RPAF 9850 Royal Canadian Air Force Total = 19 Mk 32 Superfreighter (1956–1957) G-ANWJ Silver City G-APAU Air Charter G-AOUU Air Charter G-AOUV Air Charter G-ANWK Silver City G-ANWL Silver City G-ANWM Silver City G-ANWN Air Charter Total = 9 Total Freighter production = 31 Campbell Cougar G-BAPS. first flight 20 April 1973 Accidents and incidents On 16 June 1934 De Havilland Fox Moth G-ABYO of Norman Edgar & Co was on a business charter flight from Llanvair, near Caerwent in Wales to Glasgow when the aircraft crashed near Llanfair and caught fire. The pilot, Douglas Brecknell, was thrown clear and rescued his two trapped passengers. One of the passengers, Godfrey Jones, survived with injuries, but the other, Arthur Turner, aged 41, died later of his injuries. On 20 December 1939 De Havilland Dragon G-ACJT registered to Southern Airways (part of the Straight Corporation) crashed on take-off at Weston Airport on a flight to Cardiff. It is thought the pilot, Leslie Ivor Arnott, aged 35, the sole occupant, had become incapacitated. He died in hospital of his injuries. Footnotes References Category: Defunct airlines of the United Kingdom Category: Airlines established in 1932	null	minipile	NaturalLanguage	mit	null
Hatch set forth the goals of tax reform as: "Fairness, efficiency, simplicity and American competiveness." He offered three reasons to move forward on tax reform. Hatch continued, "American families, individuals, and businesses collectively spend hundreds of billions of dollars a yearnot to mention countless hourssimply trying to comply with the tax code. Tepid growth rates for the U.S. economy have seemingly become the new normal for some. America's multinational businesses find it difficult to compete abroad and are often targets for acquisition by foreign companies." Wyden also set forth his hopes for tax reform. He noted, "What is needed is bipartisan tax reform that focuses on progressivity, helping the middle class, cleaning out flagrant tax loopholes, fiscal responsibility and giving everybody in America the chance to get ahead. In short, bipartisan tax reform would build on key principles that brought Democrats and Republicans together for major bipartisan tax reforms slightly more than three decades ago." Witnesses before the Senate Finance Committee were four former Assistant Secretaries of the Treasury for Tax Policy. They held diverse opinions, but generally supported fairness for middle class taxpayers and strengthening the economy. House Hearing on Tax Reform On July 19 the House Ways and Means Tax Policy Subcommittee held a hearing on tax reform. Subcommittee Chairman Peter Roskam (R-IL) opened the hearing and stated, "As a committee, we now have a choice. We can accept high tax rates and a confusing code or we can grow the economy, lower taxes for everyone and create a fair system that Americans can trust. I think the choice is clear." Former Chairman of the House Ways and Means Committee Bill Archer highlighted the goals of tax simplification and improving the economy. Archer noted, "I commend the efforts of this committee and particularly Chairman Kevin Brady for taking the lead to advance the indisputable goal of simplifying the code and helping to make the United States a leader in the world in terms of having a tax code that gives our country a competitive edge in the marketplaces of the world." Archer explained that when he was Chairman of the Ways and Means Committee, he felt that as the chief taxwriter in America he should also prepare his personal return. Archer explained that he prepared his tax returns, "Because I believed that I had to experience the same process as every other taxpayer. I would lock myself in my office to struggle through the entire effortusing paper and pencilnot a computer program. It was a multi-day effort!" Archer concluded his testimony by approving the effort to enable "the vast majority of Americans" to file a tax return on a postcard. The House Budget Committee also passed an appropriations bill this week that will be submitted to the full House. The bill creates an October 6 deadline for creation of a tax bill by the House Ways and Means Committee. Chairman Kevin Brady (R-TX) indicated that this deadline will be met. He noted that they will prepare a bill with "permanent tax reform that balances within the budget so we can deliver the certainty and economic growth Americans deserve." The budget committee also envisioned a revenue neutral tax bill. IRS Review of Syndicated Conservation Easements On July 13 IRS Commissioner John Koskinen sent a report on syndicated conservation easements to Senate Finance Committee Ranking Member Ron Wyden (D-OR). In the letter, Koskinen explained the IRS analysis of 40 disclosures of syndicated conservation easement transactions. These disclosures were in compliance with IRS Notice 2017-10. This Notice classified certain syndicated conservation easement transactions as "listed transactions." Koskinen noted the 40 reported transactions included both the investment amounts and the claimed charitable deductions. The aggregate charitable deductions were $217 million and the investment amounts were approximately one-ninth this amount. Executive Vice President Wendy Jackson of the Land Trust Alliance commented on the Koskinen letter. She noted, "The preliminary data show for 40 specific transactions that happened since 2010, people bought the equivalent of $9 of tax deductions for $1, on average. It is clear that in these instances, the deductions significantly exceeded the limit established by the IRS." The Land Trust Alliance previously warned their 1,000 members to "steer clear" of syndicated conservation easement transactions. Jackson continued, "In the vast majority of cases, conservation easement donors are philanthropic heroes working with nonprofit land trusts that are above reproach, and we cannot let the actions of those focused on material greed undermine a program that benefits all Americans." Editor's Note: The House Budget Committee passed a bill that directs the IRS to not regulate syndicated conservation easement transactions. Senate Finance Committee Chairman Orrin Hatch (R-UT) and Ranking Member Ron Wyden (D-OR) are researching and reviewing IRS actions with respect to syndicated conservation easements. The Land Trust Alliance's support of the IRS may be a factor in their future decisions. The IRS has announced the Applicable Federal Rate (AFR) for August of 2017. The AFR under Section 7520 for the month of August will be 2.4%. The rates for July of 2.2% or June of 2.4% also may be used. The highest AFR is beneficial for charitable deductions of remainder interests. The lowest AFR is best for lead trusts and life estate reserved agreements. With a gift annuity, if the annuitant desires greater tax-free payments the lowest AFR is preferable. During 2017, pooled income funds in existence less than three tax years must use a 1.2% deemed rate of return. Federal rates are available by clicking here.	null	minipile	NaturalLanguage	mit	null
BLOG 24th July, 2019By April In episode 244 of Semantic Mastery's weekly Hump Day Hangouts, one viewer asked if the team has any case studies that RYS stacks benefit authority sites in broad niches. The exact question was: I am building out an authority site in the health niche. It seems that RYS stacks are geared towards local GMB assets. Do you have any case studies that RYS stacks benefit authority sites in broad niches?	null	minipile	NaturalLanguage	mit	null
Hyland's Residence Window and Door PanelShown here is the back addition with a custom wood door and window panel opening out to a back deck and garden. As a south facing door and window panel the transoms over the doors work well to bring light into the interior of the house	null	minipile	NaturalLanguage	mit	null
Thelymitra imbricata Thelymitra imbricata, commonly called the broad sun orchid, is a species of orchid that is endemic to Tasmania. It has a single erect, channelled leaf and up to fifteen or more pale to dark or purplish blue, relatively large flowers. Description Thelymitra imbricata is a tuberous, perennial herb with a single erect, fleshy, channelled, light green, linear to lance-shaped leaf long and wide with a purplish base. Between three and fifteen or more pale to dark or purplish blue flowers wide are arranged on a flowering stem tall. The sepals and petals are long and wide. The column is white, bluish or pinkish, long and wide. The lobe on the top of the anther is about long and wide, brown or orange brown with a narrow blue band, gently curved with an inflated hood and a V-shaped notch. The side lobes are finger-like and have dense, toothbrush-like tufts of white hairs. Flowering occurs from late October to early December. The flowers are long-lasting, insect pollinated and open on warm sunny days. Taxonomy and naming Thelymitra imbricata was first formally described in 1998 by David Jones and the description was published in Australian Orchid Research. The name replaced the synonym Thelymitra nuda var. grandiflora Lindl.. The specific epithet (imbricata) is a Latin word meaning "overlapping like roofing-tiles and shingles". Distribution and habitat The broad sun orchid usually grows in a range of habitats including open forest, scrubland, grassland and heath in the Tasmanian midlands. References External links imbricata Category:Endemic orchids of Australia Category:Orchids of Tasmania Category:Plants described in 1998	null	minipile	NaturalLanguage	mit	null
Silencing non-SMC chromosome-associated polypeptide G inhibits proliferation and induces apoptosis in hepatocellular carcinoma cells. The present study was designed to investigate the significance of non-structural maintenance of chromosomes (non-SMC) chromosome-associated polypeptide G (NCAPG), a subunit of condensin complex I, in the development of hepatocellular carcinoma (HCC). NCAPG protein expression in human HCC and paracancerous hepatic tissues were examined using immunohistochemistry, and NCAPG mRNA expression in HCC cell lines were quantified using quantitative RT-PCR. Lentivirus-mediated RNA interference was used to silence NCAPG in HCC cells. Cell proliferation was monitored by MTT assay. Cell colony-forming capacity was measured by colony formation assay. Apoptosis was determined by flow cytometry. The results showed that increased protein expression of NCAPG was found in HCC tissues compared with the matched paracancerous hepatic tissues. At the mRNA level, increased expression of NCAPG was found in HCC cells as opposed to the normal hepatocytes. Silencing of NCAPG in BEL-7404 and SMMC-7721 cells led to decreased cell proliferation and increased apoptosis. These changes were associated with increased mRNA expressions of P53, P27, and Bad, but decreased mRNA expression of EGFR, Akt, survivin, and JNK. NCAPG might play an oncogenic role in the development of liver cancer. Further studies to clarify its role and underlying mechanisms in the development of liver cancer are warranted.	null	minipile	NaturalLanguage	mit	null
IRT Perundurai Medical College The IRT Perundurai Medical College is one of the Premier Government Medical institutions in the state affiliated to The Tamil Nadu Dr. M.G.R Medical University, Chennai. The school includes a medical college and a hospital. The school falls under the auspices of the Tamil Nadu State Transport Corporation. History On the suggestion of Lord Willington (then Viceroy of India) in 1930 a district committee to combat tuberculosis was formed in Coimbatore and the decision to start a tuberculosis sanatorium in Perundurai was made. The foundation stone was laid by Sir K.V.Reddy Naidu on 1 July 1936. The sanatorium was declared open by Sri.C.Rajagopalachari. It was renamed Ramalingam Tuberculosis Sanatorium in 1952. In 1986 the government of Tamil Nadu attached a medical college with the sanatorium. The college has 600 beds and started functioning in 1992. In 2017, the strength of the Medical College was increased from 60 students to 100 students. In 2004, doctors' quarters were added. A school of nursing was started in 2008. Graduation day ceremony (VIDAI 2018) for 2012 batch students (Dravagonz) was conducted in the newly built auditorium on 25 April 2018. The chief guests were 1. The Honourable Vice-chancellor of Tamilnadu Dr.MGR Medical University, Dr. S.Geethalakshmi MD PHD; and 2. The Honourable Erode district collector, Dr. S.Prabakar IAS. Other notable guests include Dr. T.Ramaprasad MD, Thiru Thoppu N.D.Venkatachalam MLA, Thiru V.Shanmugam Chairman of Nanda educational trust. Government to takeover the College from 2019-2020 Classes and years of entry Every class of MBBS students has assigned to itself an (unofficial) name denoting the year of their entry into the medical school. The recent batches (with their culturals name) 1995 Maestros 1997 Trendsetters 2001 Challengers [Swasam] 2002 Vibrant Victors [Mithz] 2003 Stalwarts [Inferno] 2004 Kosmocraterz [Revenant] 2005 Racing Rampantz [Hedonic] 2006 Hurricanz [Xtonant] 2007 Tantalizers [Ewiganz] 2008 Invinciblz [Xperanza] 2009 Salvadorz [Extemus] 2010 Spangblattens [Nakshatra] 2011 Xanthronz [Ignitron] 2012 Dravagonz [Festino] 2013 Xentinelz [Inceptra] 2014 Facidianz [Maghizhazhi / மகிழாழி] 2015 STRATONZ [ oliyum oliyum 19/ ஒளியும் ஒலியும் 19 ] 2016 Krenoviantz 2017 Indominerz 2018 Exustardianz 2019 Zephyrianz References External links http://irtpmc.ac.in/ Category:Medical colleges in Tamil Nadu Category:Universities and colleges in Erode district	null	minipile	NaturalLanguage	mit	null
A site that encourages smokers to quit and provides tips to friends and family on how to motivate a smoker to quit without nagging, shaming or blaming. Also check out my website with several videos on becoming smoke-free at: www.VJSleight.com and connect with me on LinkedIn at :www.linkedin.com/in/vjsleight . Friday, July 25, 2014 What is a Tobacco Treatment Specialist and how can you help me quit smoking? Can't I just quit smoking on my own? A Tobacco Treatment Specialist (TTS) is a person who has been specially trained in the treatment of nicotine addiction. I was trained at the Mayo Clinic. I also belong to a professional organization: The Association for the Treatment of Tobacco Use and Dependence(ATTUD). A TTS will use evidence based material (proven strategies) to help a smoker become smoke-free. One guideline that is used is the The Clinical Practice Guideline: Treating Tobacco Use and Dependence. This publication has delved into all of the research into tobacco treatment and has complied the best practices. Methods are rated A, B, C. A = This method has been proven to work on a consistent basis. B = These methods have conflicting information. C = No clinical controlled trials to show efficacy. Many smokers do quit on their own, just like other addictions such as alcohol, cocaine and heroin. But many need help to kick their addiction, especially nicotine. I have had former heroin addicts tell me that heroin and/or alcohol were easier to quit than smoking. Have you ever talked to a former smoker and asked what helped them to quit? They can tell you the long trial and error process they used and what ultimately worked for them. It doesn't mean that it will work for you. Working with a professional will shorten your learning curve in what will help you quit and stay quit. Here is what you can expect when working with a professional Tobacco Treatment Specialist: A detailed personal history. Every smoker is different. There is no one-size-fits-all when it comes to tobacco treatment, not even a one-size-fits-most. You will be asked about how much you smoke, for how long, your previous quit attempts, your medical and mental health history, previous or current substance use, your common triggers, assessment of your nicotine dependence and your perceived obstacles to quitting. From your detailed history, an individualized treatment plan is developed. It will include information of what medications may help and what practical counseling skills are needed for your particular situation including: emotional cues, dealing with stress, weight gain, handling withdrawals with or without medications, being around other smokers, and relapse prevention. Motivation when times are tough. Some days you will feel that nothing can ever drag you back to smoking and other days you will feel that nothing will help except a cigarette. Explanations for any questions or myths related to smoking. I have had many clients whose doctors have told them that if they quit they would: breathe better, have lower cholesterol, their neuropathy will improve etc. yet they didn't believe their doctors. Why? Because their doctors didn't take the time to fully explain what smoking is doing to their body and how the body heals itself when you quit. Someone who understands how difficult it is to become smoke-free. While I am a former smoker having quit 9 separate times for at least 3 months and I personally know how hard it is, many TTS's have never smoked but with their specialized training and after working with countless smokers, they don't need to know what it is like. Just as an OB/GYN doctor doesn't need to know how it feels to be pregnant to deliver a baby. Signs that it is time to use a TTS instead of trying to quit on your own: You have quit multiple times, only to relapse back to smoking. Have a history of other substance abuse and/or addiction, or a history of mental illness. A sense of shame or guilt that you are still smoking. Shame is when you feel there is something wrong with you that you can't quit. Guilt is when you feel you should quit and want to quit, but are still smoking. These are normal emotions that a TTS can help you work through instead of letting these emotions stop you from moving forward. You've tried everything and nothing works. A TTS will help you cut through the "noise" of quitting, helping you focus on what will work. Too often a smoker relies on the latest fad or gimmick to quit instead of what will work, or will rely on just one tool instead of developing several coping strategies. A TTS will focus on the process of quitting, not just the method, since every method will work for some smokers, NO method will work for every smoker. Call me today at 760-333-1270 for a FREE 15 minute counseling session to see how I can help you. 1 comment: O my God....I can't see this any-more. Please spread message for avoiding smoking and drugs to the whole nation. People are damn dumb to get goad for smoking without thinking about their horrible death story. Thank you so much for sharing this valuable information. My younger brother was also addicted to smoking but now my parents are trying to relieve him from smoking cessation with hypnosis . May God help us VJ Sleight, Queen of Quitting Send me a message with your questions. Subscribe to My Blog One on One Coaching Now Available I believe that EVERY smoker can become smoke-free with my help. No matter how many times your have tried, no matter how many different products you have used, no matter if you think it is hopeless, I can help you. Call me today for a FREE 15 minute coaching session at 760-333-1270 or email me for more information. As a former smoker I know how difficult it is to quit but also how rewarding it can be once you achieve your goal. Let me help you walk through the process of going from a long-time smoker to becoming smoke-free. Change is hard but you CAN do it, and I will show you how.	null	minipile	NaturalLanguage	mit	null
1. Field of the Invention The present disclosure relates generally to a method of applying a graphic image on a substrate. More particularly, the invention relates to the use of a liquid release coating formulated to form a durable first film wherein the transferred graphic material is superimposed on a print film and sandwiched between a primer coat on the one hand and a top coat of the target substrate on the other hand. 2. Description of the Related Art There are a myriad of methods of applying graphic images to a substrate. However the known methods have achieved limited success in applying complex multi colored high resolution graphic images to certain substrates, such as for example leather. Known methods of applying graphics to substrates, in particular, leather use adhesives or other material that often compromise the supple feel of the leather and don't protect the graphic from wear. Thus, many luxurious materials in which the texture of the material is paramount are often offered in monochromatic colors only. The prior art discloses equipment and methods that teach printing graphic images directly on a substrate, such as leather. Direct printing on a substrate is slow and expensive. It is additionally disadvantageous because the inks used contain hazardous ingredients and the graphic image remains unprotected and is subject to damage from wear. The prior art teaches various methods for transferring digitally created images to a target surface via heat and/or pressure. In particular, U.S. Pat. Pub. No. 2008/0043087 A1 (to Cowan) teaches a method for creating and transferring digitally created images on a film to a target surface via heat and/or pressure transfer using a modified large-format digital printer. The method generally comprises the steps of modifying a large format digital printer to convert it from heat fused toner printing to cold toner printing, preparing a transfer film, creating a digital image, applying a release layer onto the transfer film, printing the image onto the release layer on the transfer film in a reverse mirror-image manner, applying an adhesive overtop said image, and pressure transferring the image onto the target substrate and peeling away the transfer film to selectively leave the image on the target substrate. U.S. Pat. Pub. No. 2002/0131333 A1 (to Sofer et al.) discloses a method using a personal computer to create designs and or images. The design is first created on the computer and then printed onto a heat transfer sheet. The printed design on the heat transfer sheet is then heat pressed onto the leather (cow hide, calf, pig, goat, kid, sheep) material. The design may also be an image such as a picture created using a digital camera or manual camera. U.S. Pat. No. 7,699,458 B2 (to Mabbott) teaches a method of providing a surface of a material with an image, including applying to the surface an image sheet comprising (i) a flexible layer of a shape memory polymer, and (ii) an image bonded to said layer by means of an image key coat. The image sheet is bonded to the surface by means of an adhesive and a process that involves heating of the shape memory polymer to a temperature above its Glass Transition Temperature. U.S. Pat. No. 7,025,451 B2 (to Mabbott) discloses a method for transferring an image onto a non-planar surface in which an image transfer sheet comprising a shape memory polymer or like substance is used to transfer said image. U.S. Pat. No. 6,039,822 (Heyworth et al.) discusses a process of applying decals to products having rough textured surfaces, such as products made from thermoplastic resins, leather, or synthetic leather. The decals applied to the products contain detailed multicolor graphic images made from a four color printing process. The decal applying process includes applying a first clear ink layer directly to the substrate surface, applying a water-release slide-off decal on top of the first clear ink layer, and applying a second clear ink layer over the applied decal to firmly bond the decal to the substrate surface. The two ink layers encapsulate the decal on the substrate surface, maintaining the integrity of the decal. It is desirable to introduce an improved method of applying bright and complex multi graphics to a substrate, in particular luxury materials, such as for example fine leather, without altering the intrinsic nature and pliability of the leather or other substrate the graphic is adhered to and without damaging the material due to excessive heat or pressure used in the application process, while also protecting the graphic against normal wear and tear.	null	minipile	NaturalLanguage	mit	null
Java-based client spreads Skype far and wide Why should smartphone and 3 Skypephone users have all the fun? Skype has finally released a client written for mobile Java, enabling the ubiquitous VoIP pipe to be used on a wide, wide variety of phones (Skype says they've tested it on about 50, but it's likely to work on far more than that). Though it's naturally scaled down a bit to fit in its tiny target footprint, the client still manages to pack in support for Skype-to-Skype and SkypeOut calls, chat, group chat, and your buddy list -- pretty much everything you need to make it functional. If you're going to have a go at it, just make sure you're on a sufficiently generous data plan, k? [Thanks to everyone who sent this in] Update: Turns out the data plan doesn't have to be that generous. Straight from Skype: "Tom has 20 Skype contacts and signs in twice a day for a total of 90 minutes. He IMs for about 25 minutes each day and makes 20 minutes of Skype calls. Tom would use just under 1 MB of data in one month." Thanks, everyone!	null	minipile	NaturalLanguage	mit	null
Friday, April 21, 2017 Canada’s Fundamental Science Review: Good News for Basic Research! —Heidi Engelhardt, FAUW Board of Directors A comprehensive look at research in Canada The report “Strengthening the Foundations of Canadian Research”, released April 10, 2017, is the culmination of a thorough look at the federal research ‘ecosystem’ in Canada. There is a lot to like here for the entire research community. Although the report was submitted to the Minister of Science, it goes well beyond STEM disciplines. Indeed, research was defined to include both science and non-science (‘scholarly inquiry’). For this undertaking, the more important distinction was between investigator-led research focused on knowledge generation, versus ‘priority-driven’ research. The latter was defined as research with a tightly defined area of focus, oriented primarily to partnerships (with government, industry, business), or promoting knowledge translation, innovation, and commercialization. The primary focus was on investigator-led research supported by the three granting councils plus CFI, referred to as the four funding agencies. The advisory panel A nine-member Advisory Panel appointed in June 2016 consisted of six academics from diverse disciplines across Canada, the Chief Scientist of Quebec, an expat Canadian now the Silverman Professor of Physics and Public Policy at UC Berkeley and Mike Lazaridis. There were meetings with 230 researchers at different career stages, 1,275 written submissions and roundtables in five cities (Toronto, Montreal, Calgary, Ottawa, Halifax). The 280 page report is surprisingly readable. Their mandate was captured by two broad questions: Are there any overall program gaps in Canada’s fundamental research funding ecosystem that need to be addressed? Are there elements or programming features in other countries that could provide a useful example for the Government of Canada in addressing these gaps? Challenges identified It will surprise no one that one of their findings was that Canada’s research competitiveness had eroded in recent years, in association with flat-lined federal spending and redirection of funding to priority-driven and partnership oriented research. Coordination and collaboration among the four agencies was found to be suboptimal, and variability in practices was evident across these agencies beyond what could be explained by disciplinary differences. Lack of ‘life cycle’ support for both researchers and equipment/infrastructure was discussed at length. With respect to researcher support, the panel believed that the CRC program was no longer meeting its aim to “attract and retain the world’s most accomplished and promising minds”. A substantial (and rising) number of chairs are awarded to researchers already in-house or recruited from other Canadian universities; 10-15% of chairs are empty at any given time. At least part of this may be due to the fact that the funding levels of these positions have been unchanged for the past 17 years. Even more concern was expressed about the CERC (Canada Excellence Research Chairs) program, hence the recommendation that retooling the CRC program was the more sustainable strategy. With respect to trainees, levels of funding and numbers of awards for students and postdoctoral fellows have not kept pace, variously, with inflation, peer nations, or the number of applicants. The panel recommended that doctoral scholarship and PDF programs be reinvigorated, and harmonized across the tri-councils to achieve more consistency. They also recommended elimination of barriers to international portability. The growth in programs requiring cost-sharing or matching support was flagged as problematic in some jurisdictions and inappropriate for many disciplines. It was recommended that when the intent is to support independent research, matching should be used sparingly and in a coordinated and targeted manner. Highlights of recommendations Overall, 35 specific recommendations were made. Highlights include: creation of an independent National Advisory Council on Research and Innovation (NACRI) that would work closely with the soon-to-be appointed Chief Science Advisor wide ranging improvements in oversight and governance of all four agencies more money! … significant reinvestment on a multi-year basis spread across … investigator-led grants (highest priority) enhanced personnel support for researchers and trainees at different career stages targeted spending on infrastructure-related operating costs for small equipment and Big Science facilities improved coverage of the institutional costs of research Inevitably, this boils down to the reality of dollars. Carrying out these recommendations was estimated to increase annual spending across the four agencies from approximately $3.5 billion to $4.8 billion, requiring redirection of an additional 0.4% of the Government of Canada’s annual budget. While most of this funding would go to the granting councils’ core programs, a portion would be channelled to investigator-led projects involving international collaborations, multidisciplinary work, high-risk, high-reward (‘HR2’) ventures and projects requiring rapid response. Other valuable information In addition to its potential impact on national science policy, this document is a rich source of information on many topics, including: trends in research funding among select G7 nations, key east Asian countries and small peer nations (Chapter 3) a comparison of funding levels by the three granting agencies (an eye opener for some; Chapters 4, 5, 7) of particular relevance to Waterloo - Canada’s World Share in Emerging Research Areas, many of which are considered to be strengths of our institution (nanotech, bioinformatics, computer science, quantum computing, robotics and mechatronics, et al.; Appendix 1) Overall, this undertaking and its report – an impressive output in less than a year – is good news for Canadian research. It is unlikely that there will ever be enough funding to support all researchers at all institutions in a style to which they would like to become accustomed. And “reasonable people will disagree unreasonably about where the funds flow”. However, this report outlines many steps, large and small, in the right direction. The question now is whether, and when these recommendations will be implemented.	null	minipile	NaturalLanguage	mit	null
Q: Insert Into with Case on whole entry I'm creating a script to run which will take all the stock in an old system and insert into the new system. However the old system has 1000's of erroneous part number data that I want to ignore on the import. I've tried encapsulating the whole select in a case statement and iterations on that theme. It's quite a large set of data so for simplicity sake I've taken the vital information into the below code. INSERT INTO [LOT_TBL] ( Part_No Total_Stock ) --Ignore an insert if Part_No_Old NOT IN (SELECT Part_No from PART_TBL) SELECT Part_No_Old Total_Stock FROM OLD_ERP WHERE Total_Stock > 0 The PART_TBL in the new system has a list of all the valid parts, so if any on the import don't match, ignore and move on to the next one. A: You can filter with exists: insert into [lot_tbl] (part_no, total_stock) select part_no_old, total_stock from old_erp o where total_stock > 0 and exists ( select 1 from part_tbl p where p.part_no = o.part_no_old ) Or, if part_nos are unique in part_tbl, you can use a join: insert into [lot_tbl] (part_no, total_stock) select o.part_no_old, o.total_stock from old_erp o inner join part_tbl p on p.part_no = o.part_no_old where o.total_stock > 0	null	minipile	NaturalLanguage	mit	null
Q: Replacing a pattern with awk or sed I have a file with patterns like below 12345343\|559\|-2,0,-200000,-20\|20161108000000\|FL\|62,859,1439,1956\|0,0,21300,0\|S 3434344\|-100000\|20161108000000\|GL\|135\|0\|S 45454545\|214\|-2000,-2,0,0,-20\|20161108000001\|\|21,62,859,969,1956\|77440,0,0,0,0\|S Here I need to replace all the , values and get the first value in the sub set Required output: 12345343\|559\|-2\|20161108000000\|FL\|62\|0\|S 3434344\|-100000\|20161108000000\|GL\|135\|0\|S 45454545\|214\|-200000\|20161108000001\|\|21\|77440\|S I have tried sed 's/\,\|//' but didnt work A: Okay, simplest of all: $ sed 's/,[^\|]//g' ip.txt 12345343\|559\|-2\|20161108000000\|FL\|62\|0\|S 3434344\|-100000\|20161108000000\|GL\|135\|0\|S 45454545\|214\|-2000\|20161108000001\|\|21\|77440\|S Just replace , followed by non\| characters with nothing Same with perl $ perl -pe 's/,[^\|]//g' ip.txt 12345343\|559\|-2\|20161108000000\|FL\|62\|0\|S 3434344\|-100000\|20161108000000\|GL\|135\|0\|S 45454545\|214\|-2000\|20161108000001\|\|21\|77440\|S With awk, courtesy @JamesBrown $ awk '{gsub(/,[^\|]/,"")} 1' ip.txt 12345343\|559\|-2\|20161108000000\|FL\|62\|0\|S 3434344\|-100000\|20161108000000\|GL\|135\|0\|S 45454545\|214\|-2000\|20161108000001\|\|21\|77440\|S or $ awk 'gsub(/,[^\|]*/,"")+1' ip.txt 12345343\|559\|-2\|20161108000000\|FL\|62\|0\|S 3434344\|-100000\|20161108000000\|GL\|135\|0\|S 45454545\|214\|-2000\|20161108000001\|\|21\|77440\|S	null	minipile	NaturalLanguage	mit	null
I used bitcoin-iterate and gnumeric to render the current bitcoin blocksizes, and here are the results. My First Graph: A Moment of Panic This is block sizes up to yesterday; I’ve asked gnumeric to derive an exponential trend line from the data (in black; the red one is linear) That trend line hits 1000000 at block 363845.5, which we’d expect in about 32 days time! This is what is freaking out so many denizens of the Bitcoin Subreddit. I also just saw a similar inaccurate [correction: misleading] graph reshared by Mike Hearn on G+ :( But Wait A Minute That trend line says we’re on 800k blocks today, and we’re clearly not. Let’s add a 6 hour moving average: In fact, if we cluster into 36 blocks (ie. 6 hours worth), we can see how misleading the terrible exponential fit is: Clearer Graphs: 1 week Moving Average So, not time to panic just yet, though we’re clearly growing, and in unpredictable bursts.	null	minipile	NaturalLanguage	mit	null
--- abstract: 'This paper proposes a representational model for grid cells. In this model, the 2D self-position of the agent is represented by a high-dimensional vector, and the 2D self-motion or displacement of the agent is represented by a matrix that transforms the vector. Each component of the vector is a unit or a cell. The model consists of the following three sub-models. (1) Vector-matrix multiplication. The movement from the current position to the next position is modeled by matrix-vector multiplication, i.e., the vector of the next position is obtained by multiplying the matrix of the motion to the vector of the current position. (2) Magnified local isometry. The angle between two nearby vectors equals the Euclidean distance between the two corresponding positions multiplied by a magnifying factor. (3) Global adjacency kernel. The inner product between two vectors measures the adjacency between the two corresponding positions, which is defined by a kernel function of the Euclidean distance between the two positions. Our representational model has explicit algebra and geometry. It can learn hexagon patterns of grid cells, and it is capable of error correction, path integral and path planning.' author: - \| Ruiqi Gao$^{1}$[^1], Jianwen Xie$^{2}$, Song-Chun Zhu$^{1}$ & Ying Nian Wu$^{1}$\ $^{1}$University of California, Los Angeles, USA\ $^{2}$Hikvision Research Institute, Santa Clara, USA\ `{ruiqigao, jianwen}@ucla.edu`, `{sczhu, ywu}@stat.ucla.edu`\ bibliography: - 'grid.bib' title: 'Learning Grid Cells as Vector Representation of Self-Position Coupled with Matrix Representation of Self-Motion' --- Introduction ============ Imagine you are walking in your living room in the dark at night without any visual cues. Purely based on your self-motion, you know where you are while you are walking simply by integrating your self-motion. This is called path integral ([@hafting2005microstructure; @fiete2008grid; @mcnaughton2006path]). You can also plan your path to the light switch or to the door. This is called path planning ([@fiete2008grid; @erdem2012goal; @bush2015using]). You need to thank your grid cells for performing such navigation tasks. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ![Place cells and grid cells. (a) The rat is moving within a square region. (b) The activity of a neuron is recorded. (c) When the rat moves around (the curve is the trajectory), each place cell fires at a particular location, but each grid cell fires at multiple locations that form a hexagon grid. (d) The place cells and grid cells exist in the brains of both rat and human. (Source of pictures: internet)[]{data-label="fig:g1"}](./FIG/g1.png "fig:"){height=".15\linewidth"} ![Place cells and grid cells. (a) The rat is moving within a square region. (b) The activity of a neuron is recorded. (c) When the rat moves around (the curve is the trajectory), each place cell fires at a particular location, but each grid cell fires at multiple locations that form a hexagon grid. (d) The place cells and grid cells exist in the brains of both rat and human. (Source of pictures: internet)[]{data-label="fig:g1"}](./FIG/g0.png "fig:"){height=".15\linewidth"} ![Place cells and grid cells. (a) The rat is moving within a square region. (b) The activity of a neuron is recorded. (c) When the rat moves around (the curve is the trajectory), each place cell fires at a particular location, but each grid cell fires at multiple locations that form a hexagon grid. (d) The place cells and grid cells exist in the brains of both rat and human. (Source of pictures: internet)[]{data-label="fig:g1"}](./FIG/g2.png "fig:"){height=".15\linewidth"} ![Place cells and grid cells. (a) The rat is moving within a square region. (b) The activity of a neuron is recorded. (c) When the rat moves around (the curve is the trajectory), each place cell fires at a particular location, but each grid cell fires at multiple locations that form a hexagon grid. (d) The place cells and grid cells exist in the brains of both rat and human. (Source of pictures: internet)[]{data-label="fig:g1"}](./FIG/g4.png "fig:"){height=".15\linewidth"} (a) (b) (c) (d) ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Figure \[fig:g1\](a) shows Dr. May-Britt Moser, who together with Dr. Edvard Moser, won the 2014 Nobel Prize for Physiology or Medicine, for their discovery of the grid cells ([@hafting2005microstructure; @fyhn2008grid; @yartsev2011grid; @killian2012map; @jacobs2013direct; @doeller2010evidence]) in 2005. Their thesis advisor, Dr. John O’keefe, shared the prize for his discovery of the place cells ([@o1979review]). Both the place cells and grid cells are used for navigation. The discoveries of these cells were made by recording the activities of the neurons of the rat when it moves within a square region. See Figure \[fig:g1\](b). Some neurons in the Hippocampus area are place cells. Each place cell fires when the rat moves to a particular location, and different place cells fire at different locations. The whole collection of place cells cover the whole square region. The discovery of grid cells was much more surprising and unexpected. The grid cells exist in the Entorhinal cortex. Each grid cell fires at multiple locations, and these locations form a regular hexagon grid. See Figure \[fig:g1\](c). The grid cells have been discovered across mammalian species, including human. See Figure \[fig:g1\](d). In this paper, we propose a representational model to explain the hexagon patterns of the grid cells, and to explain how the grid cells perform path integral and path planning. We shall show that the grid cells are capable of error correction, which provides a justification for the grid cells. ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ![Grid cells form a high-dimensional vector representation of 2D self-position. Three sub-models: (1) Local motion is modeled by vector-matrix multiplication. (2) Angle between two nearby vectors magnifies the Euclidean distance. (3) Inner product between any two vectors measures the adjacency which is a kernel function of the Euclidean distance. []{data-label="fig:g2"}](./FIG/v1.pdf "fig:"){height=".11\linewidth"} ![Grid cells form a high-dimensional vector representation of 2D self-position. Three sub-models: (1) Local motion is modeled by vector-matrix multiplication. (2) Angle between two nearby vectors magnifies the Euclidean distance. (3) Inner product between any two vectors measures the adjacency which is a kernel function of the Euclidean distance. []{data-label="fig:g2"}](./FIG/v2.pdf "fig:"){height=".11\linewidth"} ![Grid cells form a high-dimensional vector representation of 2D self-position. Three sub-models: (1) Local motion is modeled by vector-matrix multiplication. (2) Angle between two nearby vectors magnifies the Euclidean distance. (3) Inner product between any two vectors measures the adjacency which is a kernel function of the Euclidean distance. []{data-label="fig:g2"}](./FIG/v3.pdf "fig:"){height=".14\linewidth"} \(1) Vector-matrix multiplication \(2) Magnified local isometry \(3) Global adjacency kernel ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Figure \[fig:g2\] illustrates our model. The 2D self-position of the agent is represented by a high-dimensional vector, and the 2D self-motion or displacement of the agent is represented by a matrix that acts on the vector. Each component of the vector is a unit or a cell. In Figure \[fig:g2\], $x$ denotes the 2D self-position, $v(x)$ is the high-dimensional vector representation of the 2D $x$. $\Delta x$ is the self-motion or one-step displacement. $M(\Delta x)$ is the matrix representation of $\Delta x$. The model consists of the following three sub-models. (1) Vector-matrix multiplication. The movement from the current position $x$ to the next position $x+\Delta x$ is modeled by matrix-vector multiplication, i.e., the vector of the next position $v(x+\Delta x)$ is obtained by multiplying the matrix of the motion, $M(\Delta x)$, to the vector of the current position $v(x)$. (2) Magnified local isometry. The angle between two nearby vectors equals the Euclidean distance $\|\Delta x\|$ between the two corresponding positions multiplied by a magnifying factor. (3) Global adjacency kernel. The inner product between two vectors $\langle v(x), v(y)\rangle$ measures the adjacency between the two corresponding positions, which is defined by a kernel function $f$ of the Euclidean distance $\|x-y\|$ between the two positions $x$ and $y$. One additional feature is that the whole vector $v(x)$ is partitioned into multiple sub-vectors, and each sub-vector is driven by an associated sub-matrix. The whole system is like a multi-arm clock, with each arm rotating at a magnified speed and spanning a 2D sub-manifold on a high-dimensional sphere. Our experiments show that sub-models (1) and (2) are sufficient for the emergence of the hexagon grid patterns of the grid cells. Sub-model (2) makes the vector representation robust to noises or errors due to the magnification of the distance. Sub-model (3) enables unique decoding of the position from the vector, because $f$ is unimodal and peaked at 0, and it may serve as the link between the grid cells and place cells. Together with sub-model (1), sub-model (3) enables path integral and path planning, because the adjacency $\langle v(x), v(y)\rangle$ informs the Euclidean distance $\|x-y\|$. All the three sub-models can be implemented by one-layer neural networks. Contributions and related work ============================== The following are the contributions of our work. (1) We propose a representational model for grid cells, where the self-position is represented by a vector and the self-motion is represented by a matrix that acts on the vector. (2) We show that our model can learn hexagon grid patterns. (3) We show our model is capable of path integral, path planning, and error correction. Many mathematical and computational models ([@burak2009accurate; @sreenivasan2011grid; @blair2007scale; @de2009input]) have been proposed to explain the formation and function of grid cells. Compared to previous computational models on grid cells, our model only makes very generic assumptions about the algebra and geometry of the representational scheme, without assuming Fourier plane waves or clock arithmetics. Recently, deep learning models ([@banino2018vector; @cueva2018emergence]) have been proposed to learn the grid-like units for navigation. Our work was inspired by them. Compared with these models, our model has explicit algebra and geometry. In terms of algebra, our model has explicit matrix representation of self-motion, and the change of self-position is modeled by vector-matrix multiplication. In terms of geometry, our model assumes that the vector rotates while the agent moves, and our model assumes magnified local isometry and global adjacency kernel based on the angles between the vectors. Expressing the adjacency kernel as the inner product between the vectors is related to the kernel trick ([@cortes1995support]), random Fourier basis ([@ng2002spectral]), and spectral clustering ([@ng2002spectral]). Representational model of grid cells ==================================== Consider an agent navigating within a domain $D = [0, 1] \times [0, 1]$ (actually the shape does not matter, and it can be $\R^2$). We can discretize $D$ into an $N \times N$ lattice. $N = 40$ in our experiments. Let $x = (x_1, x_2) \in D$ be the self-position of the agent. $x$ is 2D. Suppose the agent wants to represent its self-position by a $d$-dimensional hidden vector $v(x)$. We introduce the following three sub-models. Sub-model 1 about motion algebra: vector-matrix multiplication -------------------------------------------------------------- Suppose at a position $x$, the self-motion or one-step displacement is $\Delta x$, so that the agent moves to $x + \Delta x$ after one step. We assume that $$\begin{aligned} v(x+\Delta x) = M(\Delta x) v(x), \label{eq: motion}\end{aligned}$$ where $M(\Delta x)$ is a $d \times d$ matrix that depends on $\Delta x$. While $v(x)$ is the vector representation of the self-position $x$, $M(\Delta x)$ is the matrix representation of the self-motion $\Delta x$. We can illustrate the motion model by the following diagram: $$\begin{aligned} \begin{array}[c]{cccc} {\rm Motion:} & x_t & \stackrel{ + \Delta x}{\xrightarrow{\hspace{1cm}}}& x_{t + 1} \\ & \downarrow& \downarrow &\downarrow\\ & v(x_t) &\stackrel{ M(\Delta x) \times }{\xrightarrow{\hspace{1cm}}} & v(x_{t+1}) \end{array} \label{eq:diagram}\end{aligned}$$ See Figure \[fig:g2\](1). Both $v(x)$ and $M(\Delta x)$ are to be learned. We can discretize $\Delta x$, and learn a motion matrix $M$ for each $\Delta x$. We can also learn a parametric model for $M$. To this end, we can further parametrize $ M = I + \tilde{M}(\Delta x) $ such that each element of $\tilde{M}(\Delta x)$ is a quadratic (or polynomial) function of $\Delta x = (\Delta x_1, \Delta x_2)$: $$\begin{aligned} \tilde{M}_{ij}(\Delta x) = \beta_{ij}^{(1)} \Delta x_1 + \beta_{ij}^{(2)} \Delta x_2 + \beta_{ij}^{(11)} \Delta x_1^2 + \beta_{ij}^{(22)} \Delta x_2^2 + \beta_{ij}^{(12)} \Delta x_1 \Delta x_2, \label{eqn: param}\end{aligned}$$ where the coefficients $\beta$ are to be learned. The above may be considered a second-order Taylor expansion which is expected to be accurate for small $\Delta x \in \Delta$, where $\Delta$ is the allowed collection of one-step displacements, e.g., $\pm 3$ grid points in each direction on the $40 \times 40$ grid. The motion model can be considered a linear recurrent neural network (RNN). However, if we are to interpret $M$ as the weight matrix, then the weight matrix is dynamic because it depends on the motion $\Delta x$. One may implement it by discretizing $\Delta x$, so that we have a finite set of $\Delta x$, and thus a finite set of $M(\Delta x)$. Then at each time step, the RNN switches between the finite set of motion matrices. This is like the gearing operation of a multi-speed bicycle. Disentangled blocks or modules ------------------------------ For the sake of estimation accuracy and computational efficiency, we further assume that $M(\Delta x)$ is block diagonal, i.e., we can divide $v$ into $K$ blocks of sub-vectors, $v = (v^{(k)}, k = 1, ..., K)$, and $ v^{(k)}(x+\Delta x) = M^{(k)}(\Delta x) v^{(k)}(x). $ That is, the vector $v$ consists of sub-vectors, each of which rotates in its own subspace, so that the dynamics of the sub-vectors are disentangled. The assumption of disentangled blocks in our model is related to the modular organization of grid cells in neuroscience ([@stensola2012entorhinal]), where a module refers to a region of grid cells where all cells share similar grid scales and orientations. Sub-model 2 about local geometry: magnified local isometry ---------------------------------------------------------- The above motion algebra alone is not sufficient for learning the vector matrix representations, because a trivial solution is that all the $v(x)$ are the same, and the matrix $M(\Delta x)$ is always identity. We need to properly displace the vectors $v(x)$. So we shall model $\langle v(x), v(y)\rangle$ both locally and globally. Let $d$ be the dimensionality of $v^{(k)}$, i.e., the number of grid cells within the $k$-th block. For the local geometry, we assume that for each block, $$\begin{aligned} \langle v^{(k)}(x), v^{(k)}(x+\Delta x)\rangle = d(1 - \alpha_k \|\Delta x\|^2), \label{eq:isometry}\end{aligned}$$ for all $x$ and $\Delta x$ such that $\alpha_k \|\Delta x\|^2 \leq c$, i.e., $\Delta x \in \Delta({\alpha_k}) = \{\Delta x: \alpha_k \|\Delta x\|^2 \leq c\}$. In our experiments, we take $c = 1.5$. $\alpha_k$ can be either designed or learned. Based on sub-model (\[eq:isometry\]), $\\|v^{(k)}(x)\\|^2 = d$ for every $x$. The inner product on the left hand side is $d \cos(\Delta \theta)$ where $\Delta \theta$ is the angle between $v^{(k)}(x)$ and $v^{(k)}(x+\Delta x)$. $1 - \alpha_k \|\Delta x\|^2$ on the right hand side may be considered a second order Taylor expansion of a function $f(r)$ such that $f(0) = 1$, $f'(0) = 0$, i.e., $0$ is the maximum, and $f''(0) = -2 \alpha_k$. It is also an approximation to $\cos(\sqrt{2\alpha_k} \|\Delta x\|)$. Let $\omega_k = \sqrt{2\alpha_k}$, we have $$\begin{aligned} \mbox{Magnified local isometry}: \Delta \theta = \omega_k \|\Delta x\|,\end{aligned}$$ i.e., the angle between $v(x)$ and $v(x+\Delta x)$ magnifies the distance $\|\Delta x\|$ by a factor of $\omega_k$ uniformly for all $x$. See Figure \[fig:g2\](2). The factor $\omega_k$ defines the metric of block $k$. Rotation and projection ----------------------- Since $\\|v^{(k)}(x)\\|$ is a constant for all $x$, $M^{(k)}(\Delta x)$ is an orthogonal matrix, and the self-motion is represented by a rotation in the $d$-dimensional space. $\omega_k \|\Delta x\|$ is the angular speed of rotation of the sub-vector $k$. $(v^{(k)}(x), \forall x)$ forms a 2D sub-manifold on the sphere in the $d$-dimensional space. $v^{(k)}$ is like an arm of a clock except that the clock is not a 1D circle, but a 2D sub-manifold. This 2D sub-manifold becomes a local codebook for the 2D positions within a local neighborhood. For a vector $v^{(k)}$, we can decode its position by projecting it onto the 2D sub-manifold, to get $\hat{x} = \arg\max_x \langle v^{(k)}, v^{(k)}(x)\rangle$ where the maximization is within the local neighborhood. Error correction ---------------- The neurons are intrinsically noisy and error prone. For $\omega_k = \sqrt{2\alpha_k} \gg 1$, the magnification offers error correction because $v^{(k)}(x)$ and $v^{(k)}(x+\Delta x)$ are far apart, which is resistant to noises or corruptions. That is, projection to the 2D sub-manifold codebook removes the noises. Specifically, suppose we have a vector $u = v^{(k)}(x) + \epsilon$, where $\epsilon \sim {\rm N}(0, s^2 I_d)$, and $I_d$ is the $d$-dimensional identity matrix. We can decode $x$ from $u$ based on the codebook by maximizing $\langle u, v^{(k)}(y)\rangle = \langle v^{(k)}(x), v^{(k)}(y)\rangle + \langle \epsilon, v^{(k)}(y)\rangle = d(1 - \alpha_k \|y-x\|^2) + \sqrt{d} s Z$ over $y$ that is within a local neighborhood of $x$, where $Z \sim {\rm N}(0, 1)$. The optimal $y$ will be close to $x$ because if $y$ deviates from $x$ by $\Delta x$, then the first term will drop by $d \alpha_k \|\Delta x\|^2$, which cannot be made up by the second term $\sqrt{d} s Z$ due to noises, unless the noise level $s$ is extremely large. From the above analysis, we can also see that the larger $d$ is, the more resistant the system is to noise, because the first term is of order $d$ and the second term is of order $\sqrt{d}$. In addition to additive noises, the system is also resistant to multiplicative noises including dropout errors, i.e., multiplicative Bernoulli 0/1 errors. The dropout errors may occur due to noises, aging, or diseases. They may also be related to the asynchronous nature of the neuron activities in computing. Hexagon grid patterns {#sect: analytical} --------------------- While the magnified local isometry enables error correction, it also causes global periodicity. Because the angle between nearby $v^{(k)}(x)$ and $v^{(k)}(x+\Delta x)$ is magnified, when we vary $x$, the vector $v^{(k)}(x)$ will rotate at a magnified speed $\omega_k \|\Delta x\|$, so that it quickly rotates back to itself, like an arm of a clock. Thus each unit of $v^{(k)}(x)$ is periodic with $\omega_k$ determining the periodicity. Our experiments show that sub-models (1) and (2) are sufficient for the emergence of hexagon grid patterns. In fact, we have the following analytical solution (see Appendix for a proof): \[thm: 1\] Let $e(x) = (e^{i \langle a_j, x\rangle}, j = 1, 2, 3)^\top$, and $a_1$, $a_2$, $a_3$ are three 2D vectors so that the angle between $a_i$ and $a_j$ is $2\pi/3$ for $\forall i \neq j$ and $\|a_j\| = 2\sqrt{\alpha}$ for $\forall j$. Let $C$ be a random $3 \times 3$ complex matrix such that $C^C = I$. Then $v(x) = C e(x)$, $M(\Delta x) = C {\rm diag}(e(\Delta x))C^$ satisfy equation \[eq: motion\] and equation \[eq:isometry\] approximately for all $x$ and small $\Delta x$. $v(x)$ amounts to a $6$-dimensional real vector. Since the angle between $a_i$ and $a_j$ is $2\pi/3$ for $\forall i \neq j$, patterns of $v(x)$ over $x$ have hexagon periodicity. Moreover, the scale of the patterns is controlled by the length of $a_j$, i.e., the scaling parameter $\alpha$. We want to emphasize that sub-models (1) and (2) are about local $\Delta x$, where we do not make any assumptions about global patterns, such as Fourier basis. In contrast, the solution in the above theorem is global. That is, our model assumes much less than the solution in the theorem. Our experiments show that the hexagon patterns will emerge as long as the number of units is greater than or equal to 6. Sub-model 3 about global geometry: adjacency kernel {#sect: localization} --------------------------------------------------- Because of the periodicity, each block $(v^{(k)}(x), \forall x)$ does not form a global codebook of 2D positions, i.e., there can be $x \neq y$, but $v^{(k)}(x) = v^{(k)}(y)$, i.e., $v^{(k)}$ does not encode $x$ uniquely. We can combine multiple blocks to resolve the global ambiguity. Specifically, let $v(x) = (v^{(k)}(x), k = 1, ..., K)$ be the whole vector, we assume the following global adjacency sub-model for the whole vector: $$\begin{aligned} \langle v(x), v(y)\rangle = \sum_{k=1}^{K} \langle v^{(k)}(x), v^{(k)}(y)\rangle = (K d) f(\|x-y\|), \label{eqn: localization}\end{aligned}$$ where $(v(x), M(\Delta x), \alpha_k, \forall x, \Delta x, k)$ are to be learned. Recall $d$ is the number of grid cells in each block, and $K$ is the number of blocks. $f(r)$ is the adjacency kernel that decreases monotonically as the Euclidean distance $r = \|x-y\|$ increases. One example of $f$ is the Gaussian kernel ${ f(r) = \exp\left(- {r^2}/{2\sigma^2}\right). }$ Another example is the exponential kernel ${ f(r) = \exp\left(- {r}/{\sigma}\right). }$ As a matter of normalization, we assume $f(0) = 1$, which is the maximum of $f(r)$. Since ${f(0) = 1}$, $\\|v(x)\\|^2 = Kd$ for any $x$, and $\langle v(x), v(y)\rangle = (Kd) \cos \theta$, where $\theta$ is the angle between $v(x)$ and $v(y)$, and we have $$\begin{aligned} \mbox{Global adjacency}: \cos \theta = f(\|x-y\|).\end{aligned}$$ The angle between any two vectors is always less than $\pi/2$. See Figure \[fig:g2\](3). By fitting the multiple sub-vectors together, we still retain the error correction capacity due to magnified local isometry, meanwhile we eliminate the ambiguity by letting $\langle v^{(k)}(x), v^{(k)}(y)\rangle$ for different $k$ cancel each other out by destructive interference as $y$ moves away from $x$, so that we obtain unique decoding of positions. Let $C = \{v(x), x \in D\}$ be the codebook sub-manifold, error correction of a vector $u$ is obtained by projection onto $C$: $\arg\max_{v \in C} \langle u, v\rangle$. The whole vector $v$ is like a $K$-arm clock, with each $v^{(k)}$ being an arm rotating at a speed $\omega_k \|\Delta x\| = \sqrt{2\alpha_k} \|\Delta x\|$. Localization and heat map ------------------------- $(v(x), \forall x)$ forms a global codebook for $x$. It is a 2D sub-manifold on the sphere in the $(Kd)$-dimensional space. For a vector $v$, we can decode its position by its projection on the codebook manifold. Since $f(r)$ is monotonically decreasing, ${h(x) = \langle v, v(x)\rangle}$ gives us the heat map to decode the position of $v$ uniquely. Let the decoded position be $\hat{x}$, then ${ \hat{x} = \arg \max_x \langle v, v(x)\rangle. }$ We can obtain the one-hot representation $\delta_{\hat{x}}$ of $\hat{x}$ by non-maximum suppression on the heat map $h(x)$. Let $V = (v(x), \forall x)$ be the $(Kd) \times N^2$ matrix (recall the domain $D = [0, 1]^2$ is discretized into an $N \times N$ lattice), where each column is a $v(x)$. We can write the heat map $h(x) = \langle v, v(x)\rangle$ as a $N^2$-dimensional vector $h = V^\top v$, which serves to decode the position $x$ encoded by $v$. Conversely, for a one-hot representation of a position $x$, i.e., $\delta_x$, which is a one-hot $N^2$-dimensional vector, we can encode it by $v = V \delta_x$. Both the encoder and decoder can be implemented by a linear neural network with connection weights $V$ and $V^\top$ respectively, as illustrated by the following diagram: $$\begin{aligned} \begin{array}[c]{ccccc} {\rm Localization:} & v &\stackrel{ V^\top \times }{\xrightarrow{\hspace{1cm}}} & h & (\mbox{heat map and decoding to $\delta_x$})\\ & \delta_x &\stackrel{ V \times }{\xrightarrow{\hspace{1cm}}} & v(x) & (\mbox{encoding}) \end{array} \label{eq:diagram}\end{aligned}$$ Note that in decoding $v \rightarrow h(x) \rightarrow \delta_x$ and encoding $\delta_x \rightarrow v$, we do not represent or operate on the 2D coordinate $x$ explicitly, i.e., $x$ itself is never explicitly represented, although we may use the notation $x$ in the description of the experiments. Path integral ------------- Path integral (also referred to as dead-reckoning) is the task of inferring the self-position based on self-motion (e.g., imagine walking in a dark room). Specifically, the input to path integral is a previously determined initial position $x_0$ and motion sequences $\{\Delta x_1, ..., \Delta x_T\}$, and the output is the prediction of one’s current position $x_T$. We first encode the initial position $x_0$ as $v(x_0)$. Then, by the motion model, the hidden vector $v(x_T)$ at time $T$ can be predicted as: $$\begin{aligned} v(x_T) = \prod\nolimits_{t=T}^{1} M(\Delta x_t) v(x_0). \end{aligned}$$ We can then decode $x_T$ from $v(x_T)$. Path planning ------------- Our representation system can plan direct path from the starting position $x_0$ to the target position $y$ by steepest ascent on the inner product $\langle v(x), v(y)\rangle$, i.e., let $v_0 = v(x_0)$, the algorithm iterates $$\begin{aligned} && \Delta x_t = \arg \max_{\Delta x \in \Delta}\langle v(y), M(\Delta x) v_{t-1}\rangle, \\ && v_t = M(\Delta x_t) v_{t-1}, \end{aligned}$$ where $\Delta$ is the set of allowable displacements $\Delta x$. When a rat does path planning, even if it is not moving, its grid cells are expected to be active. This may be explained by the above algorithm. In path planning, the rat can also fantasize bigger step sizes that are beyond its physical capacity, by letting $\Delta$ include physically impossible large steps. In general, our representation scheme $(v(x), M(\Delta x), f(\|x-y\|))$ mirrors $(x, \Delta x, \|x-y\|)$. Thus the learned representation is capable of implementing existing path planning algorithms in robotics ([@siegwart2011introduction]) even though our system does not have explicit coordinates in 2D (i.e., the 2D coordinates $x$ are never explicitly represented by two neurons). Place cells and scale --------------------- For each $x$, we may interpret $\langle v(x), v(y)\rangle /(Kd) = f(\|x-y\|)$ as a place cell whose response is $f(\|x-y\|)$ if the agent is at $y$, or at least, we may consider $f(\|x-y\|)$ as an internal input to the place cell based on self-motion, in addition to external visual cues. For the Gaussian kernel $f(r) = \exp(-r^2/2\sigma^2)$, the choice of $\sigma$ determines the scale. In path integral, for accurate decoding of the position $x$ from the vector $v$ in the presence of noises, we want $\sigma$ to be small so that $f(r)$ drops to zero quickly. However, in path planning, for a vector $v$, we also want to know the Euclidean distance between its position $x$ to a target position $y$, which may be far away from $x$. The distance is $\|x-y\| = f^{-1}(\langle v, v(y)\rangle/(Kd))$. For accurate estimation of long distance in the presence of noises, we need $\sigma$ to be large, so that the slope of $f^{-1}$ is not too big. Perhaps we need multiple $f(r)$ with different $\sigma$, and for each $f(r)$ we have $(Kd) f(r) = \sum_{k=1}^{K} \gamma_k \langle v^{(k)}(x), v^{(k)}(y)\rangle$, where different $f(r)$ have different coefficients $(\gamma_k)$ while sharing the same $(v^{(k)}(x))$. We shall study this issue in future work. Group representation in motor cortex ------------------------------------ Where does the self-motion $\Delta x$ come from? It comes from the movements of head and legs, i.e., each step of navigation involves a whole process of path integral and path planning of the movements of head and legs (as well as arms). In general, we can use the same system we have developed for the movements of head, legs, arms, fingers, etc. Their movements form groups of actions. In navigation, the movements belong to 2D Euclidean group. In body movements, the movements belong to various Lie groups. Our method can be used to learn the representational systems of these groups, and such representations may exist in motor cortex. We leave this problem to future investigation. Learning representation ======================= The square domain $D$ is discretized into a $40 \times 40$ lattice, and the agent is only allowed to move on the lattice. We can learn $(v(x), \forall x)$ and $(M(\Delta x), \forall \Delta x)$ (or the $\beta$ coefficients that parametrize $M$) by minimizing the following loss functions. For sub-model (1) on vector-matrix multiplication, the loss function is $$\begin{aligned} L_1 = \E_{x, \Delta x} \left[ \\|v(x+\Delta x) - {M}(\Delta x) v(x)\\|^2\right], \end{aligned}$$ where $x$ is sampled from the uniform distribution on $D = [0, 1]^2$, and $\Delta x$ is sampled from the uniform distribution within a certain range $\Delta_1$ (3 grid points in each direction in our experiments). The above motion loss is a single-step loss. It can be generalized to multi-step loss $$\begin{aligned} L_{1, T} = \E_{x, \Delta x_{1}, ...\Delta x_{T}} \left[ \\|v(x+\Delta x_1 + ... + \Delta x_T) - M(\Delta x_T) ... {M}(\Delta x_1) v(x)\\|^2\right], \label{eqn: multi-step} \end{aligned}$$ where $(\Delta x_t, t = 1, ..., T)$ is a sequence of $T$ steps of displacements, i.e., a simulated trajectory. For sub-model (2) on magnified local isometry, the loss function is $$\begin{aligned} L_{2, k} = \E_{x, \Delta x} \left[(\langle v^{(k)}(x), v^{(k)}(x+\Delta x)\rangle - (d(1- \alpha_k \|\Delta x \|^2))^2\right], \end{aligned}$$ where for fixed $\alpha_k$, $\Delta x$ is sampled uniformly within the range $\Delta_{2}(\alpha_k)= \{\Delta x: \alpha_k \|\Delta x\|^2 \leq c\}$ ($c = 1.5$ in our experiments). We can define $L_2 = \sum_{k=1}^{K} L_{2, k}$. For sub-model (3) on global adjacency kernel, the loss function is $$\begin{aligned} L_3 = \E_{x, y} \left[((Kd) f(\|x-y\|) - \langle v(x), v(y)\rangle)^2\right], \end{aligned}$$ where both $x$ and $y$ are sampled uniformly from $D$. Let $v(x) = (v_i(x), i = 1, ..., Kd)$, we also impose a regularization loss $ L_0 = \sum_{i=1}^{Kd} (\E_x[v_i(x)^2] - 1)^2, $ to enforce uniform energy among the grid cell. It also helps to break the symmetry caused by the fact that the loss function is invariant under the transformation $v(x) \rightarrow Q v(x), \forall x$, where $Q$ is an arbitrary orthogonal matrix. This loss is not crucial though, so we will make it implicit for the rest of the paper. Fixing the magnitude of $\E_x[v_i(x)]$ within a certain range is biologically plausible, because $v_i(x)$ is a single cell. For mathematical and computational convenience, we can also normalize $v(x)$ so that $\\|v(x)\\|^2 = 1$, $\langle v(x), v(y)\rangle = f(\|x-y\|)$, $\langle v^{(k)}(x), v^{(k)}(x+\Delta x)\rangle = (1-\alpha_k \|\Delta x\|^2)/K$, and $\E_x[v_i(x)^2] = 1/(Kd)$. When learning a single block, we can normalize $v^{(k)}(x)$ so that $\\|v^{(k)}(x)\\|^2 = 1$, $\langle v^{(k)}(x), v^{(k)}(x+\Delta x)\rangle = 1-\alpha_k \|\Delta x\|^2$ and $\E_x[v_i(x)^2] = 1/d$. The total loss function is a linear combination of the above losses, where the weights for combining the losses are chosen so that the weighted losses are of the same order of magnitude. The loss function is minimized by Adam optimizer ([@kingma2014adam]) (lr $= 0.03$) for $6,000$ iterations. A batch of $30,000$ examples, i.e., $(x, \Delta x_t, t = 1, ..., T))$ for $L_1$, $(x, \Delta x)$ for $L_2$, and $(x, y)$ for $L_3$ are sampled at each learning iteration as the input to the loss function. In the later stage of learning ($\geq 4,000$ iterations), $\\|v(x)\\| = 1$ is enforced by projected gradient descent, i.e., normalizing each $v(x)$ after the gradient descent step. Experiments =========== Learning single blocks: hexagon patterns and metrics {#sect: single} ---------------------------------------------------- [C[.15]{}C[.75]{}]{} [$\alpha = 18$]{} & ![Learned units of a single block with fixed $\alpha$. (a) Learned single block with $6$ units. Every row shows the learned units with a given $\alpha$. (b) Learned single block with $100$ units and $\alpha = 72$.[]{data-label="fig: single units"}](./FIG/units_single_block/alpha18 "fig:"){width=".75\textwidth"}\ [$\alpha = 36$]{} & ![Learned units of a single block with fixed $\alpha$. (a) Learned single block with $6$ units. Every row shows the learned units with a given $\alpha$. (b) Learned single block with $100$ units and $\alpha = 72$.[]{data-label="fig: single units"}](./FIG/units_single_block/alpha36 "fig:"){width=".75\textwidth"}\ [$\alpha = 72$]{} & ![Learned units of a single block with fixed $\alpha$. (a) Learned single block with $6$ units. Every row shows the learned units with a given $\alpha$. (b) Learned single block with $100$ units and $\alpha = 72$.[]{data-label="fig: single units"}](./FIG/units_single_block/alpha72 "fig:"){width=".75\textwidth"}\ [$\alpha = 108$]{} & ![Learned units of a single block with fixed $\alpha$. (a) Learned single block with $6$ units. Every row shows the learned units with a given $\alpha$. (b) Learned single block with $100$ units and $\alpha = 72$.[]{data-label="fig: single units"}](./FIG/units_single_block/alpha108 "fig:"){width=".75\textwidth"}\ [$\alpha = 144$]{} & ![Learned units of a single block with fixed $\alpha$. (a) Learned single block with $6$ units. Every row shows the learned units with a given $\alpha$. (b) Learned single block with $100$ units and $\alpha = 72$.[]{data-label="fig: single units"}](./FIG/units_single_block/alpha144 "fig:"){width=".75\textwidth"}\ [$\alpha = 180$]{} & ![Learned units of a single block with fixed $\alpha$. (a) Learned single block with $6$ units. Every row shows the learned units with a given $\alpha$. (b) Learned single block with $100$ units and $\alpha = 72$.[]{data-label="fig: single units"}](./FIG/units_single_block/alpha180 "fig:"){width=".75\textwidth"} [(a) Learned single block with $6$ units]{} ![Learned units of a single block with fixed $\alpha$. (a) Learned single block with $6$ units. Every row shows the learned units with a given $\alpha$. (b) Learned single block with $100$ units and $\alpha = 72$.[]{data-label="fig: single units"}](./FIG/units_single_block/blocksize100.png "fig:"){width="\textwidth"} [(b) Learned single block with $100$ units]{} We first learn a single block with fixed $\alpha_k$ by minimizing $L_1 + \lambda_2 L_{2, k}$ (we shall drop the subscript $k$ in this subsection for simplicity). Figure \[fig: single units\] shows the learned units over the $40 \times 40$ lattice of $x$. Figure \[fig: single units\](a) shows the learned results with $6$ units and different values of $\alpha$. The scale or metric of the lattice is controlled by $\alpha$. The units within a block have patterns with similar scale and arrangement, yet different phases. Figure \[fig: single units\](b) shows the learned results with $100$ units and $\alpha=72$, indicating that the grid-like patterns are stable and easy to learn even when the number of units is large. Learning multiple hexagon blocks and metrics -------------------------------------------- [C[.06]{}\|C[.375]{}\|C[.06]{}\|C[.375]{}]{} [$\alpha_k$]{} & [Learned blocks]{} & [$\alpha_k$]{} & [Learned blocks]{}\ & & [$44.1$]{} &\ [$4.7$]{}&&[$56.3$]{}&\ [$11.9$]{}&&[$57.0$]{}&\ [$17.0$]{}&&[$61.7$]{}&\ [$17.3$]{}&&[$73.0$]{}&\ [$35.7$]{}&&[$85.7$]{}&\ [$39.1$]{}&&[$87.5$]{}&\ [$39.7$]{}&&[$94.7$]{}&\ \ ![(a) Response maps of learned units of the vector representation and learned scaling parameters $\alpha_k$. Block size equals 6 and each row shows the units belonging to the same block. (b) Illustration of block-wise activities of the units (where the activities are rectified to be positive).[]{data-label="fig: units"}](./FIG/units_multiple_blocks/group_illustration.png "fig:"){width="\textwidth"}\ [(b) Disentangled blocks]{} We learn multiple blocks by minimizing $L_1 + \lambda_2 L_2 + \lambda_3 L_3$. Instead of manually assigning $\alpha_k$, we learn $\alpha_k$ by gradient descent, simultaneously with $v$ and $M$. In Figure \[fig: units\](a), we show the learned units $v(x)$ over the $40 \times 40$ lattice of $x$ and the learned metrics $\alpha_k$. A Gaussian kernel with $\sigma = 0.08$ is used for the global adjacency measure $f(\|x-y\|)$. Block size is set to $6$ and each row shows the learned units belonging to the same block. The scales of the firing fields are controlled by the learned $\alpha_k$. Figure \[fig: units\](b) illustrates the combination of multiple blocks. For the localization model, given a vector $v$, the heat map of a single block $\langle v^{(k)}, v^{(k)}(x)\rangle$ has periodic firing fields and cannot determine a location uniquely. However, ambiguity disappears by combing the heat maps of multiple blocks, which have firing fields of multiple scales and phases that add up to a Gaussian kernel $\langle v, v(x)\rangle$. The Gaussian kernel informs the place cell, by which the location is determined uniquely. For a motion $\Delta x$, every block rotates in its own subspace with motion matrix $M^{(k)}(\Delta x)$, resulting in phase shifting in the heat map of each single block. In the subsequent experiments, we shall learn the grid cells by minimizing $L_1 + \lambda_3 L_3$ for simplicity. Path integral ------------- ![(a) Path integral prediction. The black line depicts the real path while red dotted line is the predicted path by the learned model. (b) Mean square error over time step. The error is average over $1,000$ episodes. The curves correspond to different numbers of steps used in the multi-step motion loss. (c) Mean square error performed by models with different block sizes and different kernel types. Error is measured by number of grids. []{data-label="fig: integral"}](./FIG/path_integral/path.png "fig:"){width="\textwidth"}\ [(a) Predicted path]{} ![(a) Path integral prediction. The black line depicts the real path while red dotted line is the predicted path by the learned model. (b) Mean square error over time step. The error is average over $1,000$ episodes. The curves correspond to different numbers of steps used in the multi-step motion loss. (c) Mean square error performed by models with different block sizes and different kernel types. Error is measured by number of grids. []{data-label="fig: integral"}](./FIG/path_integral/path_integral_err.png "fig:"){width="\textwidth"}\ [(b) MSE over time step]{} ![(a) Path integral prediction. The black line depicts the real path while red dotted line is the predicted path by the learned model. (b) Mean square error over time step. The error is average over $1,000$ episodes. The curves correspond to different numbers of steps used in the multi-step motion loss. (c) Mean square error performed by models with different block sizes and different kernel types. Error is measured by number of grids. []{data-label="fig: integral"}](./FIG/path_integral/path_integral_bk.png "fig:"){width="\textwidth"}\ [(c) Selection of block sizes and kernels]{} Figure \[fig: integral\](a) shows an example of path integral result (time duration $\tilde{T} = 40$), where we use single step motion loss $L_{1, T=1}$ in learning. Gaussian kernel with $\sigma = 0.08$ is used as the adjacency measure in $L_3$. We find single-step loss is sufficient for performing path integral. The mean square error remains small ($\sim1.2$ grid) even after $400$ steps of motions (figure \[fig: integral\](b)). The error is averaged over $1,000$ episodes. The motion loss can be generalized to multi-step $L_{1, T}$, as shown by equation \[eqn: multi-step\]. In Figure \[fig: integral\](b), we show that multi-step loss can improve the performance slightly. In Figure \[fig: integral\](c) we compare the learned models with fixed number of units (96) but different block sizes. We also compare the performance of models using Gaussian kernel ($\sigma=0.08$) and exponential kernel ($\sigma=0.3$) as the adjacency measure in the localization model. The result shows that models with Gaussian kernel and block size $\geq 3$, and with exponential kernel and block size $\geq 4$ have performances comparable to the model learned without block-diagonal assumption (block size $=96$). Path planning {#sect:pp} ------------- For path planning, we assume continuous $x$ and $\Delta x$. First, we design the set of allowable motions $\Delta$. For a small length $r$, we evenly divide $[0, 2\pi]$ into $n$ directions $\{\theta_i, i=1,...,n\}$, resulting in $n$ candidate motions $\Delta = \{\Delta x_i = (r \cos(\theta_i), r\sin(\theta_i)), i=1,...,n\}$. These $n$ small motions serve as motion basis. Larger motion can be further added to $\Delta$ by estimating the motion matrix $M(k \Delta x_i) = M^k(\Delta x_i)$. The starting position and destination can also be any continuous values, where the encoding to the latent vector is approximated by bilinear interpolation of nearest neighbors on the lattice. In the experiments, we choose $r=0.05$ and $n=100$, and add another set of motions with length $0.025$ to enable accurate planning. The system is learned with exponential kernel ($\sigma = 0.3$) as global adjacency to encourage connection of long distance. Figure \[fig: planning\](a) shows planning examples with six settings of motion ranges $\Delta$. Including larger motions accelerates the planning process so that it finishes with less steps. We define one episode to be a success if the distance between the end position and the destination is less than 0.025. We achieve a success rate of $>99\%$ over $1,000$ episodes for all the six settings. ![(a) Planning examples with different motion ranges. Red star represents the destination $y$ and green dots represent the planned position $\{x_0 + \sum_{i=1}^t \Delta x_i\}$. (b) Planning examples with a dot obstacle. Left figure shows the effect of changing scaling parameter $a$, while right figure shows the effect of changing annealing parameter $b$. (c) Planning examples with obstacles mimicking walls, large objects and simple mazes.[]{data-label="fig: planning"}](./FIG/path_planning/plain/path_multiple_speed_crop.png "fig:"){width="\textwidth"}\ [(a) Simple planning]{} ![(a) Planning examples with different motion ranges. Red star represents the destination $y$ and green dots represent the planned position $\{x_0 + \sum_{i=1}^t \Delta x_i\}$. (b) Planning examples with a dot obstacle. Left figure shows the effect of changing scaling parameter $a$, while right figure shows the effect of changing annealing parameter $b$. (c) Planning examples with obstacles mimicking walls, large objects and simple mazes.[]{data-label="fig: planning"}](./FIG/path_planning/obstacle/change_a_crop.png "fig:"){width=".48\textwidth"} ![(a) Planning examples with different motion ranges. Red star represents the destination $y$ and green dots represent the planned position $\{x_0 + \sum_{i=1}^t \Delta x_i\}$. (b) Planning examples with a dot obstacle. Left figure shows the effect of changing scaling parameter $a$, while right figure shows the effect of changing annealing parameter $b$. (c) Planning examples with obstacles mimicking walls, large objects and simple mazes.[]{data-label="fig: planning"}](./FIG/path_planning/obstacle/change_b_crop.png "fig:"){width=".48\textwidth"}\ [(b) Planning with dot obstacle]{} ![(a) Planning examples with different motion ranges. Red star represents the destination $y$ and green dots represent the planned position $\{x_0 + \sum_{i=1}^t \Delta x_i\}$. (b) Planning examples with a dot obstacle. Left figure shows the effect of changing scaling parameter $a$, while right figure shows the effect of changing annealing parameter $b$. (c) Planning examples with obstacles mimicking walls, large objects and simple mazes.[]{data-label="fig: planning"}](./FIG/path_planning/obstacle/line2_crop.png "fig:"){width=".465\textwidth"} ![(a) Planning examples with different motion ranges. Red star represents the destination $y$ and green dots represent the planned position $\{x_0 + \sum_{i=1}^t \Delta x_i\}$. (b) Planning examples with a dot obstacle. Left figure shows the effect of changing scaling parameter $a$, while right figure shows the effect of changing annealing parameter $b$. (c) Planning examples with obstacles mimicking walls, large objects and simple mazes.[]{data-label="fig: planning"}](./FIG/path_planning/obstacle/rectangular1_crop.png "fig:"){width=".465\textwidth"}\ ![(a) Planning examples with different motion ranges. Red star represents the destination $y$ and green dots represent the planned position $\{x_0 + \sum_{i=1}^t \Delta x_i\}$. (b) Planning examples with a dot obstacle. Left figure shows the effect of changing scaling parameter $a$, while right figure shows the effect of changing annealing parameter $b$. (c) Planning examples with obstacles mimicking walls, large objects and simple mazes.[]{data-label="fig: planning"}](./FIG/path_planning/obstacle/maze3_crop.png "fig:"){width=".465\textwidth"} ![(a) Planning examples with different motion ranges. Red star represents the destination $y$ and green dots represent the planned position $\{x_0 + \sum_{i=1}^t \Delta x_i\}$. (b) Planning examples with a dot obstacle. Left figure shows the effect of changing scaling parameter $a$, while right figure shows the effect of changing annealing parameter $b$. (c) Planning examples with obstacles mimicking walls, large objects and simple mazes.[]{data-label="fig: planning"}](./FIG/path_planning/obstacle/maze7.png "fig:"){width=".465\textwidth"}\ [(c) Various obstacles]{} The learned system can also perform planning with obstacles, where the global adjacency between the agent’s current position and an obstacle serves as a repulsive forces. Specifically, suppose $z$ is an obstacle to avoid, the agent can choose the motion $\Delta x_t$ at time $t$ by $$\begin{aligned} \label{eqn: planning_obs} \Delta x_t = \arg \max_{\Delta x \in \Delta} \left[\langle v(y), M(\Delta x) v_t\rangle - a\langle v(z), M(\Delta x)v_t\rangle^b\right], \end{aligned}$$ where $a$ and $b$ are the scaling and annealing parameters. Figure \[fig: planning\](b) shows the planning result with a dot obstacle laid on the direct path between the starting position and destination, with tuning of $a$ and $b$. We choose $a = 0.5$ and $b = 6$ in subsequent experiments. Now suppose we have more complicated obstacles $\{z_i\}_{i=1}^m$. They can be included by summing over the kernels of every obstacle $\{a\langle v(z_i), M(\Delta x) v_t\rangle^b\}_{i=1}^m$ and choosing $\Delta x_t$ at time $t$ by $\Delta x_t = \arg \max_{\Delta x \in \Delta} \left[\langle v(y), M(\Delta x) v_t\rangle - \sum\nolimits_{i=1}^m a\langle v(z_i), M(\Delta x) v_t\rangle^b\right]$. Figure \[fig: planning\](c) shows some examples, where the obstacles mimicking walls, large objects and simple mazes. The above method is related to the potential field method in robotics ([@siegwart2011introduction]). Discussion: rotationist-connectionist model? ============================================ In terms of general modeling methodology, a typical recurrent network is of the form $v_t = \tanh(W(v_{t-1}, \delta_t))$, where $v_t$ is the latent vector, $\delta_t$ is the input change or action. $v_{t-1}$ and $\delta_t$ are concatenated and linearly mixed by $W$, followed by coordinate-wise tanh non-linearity. We replace it by a model of the form $v_t = M(\delta_t) v_{t-1}$, where $M(\delta_t)$ is a matrix that is non-linear in $\delta_t$. $M(\delta_t)$ is a matrix representation of $\delta_t$. $v_t$ can be interpreted as neuron activities. We can discretize the value of $\delta_t$ into a finite set $\{\delta\}$, and each $M(\delta)$ can be stored as synaptic connection weights that drive the neuron activities. In prediction, the input $\delta_t$ activates $M(\delta_t)$. In planning or control, all the $\{M(\delta)\}$ are activated, and among them the optimal $\delta$ is chosen. The matrix representation of the above model is inspired by the group representation theory, where the group elements are represented by matrices acting on the vectors ([@fulton2013representation]). It underlies much of modern mathematics and holds the key to the quantum theory ([@zee2016group]). Perhaps it also underlies the visual and motor cortex, where neurons form rotating sub-vectors driven by matrices representing groups of transformations. One may call it a rotationist-connectionist model. Project page {#project-page .unnumbered} ============ [<http://www.stat.ucla.edu/~ruiqigao/gridcell/main.html>]{} Acknowledgement {#acknowledgement .unnumbered} =============== We thank the three reviewers for their insightful comments and suggestions. Part of the work was done while Ruiqi Gao was an intern at Hikvision Research Institute during the summer of 2018. She thanks Director Jane Chen for her help and guidance. We also thank Jiayu Wu for her help with experiments and Zilong Zheng for his help with visualization. The work is supported by DARPA XAI project N66001-17-2-4029; ARO project W911NF1810296; ONR MURI project N00014-16-1-2007; and a Hikvision gift to UCLA. We gratefully acknowledge the support of NVIDIA Corporation with the donation of the Titan Xp GPU used for this research. Proof for section \[sect: analytical\] {#sect: app1.1} ====================================== $(a_j, j = 1, 2, 3)$ forms a tight frame in the 2D space, in that for any vector $x$ in 2D, $\sum_{j=1}^{3} \langle x, a_j\rangle^2 \propto \|x\|^2$. Since $C^C = I$, we have $$\begin{aligned} \langle v(x), v(y)\rangle &=& v(x)^ v(y) \\ &=& e(x)^* C^* C e(y) \\ &=&\sum_{j=1}^{3} e^{i \langle a_j, y-x\rangle}. \end{aligned}$$ Then we have $$\begin{aligned} {\rm RE}(\langle v(x), v(x+\Delta x)\rangle) &=& \sum_{j=1}^{3} \cos(\langle a_j, \Delta x\rangle) \\ &\approx& \sum_{j=1}^{3} (1 - \langle a_j, \Delta x \rangle^2/2)\\ &=& 3 - \sum_{j=1}^{3} \langle a_j, \Delta x \rangle^2/2\\ &=& 3(1 - \alpha\|\Delta x\|^2), \end{aligned}$$ where $ \|a_j\| = 2\sqrt{\alpha}$. The self motion from $v(x)$ to $v(x+\Delta x)$ is $$\begin{aligned} v(x+\Delta x) &=& C e(x+\Delta x) \\ &=& C D(\Delta x) e(x) \\ &=& C D(\Delta x) C^{*} v(x) \\ &=& M(\Delta x) v(x), \end{aligned}$$ where $D(\Delta x) = {\rm diag}(e^{ i \langle a_j, \Delta x\rangle}, j = 1, 2, 3)$. If $K > 1$ and block size $=6$, we can fit the multiple blocks together by a Fourier expansion of the kernel function $$\begin{aligned} f(\|x-y\|) &=& \langle v(x), v(y) \rangle \\ &\approx& \sum_{k=1}^{K} \sum_{j=1}^{3} e^{i \langle a_{kj}, y-x\rangle}\\ &=& \sum_{k=1}^{K} \langle v^{(k)}(x), v^{(k)}(y)\rangle. \end{aligned}$$ Hexagon grid patterns and metrics ================================= Simulated input data -------------------- We obtain input data for learning the model by simulating agent trajectories with the number of steps equal to $\tilde{T}$ in the square domain $D$. $D$ is discretized into a $40 \times 40$ lattice and the agent is only allowed to move on the lattice. The agent starts at a random location $x_0$. At each time step $t$, a small motion $\Delta x_t$ ($\leq 3$ grids in each direction) is randomly sampled with the restriction of not leading the agent outside the boundary, resulting in a simulated trajectory $\{x_0 + \sum_{i=1}^t \Delta x_i\}_{t=1}^{\tilde{T}}$. $\tilde{T}$ is set to $1,000$ to obtain trajectories that are uniformly distributed over the whole area. Although the trajectories used for training are restricted to the lattice and with small motions, in Section \[sect:pp\] we show that the learned model can be easily generalized to handle continuous positions and large motions. In training, pairs of locations $(x, y)$ are randomly sampled from each trajectory as the input to the adjacency loss $L_3$, while consecutive position sequences $(x, \Delta x_t, t = 1, ..., T)$ are randomly sampled as the input to the motion loss $L_1$, with length specified by $T$ (which is usually much smaller than the whole length of the trajectory $\tilde{T}$). Learned single block units with different block sizes {#app: 2Dunits} ----------------------------------------------------- In ([@blair2007scale]), the grid cell response is modeled by three cosine gratings with different orientations and phases. In our model, we learn such patterns of different scales without inserting artificial assumptions. ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize2.png "fig:"){width=".2\textwidth"}\ [(a) Block size = 2]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize3.png "fig:"){width=".3\textwidth"}\ [(b) Block size = 3]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize4.png "fig:"){width=".4\textwidth"}\ [(c) Block size = 4]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize5.png "fig:"){width=".5\textwidth"}\ [(d) Block size = 5]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize7.png "fig:"){width=".7\textwidth"}\ [(e) Block size = 7]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize8.png "fig:"){width=".8\textwidth"}\ [(f) Block size = 8]{} ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize9.png "fig:"){width=".9\textwidth"}\ [(g) Block size = 9]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize10.png "fig:"){width="\textwidth"}\ [(h) Block size = 10]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize20.png "fig:"){width="\textwidth"}\ [(i) Block size = 20]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize40.png "fig:"){width="\textwidth"}\ [(j) Block size = 40]{}\ Figure \[fig: app\_units\_single\] displays the response maps of the learned single block units with different block sizes. For block sizes 4 and 5, the learned maps show square lattice patterns. For block sizes greater than or equal to 6, the learned maps show hexagon lattice patterns. Learned multiple block units and metrics {#app: 2Dunits_multiple} ---------------------------------------- ### With different block sizes [C[20pt]{}\|C[37pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$7.7$]{}&\ [$10.4$]{}&\ [$10.7$]{}&\ [$11.6$]{}&\ [$12.7$]{}&\ [$18.0$]{}&\ [$31.2$]{}&\ [$31.2$]{}&\ [$37.8$]{}&\ [$56.0$]{}&\ [$68.0$]{}&\ [$73.5$]{}&\ [$74.3$]{}&\ [$86.5$]{}&\ [$92.5$]{}&\ \ [C[20pt]{}\|C[54pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$6.7$]{}&\ [$10.6$]{}&\ [$11.0$]{}&\ [$13.9$]{}&\ [$23.4$]{}&\ [$31.3$]{}&\ [$38.9$]{}&\ [$39.3$]{}&\ [$56.7$]{}&\ [$64.5$]{}&\ [$72.3$]{}&\ [$75.4$]{}&\ [$80.5$]{}&\ [$84.4$]{}&\ [$93.0$]{}&\ \ [C[20pt]{}\|C[70.5pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$6.9$]{}&\ [$12.3$]{}&\ [$18.7$]{}&\ [$19.5$]{}&\ [$25.7$]{}&\ [$28.9$]{}&\ [$39.7$]{}&\ [$41.9$]{}&\ [$52.3$]{}&\ [$55.1$]{}&\ [$61.1$]{}&\ [$66.3$]{}&\ [$67.7$]{}&\ [$70.6$]{}&\ [$88.3$]{}&\ \ [C[20pt]{}\|C[88pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$9.1$]{}&\ [$12.4$]{}&\ [$18.5$]{}&\ [$28.6$]{}&\ [$32.8$]{}&\ [$41.9$]{}&\ [$48.6$]{}&\ [$49.9$]{}&\ [$58.0$]{}&\ [$64.5$]{}&\ [$73.0$]{}&\ [$74.9$]{}&\ [$77.8$]{}&\ [$81.7$]{}&\ [$97.1$]{}&\ \ [C[20pt]{}\|C[121pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$6.8$]{}&\ [$10.3$]{}&\ [$11.7$]{}&\ [$14.6$]{}&\ [$21.1$]{}&\ [$21.9$]{}&\ [$24.1$]{}&\ [$25.8$]{}&\ [$45.1$]{}&\ [$56.4$]{}&\ [$65.3$]{}&\ [$66.1$]{}&\ [$67.7$]{}&\ [$72.6$]{}&\ [$93.2$]{}&\ \ [C[20pt]{}\|C[137.5pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$7.2$]{}&\ [$8.5$]{}&\ [$14.5$]{}&\ [$18.5$]{}&\ [$19.5$]{}&\ [$28.1$]{}&\ [$46.9$]{}&\ [$47.8$]{}&\ [$56.2$]{}&\ [$60.4$]{}&\ [$62.3$]{}&\ [$77.3$]{}&\ [$84.9$]{}&\ [$86.3$]{}&\ [$95.4$]{}&\ \ [C[20pt]{}\|C[132pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$6.4$]{}&\ [$6.6$]{}&\ [$15.4$]{}&\ [$16.2$]{}&\ [$20.5$]{}&\ [$21.0$]{}&\ [$32.1$]{}&\ [$38.2$]{}&\ [$40.2$]{}&\ [$65.2$]{}&\ [$65.2$]{}&\ [$67.5$]{}&\ [$74.5$]{}&\ [$75.8$]{}&\ [$76.2$]{}&\ \ [C[20pt]{}\|C[147.8pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$8.8$]{}&\ [$9.3$]{}&\ [$10.5$]{}&\ [$13.9$]{}&\ [$19.3$]{}&\ [$20.4$]{}&\ [$20.9$]{}&\ [$31.6$]{}&\ [$34.9$]{}&\ [$35.7$]{}&\ [$57.5$]{}&\ [$61.3$]{}&\ [$67.5$]{}&\ [$78.7$]{}&\ [$80.0$]{}&\ \ Figure \[fig: app\_units\_multiple\] displays the response maps of the multiple block units with different block sizes. The metrics of the multiple blocks are learned automatically. ### With different shapes of area [C[20pt]{}\|C[102pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$5.9$]{}&\ [$10.2$]{}&\ [$12.0$]{}&\ [$12.6$]{}&\ [$18.3$]{}&\ [$22.5$]{}&\ [$23.9$]{}&\ [$26.3$]{}&\ [$31.7$]{}&\ [$37.9$]{}&\ [$60.2$]{}&\ [$71.8$]{}&\ [$72.0$]{}&\ [$93.7$]{}&\ [$94.4$]{}&\ \ [C[20pt]{}\|C[102pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$6.5$]{}&\ [$10.8$]{}&\ [$13.4$]{}&\ [$16.0$]{}&\ [$18.7$]{}&\ [$19.9$]{}&\ [$20.6$]{}&\ [$26.1$]{}&\ [$36.5$]{}&\ [$37.5$]{}&\ [$54.4$]{}&\ [$59.5$]{}&\ [$62.3$]{}&\ [$83.8$]{}&\ [$85.4$]{}&\ \ Figure \[fig: app\_units\_shape\] displays the response maps of the multiple block units with different shapes of the area, such as circle and triangle. Quantitative analysis of spatial activity {#app: gridness} ----------------------------------------- We assess the spatial activity of the learned units quantitatively using measures adopted from the neuroscience literature. Specifically, we quantify the hexagonal regularity of the grid-like patterns using the gridness score ([@langston2010development; @sargolini2006conjunctive]). The measure is derived from the spatial autocorrelogram of each unit’s response map. A unit is classified as a grid cell if its gridness score is larger than $0$. For those units that are classified as grid cells, grid scale and orientation can be further derived from the autocorrelogram following [@sargolini2006conjunctive]. Figure \[fig: app\_gridness\](a) summarizes the results. $76$ out of $96$ learned units are classified as grid cells. Most units with large learned $\alpha_k$ are classified as grid cells, while those units with small $\alpha_k$ are not due to the lack of a full period of hexagonal patterns. The grid scales and orientations vary among units, while remaining similar within each block. We show the histograms of the grid orientations and scales in Figure \[fig: app\_gridness\](b) and \[fig: app\_gridness\](c) respectively. Moreover, we average the grid scales within each block and make the scatter plot of the averaged grid scales and the learned $1/\sqrt{\alpha_k}$ in figure \[fig: app\_gridness\](d). Interestingly, the grid scale is nicely proportional to the learned $1/\sqrt{\alpha_k}$. [C[20pt]{}\|C[170pt]{}\|C[20pt]{}\|C[170pt]{}]{} [$\alpha_k$]{} & [Autocorrelograms of the learned units’s spatial rate maps]{} & [$\alpha_k$]{} & [Autocorrelograms of the learned units]{}\ & & [$44.1$]{} &\ [$4.7$]{}&&[$56.3$]{}&\ [$11.9$]{}&&[$57.0$]{}&\ [$17.0$]{}&&[$61.7$]{}&\ [$17.3$]{}&&[$73.0$]{}&\ [$35.7$]{}&&[$85.7$]{}&\ [$39.1$]{}&&[$87.5$]{}&\ [$39.7$]{}&&[$94.7$]{}&\ \ \ ![(a) Autocorrelograms of the learned units’ response maps. Gridness scores are calculated based on the autocorrelograms. A unit is classified as a grid cell if the gridness score is larger than $0$. The gridness score is shown in red color if a unit fails to be classified as a grid cell. For those units that are classified as grid cells, gridness score, scale and orientation are listed sequentially in black color. Orientation is computed using a camera-fixed reference line ($0^{\circ}$) and in counterclockwise direction. (b) Histogram of grid orientations. (c) Histogram of grid scales. (d) Scatter plot of averaged grid scales within each block versus the corresponding learned $1/\sqrt{\alpha_k}$. []{data-label="fig: app_gridness"}](./FIG/units_multiple_blocks/orientation_hist.png "fig:"){width="\textwidth"}\ [(b) Histogram of grid orientations]{} ![(a) Autocorrelograms of the learned units’ response maps. Gridness scores are calculated based on the autocorrelograms. A unit is classified as a grid cell if the gridness score is larger than $0$. The gridness score is shown in red color if a unit fails to be classified as a grid cell. For those units that are classified as grid cells, gridness score, scale and orientation are listed sequentially in black color. Orientation is computed using a camera-fixed reference line ($0^{\circ}$) and in counterclockwise direction. (b) Histogram of grid orientations. (c) Histogram of grid scales. (d) Scatter plot of averaged grid scales within each block versus the corresponding learned $1/\sqrt{\alpha_k}$. []{data-label="fig: app_gridness"}](./FIG/units_multiple_blocks/scale_hist.png "fig:"){width="\textwidth"}\ [(c) Histogram of grid scales]{} ![(a) Autocorrelograms of the learned units’ response maps. Gridness scores are calculated based on the autocorrelograms. A unit is classified as a grid cell if the gridness score is larger than $0$. The gridness score is shown in red color if a unit fails to be classified as a grid cell. For those units that are classified as grid cells, gridness score, scale and orientation are listed sequentially in black color. Orientation is computed using a camera-fixed reference line ($0^{\circ}$) and in counterclockwise direction. (b) Histogram of grid orientations. (c) Histogram of grid scales. (d) Scatter plot of averaged grid scales within each block versus the corresponding learned $1/\sqrt{\alpha_k}$. []{data-label="fig: app_gridness"}](./FIG/units_multiple_blocks/scatter.png "fig:"){width="\textwidth"}\ [(d) Scatter plot of grid scales and learned $1/\sqrt{\alpha_k}$]{} Ablation studies {#sect: ablation} ---------------- We conduct ablation studies to assess various assumptions in our model. ### Loss terms ![Ablation study of the components in the training loss. (a) Learn the model using only the localization loss with global adjacency. (b) Learn the model using only the localization loss with local adjacency. (c) Using global adjacency and motion loss, leaving out local adjacency. []{data-label="fig: ablation2"}](./FIG/units_multiple_blocks/loss1.png "fig:"){width=".9\textwidth"}\ [(a) $L_3$ only.]{} ![Ablation study of the components in the training loss. (a) Learn the model using only the localization loss with global adjacency. (b) Learn the model using only the localization loss with local adjacency. (c) Using global adjacency and motion loss, leaving out local adjacency. []{data-label="fig: ablation2"}](./FIG/units_multiple_blocks/loss3.png "fig:"){width=".9\textwidth"}\ [(b) $L_2$ only.]{} ![Ablation study of the components in the training loss. (a) Learn the model using only the localization loss with global adjacency. (b) Learn the model using only the localization loss with local adjacency. (c) Using global adjacency and motion loss, leaving out local adjacency. []{data-label="fig: ablation2"}](./FIG/units_multiple_blocks/loss1andloss2.png "fig:"){width=".9\textwidth"}\ [(c) $L_1 + \lambda_3 L_3$, without $L_2$.]{} We learn $v$ and $M$ with multiple blocks by minimizing $L_1 + \lambda_2 L_2 + \lambda_3 L_3$, which consists of (1) a motion loss $L_1$, (2) a local isometry loss $L_2$, and (3) a global adjacency loss $L_3$. Figure \[fig: ablation2\] shows the learned units when using only some of the components. Grid-like patterns do not emerge if using only the adjacency loss $L_3$, or only the isometry loss $L_2$. If using only the motion loss, the motion equation is approximately satisfied at the beginning of training, since both $v$ and $M$ are initialized from small values that are close to $0$. The system cannot be learned without an extra term to push $v(x)$ apart from each other. Figure \[fig: ablation2\](c) shows the learned units using the adjacency loss and the motion loss, leaving out the isometry loss. Grid-like patterns still emerge (also some strip-like patterns), although less obvious than the ones learned using the full loss. ### Assumptions of motion matrix {#app: discrete} ![Learned units by dropping the parametrization and the block diagonal assumption of the motion matrix $M(\Delta x)$.[]{data-label="fig: ablation"}](./FIG/units_single_block/discrete_blocksize2.png "fig:"){width=".2\textwidth"}\ [block size = 2]{}\ ![Learned units by dropping the parametrization and the block diagonal assumption of the motion matrix $M(\Delta x)$.[]{data-label="fig: ablation"}](./FIG/units_single_block/discrete_blocksize4.png "fig:"){width=".4\textwidth"}\ [block size = 4]{}\ ![Learned units by dropping the parametrization and the block diagonal assumption of the motion matrix $M(\Delta x)$.[]{data-label="fig: ablation"}](./FIG/units_single_block/discrete_blocksize6.png "fig:"){width=".6\textwidth"}\ [block size = 6]{}\ ![Learned units by dropping the parametrization and the block diagonal assumption of the motion matrix $M(\Delta x)$.[]{data-label="fig: ablation"}](./FIG/units_single_block/discrete_blocksize8.png "fig:"){width=".8\textwidth"}\ [block size = 8]{}\ ![Learned units by dropping the parametrization and the block diagonal assumption of the motion matrix $M(\Delta x)$.[]{data-label="fig: ablation"}](./FIG/units_single_block/discrete_blocksize10.png "fig:"){width="\textwidth"} [block size = 10]{}\ ![Learned units by dropping the parametrization and the block diagonal assumption of the motion matrix $M(\Delta x)$.[]{data-label="fig: ablation"}](./FIG/units_single_block/discrete_blocksize100.png "fig:"){width=".8\textwidth"}\ [block size = 100]{} \ [(a) With local isometry $L_2$: scaling parameter $\alpha = 72$]{}\ ![Learned units by dropping the parametrization and the block diagonal assumption of the motion matrix $M(\Delta x)$.[]{data-label="fig: ablation"}](./FIG/units_single_block/discrete_global_kernel_cut.png "fig:"){width=".85\textwidth"}\ [(b) With global adjacency $L_3$: Gaussian kernel with $\sigma = 0.08$]{} In another ablation study, we drop the quadratic parametrization by $\beta$ coefficients and the block diagonal assumption of the motion matrix. A separate motion matrix $M(\Delta x)$ is learned for each displacement $\Delta x$, and $v(x)$ is assumed to be a single block. We use either the local isometry loss $L_2$ or the global adjacency loss $L_3$ in addition to the motion loss $L_1$. The results are shown in Figure \[fig: ablation\]. With the isometry loss, the setting is similar to the one of learning single block, except that the parametrization of $M(\Delta x)$ is dropped. As shown in figure \[fig: ablation\](a), the learned units resemble the ones learned with parametrized $M(\Delta x)$, but when the block size is large, the grid-like patterns are less obvious. With the adjacency loss, grid-like patterns do not emerge any more. Modeling egocentric motion {#sect: egocentric} ========================== The model can be generalized to handle egocentric motion that involves head direction. Coupling two grid systems ------------------------- The egocentric motion consists of angular velocity in the change of head direction and the spatial velocity along the current head direction. We couple two grid systems, one for head direction and the other for the spatial position. For notational simplicity, we put the “hat” notation on top of $v$ and $M$ notation to denote the vector and matrix for the head direction. Specifically, the agent has a head direction $\theta$, which may change over time. The agent moves along its head direction with scalar motion. We can discretize the range of $\theta$, $[0, 2\pi]$, into $\hat{N}$ equally spaced values $\{\theta_{i}, i=1,...,\hat{N}\}$, and introduce a vector representation of self-direction. That is, the agent represents its self-direction by a $\hat{d}$-dimensional hidden vector $\hat{v}(\theta)$. ### Motion sub-model Suppose at a position $x$, the agent has a head direction $\theta$. The self-motion is decomposed into (1) a scalar motion $\delta$ along the head direction $\theta$ and then (2) a head direction rotation $\Delta \theta$. The self-motion $\Delta x = (\delta \cos\theta, \delta \sin\theta)$. We assume $$\begin{aligned} \hat{v}(\theta+\Delta\theta) &=& \hat{M}(\Delta \theta) \hat{v}(\theta),\\ v(x + \Delta x) &=& M(\delta, \hat{v}(\theta)) v(x), \end{aligned}$$ where $\hat{M}(\Delta \theta)$ is a $\hat{d} \times \hat{d}$ matrix that depends on $\Delta \theta$, and $M(\Delta \theta, \hat{v}(\theta))$ is a $d \times d$ matrix that depends on $\delta$ and $\hat{v}(\theta)$. $\hat{M}(\Delta \theta)$ is the matrix representation of the head direction rotation $\Delta \theta$, while $M(\delta, \hat{v}(\theta))$ is the matrix representation of scalar motion $\delta$ along the direction $\theta$. We can model $M(\delta, \hat{v}(\theta))$ by an attention (or selection) mechanism: $$\begin{aligned} && p_{i} = \frac{\langle \hat{v}(\theta), \hat{v}(\theta_{i}\rangle^b} {\sum\nolimits_{i=1}^{\hat{N}}\langle \hat{v}(\theta), \hat{v}(\theta_{i})\rangle^b},\\ && M(\delta, \hat{v}(\theta)) = \sum\nolimits_{i=1}^{\hat{N}} p_{i} M^{(i)}(\delta),\end{aligned}$$ where $M^{(i)}(\delta)$ is the matrix representation of scalar motion $\delta$ given the head direction $\theta_{i}$. The inner product $\langle \hat{v}(\theta), \hat{v}(\theta_{i}) \rangle$, that informs the angular distance between $\theta$ and $\theta_{i}$, serves as the attention weight. $b$ is an annealing (inverse temperature) parameter. If $b \rightarrow \infty$, $p = (p_i, i = 1, ..., \hat{N})$ becomes a one-hot vector for selection. We can further assume that $\hat{M}(\Delta \theta)$ and $M^{(i)}(\delta)$ are block diagonal, and learn a parametric model for each of them by the second order Taylor expansion at $\Delta \theta$ and $\delta$ respectively. ### Localization sub-model For the localization sub-model, we define the adjacency measures of self-direction and self-position separately. Let $\hat{f}(\|\theta_1-\theta_2\|)$ be the adjacency measure between two directions $\theta_1$ and $\theta_2$ . We use von Mises kernel $\hat{f}(r) = \exp((\cos(r)-1)/\sigma^2)$, where $\hat{f}(0) = 1$. For adjacency measure between self-positions $x$ and $y$, we keep it the same as described in section \[sect: localization\]. ### Loss function for learning For learning the system, we can first learn $\hat{v}$ and $\hat{M}$ (or the coefficients that parametrize $\hat{M}$) by minimizing $$\begin{aligned} \E_{\theta_1, \theta_2} \left[(\hat{f}(\|\theta_1-\theta_2\|) - \langle \hat{v}(\theta_1), \hat{v}(\theta_2)\rangle)^2\right] + \lambda \E_{\theta, \Delta \theta} \left[ \\|\hat{v}(\theta+\Delta \theta) - {\hat{M}}(\Delta \theta) \hat{v}(\theta)\\|^2\right], \end{aligned}$$ and then we learn $v$ and $M$ (or the coefficients that parametrize $M$) as before. Learned units for self-direction and self-position -------------------------------------------------- Figure \[fig: egocentric\] shows a result of learning such an egocentric motion model by displaying the response curves of the learned units in the head direction system, $\hat{v}(\theta)$, for $\theta \in [0, 2\pi]$, as well as the response maps of the learned multiple block units in the self-position system, $v(x)$, for $x \in [0, 1]^2$. ![(a) Response curves of learned units in the head direction model, $\hat{v}(\theta)$. Each block shows the units belonging to the same sub-vector in the model. The horizontal axis represents the angle within a range of \[0, 2$\pi$\], while the vertical axis indicates the values of responses. (b) Response maps of the learned multiple block units of the self-position model, $v(x)$, for $x \in [0, 1]^2$.[]{data-label="fig: egocentric"}](./FIG/egocentric/head_weights_5999.png){width="110pt"} [C[20pt]{}\|C[101pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$6.6$]{}&\ [$8.4$]{}&\ [$14.9$]{}&\ [$21.2$]{}&\ [$26.3$]{}&\ [$33.5$]{}&\ [$43.2$]{}&\ [$43.4$]{}&\ [$46.0$]{}&\ [$59.0$]{}&\ [$61.2$]{}&\ [$72.5$]{}&\ [$80.5$]{}&\ [$82.5$]{}&\ [$85.3$]{}&\ \ Clock and timestamp {#sect: 1D} ------------------- We may re-purpose the head direction system as a clock, by interpreting $\theta \in [0, 2\pi]$ as the time on a clock, and $\hat{v}(\theta)$ as a timestamp for events happening over time. This may be related to the recent neuroscience observations in [@tsao2018integrating]. Errors ====== Error correction {#app: error} ---------------- Unlike commonly used embedding in machine learning, here we embed a 2D position into a high-dimensional space, and the embedding is a highly distributed representation or population code. The advantage of such a redundant code lies in its tolerance to errors. We show that the learned system is tolerant to various sources of errors. Specifically, in both path integral and path planning tasks, at every time step $t$, we randomly add (1) Gaussian noises or (2) dropout masks to the hidden units and see if the system can still perform the tasks well. We find that the decoding-encoding process (DE) is important for error correction. That is, at each time step $t$, given the noisy hidden vector ${v}_t$, we decode it to $x_t = \arg\max_x \langle v_t, v(x)\rangle$ and then re-encode it to the hidden vector $v(x_t)$. Actually the whole process can be accomplished by projection to the codebook sub-manifold without explicit decoding, by obtaining the vector: $\arg\max_{v \in C} \langle v_t, v\rangle$, where $C = \{v(x), x \in [0, 1]^2\}$. Table \[tab: err\] shows the error correction results tested on path integral and path planning tasks. Each number is averaged over $1,000$ episodes. We compute the overall standard deviation of $\{v(x)\}$ for all $x$ and treat it as the reference standard deviation ($s$) for the Gaussian noise. For dropout noise, we set a percentage to drop at each time step. With the decoding-encoding process, the system is quite robust to the Gaussian noise and dropout error, and the system still works even if $70\%$ units are silenced at each step. Noisy self-motion input ----------------------- Besides adding noises to the hidden units, we also experiment with adding noises to the self-motion $\Delta x$, and compare the performance of path integral with the one performed in the original 2D coordinates. Specifically, at each time step, we add Gaussian noises to the self-motion $\Delta x$. For path integral, we compute the mean square error between the predicted locations and ground truth locations. Besides, we also compute the predicted locations using the 2D coordinates with the noisy self-motions. Its mean square error serves as the reference error. Table \[tab: err2\] shows the result, indicating that the error of the learned system is close to the error in the original 2D coordinates, i.e., our system does not blow up the noise. 3D environment and 1D time {#app: 3Dstart} ========================== The system can be generalized to 3D environments. Specifically, we assume the agent navigates within a domain $D = [0, 1] \times [0, 1] \times [0, 1]$, which is discretized into a $40 \times 40 \times 40$ lattice. We learn a parametric model for motion matrix $M$ in a residual form $M = I + \tilde{M}(\Delta x)$, where $\tilde{M}(\Delta x)$ is approximated by the second order Taylor expansion of $\Delta x$. We first learn a single block with fixed $\alpha_k$ by minimizing $L_1 + \lambda _2 L_{2, k}$. A batch of 500,000 examples of $(x, y)$ and $(x, \Delta x_t, t = 1, ..., T)$ is sampled online at every iteration for training. Figure \[fig: 3D\] shows the learned units. [C[.07]{}C[.93]{}]{} [$\alpha = 18$]{} & ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_0.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_1.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_2.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_3.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_4.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_5.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_6.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_7.png "fig:"){width=".11\textwidth"}\ [$\alpha = 36$]{} & ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_0.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_1.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_2.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_3.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_4.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_5.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_6.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_7.png "fig:"){width=".11\textwidth"}\ [$\alpha = 72$]{} & ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_0.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_1.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_2.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_3.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_4.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_5.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_6.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_7.png "fig:"){width=".11\textwidth"}\ [$\alpha = 108$]{} & ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_0.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_1.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_2.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_3.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_4.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_5.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_6.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_7.png "fig:"){width=".11\textwidth"}\ [$\alpha = 144$]{} & ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_0.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_1.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_2.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_3.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_4.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_5.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_6.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_7.png "fig:"){width=".11\textwidth"}\ [$\alpha = 180$]{} & ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_0.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_1.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_2.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_3.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_4.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_5.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_6.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_7.png "fig:"){width=".11\textwidth"} Next we learn multiple blocks by minimizing $L_1 + \lambda_3 L_3$, and use the learned models to perform 3D path integral and path planning. For simplicity, we remove $L_2$. We use $8$ blocks of units with block size $8$ and exponential kernel ($\sigma = 0.3$) for path planning. A batch of 200,000 examples is sampled online at every iteration for training. 3D path integral ---------------- Figure \[fig: 3d\_path\_integral\_app\] shows some results of 3D path integral with duration $\tilde{T} = 30$. Gaussian Kernel ($\sigma = 0.08$) is used as the adjacency measure. ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_2.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_8.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_17.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_19.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_29.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_31.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_33.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_66.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_71.png "fig:"){width="32.00000%"} 3D path planning ---------------- Figure \[fig: 3d\_planning\_app\] shows some results of 3D simple path planning. Exponential kernel ($\sigma = 0.3$) is used as the adjacency measure. We design a set of allowable motions $\Delta$: $m$ lengths of radius $r$ are used, and for each $r$, we evenly divide the inclination $\theta \in [0, \pi]$ and the arimuth $\alpha \in [0, 2\pi]$ into $n$ directions, which results in a motion pool with $mn^2$ candidate motions $\Delta = \{(r \sin(\theta) \cos(\alpha), r \sin(\theta) \sin(\alpha), r \cos(\theta) )\}$. We use $m = 2, n = 90$ in this experiment. ![Examples of 3D simple path planning, where the agent is capable of planning a direct trajectory.[]{data-label="fig: 3d_planning_app"}](./FIG/iclr_new_results/3d_path_planning/test00.png "fig:"){width="32.00000%"} ![Examples of 3D simple path planning, where the agent is capable of planning a direct trajectory.[]{data-label="fig: 3d_planning_app"}](./FIG/iclr_new_results/3d_path_planning/test02.png "fig:"){width="32.00000%"} ![Examples of 3D simple path planning, where the agent is capable of planning a direct trajectory.[]{data-label="fig: 3d_planning_app"}](./FIG/iclr_new_results/3d_path_planning/test08.png "fig:"){width="32.00000%"} ![Examples of 3D simple path planning, where the agent is capable of planning a direct trajectory.[]{data-label="fig: 3d_planning_app"}](./FIG/iclr_new_results/3d_path_planning/test05.png "fig:"){width="32.00000%"} ![Examples of 3D simple path planning, where the agent is capable of planning a direct trajectory.[]{data-label="fig: 3d_planning_app"}](./FIG/iclr_new_results/3d_path_planning/test23.png "fig:"){width="32.00000%"} ![Examples of 3D simple path planning, where the agent is capable of planning a direct trajectory.[]{data-label="fig: 3d_planning_app"}](./FIG/iclr_new_results/3d_path_planning/test13.png "fig:"){width="32.00000%"} 3D path planning with obstacles ------------------------------- Figure \[fig: 3d\_path\_planning\_obstacle\] shows some examples of 3D path planning with a cuboid obstacle. $a = 38$ and $b = 24$ in equation \[eqn: planning\_obs\]. ![Examples of 3D path planning with a cuboid obstacle.[]{data-label="fig: 3d_path_planning_obstacle"}](./FIG/iclr_new_results/3d_path_planning_obstacle/test00.png "fig:"){width="32.00000%"} ![Examples of 3D path planning with a cuboid obstacle.[]{data-label="fig: 3d_path_planning_obstacle"}](./FIG/iclr_new_results/3d_path_planning_obstacle/test03.png "fig:"){width="32.00000%"} ![Examples of 3D path planning with a cuboid obstacle.[]{data-label="fig: 3d_path_planning_obstacle"}](./FIG/iclr_new_results/3d_path_planning_obstacle/test05.png "fig:"){width="32.00000%"} ![Examples of 3D path planning with a cuboid obstacle.[]{data-label="fig: 3d_path_planning_obstacle"}](./FIG/iclr_new_results/3d_path_planning_obstacle/test08.png "fig:"){width="32.00000%"} ![Examples of 3D path planning with a cuboid obstacle.[]{data-label="fig: 3d_path_planning_obstacle"}](./FIG/iclr_new_results/3d_path_planning_obstacle/test10.png "fig:"){width="32.00000%"} ![Examples of 3D path planning with a cuboid obstacle.[]{data-label="fig: 3d_path_planning_obstacle"}](./FIG/iclr_new_results/3d_path_planning_obstacle/test07.png "fig:"){width="32.00000%"} Learning in 1D {#sect:1D} -------------- The system can also be applied to 1D. Inspired by [@tsao2018integrating], the learned system in 1D may serve as a timestamp of events. We assume domain $D = [0, 1]$ and discretize it into $100$ time points. A parametric $M$ is learned by a residual form $M = I + \tilde{M}(\Delta t)$, where each element of $\tilde{M}(\Delta t)$ is parametrized as a function of $(\Delta t, \Delta t^2)$. $16$ blocks of hidden units with block size $6$ are used. Figure \[fig:1D\] visualizes the learned units over the $100$ time points. The response wave of every unit shows strong periodicity of a specific scale or frequency. Within each block, the response waves of units have similar patterns, with different phases. ![Response curves of learned units in 1D. Each block shows the units belonging to the same sub-vector in the motion model. The horizontal axis represents the time points, while the vertical axis indicates the value of responses. []{data-label="fig:1D"}](./FIG/units_1D.png){width=".7\textwidth"} [^1]: Equal contributions.	null	minipile	NaturalLanguage	mit	null
Search form A Big GOP Tax Loophole Winner: Donald Trump Kevin Lamarque By Michael Rainey December 6, 2017 MOST POPULAR Commercial real estate is one of the clear winners in the Republican tax plan, according to The New York Times: “House and Senate Republicans, in their divergent bills, both offered steeply reduced rates to corporate giants, partnerships and family-owned firms across the board. But when it came time to eliminate special breaks or impose tighter standards, real estate was generally excused from the room.” Coincidentally or not, President Trump and his family stand to gain considerably from the new rules. Real estate investors will be able to use a more favorable depreciation schedule on their properties, and rental income will be taxed at a lower rate. Real estate investment trusts also do exceptionally well in the bill, and the Trump Organization has substantial deals with several REITS, including Vornado Realty Trust in New York. Income from REIT investments will be taxed at the new, lower pass-through rate, giving Trump big savings while creating what tax lawyer Steven M. Rosenthal called “giant new tax shelters” for investors. Those and other loopholes are raising plenty of eyebrows, both in shock and in eager anticipation. Rather than simplifying the tax code, the Republican plan seems to be creating more nooks and crannies that can be exploited by clever tax layers. Adam Looney of the Brookings Institution told the Times, “Suddenly, there are a dozen different tax rates that apply to different businesses, in different industries, and to different investments.” Experts expect to see a wave of restructurings and asset shifting as businesses and wealthy investors maneuver to take advantage of every new tax break in the code.	null	minipile	NaturalLanguage	mit	null
Mets infielder Jose Reyes said Sunday that there was no excuse for teammate Matt Harvey to go MIA from a game the day before. “Injuries are injuries. What happened to Harvey, that’s a different ballgame,” Reyes said without elaborating. “You’re an employee, you have to understand you need to show up for your work. That’s the rules that the team has since spring training. As a grown man, you’ve got a job to do. You have to understand: If you don’t show up, you’re going to pay the consequence.” Harvey claimed to Mets higher-ups that a “migraine” kept him from the game, Fox Sports reported. Reyes said that even if the pitcher wasn’t supposed to play, his presence was missed. “I mean, we know. When you don’t see somebody, there’s only 25 guys in the locker room,” Reyes said. “If you don’t see somebody the whole day, you’re going to say, ‘Man, what’s going on?’ ”	null	minipile	NaturalLanguage	mit	null
Home entertainment networks are becoming popular and allow media stored on or accessible by a computer to be presented on more traditional presentation devices, such as a television, in a separate room from the computer. In order for a television to present such media, it is often connected with a media rendering device, which in turn is connected with the computer over a home entertainment network. These media rendering devices often have limited functionality for providing “trick” playback capabilities such as scan forward or reverse, seek, or pause. The limited capabilities of the media rendering devices often stem from a lack of sufficient memory and/or memory buffers to store the media stream locally, which are generally required to provide the dynamic playback functions. Even if a media rendering device is equipped with appropriate memory, transmission of all of the media content required to provide dynamic playback functionality at the media rendering device may consume significant bandwidth on the home entertainment network. Excessive bandwidth consumption may impact the ability of the network to provide content to other devices on the network or provide the requisite content to the particular media rendering device within the necessary time constraints to perform the requested function.	null	minipile	NaturalLanguage	mit	null
British national Samia Shahid was asphyxiated, says forensic report LAHORE: A British woman whose husband alleges she was killed for marrying him against her parents’ wishes was murdered, police said on Wednesday. The case attracted attention because it came just days after the high-profile “honour killing” of outspoken social media star Qandeel Baloch, whose brother confessed to the crime and has been arrested. Samia Shahid, 28, a beautician from Bradford who had gone to visit her family in Pakistan, died last month in the village of Pandori in northern Punjab, the political power base of Prime Minister Nawaz Sharif. No arrests have been made so far, but Shahid’s father and a cousin have been questioned by police. Mukhtar, her second husband, told media last week that the couple had received death threats from her family in the past. He also said her family was angered that Shahid converted from the majority Sunni to the minority Shia sect of Islam after the couple married. Some 500 women are killed each year in Pakistan by relatives who feel their family has been shamed by a daughter or sister fraternising with men, eloping or otherwise infringing conservative demands on women. Last month’s murder of Qandeel Baloch, who had divided opinion in the society by regularly posting risqué photos on social media, led the government to announce that it would pass long-delayed legislation outlawing honour killing within weeks.	null	minipile	NaturalLanguage	mit	null
Introduction {#s1} ============ Extra-pair paternity (EPP) is a widespread phenomenon in birds: it has been found in three quarter of the socially monogamous bird species studied [@pone.0012006-Griffith1]. There is also striking interspecific variation in the rate of EPP, which seems to be related to ecological and social factors, which in turn are also correlated with phylogeny [@pone.0012006-Griffith1], [@pone.0012006-Petrie1], [@pone.0012006-Westneat1]. For example, species or populations with high breeding densities appear to have higher rates of EPP than those with low breeding densities [@pone.0012006-Gowaty1], [@pone.0012006-Mller1], [@pone.0012006-Westneat2], presumably because there are more opportunities for extra-pair matings in high than in low density populations. Consequently, the social system may also influence the rate of EPP, and indeed, the highest rates of EPP are found in group-living and cooperatively breeding Superb Fairy-wrens (Malurus cyaneus) where 72% of all offspring are extra-pair offspring and almost all broods contain extra-pair offspring [@pone.0012006-Double1], [@pone.0012006-Mulder1]. Another important factor that may affect the rate of EPP is the amount of paternal care provided. The larger the investment of the male is, the greater is the fitness loss faced by unfaithful females if their mates abandon the brood after detecting EPP of their female. Consequently, EPP rates should be lower in species where males provide parental care [@pone.0012006-Bennet1], [@pone.0012006-HoiLeitner1], [@pone.0012006-Mller2]. Siberian Jays (Perisoreus infaustus) are long-lived (on average 4.9 years for breeders and up to 16 years), socially monogamous birds that live in family groups consisting of the breeding pair, so-called retained offspring and additional individuals that are unrelated to the breeding pair [@pone.0012006-Blomgren1], [@pone.0012006-Ekman1]. Pair-bonds are stable and divorces occur rarely, if ever [@pone.0012006-Blomgren1], [@pone.0012006-Lillandt1]. While both retained offspring and unrelated individuals are tolerated within the territory, retained offspring are treated favourably by the parents [@pone.0012006-Griesser1], [@pone.0012006-Griesser2]. In this system with stable pair-bonds and 'prolonged brood care' [@pone.0012006-Ekman1], [@pone.0012006-Slepkovych1], females engaging in extra-pair matings would be expected to pay high costs of infidelity since raising a brood on her own or finding a new partner are likely to incur high fitness costs. Also limited possibilities of finding an extra-pair mate can be important as population densities are low (0.1--2 ind/km^2^) and territories are large, 1--4 km^2^ [@pone.0012006-Lillandt1], [@pone.0012006-Lillandt2], [@pone.0012006-Visnen1]. A female would thus have to travel several kilometers only to sample a reasonable number of potential extra-pair mates. On the other hand, unrelated group members provide candidates for extra-pair matings. Here we analysed a large data set from a long-term study of a Finnish Siberian jay population with over 1000 individuals genotyped at up to 21 microsatellites to test for evidence for extra-pair paternity in this species. Methods {#s2} ======= Study species and area {#s2a} ---------------------- Siberian jays (P. infaustus) are comparably small (ca. 80 g) corvids inhabiting boreal forests from Fennoscandia to Siberia. After becoming independent in early summer, juveniles have three options. They either (i) leave their natal family group to join another family group, (ii) establish a territory of their own, or (iii) stay within the natal family group as retained offspring [@pone.0012006-Blomgren1], [@pone.0012006-Ekman1]. Groups consist of the breeding pair and up to four additional individuals that are retained offspring or unrelated individuals [@pone.0012006-Ekman1], [@pone.0012006-Lillandt2], [@pone.0012006-Ekman2], but neither retained offspring nor do the unrelated group-members help at the nest [@pone.0012006-Ekman1]. The study area is located in Ostrobothnia (SW-Finland), near Kristiinankaupunki (62°22′N, 21°30′E). Annual monitoring of the Siberian jay population started in 1974 in a 120 km^2^ sized forest area. Subsequently, the study area has been enlarged and now covers about 1000 km^2^ divided into seven sub-areas with a maximum N-S and E-W distances of about 75 km and 50 km, respectively ([Fig. 1](#pone-0012006-g001){ref-type="fig"}). The number of breeding pairs in the area has varied from five in the early years to 50 in later years. For a more detailed description of the study area and fieldwork procedures see [@pone.0012006-Lillandt1], [@pone.0012006-Lillandt2]. Briefly, during late summer and autumn (July--October) birds are caught at feeding stations, measured, blood sampled (since 1997) and ringed with aluminium and colour rings. In some years additional observations in spring were done. All birds included in this analysis were sexed using molecular markers [@pone.0012006-Fridolfsson1]. ![Schematic map of the study area.\ Dark grey areas indicate open land (mainly arable fields). The study area is indicated by medium gray, with darker medium gray indicating areas where monitoring started in 1992 and earlier. Lighter medium gray indicates areas where monitoring started in 1998 and later. Areas outside the study area are shown in light gray. The inset map shows the location of the study area within Finland.](pone.0012006.g001){#pone-0012006-g001} Capturing and ringing of birds was approved by the institution that coordinates ringing activity in Finland (Finnish Museum of Natural History), based on the regulation by the Ministry of the Environment (No. 17/5713/2002). Procedures for blood and DNA sampling were approved by the ethical license board of University of Helsinki (No. HY 133-06). Paternity analysis and pedigree construction {#s2b} -------------------------------------------- The original pedigree for this study-population was constructed based on field observations and microsatellite markers [@pone.0012006-Lillandt3], [@pone.0012006-Lillandt4]. In short, identities of breeding partners were inferred from observations at feeding stations, and the genotypes of all offspring born in a given year were manually matched against all breeding pairs in the same year [@pone.0012006-Lillandt2], [@pone.0012006-Lillandt4]. Based on the improved genotypic data (see below) and parentage analysis using Cervus 3.0 [@pone.0012006-Kalinowski1], we re-constructed the pedigree. This was done separately per birth year to avoid the possibility that an individual\'s offspring could become assigned as its parent. We used Delta-scores, the difference in the logarithms of the likelihood ratios (LOD) of the most likely and the second most likely candidate pair, as a criterion for the confidence of the parentage assignment. Because the number of candidate parents differed between years, critical Delta-scores were calculated on an annual basis using the simulation option in Cervus. We set the proportion of the population sampled to the average annual recapture probability \[0.90±0.02, [@pone.0012006-Bergholm1]\]. The genotyping error was assumed to be 1%. This is a conservative estimate since all samples were run twice, read blindly and the resulting genotypes only accepted if the two runs gave identical results. If the results differed the sample was re-ran and re-scored. To test how sensitive our results were to this parameter, we re-run a subsample using genotyping errors of 0.1% and 2%, respectively. No qualitative differences in the assigned parentages were found. All individuals genotyped at less than six (1974--79), less than eight (1980--96) and less than nine loci (1997--2006), respectively, were excluded from the analysis. The threshold values for exclusion differed between periods because the average number of loci typed per individual differed: Initially only individuals after 2005 were genotyped for 21 markers. Not all other individuals could be successfully typed for the new markers due to different sample types (feathers vs. blood). All parents that were (possibly) alive in the given birth year were included as candidate parents in the separate runs. The most likely candidate parents as identified by Cervus were assigned as 'true' parents if they were observed as a breeding pair in the individual\'s birth year. When the most likely candidate parents were not observed as a breeding pair, but the second or third most likely candidate pair was observed as a breeding pair, the latter were assigned as parents. However, in all these cases the Delta-score was small, and no candidate pair could be assigned with 95% confidence. If none of the candidate pairs had a positive LOD-score or were observed together as a breeding pair, no parents were assigned to the individual. Normally, nests were not located and visited because of the amount of work involved with finding the nests, but also to minimise the disturbance which can increase the risk of nest predation [@pone.0012006-Armstrong1], [@pone.0012006-Sandvik1]. However, in total 37 broods were ringed in the nest. Of these, 40 offspring from 23 broods could be included in the paternity analysis. In three cases no DNA-sample from the social mother was available, but they were included regardless. Paternity analysis was carried out using Cervus assuming the social mother was the 'true' mother. Again, paternity assignments were carried out with the known genetic mothers separately per birth year since the number of candidate fathers differed between years. We used the same values for proportion of the population sampled and genotyping error as in the parentage analysis. Genetic samples were obtained from blood samples and for the early years from the tip of collected tail feathers. DNA was extracted using DNeasy Blood & Tissue kit according to the manufacturers\' instructions (Qiagen). The individuals were genotyped for 21 previously reported markers ([Table 1](#pone-0012006-t001){ref-type="table"}). Briefly, the markers were divided into groups (panels) of 3--4 markers based on the size of the PCR products and the labels used. PCR amplification was carried out in similar conditions (2 pmol of each primer, 1× Qiagen multiplex mastermix, 0.5× Q-Solution, and approximately 30 ng of DNA in a total volume of 10µl) and the same cycling profile (15 min at 95°C, followed by 30 cycles 30 s at 94°C, 90 s at 56°C and 60 s at 72°C and a final extension for 10 min) for all markers, using a commercial multiplex PCR kit (Qiagen). The PCR products were diluted 1∶750 with MQ-water and mixed with Et-ROX 400 standard (GE Healthcare, Life Sciences) according to the manufacturer\'s instructions and resolved in a MegaBace 1000 capillary sequencer (GE Healthcare, Life Sciences). Genotypes were scored with the Fragment Profiler 1.2 program (GE Healthcare, Life Sciences). Not all birds could be scored for all markers due to low quality and low concentration of DNA. This was mainly the case for the old feather samples. 10.1371/journal.pone.0012006.t001 ###### Microsatellite loci used for pedigree re-construction and extra-pair paternity analyses. ![](pone.0012006.t001){#pone-0012006-t001-1} Locus A n H~O~ H~E~ PIC N-Excl~1~ N-Excl~2~ Ref. -------- ---- ------ ------- ------- ------- ----------- ----------- ------------------------------ SJ103 18 929 0.872 0.895 0.885 0.3507 0.2121 [@pone.0012006-Fridolfsson1] SJ104 6 950 0.323 0.322 0.307 0.9458 0.8208 [@pone.0012006-Fridolfsson1] SJ105 5 909 0.482 0.503 0.408 0.8730 0.7776 [@pone.0012006-Fridolfsson1] SJ106 8 953 0.787 0.802 0.774 0.5650 0.3876 [@pone.0012006-Fridolfsson1] SJ107 10 951 0.693 0.698 0.653 0.7084 0.5346 [@pone.0012006-Fridolfsson1] SJ109 9 926 0.726 0.755 0.715 0.6450 0.4682 [@pone.0012006-Fridolfsson1] SJ110 4 934 0.668 0.653 0.587 0.7706 0.6176 [@pone.0012006-Fridolfsson1] SJ111 5 921 0.562 0.587 0.523 0.8218 0.6758 [@pone.0012006-Fridolfsson1] SJ112 4 895 0.191 0.302 0.257 0.9544 0.8706 [@pone.0012006-Fridolfsson1] SJ114 5 888 0.498 0.505 0.410 0.8718 0.7754 [@pone.0012006-Fridolfsson1] SJ116 3 861 0.48 0.482 0.379 0.8841 0.8032 [@pone.0012006-Fridolfsson1] SJ115 4 872 0.429 0.505 0.432 0.8724 0.7536 [@pone.0012006-Fridolfsson1] MJG1 2 1034 0.414 0.405 0.323 0.9179 0.8384 [@pone.0012006-Griesser3] PER1 7 1034 0.538 0.539 0.490 0.8438 0.6916 [@pone.0012006-Griesser3] Ppi1 4 1008 0.57 0.543 0.485 0.8494 0.7050 [@pone.0012006-Griesser3] PPi2 5 1029 0.747 0.728 0.681 0.6910 0.5158 [@pone.0012006-Griesser3] LTML7 3 1007 0.367 0.37 0.302 0.9316 0.8488 [@pone.0012006-Griesser3] LTML8 13 1022 0.86 0.848 0.831 0.4643 0.3000 [@pone.0012006-Griesser3] CK1B5D 2 1003 0.5 0.495 0.373 0.8774 0.8137 [@pone.0012006-Griesser3] CK2A5A 16 1033 0.803 0.807 0.787 0.5295 0.3557 [@pone.0012006-Griesser3] CKL5 12 1010 0.82 0.815 0.792 0.5296 0.3558 [@pone.0012006-Griesser3] Number of alleles (A) and number of individuals genotyped (n), observed (H~O~) and expected (H~E~) heterozygosity, non-exclusion probability for first (N-Excl~1~) and second (N-Excl~2~) parent (with first parent assigned) per locus. Ref. = reference for original publication describing the loci. Results {#s3} ======= A total of 1029 genotyped offspring could be included in the parentage analysis. In 177 cases (17.2%) no candidate parents with positive LOD scores were found and these individuals were hence regarded as immigrants into the study area. In the majority of the remaining cases (71%) the most likely candidate pair was observed as a breeding pair, and hence, assigned as parents. In 118 (11.5%) cases the most likely candidate parents had a positive LOD scores but were not observed as an actual breeding pair, but were breeding in different territories with other partners. These are thus possible cases of extra-pair paternity. However, for 76 of these the LOD and the Delta scores were so low that none of the candidate pairs could be assigned for parentage at the 95% confidence level. In the remaining 36 (3.5%) cases, the candidate pairs could be assigned at the 95% confidence level but there are several reasons why we think that none of them provides good evidence for extra-pair paternity. 1) In eight cases one or both candidate parents could already have died, because they were observed in the years before but not in the year when the individual in question was born. 2) In the majority of cases, the male or female would have had to travel quite far (mean = 14.7 km, range = 1.6--41.3 km) to seek the extra-pair mating, further than the average natal dispersal distance (mean = 5.0 km (males), 5.9 km (females), [@pone.0012006-Gienapp1]) and also further than the neighbouring territories. 3) In none of these cases social mother would have been the genetic mother, and the offspring in question were never observed in the assumed natal territory. This means that all extra-pair offspring would have dispersed in their first summer, which seems very unlikely given that a half to two thirds of the fledglings stay with their parents [@pone.0012006-Ekman2]. It becomes even more unlikely when one considers that extra-pair offspring should be of higher quality [@pone.0012006-Hasselquist1] and that it is the low-quality, sub-dominant offspring which are more likely to disperse during the first summer [@pone.0012006-Ekman2]. Four out of 40 offspring with known social father could have been EPP-offspring. However, in the years when three of these offspring hatched critical LOD and Delta-scores were low ([Table 2](#pone-0012006-t002){ref-type="table"}). This was because not all individuals could successfully be genotyped for 21 markers and the number of candidate fathers was small. This was true even for strict (95%) confidence, which means that almost all candidate fathers were possible 'true' fathers. It would hence be difficult to assign any extra-pair father as 'true' father with any confidence and consequently there is no good evidence for these three offspring really being EPP-offspring. In 2002 and 2003 critical LOD and Delta scores were reasonably high to distinguish between likely and unlikely candidates ([Table 2](#pone-0012006-t002){ref-type="table"}). 19 nestlings from eight broods in these years could be included in the analysis and in only one case an extra-pair candidate father was the most likely father. However, both this candidate father as well as the social father mismatched at one locus with the offspring and neither of them would have been likely father if tested on their own without knowledge of the social mother\'s genotype. 10.1371/journal.pone.0012006.t002 ###### Minimum number of loci for inclusion in analysis, median number of loci typed per individual, number of candidate fathers and critical LOD-scores and Delta-values (95% confidence) of the paternity analysis of offspring with known social parents, i.e. being ringed in the nest, separately per year. ![](pone.0012006.t002){#pone-0012006-t002-2} Father alone Father given known mother ------ --- ------ ----- -------------- --------------------------- ------- ------ 1976 6 10.4 17 1.15 0.25 −4.50 0.00 1980 6 13.5 15 0.27 0.16 −4.50 0.00 1984 8 12.4 6 −4.00 0.00 −9.00 0.00 1987 8 16.1 12 −1.00 0.00 −6.00 0.00 1990 8 17.3 24 1.81 0.77 −3.00 0.00 1991 8 18.5 29 2.85 1.08 −2.75 0.00 1992 8 19.2 25 2.00 0.84 −3.50 0.00 1993 8 19.1 36 3.53 1.48 −1.88 0.00 1994 8 18.8 41 3.57 1.72 −1.13 0.00 2002 8 20.8 116 5.54 2.57 2.19 1.01 2003 8 20.8 112 5.90 2.41 2.74 0.85 Locating nests did not belong to the standard field work procedure and was done only in some years. Discussion {#s4} ========== We found no evidence for extra-pair paternity (EPP) in our study population despite the fact that data set covered over 30 years and more than 1000 offspring genotyped for up to 21 microsatellite markers. This concurs with an earlier study of the same population [@pone.0012006-Lillandt4] and the results of an analysis of a smaller data set of five large families (349 individuals) genotyped for 117 microsatellite loci from the same population [@pone.0012006-Jaari1] that did not find a single case of EPP. Likewise, in a Swedish study of Siberian jays, no evidence for extra-pair paternity was found [@pone.0012006-Ekman3]. Hence, our results -- together with similar evidence from earlier studies -- provide little evidence to support the possibility that extra-pair paternity in Siberian jays would be common, or in matter of fact, occurring at all. Of course, we cannot strictly rule out the possibility that single cases of extra-pair paternity may have gone undetected. Yet, even if extra-pair paternity in Siberian jays would occur, its frequency must be very low. Due to the limited number of loci typed and the small number of candidate fathers included in extra-pair paternity analysis, critical LOD- and Delta-scores -- and thereby our ability to detect extra-pair paternity -- were low for several years. However, even in years when critical these scores were reasonably high to distinguish in between likely and unlikely candidates, little evidence for extra-pair paternity was found. Another reason why our analyses might underestimate the rate off EPP in Siberian jays is that most of the offspring were sampled after they had left the nest. This means that young that died or dispersed outside the study area before sampling were not available for analyses, and reduces the likelihood of detecting EPP. However, focussing on those 23 broods ringed in the nest and available to analyses, this possible bias could be eliminated: none of those offspring were very likely EPP-young. Hence, if some EPP young were missed due to early mortality or dispersal, their frequency is likely to have been low. If extra-pair paternity in Siberian jays is so rare as our data and earlier analyses suggest, possible reasons for this become of interest. Phylogeny explains over 50% of the among species variation in extra-pair paternity [@pone.0012006-Griffith1]. Although it is not clear whether this is due to ecological similarity of related species or an actual phylogenetic constraint, it is interesting to note that our result of no extra-pair paternity in Siberian jays is in line with the generally low rates of extra-pair paternity in other corvids \[0--1.4% extra--pair offspring, [@pone.0012006-Hall1]\]. Providing 'prolonged brood care' is beneficial in Siberian jays since retained offspring have improved survival prospects [@pone.0012006-Griesser3] and higher life-time reproductive success as compared to dispersing offspring [@pone.0012006-Gienapp1], [@pone.0012006-Ekman3]. Successful 'prolonged brood care' requires both parents and an unfaithful female being deserted by its male may face brood loss and consequently high fitness costs. While the generally low breeding densities in Siberian jays should reduce the 'availability' of extra-pair mates, this may be counteracted by the presence of unrelated males within the group. However, unrelated individuals within a family group have been forced to leave their natal family by dominant siblings [@pone.0012006-Ekman2]. Since they are therefore likely to be of low 'quality' (phenotypic or genetic), they may be unattractive candidates for extra-pair matings. Furthermore, most of the unrelated group-members will leave the group in spring to attempt to establish their own territories. The observed absence or very low frequency of EPP in Siberian jays could hence be easily explained by the high costs of EPP due to their breeding system and the reduced choice of extra-pair partners. Bo-Göran Lillandt is thanked for the field-work and access to the data. Thanks are also due to Marika Karjalainen and Sonja Jaari for help in the lab, as well as Karen Bouwman, Meng-Hua Li and an anonymous reviewer for reading and commenting on the manuscript. Competing Interests:The authors have declared that no competing interests exist. Funding:This work was funded by research grants from the Academy of Finland to PG and JM, from the Kone Foundation to PG and the Maj and Tor Nessling Foundation to JM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. [^1]: Analyzed the data: PG. Contributed reagents/materials/analysis tools: JM. Wrote the paper: PG JM.	null	minipile	NaturalLanguage	mit	null
Dave Nalle is better known for designing roleplaying games like the groundbreaking Ysgarth RPG, but during the 1970s and 1980s he designed a number of small budget but interesting board games and then in the 1990s he designed the much higher budget collectible card game Quest for the Grail. He primarily makes his living as a font designer at (see http://www.fontcraft.com ) and many of his fonts are featured on popular boardgames from other designers. He has designed several technical fonts specifically for game design. Rumor is that he has new games in development from a new company Hanged Man Games (http://www.hangedmangames.com ).	null	minipile	NaturalLanguage	mit	null
The Wall Street Journal reports that YouTube is deep in discussions with the movie studios to offer both paid (likely $3.99) and ad-supported movie rentals. This would include new releases, which would be new to YouTube. Lion's Gate, Sony and Warner Bros are all reportedly discussing such a service with Google (who owns YouTube), although details are thin. Negotiations are still ongoing, so a lot of major issues (will downloads be available? Which films would be ad-supported versus a flat fee? What about TV shows?) are still unresolved. But if YouTube could get a solid, competitive system going, they'd have a fair chance at competing with Hulu, iTunes and Crackle and maybe even turn a profit one of these days. [WSJ]	null	minipile	NaturalLanguage	mit	null
The husband of an American missionary diagnosed with the deadly Ebola virus has ended his quarantine in North Carolina and visited his wife Sunday at an isolation room at Emory University Hospital in Atlanta, a Christian missionary group announced Monday. David Writebol, who was quarantined as a precautionary measure after returning from Liberia, said his wife, Nancy, was continuing to improve. Nancy Writebol, 59, and a missionary doctor, Ken Brantly, 33, were flown from Liberia earlier this month for treatment at Emory’s special containment unit, one of just four in the country. "I have had the great joy to be able to look through the isolation room glass and see my beautiful wife again,’’ David Writebol said in a statement Monday. "We both placed our hands on opposite sides of the glass, moved with tears to look at each other again." Writebol has not had contact with his wife since she was diagnosed with Ebola in Liberia on July 26. Nancy Writebol, wearing a full-body white protective suit, was flown to Atlanta on a specially-outfitted private plane on Aug. 5. David Writebol said he had no symptoms of Ebola and was cleared by doctors to leave quarantine Sunday to visit his wife. "She was standing with her radiant smile, happy beyond words," David Writebol said of Sunday’s meeting. "She is continuing to slowly gain strength, eager for the day when the barriers separating us are set aside, and we can simply hold each other." David Writebol AP David Writebol, seen here during an interview last week in Charlotte, N.C., was able to visit his wife, who remains in an isolation ward. David Writebol, seen here during an interview last week in Charlotte, N.C., was able to visit his wife, who remains in an isolation ward. (AP) He added: "We prayed together over the intercom." "My family and I look forward to her speedy restoration, and we give thanks for continued prayers on her behalf," Writebol said. Ebola has infected at least 2,100 people and killed 1,145 in Liberia, Sierra Leone, Guinea and Nigeria, according to the World Health Organization. Two other doctors with the Charlotte-based missionary group SIM also were placed in precautionary quarantine on SIM’s campus in Charlotte, N.C., on Aug. 10. The doctors, whose names have not been released, have not been diagnosed with Ebola. Palmer Holt, a spokesman for SIM, declined to say Monday whether the two doctors were still in quarantine. Both Nancy Writebol and Brantly have been treated with the experimental drug Zmapp, which contains a mixture of antibodies. There is no effective vaccine for Ebola, but patients are given fluids and other treatments in hopes of stabilizing them long enough for their immune systems to eventually fight off the virus. In the worst Ebola outbreak in Africa since the virus first appeared in 1976, as many as 90% of those diagnosed have died, according to the WHO. The virus is spread through contact with bodily fluids. On Friday, Brantly released a statement from his isolation room at the Atlanta hospital, saying his condition continued to improve. "I am growing stronger every day," Brantly said. Brantly said he traveled to Liberia not to fight Ebola but to treat patients at a SIM-run missionary hospital in Monrovia on behalf of a North-Carolina based Christian charity, Samaritan’s Purse. But as Ebola swept through West Africa, he began treating Ebola patients, he said. "I witnessed the horror first-hand, and I can still remember every face and name," he said. He added: "As you continue to pray for Nancy and me, yes, please pray for our recovery. More importantly, pray that we would be faithful to God’s call on our lives in these new circumstances."	null	minipile	NaturalLanguage	mit	null
Non-iterative method for phase retrieval and coherence characterization by focus variation using a fixed star-shaped mask. A novel non-iterative phase retrieval method is proposed and demonstrated with a proof-of-principle experiment. The method uses a fixed specially designed mask and through-focus intensity measurements. It is demonstrated that this method is robust to spatial partial coherence in the illumination, making it suitable for coherent diffractive imaging using spatially partially coherent light, as well as for coherence characterization.	null	minipile	NaturalLanguage	mit	null
The effect of repeated applanation on subsequent IOP measurements. In studies aimed at assessing the accuracy and repeatability of non-contact tonometers, the order in which these tonometers and the Goldmann tonometer are used is usually randomised despite studies in the literature that demonstrate an ocular massage effect that occurs post-applanation but not after non-contact tonometry. The purpose of this study was to investigate the effect of repeated corneal applanation on subsequent assessments of IOP. Data were obtained from 65 left eyes of 65 young, oculovisual normals. Three sets of IOP measurements were obtained, one set with the Goldmann applanation tonometer and two with the Topcon CT80 non-contact tonometer (one set each before and after applanation with the Goldmann tonometer), in each one of two separate measurement sessions, one week apart. The average (and SD) IOP measured with the Goldmann tonometer in the first session (14.8+/-2.9 mmHg) did not vary significantly from the IOP measured with the non-contact tonometer (pre-applanation) in both sessions or with the average Goldmann IOP in the second session. The bias (mean difference +/- SD) between methods was 0.3+/-1.4 mmHg and 0.4+/-1.4 mmHg, respectively, for the first and second sessions, with the CT80 (pre-applanation) recording the higher IOP in both sessions. The within-session repeatability coefficients were +/-2.3 mmHg, +/-2.6 mmHg, +/-2.1 mmHg and +/-2.0 mmHg for the CT80 (pre-applanation) in the first and second sessions, and the Goldmann tonometer in the first and second sessions, respectively. Test-retest repeatability coefficients were +/-2.8 mmHg and +/-2.5 mmHg for the CT80 (pre-applanation) and the Goldmann tonometer respectively. Post-applanation with the Goldmann tonometer, there was a statistically significant (p<0.05) reduction (1.5+/-1.2 mmHg in session 1) in the IOP measured with the non-contact tonometer in both sessions. These results suggest that repeated corneal applanation leads to a statistically significant reduction in IOP on subsequent measurements.	null	minipile	NaturalLanguage	mit	null
Summary and Info Subterranean Rodents presents achievements from recent years of research on these rodents, divided into five sections: ecophysiology; sensory ecology; life histories, behavioural ecology and demography; environmental and economical impact; molecular ecology and evolution. It is a must for all researchers working in this field and will be of interest to zoologists, physiologists, morphologists, ecologists, and evolutionary biologists.	null	minipile	NaturalLanguage	mit	null
Institutions like Harvard, Massachusetts Institute of Technology and Stanford, among others, are developing ethics and data courses to fill tech industry demand for students who can consider the implications of inappropriate information handling or software development that unfairly targets certain users. Course topics include privacy policy pitfalls, social media responsibility and business models developing around ethical data science. Garlin Gilchrist, executive director of the University of Michigan's School of Information Center for Social Media Responsibility, said in an experts advisory statement that institutions have a unique role in providing a platform where prospective tech industry employees can learn hard data skills and the social implications around them, noting "It will take a collective effort" of higher ed researchersand "policymakers, media companies and users to establish new norms, better understand roles, and create real accountability mechanisms for all parties." Dive Insight: As more major tech companies like Facebook face public scrutiny over their handling of user data, there grows a need for graduates to know the societal implications of the software they develop. Erik Gordon, clinical assistant professor at the Ross School of Business at the University of Michigan, said Facebook is not the only company dealing with these types of privacy scandals and recognizing that its revenue model could be disrupted. "The data scandal means that Facebook has to consider a new model in which it is responsible for content. That is a costly model. It's a model that will lose posters and viewers," said Gordon in the experts advisory. "Facebook is not the only company facing threats. Twitter could be hurt even more because it may gather a higher proportion of its revenue from data than at Facebook." Subsequently, greater numbers of colleges and universities are recognizing the business case for creating blended data and ethics courses, as students become attracted to such offerings that help them stand out within the labor pool for lucrative tech jobs. For example, Dustin Loeffler, associate professor of cyber security and information systems at Maryville University, told Education Dive his institution started offering these interdisciplinary courses because of student demand. He added Maryville combined ethics and philosophy courses with technical courses because "students wanted this, they wanted to be more well-rounded." "In the last presidential election we really saw the outcomes that technology can drive. Students I've worked with have really had their eyes opened up during this time more than they ever had, and this request for this ethical component embedded in the technical curriculum has turned into a sort of organic movement," said Loeffler.	null	minipile	NaturalLanguage	mit	null
[Long-term results of the surgical treatment of hiatal hernia using the Boerema technic]. The authors analyse the results of the surgical treatment of "symptomatic hiatus hernia" by the Boerema anterior gastropexy, in 69 patients. As compared to other techniques, the observed mortality and morbidity rates are similar. The postoperative delay is greater than 2 years in 95% of the patients and 83% of them are satisfied with the treatment. Better results are actually obtained with other techniques. Nevertheless, anterior gastropexy which remains the easiest and fastest technique, may still be used in elderly or high risk patients. The Nissen fundoplication is recommended for the majority of the patients suffering from "symptomatic hiatus hernia", especially when ulcerative reflux esophagitis is present.	null	minipile	NaturalLanguage	mit	null
Co-culture of healthy human keratinocytes and T-cells promotes keratinocyte chemokine production and RORγt-positive IL-17 producing T-cell populations. Both keratinocytes and T-cells are crucial players in cutaneous immune responses. We hypothesized that direct interactions between keratinocytes and T-cell subsets could shape the nature or strength of the local immune response. We investigated direct interactions between keratinocytes and T-cell subsets, focused on keratinocyte chemokine production and T-cell phenotype and cytokine production. A newly developed in vitro serum free co-culture model using primary keratinocytes and T-cells subsets from healthy human donors was used. Keratinocyte chemokine production was analyzed with luminex, T-cell phenotype and cytokine production were analyzed with flow cytometry. Our data show that upon co-culture with CD4(pos) or CD8(pos) T-cells primary human keratinocytes increased production of functionally active chemokines CCL2, CCL20 and CXCL10 and that regulatory T-cells did not regulate keratinocyte chemokine production. Next to that, we found that keratinocytes skewed CD4(pos) and CD8(pos) T-cell populations toward an IL-17(pos) CCR6(pos) RORγt(pos) phenotype in a cell-cell contact independent manner, and that Treg were able to decrease the absolute number of IL-17 producing T-cells in keratinocyte/T-cell co-cultures. Correspondingly, freshly isolated skin-derived T-cell populations contained relatively high percentages of IL-17(pos) cells. We provide evidence that keratinocyte/T-cell communication may regulate leukocyte influx in the skin, and that keratinocytes enrich T-cell populations for Th17/Tc17 cells. Accumulation of Th17/Tc17 cells, but not chemokine production, appears under the control of regulatory T-cells. Dysregulation of these processes may well contribute to the pathophysiology of inflammatory skin diseases.	null	minipile	NaturalLanguage	mit	null
Just a few quick personal thoughts on a third year of blogging about Kenya from the U.S. The first two years of this blog have coincided with my wife’s graduate school program–she graduated in December (proud smile!) so I will need to be especially aware of evening and weekend time reading and writing about Africa. As I have mentioned, this blog has been in significant part a tool of my own education, so there is a symmetry here. At the same time, 2012 is a huge year for Kenya, and the natural opportunity for the fulfillment of the hopes and aspirations of so many of us who were involved in some way in the 2007-08 election fiasco, so I will do my best to stay highly engaged. Likewise, we once again have a simultaneous presidential campaign in the U.S., which will just makes things that much more interesting. Regardless, I do want to take advantage at present of my literal “distance” to observe and comment on larger themes and not get too sucked into the daily cycle of purported Kenyan campaign news. I learned quickly during the last campaign that every day brings big announcements breathlessly covered by the competitive Kenyan media–and of course this is available to us globally through modern ICT (and a real aspect of the campaign since the votes and especially contributions of the diaspora will be important)–but most of them are of little lasting significance. My distance from Washington will also, I hope, let me have something of a “bird’s eye view” on what is similar and what is different in the approach of the U.S. government and U.S. politicians and other actors to the Kenyan campaign and other events. Continue Reading American lawyer. Took leave from corporate career to “assist” democracy in East Africa. After stolen '07 election in Kenya and violent aftermath I have tried to bring out truth of events for those who care in hope we can learn and do better.	null	minipile	NaturalLanguage	mit	null
News Wisconsin, Edwin Witte and Social Security: A History Lesson for Ron Johnson and Paul Ryan Republicans On 75th Anniversary (8/13/10) Posted August 12, 2010 MADISON - Following is the statement of Democratic Party of Wisconsin Chair Mike Tate on the 75th Anniversary of the Social Security Act and the "Father of Social Security," Wisconsin's Edwin Witte: "Seventy-five years ago today, a Wisconsin farm boy named Edwin Witte helped enact a program made necessary by the excesses of Wall Street. At the time, poverty ran rampant amid the elderly as a direct consequence of the greedy speculation of forces far removed from the Dairy State. As an advisor to President Roosevelt, Witte took with him the example of hard work and humility learned here in Wisconsin and sought to fight back the forces conspiring against our nation's working families. Now 75 years later, Paul Ryan and Ron Johnson, who grew up privileged in Wisconsin and Minnesota respectively, have drawn some very different conclusions about the safety net woven for our seniors. In an irony that would not have escaped Witte, Ryan and Johnson, as they seek glory for themselves, now want to hand over Social Security to the very Wall Street forces that threw us into the Great Depression and that caused the economic crisis we face today. Other Wisconsin Republicans, like Scott Walker and Congressional candidate Sean Duffy, have endorsed the Ryan plan, equally blind to the irony. As we celebrate the 75th anniversary of the Social Security Act, brought into being by our own Ed Witte, we promise we will not bend to Wall Street as Ron Johnson, and Paul Ryan would have us. We will protect our seniors."	null	minipile	NaturalLanguage	mit	null
It is a common advertising and promotional technique to place coupons, discount cards, prizes or other promotional materials into containers such as cartons for breakfast cereal or snack items or into bagged products such as potato chips. The coupon is highly visible to the consumer who can then use the coupon for the intended purpose, such as for discounts on future purchases or rebates. The coupon itself may also contain a prize or other premium, often a molded plastic figure or other piece. Accordingly, the term “coupon” used herein includes any type of insert, coupon, card, sheet, receipt, warranty, prize, premium, or other part that can be advantageously handled in accordance with the invention hereinafter described. Similarly, the terms “container” and “receiving product” are used in the broadest possible context to include containers such as boxes, tubs, cans, and vessels of all kinds as well as other coupon receiving objects that can be advantageously used with the present invention, such as the fill tube of a form, fill, and seal packaging machine. Placing coupons by hand is very expensive as it is labor intensive and human hands cannot always keep up with the speed of modern automated packaging equipment. Thus, packaging equipment manufacturers have developed a variety of automated coupon inserter machines for placing coupons on or into products. Typically, coupon inserting devices operate by discharging or positioning a single coupon in each container rapidly moving along a conveyor system or into a chute or tube of some other type of product handling system. There are several methods and apparatus for placing single coupons. One requires a stack of pre-cut coupons that are individually dispensed from a downwardly sloping channel, such as the system shown in Prewer, U.S. Pat. No. 4,530,200. In that system, pusher elements and advancing rollers coact to withdraw the forwardmost coupon from the pre-cut stack. The coupon is then drawn into the downwardly sloping channel to a dispensing location. In another apparatus, shown in Gallimore, U.S. Pat. No. 4,197,113, a reciprocal vacuum head picks a coupon from a stack of pre-cut coupons and places the coupon on a conveyor system, which in turn transports the coupons to the containers. Another system, shown in Lewis et al., U.S. Pat. No. 4,354,894, requires the use of a mechanical cutting device to separate each coupon from a continuous web. Once separated, the coupons are dispensed to the containers using a conveyor system. In yet another system, a device separates a single coupon from a continuous web of coupons using a bursting technique and places the coupon into the container or places the coupon into the fill tube of a form-fill-seal packaging system. Such devices are disclosed in U.S. Pat. Nos. 5,845,462 and 6,082,079, respectively, which are assigned to the assignee of the present invention. While such systems are generally effective with flat coupons, they have not been found to be entirely effective for use in connection with thick or bulky coupons such as overwrapped plastic prizes or parts (such coupons shall be referred to herein generally as “three-dimensional coupons”). This invention relates to an improved coupon delivery system as compared to the systems described above and to solutions to some of the problems raised or not solved thereby.	null	minipile	NaturalLanguage	mit	null
1. Field of the Invention The present invention relates to a head used for thermally-assisted magnetic recording in which a light propagating through a waveguide is converted into near-field light (NF-light), a magnetic recording medium is irradiated with the NF-light, thereby anisotropic magnetic field of the medium is lowered, thus data can be written. Further, the present invention relates to a magnetic recording apparatus provided with the head. 2. Description of the Related Art As the recording densities of magnetic recording apparatuses become higher, as represented by magnetic disk apparatuses, further improvement has been required in the performance of thin-film magnetic heads and magnetic recording media. To improve the recording densities, it is necessary to decrease the size of magnetic grains that constitute a magnetic recording layer of the medium and to reduce irregularity in the boundary of record bit, thus to form minute record bits reliably. However, the decrease in size of the magnetic grains raises a problem of degradation in thermal stability of the magnetization due to the decrease in volume. As a measure against the thermal stability problem, it may be possible to increase magnetic anisotropy energy KU of the magnetic grains. However, the increase in energy KU causes the increase in anisotropic magnetic field (coercive force) of the magnetic recording medium. As a result, the head cannot write data to the magnetic recording medium when the anisotropic magnetic field (coercive force) of the medium exceeds the write field limit. Recently, as a method for solving the problem of thermal stability, so-called a thermally-assisted magnetic recording technique is proposed. In the technique, a magnetic recording medium formed of a magnetic material with a large magnetic anisotropy energy KU is used so as to stabilize the magnetization; anisotropic magnetic field of the medium is reduced by applying heat to a portion of the medium where data is to be written; just after that, writing is performed by applying write magnetic field (write field) to the heated portion. In the thermally-assisted magnetic recording, a technique is well known, which utilizes a near-field optical device (NF-optical device) as a metal piece that generates NF-light from plasmon excited by irradiated laser light, so-called plasmon antenna. For example, U.S. Pat. Nos. 6,768,556 and 6,649,894 disclose a technique in which NF-light is generated by irradiating a metal scatterer with light and by matching the frequency of the light with the resonant frequency of plasmon excited in the metal. As described above, various kinds of thermally-assisted magnetic recording systems with NF-optical devices have been proposed. Meanwhile, the present inventors have devised a NF-optical device in which laser light is coupled with the NF-optical device in a surface plasmon mode to cause excited surface plasmon to propagate to the opposed-to-medium surface, thereby providing NF-light, instead of directly applying laser light to a NF-optical device. The NF-optical device is hereinafter referred to as a surface plasmon generator. In the surface plasmon generator, its temperature does not excessively rise because laser light is not directly applied to the surface plasmon generator. As a result, there can be avoided a situation in which the end of a read head element, which reaches the opposed-to-medium surface, becomes relatively far apart from the magnetic recording medium due to the thermal expansion of the NF-optical device, which makes it difficult to properly read servo signals. In addition, there can also be avoided a situation in which the light use efficiency is degraded because thermal fluctuation of free electrons increases in the NF light generator. Here, the light use efficiency is a ratio of the intensity of NF-light emitted from the NF-optical device relative to the intensity of laser light incident to the waveguide. In a near-field light generating (NFL-generating) optical system that includes the surface plasmon generator devised by the present inventors and a waveguide through which laser light propagates, it is important to improve the light use efficiency descried above. Here, the surface plasmon generator includes a portion where the generator is coupled with the waveguide light in a surface plasmon mode. Specifically, a surface plasmon mode is induced in the portion by coupling between evanescent light that is equivalent to waveguide light seeping from the waveguide and fluctuations in charge excited on the surface of the surface plasmon generator, thereby exciting surface plasmon. Accordingly, in order to increase the light use efficiency of the NFL-generating optical system described above, it is important to enable the evanescent light to well reach a desired location in the surface plasmon generator. To that end, some artifices are needed not only in the structure of the surface plasmon generator but also in the configuration of the NFL-generating optical system including the waveguide.	null	minipile	NaturalLanguage	mit	null
Several proposals expand the existing JavaScript class syntax with new functionality. This article explains the new public class fields syntax in V8 v7.2 and Chrome 72, as well as the upcoming private class fields syntax. Here’s a code example that creates an instance of a class named IncreasingCounter:	null	minipile	NaturalLanguage	mit	null
The present invention relates to a RJ modular connector, and more particularly to a RJ modular connector having a substrate provided therein to balance electrical couplings between terminals. RJ modular connector has been widely used in telecommunication system since it was firstly created. A so-called RJ45 modular connector has been widely used in the network system. The RJ45 modular connector includes totally eight terminals. Resulting from miniaturization of the computer, all corresponding components, including connectors, have to be reduced for their dimension and size. One of the negative consequences or problem created from miniaturization is electrical coupling between terminals. When the RJ connector is used in low speed signal transmission, the couplings between adjacent terminals can be ignored in light of its effect. However, when the RJ connector is used for high speed signal transmission, the couplings between adjacent terminals create a great problem. Unless the electrical coupling can be effectively controlled within an accepted level, it is unlikely that the RJ45 modular connector can be used in the high-speed signal transmission. One of the approaches is to select a pair of terminals as a differential pair. In the differential pair, two terminals transmit the same signal but with inverted phase. By this arrangement, the couplings coupled thereto can be finally subtracted in a data processing unit. As shown in the catalog from The Siemon Company which will be submitted later with IDS, there are at least eight different patterns in selecting terminals as differential pair, i.e. T568A, T568B, USOC 4-pair, USOC 1-, 2- or 3-pair, 10BASE-T (802.3), Token Ring (802.5), 3-pair (MMJ), and TP-PMD (X3T9.5) and ATM. In each implementation, two terminals are selected as a pair in which some are close to each other, while some are apart from each other. Each pattern has its own uniqueness, while each also carries a coupling issue need to be solved. Among those patterns, T568A and T568B are widely used and in T568A, terminals 1,2 configure 3rd pair, terminals 3,6 configure 2nd pair, terminals 4,5 configure 1st pair, while terminals 7,8 configure 4th pair. In T568B, terminals 1,2 configure 2nd pair, terminals 3,6 configure 3rd pair, terminals 4,5 configure 1st pair, while terminals 7,8 configure 4th pair. Since those eight terminals are equally spaced, electrical couplings between terminals will surely create some problems, i.e. coupling or cross-talk. For example, if we take terminal 3 into consideration, terminal 3 will naturally pick up energy coupled from terminals 2, and 4 which are close to terminal 3. On the other hand, terminal 6, which carries signal having inverted phase of the signal carried by terminal 3, will also pick up energy coupled from terminals 5 and 7. However, energy coupled into terminals 3,6 from terminals 2 and 7 can not be suitably eliminated because terminals 3,6 is unlikely to establish couplings between terminals 1 and terminals 8 to balance the couplings between terminals 2,3 and 6,7. Accordingly, signals transmitted by terminals 3,6 carry noises generated by their adjacent terminals 2,7. In addition, terminals 3 and 6 will also carry noises coupled thereto from terminals 4,5 and which couplings should be also carefully taken to avoid certain noises. In order to decrease the effects of electrical coupling between the (3rd, 4th) and (3rd, 2nd) terminals, and (6th, 5th) and (6th, 7th) terminals, many approaches have been provided, such as creating electrical couplings between 3rd and 1st terminals and 3rd and 5th terminals, to balance the electrical coupling between the 3rd and 2nd terminals and 3rd and 4th terminals, and creating electrical coupling between 6th and 8th terminals and 6th and 5th terminals to balance the electrical couplings between the 6th and 7th terminals and 6th and 4th terminals. However, as mentioned above, those eight terminals are arranged in a common plane, it is impossible to create those balancing electrical couplings, i.e. (1st, 3rd), (3rd, 5th), and (4th, 6th), (6th, 8th) terminals when all terminals are located in the same level, it is unlikely to create any electrical channels therebetween to create those electrical couplings accordingly. The Siemon Company, a U.S. company, discloses a solution posted on the Internet, http://www.siemon.com/white papers/99-08-30-through-hole.asp. A hard copy thereof will be submitted with IDS for reference. As clearly shown in FIG. 4 of that reference, 6th and 2nd terminals are arranged in the first layer, while 8th, 5th, 4th, and 1st terminals are arranged in the second layer, and 7th and 3rd terminals are arranged in the third layer. The 6th terminal in the first layer has a rectangular loop having its longitudinal sides aligned with terminals 4th and 8th located in the second layer, while terminal 3 in the third layer also has a rectangular loop having its longitudinal sides aligned with terminals 5th and 1st located in the second layer. In addition, the right longitudinal loop side of the terminal 6th further includes a square corresponding to a square formed in terminal 4th. The left longitudinal loop side of the terminal 3 includes also a square with respect to the square formed on terminal 8th. Arrangements suggested by Siemon are to increase the couplings between (1st, 3rd) (3rd, 5th) and (4th, 6th), (6th, 8th) terminals thereby helping to balance electrical couplings of the terminals. However, those eight or four set sets of terminals are arranged in three different layers, and each set of terminals are separately divided by an insulative sheet material. This will no doubt increase the complexity of the connector. In addition, there are five different shapes and configurations among those eight terminals. Each terminal has its own shape which is different from each other, especially the 3rd and 6th terminals, each including the rectangular loop portion which overlap to corresponding terminals to create wanted electrical couplings. Each loop further forms the square to increase the electrical couplings with corresponding terminals having the square. The electrical couplings created can help to meet higher system requirement. The eight different configuration of the terminals will surely increase the difficulty and complexity in production. There are some other approaches that including routing terminal tails of those 3rd, 6th and 4th, 5th terminals to alter their position and affect couplings between 3rd, 2nd and 3rd, 4th; and 6th, 5th, and 6th, 7th terminals. However routing terminal tails will inevitably increase the manufacturing cost. U.S. Pat. No. 6,120,329 issued to Steinman on Sep. 19, 2000, discloses another approach to solve the above-addressed problem. Again, terminals are configured with different shapes and dimensions making the production complex. U.S. Pat. No. 5,069,641 issued to Sakamoto et al. discloses a suggestion of using printed circuit board in the RJ modular housing, however, it addresses to different issues. It is an object of this invention to provide an RJ modular connector, and more particularly to a RJ modular connector having a substrate with conductive traces provided therein to balance electrical couplings between terminals. It is still an object of this invention to provide a RJ modular connector which can be easily manufactured. In order to achieve the objective set forth, an RJ modular connector in accordance with the present invention comprises a housing defining a plug receiving section, and a terminal core receiving section. A terminal core is received in the terminal core receiving section and includes a plurality of terminals. A substrate is provided having conductive trace thereon. The terminals are securely mounted onto the substrate. An electrical connection is established between a first terminal and the conductive trace, and a portion of the conductive trace is arranged to create a first electrical coupling between the first terminal and a third terminal thereby balancing a second electrical coupling between the first terminal and a second terminal arranged between the first and third terminals.	null	minipile	NaturalLanguage	mit	null
Q: Spring JPA query findByNameAndType returns null I have an interface public interface IAllAccountsRepo extends CrudRepository and a method in that like below @Query(value = "SELECT * FROM account a where a.id in :id AND a.accountType = :accountType", nativeQuery=true) public AccountEntity findByIdAndAccountType(@Param("id") String id, @Param("accountType") String accountType); When i call this method in a helper class, where I will get a list of ids and I loop through them and pass in a filter value to the above method, but i have issues when there is no record matching the query in the database. It just stops by saying null(when there is no record in db). I do not want to through exception, need to ignore and proceed if i can do that. Is there anyway i can code it to ignore the null and proceed? or do i need criteria query or any other? for (String id : accountIdList) { accountEntityTemp = iAllAccountsRepo.findByIdAndAccounttype(id, accounttype); System.out.println("bs" + accountEntityTemp.getId()); if (accountEntityTemp != null) { accountsEntityList.add(accountEntityTemp); } } accountEntityTemp = null for one id and accounttype and i'm getting the below error. 2015-12-10 14:20:03.784 WARN 10524 --- [nio-8080-exec-1] .m.m.a.ExceptionHandlerExceptionResolver : Handler execution resulted in exception: null Thanks. A: Uhm... First of all please.. @Query(value = "SELECT * FROM account a where a.id =:id AND a.accountType = :accountType", nativeQuery=true) public AccountEntity findByIdAndAccountType(@Param("id") String id, @Param("accountType") String accountType); That being said... Just.. why? You're extending crudrepository, so you could as well just write AccountEntity findByIdAndAccountType(String id, String accountType) IF your attributes on AccountEntity bean are named Id AccountType or change id to Integer, as I don't know its type.. plus man, some care of potential NPE.. you told us it's possible no accountentity is found... yet you do accountEntityTemp = iAllAccountsRepo.findByIdAndAccounttype(id, accounttype); System.out.println("bs" + accountEntityTemp.getId()); /// Null pointer here potentially... if (accountEntityTemp != null) { accountsEntityList.add(accountEntityTemp); } at most change it to accountEntityTemp = iAllAccountsRepo.findByIdAndAccounttype(id, accounttype); if (accountEntityTemp != null) { System.out.println("bs" + accountEntityTemp.getId()); accountsEntityList.add(accountEntityTemp); }	null	minipile	NaturalLanguage	mit	null
Q: expanding and collapsing menu items I have a menu made of divs containers and when I mouse over the menu item i want to exand the next element that has a class called container the thing I want to know is when they are expand and I go back to the previous div like back two divs I want the others to contract there widths so if three divs are open and i go back to the first div container the last or others in front contract there width to 0 except the next div cos it displays the next menu items how do do this any examples would be appreciated. <div class="container> <div class="menu"> <div>Menu Item 1</div> <div>Menu Item 2</div> <div>Menu Item 3</div> <div>Menu Item 4</div> </div> </div> <div class="container> <div class="menu"> <div>Menu Item 5</div> <div>Menu Item 6</div> <div>Menu Item 7</div> <div>Menu Item 8</div> </div> </div> <div class="container> <div class="menu"> <div>Menu Item 9</div> <div>Menu Item 10</div> <div>Menu Item 11</div> <div>Menu Item 12</div> </div> </div> $('.container .menu .menu-item').mousenter(function() { $(this).closest('.container').next('.container').css('width' 200); }); A: Wow, that was a long sentence...please use punctuation (and run grammar check). In answer to your question, you could set all the containers' widths to 0 before running the next line of your code, like this: $('.container').css('width': 0); $(this).closest('.container').next('.container').css('width' 200); If you use this method you should probably also save $('.container') in a variable for better performance. Is that what you wanted to do? If not, please explain your question a little more clearly.	null	minipile	NaturalLanguage	mit	null
Category: India East Godavari District, Andhra Pradesh, India (2nd May 2010) While India is known for its sweet tooth and a range of tasty sweet foods, I have seldom seen how they are actually made. Fortunately, I got this opportunity rather unexpectedly while travelling through the villages of East Godavari district in the Southern Indian state of... Continue Reading →	null	minipile	NaturalLanguage	mit	null
Q: Qt の GridLayout にて、予め指定したグリッド数でカラムを分割したい Qt上のグリッドレイアウトで悩んでいますいくつかのカラム数に分割してラベルを配置したいのですがあらかじめ縦横の分割数を設定することは可能でしょうか lblDummyMainUpLeft = new QLabel(); lblDummyMainBottomRight = new QLabel(); //左上 lblDummyMainUpLeft->setText("topleft(0,0)"); lblDummyMainUpLeft->setStyleSheet("border:2px solid red;"); //右下(4,5)のところに配置したい lblDummyMainBottomRight->setText("bottomright(4,5)"); lblDummyMainBottomRight->setStyleSheet("border:2px solid red;"); //QGridLayout上に配置 gridmain->addWidget(lblDummyMainUpLeft,0,0,1,1); gridmain->addWidget(lblDummyMainBottomRight, 4, 5 , 1 , 1); //●Y=1,X=1に配置されてしまう本当は細かく分割した箱があって、2個目のラベルを右下に配置したいのですが、2分割しかされませんでしたあらかじめ縦横の分割数を決定しておくことは可能でしょうか・・・まあ、透明なラベルを個数分敷き詰めれば上手く行くと言えば行くのですがちょっとスマートじゃないな・・と・・ A: ありがとうございます。複数の解像度で動作して、基本は等間隔で並ぶのでカラムごとに最小、最大を一々求めるのは上手く行かなかったですとりあえず、あらかじめダミーのラベル(この場合は横に5列、縦に4列)のからのラベルを敷き詰めてそれから本命のパーツをはめ込んで上手く行ったのでそれで解決としました	null	minipile	NaturalLanguage	mit	null
Extra Credits Extra Credits is a video lesson series currently presented by James Portnow, narrator Matt Krol, and artists David "D" Hueso, Lilienne "Lil" Chan, Scott DeWitt, Nick DeWitt, and Dan Jones. The series of videos discuss issues pertinent to video games and game studies, particularly discussing issues concerning video game development, addressing the legitimacy of video games as art, and creating intellectual discourse on important issues in gaming culture. The series was developed directly from a series of lecture videos by animator Daniel Floyd, informally known as "Video Games And...", which ran sporadically from February 17, 2008 to April 16, 2010 with certain episodes written by Portnow. The series originally aired on The Escapist from July 28, 2010 to August 10, 2011, before being split off over a financial dispute. Between September 7, 2011 and December 31, 2013, the show aired on PATV, a distribution channel hosted by Penny Arcade, whose downsizing of partner services after the latter date was cited as the reason for the show's subsequent "move" to YouTube, where the show is currently aired. In addition, the episodes have been syndicated on many websites, including ScrewAttack. History 2008-2011: Beginnings The series has its roots in 2008 when co-creator Daniel Floyd created two video presentations for his respective art history and media theory classes at Savannah College of Art and Design. Floyd states that the style of his presentations was "loosely modeled" after Zero Punctuation. The assignment had a time limit of ten minutes, so Floyd sped up his voice by 10% to meet that limit, an effect that continued in subsequent episodes. He put it on YouTube just to see if anyone had interest and to his surprise the videos viewers hits grew very large very quickly. James Portnow had been referenced in these early videos and decided to contact Floyd about the possibility of working together to make more videos. Portnow wanted Dan to continue using his original created format of videos with animated Dan giving lectures at the podium about articles that would be written by Portnow. These were not part of an officially-named series, though this early collection eventually went by "Video Games and...". A blog maintained by creator Floyd for the videos used the secondary title "Talking About These", and certain videos also went by "Game Design Corner". One episode also features journalist Leigh Alexander from Gamasutra in a discussion about video games and their female audience. In July 2010, an announcement was made that the series would be a featured series for The Escapist, where weekly episodes of the series began, as well as the introduction of the new title, Extra Credits. Since Floyd had started working at Pixar Canada at the time, Portnow also enlisted colleague Allison Theus to handle the art. The first episode, "Bad Writing", debuted on July 28 and would since be on The Escapist for the next year. In May 2011, The Escapist and the show's creators hosted the Extra Credits Innovation Awards at LOGIN 2011, which was meant to praise developers who were willing to take risks and push the boundaries of video games as a medium. Awards were intentionally nonstandard compared to other awards frequently presented, focusing on ingenuity rather than success, including the categories: Innovation in Game Design, Innovation in Narrative Delivery, Most Unbelievable Awesome Fun, Genre Buster Award, Positive Impact Innovator, and LOGIN Special Award for Innovation in Multiplayer. 2011-2016: Dispute and revival On June 28, 2011, Portnow announced through the show's Twitter account that Theus had a radial tear in her shoulder (likely a separated shoulder) that could potentially end her career. A two-month crowdfund project on RocketHub was created with a goal of $15,000, which eventually raised around $104,000. The crew, overwhelmed at the response, decided to start an independent game publisher with the excess profits. Around the end of July, The Escapist privately contacted Portnow with a disputing claim for the funds. Alexander Macris, then-content director for The Escapist, led the claim and stated the money should have been used to create more episodes of Extra Credits and to compensate parent company Themis Media for donation incentives, such as premium memberships and T-shirts. As a result, Extra Credits broke ties with The Escapist, and after a brief four-week stint posting directly to YouTube, the show was picked up by Penny Arcades PATV network. The indie fund would ultimately be created under Extra Credits LLC, which was started on November 18, 2011 and holds the show's unregistered IP rights. Starting with episode 100, Elisa "LeeLee" Scaldaferri (creator of former Escapist webcomic Name Game) became an official staff artist for the show, to rotate episode productions with Theus. Later, Theus departed from the series to work full-time at Retro Studios (though she still contributes to spin-off mini-series) and was replaced by webcomic artist Scott DeWitt. In December 2013, Penny Arcade announced the downsizing of its services, including the detachment of Extra Credits and other partner shows from PATV. The crew announced that their official YouTube channel, which was previously intended to be an outlet for syndication, would become the official release outlet starting at the beginning of 2014. The first videos officially released since then were a previously-broadcast live Q&A video and the episode "The Good We Do". 2017-present: New team and departures On 2017 the show's Twitch channel was relaunched, with nightly hosts including Echo Diaz and Will Overgard. On May 23, 2018, in the episode "Choice Paralysis - Too Much Of A Good Thing", Daniel Floyd announced that he and Carrie would be leaving Extra Credits, and that Matt Krol would take over as new narrator and showrunner. Krol was a television producer and podcast host who frequently guest hosts with Portnow on the show's Twitch channel. A series of Extra History and a spinoff called Extra Politics were completed ahead of the announcement and aired throughout June of that year. On October 30, 2019, however, in the episode "The Perfect Horror Protagonist - Writing a Character for Fun & Terror", Krol mentioned that James Portnow, the only member of the original lineup, is leaving Extra Credits after 10 years of being the show's writer, even though his scripts will be used for future episodes. Members Controversy Will Overgard was laid off after a harassment claim was privately reported, though the exact events are disputed. On June 9, 2018, former media director Soraya Een Hajji went public on Twitter about leaving the show due to growing tensions with Portnow after their romantic relationship had ended. Extra Credits responded with a statement on their website in which they confirmed there had been a complaint but stated that an investigation "found no evidence of improprieties with regards to the claims of workplace harassment." Format The show is presented in the style of a lecture hall, and addresses the topic of the week with illustrations and random imagery from various sources on the internet, with a strong focus on visual puns. The tone is generally light-hearted and often humorous, but always didactic, intended to educate the audience and encourage discussions on the presented subject. Generally, the show's topics target the perspective of a game designer rather than average gamers. The opening song, "Penguin Cap" by CarboHydroM, is a cover of the "Slide" music cue from Super Mario 64. Ending songs vary between episodes, but are typically sourced from OverClocked ReMix, where Floyd was a former contributor. Notably, Floyd hinted occasionally about another arrangement from CarboHydroM that he wanted to use as his departing outro song, which was revealed to be a cover of the end credits music from Super Mario Kart called "Secret 1000cc Mode" on his final Extra Credits episode in May 2018. Extra Credits for most of its history was produced and narrated by Floyd, who used pitch-shifting to create a unique, high-pitched voice. Portnow is credited for writing episode scripts, which are refined by Floyd or Krol for recording. Floyd was also responsible for editing videos, but later assigned these duties to his wife, Carrie. Original art was drawn by Theus in the first years of the show, but episodes were split between Scaldaferri and DeWitt. Since October 2014, episodes have been split between Dan Jones and DeWitt. Occasionally, guest artists have been invited during production droughts and spin-off series, most notably webcomic artist Erin Siegel, who had made repeated appearances. While Extra Credits discusses new topics every week as they apply to video games, there are some topics which are more frequently addressed than others, including: poor narrative creation, level design, gamification, tangential learning, sexuality and gender discrimination both within games and in the gaming community, and diversity in games (including gender, sexuality, and racial diversity). The show is also frequently critical of the triple-A video game industry. Extra Credits is also a big proponent of independent developers, although it has been frequently stated that they don't want to see only "art house" games either. "No one on this show wants every game to try to be gaming's Ulysses or even gaming's Blood Meridian. But we really would like to see a few more Mass Effects, Portals, Bioshocks, even Call of Duty 4s." Business operations have been handled by Kate Donaldson until the end of 2013, and have been handled from then until 2018 by Soraya Een Hajji, who is also a volunteer director for GaymerX. Een Hajji also began writing Extra History in 2017 to assist Portnow in scheduling. Community July 1, 2011 marked the creation of a fan-operated community surrounding Extra Credits with a Steam group indirectly started in response to Theus' injury, and which was supported by Portnow. Group chat sessions ultimately led to the creation of a web forum, Extra Curricular, during the night of the 15th. The forum was publicly acknowledged by Portnow on July 21 and August 25, and was re-launched on a new official domain for the show around January 10, 2012. Meant for PAX East 2012, a tribute video to Extra Credits was also made featuring some fans and colleagues of the crew. This was the basis for an independent testimonial program. After Extra Credits had established its home on YouTube, on January 12, 2016, plans were announced to shut down the official website, including the Extra Curricular forum. The forum was independently spun off as Bonus Points, while a semi-official Discord server was established to fill the community gap and a new official website was launched in late 2017. On August 6, 2018 Extra Credits announced their first game jam hosted on itch.io, running from August 16 - August 18. The jam hosted 1,158 participants, and finished with 328 entries, a little over 28% participation (an average game jam has approximately 25% participation). In a blog post following the jam, Extra Credits indicated they would like to host more events like the jam and "By hosting more opportunities in the future for people to creatively collaborate, we hope that more people are enabled to make cooler things--because learning matters." Serials Since partnering with PATV, all official episodes have been re-categorized into seasons of 26 each for technical constraints on their site. The only videos to not follow this format are the pre-Escapist videos, which are exclusively held by Floyd but have each been eventually replaced by updated official episodes. Mini-series and spin-offs During the show's run, the creators have been occasionally requested to create game-specific mini-series based on Extra Credits. The first one was Extra Credits: Firefall, which spanned 5 episodes and was requested by Red 5 Studios to help reinforce the game design decisions in their video game Firefall. After moving to YouTube, the team decided to make use of their space to expand their channel with new series running on different days of the week. First announced on March 24, 2013 and debuted 4 days later, James Recommends is an extension of previous "Games You Might Not Have Tried" episodes of the main series, and features Portnow discussing the merits of less-popular games which he finds unique. The following week, Floyd announced Extra Remix, which features spotlights on promising members of the video game music community, namely through OverClocked ReMix. Portnow also brought in colleague Dan Emmons to run Design Club, a series supplemented by live streams in which Emmons discusses the merits of design as they pertain to specific games or levels. Extra Frames is a series of videos produced by Floyd in which he discusses video game animation, which has since rebranded to New Frames Plus(see PlayFrame below). A new series began in late 2017 titled Extra Sci-Fi, which examines works of science-fiction and their cultural impact. Another spin-off, titled Extra Mythology, began in early 2018, examining myths from different early religions. On June 4, 2018, Extra Credits launched an 8-episode mini-series named Extra Politics that exploring the United States political system from a game design perspective. Extra HistoryExtra History is a spin-off on the main channel focused on topics in history. It started out as a mini-series requested by Creative Assembly to deal with the Punic Wars, in which their video game Total War: Rome II was set. On August 23, 2014, the crew announced a campaign through Patreon to fund the continuation of Extra History full-time. This campaign gained over $2,500 within a 24-hour period, and as of June 2018 lists over $15,000 in monthly pledges. Topics are chosen by a monthly poll seeded with suggestions made by Patreon supporters. The show has its own dedicated staff, including art by David Hueso, Lilienne Chan, and Nick DeWitt, and music by Dean and Sean Kiner. Twitch channel The show's official Twitch channel was launched in 2013 as a live supplement on certain weekdays. It originally ran with Design Club Live and Allison's Art Corner, hosted by Dan Emmons and Allison Theus respectively. Emmons departed within a few years, and the channel went dormant. It was relaunched in 2017 with the hiring of professional streamer Will Overgard to be production lead for the channel. Overgard frequently streamed video games on the channel until his removal in April 2018. Various gameplay and discussion streams have since been aired by Echo Diaz, David Hueso, James Portnow, and Matt Krol. PlayFrame Extra Credits launched a sister channel called Extra Play on December 14, 2014, but it did not become active until October 2015, when Side Quest, a Let's Play series of Dark Souls with Floyd and Portnow, was moved from the main channel to Extra Play. The purpose of this channel is to provide a place for the team to post more casual, less-scripted videos that wouldn't fit on Extra Credits. Besides Side Quest, the channel runs several other let's play series. In Guest Play, Floyd brings in people who also work in the gaming industry to discuss design elements in video games, which often features other members of the Extra Credits team. Floyd also started an unnamed series of videos discussing animation in video games, which has since been named Extra Frames and moved to Extra Credits on May 5, 2016. Portnow has started Destiny Whaaat? and Tea & Hearthstone. He discusses questionable design choices in Destiny in the former and analyzes aspects of Hearthstone in the latter. Dan Jones, one of the artists of Extra Credits has started a Pokémon Nuzlocke Challenge of Pokémon Diamond. Since leaving Extra Credits, Floyd took personal ownership of the channel (as well as Extra Frames series, see Mini-series and spin-offs above) and renamed it PlayFrame''''', with future content to be announced. References External links Official site Category:2008 web series debuts Category:Non-fiction web series Category:American web series Category:Internet properties established in 2010 Category:2010 web series debuts Category:Online edutainment Category:Gaming-related YouTube channels Category:Video game critics	null	minipile	NaturalLanguage	mit	null
Introduction ============ Pregnancy involves a greater risk of malaria[@B01]. The prevalence and severity of gestational malaria (GM) that occurs during pregnancy has been studied in Africa, Latin America, Oceania and Asia[@B02]. What is known about GM and placental malaria (PM) relates to Plasmodium falciparum and very little is known about the role of P. vivax [@B03]. Gestational malaria patients usually present with anemia[@B04]. A review of seven Latin American studies on GM confirms the clinical effects of the infection with P. falciparum as the main causing species[@B05]. During a normal pregnancy the immune response undergoes specific changes to allow successful implanting and development of the fetus. Therefore, a Th2 profile is observed in successful pregnancies, while presence of a Th1 cytokine (pro- inflammatory) profile results in spontaneous abortion due to direct cytotoxic effects on the trophoblast. Plasmodium infection in the mother changes the protective cytokines balance and increases the Th1 responses leading to complications such as anemia, abortion, stillbirth, low birth weight, among other. The normal anti-inflammatory status observed in the uninfected placenta is mediated by the increased production of cytokines, such as interleukin (IL)-10, and transforming growth factor β (TGFβ) which probably suppress the immune response mediated by cells. During GM-PM, this type of response is required to control symptoms, while the parasite is cleared by other mechanisms [@B06]. The most studied cytokines in the physiopathology of P. falciparum GM are tumor necrosis factor (TNF), gamma interferon (IFNγ) and IL- 10, but other cytokines and chemokines have also been explored[@B07]. Many cytokines changes during GM-PM might be involved in the pathogenesis of gestational malaria resulting in low birth weight, intrauterine growth restriction, and preterm delivery. During placental infection, increased production of TNF and IFNγ results in injury of the villous trophoblast[@B08]. Furthermore, macrophage inflammatory protein 1-beta (MIP-1β), TNF and IL-8 have been associated with low birth weight and intrauterine growth restriction; and Interleukin 1β, IL-6, IL-8 and TNF have all been involved in pre-term delivery[@B09] ^,^ [@B10]. Accumulation of inflammatory cells, particularly macrophages and monocytes, in the inter-villous space, results after increased MIP-1β. Consequently, both the trophoblastic morphology and placental cytokine production are affected [@B11]. About 25% of women with GM have placental monocyte infiltrates at the time of delivery and this has been identified as a key factor and predictor of low birth weight. It has been suggested that infiltrating monocytes represent a significant source of pro-inflammatory cytokines in the infected placenta[@B12]. Currently, no reports have been made on the immune balance during GM-PM by P. vivax, a species highly endemic in Asia and America. The aim of this research was to describe the expression profile of the pro-inflammatory cytokines TNF, IFNγ, IL-1β, the anti-inflammatory cytokines IL-10, IL-6, TGF-β and the chemokines IL-8 (CXCL8), MIP-1 β (CCL4) and MCP-1 (CCL2), in pregnant women and placentas infected with P. vivax at the time of delivery as well as to describe the association with clinical and epidemiological characteristics. Materials and methods {#s1} ===================== Study site {#s1a} ---------- The study was carried out in north-west Colombia in the locality of Puerto Libertador (Cordoba department). Between Antioquia and Cordoba departments lays the malaria endemic region known as Uraba-Altos Sinu/San Jorge-Bajo Cauca, which has an estimated area of 43,506 km2 and a malaria at-risk population of 2.5 million distributed in 35 municipalities. This large region generates over 60% of malarial cases in Colombia: 18% in Córdoba and 42% in Antioquia. P. vivax predominates over P. falciparum malaria in approximately a 2:1 ratio[@B13]. In 2006-2007, Antioquia and Córdoba contributed, on average, 61,458 cases of malaria, or 60.2% of the total for Colombia. Those two departments during the same years contributed 72.1% of the cases of P. vivax, 34.4% of the cases of P. falcpiarum, and 45.7% of the cases by both especies[@B14]. Subjects for the current study were recruited at the local hospital and the antenatal clinic of \"CAMU Divino Niño\", in Puerto Libertador. Study type, design and sample size {#s1b} ---------------------------------- Volunteers were enrolled as part of a descriptive, prospective and transversal study, between June 2010 and June 2012. The sample size was defined by convenience and the lengthy period of recruitment was the result of severe and prolonged political turmoil in the region, which also jeopardized a random inclusion of subjects. Therefore, recruitment took place in a sequential fashion until the sample size for the study was reached. Subjects were grouped as follows: a) parturient women with P. vivax GM at delivery (GM+); b) healthy pregnant women without GM during pregnancy and at childbirth (GM-). Recruitment took place regardless on the presence clinical signs of malaria infection at the time of diagnosis. Thirty-five pregnant participants were enrolled: 15 with GM at delivery (GM+), and 20 without GM at the antenatal clinic or at delivery (GM-). Criteria for inclusion and exclusion {#s1c} ------------------------------------ Inclusion criteria were\>1 year residency in the study region, general good health and no history of serious disease, signature of the voluntary consent form, hospital delivery and attendance to at least three antenatal check-ups. Exclusion criteria were withdrawal of the voluntary consent and the finding of a PCR positive for P. falciparum infection. Collection of clinical data {#s1d} --------------------------- Clinical data were collected after review of the antenatal clinical records and delivery charts. Information on mother´s age, weeks of gestation, parity, mother´s hemoglobin and newborn weight, was recorded. Sample collection and preparation {#s1e} --------------------------------- Whole blood samples from mother´s peripheral blood and placenta were obtained at delivery rooms in the local hospitals of Puerto Libertador. The mother\`s sample was obtained by finger prick and placental blood was obtained from the lake formed following a wash with saline (0.9%) and removal of a 3x3x3 cm section in the area of the cord\'s insertion on the maternal side of the organ. These samples were used to perform thick and thin smear examination and PCR as detailed below. In addition, 4ml of maternal peripheral blood were collected and immediately stored in liquid nitrogen, this and a RNA later^(r)^ preserved tissue fragment obtained from the placenta, were processed for expression of cytokines and chemokines. Diagnosis of Plasmodium infection {#s1f} --------------------------------- The presence of Plasmodium vivax was confirmed in maternal and placental blood by thick smear and a nested polymerase chain reaction (PCR) according to standard published methods[@B15] ^,^ [@B16]. Diagnosis by microscopy was carried out in the field site by a trained technician with certified experience in malaria diagnosis. Parasitaemia was calculated after observation of fields corresponding to 200 leukocytes and a constant of 8,000 leucocytes/μL. A sample was considered negative after observation of 500 high power fields. Diagnosis of infection by PCR was performed to whole blood samples collected onto Whatman 3MM filter paper, from which DNA was extracted using Chelex100^(r)^ (Sigma(tm)). Amplification was carried out using a nested PCR assay to detect the 18 s rRNA gene of P. vivax, according to previously published procedures[@B16]. The positive reaction control consisted of DNA from a well characterized field isolate of P. vivax. Amplification products were resolved in a 2% agarose gel using ethidium bromide and visualized under UV light. Samples were processed once as long as controls were confirmed to operate in optimal conditions, otherwise, the assay was repeated until successful performance of controls. For the GM+ group, at least one positive test was required for allocation and all tests were required negative for the GMC- group. Term definitions {#s1g} ---------------- The following definitions were applied: A) Low birth weight: \<2,500 grams. B) Preterm delivery: a pregnancy concluded before 37 weeks. F) Maternal anaemia: haemoglobin \<11 g/dL, G) Full term pregnancy: \>38 weeks. H) Gestational or pregnancy malaria: plasmodial infection diagnosed in a pregnant woman after examination of maternal peripheral blood. I) Placental malaria: plasmodial infection diagnosed in placenta after examination of placental blood. Cytokines and chemokines expression analysis {#s1h} -------------------------------------------- Relative quantitation for expression analysis was performed using a reverse-transcription real time PCR assay (RT-PCR). Total RNA was extracted using QIAamp RNA Blood Mini^(r)^ (QIAGEN) and cDNA was synthesized using First Strand cDNA Synthesis^(r)^ (Fermentas). The quality of the cDNA was confirmed by using a conventional PCR for the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene. The reaction was set up in an Applied Biosystems Step One Plus system using TaqMan^(r)^. Results were read at 530 nm. the following genes were analyzed for expression: TNF, IFNγ, IL-1β , IL-10, IL-6, TGF-β, IL-8, MIP-1 and MCP-1 . The efficiency of the PCR reactions was determined based on mRNA extracted from a stimulated BeWo cell culture or peripheral mononuclear cells from a donor. cDNA was serially diluted and expression of β-actin was used to normalize the assays using the delta delta CT method (ΔΔCt). The reaction was performed in a final volume of 10 uL containing 1 uL DNA, 5ul TaqMan(r) master mix (Applied Biosystems), and 0.5 uL of 20X TaqMan assay mix (primers and probes for each cytokine/chemokine). All primers were supplied by Applied Biosystems. Reactions were performed at Laboratory of Tropical Diseases of the University of New Mexico, USA. Statistical analyses {#s1i} -------------------- Data were analyzed using SPSS 10.0 (SPSS IBM, Armonk, NY). Proportions and medians were obtained. Significance was established at p\<0.05%. The analysis included comparisons with using Mann-Whitney U test. Bivariate linear correlations were analyzed using Spearman´s rho coefficient. Ethical issues {#s1j} -------------- The study protocol was reviewed and approved by Ethics Committee of Instituto de Investigaciones Medicas, Universidad de Antioquia (acta 012: project Colciencias code 111549326134, contract 611 de 2009). Volunteers were recruited in accordance with national guidelines (Resolution No. 008430 of October 4, 1993, Republic of Colombia, Ministry of Health), as well as international guidelines (Declaration of Helsinki and its amendments, World Medical Association (WMA), Edinburgh, Scotland, October 2000). Subjects were assigned a code which was known only by the researchers. Results {#s2} ======= Characteristics of the population studied. {#s2a} ------------------------------------------ A total 35 pregnant women were included in the study, 15 were allocated to the GM+ group and 20 to the GM-. . No significant differences were observed in the clinical and epidemiological variables between the two groups ([Table 1](#t01){ref-type="table"}). In both groups, there was a significant linear correlation between age and parity (rho = 0.868, p = 0.000) and parity and birth weight (rho = 0.628, p = 0.000). Pre-term delivery was observed in the GM+ group and absent in the GM- group. Table 1Characteristics of the study groups with and without gestational malaria Expression of pro-inflamatory/anti-inflamatory cytokines and chemokines in placental tissue and maternal peripheral blood. {#s2b} -------------------------------------------------------------------------------------------------------------------------- When comparing the expression of pro-inflammatory and anti-inflammatory cytokines in placental tissue in the GM+ and GM- groups, an increase in the levels of pro-inflammatory cytokines (TNF, IFNg and IL1β) was observed in the former. Significance in this finding was confirmed for TNF. Regarding the anti-inflammatory cytokines, these were lower in the GM+ group versus the GM- group; however, no significance could be confirmed in this result. Similarly, the chemokine MCP-1 was observed high in the GM+, but no significant difference was confirmed ([Table 2](#t02){ref-type="table"}). Table 2Levels of cytokine and chemokine expression in the placental tissue of pregnant women with malaria by P. vivax at delivery (P+) and without it at delivery or during prenatal care (PC-). In maternal blood, all changes were not statistically significant. However, pro-inflammatory cytokines (TNF, IFNg and IL-1β) were higher in the GM+ group with respect to the GM- group. In addition, all anti-inflammatory cytokines, but TGF-β, were increased in the GM+ group when compared to GM-. As for the chemokines, IL-8 and MIP-1 were lower, and MCP-1 higher, in the GM+ group when compared to GM-. Table 3Levels of cytokine and chemokine expression in maternal peripheral blood of pregnant women with malaria by P. vivax at childbirth (GMP+) and without it at birth or during prenatal care (GMP-C-). Discussion ========== This reports for the first time on the status of cytokines and chemokines in women with GM in a P. vivax endemic region of America. The technique used to measure the expression of immune mediators is precise and sensitive. Volunteers were selected from the general population, particularly those regularly attending the hospital facilities in Puerto Libertador. Therefore, the study represents the typical population which seeks health services in the region. An obvious limitation in this work is the reduced number of women with GM, which is the result of the current socio-political instability in the area. Despite the small sample size, the results obtained are consistent and suggest a clear trend. The study contributes to outline the epidemiology of malarial infection during pregnancy in a highly endemic region of the country, since it includes subjects whose peripheral and placental blood was monitored for P. vivax infection using standard microscopy and contributes with the evidence, so far gathered, on the deleterious effects of this species [@B17]. Other authors have reported on the particular predisposition to acquire malaria, regardless of the species, according to mother´s age, parity and gestational age [@B18]. In the current study, women in the GM+ group were younger, with less parity and fewer weeks of pregnancy than those in the GM- group. Others have also reported on P. vivax as responsible of low birth weight, maternal anemia and preterm delivery[@B17]. In this study, no significant differences were observed on mother´s haemoglobin levels or the newborn´s weight. However, children born from mothers with GM+ had a mean 215g less weight. In addition, preterm delivery occurred in high proportion (18%) in the same group. Preterm delivery is a recognized cause of neonatal mortality [@B09] ^,^ [@B19]. Pro-inflammatory and anti-inflammatory cytokines and chemokines were found altered during GM by P. falciparum and this was associated with abortion, stillbirth, preterm delivery, intrauterine growth restriction, low birth weight and maternal anemia[@B04] ^,^ [@B20]. However, for P. vivax there is no report on this matter. We found an increased expression of all pro-inflammatory cytokines studied, both in maternal peripheral blood and in placental tissue. Although differences between the groups were not significant, the probability values observed strongly suggest that the sample size might have influenced this outcome. Similar to the findings herein reported, studies with P. falciparum GM also showed increased expression of TNF and IL1β but not IFNγ [@B21] ^,^ [@B22] ~.~In other reports on P. falciparum GM, increased TNF has been associated with fetal growth restriction, spontaneous abortion and maternal anemia [@B22] ^,^ [@B23]. Likewise, the increase in IL-10 has been associated with preterm delivery and increased IFNγ with spontaneous abortion. The beta chemokine MCP-1 has also been reported to increase in GM and PM by P. falciparum [@B24] ^,^ [@B25] and it has been associated with immune cell recruitment in the placenta, specifically monocyte. This chemokine might also be involved in mononuclear recruitment in P. vivax infected placentas. Moreover, a rise on IL-8 has been reported in placentas with active P. falciparuminfection [@B10] ^,^ [@B26]. In the current study, monocytes-macrophages infiltrates (data not shown) were observed in infected placentas and the concomitant finding of high IL-8 might explain this observation. Alternatively, other have implicated hemozoin or parasite´s persistence in the immune alterations observed in the placenta during malaria infection [@B27]. In summary, in women with GM at delivery pro-inflammatory cytokines tend to be elevated both in maternal blood and placental tissue, anti-inflammatory cytokines were high in the mother and low in the placenta and the chemokines were reduced in both compartments, but MCP-1 which was observed high in placenta and mother. The results seemed to be strongly affected by the relative small number of women with GM by P. vivax at the time of delivery. To consolidate these findings it is necessary to carry out additional studies with more women both in this region and elsewhere in the country. The authors are grateful to the staff and directives of the Puerto Libertador local hospital, to the patients for their participation and to Zac Karim and Prakasha Kempaiah of University of New Mexico for their assistance in performing some diagnostic procedures. Funding Sources: Universidad de Antioquia-Estrategia Sostenibilidad 2013-2014; Colciencias (project 111549326134). [^1]: Conflict of interest:The authors declare that there are no conflicts of interest.	null	minipile	NaturalLanguage	mit	null
Q: How to edit my query SQL Server to get result faster I tried a query on SQL Server using Java like this SELECT * FROM DATA1 WHERE Project NOT IN (SELECT DISTINCT Project FROM DATA1 WHERE Resource = 'I-FINAL') ORDER BY RECORDID DESC It runs slowly for about 1 minutes. But when I ran it with this query SELECT * FROM DATA1 ORDER BY RECORDID DESC It was really fast about 100 ms. I guess my problem is NOT IN caused it. I do not know to make new query to get result faster. A: You can try an exclusion join: SELECT d.* FROM DATA1 d LEFT JOIN ( SELECT DISTINCT Project FROM DATA1 WHERE Resource = 'I-FINAL' ) d0 ON d0.Project = d.Project WHERE d0.Resource IS NULL ORDER BY d.RECORDID DESC or NOT EXISTS SELECT * FROM DATA1 d WHERE NOT EXISTS (SELECT 1 FROM DATA1 d0 WHERE d0.Project = d.PROJECT AND d0.Resource = 'I-FINAL') ORDER BY d.RECORDID DESC Neither has any guarantee to run faster. The thing that is most likely to be effective is evaluating indexes on the table, but we don't have enough info in the question to tell you what to change.	null	minipile	NaturalLanguage	mit	null
Pages Monday, May 14, 2012 The Foreign Bride (1964) Iran This poster is part of a lot I obtained from an eBay seller years ago. It is safe to say this poster is scarce, because that is true of most Iranian film posters. In any case it was a chance acquisition, one of a very small number of film posters I have from Iran. It was made to advertise a film released during the time of the late shah of Iran. The film itself was not one of the ones that are shown to people who study Persian in American universities, I assume because it was not perceived to have any social significance. For a collector it could be part of a topical collection of posters for films about strange brides. Socially significant or not, according to Iranian film encyclopedist Jamal Omid the film found some commercial and critical success. In 1964 Iranian films that showed signs of religious piety were not nearly as common as they are now, and this one was praised by a Muslim cleric because of a scene in which its protagonist finds a quiet corner to pray. When published this praise helped bring audiences to theaters. It also received a letter of commendation from the Ministry of the Interior Exhibition Commission, the third Delfan Bronze Medal in the international division at the First Ministry of Education International Film Festival as well as the Second Golden Lion Medal. The film was shown at the First Tashkent Festival and was popular with audiences in the Soviet Union. It was also popular with the public in Tehran. The film tells the story of taxi driver Hoseyn who is unable to marry his fiance because of financial problems and is working overtime. He gets involved with a foreign girl named Maria, who soon decides she wants to marry him. After a few incidents the taxi driver decides he prefers to marry his fiance.	null	minipile	NaturalLanguage	mit	null
Recent findings suggest that a significant proportion of the genetic variance in complex psychiatric disorders can be explained by a collection of individually rare, highly penetrant genetic variants. Each of these copy number variants (CNVs) may be a risk factor for disease, and many are non-recurrent and sporadic. Optimally, the identification of specific mutations would result in personalized treatment interventions tailored to the underlying biology of the mutation. We have identified a complex structural rearrangement at 9p24.1 that segregates with psychosis in one family. One gene in the rearranged region, glycine decarboxylase (GLDC), is involved in the degradation of glycine in glia cells and is triplicated in mutation carriers. Glycine is a co-agonist for the N-methyl-D-aspartate receptor (NMDAR). Carriers of the GLDC triplication would be expected to have low levels of brain glycine, resulting in NMDAR-mediated hypofunction, which has been strongly implicated in the pathophysiology of schizophrenia. The carriers of this mutation are strong candidates to benefit from glycine augmentation of their psychotropic drug regimens. One aim of this R21 application is to carry out a proof-of-principle double-blind placebo-controlled glycin augmentation trial in carriers of this mutation and to assess changes in clinical symptoms and neurocognitive function. We also propose to carry out targeted neurobiological follow-up of mutation carriers and non-carriers in the same family in order to characterize the brain structural, functional and neurochemical properties of this mutation. These studies will probe glycine homeostasis using proton magnetic resonance spectroscopy, assess the relationship between brain and plasma glycine levels following an acute oral dose of glycine, and examine brain pathways (magnocellular) implicated in dysregulation of NMDA-mediated neurotransmission. The same procedures (except for the glycine loading scans) will be re-administered to carriers after six weeks of open label glycine augmentation. The results will significantly enhance our understanding of the neurobiology of rare CNVs associated with psychosis and their relevance to disease pathophysiology. More importantly, the results will, for the first time, link pathophysiology and a medically actionable treatment intervention to underlying genetics, with potential benefit to other patients with neuropsychiatric disease who have mutations in either the same gene or in other genes/pathways that are impacted by the same or related aberrant biological processes.	null	minipile	NaturalLanguage	mit	null
Former president Pervez Musharraf knew that Osama bin Laden was hiding in the garrison town of Abbottabad and the Pakistani intelligence itself had made the safe house that sheltered him, a former...... Former PCB chairman Ijaz Butt has welcomed the planned revival of bilateral cricket ties with India, but has asked the BCCI to compensate it financially for the cancelled series of 2009. Butt, who...... Former PCB chairman Ijaz Butt has said that the BCCI's top brass has assured him that the Pakistan players will be allowed to play in the next edition of the Indian Premier League in 2013. Butt met......	null	minipile	NaturalLanguage	mit	null
Function Definition Specifies the mapping of the near clipping plane to window coordinates. The initial value is 0. farVal Specifies the mapping of the far clipping plane to window coordinates. The initial value is 1. Description After clipping and division by w, depth coordinates range from -1 to 1, corresponding to the near and far clipping planes. glDepthRange specifies a linear mapping of the normalized depth coordinates in this range to window depth coordinates. Regardless of the actual depth buffer implementation, window coordinate depth values are treated as though they range from 0 through 1 (like color components). Thus, the values accepted by glDepthRange are both clamped to this range before they are accepted. The setting of (0,1) maps the near plane to 0 and the far plane to 1. With this mapping, the depth buffer range is fully utilized. Notes It is not necessary that nearVal be less than farVal. Reverse mappings such as nearVal = 1, and farVal = 0 are acceptable. The type of the nearVal and farVal parameters was changed from GLclampf to GLfloat for glDepthRangef and from GLclampd to GLdouble for glDepthRange. This change is transparent to user code.	null	minipile	NaturalLanguage	mit	null
Britons will work for 149 days to pay their taxes in 2011, according to respected free-market think tank the Adam Smith Institute. Every penny earned in the UK between January 1 and May 29 will be taken by the taxman to support government expenditure. This means that Tax Freedom Day, the day when people stop working for the government and start working for themselves, will come on May 30 in 2011. The most up to date government statistics suggest that Tax Freedom Day came on May 27 in 2010. This means that Britons will spend three extra days working to pay their taxes in 2011, compared with the year before. The main reason for this is that the government has raised VAT, in order to help reduce the UK’s record budget deficit. “As well as hitting every household in the country, the VAT hike is going to dent consumer confidence and put a dampener on our economic recovery – as the Office of Budget Responsibility has already pointed out.” He added: “The government is right to give priority to cutting spending and plugging the deficit. But as Tax Freedom Day shows, Britons are still desperately overtaxed. The fact that we spend almost five months working for the State – and only seven months working for ourselves and our families – is a shocking indictment of big, wasteful government.” Dr Eamonn Butler, director of the Institute, added: “The coalition should examine the possibility of making targeted tax cuts now to encourage economic growth. But in the long term, they need to fundamentally overhaul the entire tax system. Lower, simpler, flatter taxes would be fairer for individuals, and better for the economy.”	null	minipile	NaturalLanguage	mit	null
INTRODUCTION {#sec1-1} ============ Delayed childbearing, voluntary or involuntary, is a common feature in couples visiting fertility clinics. Majority of the fertility clinics perform ovarian reserve tests (ORTs) as part of the evaluation of women with infertility prior to In Vitro fertilization. Diminishing ovarian reserve is a phenomenon noted in women during mid to late thirties and at times earlier, reflecting the declining follicular pool and oocyte quality.\[[@ref1]\] This age-related decline of follicles in the human ovary is believed to more than double when numbers fall below a critical figure of 25,000 at \~37.5 years of age.\[[@ref2]\] Assuming fixed time differences between reproductive milestones, fertility will not be lost completely for 4 years, on average, following the onset of this phase.\[[@ref3]\] ORTs provide an indirect estimate of a woman\'s remaining follicular pool. An ideal ORT should be easy to perform, reproducible, and the decisions based on their results should help differentiate women with a normal and poor ovarian response. This should in turn help identify and counsel couples with negligible chance of conception against any expensive and repeated treatment. However, the availability of multiple ovarian reserve markers suggests that none is ideal. Largely, these tests have been used in subfertile women prior to the first IVF attempt to predict a poor ovarian response. More recently, their value in predicting hyper-response and thus using safe stimulation regimes to prevent OHSS is also explored.\[[@ref4][@ref5]\] Their role in the assessment of ovarian reserve in subfertile women not necessarily undergoing IVF or in general population, to identify those at the risk of diminished ovarian reserve, is still poorly understood. The initial evidence suggested that various ORTs have a good predictive value for pregnancy.\[[@ref6]\] However, in the recent years it has been understood that these tests are effective in predicting the ovarian response to stimulation and not for the prediction of pregnancy or its outcome.\[[@ref7]\] The interpretation of the results is further complicated by the lack of uniform definitions for poor or hyper-responders and uniform threshold values to identify abnormal results. Biological (age), biochemical, biophysical, and histological tests have been used to identify ovarian reserve \[[Figure 1](#F1){ref-type="fig"}\]. ![Types of ovarian reserve tests](JHRS-4-108-g001){#F1} A literature search was made using the key words "ovarian reserve" and "ovarian reserve tests," using MEDLINE (1966--2011). A total of 308 articles were found. Further searches were made for individual ORTs using their titles as key words. Appropriate cross-references were manually searched. Age {#sec2-1} --- It is long established that ovarian reserve reduces progressively with age.\[[@ref8]\] Fecundity in both natural and stimulated ovarian cycles declines with maternal age, beginning in the late 20s and becoming more abrupt in the late 30s \[[Figure 2](#F2){ref-type="fig"}\]. This decline has been observed in population-based studies,\[[@ref9]\] and in women undergoing ovulation induction or IVF.\[[@ref10]\] Even though fertility does not decline uniformly in women, age is known to be the most important factor determining the pregnancy potential in regularly cycling women.\[[@ref11]--[@ref13]\] However, chronological age alone has a limited value in predicting individual ovarian responses.\[[@ref14]--[@ref17]\] This has led to the development and use of various biochemical and biophysical markers of ovarian reserve. ![Quantitative (solid line) and qualitative (dotted line) decline of the ovarian follicle pool, which is assumed to dictate the onset of the important reproductive events (reproduced and adapted with permission from\[[@ref8]\]).](JHRS-4-108-g002){#F2} Basal follicle stimulating hormone {#sec2-2} ---------------------------------- Basal follicle stimulating hormone (FSH) levels measured on day 3 of the menstrual cycle is the most widely used ORT to assess the ovarian response to stimulation, for over two decades now.\[[@ref14]\] An increase in FSH levels occurs due to follicle depletion. The measurement of FSH is easy, and inexpensive. However, it is known to have diurnal, intra- and intercycle variability.\[[@ref18][@ref19]\] There is no universally accepted cut-off value to identify a poor response. A wide range in threshold values up to 25 IU/L has been used to define abnormal levels of basal FSH. Meta-analysis and systematic reviews have failed to identify any combination of specificity and sensitivity for basal FSH as a test of poor response or prediction of non pregnancy. In regularly cycling women, FSH can predict a poor response adequately only at very high levels, and hence will be helpful only to a small number of women as a screening test, for counselling purposes.\[[@ref20][@ref21]\] It is understood that the ovarian aging begins several years before any elevation in FSH levels is noted and hence a normal test cannot rule out a poor ovarian response in some women. Combined with other markers it can be used to counsel couples regarding a poor response but should not be used to exclude regularly cycling women from ART. The usefulness of basal FSH in a general subfertile population or elevated levels in young, regularly cycling women is unclear.\[[@ref22]\] Anti-Mullerian hormone {#sec2-3} ---------------------- Anti-Mullerian hormone (AMH) is a dimeric glycoprotein exclusively produced by granulosa cells of preantral (primary and secondary) and small antral follicles (AFs) in the ovary. The production of AMH starts following follicular transition from the primordial to the primary stage, and it continues until the follicles reach the antral stages, with diameters of 2-6 mm.\[[@ref23]--[@ref25]\] The number of the small AFs is related to the size of the primordial follicle pool. With the decrease in the number of the AFs with age, AMH production appears to diminish and become undetectable at and after menopause.\[[@ref26]\] AMH levels strongly correlate with basal antral follicle count (AFC) measured by transvaginal ultrasonography.\[[@ref5]\] Unlike other biochemical markers, it can be measured on any day of the cycle\[[@ref27][@ref28]\] and does not exhibit intercycle variability.\[[@ref29]\] Various threshold values, 0.2--1.26 ng/ml, have been used to identify poor responders with 80--87% sensitivity and 64--93% specificity.\[[@ref30]--[@ref32]\] With better understanding of its clinical implications, AMH is now known to have the ability to predict a hyper-response as well.\[[@ref5][@ref33]\] The use of nomograms identifies the age-related physiological decline in the AMH levels and thus ovarian reserve, and abnormal deviations can be used for counselling couples wishing to delay childbirth.\[[@ref34][@ref35]\] Available evidence does not suggest that serum AMH can be used as a marker to predict pregnancy.\[[@ref36][@ref37]\] However, the evaluation of follicular fluid AMH has shown that oocytes obtained from follicles with higher levels of AMH have a better fertility potential compared to those with lower AMH levels.\[[@ref38]\] Longitudinal studies in fertile women have shown a clear decline in AMH levels with age and it is the earliest marker to show a decline longitudinally in young women\[[@ref39][@ref40]\] offering the probability of a screening test for women wishing to delay childbirth. It is considered that at levels 0.5--1.26 ng/ml, AMH indicates perimenopausal transition within 3--5 years.\[[@ref41]\] Levels within this range still suggest favorable results with ART. Of all the ORTs available, AMH has a unique place in that it may be applicable as a screening test in a general subfertile population.\[[@ref41]\] Inhibin B {#sec2-4} --------- Inhibin B is a heterodimeric glycoprotein released by the granulosa cells of the follicle. Women with a low day 3 inhibin B concentration (\<45 pg/ml) have a poor response to superovulation for IVF and are less likely to conceive a clinical pregnancy.\[[@ref42]\] It is also noted that a decrease in inhibin B probably precedes the increase in the FSH concentration.\[[@ref43]\] However, other investigators have failed to show any added predictive value for inhibin B as a measure of ovarian reserve\[[@ref44][@ref45]\] and nonoccurrence of pregnancy.\[[@ref42]\] At very low threshold levels, the accuracy in the prediction of a poor response and nonpregnancy is only modest\[[@ref19]\] and hence its routine use cannot be recommended. An exaggerated inhibin B response to exogenous FSH ORT has been found to be a predictor of hyper-response in a subsequent cycle.\[[@ref46]\] Basal estradiol {#sec2-5} --------------- Basal estradiol (E2) has been evaluated as a marker of ovarian reserve in women, prior to IVF. An elevated basal E2 level may mask abnormal FSH levels and hence, FSH levels alone may not be predictable of the ovarian response in such women. Initial studies did show an association between an elevated basal E2 level and a poor ovarian response,\[[@ref47]--[@ref49]\] using different values to define elevated estradiol. A large study showed that a poor ovarian response was more commonly seen in those with \<20 or \>80 pg/ml of estradiol but did not show any correlation to the pregnancy rate.\[[@ref50]\] A meta-analysis concluded that as basal E2 does not add to the predictive value of other commonly used ORTs, its routine use in clinical practice is not recommended.\[[@ref21]\] Clomiphene citrate challenge test {#sec2-6} --------------------------------- Clomiphene citrate challenge test (CCCT) is a dynamic test involving the administration of 100 mg of clomiphene citrate from the fifth day of the cycle for 5 days. Basal FSH is estimated on day 3 of the cycle and stimulated FSH levels on day 10. Abnormal values on day 3 or day 10, or on addition of the two, is considered as a predictor of a poor ovarian response. However, a meta-analysis has shown that CCCT is no better than basal FSH in predicting a clinical pregnancy.\[[@ref51]\] In addition, it has the drawback shared by all dynamic tests in that it is expensive, more invasive, more time consuming, and associated with the possible side effects of administered drugs.\[[@ref52]\] Exogenous follicle stimulating hormone ovarian reserve test {#sec2-7} ----------------------------------------------------------- This dynamic test involves the measurement of basal FSH and estradiol followed by the administration of 300 IU FSH on day 3 of the cycle. The serum estradiol concentration is determined 24 h later. It is found to be better than CCCT in predicting hyper-responders and inferior to the latter in predicting a poor response. But, in view of the high rate of false positives, the authors did not recommend this test alone for the identification of hyper-responders.\[[@ref4]\] Gonadotrophin releasing hormone agonist stimulation test {#sec2-8} -------------------------------------------------------- It involves the assessment of serum estradiol on day 2 of the cycle followed by the subcutaneous administration of GnRHa (Triptorelin) 100 μg. A change in estradiol levels is noted by repeating the test 24 h later on day 3. A rise in estradiol is considered to be indicative of good ovarian reserve. It is found to have a good ability for the prediction of poor ovarian reserve but is not superior to inhibin B or AFC in this regard.\[[@ref53]\] ULTRASOUND PARAMETERS {#sec1-2} ===================== Antral follicle count {#sec2-9} --------------------- AFs are measured by transvaginal ultrasonography in the early follicular phase, by taking the mean of two perpendicular measurements. The numbers of follicles in both ovaries are added for the total AFC. AFC has long been used as a marker of ovarian reserve.\[[@ref30][@ref40]\] A count of 8--10 is considered as a predictor of a normal response. Different diameters are used to define AFs -- those measuring 2--6 and 7--10 mm. There is no consensus regarding the size of AFs which truly represent ovarian reserve. It is found that the number of AFs 2--6 mm in size declines with age and correlates with other markers such as FSH and CCCT but that of 7--10 mm sized remains constant\[[@ref54]\] and hence, the former appears to be a more reliable marker of ovarian reserve. Repeated measurements have shown that there is only a limited intercycle variability.\[[@ref55]\] AFC is considered to have the best discriminating potential for a poor ovarian response compared to the total ovarian volume and basal serum levels of FSH, E2, and inhibin B on day 3 of the cycle but lacks the sensitivity and specificity to predict the nonoccurrence of pregnancy.\[[@ref52][@ref56]\] More than 14 AFs are considered to be a good predictor of hyper-response.\[[@ref57]\] 3D ultrasound does not have any advantage over 2D ultrasound in the assessment of ovarian reserve.\[[@ref58]\] Ovarian volume {#sec2-10} -------------- The ovarian volume is measured by transvaginal ultrasonography applying the formula for an ellipsoid (D1 × D2 × D3 × π/6). The volume of each ovary is calculated by measuring in three perpendicular directions. The volumes of both ovaries are added for the total basal ovarian volume (BOV). The ovarian volume remains unchanged till the perimenopausal period and does not add to the predictive value of AFC.\[[@ref56][@ref57]\] A decline in the ovarian volume is a late event noticed in women \>40 years.\[[@ref59]\] Ovarian vascularity {#sec2-11} ------------------- The observation of the ovarian Doppler flow during ovarian stimulation has been studied in IVF cycles. The increase in the Doppler flow noted during stimulation is considered not to provide additional information to AFC.\[[@ref60]\] Ovarian biopsy {#sec2-12} -------------- Ovarian biopsy done at laparoscopy or laparotomy has shown that the follicular density reduces with age and is correlated with the ovarian volume in women \>35 years of age.\[[@ref61]\] Also, women with unexplained infertility have fewer follicles than those with tubal factor infertility. However, the distribution of follicles is not uniform within the ovary and hence the biopsy may not represent the true follicular density.\[[@ref62]\] It is understood that an invasive ovarian biopsy does not add to the information available through noninvasive modalities and it is not recommended to be used as an ORT.\[[@ref63]\] DISCUSSION {#sec1-3} ========== Women in their mid to late 30s and early 40s constitute an important part of the infertile population and many of them require expensive treatments including assisted reproductive technologies. Performing an ORT is an effort toward estimating the primordial follicle pool. It is well understood that the ovarian follicular pool and hence fertility declines with age. However, there is a large individual variation in its onset.\[[@ref1]\] The ideal parameter to estimate ovarian reserve would be easily measurable, minimally invasive, inexpensive, and have good predictive value for the outcome being assessed. Majority of the ORTs available are not expensive but need very high threshold levels to identify majority of poor responders.\[[@ref21]\] Even though ORTs primarily have been used to identify poor responders, and counsel such women to avoid repeated ineffective treatment, it is now known that some of them are able to predict a hyper-response. This helps avoid maximal ovarian stimulation in such women and minimize the risk of life-threatening OHSS without compromising the pregnancy rate.\[[@ref33]\] Majority of the ORTs, including the most widely used basal FSH levels, show abnormal values late in a woman\'s reproductive life to be of practical help.\[[@ref20][@ref21]\] Abnormal results indicate a much compromised ovarian reserve, implicating that all interventions would be ineffective which is compounded by a huge emotional and financial burden to such couples. Basal E2 and inhibin B are not found to be any better predictive value than FSH. Though FSH induced increase in the inhibin B level may be useful in predicting hyper-response, AMH and AFC are the basal markers found to predict the ovarian response, both poor and hyper, with a high sensitivity and specificity and are comparable in this regard.\[[@ref5]\] Serum AMH levels show minimal intra- and intercycle fluctuations and thus can be performed at any stage of the menstrual cycle. They show distinct age-related declines at a very young age, much earlier than other markers including AFC.\[[@ref40][@ref64]\] Nomograms have been developed for AMH for infertile women which should help identify those with diminishing ovarian reserve at any given time in the general subfertile population and thus providing an opportunity to counsel couples appropriately regarding reproductive performance. This would also enable them to go through effective modalities of treatment when the chances of achieving a pregnancy are reasonably good.\[[@ref34][@ref35][@ref65]\] AMH is the only ORT found to be useful in evaluating the residual ovarian reserve in young women treated for malignancies with chemotherapy or radiotherapy.\[[@ref66]\] Dynamic tests do not add to the value of baseline tests and hence cannot be recommended as a diagnostic tool with the available evidence.\[[@ref67]\] Attempts to improve the predictive value of ORTs by using multiple markers instead of single basal marker have not been found to be beneficial.\[[@ref30][@ref68][@ref69]\] It is clear from the current evidence that ORTs cannot be used as diagnostic tests for a poor ovarian reserve but should be used as screening tests, and the first IVF attempt remains the diagnostic tool to identify a poor response.\[[@ref21]\] AFC and AMH can be used as diagnostic tools to identify hyper-responders and treatment strategy modified accordingly to minimize OHSS.\[[@ref5][@ref33]\] Despite the multitude of ORTs available, age remains the best predictor of pregnancy. A poor predictive value of ORTs in this regard may be due to the fact that chance of pregnancy after IVF depends on many other factors than ovarian reserve alone and that the pregnancy outcome after an ORT is usually assessed in the first IVF cycle alone which may not adequately represent a woman\'s true reproductive potential.\[[@ref21]\] CONCLUSIONS {#sec1-4} =========== ORTs do have a moderate ability to predict poor and hyperresponse.The information can influence the treatment protocol to be chosen for IVF but should not be used to exclude anyone from first attempt at IVF.The present evidence shows that AFC and AMH appear to be the most useful markers of ovarian reserve in addition to chronological age. In addition AMH has the ability to be applied to the general population for identification of diminishing ovarian reserve before it reaches a critical level below which no effective treatment can be offered.This may help women who wish to delay pregnancy to make an informed decision. Source of Support: Nil, Conflict of Interest: None declared.	null	minipile	NaturalLanguage	mit	null
Q: Table Alignment (Making the word from 1 row into 2 row) Would like to adjust the table in better looking, tried both methods, not working. Make the first column letter into 2 row. Make all the content to left-hand side All the column around same length \documentclass[12pt,oneside]{book} \usepackage{showframe} \renewcommand\ShowFrameLinethickness{0.15pt} \renewcommand\ShowFrameColor{\color{red}} \usepackage{makecell,siunitx} \usepackage{booktabs} \usepackage{tabulary,siunitx} \usepackage{makecell, multirow, tabularx} %for table multirow %for table multirow \begin{document} \renewcommand\theadfont{\small\bfseries} \begin{table}[!ht] \centering \begin{tabularx}{\textwidth}{>{\raggedright\arraybackslash}Xcclc} \toprule \thead[l]{} & & \thead{Value Label} & \thead{N} \\ \midrule \multirow{2}{}{\textbf{Example}} & 1 & Example Example Example & 20\\ \cline{2-4} & 2 & Example Example Example Example & 20 \\ \cline{1-4} \multirow{2}{}{\textbf{Example Example Example}} & 1 & AM & 20\\ \cline{2-4} & 2 & FM & 20 \\ \bottomrule \end{tabularx} \end{table} \setlength\extrarowheight{1pt} \renewcommand{\arraystretch}{1.2} \begin{table}[h!] \centering \begin{tabularx}{\textwidth}{@{}Y{3}{W}@{}} \toprule & & \small {\textbf{Value Label}} & \small {\textbf{N}} \\ \midrule \multirow{2}{}{\textbf{Example}} & 1 & Example Example Example & 20\\ \cline{2-4} & 2 & Example Example Example Example & 20 \\ \cline{1-4} \multirow{2}{}{\textbf{Example Example Example}} & 1 & AM & 20\\ \cline{2-4} & 2 & FM & 20 \\ \bottomrule \end{tabularx} \end{table} \end{document} A: Changing {} to {=} fixes the linebreak in multirows when you change first and third column to a left aligned X column. To reduce typing, I defined such column as a new columntype. In addition, by using array's new w column, you can fix both width and alignment. I fixed the width to 2 cm, but change those values if you prefer wider or narrower second and fourth column. Example 1 Since you cannot use a new version of array, I changed the second and fourth column to a fixed width p-column, with contents centred. For readability, I defined a new columntype V. In addition, I limited the width of the whole tabular to 0.7\linewidth. I also chosed fontsize \small. \documentclass[12pt,oneside]{book} \usepackage{showframe} \renewcommand\ShowFrameLinethickness{0.15pt} \renewcommand\ShowFrameColor{\color{red}} \usepackage{makecell,siunitx} \usepackage{booktabs, array} \usepackage{tabulary,siunitx} \usepackage{makecell, multirow, tabularx} %for table multirow %for table multirow \begin{document} \setlength\extrarowheight{1pt} \renewcommand{\arraystretch}{1.2} \newcolumntype{Y}{>{\raggedright\arraybackslash}X} \newcolumntype{V}{>{\centering\arraybackslash}p{1cm}} % Centred fix width column \begin{table} \small \centering \begin{tabularx}{0.7\textwidth}{@{}YVYV@{}} % Limit the width of the tabular \toprule & & \small {\textbf{Value Label}} & \small {\textbf{N}} \\ \midrule \multirow{2}{}{\textbf{Example}} & 1 & Example Example Example & 20\\ \cmidrule{2-4} & 2 & Example Example Example Example & 20 \\ \cmidrule{1-4} \multirow{2}{=}{\textbf{Example Example\newline Example}} & 1 & AM & 20\\ \cmidrule{2-4} & 2 & FM & 20 \\ \bottomrule \end{tabularx} \end{table} \end{document} Example 2 \documentclass[12pt,oneside]{book} \usepackage{showframe} \renewcommand\ShowFrameLinethickness{0.15pt} \renewcommand\ShowFrameColor{\color{red}} \usepackage{makecell,siunitx} \usepackage{booktabs, array} \usepackage{tabulary,siunitx} \usepackage{makecell, multirow, tabularx} %for table multirow %for table multirow \begin{document} \setlength\extrarowheight{1pt} \renewcommand{\arraystretch}{1.2} \newcolumntype{Y}{>{\raggedright\arraybackslash}X} \begin{table} \centering \begin{tabularx}{\textwidth}{@{}Yw{c}{2cm}Yw{c}{2cm}@{}} \toprule & & \small {\textbf{Value Label}} & \small {\textbf{N}} \\ \midrule \multirow{2}{*}{\textbf{Example}} & 1 & Example Example Example & 20\\ \cmidrule{2-4} & 2 & Example Example Example Example & 20 \\ \cmidrule{1-4} \multirow{2}{=}{\textbf{Example Example\newline Example}} & 1 & AM & 20\\ \cmidrule{2-4} & 2 & FM & 20 \\ \bottomrule \end{tabularx} \end{table} \end{document}	null	minipile	NaturalLanguage	mit	null
Two things came to light in the past couple of days. The Cleveland Browns brought on former Washington Redskins offensive coordinator Kyle Shanahan to run their offense, and word got loose that Shanahan “loves” his former pupil, Kirk Cousins. With Shanny junior now in Cleveland and Cousins already making it known that he’s open to a trade, the dust could end up settling in such a fashion that could land Cousins in Cleveland. Cleveland seems intent on separating itself from failed first round experiment Brandon Weeden, while Jason Campbell is a cut candidate. The only other quarterback on the roster is Brian Hoyer and the Browns are also expected to be in the mix for a quarterback in the first round of this year’s draft. The likes of Johnny Manziel, Teddy Bridgewater and Blake Bortles have had their name brought up in draft rumors involving the Browns. However, is the Cleveland brass agree with Shanahan and are high on Cousins, perhaps they’d pass up spending a first rounder on a quarterback and trade a mid-round pick to get their guy in Cousins. It could end up matching up, but solely banking on Cousins still seems to be a reach. A former fourth round pick, Cousins has flashed starter ability, but doesn’t have elite arm strength and has been inconsistent in his starts. On the plus side, he knows Shanahan’s offense and has the intelligence and skill-set to succeed in the right situation. That being said, Cousins is a safe option that wouldn’t involved much risk and arguably doesn’t carry a ton of upside. Drafting a quarterback high in the 2014 NFL Draft clearly carries risk, but all of this year’s top passers all carry solid potential – specifically Manziel and Bortles. Cleveland seemed to be exercising the safe route by trading away Trent Richardson for a second first round draft choice last season, but at some point they need to land difference-makers on offense. They have two in Josh Gordon and Jordan Cameron already, but adding a true star under center has to be the next move to take their team to the next level. Swinging a trade for Cousins probably won’t accomplish that.	null	minipile	NaturalLanguage	mit	null
As the proprietor of a bed & breakfast in Oaxaca, Mexico, I frequently field inquiries from travelers with plans to visit the city who are intent upon bringing the family dog or cat along for the vacation. They initially ask if pets are permitted in our guest level, and then after receiving a reply in the negative, in a second email ask for names of alternate hotels or other accommodations which do accept pets. The advice is always the same, but the inquiries keep coming. This pet lover and owner of a brindle boxer is not a pet psychologist, nor professes to intimately know whats right or wrong when it comes to decisions about the family dog or cat (or ones children for that matter lord knows weve made and will continue to make mistakes raising our daughter), nor the impact that leaving a pet behind could have on the mutt or his parents or siblings. However, there are certain factors which ought to at least be considered prior to deciding definitively to take Fido or Tabby along for the trip. Yes, Some Hotels and Bed & Breakfasts in Oaxaca Do Accept Pets, Including Dogs and Cats Of course virtually every major tourist city in the civilized world includes the odd hotel, guest house or bed & breakfast which accepts pets, at minimum dogs and cats. Oaxaca is no exception. For example, a couple of members of the Oaxaca Bed & Breakfast Association are happy to extend invitations to the four legged. But most shun the thought of even the possibility of a cat meowing or dog barking, and therefore having to contend with complaints from pet-less guests. Certainly there are exceptions; but what might it reveal about the quality of lodging if the owner is struggling to rent out rooms to the extent that he feels compelled to accept dogs, cats, rats, parrots, snakes and lizards? Your choice of lodging is dramatically reduced by restricting the selection to accommodations in Oaxaca which accept pets. Is the vacation for the Homo sapiens in the family, or for the canines and felines? But Think of the Poor Pet, No Matter How Attached You Insist He is To the Family Believe it or not, family pets are in fact different from the human members of the family, no matter how much we might treat them the same as we treat ourselves, no matter that they sleep with us in our beds, no matter they might pick up on our emotions and even thoughts. After the first couple of hours of the road trip to Oaxaca, will the pet not be less patient than the children? Is he capable of playing board games in the car? Would he be happier being cared for in a quality facility back home where he can frolic with his own kind? When we vacation we board Tito with a dog trainer. Now, seven years later, whenever we begin to gather up his food and water bowls, and leash and choke chain for the ride, he becomes unimaginably excited, sensing that hes off once again to the country club. Pet Owners with a Dog or Cat Accompaniment in Oaxaca are Otherwise Restricted Many ruins and cultural sights do not permit pets, leashed or otherwise. Yes, the dog or cat can be left in the car, windows left slightly ajar. But do you want to run the risk of returning to the parking lot and finding Fido has fled the coup with the help of a Oaxacan anxious to turn the catch into coin? Do you want to constantly be obsessing about that possibility rather than expending all of your energies enjoying Monte Albán, Mitla or a marketplace? Bringing the pet will on balance dramatically restrict your ability to enjoy a number of priority tourist sights. If Still Not Convinced, Consider Boarding the Pet in Oaxaca, and Compare Costs True enough, boarding costs in the US and Canada are prohibitive for most of us. Accordingly, as a last ditch effort to convert the otherwise committed, consider boarding the beast here in Oaxaca. The advantages of doing so include: The cost is about a quarter of what it costs back home. Your vacation will have no restrictions in terms of the sights which you can see. You hopefully will not be constantly obsessing about how your dog or cat is doing; and you wont have to incur long distance calls to assure yourself. Your pet can still enjoy spending quality time with the rest of the family driving through the American mid-West. You can drop by to see him daily and exchange stories about how the day went. Most boarding facilities have posted visiting hours. Hell be having the vacation of a lifetime, and perhaps even pick up a bit of Pet-Spanish. You wont have any such restrictions on selecting a hotel or B & B, and accordingly your vacation in Oaxaca will be that much more relaxing and enjoyable. Since pet boarding facilities in Mexico invariably have dog psychologists on staff, you can kill the proverbial two birds with one stone use the first half hour for the dog to deal with his stress, and the other half hour for yourself. Together with his wife Arlene, Alvin Starkman operates Casa Machaya Oaxaca Bed & Breakfast (http://www.oaxacadream.com ). Alvin has written over 200 articles about life and culture in Oaxaca, assists tourists in planning their visit to Oaxaca and tour of its central valleys, and with Chef Pilar Cabrera arranges culinary tours of Oaxaca (http://www.oaxacaculinarytours.com).	null	minipile	NaturalLanguage	mit	null
GCR Class 8B GCR Class 8B was a class of 25 two-cylinder steam locomotives of the 4-4-2 wheel arrangement built between 1903 and 1906 for the Great Central Railway. They were nicknamed "Jersey Lillies" after the famous music star Lillie Langtry. GCR era Facing a potential rise in passenger traffic, the Great Central Railway placed an order for 2 pairs of different locomotives - one pair being the 4-6-0 GCR Class 8C, the other pair being this 4-4-2 locomotive. The two locomotives shared as many common components as possible to allow easy conversion of the 8Bs to the 4-6-0 configuration - and both designs borrowed heavily from John G. Robinson's earlier GCR Class 8. However, due to a much smaller than anticipated traffic increase, no further Class 8Cs were built, and instead a further 25 Class 8Bs were ordered and built between 1904 and 1906 - built with larger fireboxes as there was no longer a need to convert the locomotives to a 4-6-0 configuration. In 1909 and 1910, the original locomotives also received this larger firebox. Despite Robinson commencing the conversion to superheaters in 1912, the conversion was not actually completed until 1936. At the same time, any locomotive requiring cylinder replacement saw both larger cylinders and piston valves being fitted - 20 of the class would eventually receive this modification. From 1921, the Ramsbottom safety valves were phased out and removed, to be replaced by Ross pop safety valves. Experimental locomotive Following a high-speed incident that caused severe damage to its frame and cylinders, No. 1090 was rebuilt with 3 simple expansion cylinders in 1908, as a comparison to the GCR Classes 8D and 8E. These cylinders had their Stephenson valve gear replaced with Walschaerts valve gear, which was the only application of this valve gear, excluding railcars, on a GCR locomotive. The experiment was reverted in 1922 when No. 1090 was rebuilt, with the original 2 cylinders and Stephenson valve gear being refitted. Post-Merger Following the merger of the GCR into the London & North Eastern Railway, the class became known as the LNER Class C4. In 1925, several C4s were fitted with the LNER's trademark "Flowerpot" chimney, with one locomotive, No. 6085, also modified to fit the LNER composite gauge - a modification that the remainder of the class underwent between 1936 and 1939. In 1929, a further LNER classification change was made - the non-superheated locomotives were designated Class C4/1, those fitted with superheaters but still utilized slide valves Class C4/2, and those with both superheaters and piston valves became Class C4/3. By 1932, the re-gauged No. 6085 had been given the designation Class C4/4 - which became more populated as Class C4/3s were cut down. By 1939, all Class C4/1s and Class C4/3s had been redesignated as either Class C4/2s or Class C4/4s - by this time all locomotives were both superheated and had also been cut down to the LNER composite gauge. Withdrawal Following an accident at Banbury in 1939, the first locomotive, No. 6090 (the same engine as No. 1090, which had already been modified after a previous accident), was withdrawn from service. The rest of the class began being withdrawn from 1945, although 20 locomotives made it into British Rail hands following the nationalisation of the British railways. The last locomotive was withdrawn in 1950, and none survived into preservation. References External links The Robinson C4 (GCR Class 8B) 4-4-2 Atlantics 08B Category:4-4-2 locomotives Category:Railway locomotives introduced in 1905 Category:Scrapped locomotives Category:Standard gauge steam locomotives of Great Britain Category:2′B1′ n2 locomotives Category:2′B1′ h2 locomotives	null	minipile	NaturalLanguage	mit	null
Q: How does the container get passed to a fragment? I'm attempting to understand someone else's code. They are using fragments (which I'm rather hazy on). I know that a fragment starts up with onCreateView(LayoutInflater inflater, ViewGroup container, Bundle savedInstanceState .. but I can't fathom where the "container" was set up. where should I look? A: container is handled by the Android framework, it typically refers to View passed by id in methods like FragmentTransaction's add(int containerViewId, Fragment fragment) or replace(int containerViewId, Fragment fragment). For example, this is from the Developer's Guide: ExampleFragment fragment = new ExampleFragment(); fragmentTransaction.add(R.id.fragment_container, fragment); fragmentTransaction.commit();	null	minipile	NaturalLanguage	mit	null
Q: Django : Access model data in template using Class-based generic views I'm trying to display the model data in the template. When I don't have any filtering, it works fine! class UserLogList(ListView): context_object_name = 'data' queryset = UserLog.objects.all().values('user_id__username','event_id','time') But if I want to have some filtering, example if I want to get the details based on the user_id where user_id = 1. I can get the user id from the request object or self.request object. So to achieve this, I did the following in my views.py class DisplayUserActivity(ListView): template_name = 'user_activity.html' uid = self.request.user.id def get_object(self): uid = self.request.user.id object = super(DisplayUserActivity,self).get_object() object.data = UserLog.objects.filter(user_id = uid).values('user_id__username','event_id','time') return object and my template file: {% block content %} <h2> Logs </h2> <table border="1" style="width:50%"> <tr> <th> User Name </th> <th> Description </th> <th> Time </th> </tr> {% for user in data %} <tr> <td> {{user.user_id__username}}</td> <td> {{user.event_id}}</td> <td> {{user.time}} </td> {% endfor %} </tr> </table> {% endblock %} What am I missing? A: I think you need a method called get_queryset instead of get_object when extending the generic ListView. EDIT: Regarding your edit, theres an issue with your template {% for user in data %} should be {% for user in object_list %} But I suspect there are deeper problems here which are hard to decipher. My advice is to look through your code and the Django documentation more carefully, and possibly switch to a custom written view until you are more comfortable. :)	null	minipile	NaturalLanguage	mit	null
Welcome to the WHO/Europe Health Economic Assessment Tool (HEAT). 29 October 2014 New dates for free online trainings in English and German Thanks to support from the Swiss Federal Office for Public Health and the collaboration with the European Cyclists’ Federation we are pleased to announce the continuation of the free live online trainings in English and German on how to use HEAT. Please see here for the new dates and registration: Introduction This tool is designed to help you conduct an economic assessment of the health benefits of walking or cycling by estimating the value of reduced mortality that results from specified amounts of walking or cycling. The tool can be used in a number of different situations, for example: when planning a new piece of cycling or walking infrastructure. HEAT attaches a value to the estimated level of cycling or walking when the new infrastructure is in place. This can be compared to the costs of implementing different interventions to produce a benefit–cost ratio (and help to make the case for investment) to value the reduced mortality from past and/or current levels of cycling or walking, such as to a specific workplace, across a city or in a country. It can also be used to illustrate economic consequences from a potential future change in levels of cycling or walking. to provide input into more comprehensive economic appraisal exercises, or prospective health impact assessments. For example, to estimate the mortality benefits from achieving targets to increase cycling or walking, or from the results of an intervention project.	null	minipile	NaturalLanguage	mit	null
~HEATTORNEY GENERAL OF TEXAS Aus- 11.- letter of ikke 15th reqw8t4 cur Q&aklon Qn the ~Bhbm we lm?intly rwd#ed a#.!don 0-907 coastruiy the mlldity 8nd eonrtfttitlawllty of H.l% 20!5passed by the Fort~-1slxth Legirlatw, we enelow a eog;r of mid oginlen fez your oonridwtioA. The plaia provirAoA or th8 ZWWAtly enaated strtutr (a.23, would give aa afilcnr the right to one-harf of hi8 oosts the amviot laid out hlr fine arg oomE5 without labor, Ike ~aflmr the eff8etSve date of the bill. ‘Artiale lOfj& The county &all not be liable te the 0rne aad witabss bav* ooetr in a aiaaaor a8e wh8re defeadant p8yr hi8 fina and costs. !rhe eotlaty 8hall be limb10 r0r 0nr-holr of the fee8 of the offioerr Of thOOW%, WhW thOt%mAdSmt fad tOpqhi8 riA8 8Ad lays his fina out la the aounty jail or diW.!h8X3&~8 the saw by - of rorklng au& tine out on the uounty mN.ds or QA any uouaty p?ojbut. AAd to puy such half of oortr the aouaty alerIc shall Issue hlr warrent on tb8 Cou& Yreaurer IA hvDr of BuOh of?ioU to be pald OIPtofthej(Dd8ndBrLdgemAdaro~r rundraot 0therwl.w approprmed,” ‘prurtin(c tha abova Urtirhctori~ UtSWrS y0U.V qW8tiOA, Ip- mws m truly &22OlWiU(upIIRIIWTRXkE	null	minipile	NaturalLanguage	mit	null
Commensurate CO2 Capture, and Shape Selectivity for HCCH over H2CCH2, in Zigzag Channels of a Robust Cu(I)(CN)(L) Metal-Organic Framework. A novel copper(I) metal-organic framework (MOF), {[Cu(I)2(py-pzpypz)2(μ-CN)2]·MeCN}n (1·MeCN), with an unusual topology is shown to be robust, retaining crystallinity during desolvation to give 1, which has also been structurally characterized [py-pzpypz is 4-(4-pyridyl)-2,5-dipyrazylpyridine)]. Zigzag-shaped channels, which in 1·MeCN were occupied by disordered MeCN molecules, run along the c axis of 1, resulting in a significant solvent-accessible void space (9.6% of the unit cell volume). These tight zigzags, bordered by (Cu(I)CN)n chains, make 1 an ideal candidate for investigations into shape-based selectivity. MOF 1 shows a moderate enthalpy of adsorption for binding CO2 (-32 kJ mol(-1) at moderate loadings), which results in a good selectivity for CO2 over N2 of 4.8:1 under real-world operating conditions of a 15:85 CO2/N2 mixture at 1 bar. Furthermore, 1 was investigated for shape-based selectivity of small hydrocarbons, revealing preferential uptake of linear acetylene gas over ethylene and methane, partially due to kinetic trapping of the guests with larger kinetic diameters.	null	minipile	NaturalLanguage	mit	null
Q: weighted cross entropy for imbalanced dataset - multiclass classification I am trying to classify images to more then a 100 classes, of different sizes ranged from 300 to 4000 (mean size 1500 with std 600). I am using a pretty standard CNN where the last layer outputs a vector of length number of classes, and using pytorch's loss function CrossEntropyLoss. I tried to use $weights = \frac{max(sizes)}{sizes}$ for the cross entropy loss which improved the unweighted version, not by much. I also thought about duplicating images such that all classes ends up to be of the same size as the larges one. Is there any standard way of handling this sort of imbalance? A: If you are looking for just an alternative loss function: Focal Loss has been shown on imagenet to help with this problem indeed. Focal loss adds a modulating factor to cross entropy loss ensuring that the negative/majority class/easy decisions not over whelm the loss due to the minority/hard classes. I would look into using that is it seems to be really promising. Link To Focal Loss Paper: https://arxiv.org/pdf/1708.02002.pdf A: To handle class imbalance, do nothing -- use the ordinary cross-entropy loss, which handles class imbalance about as well as can be done. Make sure you have enough instances of each class in the training set, otherwise the neural network might not be able to learn: neural networks often need a lot of data. Assuming you care about global accuracy (rather than the average of the accuracy on each individual class, say), I wouldn't bother with a weighted cross-entropy loss or duplicating images. Your training sounds rather small. To deal with that, you might try starting from an existing pre-trained model and fine-tune the last few layers. Also use image augmentation.	null	minipile	NaturalLanguage	mit	null
1. Field of the Invention The present invention relates to an auto telephone answering apparatus for recording an incoming message (to be referred to as an ICM hereinafter) while the called telephone is unattended. 2. Description of the Prior Art In a conventional auto telephone answering apparatus, a recorded outgoing message (to be referred to as an OGM hereinafter) stating that the called party is out and that an ICM will be recorded is played back and sent to the calling party upon reception of a call, and an ICM is then recorded. A conventional auto telephone answering apparatus of this type has a selector switch for selecting an auto answer mode or a listen mode. When a user or subscriber is leaving the phone unattended, the selector switch is set in the auto answer mode. For example, U.S. Pat. No. 4,421,954 describes an auto telephone answering apparatus using a 1MD (One Mechanical Deck) system in which a single tape can sequentially record an OGM and a plurality of ICMs. When the auto telephone answering apparatus is being set in the auto answer mode, an OGM is first played to make certain that the OGM is properly recorded in a predetermined tape format. After the OGM is played, the tape is rewound to the beginning of the OGM and is ready for an incoming call. When the first incoming call is received, the OGM is played and sent to the calling party, and an ICM is recorded on the tape. When recording of the ICM is completed, the tape is rewound to the beginning of the OGM and is ready for the next incoming call. When the second incoming call is received, the OGM is played and sent to the calling party. Then, the tape is fast forwarded to skip the first ICM, and the second ICM is recorded after the first ICM. After the second ICM is recorded, the tape is again rewound to the beginning of the OGM and is ready for the next call. The same operation is repeated automatically to sequentially record a plurality of ICMs. When the recorded ICMs are to be played back, the user sets the switch to select the listen mode and depresses a play button. The ICMs are played sequentially starting from the first recorded ICM. When the ICMs are being played back, a conventional auto telephone answering apparatus normally goes into a stop mode when all ICMs have been played back or when ICM playback is manually interrupted to permit the user to attend to some other urgent business. If the user again leaves the telephone unattended while the apparatus is in the stop mode, he may forget to set the switch in the auto answer mode, thus resulting in the failure to record subsequently received ICMs. In another conventional auto telephone answering apparatus, the auto answer mode is cancelled when a tape cassette is inserted or ejected with the apparatus in its auto answer mode. When a plurality of tapes with different OGMs are prepared and used for different purposes, the user must set the switch to establish the auto answer mode each time he replaces one tape with another, thus inconveniencing the user. Furthermore, since only the beginning of an OGM need be checked to determine the OGM content, the user often interrupts OGM playback before completion thereof. To do this, the user depresses the stop button or sets the selector switch in the auto answer mode. If the stop button is depressed for that purpose, the selector switch must be thereafter set in the auto answer mode to ensure that incoming messages will be recorded. However, the user often forgets to do this, resulting in the failure to record ICMs.	null	minipile	NaturalLanguage	mit	null
Comments (2) WOW! This is both beautiful and touching. Perhaps I should have passed by this LO without blowing it up and reading it. But I did. Today is January 19th...tomorrow is my 34th birthday. I should be happy...but my birthdays are bitter sweet. Tomorrow will mark the 18th anniversary of me learning I lost my first baby...I don't call it her (long story why I say "her") birthday because the remains were delivered later...and she died a bit before I began to "miscarry", exactly how long be for I'm not sure. I remember that birthday...it was supposed to be my "Sweet 16". It was anything but. First, I woke up bleeding that morning...spent 1/2 the morning at the ER, the other half of the day at an OB/GYN, the night on bed rest. At the OB's office, first they could find no heartbeat. Then, what the ultrasound showed still haunts me...there was part of a baby, only a skull with eye sockets, a nose indention, the form of closed lips......where did the rest of her go I wondered. I found out the answer to that question on January 24th. Gestational Trophoblastic Tumor...my oncologist told me, "Your baby saved your life. The cancer killed her before it began killing you. Had the baby not been forming you would not have the chance of survival that you do." They disected her "remains" and ran MANY tests. Only my OB and onco refered to the baby as "her", everyone else just called her "it". But, I named her anyways, my own coping mechanism..November Nicole...my precious angel. WOW! This is sooooo beautiful and sad at the same time. It touched my heart. I know the feeling. On March 1989 I lost a baby on my 13 week of pregnancy. He had an extra chromosome on the 13th pair. I got to know it was a boy so I named him Alan. I had another boy a year later, I have 3 kids but my youngest is not the third, he will always be the fourth. Alan is my third kid. It never goes away. I will always remember him sucking his thumb in the sonogram. Thanks for sharing this, you did a great job.	null	minipile	NaturalLanguage	mit	null
Tag Robert A. Burt Robert A. Burt— The judicial task is not mechanistic but properly and necessarily involves judgment. In particular, judges must understand themselves as ultimately promoting equal deliberation among conflicting parties rather than imposing their own calculus of equality on the parties. This understanding is not alien to the judicial function; it About The Blog The Yale Press Log is the official blog of Yale University Press. Founded in 2005, the Log has since chronicled updates and breaking news about authors, books, publishing, museums, awards, contests, events, podcasts, book trailers, and reading.	null	minipile	NaturalLanguage	mit	null
Eldon Piper Birth Name Eldon Piper Titles Lord of Pinkmaiden Gender Male Date Of Birth 3rd of the 12 Moon of 69 AC Culture Andal Religion Faith of the Seven Physical Information Build Muscular Height 6'2 Weight 190 Relations Father Robin Piper Mother Cyrenna Piper nee Toyne Spouse(s) Sarra Piper nee Vance Children Kylar Piper (7) Grover Piper (6) Siblings Lynora Piper (Deceased) Moriah Piper (26) Marla Piper (25) Forrest Piper (24) Liege Agnes Tully Heir Kylar Piper META Player Username /u/GrimmFury Name on Discord Grimm Auxiliary Character Forrest Piper Alternative Characters Clyve Caron, Corwin Caron, and Wyndylyn Manderly Lord Eldon Piper is the second-born son of Lord Robin Piper and Cyrenna Piper. A brash and arrogant man, he became known throughout the realm for his prowess in combat, even making a name for himself in Myr for a short time. After the death of his father and older brother, Lord Robin Piper and Ser Harwood Piper, he found himself the ruling Lord of Pinkmaiden. He now works to build up his lordship alongside his younger brother, Forrest. Appearance and Character Edit Eldon stands moderately tall and is built of lean muscle due to the vigorous training that he commits himself to. While hints of red can still be seen in his hair, his mother's Toyne blood can be seen as well through his hazel eyes and darker hair color. He often dresses in black tunics as opposed to his house colors as he views wearing one's banner as naive and foolish in times of both peace and war; he would much rather simply be another face in the crowd. In terms of Eldon's personality, Eldon gradually became known for his boisterous antics from a very young age. His older brother, Harwood, excelled greatly at nearly any task that he was given, and made a habit of displaying his greatness to his siblings. Although their mother would take him aside and scold him mildly, his father did not ever seem to mind it. Because of this, Eldon found that misbehavior was the only manner in which he could receive any sort of attention and found himself in less than ideal situations throughout his upbringing. History Edit Born inside of Pinkmaiden Castle in 69 AC, Eldon was merely the second of seven siblings that his parents would bring into the world. He spent the first ten years of his life being a general annoyance to his siblings, especially Harwood, and attempting to "explore" the exciting world that he would always gaze out at longingly. During a feast held for the realm, he took a particular liking to the Peacock sigil of House Serretts of Silverhill. Running in between the different areas of the feast, Eldon left behind all decorum and found himself laughing and playing with the children of Lord Otho Serrett, especially Daryn and Oscar. Because of this taking place, their father decided it to be the perfect opportunity to push Eldon onto another family. This was only more emphasized by Lord Piper when he heard of the strict nature in which Lord Otho Serrett did pretty much everything. It was at Silverhill that Eldon was trained in swordsmanship as well as commanding those in times of war, and he find a fierce rival in Daryn Serrett. The heir to Silverhill treated much of his family as Harwood treated the rest of the Pipers. This rivalry pushed Eldon to become more adept at his sparring skills while Daryn became more familiar with the art of warfare. Endless hours of sparring against both Daryn as well as other knights left Eldon with a keen eye for exploiting weaknesses in an enemy's defenses; a tactic that he often utilized in order to introduce any foe to the ground scrambling after being disarmed. That being considered, this rivalry also finally allowed Eldon to feel connected to someone else in the forms of Victaria and Oscar Serrett. Both members of the family in which he served as a ward felt the neglect of love from their father, and became good friends of Eldon on nights where Daryn and Otto were spending their nights with nobility. In a strange way, Eldon became an older brother figure to Oscar. His constant antics attempting to break the sober-faced "winter child" of the ridicule and neglect that he faced by those that shared his same blood. A few moons before his seventeenth nameday, the solemn maester of House Serrett shuffled into his cramped quarters and handed him a short missive. His brother was to be wed to Selyse Bywater, and a tourney would be held in their honor. Eldon was invited to come and stay back at Pinkmaiden to participate in the tourney in order to assess whether or not he had become the man that Robin wanted him to be. Eldon wished Oscar and Victaria the best wishes and invited them to come. An invitation that Otto would sadly decline on their behalf. At the tourney, he displayed his expertise swordsmanship, much to the dismay and awe of Harwood. For some reason, it took this display for his father and older brother to finally recognize him; recognition that Eldon was not able to wholly accept, but he appreciated it nonetheless. Coming in second place at his first tourney, his father appointed him a scout commander and knighted him at the feast held after the event. It was also after this event that he first laid eyes on his beloved, Sarra Vance. With one look, his heart was hers to command, and they maintained a mischievous tryst while also courting one another. It was two years later that they would wed, and she would give birth to their first child, Kylar Piper. A mere year later, she would fall ill with Grover Piper. A chill having taken her, she gave birth in constant pain and passed out unconscious throughout her delivery of the sickly boy. It was only after an hour of her not waking back up that the handmaidens realized she had died of exhaustion just after giving birth. Not a week later, he read the missive that told him of his sister, Lynora Piper, had passed away while at Atranta. Two losses that Eldon thought himself not strong enough to take both hit him harder than he could have ever prepared himself for. Despite his attempts to comfort, Lord Robin was not able to convince the son he had given up all those years ago that things would turn out alright, and this led Eldon to follow a dream that he had always held. A dream of exploration. Through a small missive left to his skilled steward of a brother, Forrest, Eldon rode east to Maidenpool and used a sizable amount of Pinkmaiden's treasury to sail for Myr. A city that had been fabled to him throughout his childhood. There, he bought a small hovel and began to learn his way around the city and sold his sword for whatever noble may have needed protection. Jobs connected to contacts and before he knew it, he found himself working under another man from his home. After three months of protecting petty lords seeking trade deals, he began to lead men under Albar Vance, and quickly worked his way up the ranks; even to the point where his own son, Accalon, became another rival of his. It was also in Myr that he began to learn the technique of weaving daggers into one's combat. Small strikes that could debilitate an enemy if done correctly. His second-in-command became a close friend as well. Qosh hailed from the scummy underbelly of Myr and mainly dispatched those that the various magisters found troublesome. Through months of training, Qosh passed on his main method of killing them quickly, and Eldon seemed to be a natural at utilizing poisons against any who would stand against them in Myr. On the evening of the eleventh moon in 92 AC, Eldon was leading men under the orders of Albar and Accalon. Eldon, in his haste to dispatch the vagabonds on the outskirts of town, ignored the advice of Accalon and charged directly into the den of vipers thinking them to not be a threat. Despite his prowess, the ambush was more than Qosh as well as any of his other men could take. It seemed that the vagabonds had actually been sellswords in the employ of an opposing magister vying for influence in the region. Rumors of them being simply primarily thieves had simply been the product of his subversion. Once again, Eldon turned his back and decided that facing the lessons of his failures was a burden too weighty for him to ever bear. Having barely escaped with his life and knowing he had failed his commander, he set sail back to King's Landing in the hopes that he might fight respite back home amongst the family that he had forsaken. Upon landing in the capital, Eldon received the grave news of the King's comments toward the realm and could feel the tension of the Rosegold building. When he arrived home, he was imprisoned by his father in a passionate rage. The family argued for seven days and seven nights while Forrest sent little Kylar and Grover to meet their neglectful father in his cell. It was only after Eldon asked to play outside with his children that Cyrenna convinced Robin to allow Eldon freedom to father his children. But times of peace would not last for long, and Eldon knew he had to protect his family that had forgiven him for so much. During the initial stages of the Rosegold Rebellion, he found himself a sworn sword in the employ of his liege at Riverrun. In the midst of the night, he would stare out and wonder what ever became of the Serretts, knowing fully that he might have to stand against Daryn or even worse...Oscar if they ever marched so far north. It was only later that he would come to know that it was not the Serretts, but a Lannister that had cut down both his father as well as his older brother in the Battle of Tumbler's Fall; a memory that burned itself into his mind since that very night. Despite the loss and grief, Eldon made his way back to Pinkmaiden and worked alongside his sisters and brother to fortify and defend their home from any Western advance. And soon after, news came that peace had been restored. The deaths of his father and his brother, both men that he had never been able to truly reconnect with, took place simply because of a drunken king's comments. These truths burrowed themselves within his heart, and continue to motivate him to this very day as he leads the remaining members of his family toward more influence, power, wealth, and protection. Still seemingly a stranger to his many siblings, he enjoys spending time with the sisters that he barely spent any precious moments with throughout his upbringing. Ambivalent in most of his actions, Eldon seeks to use his skills both to bring his House more prestige and to bolster the influence of the Riverlands over its enemies. Family Tree Edit http://www.familyecho.com/?p=START&c=smyhm9yyz7&f=165458493399838980	null	minipile	NaturalLanguage	mit	null
Five known melanosome-specific proteins currently serve as immune targets for melanoma, i.e. TYR, TRP1/gp75, TRP2/Dct, Pmel17/gp100 and MART1. Host cellular and humoral immune responses play important roles in autoimmune pigmentary diseases (e.g. vitiligo) but are usually unable to control the growth of primary melanomas or their metastases. We are attempting to identify novel melanocyte-specific proteins expressed by less differentiated melanocytic cells that should provide more immune targets for diagnosis and/or therapy of melanoma. We are also looking at approaches to regulating the expression of genes in melanocytic cells which modulate their growth, and are mapping loci that are closely linked to the growth and metastases of melanomas in various locations on the body. Molecular approaches to clone pigment-related genes have been highly successful, but despite that only 50% of the >200 known pigment-related genes have been cloned leaving many potential melanocyte-specific targets to be identified. Tissue microarray and proteomics approaches to define markers of melanoma progression have also identified useful tumor markers. We have used a more direct approach, i.e. to purify melanosomes and use mass spec microsequencing to identify their protein constituents. We identified 1,500 proteins in melanosomes of all stages of maturation, with 600 in any given stage;they include 16 homologous to mouse coat color genes and many associated with human pigmentary diseases. As a result, we successfully published online the first global proteome database, an early gold standard for future proteomics studies on melanosomes. This project is now focused on identifying novel and specific melanosomal proteins that may prove to be useful targets for the immunodiagnosis and/or immunotherapy of melanoma. We are examining differences in proteins expressed in various stages of melanosomes produced by pigmented and/or by amelanotic melanoma cells. Special emphasis will be made to identify new markers potentially suitable to identify amelanotic melanomas, which are difficult to detect and are highly aggressive. We have also identified the processing and trafficking of GPNMB as another potential marker for melanoma cells. Our research has focused on one of the most frequent causes for failure to detect highly aggressive melanomas, which is the lost expression of melanoma antigens. We have found that melanoma cells lose expression of critical melanoma antigens such as Pmel17/gp100. Further, our work has revealed that Pmel17 expression and processing is tightly linked to the growth of melanoma cells via other critical intracellular signaling intermediates. We have identified SOX9 as a critical transcription factor involved in regulating melanocyte function and proliferation, which is down-regulated in a large number of melanoma cells. Up-regulation of SOX9 expression in melanoma cells is an effective way to inhibit their growth and to decrease their metastatic potential. We have identified approaches to up-regulate SOX9 expression using existing pharmaceutical agents that not only increases SOX9 expression, but increases the sensitivity of melanoma cells to retinoic acid, which might prove to be an effective way to target tumors in melanoma patients. We have also recently identified NUAK2 as an important factor associated with the growth and metastasis of acral melanomas. We are collaborating with Dr. Gottesman's MDR group to define yet another unexpected function of melanosomes, which involves the specific expression of an MDR protein (ABCB5) in melanocytes and its localization in melanosomes. MDR mechanisms underlying the intractability of melanomas to chemotherapy remain largely unknown but are a critical therapeutic challenge. We found that MDR (at least in some melanomas) involves the sequestration of cytotoxic drugs within subcellular organelles (including melanosomes), which significantly reduces their nuclear localization and efficacy. Our study provides evidence that melanosomes contribute to the refractory nature of melanoma cells by sequestering cytotoxic drugs and increasing melanosome-mediated export of drugs. Preventing sequestration of cytotoxic drugs by inhibiting the functions of melanosomes may have great potential as an approach to improve the chemosensitivity of melanoma tumors. We hypothesize that ABCB5 plays an important role in normal melanosomes to ensure that cytotoxic intermediates of melanin synthesis remain within that organelle, which are eventually lost by desquamation of the skin or growth of hair, and we are testing that hypothesis. Regarding our studies of pigmentary disorders, mutations in the TYR gene result in OCA1, the most dramatic and severe form of that disease, where little or no melanin is produced in the hair, skin or eyes. Mutations in the gene encoding TYRP1 affect its interactions with TYR, and result in the hypopigmented phenotype of OCA3. Mutations in Tyr or Tyrp1 elicit the retention of TYR in the ER and its degradation by proteasomes, revealing that OCA1 and OCA3 are in fact ER-processing diseases. OCA2 and OCA4 are relatively severe forms of OCA which arise from mutations in the P and MATP loci, respectively. Both encode highly similar proteins with 12 transmembrane motifs. We found that both OCA2 and OCA4 result from altered trafficking of TYR after processing in the ER and Golgi en route to melanosomes, which reduces pigmentation despite the presence of functionally active TYR. We are testing the hypothesis that P and MATP affect the pH of sorting vesicles leading to disrupted trafficking of TYR to melanosomes. Our studies on the disrupted processing and sorting of TYR in OCA2 and in OCA4 melanocytes explains their hypopigmented phenotypes will provide new insights into the involvement of transporters in the normal physiology of melanocytes. Mutations in sorting determinants also result in a hypopigmentary disease known as HPS, which is due to the misrouting of many cellular components (including melanocyte-specific proteins) and thus has effects on other types of tissues as well as pigmented ones. We are characterizing novel forms of HPS mutations and the mechanisms of disrupted trafficking in mouse melanocyte models and are in the process of characterizing the functions of P and MATP.	null	minipile	NaturalLanguage	mit	null
The present invention relates to disc brakes for vehicles, and in particular to brake pads in disc brakes, such as air-operated disc brakes utilized on commercial vehicles. An example of a commercial vehicle air-operated disc brake is shown in FIG. 1. In the FIG. 1 embodiment the disc brake 1 includes a brake disk 2 which rotates in direction A about its rotation axis B. A brake caliper 3 straddling the brake disk 2 is affixed to a carrier mount 4 which in turn is fixed to a vehicle axle, typically via a torque plate or a brake spider (not illustrated). In this embodiment the carrier mount 4 receives and supports both the caliper 3 and the brake pads 6. The caliper 3 is actuated in this embodiment by a pneumatic actuator (not illustrated) mounted at the actuator mounting face 5 of the caliper. The actuator acts upon a brake pad application mechanism contained within caliper 3 to press the brake pads 6 against the brake disk 2 to slow the vehicle. The present invention is not restricted to a particular type of brake actuator, for example, a pneumatic actuator or an electrically-driven actuator may be used. Nor is the invention limited to a particular type of brake caliper mount arrangement. For example, the brake caliper may be mounted in a fixed manner on a carrier or may be a sliding caliper. In disc brake applications such as commercial vehicle disc brakes the brake pads typically have had a generally rectangular shape, in part due to the limitations on the size and configuration of the disc brake components (the disc brake having to exist within a highly-space constrained envelope provided by wheel rims), and in part due to cost and structural limitations discussed further below. An example of such a previous brake pad is shown in FIG. 4. A common feature of a previous brake pad 20 is their having essentially parallel lateral sides 22, 23, i.e., the brake pad sides facing in the circumferential direction of the brake disc toward adjacent brake pad abutment surfaces are parallel to one another. The generally rectangular shape may include radially inner and radially outer sides of the brake pad 24, 25 that are slightly curved to generally follow the curvature of the brake disc as shown in FIG. 4, or in the case of the radially outer side, follow the shape of an adjacent outer region of the brake caliper (not illustrated). The use of parallel lateral sides of the brake pad has in part been the de facto standard in commercial vehicle disc brakes in part due to practical manufacturing considerations (for example, less costly machining of brake pad abutment surfaces and parallel-sided brake pad backing plates) and in part due to structural reasons to ensure adequate brake pad abutment strength, wear, and braking force absorption performance. With their generally rectangular shape, the previous commercial vehicle disc brake pads have presented to the brake disc essentially constant width and height profiles from one lateral side of the brake pad to the other. Such brake pad shapes have several disadvantages during brake operation. Among these is the fact that the specific braking energy transfer from the brake disc to the brake pad is not constant across the radial height of the brake pad. Instead, the energy transfer varies as a function of radial height relative to the rotation axis of the brake disc (i.e., braking torque varying as a function of the distance from the brake disc rotation axis, where force×distance=torque), and as a function of the length of the friction surface of the brake pad friction material at different radial heights. As a result, the energy transfer to the brake pad, and the resulting localized wear of the brake pad, is inconsistent across the face of the brake pad friction material. This can lead to premature wear of the friction material in some areas of the brake pad and thereby shorten the time before the brake pad must be replaced. The present invention addresses this and other problems by providing a brake pad with more efficient and even braking energy transfer distribution across the face of the brake pad lining material. The approach of the present invention provides for more even pad lining material wear, thereby extending service life of the brake pad. The improved brake pad performance also enables reduction in overall brake size by allowing the use of smaller brake pads while still providing satisfactory braking performance. In an embodiment of the present invention, the brake pad lining material, and preferably the brake pad backing plate carrying the lining material, has a generally arc-shaped profile, with the radially outer portion of the lining material having a width in the circumferential direction that is longer than the width of the lining material at the radially inner portion of the brake pad. Preferably, the width of the brake pad lining material as a function of radial distance from the brake disc rotation axis is established by generally aligning the lateral sides of the lining material along radial lines that intersect at or near the rotation axis of the brake disc. The lateral sides of the brake pad need not be exactly aligned with the radial lines from the rotation axis; rather the present invention contemplates the greatest lining material width at the radially outer region of the brake pad, while the width is smaller at the radially inner region of the lining material. The closer the intersection is to the center of the brake disc rotor, the more efficient the energy distribution at the pad-disc interface. Another further advantage of the present invention is that the reduced width in the radially inner region of the brake pad permits the abutment faces of the brake pad carrier and the lateral sides of the brake pad to meet along a line that is more nearly perpendicular to a radius from the rotation axis. This arrangement allows the transfer braking forces between the lateral side of the brake pad and pad abutment surface of the pad carrier at or nearly normal to the abutment line. This provides for more uniform distribution of the abutment forces over the abutment surface, i.e., more even (and thus lower) contact pressures, helping minimize brake pad vibrations and associated brake noise, improved fatigue life performance and reduce component wear. In addition, the arrangements can help in reducing the effects of “pad kick,” an in-place rotation of the brake pad that can generate undesired brake application noise due to pad vibrations, increase fatigue damage to typical brake pad retaining hardware (e.g., over-pad leaf springs) and increase wear and damage to the brake pad and/or brake caliper mounting structure. An illustration of pad kick is provided in FIG. 4. When a brake pad 101 is applied against a friction surface of a brake disk (not illustrated) which is rotating in direction DR, the brake disk's rotation induces motion and reaction forces between the brake pad 101 and its adjacent mount abutment surfaces (not illustrated). At the leading edge 102 of the brake pad the brake pad attempts to move upward in direction LU in response to the friction forces along the face of the brake pad (illustrated here by force arrows across the face of brake pad 101). At the trailing edge 103 of the brake pad, the brake pad attempts to move downward in direction TD. However, because the brake pad 101 is constrained by adjacent mount abutment surfaces, the overall motion of the brake pad is generally a rotation about an axis parallel to the brake disk rotation axis. This motion may be unilateral during the brake application, or may manifest itself as a moderate-to-severe oscillation of the brake pad in its mount, significantly increasing wear of the abutting brake pad and mount surfaces. One of ordinary skill in the art will recognize that the brake pad support function may be provided by a brake caliper mount designed to support the brake pads, or by a brake pad carrier which is separate from the caliper mounting structure. For convenience in this description, the terms caliper carrier, caliper mount and brake pad carrier may be interchanged without intending to limit the brake par supporting structure to any specific brake pad and brake caliper carrying structure. A further advantage of the present invention is that the reduced width in the radially inner region of the brake pad permits brake pad retention features, such as those disclosed in co-pending application Ser. No. 14/640,152, to be moved closer together to enable further reduction in the size of the disc brake components while maintaining a desired level of braking performance and/or or increasing braking performance by increasing brake pad lining surface area while still keeping overall brake size within the space-constrained envelope of the wheel rim and other nearby components. Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings.	null	minipile	NaturalLanguage	mit	null
We're about: Meet other atheists, agnostics, and people with different religious backgrounds in Korea. We share ideas mostly about atheism and rational thought, debunk superstitions, and discuss morality and what it means to be human.	null	minipile	NaturalLanguage	mit	null
ShortLink v2.5 is a Premium URL Shortner ASP.Net Project. They have a url shortner that help you most to short your link easily and provides a plateform where anyone can short their url. for more information about this script please click On Demo Button. DemoDownload	null	minipile	NaturalLanguage	mit	null
Two weekly sessions of combined aerobic and resistance exercise are sufficient to provide beneficial effects in subjects with Type 2 diabetes mellitus and metabolic syndrome. This study was performed to establish whether only 2 sessions per week of combined aerobic and resistance exercise are enough to reduce glycated hemoglobin (HbA(1c)) and to induce changes in skeletal muscle gene expression in Type 2 diabetes mellitus (DM2) subjects with metabolic syndrome. Eight DM2 subjects underwent a 1-yr exercise program consisting of 2 weekly sessions of 140 min that combined aerobic [at 55-70% of maximal oxygen uptake (VO(2max))] and resistance circuit training [at 60-80% of 1 repetition maximum (RM)]. The training significantly improved VO(2max) (from 33.5+/-3.8 ml/kg/min to 38.2+/-3.5 ml/kg/min, p=0.0085) and muscle strength (p<0.05). Changes over baseline were significant for HbA(1c), reduced by 0.45% (p=0.0084), fasting blood glucose (from 8.8+/-1.5 to 6.9+/-2.2 mmol/l, p=0.0132), waist circumference (from 98.9+/-4.8 to 95.9+/-4.6 cm, p=0.0054), body weight (from 87.5+/-10.7 to 85.7+/-10.1 kg, p=0.0375), systolic blood pressure (from 137+/-15 to 126+/-8 mmHg, p=0.0455), total cholesterol (from 220+/-24 to 184+/-13 mg/dl, p=0.0057), and LDL-cholesterol (from 150+/-16 to 105+/-15 mg/dl, p=0.0004). Mitochondrial DNA/nuclear DNA ratio at 6 and 12 months did not change. There was a significant increase of mRNA of peroxisome proliferator- activated receptor (PPAR)-gamma after 6 months of train - ing (p=0.024); PPARalpha mRNA levels were significantly increased at 6 (p=0.035) and 12 months (p=0.044). The mRNA quantification of other genes measured [mitochondrially encoded cytochrome c oxidase subunit II (MTCO2), cytochrome c oxidase subunit Vb (COX5b), PPARgamma coactivator 1alpha (PGC- 1alpha), glucose transporter 4 (GLUT 4), forkhead transcription factor BOX O1 (FOXO-1), carnitine palmitoyltransferase 1 (CPT-1), lipoprotein lipase (LPL), and insulin receptor substrate 1 (IRS-1)] did not show significant changes at 6 and 12 months. This study suggests that a twice-per-week frequency of exercise is sufficient to improve glucose control and the expression of skeletal muscle PPARgamma and PPARalpha in DM2 subjects with metabolic syndrome.	null	minipile	NaturalLanguage	mit	null
This is a blog dedicated to highlight the issue of Christian Persecution in India. The posts here in contain information about Christian Persecution in India from various sources with links and some exclusive to us. No Copyright infringement is intended. This is only for the purpose of spreading awareness about the ongoing Christian persecution in India. We have no political affiliations. We hope for a nation where all could live in peace with each other. Sunday, October 29, 2006 NEW DELHI, October 27 (Compass Direct News) - Ostracized by their village for the past year, two converts of a church in Madhya Pradesh state's Shahdol district have been beaten for their refusal to return to the Hindu fold. Santu Prasad Barmaia and Kunjan Prasad Barmaia, both farmers and members of a Gospel for Asia church in Paralia village, were attacked by a group of 12 villagers on October 19. The attack took place in the morning, when the two were on their way to their fields, a local Christian requesting anonymity told Compass. Both men suffered internal injuries. Police have not arrested the culprits, the source said, in spite of the fact that the victims named them in a complaint filed at the Amarkantak police station. Police officials could not be reached for comment. The source explained that villagers were angry with the Christians for declining to participate in Hindu rituals since receiving Christ four years ago. "The villagers had been persistently putting pressure on them to 'reconvert' to Hinduism," he said. He added that in the past year villagers have refused to allow the two men, the only Christians in the village, to take water from the hamlet's common well to pressure them to return to Hinduism. In spite of their limited resources, the Christians dug their own well. "Earlier, some miscreants vandalized a Hindu temple in the village and the blame fell on the Christians," the source said. "Later, however, police investigation revealed that they had not done it. Yet the villagers continued to treat them with contempt." Beaten Pastor Jailed In Barghat village in Madhya Pradesh's Seoni district, Pastor Haroon Jonathan continues to languish in jail after police officials failed to fulfill a promise to release him on bail. Jonathan faced charges of "hurting religious sentiments" and "forced conversion" after he was attacked by Hindu extremists in September. Still recovering from his injuries, he turned himself in to police on October 15 after officers promised that he would be bailed out the following day. But submission of formal charges is a prerequisite for obtaining bail, and police did not file them before courts shut down for Diwali (Hindu festival) from October 18 to October 26, said another local source. At press time it was not clear when the charges would be formally filed. Jonathan and several other Christian family members were arrested on September 10 after some 70 Hindu extremists allegedly belonging to the Jagran Dharma Seva ("Service to Awaken Faith") burst into the house church and attacked the congregation. (See Compass Direct News, "More Christians Attacked in Madhya Pradesh, India," September 15). They dragged Jonathan and his wife Anita out of the house, along with in-laws Sunil Prem and his wife Sunita. The four were detained for hurting religious sentiments, promoting religious animosity and forced conversion under the Indian Penal Code and Sections 3 and 4 of the Madhya Pradesh Freedom of Religion Act, or "anti-conversion law." Police claimed to have a tape recording of Jonathan urging people to get rid of any idols or pictures of Hindu deities. The Christians were released on bail, but two more cases were filed against Jonathan, and he was declared as "absconding." On October 18, about 600 local Christians held a rally in Seoni district to protest the increasing attacks in Madhya Pradesh. Jonathan was supposed to have been one of the leaders of the rally. Local police under intense pressure to file charges against owner of prayer meeting home. MUMBAI, India, October 26 (Compass Direct News) - Police this morning arrested a recent convert in Mayapuri, Madhya Pradesh state for the second time in three days in an apparent attempt to pressure him to give evidence that his pastor forcibly converted him. By nightfall in India, the new believer was charged with "insulting religious beliefs." Dewas Gate police again detained Ramesh Thakur, 37, at 9 a.m. after having arrested him on Tuesday (October 24) and releasing him the next day after intense questioning. The pastor of his church in the Mayapuri area of Ujjain district, Jagdish Bharti, had been arrested last June on charges of "insulting religious beliefs" and is still fighting those charges, with his next hearing set for Monday (October 30). R.R. Malvi, police in-charge of the Dewas Gate police station, told Compass that Thakur would continue to be detained while investigations are underway. When Thakur, his pastor and others were arrested on June 4, he was released the same day on bail after four hours of interrogation without being charged. The church holds Sunday prayer meetings at the home of Thakur. "On Tuesday the police barged into Ramesh Thakur's house and ordered him to produce all house documents," Pastor Bharti of the Bethel Fellowship Church told Compass. "However, since he did not have any papers on hand, they took him to the police station, where he was threatened with dire consequences if he were shielding me." The pastor added that police officials inquired, in an intimidating manner, whether Thakur was given the house as an allurement to become Christian. Though Thakur has not yet been baptized, he received Jesus as savior six months ago and has been praying and worshiping at the Bethel Fellowship Church since then. Bharti told Compass that since their arrest on June 4, the Hindu extremist Rashtriya Swayamsevak Sangh (RSS) and its youth wing, the Bajrang Dal, have subjected them to insults, abusive language and threats. Political Pressure to Charge Christians Dilip Akodiya of the Bethel church told Compass that officer Malvi informed him that he was under tremendous political pressure to charge Thakur. Viju Varghese, Global Council of Indian Christians coordinator in Madhya Pradesh, told Compass that the RSS had offered Thakur 25,000 rupees (US$552) to implicate Pastor Bharti in a charge of "allurement" to convert. Indira Iyengar, a former member of the Madhya Pradesh State Minorities Commission, told Compass "The harassment of the Christians just keeps spiraling upwards. Pastor Jagdish and Ramesh Thakur have been continuously harassed by the police, as well as by the Bajrang Dal." Bharti and 15 other Christians had been arrested on June 4 after a mob of Hindu extremists stormed their home prayer meeting in Mayapuri and dragged them to a nearby temple to force them to bow before local gods. Saturday, October 21, 2006 The Chhattisgarh government is targeting a Catholic voluntary health service in Ambikapur diocese after some people charged it with illegal conversion activities, a Church official has said. Since 1995, the Raigarh-Ambikapur Health Association has been functioning from Pathalgoan. The government of undivided Madhya Pradesh state had entrusted it with its Integrated Child Development Services program in one of the 19 Blocks in the district of Surguja. "It has functioned wonderfully well. So much so in the years 1999-2000 this NGO had received state's Birsa Munda award. Satisfied with its works, the MP government had decided to entrust it with yet another Block namely, Odgi Block in Surguja, the same responsibility," a diocesan official said. But "the picture is totally different" now because of motivated allegations of some fanatic groups that accuse the voluntary group of "conversion activities" in the villages where it works. "Inquiries were made from Raipur and even from central government. But their report was in our favor. Accusations of conversions were proved baseless," the Church official said. However, the state government has taken some steps against the organization, the officials said. Since April 2006 some 340 employees were denied of their salary. There are two Religious Sisters belonging to St. Joseph of Lyons Congregation working for of the program, appointed by the government. Seventeen supervisors work under them, who are in charge of 327 workers and co-workers spread out in villages.The government has taken steps to terminate the two religious sisters and 17 supervisors saying that they are improperly appointed. However, the 327 village workers will not be removed from their job, diocesan officials said. The diocese of Ambikapur was erected on December 14, 1977 by dividing Raigarh-Ambikapur diocese. The diocese is co-extensive with the present civil districts of Surguja and Korea in the northern part of the State of Chhattisgarh. Friday, October 06, 2006 Disinformation Campaign against Christians in Jaunpur, UPThe Times of India (Lucknow) reported on 5 Oct 2006 at 0257 hrs on its online internet edition that “Over 300 villagers adopt Christianity” in Belhara village in Jaunpur district, Uttar Pradesh. The report further went on to mention that 350 men and women embraced Christianity in a conversation ceremony held on Oct 3rd. There could not be a worse misrepresentation of facts here. The only iota of truth in the entire news report was that a gathering of a large number of people had taken place on the 3rd, in the home of Sanjay Singh. Some were Christians and some non-Christians who had voluntarily assembled from the nearby villages in Kudupur, who had come together for prayer. Some of them may have been first generation converts, but none of them had embraced Christianity that day in that particular prayer meeting held in the home of Sanjay Singh.Distorted versions of similar news have been featuring everyday in the local edition of the Hindi newspaper, Dainik Jagran since October 3rd. This is inciting the radical Hindutva outfits such as the Vishva Hindu Parishad to take up the issue and with the help of the local authorities bully the local Christian leaders. On October 4, a large team of 70 people including police and VHP personnel barged into Sanjay Singh’s home in order to question him and his involvement in the alleged ‘conversion’ meeting. Apart from the evangelist, Rajendra Chouhan who was leading the prayer meeting on the 3rd, Sanjay Singh was perceived as the ‘co-accused’ since the prayer meeting was being held in his home. They went on to take Sanjay to the police station known as the Kotwali Line Bazaar. He was questioned extensively regarding the prayer meeting and his willful conversion to Christianity was raised up as a big issue. The officials threatened him to go back to the faith of his fore-fathers, and if he didn’t he may have to face ugly consequences. Further, bribe was demanded of him if he wanted to leave the police station that night. The next day on October 5, another team of investigating officers landed up at Sanjay Singh’s home. They alleged to have proof regarding his involvement in forceful conversion of villagers of the area, and that they would check the water well since sources had tipped them off that statues and idols of Hindu gods had been thrown into the well. A thorough investigation by the police team revealed no idol in the well. Incensed at not finding anything, the VHP people present along with the investigating officers broke down portions of the wall of Sanjay Singh’s house. The fact of the matter is that due to rash and biased reporting by a national daily, the lives of many Christians in Jaunpur district are in danger. There are several Christians who have been have been taken in for questioning on October 6, in an unjust manner in Badlapur Police Station, also in Jaunpur district. The four men: Rajesh, Sangram, Rajpath and Lalman were beaten up and interrogated as if they were hardened criminals. The only thing against them is that they are Christians who were present for the meeting on the 3rd at Sanjay Singh’s home.At this moment, Sanjay Singh and his home need protection from Hindutva radical forces. Sanjay Singh was taken in for questioning again today, October 6th, and still hasn’t been released by the authorities.At this moment evangelist, Rajendra Chauhan needs protection for his regular prayer meetings held on Saturdays (10 am – 4 pm) and on Sundays (10 am – 2 pm) held in Kudupur - Bagcha, of Jaunpur district. The VHP people have warned the Christians that they will carry out a re-conversion ceremony on October 8th, and bring back all the converted Christians residing in the area, back to the Hindu fold. Vijayesh LalAssociate CoordinatorCenter for Human RightsEvangelical Fellowship of India	null	minipile	NaturalLanguage	mit	null
Estradiol-17 beta has a biphasic effect on oxytocin secretion by bovine granulosa cells. The peptide hormone oxytocin (OT) and its mRNA are synthesized by bovine granulosa cells. Bovine granulosa cells isolated before the preovulatory LH/FSH surge secrete low amounts of OT and respond to gonadotropins with an increase in OT secretion. After the LH/FSH surge, basal OT secretion increases 20-fold. At the same time, dramatic changes in steroidogenesis occur in the preovulatory follicle. Estradiol-17 beta production is high before and declines after the LH surge. The objective of this study was to determine whether steroid hormones, particularly estradiol-17 beta, influence OT secretion by bovine granulosa cells. Heifers (n = 5) were injected with prostaglandin F2 alpha (PGF2 alpha) on Day 7 of the estrous cycle to induce luteolysis. Preovulatory follicles were obtained during the ensuing follicular phase, 24 h after PGF2 alpha injection (about 24-36 h before the expected time of the preovulatory LH/FSH surge). Granulosa cells were isolated and cultured for 5 days in defined medium containing graded doses (0, 0.001, 0.01, 0.1, 1, 10 micrograms/ml) of estradiol-17 beta, testosterone, or progesterone. Media were collected daily and assayed for OT by radioimmunoassay. Addition of 0.001 or 0.01 micrograms estradiol-17 beta/ml stimulated OT secretion by granulosa cells by about 75% during the last 2 days of culture (p < 0.01). In contrast, estradiol-17 beta at high doses (1 and 10 micrograms/ml) inhibited OT secretion by 45-85% (p < 0.01). Therefore, estradiol-17 beta had a biphasic effect on OT secretion by granulosa cells.(ABSTRACT TRUNCATED AT 250 WORDS)	null	minipile	NaturalLanguage	mit	null
blog I was jointly commissioned by Jinju International Music Festival and Ensemble Opus to write a piano quartet to be performed in Jinju. The Music Festival that has been going on in Jinju is to commemorate Lee Sang Geun, a composer I was jointly commissioned by Jinju International Music Festival and Ensemble Opus to write a piano quartet to be performed in Jinju. The Music Festival that has been going on in Jinju is to commemorate Lee Sang Geun, a composer Changak contemporary music society hosted its annual exchange performance with composers from Xian, China. My work for geomungo and classical guitar was performed again by two great performers, Eun-ja Yoon(윤은자) and Jung-Ryul Kim(김정열). The link contains their premiere in Changak contemporary music society hosted its annual exchange performance with composers from Xian, China. My work for geomungo and classical guitar was performed again by two great performers, Eun-ja Yoon(윤은자) and Jung-Ryul Kim(김정열). The link contains their premiere in Works by Yamamoto Tetsuya, Francesco Filidei, Sirin Nah, Eunkung Park, Sangbong Nam and Jee Soo Shin were performed in February 2014 in Seoul Citizens Hall. Preparation for the event, especially for the performance of Filidei was a rather peculiar sight Works by Yamamoto Tetsuya, Francesco Filidei, Sirin Nah, Eunkung Park, Sangbong Nam and Jee Soo Shin were performed in February 2014 in Seoul Citizens Hall. Preparation for the event, especially for the performance of Filidei was a rather peculiar sight It was an honour to have my work presented alongside with works of Brahms and Penderecki at the winter season of Seoul International Music Festival which took in the week of 16.-20.December 2013 My piano quartet was performed on It was an honour to have my work presented alongside with works of Brahms and Penderecki at the winter season of Seoul International Music Festival which took in the week of 16.-20.December 2013 My piano quartet was performed on impressions@nokha from ulkat films on Vimeo. At this performance, the performers reacted to certain behavioural patterns of the audience, who were given the freedom to wander around the tiny courtyard of a hanok(traditional Korean house) while the performers played impressions@nokha from ulkat films on Vimeo. At this performance, the performers reacted to certain behavioural patterns of the audience, who were given the freedom to wander around the tiny courtyard of a hanok(traditional Korean house) while the performers played	null	minipile	NaturalLanguage	mit	null
Since Present Franklin Delano Roosevelt met with King Ibn Saud on Valentine's Day 1945, the U.S. and Saudi Arabia have maintained a close relationship. For decades, however, critics have warned that this relationship is a fundamentally dysfunctional — and destructive — one. Advertisement: Although a brutally repressive theocratic absolute monarchy that imprisons, tortures and beheads peaceful pro-democracy activists, Saudi Arabia provides its Western allies with a stable, cheap and plentiful oil source and is one of the biggest purchaser of Western weapons. In turn, however, the Saudi regime uses its gargantuan oil revenue to spread its Wahhabi religious fundamentalism throughout the world, and even funnels weapons and supplies to extremist Islamist groups. Peace activists in the U.S. are hoping to change the U.S. relationship with the Saudi regime. In Washington, D.C., on March 5 and 6, approximately 250 activists, human rights experts and scholars gathered for what may have been the first international summit to challenge the U.S. relationship with the theocratic dictatorship in Saudi Arabia. Advertisement: The 2016 Summit on Saudi Arabia was organized by the peace group CODEPINK. It was co-sponsored by a panoply of other organizations, including the Institute for Policy Studies, the Institute for Gulf Affairs, Just Foreign Policy, the D.C. branch of the Women's International League for Peace and Freedom and even the Nation magazine. An important co-sponsor was the Coalition to End the U.S.-Saudi Alliance, a new advocacy group that is pushing for the U.S. to cut its ties with the Middle Eastern monarchy over its brutal human rights violations. The 2016 Summit on Saudi Arabia featured a Who's Who of Saudi dissidents and specialists, along with representatives from the rights organizations Amnesty International, Human Rights Watch and Reprieve. Advertisement: Salon attended the summit, which was filmed and archived by Baltimore-based independent media outlet the Real News. CODEPINK co-founder Medea Benjamin noted that her organization invited supporters of the Saudi regime to appear at the summit, offering them an opportunity to give their side of the story. "We begged members of the Saudi embassy to speak," she said, but no one agreed to do so. Advertisement: Ray McGovern, a former longtime CIA analyst turned anti-war activist, also attended. "Why do American politicians become incontinent when someone mentions the words 'Saudi Arabia'?" he joked. Saudi activist Mohammed al-Nimr spoke at the summit. Mohammed is the son of Sheikh Nimr al-Nimr, a prominent leader in the kingdom's Shia Muslim minority community whom the Saudi regime arrested and executed for leading a peaceful uprising in 2011 and 2012. Salon obtained an exclusive interview with Mohammed, which will be published separately. Renowned scholar Vijay Prashad, a leading expert on foreign policy and international affairs, was the keynote speaker. Advertisement: Prashad detailed what he called "the foreign policy of the 1 percent" — the foreign policy practiced today, one that is based on control of natural resources like oil, the opening of new markets for multinational corporations, expansion of U.S. influence, and an increase in arms sales and militarism. Warning of "suicidal death pact between the U.S. and Saudi Arabia," Prashad proposed the possibility of a foreign policy of the 99 percent, which would be based on respect for human rights, democracy and diplomacy. Salon also sat down with Prashad to discuss the disastrous U.S.-backed wars in Libya, Iraq and Syria. This interview will be published separately. Advertisement: Ali al-Ahmed, a renowned Saudi analyst and the founder of the independent think tank the Institute for Gulf Affairs, kicked off the summit, lamenting that the royal family has "hijacked our country, hijacked our religion." Stressing that it is important to distinguish the Saudi regime from the Saudi people, al-Ahmed said "I am dedicating my life to ending the Saudi monarchy, and any absolute monarchy we have in the region." Al-Ahmed pointed out the irony that the U.S., which was founded in a revolution that challenged the British absolute monarchy, has for decades propped up the Saudi monarchy. "The largest concentration of absolute monarchies in the world are in the Gulf," he noted, and these oil-rich countries, especially Saudi Arabia, have a big influence on Western politics. Advertisement: He noted that the Saudi regime has given tens of millions of dollars to the Clinton Foundation, the Carter Center and the Bush family, while funding prestigious schools like Yale, Harvard and Georgetown. More personally, as a Muslim, al-Ahmed stressed that he is particularly disgusted by what the Saudi monarchy does in the name of Islam. "Saudi Islam is not Islam; it's an Islam of an absolute monarchy," he said. The Saudi scholar argued that the monarchy had "hijacked Islam" and used it as a tool "I am a Muslim, and in my religion monarchies are forbidden," he said. "Islam forbids monarchy. Anyone who tells you otherwise is lying to you." Even in the U.S., al-Ahmed says he has faced some repression for his outspoken activism. Several years ago, he says he was quietly placed on a U.S. government no-fly list, and effectively banned from travel. Al-Ahmed says he threatened to make this public and protested, and was eventually given his travel documents. Advertisement: He warned fellow Americans that the close U.S. relationship with the Saudi regime is harming them too. "The Saudi oil war is hurting the United States," al-Ahmed said. He argued the U.S. reliance on Gulf oil is preventing a move toward alternative, renewable energy sources and is damaging the environment. Al-Ahmed additionally emphasized that the Saudi regime is supporting extremism throughout the world. "Without removing the Saudi monarchy from power, the terrorism will continue," he said. He implored Americans to speak out against their government's policies. "It's really important that you support us, because you are freer. You can speak out; we can't," he said. Advertisement: "We are killing for speaking out," al-Ahmed added, noting the "thousands of political prisoners" languishing in Saudi dungeons. "We need to liberate our people from the Saudi monarchy." Abdulaziz al-Hussan, a Saudi human rights lawyer, also spoke of the plight of reformists in the kingdom. "If you support democracy in Saudi, you will be considered a terrorist," he lamented. Al-Hussan said the 47 people executed by the Saudi regime in January were killed "without due process." Although state-sponsored sectarianism is a big problem in Saudi Arabia, al-Hussan said, at the end of the day, nobody in Saudi absolute monarchy, outside of the royal family, has rights, regardless of whether they are Sunni or Shia. When he worked as a human rights lobbyist in Europe, al-Hussan recalled being "depressed by how nobody wanted to say anything about human rights in Saudi, because of all the money." He criticized "hypocrite governments in the West, who support the violation of human rights for business interests. Al-Hussan said he has seen how the regime's brutality and torture radicalizes people. "You created them, through violence, state violence," he declared. "To stop the violence, we must stop the injustice." He added, "I will never be on the side of the oppressor; I will always be on the side of the oppressed." Saudi journalist Ebtihal Mubarak headed a panel on women's rights in Saudi Arabia. She spoke of the "gender apartheid" that exists in the kingdom. She recalled using this term once on CNN to describe the Saudi regime, "and it upset them," Mubarak said. "Reality should upset them," she added. In Saudi society, women are essentially second-class citizens. They are banned from driving, can only travel when accompanied by a male guardian and face severe legal restrictions. Mubarak was joined by Kristine Beckerle, a fellow at Human Rights Watch, who specializes in Saudi Arabia. Beckerle emphasized that the Saudi regime's male guardianship system is the biggest impediment to women's rights. The "imposition on women's movement goes far behind driving," Beckerle noted. It is illegal for Saudi women to travel abroad without approval of a male guardian, for instance. And the laws for male guardianship are so strange that a 44-year-old mother's 23-year-old son can be considered her legal guardian and could have complete control over her. Male guardians can file legal claims against women in court for "disobedience." In cases where women try to take legal action against male guardians for abuse, then, Beckerle explained, their male legal guardians can file counter-claims for disobedience, and send the woman to prison. "The very fact that male guardianship exists is a huge violation of human rights," Beckerle said. Women getting punished for the crime of their male assailants is not uncommon in Saudi Arabia. Mubarak also pointed out that even Saudi rape survivors have been imprisoned and sentenced to public lashings. There is no civil society in Saudi Arabia. There are no non-governmental organizations, no independent groups and no dissenting political parties. Women face large political, systemic barriers, then, in their fight for equality and justice. Mubarak lamented that the problem that gets the most attention in the West is the Saudi ban on women driving, "but there are much more catastrophic problems that women face," she said. Saudi men "have all this power in their hands," Mubarak said. But this is not necessarily because they are uniquely patriarchal, she stressed — women in Western countries face structural impediments to equality too — but rather because Saudi men are given this much power in an autocratic regime. The Saudi regime's "favorite narrative" is that the Saudi people are very conservative, but the monarchy is a progressive force that can balance these supposed widespread views, Mubarak explained. But she said this argument is false. "There are certain things the government could do tomorrow that could really help women's lives," Beckerle noted. She also pointed out that coverage of the Saudi regime in the Western media is often very euphemistic. Reports will applaud minor developments as a "small steps for Saudi women" while ignoring the much larger structural oppression Saudi women face in a regime strongly backed by Western governments. Experts from leading human rights organizations also spoke of the Saudi regime's egregious record. Julianne Hill, of Reprieve, discussed the widespread use of executions and torture in Saudi Arabia. Seventy-two percent of people on death row were on for non-violent offenses, mostly involving drugs or dissent, she explained. Sixty-nine people of those executed by the Saudi regime were killed for non-violent offenses. Saudi courts are political, not impartial, Hill explained, and torture is frequently used to extract confessions from people who were arrested. In most cases, confessions are the primary basis for sentencing. Hill recalled an incident in which a young man who was imprisoned and tortured by the Saudi regime signed a blank sheet of paper as a "confession." Text was later put on the paper he signed, although he never even saw the text. Foreign nationals who do not speak Arabic are often forced to sign confessions they don't understand, Hill explained, and these kinds of confessions have been used to justify executions. The Saudi regime also often arrests and sentences to death juveniles. Saudi Arabia is a signatory on Convention on the Rights of the Child human rights treaty, however, so it waits until the minors it sentenced to death become adults; then it kills them. Sharat Lin, an expert on the exploitation of migrant labor in Saudi Arabia, also spoke about the plight of mostly South Asian immigrants in the Saudi regime. Lin worked in Saudi Arabia for several years, but was eventually expelled from the country for reporting on corruption in his job. Gulf regimes frequently rely heavy on migrant workers, whom they intensely exploit, sometimes in slave-like conditions. In Saudi Arabia, migrant workers are paid significantly less, and Saudi nationals are preferentially treated throughout the economy. Blasting "the totalitarian government which is controlled by the royal family," Lin noted that "corporate America played a role in creating a highly discriminatory" environment in Saudi Arabia. Sunjeev Bery, advocacy director for Middle East North Africa issues at Amnesty International USA, criticized the U.S. for its hypocrisy on the Saudi regime. Islamophobic pundits in the West frequently ask "Where are the Islamic reformers?," Bery noted, but "a major U.S. ally has put them in prison." Bery explained that all public gatherings in Saudi Arabia are essentially prohibited, unless they receive approval by the regime. He also pointed out that the rights of other minority groups — such as the religious rights of Filipino Christian workers — are not at all respected. The Amnesty official expressed special concerns about the brutal war Saudi Arabia has been leading in Yemen since March 2015. A coalition led by Saudi Arabia has relentlessly bombed civilian areas in Yemen for approximately a year. The Saudi-led coalition has targeted hospitals, residential homes, refugee camps and even an Oxfam humanitarian aid warehouse. It has even dropped widely banned cluster munitions on civilian areas. Human rights organizations and the U.N. have accused the U.S.-backed, Saudi-led coalition of war crimes. Bery said the Saudi regime declared an entire province in Yemen to be a legitimate military target, with no differentiation between military and civilian, in violation of the laws of war. "From Amnesty International's perspective, there is no legal basis" for the U.S. support for the Saudi regime in its war on Yemen, Bery said. "There is no legal justification." He pointed out that, because the U.S. media has barely reported on the U.S.-backed war in Yemen, "most people don't even know." The Amnesty official also pointed out that Saudi Arabia's "reckless mass bombardment of Yemen is expanding the operating space of al-Qaida and ISIS — that is a fact." There were several more panels at the summit. Institute for Policy Studies analyst Phyllis Bennis spoke of the history of the U.S.-Saudi relationship. She detailed how Saudi Arabia's position as an oil giant emerged, with the company Aramco, and argued the U.S.-Saudi oil pact "was not only about access; it was more about control." In the Cold War, Bennis recalled that the Saudi regime was a reliable opponent of leftist and Arab nationalist movements, which the U.S. opposed. Describing U.S. foreign policy in the Middle East in its fight against communism, Bennis quoted President Dwight D. Eisenhower, who quietly insisted to White House staff "we should do everything possible to stress the 'holy war' aspect." Activist and writer Raed Jarrar spoke of the overall disastrous U.S. policy in the Middle East, describing it as a source of instability, death and destruction. The U.S. should "stop being accomplices to and supporters of crimes committed in the region," he argued. William Hartung, the director of the Arms and Security Project at the Center for International Policy, detailed how the U.S. has ramped up enormous arms sales to Saudi Arabia in recent years. Likening the Obama Doctrine to the Nixon Doctrine, Hartung noted that there have been at least $195 billion arms sales under Obama, more than any administration since WWII, and that much of this has gone to the Saudi regime. The war in Yemen, which he called "the silent war," "is essentially one big war crime, wrapped into one campaign," Hartung said. Scholar Robert Vitalis argued analysts should look beyond just oil at other reasons the U.S. maintains a close relationship with the Saudi regime. Bahraini politician and human rights activist Matar Matar spoke of Saudi influence over Bahrain, and the U.S.-backed invasion of Saudi troops in order to quell the 2011 pro-democracy uprising. He recalled Bahraini activist Ali Sager, who was imprisoned by the Western-allied regime and tortured to death. Matar also criticized U.S. imperialism in his country, and spoke of the "de-democratization of Bahrain" after it became home to the U.S. Navy Fifth Fleet. Activist Mohammed al-Shami also spoke of Saudi war in Yemen and the history of Saudi influence over the impoverished country in the southern Arabian Peninsula. Jamal Abdi, of the National Iranian American Council, spoke of how the Saudi regime tried to jeopardize the U.S. nuclear deal with Iran. Abdi criticized the visa restrictions the U.S. imposed on Iranians and Iranian dual nationals. He also spoke of how the U.S. is essentially "renting" the Saudi army to carry out the war in Yemen, and potentially even Syria. Daniel Arshack, the lawyer for the imprisoned Saudi attorney and human rights activist Waleed Abu al-Khair, blasted the hypocrisy of the U.S., a country founded on opposition to monarchism, propping up the most oppressive absolute monarchy on the planet. Sanam Naraghi-Anderlini, the executive director of the International Civil Society Network, wrapped up the summit with a reflection on the Saudi regime's egregious human rights record and large influence in the U.S. Naraghi-Anderlini noted that Saudi Arabia spends at least $240,000 per month on PR firms in Washington, D.C. alone, and works with lobbying powerhouses like the Podesta Group. She accused the Saudi regime of spreading "stealth sectarianism," of framing its political conflict with Iran "as a sectarian issue," while simultaneously "spreading Wahhabi sectarianism." "We need to stop thinking that being against something is enough," Naraghi-Anderlini said, and called for further political action. The growing conversation around challenging the close U.S. relationship with Saudi Arabia, she added, is "the most important foreign policy discussion having right now, and it's not on TV."	null	minipile	NaturalLanguage	mit	null
Dairy Farm Business Strategic Review results in $3.65 million in new investment Rural Business Support’s highly successful Dairy Farm Business Strategic Review has assisted more than 50 dairy family businesses in the past two years, contributing to more than $3.65 million in new investment by the program’s participants. The pilot program in 2016 was funded by a grant from the South Australian Government through PIRSA. The rollout in 2017 was funded by DairySA, the SA Dairy Industry Fund and PIRSA. RBS also acknowledges the support of the dairy industry at state and national level. This is what some of the dairy families had to say about the program. “Absolute necessity” “I was sceptical – but it’s useful and full of fresh ideas” “Great way to evaluate where your business is at and where you are heading” “We have greater understanding of our farm productivity and profitability” “Very helpful for assessing future investment plans” “It is not intimidating – the facilitators are respectful and knowledgeable” “Great that it is a specific and tailored plan for every farm” “The program gives you goals, deadlines and the confidence to move forward” “Well organised and to the point” “Definitely do it!” “As a participant in the pilot I recommend this to all dairy families” – John Hunt SADA Building on its success in the dairy industry, the Farm Business Strategic Review has also been piloted with 10 pork families. In 2018 the Grains Industry Farm Business Strategic Review will be rolled out – find out more here.	null	minipile	NaturalLanguage	mit	null
Our location on the south shore of Lady Bird Lake, in the heart of the new Lakeshore District, puts us just minutes from everywhere you want to be in Austin. And we mean minutes. By car, by bike - or with your own running shoes - you can get where you’re going without the hassles of traffic and wasted time. With rents significantly lower than downtown, and transportation costs - including cab fares - far lower than what you’ll rack up further out, you’ll have extra money in your pocket. That’s freedom to have an extra drink at Liberty bar, catch another show at Emo's, or even head to the airport for a weekend getaway.	null	minipile	NaturalLanguage	mit	null
--- author: - 'Nathan Musoke,' - Richard Easther bibliography: - 'bib.bib' - 'autobib.bib' title: 'Expectations for Inflationary Observables: Simple or Natural?' --- Introduction {#sec:introduction} ============ Inflation has been part of the conventional cosmological narrative of the evolving universe since the early 1980s [@Guth:1980zm; @Linde:1981mu; @Albrecht:1982wi] and can account for key observations, including the overall flatness, isotropy, homogeneity of the universe, and the nearly scale-invariant spectrum of perturbations. However, there is no clear and compelling “standard model” of inflation, making it difficult to formulate conclusive tests of the overall paradigm. There are two broad approaches to establishing generic properties of the inflationary phase within the framework of slow-roll inflation driven by a single scalar field with a canonical kinetic term. The first stipulates that the inflationary potential is algebraically [simple]{}, with monotonic derivatives and an elementary algebraic form [@Boyle:2005ug; @Bird:2008cp; @Boyle:2008ri; @Ijjas:2013vea]; the quadratic and quartic potentials are the canonical examples. For simple scenarios the tensor to scalar ratio $r$ is typically $r \gtrsim 0.1$, while values of $r\lesssim 0.01$ appear fine-tuned. However, relatively large values of $r$ suggest that the inflaton field makes a super-Planckian excursion during the course of inflation [@Lyth:1996im]. At large VEVs generic Planck scale operators contribute significantly to the potential; these contributions must be fine-tuned if the potential is smooth and flat over a trans-Planckian field range, a violation of technical [naturalness]{}. From this perspective, a very small ($r\ll10^{-3}$) tensor background is the more likely outcome. As a consequence, [simple]{} and [natural]{} are far from synonymous in the context of inflation. The tension between these viewpoints is resolved if a symmetry suppresses Planck-scale and other very high energy corrections to the potential. Within string theory, this approach leads to the identification of scenarios such as monodromy inflation [@Baumann:2014nda; @Silverstein:2008sg; @McAllister:2008hb; @Flauger:2009ab] which generate a significant tensor spectrum in a framework whose stability against ultraviolet corrections can be directly assessed. Likewise, an effective single-field model can arise as a cooperative effect among many individual fields, each of which makes a sub-Planckian excursion [@Liddle:1998jc; @Copeland:1999cs; @Kanti:1999vt; @Kanti:1999ie; @Dimopoulos:2005ac; @Easther:2005zr]. The status of inflationary models is usefully discussed from a Bayesian standpoint [@Easther:2011yq; @Planck:2013jfk; @Martin:2013nzq; @Ade:2015lrj]. Rather than performing parameter estimation for empirical observables associated with the primordial perturbations such as $n_s$ (spectral index), $r$, $A_s$ (amplitude), $\alpha_s$ (running) or $f_{NL}$ (non-Gaussianity), candidate inflationary models can be defined by the [prior]{} specifying the functional form of the model and the distributions from which its free parameters are drawn. In many cases a natural measure on the inflationary parameter space map to highly non-uniform and strongly correlated distributions for $n_s$, $r$ and $\alpha_s$ [@Easther:2011yq; @Adshead:2010mc]. Furthermore, Bayesian methodology addresses the inflationary model selection problem via the [evidence]{} for each identified inflationary scenario. For a model with an $m$-dimensional parameter vector $\bar a$ drawn from a joint distribution $P(\bar a)$ the evidence is $$\label{eq:evidence} E= \int da^m P(\bar a) {\cal L}(\bar a)$$ where ${\cal L}(\bar a) $ is the likelihood derived from a specified set of observations and $P(\bar a)$ is normalised to unity [@Jenkins:2011va; @Easther:2011yq; @Planck:2013jfk; @Martin:2013nzq; @Ade:2015lrj]. If two models $M_1$ and $M_2$ are [a priori]{} equally likely, $E_1/E_2$ is the odds ratio for the two scenarios; if the relative prior likelihood of $M_1$ and $M_2$ is $P(M_1) / P(M_2)$ then the odds ratio becomes $E_1 P(M_1)/E_2 P(M_2)$. Quantitative treatments of inflationary model selection typically assume that the $P(M_j)$ are equal, where $j$ labels the models under consideration. The statement that a model is fine-tuned can reflect external knowledge regarding the model’s physical origin, resulting in a stipulation that the corresponding $P(M_i)$ is small. Alternatively, fine-tuning may become apparent when parameter estimation reveals that the posteriors of one or more free parameters differ greatly from a physically motivated prior. In some cases this tuning, and thus the impact on $P(M_j)$, can be quantified. For example, given a “new physics scale” $\Lambda$ it is well-known that the effective mass $m^2$ of a scalar field with bare mass $m^2_b$ is $$m^2 = m^2_b + f_2 \Lambda^2$$ where $f_2$ is expected to be of order unity [@Baumann:2014nda]. With $\Lambda \sim {\ensuremath M_\text{Pl}}$, a uniform distribution for $f_2$, and in the absence of an underlying symmetry controlling $f_2$ it can appear that $P(M_{\tiny \rm quad }) \sim 10^{-11}$ since successful quadratic inflation requires $m^2 \sim 10^{-11} {\ensuremath M_\text{Pl}}^2$. While attempts to identify truly canonical attributes of the inflationary paradigm have been largely futile, the accuracy and precision of measurements of the primordial perturbations has improved dramatically over the last 25 years [@Adam:2015rua; @Ade:2015xua; @Ade:2015lrj]. In particular, current constraints on $n_s$ and $r$ barely with overlap the region of parameter space open to the quadratic model, while the quartic potential has been disfavoured by observations since the first WMAP data release [@Peiris:2003ff]. It is thus unlikely that very simple implementations of the inflationary paradigm are consistent with observational constraints. In Bayesian terms, this allows us to update inflationary priors in light of data. Consequently, although we cannot draw inferences about the detailed structure of high energy physics, we can state with increasing confidence that (for example) it is unlikely our universe underwent a period of inflation driven by a potential that is quadratic or steeper. The immediate goal of this paper is to fully assess the possible observable consequences of inflation due to a single scalar field with a 4-th order polynomial. This is the most general renormalizable potential for a minimally coupled scalar field. Moreover, this is the simplest polynomial that supports inflection point inflation [@Okada:2016ssd; @Allahverdi:2006iq; @Lyth:2006ec; @BuenoSanchez:2006rze; @Martin:2013nzq] while being bounded below, so it yields both large field and small field inflation [@Dodelson:1997hr]. Clearly this is not a new model; to our knowledge this scenario was first explicitly analysed in 1990 [@Hodges:1989dw; @Hodges:1990bf], with a focus on its ability to support designer scenarios with broken scale invariance in the large-field regime. In addition, Ref. [@Bird:2008cp] gives a Monte Carlo sampling of the parameter space, Ref. [@Destri:2007pv] presents an analysis of possible observable outcomes with constraints from early WMAP data, Ref. [@Aslanyan:2015hmi] provides up-to-date constraints on potential parameters, and Ref. [@Fowlie:2016jlx] performs a Bayesian analysis in the context of the hierarchy problem. Our treatment adds to previous discussions by a) presenting a more complete analysis of the possible observables including the spectral running; b) stating clear “inflationary priors” that will facilitate parameter estimation and model selection calculations; c) treating these model specifications as hyperpriors for a generative model [@Price:2015qqb] of the spectrum and computing distributions for the usual spectral parameters, showing that these are highly nonuniform; d) providing a qualitative analysis of the extent to which these inflationary priors can be updated with reference to present-day data, and e) showing that data from plausible future experiments could potentially rule out [all]{} inflationary scenarios based on the single-field 4-th order potential. In particular, although the catalog of inflationary behaviours available to a 4-th order polynomial potential populates a substantial subset of the $\{n_s,r,\alpha_s\}$ parameter-space, a significant fraction of this region is revealed to be incompatible with the potential and near-future experiments will have the ability to exclude the full parameter space. This is a key result of this paper: the 4-th order polynomial – the most complex potential compatible with the tree-level action of a single, renormalizable, minimally coupled scalar field – can be falsified by experiments that are part of the current roadmap for experimental cosmology. The physical basis of this result is that parameter combinations that predict smaller values of $r$ tend to have larger values of $\alpha_s$ [@Boyle:2008ri; @Adshead:2010mc; @Munoz:2016owz]. We do not find scenarios where both parameters are vanishingly small and $n_s$ lies inside its currently permitted range, so even null results for both $r$ and $\alpha_s$ could rule out a 4-th order potential. This analysis sets the stage for a broader discussion of the status of fine-tuning in inflationary cosmology. Our results allow us to construct priors based on a variety of physically motivated expectations for values of parameters in the potential, from which we derive distributions for $n_s$, $r$ and $\alpha_s$. These are typically highly non-uniform and effectively quantify the degree of tuning associated with different values of the empirical spectral parameters. Furthermore, in some regions of parameter space the pre-inflationary initial conditions must themselves be chosen carefully in order for inflation to begin, further heightening the degree of tuning these models require. The prospect of all putatively simple models being ruled out by observations forces a closer evaluation of the naturalness of these scenarios. Given that even simple potentials are more plausible when embedded in more complex theories we argue that this development need not immediately undermine confidence in the overall inflationary paradigm. However, if the simplest potentials are ruled out, arguments that inflation is natural must increasingly be framed within the context of more general discussions about the properties and nature of ultra-high energy physics. Inflationary Dynamics {#sec:the_model} ===================== A minimally coupled scalar field with a canonical kinetic term and potential $V(\phi)$ obeys the Klein-Gordon equation, $$\ddot{\phi}+3H\dot{\phi}+V'(\phi) = 0\,,$$ where $H$ is the Hubble parameter. The scale factor $a(t)$ is described by the usual Friedman equation $$H^2 = \left(\frac{\dot{a}}{a}\right)^2 = \frac{1}{3{\ensuremath M_\text{Pl}}^2}\left[\frac{1}{2}\dot{\phi}^2 + V(\phi)\right]\, ,$$ where ${\ensuremath M_\text{Pl}}$ is the (reduced) Planck mass. Our analysis is based on the generic quartic potential, the most complicated renomalizable tree-level action a single scalar field can possess $$V(\phi) = \sum_{i=0}^4 c_i \phi^i\, .$$ We require that the potential has a global, stable minimum at $\phi_\text{min}$ with $V(\phi_\text{min}) = 0$; a linear shift can always give $\phi_\text{min} = 0$. As a consequence of these criteria we fix $c_0 = c_1 = 0$, $c_2 > 0$ and $c_4 >0$ so $$\label{eq:v_phi} V(\phi) = \frac{m^2}{2} \phi^2 - \frac{g}{3} \phi^3 + \frac{\lambda}{4} \phi^4$$ with $\lambda > 0$. We also choose $g \ge 0$ without loss of generality since the underlying theory is invariant under $\phi \rightarrow -\phi$ if $g \rightarrow -g$. Inflationary observables may be characterised by the potential slow roll parameters [@Liddle:1994dx] $$\begin{aligned} \label{eq:epsilon_approx} \epsilon &= \frac{{\ensuremath M_\text{Pl}}^{2}}{2} \left( \frac{V'}{V} \right)^2 \, , \\ \label{eq:eta} \eta &= {\ensuremath M_\text{Pl}}^{2} \frac{V''}{V} \, , \\ \label{eq:xi} \xi &= {\ensuremath M_\text{Pl}}^{4} \frac{V'}{V} \frac{V'''}{V} \, .\end{aligned}$$ Inflation occurs when $\epsilon \lesssim 1$. The slow roll parameters specify the inflationary observables, $$\begin{aligned} \label{eq:n_s} n_s - 1 &\approx -6 \epsilon + 2 \eta \, , \\ r &\approx 16 \epsilon \, , \\ \alpha_s &\approx 16 \epsilon \eta - 24 \epsilon^2 - 2 \xi \, .\end{aligned}$$ These quantities are evaluated at the field value ${\ensuremath \phi_{N}}$ corresponding to the instant at which the corresponding mode leaves the horizon, $N$ $e$-folds before the end of inflation, with $$\label{eq:N_integral} N = \frac{1}{{\ensuremath M_\text{Pl}}^2} \int_{\phi_{end}}^{{\ensuremath \phi_{N}}} \frac{V(\phi)}{V'(\phi)} d \phi .$$ A 4th-order potential can have up to three local extrema. Given that $\lambda > 0$, $V(\phi)$ may have either two local minima (including a global minimum) and a local maximum, a global minimum and a saddle point, or a single, global minimum. The ratio $M_{Pl} V'/V$ goes to zero at large $\phi$ so this potential certainly supports inflation at very large field values. However, the potential can have an inflection point at arbitrary values of $\phi$, in the vicinity of which $V'/V$ is small enough to support inflation. Consequently, there are two distinct inflationary regimes – the large-field case and a possible small field case around an inflection point – and we analyse them separately. Small Field: Observables From Inflection Point Inflation {#sec:analysis} ======================================================== Inflection point potentials have been studied in many contexts. Some are motivated by particle physics, e.g. an inflection point added to monomial chaotic models through radiative corrections [@Ballesteros:2015noa], Higgs potentials [@Okada:2016ssd], the minimal supersymmetric standard model (MSSM) [@Allahverdi:2006iq; @Lyth:2006ec; @BuenoSanchez:2006rze; @Martin:2013nzq], D-brane inflation [@Baumann:2007np; @Baumann:2007ah], or loop inflection-point inflation [@Dimopoulos:2017xox]. The 4-th order model looked at here is discussed by Martin, Ringeval and Vennin [@Martin:2013tda], who dub it Renormalizable Inflection Point Inflation.[^1] We begin by noting that the potential has an exact saddle point at $\phi = g/2\lambda$ when $m^2 = \frac{g^2}{4 \lambda}$ and reparameterize via $$m^2 = \frac{g^2}{4 \lambda} (1 + \delta) \, . \label{eqn:mmpert}$$ If the dimensionless parameter $\delta$ is negative we have a trapping potential[^2] and $\delta =0$ is the saddle point limit. Our first task is to determine the overall inflationary region inside the potential. The slope $V'$ is minimized at $$\phi_\text{inf} = \frac{g \bigl( 2 \pm \sqrt{1-3\delta} \bigr)}{6 \lambda} \, . \label{}$$ The positive root coincides with the saddle location when $\delta=0$ and this inflection point only exists if $\delta<1/3$. We will see that a realistic inflationary phase requires $\delta \ll 1/3$, so we write $$\phi_\text{inf} \approx \frac{g}{2 \lambda} \Bigl(1 - \frac{\delta}{2}\Bigr) = M \Bigl(1 - \frac{\delta}{2}\Bigr) \label{}$$ and make the identification $g = 2 \lambda M$. Changing variables to $\psi = \phi - \phi_\text{inf}$ and dropping terms beyond first order in $\delta$ gives $$V(\psi) = \frac{\lambda}{12} \left[ M^{4} (1 + 6 \delta) + 12 M^{3} \delta \psi + 2 M \psi^{3} \left(- 3 \delta + 2\right) + 3 \psi^{4} \right] . \label{potential_psi}$$ Note that the quadratic term would be proportional to $\delta^2$ and is thus absent in this approximation. The overall minimum lies at exactly $\psi=-M$ with $V(-M)=0$. The shape of the potential is determined by the parameters $M$ and $\delta$, while its overall scale is fixed by $\lambda$. Since inflation occurs when $\phi \approx M$ the total field excursion is of order $M$. In this section we assume $M \le {\ensuremath M_\text{Pl}}$, i.e. small field inflation. The $\psi^4$ term in equation (\[potential\_psi\]) ensures the potential is bounded below. During a viable inflationary phase $V'/V$ and $V''/V$ are both small. Dropping higher order terms in $\delta$ and noting that $V$ changes much more slowly than $V'$ and $V''$ near $\psi=0$, we approximate the slow roll parameters as $$\begin{aligned} \label{eq:epsilon_approx_inf} \epsilon & \approx \frac{72 {\ensuremath M_\text{Pl}}^{2}}{M^2} \left( \delta + \frac{\psi^2}{M^2} \left( 1 - \frac{3}{2} \delta \right)\right)^{2} \\ \label{eq:eta_inf} \eta & \approx 12 \frac{{\ensuremath M_\text{Pl}}^{2} \psi }{M^{3}} \left(2 - 3 \delta\right) \\ \label{eq:xi_inf} \xi & \approx 288 \delta \frac{{\ensuremath M_\text{Pl}}^{4}}{M^{4}} \left(1 + 3 \frac{\psi}{M}\right) \,.\end{aligned}$$ To have any inflation at all we need $\epsilon<1$ at $\psi=0$, so $$\label{eq:delta_max} \delta \lesssim \frac{\sqrt{2}}{12} \frac{M}{{\ensuremath M_\text{Pl}}} \equiv \delta_{\text{max}}\, .$$ If $M \lesssim {\ensuremath M_\text{Pl}}$ this immediately implies $\delta \lesssim 0.1$, justifying our decision to retain only terms first order in $\delta$. We also need the higher order slow roll parameters to be small. By definition, $V''=0$ at an inflection point, so $\eta=0$ when $\psi=0$ and we do not find a new constraint. However, writing $\delta = c\delta_{\text{max}}$ and substituting into $\xi$ we find $$\xi \approx +c \frac{24 \sqrt{2} {\ensuremath M_\text{Pl}}^3}{M^3} \, .$$ The full hierarchy of slow roll equations (in either the potential or Hubble slow roll formalism [@Liddle:1994dx]) shows that $d \epsilon /d N$ and $d \eta /d N$ are large if $\xi \ge 1$ so the inflationary region of the potential is very narrow and the number of $e$-folds $N$ less than unity. Consequently, $N$ and $\alpha_s$ are correlated in generic slow roll models [@Easther:2006tv]; current observational bounds on $\alpha_s$ and ensuring $N \gtrsim 30$ both require $\|\xi\| \lesssim 0.01$ at $\psi=0$, or $$c \lesssim \frac{0.01}{24 \sqrt{2}} \left(\frac{M}{{\ensuremath M_\text{Pl}}}\right)^3 \, .$$ Since $\delta = c \delta_{\text{max}}$, combining with equation yields $$\label{eq:delta_max2} \delta \lesssim \frac{0.01}{288} \left(\frac{M}{{\ensuremath M_\text{Pl}}}\right)^4 \,;$$ decreasing $M$ by an order of magnitude decreases this upper bound on $\delta$ by four orders of magnitude. If $M \sim 10^{-2} {\ensuremath M_\text{Pl}}$ the cubic term is tuned to parts in $10^{12}$, independently of the constraint on $\lambda$ required to produce a suitable amplitude for the perturbation spectrum. This relationship is illustrated in Figure \[fig:N\_total\]. Similar tuning requirements have been seen in the analysis of other models with inflection points, including MSSM motivated potentials [@BuenoSanchez:2006rze] and accidental inflation [@Linde:2007jn]. This fine tuning can be reduced by adding a constant term to the potential , decreasing $V'/V$ and effectively flattening the potential [@Enqvist:2010vd; @Hotchkiss:2011am]. The trade-off is that $V(\phi_{\text{min}}) > 0$, making the model unrealistic in the absence of a mechanism to subsequently ensure that the vacuum energy becomes vanishingly small. ![ The total number of $e$-folds of inflation $N$ as function of $\delta$ for representative values of $M$, found by numerically integrating . The value of $\delta$ required for a fixed number of $e$-foldings scales as $(M/{\ensuremath M_\text{Pl}})^4$, consistent with the constraint . []{data-label="fig:N_total"}](N_total){width="0.8\linewidth"} To compute $N$ note that inflation begins and ends when $\epsilon \approx 1$, or $$\begin{aligned} \label{eq:psi_end_sq} {\ensuremath \psi_{\text{end}}}^{2} &\approx \frac{M^2}{1 - \frac{3}{2}\delta} \left( -\delta \pm \frac{\sqrt{2}}{12} \frac{M}{{\ensuremath M_\text{Pl}}} (1+6\delta) \right) \, . \end{aligned}$$ Since $\delta \ll \delta_\text{max}$, inflation ends at $$\begin{aligned} \label{eq:psi_end} {\ensuremath \psi_{\text{end}}}&\approx - \frac{2^{\frac{1}{4}} \sqrt{3}}{6} M \sqrt{\frac{M}{{\ensuremath M_\text{Pl}}}} .\end{aligned}$$ When expressed as a function of $\psi$ the minimum of the potential is at $\psi=-M$; the relative width of the inflationary saddle scales as $\sqrt{M/{\ensuremath M_\text{Pl}}}$ and $\psi_{\text{begin}} \approx - {\ensuremath \psi_{\text{end}}}$. We can now evaluate the integral in ; if $\delta=0$ it is formally divergent for ${\ensuremath \psi_{N}}\ge 0$, and $N$ is apparently infinite. For $\delta \ne 0$ can be solved approximately by setting $V= V(0)$ and taking only the two lowest order terms in $V'$: $$\begin{aligned} N &\approx \frac{1}{12} \frac{M^3}{{\ensuremath M_\text{Pl}}^2} \int_{{\ensuremath \psi_{\text{end}}}}^{{\ensuremath \psi_{N}}} \frac{ 1 }{ M^{2} \delta + \psi^{2} } d \psi \\ &= \label{eq:N_integral_soln} \begin{cases} \frac{1}{12} \left(\frac{M}{{\ensuremath M_\text{Pl}}}\right)^2 \frac{1}{\sqrt{\delta}} \arctan\left( \frac{1}{\sqrt{\delta}} \frac{\psi}{M} \right) \bigg\|_{{\ensuremath \psi_{\text{end}}}}^{{\ensuremath \psi_{N}}} & \delta \ne 0 \\ - \frac{1}{12} \frac{M^{3}}{{\ensuremath M_\text{Pl}}^2} \frac{1}{\psi} \bigg\|_{{\ensuremath \psi_{\text{end}}}}^{{\ensuremath \psi_{N}}} & \delta = 0 \end{cases} \,.\end{aligned}$$ These expressions apparently disagree in the limit $\delta\to0$ but the identity $\arctan(x) = -\arctan(1/x) - \pi/2$ makes their overlap manifest when ${\ensuremath \psi_{N}}$ has the same sign as ${\ensuremath \psi_{\text{end}}}$: $$\begin{aligned} N &\approx - \frac{1}{12} \left(\frac{M}{{\ensuremath M_\text{Pl}}}\right)^2 \frac{1}{\sqrt{\delta}} \arctan\left( \sqrt{\delta} \frac{M}{\psi} \right) \bigg\|_{{\ensuremath \psi_{\text{end}}}}^{{\ensuremath \psi_{N}}} \\ &\approx - \frac{M^{3}}{12 M_{pl}^{2} \psi} + \frac{\delta}{36} \frac{M^{5}}{{\ensuremath M_\text{Pl}}^{2} \psi^{3}} \qquad \text{for} \qquad 0 \leq \frac{\sqrt{\delta} M}{{\ensuremath \psi_{N}}} \ll 1 \,.\end{aligned}$$ Consequently, when $\delta \rightarrow 0$ and $M < {\ensuremath M_\text{Pl}}$ the field value at the pivot scale is approximately $$\label{eq:psi_n_approx} {\ensuremath \psi_{N}}\approx - \frac{1}{12} \frac{M^3}{{\ensuremath M_\text{Pl}}^2} \frac{1}{N} .$$ We need $\delta \ll 1$ for successful inflation but equation (\[eq:psi\_n\_approx\]) is valid only when $\delta$ is smaller than the bound in eq. : as this bound becomes saturated the inflationary phase is relatively short and the pivot scales leaves the horizon when $\psi_N>0$. In this case $\eta$ changes sign during the observationally relevant phase of inflation and when $\eta$ is positive $n_s$ can exceed unity. However, for fixed $N$ there is a lower limit on $n_s$. This behaviour can be deduced from a slow roll analysis, and is apparent in the plots of $n_s$ and $r$ shown in Ref. [@Bird:2008cp] for the spectral parameters 60 $e$-folds before the end of inflation. Similar behaviour is also seen in the related model studied in Ref. [@BuenoSanchez:2006rze]; for a given $r$ there is sharp lower bound on $n_s$, and no clear upper bound. The matching equation connects present-day scales to the inflationary era [@Liddle:2003as; @Adshead:2008vn; @Adshead:2010mc]; assuming instant thermalization after inflation it is $$\begin{aligned} N &= 56.12 + \frac{1}{4} \log \frac{2}{3} + \log\left(\frac{V_N^{1/4}}{V_\text{end}^{1/4}}\right) + \log\left(\frac{V_N^{1/4}}{10^{16} \text{~GeV}}\right) \\ \label{eq:matchin_equation_with_subs} &\approx 61 + \frac{1}{4} \log \lambda + \frac{1}{4} \log\left( \frac{ \bigl[ M^4 + 12 M^3 \delta {\ensuremath \psi_{N}}]^{1/2} }{ {\ensuremath M_\text{Pl}}\bigl[ M^4 + 12 M^3 \delta {\ensuremath \psi_{\text{end}}}]^{1/4} } \right) .\end{aligned}$$ ![ Spectral parameters for three values of $M$, varying $\delta$ across its permissible range. The values of $\lambda$ and $N$ are fixed by simultaneously matching the amplitude to the observed value of $A_s$ and solving the matching equation assuming instant reheating. We include indicative bounds on $n_s$ (blue) and $\alpha_s$ (red); 68% confidence level results from Planck [@Ade:2015lrj]. The points at the ends of the lines in the top left figure denote $\delta=0$. []{data-label="fig:spectrum_N_matching"}](inflection_point_spectrum-matching_N){width="0.95\linewidth"} Finally, the parameter $\lambda$ is fixed by the amplitude of the scalar perturbations: $$\begin{aligned} \label{eq:scalar_amplitude} A_s &= \frac{1}{12 \pi^2 {\ensuremath M_\text{Pl}}^6} \frac{V^3}{V'^2} = \frac{\lambda}{20736 \pi^{2}} \frac{ M^7 \left(M + 12 {\ensuremath \psi_{N}}\delta \right)^{3} }{ {\ensuremath M_\text{Pl}}^{6} \left(M^{2} \delta + {\ensuremath \psi_{N}}^{2} \right)^{2} } \, .\end{aligned}$$ The value of $A_s$ is well-measured [@Ade:2015xua]; in our numerical examples we take $A_s = 2.2 \times 10^{-9}$. In the limit $\delta \rightarrow 0$ equations and give an expectation for the height of the potential: $$\lambda = \pi^2 A_s \left(\frac{M}{{\ensuremath M_\text{Pl}}}\right)^2 \frac{1}{N^4} \, . \label{eq:lambda_small_field}$$ In Figure \[fig:spectrum\_N\_matching\] we show spectral parameters as a function of $\delta$ computed self-consistently from the matching equation along with current bounds on these parameters.[^3] For any sub-Planckian $M$ the scalar-tensor ratio $r$ is very small, with $r\sim 10^{-14}$ for $M=0.1 {\ensuremath M_\text{Pl}}$. Moreover, when $\delta \rightarrow 0$, $n_s$ is below the observationally allowed range, $n_s \lesssim 0.93$ vs $n_s = 0.9677\pm0.0060$. However, $n_s$ increases as $\delta$ approaches the bound in equation and so this model is consistent with current data. ![ We plot spectral parameters for three values of $M$ and two values for $N$, while varying $\delta$ across its permissible range. As in Figure \[fig:spectrum\_N\_matching\] we have plotted current constraints on $n_s$ (blue) and $\alpha_s$ (red), and $\delta$ varies along each of the curves. Note that the curves for $\alpha_s$ vs $n_s$ coincide. []{data-label="fig:spectrum_N_fixed"}](inflection_point_spectrum-fixed_N){width="0.95\linewidth"} Interestingly, $\|\alpha_s\|$ also increases with $\delta$, providing leverage to test the model as constraints on the spectrum improve. CMB-S4 in the microwave background “roadmap” aims to measure the running with an uncertainty of $0.002$ to $0.003$ [@Abazajian:2016yjj; @Munoz:2016owz], while the Square Kilometer Array (SKA) may reduce the 1-$\sigma$ bounds on $\alpha_s$ to $0.0018$ (SKA1) or $0.00092$ (SKA2) [@Pritchard:2015fia]; combining data from CMB-S4 and SKA2 would put even tighter constraints on $\alpha_s$ [@Munoz:2016owz]. Consequently, planned future observations could conclusively falsify this model. These conclusions would not change significantly if we drop the assumption of instant thermalization; Figure \[fig:spectrum\_N\_fixed\] shows the spectral parameters as a function of $N$. In the $\delta =0$ limit, increasing $N$ pushes $n_s$ closer to the observationally allowed range. Physically, this would require a post-inflationary phase where the equation of state $w > 1/3$, which is technically feasible but has little motivation. Even then the $\delta =0$ limit cannot easily be made consistent with the data. Conversely, if thermalization is preceded by a substantial matter dominated phase, $n_s$ is moved further away from unity. Likewise, the running $\alpha_s$ depends on $N$, but $\left\| \alpha_s \right\|$ remains above $10^{-3}$ for any reasonable configuration. This analysis takes place in the slow roll limit. This amounts to a constraint on the initial conditions since, if the inflaton arrives at the plateau with a significant kinetic energy, it will experience “ultra slow-roll” and “overshoot” before inflation can commence [@Itzhaki:2007nk; @Dimopoulos:2017ged]. To show this we make the simplifying assumptions that $\ddot{\phi} + 3H \dot{\phi} \approx 0$ and $\dot{\phi}^2 \approx V$ as the field-point approaches the inflationary plateau; the latter condition is equivalent to requiring that $\rho + 3p \approx 0$, which is the condition for the onset of inflation [@Lidsey:1995np]. In this limit, the field velocity is approximately $\dot{\phi}_0 \exp{(-3 H t)}$ where $\dot{\phi}_0$ is the velocity at a given initial time. Via equation (\[eq:psi\_end\_sq\]) the total width of the inflationary plateau is roughly $M \sqrt{M/{\ensuremath M_\text{Pl}}}$. Putting all this together (and recalling that $H \sim \sqrt{V}/{\ensuremath M_\text{Pl}}$) we see that $3H\Delta t \sim (M/{\ensuremath M_\text{Pl}})^{3/2}$ so for $M<{\ensuremath M_\text{Pl}}$ the field velocity will not change dramatically as it evolves through the region containing the inflection point. Consequently, inflation cannot commence unless $\dot{\phi}^2 \ll V(\phi)$ initially. Imposing this condition is strong tuning unless the model is embedded inside a larger dynamical system in which this situation occurs naturally – a stipulation that undercuts any claim to simplicity. Large Field Inflation ===================== We now turn our attention to the large field limit. As previously, there is no minimum other than the origin if $g \le 2 \sqrt{\lambda} m$. When $M\lesssim {\ensuremath M_\text{Pl}}$ and $\phi \sim M$, inflation requires $\delta \ll 1$; when $M \gtrsim {\ensuremath M_\text{Pl}}$ and $\phi \gtrsim {\ensuremath M_\text{Pl}}$ inflation will occur whether or not the potential possesses an inflection point. Moreover, negative values of $g$ are consistent with inflation in this regime; in that case all nontrivial derivatives of the potential are positive. We will find it convenient to define $g= 2 \sqrt{\lambda} m \Delta$ and again use $M = g/2\lambda$ to write $$\begin{aligned} \label{eq:} m &= \sqrt{\lambda} M \, , \\ g &= 2 \lambda M \Delta \, .\end{aligned}$$ This allows us to express $V(\phi)$ as $$\label{eq:potential_large_field} V(\phi) = \lambda \left( \frac{M^2}{2} \phi^2 - \frac{2}{3}\Delta M \phi^3 + \frac{1}{4}\phi^4 \right) \, .$$ and we have not dropped any terms from the potential. The contribution of the cubic term, $\frac{2}{3}\Delta M \phi^3 / V(\phi)$, is maximized at $\phi=\sqrt{2} M$ so the transition from a quadratic to quartic potential occurs when $\phi \sim M $ even if $V'$ increases monotonically. In the near-saddle point limit $\Delta \sim 1/\sqrt{1+\delta}$, where $\delta$ is the expansion parameter from the small field case. Large field inflation occurs for any value of $\Delta$, although $\Delta \le 1$ is needed to avoid a trapping potential. As in the small field case, $\lambda$ sets the amplitude of the perturbations but does not influence the inflationary dynamics. We restrict our attention to scenarios where the velocity is consistent with slow roll; additional possibilities arise if we allow transient velocities but have little physical motivation. The $\{M,\Delta\}$ parameter space contains a number of distinguishable large field scenarios, which we now enumerate: - [Effective Quadratic Potential]{} If $M\gg 10 {\ensuremath M_\text{Pl}}$, the potential is effectively quadratic throughout the cosmologically relevant phase of inflation. - [Effective Cubic Potential]{} If $\Delta \gg 1$ and $M \gtrsim {\cal{O}}(\text{few}){\ensuremath M_\text{Pl}}$, the potential is effectively cubic during the cosmologically relevant phase of inflation. - [Effective Quartic Inflation]{} If $M \lesssim {\ensuremath M_\text{Pl}}$ the potential is effectively quartic for $\phi \gtrsim {\ensuremath M_\text{Pl}}$ and the resulting spectrum will be incompatible with the data [@Peiris:2003ff; @Adam:2015rua; @Ade:2015xua; @Ade:2015lrj]. - [Exact Saddle Point: Eternal Inflation]{} Here $\Delta = 1$ and $M \gtrsim 2{\ensuremath M_\text{Pl}}$. If $\phi$ is initially larger than $M$, the field dynamics have an attractor solution with $\phi\rightarrow M$ as $t \rightarrow \infty$ and inflation never ends. In the slow roll limit, $$\begin{aligned} &3 H \dot{\psi} + \lambda M \psi^2 \approx 0 & \label{hpsi}\\ \Rightarrow & \psi \approx \frac{M}{2 {\ensuremath M_\text{Pl}}\sqrt{\lambda}} \frac{1}{t}\end{aligned}$$ where again $\phi = \psi+M$ and $H$ is effectively constant. The neglected terms in equation (\[hpsi\]) all scale as $t^{-2}$ or beyond as $\psi \rightarrow 0$ so this solution has a non-trivial basin of attraction establishing that slow roll remains valid even as $V'$ vanishes identically. Consequently this configuration supports eternal inflation and semiclassical evolution must begin with $\phi < M$, both from the perspective of the field configuration in the primordial universe and in numerical treatments of the inflationary dynamics. - [Large Field Saddle Point Inflation]{} The most complex possibility is a saddle point lying in the cosmologically relevant segment of the potential, e.g. with $M \sim {\cal{O}}(\text{few}){\ensuremath M_\text{Pl}}$ and $0 \lesssim \Delta < 1$. In the large-field regime, $V'/V$ is necessarily small but is further suppressed in the vicinity of a (near)-saddle point. The perturbation amplitude scales as $V^3/V'$ so when $V'$ passes through a local minimum there is a corresponding feature in the spectrum. The height of the feature is correlated with its width (as a function of comoving wavenumber, $k$) since $N \sim V/V'$, “stretching” the feature over a larger range of $k$-values if $V'$ approaches zero. As explored below, this scenario produces a range of outcomes including the counterintuitive possibility that the scalar amplitude is reduced relative to a comparable monomial case at the same energy density. - [Punctuated Inflation]{} If ${\ensuremath M_\text{Pl}}\lesssim M \lesssim 2{\ensuremath M_\text{Pl}}$ and $\Delta \approx 1$ a punctuated inflationary scenario is possible [@Jain:2008dw; @Jain:2009pm], as illustrated in Figure \[fig:traj\]. These solutions arise when $\Delta$ is very close to unity and in the exact $\Delta=1$ limit. When ${\ensuremath M_\text{Pl}}\lesssim M \lesssim 2{\ensuremath M_\text{Pl}}$ the $\Delta = 1$ limit is far enough from perfect slow roll to evade the eternal inflation solution above. ![ Spectral parameters $r$ and $n_s$ as a function of $\Delta$ and $N$, the number of $e$-folds before the end of inflation. In each case $M=8{\ensuremath M_\text{Pl}}$. []{data-label="fig:large-M-N_Delta-M010"}](surface-M=8-r.png "fig:"){width="0.9\linewidth"} ![ Spectral parameters $r$ and $n_s$ as a function of $\Delta$ and $N$, the number of $e$-folds before the end of inflation. In each case $M=8{\ensuremath M_\text{Pl}}$. []{data-label="fig:large-M-N_Delta-M010"}](surface-M=8-n_s.png "fig:"){width="0.9\linewidth"} - [Hilltop Inflation]{} If $\Delta>1$ hilltop inflation results; hilltop inflation yields a relatively large value of $r$ unless the quadratic term in the Taylor expansion vanishes almost exactly [@Kinney:1995ki; @Easther:2006qu], a situation that cannot occur for this potential. ![ The tensor to scalar ratio $r$ is plotted for three models, quadratic (blue), quartic (orange) and $M=8{\ensuremath M_\text{Pl}}$ and $\Delta = 0.75$ (green); data computed with ModeCode assuming instant preheating with $\lambda$ chosen to reproduce the observed density perturbation amplitude. The tensor amplitude of the inflection point scenario can exceed that of either monomial scenario. []{data-label="fig:r_values"}](compare-r){width="0.7\linewidth"} ![ Trajectory for a set of parameters ($M=8 {\ensuremath M_\text{Pl}}$, $\Delta=0.935$, $\lambda = 1.6 \times 10^{-11}$) yielding a large tensor-scalar ratio $r = 0.8$ when $N$ is fixed at $55$. []{data-label="fig:large-r-traj"}](traj-large-r-M=008){width="0.7\linewidth"} Some of these scenarios are limited to a narrow region of the $\{M,\Delta\}$ parameter space but unlike the small-field regime there is no need for tuning to ensure that inflation takes place. In most cases the power spectrum can be well-understood in the slow-roll limit, but there are regions of parameter space for which this approach would be inadequate and we have implemented both the small field and large field scenarios in ModeCode [@Price:2014xpa], which we use to generate the results shown here.[^4] ![ The parameter $\epsilon_{H}$, $N$ $e$-folds before the end of inflation; $\epsilon_{H} < 1$ if the expansion of the universe is accelerating. Each plot is with $\Delta = 0.9999$. For small $M$, the inflaton rolls through the inflection point without inflation resuming; inflation is effectively quartic. For $1.06 {\ensuremath M_\text{Pl}}\lesssim M \lesssim 2.04{\ensuremath M_\text{Pl}}$ inflation pauses briefly. For larger $M$ all of the observationally relevant portion of inflation occurs in the vicinity of the inflection point. []{data-label="fig:traj"}](traj-punctuated){width="0.95\linewidth"} ![ The top plot is of $n_s$ and $r$ as functions of $\Delta$ when $M = 4 {\ensuremath M_\text{Pl}}$. The lower plot shows that large values of $r$ are accompanied by a higher energy scale at horizon crossing as $\lambda$ must increase to match the observed perturbation amplitude when $V/V'$ decreases. []{data-label="fig:large-M-Delta-cut-M=004"}](vary-Delta-cut-M=004){width="0.95\linewidth"} The most interesting scenarios from our perspective are those with $0\le\Delta\le1$ and ${\ensuremath M_\text{Pl}}<M \lesssim 20 {\ensuremath M_\text{Pl}}$. Figure \[fig:large-M-N\_Delta-M010\] shows the astrophysical observables $n_s$ and $r$ as a function of $\Delta$ and $N$, the number of remaining e-folds. These plots show that $n_s$ varies significantly thanks to the “feature” in the potential. However, for these scenarios $r$ can be counter-intuitively large: the cubic term reduces both $V$ and $V'$ but the impact on $V$ is larger than that on $V'$, increasing $\epsilon$ and thus $r$ relative to values seen with monomial potentials. A representative scenario is shown in Figure \[fig:r\_values\]. Given the observational constraints on $r$ this significantly reduces the area of the $\{M,\Delta\}$ plane that yields observables compatible with current data, and runs contrary to the naive expectation that a flatter potential necessarily leads to a lower value of $r$. As illustrated by Figure \[fig:large-r-traj\], models with a large $r$ are those where the inflaton is approaching the plateau in the potential as astrophysical modes leave the horizon. In these cases $\epsilon$ and thus $r$ is significantly scale dependent. Models with large $r$ are now primarily of academic interest, but note that the tensor amplitude is proportional to $V$ and thus slowly decreasing; the rapidly increasing scalar amplitude drives the scale-dependence of $r$. The punctuated inflation scenarios can be understood as extreme versions of this situation. Recalling that $$\epsilon_H = \frac{1}{2} \frac{1}{{\ensuremath M_\text{Pl}}^2} \left(\frac{d \phi}{d N}\right)^2$$ is exactly unity when accelerated expansion ends, Figure \[fig:traj\] shows several punctuated scenarios in which inflation pauses briefly before resuming. Interestingly, these scenarios only exist when $M\gtrsim{\ensuremath M_\text{Pl}}$. For smaller values of $M$ the field rolls past the plateau before inflation can resume, further demonstrating the “ultra slow-roll” and “overshoot problem” faced by the small field models. For any model the specific value of $\lambda$ can be obtained by self-consistently solving the matching equation for $N$ and matching to the observed spectral amplitude. Given this constraint, a large value of $r$ implies that the energy density during inflation is higher than that in the low $r$ configurations. The height of the potential at the pivot scale is shown as a function of $\Delta$ in Figure \[fig:large-M-Delta-cut-M=004\], assuming instant thermalisation. In Figure \[fig:large-M-vary-Delta-spectrum-MultiModeCode\] we show $n_s$ and $r$ measured at the pivot scale for a range of $M$ and $\Delta$. The limit $\Delta\rightarrow1$ is a saddle point model with the field rolling away from a plateau toward the global minimum; in these cases $r$ can be very small and $n_s$ lies below the observationally permitted range. A preference for relatively large values of the running (as compared to typical single-term potentials [@Adshead:2010mc]) is clear, and we we also see that models in which the running is small typically have large values of $r$, an observation we explore in detail in the following Section. ![ In the top two panels $\Delta$ runs from $[0, 1]$ values of $n_s$ and $r$ consistent with current data are shown in blue and green. The lower two rows show trajectories for fixed $\Delta$ and $0.1 {\ensuremath M_\text{Pl}}< M < 100 {\ensuremath M_\text{Pl}}$. The inflationary phase is at large $\phi$ and we assume instant preheating with $\lambda$ chosen to reproduce the observed amplitude at the pivot. The small discontinuity at $M \sim ~1$ corresponds to the transition between the first and second cases of Figure \[fig:traj\]. []{data-label="fig:constraints"}](vary-Delta-spectrum "fig:"){width="0.8\linewidth"} ![ In the top two panels $\Delta$ runs from $[0, 1]$ values of $n_s$ and $r$ consistent with current data are shown in blue and green. The lower two rows show trajectories for fixed $\Delta$ and $0.1 {\ensuremath M_\text{Pl}}< M < 100 {\ensuremath M_\text{Pl}}$. The inflationary phase is at large $\phi$ and we assume instant preheating with $\lambda$ chosen to reproduce the observed amplitude at the pivot. The small discontinuity at $M \sim ~1$ corresponds to the transition between the first and second cases of Figure \[fig:traj\]. []{data-label="fig:constraints"}](vary-M-spectrum "fig:"){width="0.99\linewidth"} \[fig:large-M-vary-Delta-spectrum-MultiModeCode\] Fine-tuning, Priors and Testability =================================== The preceding Sections catalog the wide range of inflationary dynamics associated with the quartic polynomial potential. We now use these analyses to specify priors for these scenarios that will facilitate parameter estimation and model selection calculations. In principle, one can work with a generic quartic potential with priors specified in terms of the slow roll parameters[^5] but here we build on the analysis of the previous sections to parametrize these inflationary scenarios.[^6] In particular, these priors will facilitate parameter estimation and model selection calculations, see e.g. [@Peiris:2006ug; @Mortonson:2010er; @Easther:2011yq; @Planck:2013jfk; @Martin:2013nzq; @Ade:2015lrj], for these scenarios. Specifying the distributions from which the parameters are drawn is a necessarily qualitative process. However, the choices made when constructing these distributions weight the evidence integrals (via equation ) and this issue can be particularly pressing for multiparameter models. Approaches to specifying “maximal entropy” priors for inflationary models were examined carefully in Ref. [@Easther:2011yq]. Here the overall amplitude of the spectrum is set by a multiplicative parameter in front of the potential in both the large and small field regimes. In the small field case we can estimate the likely value of $\lambda$ (via equation (\[eq:lambda\_small\_field\])) but in the large field case we have to allow a large enough range of $\lambda$ to account for scenarios like those in Figure \[fig:large-M-Delta-cut-M=004\]. We also apply a further cut – any parameter choice for which the spectral amplitude does not satisfy $10^{-11} \le A_s \le 10^{-7}$ is excluded from the prior volume. This will have no impact on the posterior distributions but protects against a “volume effect” when calculating evidence [@Easther:2011yq], a task we will pursue in a followup publication. Small Field ----------- To handle the small field case we first make the following parameterization $$\begin{aligned} \delta &=& \frac{\tilde{\delta}}{288} \left( \frac{M}{{\ensuremath M_\text{Pl}}} \right)^4\\ \lambda &=& 10^{-9} \pi^2 \tilde{\lambda} \left(\frac{M}{{\ensuremath M_\text{Pl}}}\right)^2 \frac{1}{50^4} \, .\end{aligned}$$ Inflationary solutions in this regime need an almost-exact inflection point for which the potential is described by equation (\[potential\_psi\]). In this setting, $M$ is an unknown energy scale and by assumption $M\le{\ensuremath M_\text{Pl}}$. The lower bound $M_{\rm min}$ is less clear; in principle it could be as low as the TeV scale, the minimal energy at which we can reasonably expect to see new physics, but in this limit the required tuning would be extreme. - [Small field, log prior: ]{} If $M$ corresponds to an unknown scale it is appropriate to draw it from a logarithmic or Jeffries prior: $$\begin{aligned} &\log_{10}{\left(\frac{M_{\rm min}}{{\ensuremath M_\text{Pl}}}\right)} \le \log_{10}{\left(\frac{M}{{\ensuremath M_\text{Pl}}}\right)} \le 0 \, ,& \nonumber \\ & 0 \le \tilde \delta \le 1 \, , &\\ &-5 \le \log_{10}(\tilde \lambda) \le 5 \nonumber \, .&\end{aligned}$$ - [Small field, uniform prior: ]{} If $M$ is assumed to be associated with an intrinsically high scale it is self-consistently drawn from a uniform prior, or $$\begin{aligned} &\frac{M_{\rm min}}{{\ensuremath M_\text{Pl}}} \le \frac{M}{{\ensuremath M_\text{Pl}}} \le 1 \, ,& \nonumber \\ & 0 \le \tilde \delta \le 1 \, , &\\ &-5 \le \log_{10}(\tilde \lambda) \le 5 \nonumber \, .&\end{aligned}$$ Inflationary models typically require a “small parameter” to ensure that the perturbation amplitude matches observation. However, this potential requires not one but two small parameters – $\lambda$ to set the overall scale of the potential and fix the perturbation amplitude, and $\delta$ to quantify the departure of the inflection point at $\psi=0$ from an exact saddle. As we saw in Section 3, inflation will only occur when $\delta \lesssim (M/{\ensuremath M_\text{Pl}})^4$. Given current constraints on $n_s$ the limit $\delta \equiv 0$ is excluded by the data, as illustrated by Figures \[fig:spectrum\_N\_matching\] and \[fig:spectrum\_N\_fixed\]. Consequently, the posterior for $\tilde{\delta}$ will differ substantially from the prior. If a symmetry is responsible for generating the saddle point it must be weakly broken by higher order contributions,[^7] but these corrections must be exceptionally small to prevent the inflection point phase from being completely destabilized. Moreover, beyond the tuned parameters and the “overshoot” problem analysed in Section 3, models in which inflation is supported by a narrow range of field values typically need highly homogeneous initial field configurations [@Goldwirth:1989pr; @East:2015ggf; @Clough:2016ymm], partially undermining the explanatory power of inflation. These problems could be ameliorated if small field inflation is preceded by a tunnelling event [@Allahverdi:2008bt] but extra structure would need to be added to the theory to permit this, undercutting any claim to simplicity. We have not attempted to “score” the dynamical tunings when constructing the priors, but these are more pronounced at lower values of $M$ which are disfavoured in the uniform prior relative to the log prior. Large Field ----------- We now consider the large field case for which relevant values of $M$ lie between ${\ensuremath M_\text{Pl}}$ and (generously) $50 {\ensuremath M_\text{Pl}}$ – beyond this we are in the quadratic limit of the theory and increasing $M$ will have little impact on observables; given this relatively limited range we draw $M$ from a uniform distribution. Conversely, we can draw $\|1-\Delta\|$ from either a logarithmic or a uniform distribution, depending on whether we understand the inflection point as arising from a (near) symmetry or an accidental cancellation, respectively. Further, $\Delta-1$ can have either sign and these cases are physically distinct, since $\Delta>1$ yields a local maximum with a trapping potential for which the onset of inflation and associated initial conditions problem differs significantly from the case where field values can be arbitrarily large.[^8] - [Large field, log prior: ]{} This scenario is appropriate if it is assumed that a near-saddle point is required by the symmetries of some underlying theory. $$\begin{aligned} &{\ensuremath M_\text{Pl}}\le M \le 50 {\ensuremath M_\text{Pl}}\, , &\nonumber \\ & -6 \le \log_{10}(\|\Delta -1\|) \le 0 \, , &\\ &-15 \le \log_{10}( \lambda) \le -5 \nonumber \, .&\end{aligned}$$ - [Large field, uniform prior: ]{} This scenario is appropriate if the near-inflection point arises from an “accidental” cancellation of terms. $$\begin{aligned} &{\ensuremath M_\text{Pl}}\le M \le 50 {\ensuremath M_\text{Pl}}\, ,& \nonumber \\ & 0< \|\Delta-1\| \le 2 \, ,&\\ &-15 \le \log_{10}( \lambda) \le -5 \nonumber \, .&\end{aligned}$$ The ranges of some free parameters (e.g. the upper bound on $M$) cannot be inferred from fundamental principles and so we set the endpoints such that further extending the range would not introduce new possible combinations of empirical observables. ![The prior probabilities for the empirical spectral variables derived for the log (top) and uniform hyperpriors (bottom) describing large field inflection point models. []{data-label="fig:derived_priors"}](logprior.png "fig:"){width="0.95\linewidth"} ![The prior probabilities for the empirical spectral variables derived for the log (top) and uniform hyperpriors (bottom) describing large field inflection point models. []{data-label="fig:derived_priors"}](uniformprior.png "fig:"){width="0.95\linewidth"} \ ![ Joint distributions for the large field, log prior inflection point scenario, measured $N=55$ $e$-foldings before the end of inflation, with observables computed in the slow roll approximation. The top plot shows the joint distribution of $r$ and $n_s$; the lower plots show $r$ and $\alpha_s$ – the left hand plot is restricted to parameter combinations for which $.9<n_s<1.1$ while the right hand plot shows only those with $0.95<n_s<0.97$. []{data-label="fig:joint_distro"}](cut1.png "fig:"){width="0.49\linewidth"} ![ Joint distributions for the large field, log prior inflection point scenario, measured $N=55$ $e$-foldings before the end of inflation, with observables computed in the slow roll approximation. The top plot shows the joint distribution of $r$ and $n_s$; the lower plots show $r$ and $\alpha_s$ – the left hand plot is restricted to parameter combinations for which $.9<n_s<1.1$ while the right hand plot shows only those with $0.95<n_s<0.97$. []{data-label="fig:joint_distro"}](cut2.png "fig:"){width="0.49\linewidth"} These models can viewed as hyperpriors for hyperparameters $\Delta$ and $M$ in a Bayesian network that defines a generative model yielding $n_s$, $r$ and $\alpha_s$ [@Price:2015qqb]. If the running is large the scale dependence of $\alpha_s$ may also be nontrivial; however these scenarios are generically also those for which $r$ is much larger than observationally permitted. In what follows we will assume instant reheating and that the spectrum can be fully described by $r$, $\alpha_s$ and $n_s$. The resulting distributions of spectral variables for large field inflection point scenarios are shown in Figure \[fig:derived\_priors\] and they are anything but uniform. For both scenarios there is considerable support for models with $r<0.1$. Figure \[fig:joint\_distro\] shows joint distributions for the spectral parameters generated from the logarithmic large field prior. The degree of fine-tuning required to produce any given set of observables can be inferred from these plots, relative to the specified hyperprior. This distribution is peaked at $n\approx 0.963$, $r\approx0.14$, a pairing broadly consistent with quadratic inflation. However, the distribution of $r$ in Figure \[fig:derived\_priors\] reveals that there is an overall preference for $r<0.1$ with the logarithmic prior. The distribution for $r$ derived from a uniform prior on $\Delta$ has a similar peak but favours larger values of $r$ relative to the logarithmic case. These results can be contrasted with the tuning criterion advocated by Boyle, Steinhardt and Turok [@Boyle:2005ug] for which the “least tuned” region of the $\{n_s,r\}$ plane is larger than the peak found here, while ascribing a high level of tuning to regions of parameter space that are not strongly disfavoured by this Bayesian analysis.[^9] A second noteworthy feature of the joint distributions is that some combinations of parameters cannot be produced by any configuration of the 4-th order potential, so future observations could comprehensively falsify the overall scenario. “Excluded regions” exist in both the $\{n_s,r\}$ and $\{\alpha_s,r\}$ planes. For example, if $n_s$ and $r$ had been accurately measured to be $0.93$ and $0.1$ respectively all 4-th order potentials would be ruled out; however $n_s$ is now known to be larger than this limit.[^10] However, the permitted pairings of $\{\alpha_s,r\}$ are restricted by limits on $n_s$ so we can update these priors in the light of observational evidence, as illustrated by Figure \[fig:joint\_distro\]. Looking again at Figure \[fig:joint\_distro\] we see that small values of $r$ are correlated with relatively “large” values of $\alpha_s$, in contrast to most widely studied, simple models of single field inflation for which the running is typically $\alpha_s \sim -{\cal{O}}(\text{few}) 10^{-4}$ [@Adshead:2010mc]. Likewise, the distributions for $\alpha$ shown in Figure \[fig:derived\_priors\] peak at $\|\alpha_s\| < 10^{-3}$. Projections suggest that SKA2 will be able to measure $\alpha_s$ to a precision of $0.001$ [@Pritchard:2015fia] and Stage-IV CMB experiments likewise hope to measure $r$ to a precision of $0.001$ [@Abazajian:2016yjj Table 6-2]. Consequently, even if future high-precision cosmological measurements only put tight upper bounds on the running and the tensor amplitude this would suffice to rule out all possible inflationary scenarios built upon a single minimally coupled field with a 4-th order polynomial potential.[^11] Figures \[fig:derived\_priors\] and \[fig:joint\_distro\] were obtained using the slow roll approximation with a fixed number of $e$-folds, rather than a self-consistent solution of the matching equation. For an extreme post-inflationary equation of state the pivot scale may be pushed to larger values of $N$, which typically reduces the running. However, Figure \[fig:squares\] shows the allowed regions of parameter space for two specified sets of bounds on the spectral parameters obtained from self-consistent solutions to the matching equation. These results are consistent with Figure \[fig:joint\_distro\] – if $\alpha \approx -0.002$ and $r<0.001$ a nontrivial region of parameter space (if $1-\Delta$ is drawn from a logarithmic prior) would be consistent with these observations, but if $\|\alpha\| \approx 0.001$ the overall model space is excluded. ![ Contours in the $M$-$\Delta$ plane corresponding to the assumption that $\delta_{\alpha_s} < 0.001$ and $r<0.001.$ Measurements of this precision are consistent with SKA2 [@Pritchard:2015fia] and Stage-IV CMB experiments [@Abazajian:2016yjj Table 6-2]. []{data-label="fig:squares"}](contour-future-alpha=-2e-3 "fig:"){width="0.8\linewidth"} ![ Contours in the $M$-$\Delta$ plane corresponding to the assumption that $\delta_{\alpha_s} < 0.001$ and $r<0.001.$ Measurements of this precision are consistent with SKA2 [@Pritchard:2015fia] and Stage-IV CMB experiments [@Abazajian:2016yjj Table 6-2]. []{data-label="fig:squares"}](contour-future-alpha=0.pdf "fig:"){width="0.8\linewidth"} In contrast to the small field case, the large field scenarios are likely to need no significant tuning of their initial conditions. Matching the overall amplitude of the perturbations will constrain $\lambda$ but inflation occurs for generic values of $\Delta$ and $M$. Discussion {#sec:discussion} ========== We have reviewed the inflationary scenarios generated by a 4-th order polynomial potential. This topic was first addressed in 1990 [@Hodges:1989dw; @Hodges:1990bf] and has been the subject of numerous subsequent analyses. Our treatment is based on a parametrization of $V(\phi)$ which makes it easy to identify the inflationary regimes the potential supports and adds to previous discussions by including the spectral running among the possible observables. The simplest potentials, both of which are at odds with observations, are the quadratic and quartic models. The 4-th order polynomial is the next-most-simple scenario that is bounded below. It also marks a critical threshold in the inflationary model space as it is the most complex potential consistent with a renormalizable scalar field theory. This potential has far richer phenomenology than the simplest models – we catalogued eight different supported inflationary regimes (including the small field case). However, this scenario is not arbitrarily complex and many combinations of the spectral parameters $n_s$, $r$ and $\alpha_s$ cannot be generated by any configuration of the potential. Interestingly, the 4-th order model has previously been used to explore questions of tuning and naturalness in inflationary models [@Boyle:2005ug; @Bird:2008cp; @Boyle:2008ri; @Ijjas:2013vea]. Our treatment allows us to give a quantitative and fully Bayesian assessment for the naturalness of any combinations of cosmological observables this potential can produce. As part of our analysis we have written down priors that describe the distributions of free parameters in the 4-th order scenario, looking at both the large field and small field regimes. The free parameters in the potential can be viewed as hyperparameters in a generative model for the spectral parameters and the resulting prior distributions are computed in Section 5.2, with examples plotted in Figures \[fig:derived\_priors\] and \[fig:joint\_distro\]. In the large field scenarios the joint distributions for $n_s$ and $r$ are sharply peaked around the values expected from quadratic inflation but a wide range of tensor amplitudes can be generated within these scenarios. This is clearly true for the large field log prior example but even with a uniform prior case there is still non-zero support for small values of $r$; these cases are somewhat disfavoured relative to those with $r\gtrsim 0.1$ but the level of tuning involved to produce a tensor amplitude in the range $0.001 \lesssim r \lesssim 0.1$ would not be outlandish from this perspective. Conversely, this analysis has shown that there are combinations of $n_s$, $r$ and $\alpha_s$ which cannot be produced by a 4-th order potential for any choice of parameter values. In particular, given current limits on $n_s$, if $r$ and $\alpha_s$ are simultaneously constrained to have magnitudes smaller than $10^{-3}$ no scenarios we have identified within this potential would survive. Such a result that would represent a significant threshold in the understanding of inflationary phenomenology, and thus provides a target for the designers of future experiments. It is worth considering what we would learn if future experiments do rule out the 4-th order potential. Clearly, if algebraic simplicity is held to be synonymous with naturalness this would diminish the credibility of the inflationary paradigm. However, the only small-field (i.e. $\phi \lesssim {\ensuremath M_\text{Pl}}$ at all times) scenario that the 4th-order potential supports is the inflection point scenario described in Section 3, for which the parameters in the potential and the initial field configuration are both highly tuned. Conversely, potentials with a higher degree of algebraic complexity can support inflation at lower scales (and thus smaller field excursions) without fine-tuned initial conditions [@East:2015ggf]. These potentials typically have large plateau, which can be a consequence of possible symmetries in the underlying theory of high energy particle physics but cannot be constructed from a quartic polynomial. If natural models are those where the inflationary dynamics is the consequence of a fundamental symmetry rather than happenstance, the most natural small-field scenarios are [necessarily]{} more complex than the 4-th order polynomial, and metrics based on naturalness as opposed to simplicity will yield contradictory conclusions about the likelihood of inflation. Conversely, the 4-th order potential supports large-field inflation without needing dramatic tunings to either the potential parameters or initial state. However, the robustness of this potential against corrections from Planck-scale operators is again a question of high energy physics rather than the simplicity of its algebraic form [@Lyth:1996im; @Baumann:2014nda]. Consequently, the one inference we can draw is that in all cases the naturalness or prior likelihood of an inflationary scenario is best assessed in terms of the theory or theories of fundamental physics that are hypothesised to give rise to its potential, rather than the form of the potential itself. We thank Shaun Hotchkiss, Kei-ichi Maeda, Mason Ng, and Hiranya Peiris for useful conversations on this topic. Part of this work was completed during a visit to the Centro de Ciencias de Benasque Pedro Pascual \[RE\]. We made use of Matplotlib, NumPy and SymPy [@Hunter:2007ouj; @vanderWalt:2011bqk; @Meurer:2017yhf]. [^1]: Section 4.18 of Ref [@Martin:2013tda] treats the $\delta=0$ case (in our notation) while Section 5.7 discusses the general $\delta\ne0$ case; we give a unified account of both situations and our conclusions regarding the tuning required for inflation and the overall falsifiability of the scenario are new. [^2]: Such a potential would support hilltop inflation but this possibility does not change any of our conclusions as it yields an $n_s$ even more inconsistent with observations – see for example [@Martin:2013tda Section 5.7, Figure 125]. [^3]: We do not plot joint probability distributions on $r$, $n_s$ and $\alpha_s$; as we will see later, $\alpha_s$ may be strongly scale dependent for some parameter choices and direct observational constraints on this potential will be obtained in a forthcoming analysis. [^4]: ModeCode was modified to add the potential ; the initial conditions must be chosen with some finesse and the stopping condition must account for the possibility of punctuated inflation. [^5]: As done in [@Aslanyan:2015hmi] for potential slow roll parameters, or [@Norena:2012rs] for a three parameter Hubble Slow Roll analysis; in the latter case the potential is not strictly a quartic polynomial. [^6]: In the context of Bayesian model selection, two “models” with the same algebraic specification and which differ only in the joint distribution from which their parameters are drawn and are viewed as distinct scenarios, since the evidence integral will be weighted differently for each case. [^7]: We justified the choice of a 4-th order polynomial, in part, by appealing to renomalization requirements but the actual inflaton dynamics will be controlled by the semi-classical potential which includes all loop corrections to the tree-level action. [^8]: In principle we could have also considered a small-field hilltop scenario but it cannot yield physically reasonable spectra. [^9]: This statement is, to some extent, dependent on the choice of upper bound on $M$ in the priors – if the upper bound becomes arbitrarily large the joint distributions will become more peaked at the values associated with purely quadratic inflation. However, simply doubling this bound (to $100{\ensuremath M_\text{Pl}}$) would not materially change our conclusions. [^10]: The same structure in the $\{n_s,r\}$ plane is visible in the plots of Refs [@Boyle:2005ug; @Bird:2008cp]. [^11]: A similar correlation between $r$ and $\alpha_s$ is observed in Ref. [@Boyle:2008ri] in the context of the Hubble Slow Roll approximation, in which the Hubble parameter $H$ is represented as a finite order polynomial in $\phi$.	null	minipile	NaturalLanguage	mit	null
NOT RECOMMENDED FOR FULL-TEXT PUBLICATION File Name: 12a0928n.06 FILED Nos. 11-5550, 11-5609, 11-5664 Aug 21, 2012 UNITED STATES COURT OF APPEALS LEONARD GREEN, Clerk FOR THE SIXTH CIRCUIT UNITED STATES OF AMERICA, Plaintiff-Appellee, v. ON APPEAL FROM THE UNITED STATES DISTRICT COURT FOR RODNEY EDWARD MOORE, THE WESTERN DISTRICT OF JAMES LAMONT DUNBAR, and KENTUCKY DWAYNE MICHAEL JOSEPH JR., Defendants-Appellants. / Before: GUY, and CLAY, Circuit Court Judges; HOOD, District Court Judge.* DENISE PAGE HOOD, District Court Judge. Defendants James Dunbar, Rodney Moore, and Dwayne Joseph, Jr. were charged in a five-count, twenty-one defendant indictment for conspiracy to distribute more than fifty grams of cocaine base in violation of 21 U.S.C. §§ 841(a)(1), (b)(1)(A) and 846. All three Defendants proceeded to trial. Defendants now make several evidentiary and constitutional challenges to the district court’s sentence and also argue that the Fair Sentencing Act should apply to their pre-Act offenses. For the reasons stated below, the district court is AFFIRMED in part and the cases are REMANDED back to the district court for sentencing pursuant to Dorsey v. United States, Nos. 11-583 and 11-5721, 2012 U.S. LEXIS 4664 (June 21, 2012). * The Honorable Denise Page Hood, United States District Judge for the Eastern District of Michigan, sitting by designation. Nos. 11-5550, 11-5609, 11-5664 I. BACKGROUND In June 2007, based on information received from a confidential informant, the Drug Enforcement Agency (DEA) began investigating a drug trafficking conspiracy in Christian County, Kentucky. In July 2009, the grand jury returned a five-count indictment against 21 individuals, including Defendants Dunbar, Moore, and Joseph. Dunbar, Moore, and Joseph were all charged with conspiracy to distribute more than 50 grams of cocaine base in violation of 21 U.S.C. §§ 841(a)(1), (b)(1)(A) and 846 and a forfeiture count. The indictment alleged that the conspiracy took place from June 2007 until June 2009. Moore was also charged with being a felon in possession of a firearm in violation of 18 U.S.C. §§ 922(g)(1) and 924(a)(2). Trial began on January 11, 2011. The jury returned guilty verdicts for Dunbar, Moore, and Joseph on January 18, 2011 for conspiracy to distribute 50 or more grams of cocaine base. A. James Dunbar In June 2010, the government filed a Rule 404(b) notice of its intent to use evidence of Dunbar selling crack cocaine on September 11 and 12, 2008. The government noted that it was not required to file a Rule 404(b) notice because the instances “happened during the period of the conspiracy and [were] relevant to and directly probative of conspiratorial intent.” The government admitted evidence of a third transaction, which took place on October 15, 2008, but it did not file a 404(b) notice. The government also filed its intent to seek life imprisonment given Dunbar’s two prior felony drug convictions. 2 Nos. 11-5550, 11-5609, 11-5664 Dunbar requested that the district court exclude evidence of his prior convictions and criminal activities.1 The district court found that evidence of Dunbar selling crack cocaine in September 2008 was probative of intent and direct evidence of Dunbar’s participation in the conspiracy. At trial, co-conspirator Demetrius Williams identified Dunbar’s voice on telephone conversations. He testified that Dunbar purchased crack cocaine from Williams during the period of 2007 until 2008. Dunbar was sentenced on April 28, 2011. Dunbar argued that the Fair Sentencing Act should be applied retroactively and the imposition of a mandatory life sentence was cruel and unusual punishment in violation of the Eighth Amendment. The district court rejected Dunbar’s arguments finding that the holding in United States v. Carradine, 621 F.3d 575 (6th Cir. 2010), precluded the district court from applying the Fair Sentencing Act retroactively. The district court also rejected Dunbar’s cruel and unusual argument. B. Rodney Moore At trial, Williams testified that Moore “cooked” crack cocaine for him, which is the process used to turn powder cocaine into crack cocaine. On cross-examination by co-defendant Dunbar, DEA Agent Daren Atkins testified that the confidential informant identified Moore as a “crack cook.” The government did not call the confidential informant to testify. A task force officer also testified that, when arrested, Moore admitted that he was involved with the distribution of a small amount of crack cocaine and had the ability to cook powder cocaine into crack cocaine. A search 1 The district court granted the motion in part by excluding Dunbar’s past convictions for trafficking cocaine because sufficient notice was not provided. 3 Nos. 11-5550, 11-5609, 11-5664 of Moore’s residence revealed a baggie of cocaine, which Moore admitted was his. There was also other testimony that Moore had cooked crack cocaine on different occasions. Moore moved for a new trial on the basis of the hearsay statements solicited from Agent Atkins. Specifically, Moore argued that his Sixth Amendment right to confrontation had been violated when the government failed to call the confidential informant as a witness. The district court denied the motion finding that the statement was not introduced for the truth of the matter asserted but rather to bolster the confidential informant’s credibility. The district court also noted that if there was an error it was harmless given the evidence against Moore. Moore was sentenced on April 27, 2011. Moore argued that the Fair Sentencing Act should apply retroactively. After finding that the Fair Sentencing Act was not retroactive, the district court sentenced Moore to a term of life imprisonment. C. Dwayne Joseph At trial, Williams identified Joseph’s voice on a series of recorded telephone conversations and indicated that the two were discussing a drug deal. The evidence showed that Joseph purchased crack cocaine from Williams on several occasions between 2007 and 2008. During the testimony of co-defendant Alvin Quarles, the government asked whether Quarles remembered telling the government that he had observed Joseph cook crack cocaine. Joseph objected to the questioning as being beyond the scope of direct and cross examination. The district court allowed it, noting that the court had allowed all counsel to go beyond the scope of examination. The government then called Agent Atkins to testify to the statement Quarles made. The government argued that the 4 Nos. 11-5550, 11-5609, 11-5664 statement was a prior inconsistent statement that was only offered to impeach Quarles’ testimony. The district court allowed it over objection. II. ANALYSIS A. Fair Sentencing Act Dunbar, Joseph, and Moore all argue that the Fair Sentencing Act, which took effect on August 3, 2010, should be applied retroactively because they were sentenced after the Act was passed. The Supreme Court in Dorsey v. United States, in considering whether the Fair Sentencing Act should apply retroactively, determined that there were six reasons that weighed in favor of applying the Act retroactively. 2012 U.S. LEXIS 4664 (2012). First, the savings statute allows Congress to apply the Act to pre-Act offenders without the Act expressly stating so. Id. at 24. Second, the Sentencing Reform Act requires that defendants are sentenced based on the Guidelines in effect when they are sentenced and not when the offense was committed. Id. at 26. Third, the language requiring that the Act take effect as soon as possible shows Congress’ intent to apply the Sentencing Reform Act’s principle of sentencing defendants based on the Guidelines in effect when the defendant is sentenced and not when the offense was committed. Id. at 27. Fourth, the inability to apply the Act to pre-Act offenders would create a sentencing disparity that Congress intended to prevent, namely that two individuals in possession of either crack or powder cocaine would receive “radically different sentences.” Id. at 29. Fifth, failing to apply Act Guidelines to pre-Act defendants would exacerbate the problem by creating new anomalies, i.e., disproportionate sentences. Id. at 30. Finally, the Supreme Court found that there were no strong reasons against applying the Act to pre-Act offenders. Id. at 34. In consideration of the above, the Supreme Court 5 Nos. 11-5550, 11-5609, 11-5664 concluded that “Congress intended the Fair Sentencing Act’s new, lower mandatory minimums to apply to the post-Act sentencing of pre-Act offenders.” Id. at *36. In light of Dorsey, the district court erred when failing to apply the Act sentencing guidelines to Joseph, Moore, and Dunbar. Their cases must be remanded back to the district for resentencing in line with Dorsey. B. Dunbar 1. 404(b) Evidence Dunbar argues that the district court erred in admitting the September 11 and 12, 2008 Rule 404(b) evidence and not giving a cautionary instruction to the jury. Dunbar also takes issue with the district court’s admission of evidence of a related transaction on October 15, 2008. A prior Rule 404(b) notice was filed for the September acts, but not the October act. Dunbar contends that the applicable standard of review should be abuse of discretion because the district court had reason to be aware of the need to give cautionary instructions. Dunbar further argues that he did not have sufficient notice to make a contemporaneous objection to the admission of the evidence. The government asserts that the plain error standard of review applies because Dunbar failed to make a contemporaneous objection. In United States v. Davis, this Court considered a conspiring defendant’s objection to the admission of prior act evidence. 547 F.3d 520, 526 (6th Cir. 2008). The defendant objected to the admission of prior acts evidence and was overruled. Id. The Davis court noted that plain error review was not appropriate under the circumstances because, although the defendant did not make a contemporaneous objection to the admission, the defendant had brought the issue to the district 6 Nos. 11-5550, 11-5609, 11-5664 court’s attention, by motion in limine, before the evidence was admitted. Id. at 528. Although Dunbar failed to make a contemporaneous objection to the admission of the evidence, he objected to the Rule 404(b) notice in advance of trial. The district court was put on notice that something could be wrong. The Court will examine the admission of evidence under abuse of discretion. United States v. Davis, 514 F.3d 596, 611 (6th Cir. 2008). A district court’s decision to admit evidence “should remain undisturbed unless (we are) left with the definite and firm conviction that the district court clearly erred in its judgment after weighing the relevant factors, improperly applied the correct law, or inappropriately used the wrong legal standard.” Tisdale v. Fed. Express Corp., 415 F.3d 516, 535 (6th Cir. 2005) (quoting Shanklin v. Norfolk So. Ry. Co., 369 F.3d 978, 988 (6th Cir. 2004) (internal alterations omitted)). This Court applies the harmless error rule to evidentiary errors. United States v. Baker, 458 F.3d 513, 520 (6th Cir. 2006). This Court must determine whether “it was more probable than not that the error materially affected the verdict.” Id. (quoting United States v. Pugh, 405 F.3d 390, 401 (6th Cir. 2005)). Federal Rule of Evidence 404(b) precludes the admission of extrinsic evidence of prior bad acts to prove the defendant’s criminal propensity. However, such evidence is admissible to prove motive, opportunity, intent, preparation, plan, knowledge, identity, or absence of mistake or accident, provided the government gives reasonable notice in advance of trial. Fed. R. Evid. 404(b)(2). Admission of 404(b) evidence requires the district court to first determine if there is sufficient evidence “that the act occurred and that the defendant was the actor.” Huddleston v. United States, 485 U.S. 681, 689 (1988); United States v. Gessa, 971 F.2d 1257, 1261- 62 (6th Cir. 1992). The next inquiry is whether the evidence is probative of a material issue. Huddleston, 485 U.S. at 686. 7 Nos. 11-5550, 11-5609, 11-5664 The district court must then determine whether the relevant matter is actually “in issue.” United States v. Feinman, 930 F.2d 495, 499 (6th Cir. 1991). The evidence “must deal with conduct substantially similar and reasonably near in time to the offenses” for which the defendant is tried. Id. Finally, the court must consider the probative value of the evidence and whether it is substantially outweighed by the danger of unfair prejudice, confusion, or misleading the jury. Fed. R. Evid. 403; also Feinman, 903 F.2d at 499. However, this inquiry is irrelevant and Rule 404(b) is not implicated when prior acts evidence “is part of a continuing pattern of illegal activity.” United States v. Barnes, 49 F.3d 1144, 1149 (6th Cir. 1995). Dunbar contends that the trial testimony directly contradicted the district court’s finding that the September 11 and 12, 2008 drug buys were direct evidence of the conspiracy. Dunbar notes that the ATF agent admitted that the September drug buys were part of a separate investigation. The government counters that no Rule 404(b) cautionary instructions were required because the drug sales were evidence of a continuing pattern of criminal activity. The September drug buys being part of a separate investigation is irrelevant to whether they were direct evidence of the conspiracy itself or probative of intent. The drug buys occurred during the conspiracy in question and are of the same type of conduct that was at issue in the conspiracy. Regardless of whether the September drug buys were direct evidence of the conspiracy itself, they were probative of intent. The district court did not abuse its discretion by admitting the evidence of the September drug buys. Dunbar contends that the district court erred in allowing the introduction of evidence of the October 15, 2008 drug buy. The government did not provide a 404(b) notice of the October drug buy as it had done with the September drug buys. However, the October drug buy with the 8 Nos. 11-5550, 11-5609, 11-5664 September drug buys could all be properly admitted as direct evidence of the conspiracy. As with the September drug buys, evidence of the October incident was also properly admitted as evidence of intent and, therefore, notice was not required. Introduction of that evidence was harmless. Finally, Dunbar argues that the district court should have provided a cautionary instruction for the 404(b) evidence. Dunbar failed to make a contemporaneous objection to the district court’s failure therefore the Court will apply plain error review. Davis, 547 F.3d at 528. Because the September and October drug buys were direct evidence of the conspiracy itself as evidence of a “continuing pattern” of the same nature and type of criminal conduct, the district court was not required to give a cautionary instruction. There was no error. 2. Eighth Amendment Dunbar argues that a mandatory life sentence for conspiracy to distribute 50 grams or more of cocaine is cruel and unusual punishment in violation of the Eighth Amendment when the charged offense was nonviolent and his prior convictions were also nonviolent. The Court must review constitutional challenges to a sentence de novo. United States v. Graham, 622 F.3d 445, 552 (6th Cir. 2010). A severe mandatory life sentence may be cruel but is not necessarily unusual in a constitutional sense. See Harmelin v. Michigan, 501 U.S. 957, 994 (1980). Case law is overwhelmingly against Dunbar’s argument. See Graham, 622 F.3d at 452 - 53 (listing cases that have rejected such Eighth Amendment claims). However, in light of the recent holding in Dorsey v. United States, Dunbar’s argument is moot. 9 Nos. 11-5550, 11-5609, 11-5664 C. Joseph 1. Right to Fair Trial Joseph contends that the district court abused its discretion and violated his right to due process and a fair trial by allowing the government to ask co-defendant Alvin Quarles a question beyond the scope of direct or cross examination and then permitting the government to call Agent Atkins to impeach this prior testimony, eliciting prejudicial hearsay. Specifically, on re-direct the government asked Quarles whether he had observed Joseph cooking crack cocaine even though Quarles had not been asked about Joseph on direct or re-direct. Quarles denied having observed Joseph so engaged, and the government asked whether he remembered telling the government that he had observed such activity. Joseph objected. Quarles did not answer the question. The government then called Agent Atkins to impeach Quarles by testifying that Quarles had stated that he observed Joseph cook crack cocaine. Joseph declined the district court’s offer to give the jury a limiting instruction. The admission of evidence is reviewed under the abuse of discretion standard. Gibson v. United States, 271 F.3d 247, 254 (6th Cir. 2001). However, “[t]o the extent that [a defendant’s] claims sound in due process, we review them de novo.” United States v. Moncivais, 492 F.3d 652, 658 (6th Cir. 2007). Joseph argues that the government offered Quarles’ testimony as “mere subterfuge” to get otherwise inadmissible hearsay admitted as a prior inconsistent statement. Federal Rule of Evidence 613(b) allows a party to admit extrinsic evidence of a prior inconsistent statement “if the witness is given an opportunity to explain or deny the statement and an adverse party is given an opportunity 10 Nos. 11-5550, 11-5609, 11-5664 to examine the witness about it.” Fed. R. Evid. 613(b). The prosecution cannot impeach a witness that it knows will give adverse testimony merely to get in evidence that would be otherwise inadmissible. See Apanovitch v. Houk, 466 F.3d 460, 485 (6th Cir. 2006); United States v. Morlang, 531 F.2d 183, 189 (4th Cir. 1975). The record does not support a finding that the impeachment testimony was provided merely to get in otherwise inadmissible evidence. Joseph has not offered any evidence that the government knew that Quarles would recant his story. Once Quarles testified that he had not said that he observed Joseph cook crack cocaine, the government could call Agent Atkins to testify to Quarles’ prior inconsistent statement. This evidence was offered to impeach the witness and not as substantive evidence against Joseph. The district court offered to give the jury a limiting instruction, but Joseph declined the offer. Nor does the admission of the evidence violate Joseph’s right to due process and a fair trial. Joseph cites United States v. Shoupe, to support his proposition. 548 F.2d 636 (6th Cir. 1977). The Shoupe court held that “the recitation by the prosecutor of the entire substance of a witness’s disavowed, unsworn prior statements, which, if credited by the jury, would be sufficient to sustain a conviction, abridged defendants’ right to a fair trial.” Id. at 643. The Shoupe court noted that the district court failed to provide any protections for the defendants in light of the evidence solicited. Id. at 644 (noting that one prior “trial court protected the rights of the accused by limiting the scope of impeachment” and another “determined in advance, through independent evidence, that the statements were reliable”). Shoupe is distinct from the present case. Here, the district court attempted to limit the scope of the impeachment evidence but Joseph declined the offer to provide a limiting instruction to the jury. Furthermore, the government used Agent Adkin’s testimony to 11 Nos. 11-5550, 11-5609, 11-5664 impeach Quarles inconsistent testimony as opposed to attempting to testify for Quarles on the basis of a prior inconsistent statement, knowing that Quarles would give an inconsistent response. The statement that the witness observed Joseph cooking crack cocaine alone would not have sustained the conspiracy conviction. The Court does not find that Joseph’s due process rights were violated. 2. Variance Joseph argues for the first time on appeal that there was a variance because the evidence offered at trial was substantially different than the evidence charged in the indictment. In the alternative, Joseph contends that the indictment was constructively amended. “A variance to the indictment occurs when the charging terms of the indictment are unchanged, but the evidence at trial proves facts materially different from those alleged in the indictment.” United States v. Caver, 470 F.3d 220, 235 (6th Cir. 2006); see United States v. Blackwell, 459 F.3d 739, 762 (6th Cir. 2006) (“A variance occurs when an indictment alleges one large conspiracy but the evidence at trial establishes multiple conspiracies”). “[A] variance rises to the level of a constructive amendment when the terms of the indictment are in effect altered by presentation of evidence and jury instructions which so modify essential elements of the offense charged that there is a substantial likelihood that the defendant may have been convicted of an offense other than that charged in the indictment.” United States v. Barrow, 118 F.3d 482, 488 (6th Cir. 1997) (quoting United States v. Hathaway, 798 F.2d 902, 910 (6th Cir. 1986)). The Court reviews the record de novo to determine if there was a variance. Caver, 470 F.3d at 235. However, the Court will review the record for plain error if the issue of variance was not raised in the district court. Id. A variance is not reversible error unless the substantial rights of the defendant were 12 Nos. 11-5550, 11-5609, 11-5664 affected; but, a constructive amendment is per se prejudicial. United States v. Solorio, 337 F.3d 580, 590 (6th Cir. 2003). The substantial rights of a defendant are affected if the defendant was convicted based on a conspiracy that he did not participate in. Blackwell, 459 F.3d at 762. Joseph bases his contention on the testimony of Trey Galbraith who testified that Joseph engaged in powder cocaine transactions in Clarksville, Tennessee. Joseph contends that he was surprised by the testimony because it was not alleged to be part of the conspiracy to distribute crack cocaine alleged in the indictment. The majority of the evidence presented against Joseph involved his participation in transactions involving powder cocaine, but there was evidence showing that powder cocaine is cooked into crack cocaine. Williams testified that he sold crack cocaine to Joseph and identified Joseph’s voice on an audio recording requesting more crack cocaine. This evidence, coupled with other evidence presented at trial showing that Joseph was involved in the selling of powder cocaine in order to make crack cocaine, was sufficient to connect Joseph to the conspiracy absent Galbraith’s testimony. The instructions asked the jury to determine whether there was a conspiracy in terms of cocaine base or crack cocaine. The evidence presented at trial was consistent with the evidence charged in the indictment. Joseph’s substantial rights were not violated. D. Moore Moore argues that the district court erred in denying his motion for a new trial based on his claim that his Sixth Amendment right to confrontation was violated when the hearsay statement that Moore was a “crack cook” was offered to prove the truth of the matter asserted. The Court usually reviews the district court’s denial of a motion for a new trial for abuse of discretion. United States v. Pierce, 62 F.3d 818, 823 (6th Cir. 1995). However, given that Moore did not make a 13 Nos. 11-5550, 11-5609, 11-5664 contemporaneous objection to the complained of error, the Court will apply plain error review. United States v. Koeberlein, 161 F.3d 946, 949 (6th Cir. 1998). In Crawford v. Washington, 541 U.S. 36, 53 - 54 (2004), the Supreme Court held that the Confrontation Clause of the Sixth Amendment does not allow the “admission of testimonial statements of a witness who did not appear at trial unless he was unavailable to testify, and the defendant had had a prior opportunity for cross-examination.” The statements of a confidential informant are testimonial and, therefore, may not be offered to establish the truth of the matter asserted unless the accused has an opportunity to cross examine the speaker. United States v. Cromer, 389 F.3d 662, 670 - 71 (6th Cir. 2004). The confidential informant was not called to testify. However, Moore’s co-defendant Dunbar attacked the confidential informant’s credibility when he asked Agent Atkins whether she had provided information regarding the Defendant’s connection to crack cocaine. Agent Atkins responded that the confidential informant had stated that Moore cooked crack cocaine. This statement appears to have been offered to show that the confidential informant gave reliable information and was in response to defense counsel’s own questioning. The statement, however, could be viewed as testimonial and, therefore, raise a Crawford issue. Regardless, any potential error was harmless in light of the other evidence, including Moore’s own admission, establishing that Moore was connected to the conspiracy as a cook. See United States v. Hayes, 218 F.3d 615, 623 (6th Cir. 2000)(citing Delaware v. Van Ardsdall, 475 U.S. 673, 684 (1986)). 14 Nos. 11-5550, 11-5609, 11-5664 III. CONCLUSION AFFIRMED IN PART and REMANDED back to the district court for resentencing. 15	null	minipile	NaturalLanguage	mit	null
Q: what is BOOL WINAPI return type I came across a function definition in c++ as follows: (source) BOOL WINAPI GetProcessMemoryInfo( _In_ HANDLE Process, _Out_ PPROCESS_MEMORY_COUNTERS ppsmemCounters, _In_ DWORD cb ); What is the return type here. Is it BOOL WINAPI or BOOL? Where is this type defined? A: BOOL is a typedef for int. WINAPI is a macro specifying the calling convention (__stdcall, __cdecl etc.) of the function. typedef int BOOL; #define WINAPI __stdcall See MSDN for details. It's basically equivalent to: int __stdcall ...	null	minipile	NaturalLanguage	mit	null
Cairo offices torched as Egypt death toll mounts Published duration 15 August 2013 media caption James Reynolds in Cairo: "[Wednesday] was one of the most violent days in Egypt's recent history" Hundreds of Muslim Brotherhood supporters have set fire to a government building in Giza, near the Egyptian capital, Cairo. The move comes a day after security forces broke up the Brotherhood's protest camps, leaving hundreds dead. Brotherhood members had been protesting for weeks about the army's overthrow of President Mohammed Morsi in July. The government says 525 died nationwide on Wednesday, but the final toll is likely to be significantly higher. Scores of bodies have not been registered, because the official count only includes bodies which have passed through hospitals. The BBC's Khaled Ezzelarab has reported seeing at least 140 bodies wrapped in shrouds at the Eman mosque, close to the main protest camp at Rabaa al-Adawiya Square. These will not have been counted in the official toll. The Muslim Brotherhood insists that more than 2,000 people died. It says 300 bodies were taken to the Eman mosque, and other bodies were taken to sports halls. Reports speak of disputes between bereaved relatives and officials entrusted with documenting the causes of death. The Muslim Brotherhood, the main source of Mr Morsi's support, had called for marches on Thursday, both in Cairo and Egypt's second city, Alexandria, to protest against Wednesday's deaths. After attempting to storm the building housing the local government in Giza - Cairo's twin city on the west bank of the Nile - the protesters were repelled by police, according to state television. Local TV footage showed two buildings burning, and firefighters evacuating employees. State-run Nile News TV also reported clashes between Muslim Brotherhood members and residents in a suburb of Alexandria. 'Serious massacre' Armoured bulldozers had moved into the two protest camps in Cairo shortly after dawn on Wednesday morning. The smaller of the two protest camps, at Nahda Square, was cleared quickly but clashes raged for several hours in and around the main encampment at Rabaa al-Adawiya. The mosque of the same name was damaged by fire. Mobs later carried out reprisal attacks on government buildings and police stations as well as churches belonging to the country's Coptic Christian minority. In a televised address on Wednesday evening, Egyptian interim Prime Minister Hazem Beblawi defended the operation, saying the authorities had to restore security. He declared a state of emergency, but said this would be lifted as soon as possible. Many countries have condemned the Egyptian security forces' actions. Navi Pillay, the UN High Commissioner for Human Rights, has demanded an independent, impartial inquiry into what happened on Wednesday. "The number of people killed or injured, even according to the government's figures, point to an excessive, even extreme, use of force against demonstrators," Ms Pillay said in a statement. Turkish Prime Minister Recep Tayyip Erdogan described the events as a "very serious massacre". US President Barack Obama is due to give a statement on the issue soon. Mr Morsi, Egypt's first democratically elected president, was ousted by the military on 3 July.	null	minipile	NaturalLanguage	mit	null
IN THE COMMONWEALTH COURT OF PENNSYLVANIA Lallie Robinson, : Petitioner : : v. : : Workers' Compensation Appeal : Board (Service Plus Delivery : Systems, Inc. and State Workers' : Insurance Fund), : No. 2013 C.D. 2014 Respondents : Argued: October 5, 2015 BEFORE: HONORABLE BERNARD L. McGINLEY, Judge HONORABLE MARY HANNAH LEAVITT, Judge1 HONORABLE ROCHELLE S. FRIEDMAN, Senior Judge OPINION NOT REPORTED MEMORANDUM OPINION BY JUDGE McGINLEY FILED: January 8, 2016 Lallie Robinson (Petitioner/Claimant) petitions for review from an order of the Workers’ Compensation Appeal Board (Board) that affirmed Workers’ Compensation Judge Lawrence C. Beck’s (WCJ Beck) grant of Service Plus Delivery Systems, Inc.’s (Employer) and the State Workers’ Insurance Fund’s (SWIF) (collectively, Respondents) petition to review compensation benefits offset (review petition). I. WCJ Beck’s Decision The parties agree that “[t]he facts are not genuinely in dispute on the issues pertaining to the present appeal.” Brief for Petitioner at 16. 1 This case was assigned to the opinion writer before January 4, 2016, when Judge Leavitt became President Judge. WCJ Beck made the following pertinent findings of fact: 1. On July 6, 2010, Workers’ Compensation Judge Christina Barbieri circulated a decision granting Claimant’s Claim Petition and Penalty Petition.[2] (Emphasis added.) 2. Judge Barbieri found that, on March 10, 2006, Claimant suffered a large eccentric disc herniation at C7- C8, which impinged the C7-C8 nerve root, causing cervical radiculopathy at C7-C8 and 1, exacerbation of pre-existing but symptomatic bilateral acromioclavicular arthropathy, bilateral post-traumatic shoulder impingement syndrome, exacerbation of a pre-existing mildly symptomatic cervical spondylosis, exacerbation of cervical radiculopathy and clinical evidence of right neurogenic thoracic outlet syndrome. Claimant suffered his injuries as the result of a motor vehicle accident.[3] 3. In support of its Review Petition, Employer submitted the March 29, 2011 deposition of James Jordon, Esquire. (Emphasis added.) This Judge has reviewed Mr. Jordan’s testimony and summarizes it as follows: a. Mr. Jordon is assistant counsel for the State Workers’ Insurance Fund (SWIF). In his capacity as assistant counsel, Mr. Jordon is point of contact with counsel for claimant’s [sic] in third-party actions . . . . In this role, Mr. Jordon has access to SWIF’s payment records with regard to a claimant’s medical and indemnity benefits. 2 Petitioner filed a claim petition and alleged that he was totally disabled since March 10, 2006. Petitioner also filed a penalty petition and alleged numerous violations of the Workers’ Compensation Act (Act), Act of June 2, 1915, P.L. 736, as amended, 77 P.S. §§ 1-1041.4, 2501- 2708, which included failure to investigate. Petitioner requested fifty percent in penalties, unreasonable contest fees and workers’ compensation benefits with statutory interest. Employer and SWIF denied the allegations of the claim and penalty petitions. 3 On March 10, 2006, Petitioner was operating a van for Employer when his vehicle was rear-ended by one vehicle which forced his vehicle into another vehicle. Brief of Respondents (Service Plus Delivery Systems, Inc. and State Workers’ Insurance Fund) at 7. 2 b. Mr. Jordon is familiar with Claimant’s subrogation file. As part of Claimant’s subrogation file, a Notice of Subrogation was sent to Claimant and Claimant’s third party counsel, Lowenthal & Abrams, on February 21, 2008. (Emphasis added.) c. Despite the claim being originally denied, medical benefits in the amount of $17,494.83 were paid as of November 21, 2008. Mr. [James B.] Mogul [Petitioner’s attorney] had discussed third party recovery with John Aris, Esquire, of Lowenthal & Abrams in 2008. (Emphasis added.) d. On February 12, 2009, SWIF received a check for $9,494.70 from Lowenthal & Abrams. (Emphasis added.) e. On June 24, 2009, SWIF received a check for $1,663.22 from Lowenthal & Abrams. (Emphasis added.) f. Mr. Jordon believed these amounts were for reimbursement of SWIF’s medical lien at the time. There were no other liens at that time. Mr. Jordon did not deem SWIF’s receipt of these amounts to be a waiver of SWIF’s future lien. (Emphasis added.) g. Mr. Jordon did not sign any agreement waiving SWIF’s future subrogation rights against Claimant’s third party recovery. To Mr. Jordon’s knowledge, no one else at SWIF agreed to waive SWIF’s subrogation rights. h. Claimant first began receiving indemnity benefits, pursuant to Judge Barbieri’s July 6, 2010 decision, on August 10, 2010. i. As of November 1, 2010, SWIF had paid Claimant $97,151.55 in indemnity benefits. (Emphasis added.) j. As of November 1, 2010, SWIF had paid Claimant $27,468.36; however, $8,044.09 in litigation costs was incorrectly included in that amount. This amount ($19,424.27) is the net amount of benefits paid after the 3 $9,494.70 and $1,663.22 payments from Lowenthal & Abrams were previously deducted. k. As of March 29, 2011, SWIF had paid $134,736.42 in indemnity and medical benefits. (Emphasis added.) 4. In opposition to Employer’s Review Petition, Claimant submitted the September 8, 2011 deposition testimony of John Aris, Esquire. This Judge has reviewed Mr. Aris’ testimony and summarizes as follows: a. Mr. Aris is an associate attorney for Lowenthal & Abrams and represented Claimant in the third party and under-insured motorist (UIM) claims arising out of the March 10, 2006 motor vehicle accident. b. Mr. Aris explained that the third party recovery against Sharon Merriweather, the driver of the vehicle which struck Claimant’s vehicle, settled for $15,000.00. These represented the policy limits of Ms. Merriweather’s automobile insurance. The matter settled in or about December 2008. c. On February 6, 2009, Lowenthal & Abrams forwarded to SWIF a check for $9,494.70. A second check in the amount of $1,663.22 was sent on March 25, 2010; as of June 10, 2010, it had not been cashed. d. Mr. Aris believed that SWIF’s lien, at the time, had been satisfied in full. He did not ask SWIF to compromise its lien. (Emphasis added.) e. Mr. Aris had no conversations with Mr. Jordon regarding any potential future payments or the waiver of any future lien. (Emphasis added.) f. Following the settlement of Claimant’s third party claim, Mr. Aris instituted a civil action against United States Fire Insurance Company for UIM benefits. g. On March 23, 2010, Claimant and United States Fire Insurance Company engaged in binding arbitration . . . [t]he arbitrator determined the value of Claimant’s case 4 to be $110,000.00. As $15,000.00 had already been tendered to Claimant through the third party settlement, United States Fire Insurance Company was liable for $95,500.00. (Emphasis added.) 5. Mr. Aris’ cost incurred in prosecution of Claimant’s UIM claim was $7,056.34. 6. Mr. Aris’ contingent attorney fee for the prosecution of Claimant’s UIM claim was 1/3 ($31,666.66), pursuant to the representation of Claimant’s counsel at the January 11, 2011 hearing on this matter. 7. The schedule of distribution for the recovery of Claimant’s third party claim included a $5,000.00 contingent attorney fee and $505.30 in litigation costs and expenses. WCJ Beck’s Decision, January 7, 2013, Findings of Fact (F.F.) Nos. 1-7 at 3-5; Reproduced Record (R.R.) at 135a-37a. WCJ Beck granted Respondents’ review petition and concluded: 2. Employer’s right to subrogation against Claimant’s third party and UIM benefits is absolute and has not been waived. (Emphasis added.) 3. Employer’s reimbursement rate on future compensation liability is 40.2%. 4. Employer is responsible for 40.2% of any future weekly benefits and medical benefits until it recovers $91,809.78. 5. Following the recovery of $91,809.78, Employer shall be responsible for 100% of any compensation liability. (Emphasis added.) 6. Employer’s contest has been reasonable at all times. 5 WCJ Beck’s Decision, Conclusions of Law (C.L.) Nos. 2-6 at 6; R.R. at 138a. The Board affirmed and concluded that “[a]lthough the UIM (Under Insured Motorist) settlement occurred in March of 2013 and at that time, a decision had not been rendered finding Defendant [Employer] liable for workers’ compensation benefits, Defendant [Employer] was still entitled to recover its lien.” Board’s Opinion, October 9, 2014, at 4. “Therefore, because subrogation is mandatory and the purpose of subrogation would not be served if we were to find that Defendant [Employer] was not entitled to subrogation in these circumstances, we see no error in the Judge granting Defendant’s [Employer’s] Review Offset Petition.” Board’s Opinion, October 9, 2014, at 4-5. II. Issues A. Whether WCJ Beck Failed To Issue A Reasoned Decision? Initially, Petitioner contends4 that WCJ Beck failed to render a reasoned decision because his decision did not provide for meaningful appellate review. Specifically, Petitioner asserts that WCJ Beck devoted only one sentence that could be considered a legal analysis of the case. WCJ Beck did not address the real issue. Petitioner asserts that WCJ Beck failed to provide adequate reasons for what evidence he rejected and what evidence he accepted “in order to ensure that a legally erroneous basis will not lie undiscovered and will allow meaningful appellate review of possible legal error.” Brief for Petitioner at 22. Petitioner contends that WCJ Beck failed to render credibility determinations and never indicated what testimony he accepted and what testimony he rejected. 4 This Court’s review is limited to a determination of whether an error of law was committed, whether necessary findings of fact are supported by substantial evidence, or whether constitutional rights were violated. Vinglinsky v. Workmen’s Compensation Appeal Board (Penn Installation), 589 A.2d 291 (Pa. Cmwlth. 1991). 6 Respondents counter that Petitioner waived the issue of whether WCJ Beck issued a reasoned decision because he failed to raise this issue on appeal to the Board. In Wheeler v. Workers’ Compensation Appeal Board (Reading Hospital and Medical Center), 829 A.2d 730, 734 (Pa. Cmwlth. 2003), this Court addressed the criteria necessary to determine whether an issue was waived: It is well established that an issue is waived unless it is preserved at every stage of the proceeding. Nabisco Brands, Inc. v. Workers’ Compensation Appeal Board (Tropello), 763 A.2d 555 (Pa. Cmwlth. 2000). The strict doctrine of waiver applies to a workers’ compensation proceeding. Hinkle v. Workers’ Compensation Appeal Board (General Electric Co.), 808 A.2d 1036 (Pa. Cmwlth. 2002) . . . . The purpose of the waiver doctrine is to ensure that the WCJ is presented with all cognizable issues so that the ‘integrity, efficiency, and orderly administration of the workmen’s compensation scheme of redressed for work-related injury’ is preserved . . . . (Citations omitted and emphasis added.) Here, the record reveals that after WCJ Beck granted Respondents’ review petition, Petitioner appealed to the Board and alleged the following errors: Conclusion of Law No. 2. Judge Beck committed a reversible error of law when his Honor found that the right of subrogation is absolute and can be abrogated only by choice. Claimant satisfied the third-party lien that was in existence at the time of the settlement of the third-party case. There was no other existing lien at the time that claimant’s third party case was settled . . . . Judge Beck erred in finding that the issue is whether or not State Workers’ Insurance Fund had waived its third- party lien. Claimant never argued or asserted that State Workers’ Insurance Fund had waived its third-party lien . . . . Claimant never had any established entitlement to 7 any workers’ compensation benefits, until the Judge granted the claim petition and awarded benefits. None of that existed at the time that the third-party case was settled. Defendants had no lien in addition to the lien already satisfied in full when the third-party case was settled. Therefore, Judge Beck committed a reversible error of law. Judge Beck did not address the critical issues in this case at all. (Emphasis added.) Appeal from Judge’s Findings of Fact and Conclusions of Law, January 22, 2013, at 1 and 3; R.R. at 130a and 132a.5 Clearly, Petitioner failed to raise the issue that WCJ Beck’s decision was unreasonable before the Board. Pa. R.A.P. 1551(a) provides that “[r]eview of quasijudicial orders shall be conducted by the court on the record made before the government unit . . . [n]o question shall be heard or considered by the court which was not raised before the government unit . . . .” (Emphasis added.) Therefore, this issue is waived on appeal to this Court. B. Whether The Board Erred As A Matter Of Law Because “Only A Lien On A Third-Party Case That Actually Exists In Fact And Not In Theory Can Be Satisfied?”6 5 Petitioner responded: This allegation could not be further from the truth. Petitioner did raise this issue with the . . . Board. Petitioner argued to the . . . Board and to this Honorable Commonwealth Court . . . that [WCJ Beck] issued an unreasoned decision because he failed to address the genuine issue in this case. . . . This argument formed the core of petitioner’s appeal to the . . . Board and the appeal to this . . . Court . . . . Reply Brief for Petitioner at 1-2. This Court must disagree. Petitioner’s allegation of error was that WCJ Beck failed to address the genuine issue in the present matter, not that he failed to issue a reasoned decision. 6 Brief for Petitioner, Statement of Questions Involved at 2. 8 Petitioner next contends that he did not contest the issue of whether Respondents have a right to subrogation. Specifically, Petitioner contends that when he received the third-party award, WCJ Barbieri did not rule on his claim petition. Petitioner states that the existing subrogation lien of $11,157.92 was paid in full at the time of the third party settlement. Petitioner concludes that SWIF failed to establish legal entitlement to a future reimbursement of a lien which did not exist at the time of the third-party settlement. Respondents counter that this Court has previously recognized that employers have an absolute right to immediate payment of a past-due lien from the recovery fund after payment of attorneys’ fees and litigation expenses. Respondents state that at no time did it either explicitly or impliedly waive its future right to subrogation with respect to Petitioner’s still-pending workers’ compensation claim. Respondents pose that Petitioner could have choosen not to pursue the workers’ compensation claim to its conclusion and just accepted the third party settlement and arbitration award. As a result of the compensation award by WCJ Barbieri, Respondents’ subrogation lien increased. Respondents caution that to allow Petitioner to keep the entire third party settlement/award after it paid a total of $134,736.42 in indemnity and medical benefits would result in a double recovery. Section 319 of the Act, 77 P.S. § 671, provides: Where the compensable injury is caused in whole or in part by the act or omission of a third party, the employer shall be subrogated to the right of the employe . . . against such third party to the extent of the compensation payable under this article by the employer; reasonable attorney’s fees and other proper disbursements incurred in obtaining a recovery or in effecting a compromise 9 settlement shall be prorated between the employer and employe . . . . The employer shall pay that portion of the attorney’s fees and other proper disbursements that the amount of compensation paid or payable at the time of recovery or settlement bears to the total recovery or settlement bears to the total recovery or settlement. Any recovery against such third person in excess of the compensation theretofore paid by the employer shall be paid forthwith to the employe . . . and shall be treated as an advance payment by the employer on account of any future installments of compensation. In Murphy v. Workers’ Compensation Appeal Board (City of Philadelphia), 871 A.2d 312 (Pa. Cmwlth. 2005), this Court reiterated the employer’s absolute right to subrogation: The rationale underlying the right to subrogation is threefold. First, it prevents double recovery for the same injury by the claimant. Second, it prevents the employer from having to make compensation payments which resulted from the negligence of a third party. Finally, it prevents a third party from escaping liability for his negligence. (Emphasis added.) Id. at 317. This Court concurs with the Board’s analysis that Respondents were entitled to subrogation: In the instant case, the Judge found that despite the fact that the claim had been originally denied, medical benefits in the amount of $17,494.83 had been paid by defendant [Respondents] as of November 21, 2008 (Finding of Fact No.3(c)). In December 2008, Claimant settled a third-party claim against the driver involved in his vehicular accident for $15,000.00 (Finding of Fact No. 4(b)). On February 12, 2009, Defendant [Respondents] received a check in the amount of 10 $9,494.70 from Claimant’s Counsel and on June 24, 2010, Defendant [Respondents] received a check in the amount of $1,663.22 from Counsel (Finding of Fact No. 3(d) & (e)). It was believed that these checks were for the reimbursement of Defendant’s [Respondents’] medical lien at the time (Finding of Fact No. 4(f)). On July 6, 2010, Judge Barbieri issued the Decision granting the Claim Petition and Claimant began receiving benefits pursuant to that Decision on August 10, 2010 (Findings of Fact Nos. 1 & 3(h)). As of November 1, 2010, Defendant [Respondents] had paid $97,151.55 in benefits (Finding of Fact No. 3(i)). As of March 29, 2011, Defendant [Respondents] had paid $134,736.42 in indemnity and medical benefits (Finding of Fact No. 3(k)). While Claimant’s Claim Petition was pending, on March 23, 2010, Claimant and United States Fire Insurance Company engaged in binding arbitration and pursuant to that determination, Claimant settled his UMI [Under Insured Motorist] claim for $95,000.00 (Finding of Fact No. 4(g)). (Emphasis added.) The Judge determined that defendant [Respondents] did not expressly or impliedly waive its right to subrogation (Discussion). As a result, he found that Defendant [Respondents] was entitled to a recovery of $91,809.78 and it was responsible for 40.2% of any future weekly benefits and medical expenses until it recovers $91,809.78. We observe no error in this conclusion. (Emphasis added.) Although the UMI settlement occurred in March of 2013 and at that time, a decision had not been rendered finding Defendant [Respondents] liable for workers’ compensation benefits, Defendant [Respondents] was still entitled to recover its lien. Defendant did subsequently make payment to claimant for workers’ compensation benefits. Pursuant to Section 319 of the Act, the right to subrogation is ‘absolute’ and just because Claimant settled his UMI claim prior to his workers’ compensation claim, does not render 11 Defendant’s right to subrogation invalid. Subrogation prevents double recovery for the same injury and relieves the employer of liability occasioned by the negligence of a third party. Since Defendant [Respondents] was eventually found liable for workers’ compensation benefits and did make payment for those benefits, disallowing subrogation in these circumstances where a lien had not been asserted because the party had not yet been found liable at the time of the settlement would be in direct contradiction to the mandatory language contained in Section 319. . . . (Emphasis added.) Board’s Opinion at 3-5. Accordingly, this Court affirms the WCJ’s grant of Respondents’ review offset petition. ____________________________ BERNARD L. McGINLEY, Judge 12 IN THE COMMONWEALTH COURT OF PENNSYLVANIA Lallie Robinson, : Petitioner : : v. : : Workers' Compensation Appeal : Board (Service Plus Delivery : Systems, Inc. and State Workers' : Insurance Fund), : No. 2013 C.D. 2014 Respondents : ORDER AND NOW, this 8th day of January, 2016, the order of the Workers’ Compensation Appeal Board in the above-captioned matter is affirmed. ____________________________ BERNARD L. McGINLEY, Judge	null	minipile	NaturalLanguage	mit	null
#Thu Sep 28 22:00:15 CEST 2017	null	minipile	NaturalLanguage	mit	null
Kevin Kelly (politician) Kevin Kelly (born August 18, 1953) is an American politician from Maryland and a member of the Democratic Party. He served in the Maryland House of Delegates, representing District 1B in Allegany County for six terms, from 1987 until 1995, and again from 1999 until 2015. Kelly was a member of the Judiciary Committee and its Civil Law and Procedure Subcommittee. Background Kelly was born in Cumberland, Maryland on August 18, 1953. He graduated from Bishop Walsh School in 1971. After high school he attended Frostburg State University where he got his B.S. in Political Science. After Frostburg he attended the University of Baltimore School of Law where he attained his J.D. in 1978. Kelly was admitted to the Maryland bar in 1980. Education Kevin Kelly received his education from the following institutions: JD, University of Baltimore School of Law, 1978 BS, Political Science, Frostburg State College, 1975 Political experience Kevin Kelly has had the following political experience: Delegate, Maryland State House of Delegates, 1999-2015 Delegate, Maryland State House of Delegates, 1987-1995 Current legislative committees Kevin Kelly has been a member of the following committees: Judiciary, Member Subcommittee on Civil Law and Procedure, Member In the legislature Kelly was first elected to the General Assembly in 1986, serving through 1994, and was re-elected in 1998. Kelly was defeated in the 2014 Maryland general election after serving 20 years in the Maryland House of Delegates. Election 2014 general election Voters to choose one: {\| class="wikitable" !Name !Votes !Percent !Outcome \|- \|- \|Kevin Kelly, Dem. \|4,623 \|40.9% \|Lost \|- \|- \|Jason C. Buckel, Rep. \|6,664 \|58.9% \|Won \|} 2010 general election Voters to choose one: {\| class="wikitable" \|- !Name !Votes !Percent !Outcome \|- \|- \|Kevin Kelly, Dem. \|6,226 \| 51.26% \| Won \|- \|- \|Mary Beth Pirolozzi, Rep \|5,908 \| 48.64% \| Lost \|} 2006 general election Voters to choose one: {\| class="wikitable" \|- !Name !Votes !Percent !Outcome \|- \|- \|Kevin Kelly, Dem. \|6,489 \| 55.7% \| Won \|- \|- \|Mark A. Fisher, Rep. \|5,151 \| 44.2% \| Lost \|} 2002 general election Voters to choose one: {\| class="wikitable" \|- !Name !Votes !Percent !Outcome \|- \|- \|Kevin Kelly, Dem. \|6,654 \| 55.7% \| Won \|- \|- \|Tricia Wolfe, Rep. \|5,286 \| 44.3% \| Lost \|- \|Other \|4 \| 0.0% \| Lost \|} 1998 general election Voters to choose one: {\| class="wikitable" \|- !Name !Votes !Percent !Outcome \|- \|- \|Kevin Kelly, Dem. \|5,232 \| 51% \| Won \|- \|- \|Tricia Wolfe, Rep. \|4,991 \| 49% \| Lost \|} 1990 general election Voters to choose two: {\| class="wikitable" \|- !Name !Votes !Percent !Outcome \|- \|- \|Kevin Kelly, Dem. \|11,579 \| 41% \| Won \|- \|- \|Betty Workman, Dem. \|11,413 \| 40% \| Won \|- \|- \|Dolores Chase Morgan, Rep. \|5,321 \| 19% \| Lost \|} 1986 general election Voters to choose two: {\| class="wikitable" \|- !Name !Votes !Percent !Outcome \|- \|- \|Betty Workman, Dem. \|8,195 \| 29% \| Won \|- \|- \|Kevin Kelly, Dem. \|7,858 \| 28% \| Won \|- \|- \|Robert M. Hutcheson, Rep. \|6,151 \| 22% \| Lost \|- \|- \|William R. Davis, Rep. \|5,984 \| 21% \| Lost \|} References Notes Category:Members of the Maryland House of Delegates Category:Living people Category:1953 births Category:People from Cumberland, Maryland Category:Maryland Democrats Category:Frostburg State University alumni Category:University of Baltimore School of Law alumni Category:21st-century American politicians	null	minipile	NaturalLanguage	mit	null
India's Got Talent 5 - High on emotions and Outstanding! A multitude of talent is on display in this show of skill, perseverance and aptitude. While the daredevil stunts leave you gaping in wonder; some of the acts make you go all teary eyed bringing a lump to your throat! India's Got Talent 5 is a reality show for common people from India who have unusual skills and who come over to highlight their talent. There is no age limit and people from all over India in solo or group can perform and compete to win the title and the prize. What works - The contestants! They are the best amongst the lot of reality shows we see on air these days. These is a farmer, tailor, teacher, accountant, hospital attendant, students, make-up artist amongst many others who want to do excel in something other than their profession and are making the most of this opportunity. Maybe because there is a plethora of shows on Indian Television which focus only song and dance but here we have singing, dancing and other creative skills along with stunts on display. The back story of many of the contestants too is quite interesting and pulls at your heart strings when we see it on screen. So along with a cute, fat boy in the first episode dancing to Salman Khan numbers we also have the stuntbaaz Balram who set his body on fire before jumping off in a swimming pool along with Bhawna, the sensuous dancer from Tollywood who did a sensational pole dance. The show has now had six episodes on air and along with superb solo acts there has been an excellent team effort in various unusual group performances too. The most impressive performances till now have been that of the ever hopeful one legged Shubrit Kaur's dance, the 3 year old chhota packet Sarika Bijli's performance, Sanjay Kumar the farmer who did a remixed MJ version, the magician Hassan Rizvi, the balloon act by Sarvanna, the UV act from Silver Steppers, the stunt man by Sunil Kumar, the Star Guides group of blind boys from Victoria Memorial blind school in the category 5 - 17 years of age who did the pole Mal-Khamb amongst many others. We also like all the three judges who appear to be fair and sweet to the contestants and have uniformity while making the decision. Malaika Arora Khan comes across as the yummy mummy who understands what it means to have little kids practice and perform, Karan Johar is forever encouraging while Kirron Kher who has been in a judge in all the previous seasons of the show is the best amongst the lot! She is visibly scared and upset while watching some of the dare devil performances but that does not hamper her judgement as she excitedly claps her hands or frankly says no' when the need be! The hosts Mantra and Bharti Singh have excellent comic timings which suit the show. While we have always seen the funny side of Bharti, here even she is biting her nails and gets emotional when she sees any unusual performances. We also like the last bit in the show which has the uncut version of what the judges are doing when not shooting. It is just raw footage of couple of minutes wherein they are singing or generally pulling each other's leg but it is fun to see them do so! What doesn't work - Actually, nothing but since the show is all about talent they should try to keep the sympathy factor a little low so that there is equality between all contestants. In fact in almost all the talent based reality shows we have disabled contestants which is a good way to boost their morale but with no offense meant if there are so many of them then someone should have a separate show for such contestants. Many shows need the Bollywood touch which works for the films getting promoted as well as for the show and here too we saw celebs like Madhuri Dixit, Remo Fernandes and others coming in but even without them the show can leave a distinguished mark. Our take - The show has been getting good ratings on the TRP meter and is popular with the mass audience. We are still watching the auditions wherein the judges are giving them a yes or no for the next round and given the nature of contestants the final rounds are going to be nail biting. As it is when we watch some of the performers it is not unusual to get goosebumps and tears in the eyes to see all the struggle that these people go through. It brings to fore exclusive talent from small towns of India, people from humble backgrounds who despite all odds and difficulties manage to pursue their passion to reach this stage. This is one show you can watch with your family and feel proud of each and every contestant. In fact, children from metros who get all things easily and are becoming increasingly lazy as they engage in inane activities need to watch this show just to see the real India and the confident talent that lies within it! Like the judges have said time and again on the show seeing the struggle of some of the contestants will make each one of us a better person. Disclaimer: All Logos and Pictures of various Channels, Shows, Artistes, Media Houses, Companies, Brands etc. belong to their respective owners, and are used to merely visually identify the Channels, Shows, Companies, Brands, etc. to the viewer. Incase of any issue please contact the webmaster.	null	minipile	NaturalLanguage	mit	null
A PILOT sparked an armed response after accidentally triggering the hijack alarm on board a plane. Dutch military police were called to a suspicious situation on board a plane at Schiphol airport, Amsterdam. 2 A suspected hijacking has been reported at Schiphol Airport in Amsterdam Credit: Twitter / @vikasjournolko 2 Dutch police were seen milling around after the threat was worked out to be an error Credit: AP:Associated Press Reports on Twitter earlier suggested that three men armed with knives were trying to take control of an outbound Air Europe flight to Madrid. "There is a suspicious situation and that's all I can say," a spokesman for the military police said. However the airline later confirmed that the hijack alarm was triggered by mistake, adding that "nothing has happened". Images showed crowds of people in the airport and armed police behind a cordon. Schiphol Airport's official Twitter account tweeted: "The Royal Netherlands Marechaussee is currently investigating a situation on board of a plane at Amsterdam Airport Schiphol. We keep you posted."	null	minipile	NaturalLanguage	mit	null
Reviews from a small country Dead And Breathing, Theatre Review. Unity Theatre, Liverpool. Liverpool Sound and Vision Rating * * * * * Cast: Lizan Mitchell, Kim Tatum. Aside from yourself and your loved ones being healthy and happy, all that you can ever hope for in life is either being part of history, having your name linked to the times you live and have your name roll off the extensive tongue as if attached to a medieval proclamation, complete with booming voice reading out your virtues and perhaps a heroic deed or two; or seeing history made, knowing you were alive when the Earth shattering, the amazing or the downright incredible happened and perhaps seeing someone else have their moment in your company…being witness to the most awesome of performances. Whichever way you see history, it comes at the most unexpected of times, it hits you between the eyes and reminds you of what it means to be alive and in Chisa Hutchinson’s play Dead and Breathing, that feeling is intensified, brutally chiselled into a statue and giving absolute reverence; for in Lizan Mitchell’s performance as Carolyn, a woman living with stage three cancer and the bitterness of death having had the temerity not to have claimed her crotchety old and cantankerous soul yet, one of the most outstanding moments in Liverpool theatre, certainly in the last ten years, opened up before the Unity Theatre’s audience’s eyes. Whilst in a very different play, it could not helped be thought that Ms. Mitchell, aided beautifully by Kim Tatum in this particular two hander, had the air of the late, great Jessica Tandy in Driving Miss Daisy, the assuredness of spite, the grip of fear and the tongue of a devil were heartbreakingly brilliant, the soft squeal of excited panache as the play unfolded, this is award winning presence, and to witness it is to hopefully understand the joy of living. Dead and Breathing, perhaps something in which we all cling too, just barely surfacing above the waterline, taking in life but not living it, forgetting that seize the day is not just some mantra spoken by a comic genius, but is the most honest and yet destructive force, the most studious of pursuits that we can achieve and it often takes the nudge from the person we would least like to be around to fulfil that affirmation of life. A play of incredible depth, of the passion that beats between life and death and of looking kindness in the face, no matter what clothes it wears; Dead and Breathing is breath-taking.	null	minipile	NaturalLanguage	mit	null
When using ProGuard, you should be aware of a few technical issues, all of which are easily avoided or resolved: - For best results, ProGuard's optimization algorithms assume that the processed code never intentionally throws NullPointerExceptions or ArrayIndexOutOfBoundsExceptions, or even OutOfMemoryErrors or StackOverflowErrors, in order to achieve something useful. For instance, it may remove a method call `myObject.myMethod()` if that call wouldn't have any effect. It ignores the possibility that `myObject` might be null, causing a NullPointerException. In some way this is a good thing: optimized code may throw fewer exceptions. Should this entire assumption be false, you'll have to switch off optimization using the `-dontoptimize` option. - ProGuard's optimization algorithms currently also assume that the processed code never creates busy-waiting loops without at least testing on a volatile field. Again, it may remove such loops. Should this assumption be false, you'll have to switch off optimization using the `-dontoptimize` option. - When obfuscating, ProGuard writes out class files named "`a.class`", "`b.class`", etc. If a package contains a large number of classes, ProGuard may also write out "`aux.class`". Inconveniently, Windows refuses to create files with this reserved name (among a few other names). It's generally better to write the output to a jar, in order to avoid such problems. Alternatively, you can use the Uniform Naming Convention (UNC) for your Windows paths, which doesn't suffer from the constraint.	null	minipile	NaturalLanguage	mit	null

Cadmium concentrations in human kidneys from the UK. The concentration of cadmium in the cortex and medulla of nearly 1000 kidneys obtained at autopsy was determined by atomic absorption spectrophotometry. Particular care was taken over the analytical procedures to ensure the accuracy and precision of the results; intrakidney variability was examined and found to be small. The frequency distributions of cadmium concentrations were approximately lognormal. There was much variability in cadmium concentrations between individuals, with geometric coefficients of variation for both cortex and medulla of around 100%. Cadmium concentrations varied with age and smoking habits, but not sex. Values were successively higher than those in the previous age-group up to 50-59 years (geometric mean 19 micrograms/g), after which they were successively lower; on average, heavy smokers had cadmium concentrations some 15-20% higher than those in light smokers who in turn had values some 15-20% higher than those in non-smokers. No definite conclusions could be reached on the variation of cadmium concentrations with either cause of death or location, or over time. The present study, the first of its kind in the UK, has provided benchmark data; its results are broadly in line with those from previous but smaller studies in other countries.

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You can't blame the Cleveland Browns for wanting to get this one right. A franchise that historically hasn't had much luck in the draft, Cleveland is leaving no stone unturned in their quest to draft someone who'll actually be on the roster four years from now. According to CBS Sports, now-departed team president Joe Banner commissioned the study last year, and current management decided to let it play out - the money had already been spent. Jason La Canfora says the study was extremely thorough: "[it evaluated] decades of successful NFL quarterbacks and [took] all sorts of variables into consideration...and ultimately pointed to Teddy Bridgewater having the best success rate of this year's group of quarterbacks." It's hard to find a consensus on Bridgewater - some draft analysts - like our own Tom Downey - agree with the study, while others are far from optimistic about his NFL future. The Browns have the fourth pick in tonight's draft, and we'll find out then if they decided to take the results of their $100,000 study to heart. Our latest mock draft has them going in a slightly different direction, and it's

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Q: In BroadcastReceiver, getResultCode() always returns -1 for SMS sent and delivered actions Following most people I guess, I am deriving my SMS handling code from http://mobiforge.com/developing/story/sms-messaging-android. I am trying to catch the broadcasts for sent and delivered messages, with this code (for sent messages): appContext.registerReceiver(new BroadcastReceiver() { @Override public void onReceive(Context arg0, Intent arg1) { Log.i("Debug", "My embedded receiver: " + String.valueOf(getResultCode())); } }, new IntentFilter("iam.applications.SmsReceiver.SMS_SENT")); This always results in getResultCode() returning a value of -1, even when the SMS is successfully sent. I don't know of another way to tell whether my SMS was sent or not. I have also subclassed BroadcastReceiver to see if that makes any difference, but it does not. -1 is always returned: @Override public void onReceive(Context context, Intent intent) { String action = intent.getAction(); Log.i("Debug", "Result code in onReceive: " + String.valueOf(getResultCode())); } My creation of the PendingIntent looks like this (snippet from a for-loop for processing parts of long SMS messages): Intent sentIntent = new Intent( "iam.applications.SmsReceiver.SMS_SENT"); sentIntent.putExtra(SmsHandler.PHONE_NUMBER, phoneNumber); sentIntent.putExtra(SmsHandler.MESSAGE, message); sentPIArray.add(PendingIntent.getBroadcast(appContext, (int) Calendar.getInstance().getTimeInMillis(), sentIntent, PendingIntent.FLAG_UPDATE_CURRENT)); A: I'm a big idiot: // Field descriptor #14 I public static final int RESULT_OK = -1;

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The lived experiences of midwives with spirituality in childbirth: mana from heaven. The purpose of this study was to describe the lived experiences of midwives who experienced the phenomenon of spirituality when they attended births. The research design was descriptive, using a transcendental phenomenological approach reflected in Moustakas' model. Purposive and snowball sampling were used to recruit the sample of 10 certified nurse-midwives. The major findings of this study consisted of 5 theme categories that revealed the essential structure of the midwives' lived experiences of spirituality during childbirth: belief in the existence of a higher power, the essence of spirituality, birth is spiritual, the essence of midwifery, and relationships. The midwives in the study experienced spirituality as an integral and essential component of childbirth. The midwives reported using elements of spirituality as instruments that helped them assist their clients through the process of pregnancy and birth. The midwives also revealed their dependence on spirituality and belief in a higher being who guided their lives and their calling to midwifery.

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people are angrier at women who claim to hate men than at men who actually hate, rape, kill and abuse women. ok then.

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WATCH: Lafontaine Tunnel work: "significant" impact on traffic There's another major roadwork project heading your way and that means more traffic problems. Work on the 50-year-old Lafontaine Tunnel will begin after the new Champlain Bridge is up and running, sometime around 2020. That will take about four years and result in traffic disruptions, said junior minister for major transport projects Marie-France Bérard. "Two years will have significant impact on mobility, two years will be partial because we will work (at) night or not where cars or trucks are using (the tunnel)," said Bérard at a news conference updating the project. Bérard said they will introduce mitigation measures before that to try to change motorists' habit and ease traffic congestion, such as increased bus service and more incentive parking at bus, metro and train stations. Jr minister in charge of major transport projects Marie-France Bérard says they hope to change motorists' habits before work begins. #CJADpic.twitter.com/vy7dSqe1p6 Revamping the tunnel will include repaving, modernizing the lighting, ventilation and drainage, redoing the walls and ceiling, and adding an extra layer of fire protection. Officials said it's too early to say whether the work will be around the clock. The newly refurnished tunnel will not have tolls. The project will not be a private-public partnership but rather a formula that will see the company responsible for the design, the construction and the finaincing, making the company accountable not only to the government but to the lenders for the financing of the project. Reports say the project will cost an estimated one billion dollars. As many as 100,000 cars and 15,000 trucks pass through the tunnel every day. Quebec school boards ran a collective $141 million dollar surplus last year, but the president of the Quebec Federation of School Boards says given that the annual school board budget is $11 billion, the surplus is modest.

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CIVIL SERVICE COMPENSATION SCHEME That this House is concerned by the Government's proposed reforms of the Civil Service Compensation Scheme (CSCS); notes the proposal to drastically cut civil service compensation payments by between 25 and 60 per cent, affecting thousands of civil servants across the UK; is alarmed that these reforms are being brought forward at the same time as hundreds of government offices are closing and departments are facing immense pressure to downsize, putting thousands of civil service jobs at risk; is aware that the then Minister for the Cabinet Office introduced changes to the CSCS in 2010 which he described as fair and sustainable in the long term; further notes that an equality impact assessment on these proposed new reforms has not been carried out; is concerned that cuts to the CSCS may affect older workers, women, those with disabilities and BME civil servants; notes that civil servants across the UK are facing an uncertain future and that additional uncertainty regarding exit payments has had a negative impact on staff morale and health; and therefore calls on the Government to halt its plans to further cut the CSCS and instead invest in the civil service through staff training, decent pay rises and honouring the terms and conditions of all civil servants.

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Ecotin modulates thrombin activity through exosite-2 interactions. Ecotin is a Escherichia coli-derived protein that has been characterized as a potent inhibitor of serine-proteases. This protein is highly effective against several mammalian enzymes, which includes pancreatic and neutrophil-derived elastases, chymotrypsin, trypsin, factor Xa, and kallikrein. In this work we showed that ecotin binds to human alpha-thrombin via its secondary binding site, and modulates thrombin catalytic activity. Formation of wild type ecotin-alpha-thrombin complex was observed by native PAGE and remarkably, gel filtration chromatography showed an unusual 2:1 ecotin:enzyme stoichiometry. Analysis of the protease inhibitor effects on thrombin biological activities showed that (i) it decreases the inhibition of thrombin by heparin/antithrombin complex (IC50=3.2 microM); (ii) it produces a two-fold increase in the thrombin-induced fibrinogen clotting; and (iii) it inhibits thrombin-induced platelet aggregation (IC50=4.5 microM). Allosteric changes on thrombin structure were then evaluated. Complex formation with ecotin caused a three-fold increase in the rate of thrombin inhibition by BPTI, suggesting a displacement of the enzyme's 60-loop. In addition, ecotin modulated the enzyme's catalytic site, as demonstrated by changes in the fluorescence emission of fluorescein-FPRCK-alpha-thrombin (EC50=3.5 microM). Finally, solid phase competition assays demonstrated that heparin and prothrombin fragment 2 prevents thrombin interaction with ecotin. Altogether, these observations strongly support an ecotin interaction with thrombin anion-binding exosite-2, resulting in modulation of its biological activities. At this point, ecotin might be useful as a new tool for studying thrombin allosteric modulation.

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86*m**3/5 - 4722*m**2 + 209738*m/5 - 36788 = 0. -1082, -17, 1, 5 Let 27*t**4/2 - 233208*t**3 - 622041*t**2/2 + 906915*t + 1295700 = 0. What is t? -5/3, 2, 17276 Factor 2*m**3/7 + 74*m**2/7 - 12356*m/7 + 24400/7. 2*(m - 61)*(m - 2)*(m + 100)/7 Find i, given that -i**5/4 + 215*i**4/2 + 11703*i**3/4 + 17442*i**2 = 0. -17, -9, 0, 456 Factor -2*m**3/15 + 725896*m**2/15 + 1451798*m/15 + 145180/3. -2*(m - 362950)*(m + 1)**2/15 Factor -2*d**2/13 + 216020*d/13 + 7779312/13. -2*(d - 108046)*(d + 36)/13 What is f in 3*f**2/2 + 5320998*f - 53210055/2 = 0? -3547337, 5 Factor t**5/2 - 97*t**4 + 6561*t**3 - 195426*t**2 + 4884165*t/2 - 8085825. (t - 90)*(t - 33)**3*(t - 5)/2 Factor 2*t**3 - 436870*t**2 - 1747522*t + 2184390. 2*(t - 218439)*(t - 1)*(t + 5) Solve -45*v**5 - 94965*v**4 - 25692470*v**3 - 158491270*v**2 + 114239075*v - 19516805 = 0. -1793, -311, -7, 1/3 Factor 4*g**2 + 233656*g + 467296. 4*(g + 2)*(g + 58412) Factor o**2/5 - 385438374*o/5 + 37140685037940969/5. (o - 192719187)**2/5 Find p such that -2*p**3 - 2244312*p**2 + 17954592*p - 35909248 = 0. -1122164, 4 Find j, given that -j**5/3 + 3029*j**4 - 18162*j**3 - 18*j**2 + 163485*j - 245187 = 0. -3, 3, 9081 Factor 464840820*d**3 + 932092140*d**2 + 4824125*d + 6250. 5*(d + 2)*(9642*d + 25)**2 Factor -3*p**2 - 42024*p + 1432284. -3*(p - 34)*(p + 14042) Find y such that -4*y**2 - 262220*y + 2098016 = 0. -65563, 8 Solve 2*f**2 - 14474*f - 19864120 = 0. -1180, 8417 What is u in -u**2/2 - 29657*u/2 + 608809 = 0? -29698, 41 Factor -25*m**2/4 + 95495*m/4 + 12513115/2. -5*(m - 4066)*(5*m + 1231)/4 Find n, given that 20*n**4 + 7444305*n**3 - 13027700*n**2 - 39082695*n + 33499530 = 0. -372217, -2, 3/4, 3 Factor -2*k**2 - 1101866*k + 52894176. -2*(k - 48)*(k + 550981) Factor -k**2/9 - 5380*k/9 + 430100/3. -(k - 230)*(k + 5610)/9 Suppose 2*x**5 + 836*x**4 - 31448*x**3 + 124636*x**2 + 2695350*x = 0. What is x? -453, -7, 0, 17, 25 Suppose -7*i**4/3 - 15878*i**3/3 + 17583979*i**2/3 + 5025290*i/3 = 0. What is i? -3083, -2/7, 0, 815 Factor 2*w**3 + 1188738*w**2 + 176640225888*w + 883171411240. 2*(w + 5)*(w + 297182)**2 What is a in 5*a**4 - 3770*a**3 - 3795*a**2 + 15080*a + 15100 = 0? -2, -1, 2, 755 Let i**4/4 + 1382519*i**3/4 + 159279783570*i**2 + 24467392300046800*i - 24467551580176000 = 0. Calculate i. -460840, 1 Find g such that 361*g**4/4 + 3553*g**3/4 - 61889*g**2/2 + 170816*g - 270504 = 0. -26, 68/19, 9 Let -2*q**3/3 + 2670258*q**2 - 2673836813200*q - 104280989540000/3 = 0. What is q? -13, 2002700 Determine g, given that -81*g**4/10 - 16353*g**3/5 - 956269*g**2/10 + 47347386*g - 1697548410 = 0. -258, 505/9 Find a such that 5*a**3 - 8935*a**2 - 1014380*a + 2064460 = 0. -109, 2, 1894 Factor -3*m**2/4 + 77607*m/4 + 194848605/2. -3*(m - 30174)*(m + 4305)/4 Solve 189*a**3 + 74139*a**2 - 264320688*a + 75514140 = 0 for a. -1395, 2/7, 9022/9 Factor -3*v**2 + 35019*v - 7525278. -3*(v - 11454)*(v - 219) Factor 2*m**3/15 - 64*m**2/15 - 274*m/5 - 252/5. 2*(m - 42)*(m + 1)*(m + 9)/15 Factor 90*h**5 - 585628*h**4/9 - 482*h**3/3. 2*h**3*(h - 723)*(405*h + 1)/9 Factor -2*l**2/3 + 43802*l/3 + 5614308. -2*(l - 22279)*(l + 378)/3 Factor 142*j**2/7 + 24700*j/7 + 1062528/7. 2*(j + 96)*(71*j + 5534)/7 Suppose -5*c**4 + 505*c**3 - 9520*c**2 - 93100*c = 0. Calculate c. -7, 0, 38, 70 Find r such that 361*r**5 - 26144*r**4 - 1294986*r**3 + 11182824*r**2 + 20026305*r + 8213400 = 0. -39, -15/19, 9, 104 Find d such that -2*d**3/9 - 66362*d**2/9 - 3511672*d/9 - 3445312/9 = 0. -33128, -52, -1 Factor 4*o**4 + 2188*o**3 + 27816*o**2 + 25632*o. 4*o*(o + 1)*(o + 12)*(o + 534) Determine n so that n**2 + 28304986*n + 200293058115049 = 0. -14152493 What is f in 2*f**2 - 8383980*f - 25151958 = 0? -3, 4191993 Suppose -4*l**3/3 + 12073876*l**2/3 - 48295420*l/3 - 20123100 = 0. Calculate l. -1, 5, 3018465 Let -3*b**5 + 23241*b**4 - 45486246*b**3 + 1838199162*b**2 - 23517675543*b + 90098001021 = 0. What is b? 7, 17, 3853 Determine q so that -q**4/5 + 12997604*q**3/5 - 42234401439972*q**2/5 - 33787593938592*q + 506813441164992/5 = 0. -6, 2, 6498804 Find a, given that -a**4 - 843*a**3 - 232776*a**2 - 21135280*a = 0. -355, -244, 0 Factor 3*y**3/2 + 84081*y**2/2 - 378486*y. 3*y*(y - 9)*(y + 28036)/2 Let -3*h**3 - 101301*h**2 - 428868048*h + 7944735260700 = 0. Calculate h. -20146, 6525 Suppose 3*w**2 + 1032279*w/4 + 258069/4 = 0. Calculate w. -86023, -1/4 Determine p, given that -2*p**4/5 - 3002798*p**3/5 - 1127097977196*p**2/5 + 225421397120*p + 450840392000 = 0. -750700, -1, 2 Let -40*q**4 - 136325*q**3 - 153320*q**2 - 17035*q = 0. Calculate q. -3407, -1, -1/8, 0 Let 2*i**4/15 + 422*i**3/15 + 17126*i**2/15 + 53118*i/5 - 312984/5 = 0. What is i? -161, -27, 4 Let -2*g**2 - 1523123984*g - 289988333829504032 = 0. Calculate g. -380780996 Factor -s**3 + 119*s**2 + 39734*s + 1116864. -(s - 277)*(s + 32)*(s + 126) Factor 3*i**3/5 - 232839*i**2/5 + 651861*i - 11407053/5. 3*(i - 77599)*(i - 7)**2/5 Factor -j**2/4 - 1685*j/2 + 3374. -(j - 4)*(j + 3374)/4 Determine i so that -3*i**5/2 - 24*i**4 + 4281*i**3/2 - 31551*i**2 + 160212*i - 210912 = 0. -52, 2, 8, 13 Factor -l**2/3 - 489957736*l/3 - 60014645766561424/3. -(l + 244978868)**2/3 Find k, given that -2*k**5/7 + 2462*k**4/7 + 29886*k**3/7 - 9450*k**2 - 1208196*k/7 = 0. -9, 0, 6, 1243 Suppose -1471369*s**2/7 - 7848110*s/7 - 10465225/7 = 0. Calculate s. -3235/1213 Factor d**2/2 + 127800092*d + 8166431757604232. (d + 127800092)**2/2 Determine k so that -2*k**3/19 - 175288*k**2/19 + 1227114*k/19 = 0. -87651, 0, 7 Suppose 4*o**4/3 - 662868*o**3 - 6628772*o**2 - 61647844*o/3 - 19886440 = 0. What is o? -5, -3, -2, 497161 Solve -614*m**2 + 29646*m - 177436 = 0. 7, 12674/307 Factor -4*w**2 + 1002152*w + 1002156. -4*(w - 250539)*(w + 1) Let t**4/3 - 232*t**3 + 109349*t**2/3 + 713442*t + 3297240 = 0. Calculate t. -9, 284, 430 Determine r so that -2*r**5 + 52*r**4 + 438*r**3 - 1728*r**2 = 0. -9, 0, 3, 32 What is m in -2*m**3/5 + 105054*m**2/5 + 9677664*m/5 + 222683608/5 = 0? -46, 52619 Determine t so that 2*t**5/11 - 399624*t**4/11 - 3996368*t**3/11 - 1307916*t**2 - 21580722*t/11 - 10790388/11 = 0. -3, -1, 199822 Factor 3*f**2 + 51047592*f + 217154720749872. 3*(f + 8507932)**2 Let -4*h**3 + 2931580*h**2 + 4*h - 2931580 = 0. Calculate h. -1, 1, 732895 Factor 4*c**3 - 53728*c**2 + 218547540*c - 280343939976. 4*(c - 7186)*(c - 3123)**2 Solve 4*g**2/3 - 6177488*g + 7155254623152 = 0 for g. 2316558 Factor -5*g**3 - 2105*g**2 - 78470*g - 216600. -5*(g + 3)*(g + 38)*(g + 380) Suppose -3*x**2/4 + 1902960*x - 1207085587200 = 0. What is x? 1268640 Suppose -h**3/4 - 95147*h**2/4 + 2284081*h/4 - 2188933/4 = 0. Calculate h. -95171, 1, 23 What is b in -129*b**4/2 - 12516*b**3 - 698409*b**2/2 + 344985*b + 16800 = 0? -160, -35, -2/43, 1 Let 2*t**3 - 442*t**2 - 50464*t = 0. Calculate t. -83, 0, 304 Find q such that q**3 - 361*q**2 + 719*q - 359 = 0. 1, 359 Determine l, given that 97*l**4/9 + 11090*l**3/3 - 33905*l**2/9 - 22130*l/3 + 688/9 = 0. -344, -1, 1/97, 2 Solve -2*y**3 - 189088*y**2 + 756378*y - 567288 = 0 for y. -94548, 1, 3 Let 3*a**4/4 - 5711*a**3/4 + 172283*a**2/4 + 61871*a/4 - 58063/2 = 0. Calculate a. -1, 2/3, 31, 1873 Factor -3*i**4 - 13228104*i**3 - 14581894619568*i**2. -3*i**2*(i + 2204684)**2 Find y, given that -y**5/3 + 182*y**4/3 - 3016*y**3 + 62096*y**2/3 + 531824*y/3 - 414176 = 0. -6, 2, 14, 86 What is q in -3*q**4 + 28011*q**3 + 504903*q**2 + 2497569*q + 2020680 = 0? -9, -8, -1, 9355 Determine u so that u**4/5 - 6304*u**3/5 + 711961*u**2/5 - 1398714*u/5 = 0. 0, 2, 113, 6189 Find i such that -2*i**4/9 - 760*i**3/3 - 183082*i**2/3 - 4174888*i/9 + 5843200/3 = 0. -800, -332, -11, 3 Find v, given that -6*v**4/11 + 522*v**3/11 + 134472*v**2/11 - 1242360*v/11 + 1942752/11 = 0. -118, 2, 7, 196 Solve 5*y**3 + 7265*y**2 + 2374335*y - 12053925 = 0. -951, -507, 5 What is o in -17150*o**5/3 + 102896*o**4/3 - 188626*o**3/3 + 102856*o**2/3 + 8*o = 0? -2/8575, 0, 1, 2, 3 Suppose -4*m**2/3 - 502031686*m/3 + 83671948 = 0. What is m? -125507922, 1/2 Determine i so that 3*i**2/5 + 53862*i/5 + 430704/5 = 0. -17946, -8 Let -3*z**4 + 70320*z**3 + 844452*z**2 - 4221552*z + 4502784 = 0. Calculate z. -16, 2, 23452 Factor 2*t**2/5 - 3114*t/5 - 356096/5. 2*(t - 1664)*(t + 107)/5 Find d such that -d**2/2 - 125503*d/2 - 125501 = 0. -125501, -2 D

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Kavacham is a Sanskrit word for armour and Stotras are hymns sung in praise and worship. So, together Kavacha Stotras are hymns which are sung to obtain divine protection. Here in Kavacha Sangraha, we present you a collection of various Kavachams- which are the Kavacha Stotras. Usually such hymns are sung to obtain specific protection at specific times in one’s life and then there are other kavacham stotras which are typically sung to obtain general armour of divine’s blessings- to protect oneself from general problems and mishaps in day to day living. There are kavacham which are sung to various divine energies, such as those covered in this app- e.g. Ganesh Kavacham, Gayatri Kavacham, Shiva Kavacham etc. This is a prayer app-tool. You can use the favorites feature to mark the parts you are praying or contemplating and then use the Journal feature to write down any guidance, insight or directives you receive. Then using standard iOS features such as copy-paste, text and email; you can share your insights with others. Please note (check screen shots) that the menu commands, text editor and other app features are in English. The actual Kavacha Sangraha content is presented in Devanagri script with English transliteration.

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The Comparison of Experiential Avoidance, [corrected] Mindfulness and Rumination in Trauma-Exposed Individuals With and Without Posttraumatic Stress Disorder (PTSD) in an Iranian Sample. The aim of this study was to compare experimental avoidance, mindfulness and rumination in trauma-exposed individuals with and without PTSD in an Iranian sample. The method of the study was retrospective. The statistical population of the study composed of all people under the auspices of Committee on Relief or Martyr Foundation because of exposure to at least one traumatic event in Gilan-Gharb city (Iran) (N=1708). One hundred people, selected randomly by stratified sampling method, responded to Mississippi PTSD scale and the questionnaires of experimental avoidance, mindfulness and rumination individually. Subjects were divided into two groups of with and without PTSD based on Mississippi PTSD scale and structured clinical interview. Multivariate analysis of variance (MANOVA) test was used for analyzing data. Results showed that although the mean scores of the group with PTSD were significantly higher than the group without PTSD in variables of experimental avoidance (P<0/001, F=63/8) and rumination (P<0/001, F=21/34), the mean scores of the group with PTSD were significantly lower than the group without PTSD in the overall score of mindfulness (P<0/05, F=6/64) and variables of observing (P<0/05, F=8/27) and action description (P<0/05, F=9/19). These results show that the experimental avoidance and rumination are as the risk factors and mindfulness as the protective factor PTSD in people faced with trauma.

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After seizing power in a bloody CIA-backed coup, General Augusto Pinochet ruled Chile with a rod of iron for two decades, during which human rights violations became the norm of Chilean life. Hailing from an upper-middle class background, Pinochet entered the military academy in Santiago at the age of 18, graduating three years later as a second lieutenant. By 1968 he had risen to the rank of brigadier general. In 1970, Salvador Allende, a Marxist, became president of Chile with the backing of the Christian Democrats, and began restructuring Chilean society along socialist lines. In the process he expropriated the US-owned copper-mining companies, alienating the US government and foreign investors. He further annoyed Washington by establishing relations with Cuba and Communist China, which the United States did not recognise at that time. As a result, America imposed tough economic sanctions and the CIA spent millions of dollars destabilising the Allende regime, much of it going into Pinochet’s pockets. By 1972, the Chilean economy had collapsed. With no foreign investment, production had come to a standstill. There were widespread strikes, inflation, food shortages and civil unrest. With the backing of armed forces, Pinochet staged a military coup on 11 September 1973. It was bloody even by Latin American standards. The navy seized the key port of Valparaiso, while the army surrounded the presidential palace in Santiago. Allende refused to step down. When the palace was overrun a few hours later, he was found dead. It appears that he shot himself rather than face inevitable torture and execution. A junta took over and declared marital law. Those who violated the curfew were shot on sight. Pinochet was named president two days later. He broke off relations with Cuba – Nixon had staged his famous rapprochement with China by then – and moved against Allende’s supporters. Some 14 000 would be tried and executed or expelled from the country, while Pinochet claimed he was only trying to ‘restore institutional normality’ of Chile. In June 1974 Pinochet assumed sole power, with the rest of the junta relegated to an advisory role. Under Pinochet’s tyrannical rule, it is estimated that 20 000 people were killed and torture was widespread. While Pinochet continued to maintain tight control over the political opposition, he was rejected by a plebiscite in 1988. He eventually stepped down in 1990 after immunity from prosecution in Chile. He stayed on as army chief of staff. However, during a shopping trip to London in October 1998, he was arrested on a Spanish warrant charging him with murder. He was later accused of torture and human rights violations. For 16 months, he fought his extradition through the British courts, and then in January 2000, Home Secretary Jack Straw decided that he was too ill to stand trial and sent him back to Chile.

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In a letter to customers, the Apple CEO called the move from the EU “unprecedented” and “harmful.” Cook laid out the case that Apple, which has had operations in Ireland since 1980 and currently employees close to 6,000 people in the country, fully abides by international and local law with the rate of tax that is pays in the European country. “The European Commission has launched an effort to rewrite Apple’s history in Europe, ignore Ireland’s tax laws and upend the international tax system in the process. The opinion issued on August 30th alleges that Ireland gave Apple a special deal on our taxes,” Cook wrote. “This claim has no basis in fact or in law. We never asked for, nor did we receive, any special deals. We now find ourselves in the unusual position of being ordered to retroactively pay additional taxes to a government that says we don’t owe them any more than we’ve already paid,” he added. Cook acknowledged that tax laws for companies that do business globally are challenging. He argued, however, that by paying its taxes “where the value is created,” Apple has done nothing wrong and it is being unfairly targeted by the EU. “Nearly all of our research and development takes place in California, so the vast majority of our profits are taxed in the United States. European companies doing business in the U.S. are taxed according to the same principle. But the Commission is now calling to retroactively change those rules, “Beyond the obvious targeting of Apple, the most profound and harmful effect of this ruling will be on investment and job creation in Europe. Using the Commission’s theory, every company in Ireland and across Europe is suddenly at risk of being subjected to taxes under laws that never existed,” Cook said. Cook explained that Apple supports international tax reform, but it would rather have that debate with impacted countries and their leaders than with the EU. He added that measures should take action going forward, not retroactively as the EU’s directive is. Apple plans to appeal the decision. Cook said he is “confident” that it will prevail.

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Design and fabrication of computer-generated beam-shaping holograms. For the design of computer-generated holograms reconstructing certain intensity patterns with phase freedom, we use an object-oriented approach. The given intensity pattern is decomposed into elementary objects for which appropriate phase-only hologram functions can be constructed. The total hologram function is found by the subsequent superposition of its constituents, with a relative amplitude and phase weighting for each of them. Thus, the degrees of freedom are dramatically reduced compared with those of sampling approaches. The design algorithm allows us to compensate on the one hand for the intensity and phase distribution of the impinging laser beam and on the other hand for the shape of the hologram aperture. We report on the computer-aided design of such holograms, as well as their fabrication through the use of laser lithography and reactive ion etching. Optical reconstructions are shown.

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Introduction {#s1} ============ Juvenile Dermatomyositis (JDM) is a systemic immune-mediated disease of childhood. It is the most common idiopathic inflammatory myopathy in children, with an incidence of 2--4/million/year ([@B1]). Although the exact etiology is still elusive, both genetic and environmental factors are thought to play a role in the development of the disease ([@B2]--[@B5]). JDM is characterized by inflammation of skeletal muscles and skin, leading to muscle weakness and a typical skin rash of the face and hands (heliotrope rash and Gottron\'s papules, respectively), which are also used as classification criteria ([@B6], [@B7]). Next to the muscle and skin, other organs can be affected. Vital organ involvement, especially of the lungs, is still the major cause of death in JDM patients ([@B8], [@B9]). Although rare, cardiac involvement and microangiopathy of the intestine, brain and kidneys have been described ([@B10]). Thus, rather than being confined to specific tissues, JDM is a truly systemic disease, which can affect multiple organ systems. Before the introduction of corticosteroids as a treatment option, mortality and morbidity among JDM patients were high, and long-term outcomes were not the primary focus. Since then, mortality rates have dropped from over 30% to 2--3% ([@B11]). With increasing survival, long-term outcomes become an important concern of patients and physicians, as patients\' quality of life and societal participation depend on it. Long-term outcomes are likely dependent on various factors such as disease severity and activity, response to treatment and medication side effects which together determine the cumulative organ and tissue damage. Especially low-grade inflammation and extramuscular manifestations of the disease are difficult to investigate in routine clinical care and may therefore be overlooked. Unrecognized, local inflammation leading to tissue damage and subsequent organ dysfunction may have serious consequences for short-term and long-term outcomes. So far, reliable assessment of disease activity and the type and extent of tissue involvement has been rather challenging. Current clinical tools for assessment of disease activity require active collaboration of patients, which can be difficult for young, unwell children. Detecting low-grade inflammation or differentiating clinically between various causes of muscle impairment is even more challenging. Hence, there is a great need for minimally invasive, objective and reliable diagnostic tools for the assessment and monitoring of (low-grade) disease activity and related organ involvement. Optimally, such tools could guide clinical decision making, facilitate individually tailored treatment regimens, and reduce the risk of over- and under-treatment. In this review we will discuss the types of (extra)muscular tissue involvement that have been described in JDM and their relation to vasculopathic changes, critically assess the available diagnostic and monitoring tools and reflect on the immunopathogenic implications of identified markers. Signs of Systemic Disease Activity in JDM Based on affected Tissues and Organs {#s2} ============================================================================== JDM patients can present with a spectrum of symptoms. Most, but not all patients, have the classic combination of muscle involvement and typical skin rashes. Approximately 1--5% of JDM patients present with amyopathic JDM, but it was estimated that 26% of these patients will eventually progress to classical JDM, which can occur up to years after onset ([@B12]). This indicates that the phenotype can evolve over the course of the disease, possibly also dependent on treatment. True amyopathic JDM however is very rare and mild muscle involvement may be present but missed ([@B13]). Amyopathic JDM generally has a relatively mild disease course with fewer systemic manifestations, less required immunosuppressive treatment and a good prognosis ([@B12], [@B14], [@B15]). (Sub)Cutaneous and Other Extramuscular Symptoms ----------------------------------------------- Cutaneous symptoms can range from the pathognomonic heliotrope rash and Gottron\'s papules, to photosensitive rashes such as malar and truncal erythema, and severe complications such as skin ulceration and dystrophic calcinosis. Calcinosis occurs in 12--47% of patients and can occur in the skin and in subcutaneous, myofascial, or muscle tissue. Most often it is a long-term complication and its presence has been associated with delayed diagnosis and more severe disease with poorer functional outcomes. Effective treatment of calcinosis is still challenging, but aggressive high-dose immunosuppression or, in very severe cases, autologous stem cell transplantation have been shown to be able to reverse calcinosis, suggesting that chronic (low-grade) inflammation may be accountable for calcifications ([@B16]--[@B20]). Cutaneous and oral ulceration affects up to 30% of patients and is thought to result from occlusive endartheropathy of the small vessels ([@B10], [@B21]). Lipodystrophy affects 8--14% of JDM patients and is often associated with hormonal and metabolic changes ([@B10], [@B22]--[@B24]). We suspect that patients with lipodystrophy may therefore have an increased risk of cardiovascular events in the long-term. Limb edema and arthritis are also common, occurring in 11--32 and 23--58% of patients, respectively ([@B10]). Next to the skin and musculoskeletal system, other organ systems can be involved, of which the lung is the most frequently affected. Up to 75% of children with JDM develop respiratory involvement, which may result from a complication of respiratory muscle weakness or immunosuppressive therapy, or from interstitial lung disease (ILD) ([@B25], [@B26]). ILD occurs in 8--19% of juvenile myositis patients and has been described as the major cause of death in JDM ([@B27]--[@B30]). Cardiac involvement may be present subclinically more often than recognized, as even in JDM patients without clinical cardiac dysfunction abnormal ECG and echocardiographic findings are relatively common ([@B31]--[@B33]). Conduction abnormalities and myocarditis have been reported, and systolic and diastolic dysfunction was found after long-term follow-up ([@B34]--[@B37]). Cardiac complications are thought to result from myocarditis and coronary artery disease as well as involvement of the small vessels of the myocardium ([@B38]). Involvement of the gut or neural system are rare complications of JDM and are also thought to result from an underlying small vessel angiopathy or vasculitis ([@B39]--[@B41]). Intestinal consequences of the small vessel angiopathy include ulceration, perforation, hemorrhage, pneumatosis intestinalis and malabsorption ([@B42]--[@B44]). Vasculopathy ------------ The pathologic changes underlying symptoms and tissue damage in the skin, muscles, and vital organs have a common factor: in all the affected tissues typical vasculopathic changes are observed, which include loss of capillaries (capillary dropout), perivascular inflammation, and (occlusive) small vessel angiopathy ([@B21], [@B45]). In a recently reported French JDM cohort of 116 patients, vasculopathy-related complications were the main cause of admission to the intensive care unit, illustrating the severity and relevance of vascular involvement in JDM ([@B46]). These complications include life-threatening disorders like systemic capillary leak syndrome, recently also described in 3 patients with JDM ([@B47]). Deposition of complement, immune complexes and anti-endothelial antibodies is thought to play an important role in endothelial damage and subsequent capillary dropout ([@B48]--[@B54]). Clinically, the severity of vasculopathy and the disease phenotype have also been linked. The presence of prominent vascular injury in muscle biopsies identified a subgroup of patients with more severe clinical presentation and outcomes, including profound muscle weakness, limb edema and gastrointestinal involvement ([@B55]). This suggests that local vasculopathic changes can reflect systemic vasculopathy and the resulting clinical symptoms. Nailfold capillaroscopy, a commonly and easily used indicator of disease activity in clinical practice, is also based on this principle. The pathologic changes observed in nailfold capillaries, such as capillary dropout, branching and dilatation, likely reflect the systemic blood vessel abnormalities. Loss of end row nailfold capillaries is significantly associated with clinical disease activity scores for muscle and skin and can thus be used as a marker of skin and muscle activity. Nailfold capillaroscopy is especially suited as a non-invasive tool to follow up changes in disease activity over time in patients ([@B56]--[@B59]). Taken together, JDM is a truly systemic disease in which not only the muscles and skin are affected, but also vital organs can be involved. The presence of typical vasculopathic changes in the various affected tissues points toward a central role for systemic endothelial dysfunction in the pathogenesis of JDM. Monitoring of Disease Activity and Tissue Involvement {#s3} ===================================================== During clinical follow-up, monitoring of disease activity is crucial to determine the rate of medication tapering or to assess the requirement for intensification of immunosuppressive therapy. Next to clinical evaluation, various tools have been investigated for monitoring of disease activity, among which autoantibodies and other circulating biomarkers, and histopathologic evaluation of muscle biopsies, as well as several imaging techniques. Clinical Assessment ------------------- The primary and most important evaluation of disease activity involves clinical assessment by experienced clinicians and health care professionals. Over the past years, several scoring tools have been devised for internationally standardized evaluation of disease activity ([@B60]). The most commonly used tools are now the childhood myositis assessment scale (CMAS), manual muscle testing of 8 muscle groups (MMT-8), physician\'s and patient\'s global assessment on a visual analog scale (PGA), cutaneous assessment tool (CAT), cutaneous dermatomyositis disease area and severity index (CDASI), disease activity score (DAS), myositis disease activity assessment tool (MDAAT) and childhood health assessment questionnaire (CHAQ) ([@B61]--[@B69]). Combined scoring systems are currently being developed ([@B70]). The Pediatric Rheumatology International Trials Organization (PRINTO) has composed criteria for defining clinically inactive disease ([@B71]). A recent re-evaluation of these PRINTO criteria showed that skin disease may be underestimated as a factor in the assessment of disease activity ([@B72]). Clinical measures of disease activity, however, have limited capacity to detect low-grade inflammation in the tissues which does not cause overt symptoms, but may still contribute to tissue damage in the long term. Moreover, it is challenging to differentiate between various underlying causes of symptoms by clinical assessment. For example, muscle weakness may result from an ongoing inflammatory process, from medication side effects (e.g., steroid myopathy), muscle damage or effects of immobility. Biological assessment of the affected tissues and organs can therefore be helpful or even necessary to aid clinical decision-making concerning medication dose and additional interventions. Biomarkers for Disease Course, Activity, and Tissue Involvement --------------------------------------------------------------- Laboratory investigation of blood is a minimally invasive and time-efficient procedure, especially compared to muscle biopsy and some of the imaging methods. It is therefore particularly suited as a method for serial sampling during clinical follow-up. Laboratory investigation can be used for measurement of autoantibodies and for biomarkers related to disease activity and specific (extra)muscular symptoms. ### Autoantibodies Antibodies found in myositis include myositis-specific autoantibodies (MSA), relatively specific to myositis, and myositis-associated antibodies (MAA), which are observed both in myositis and other connective tissue diseases ([@B6]). In the past years, different disease phenotypes have been linked to the presence of autoantibodies and particularly myositis-specific autoantibodies ([@B16]). The frequencies of autoantibodies in juvenile patients differ substantially from adult DM patients ([@B73]). Anti-TIF1 (p155/140) and anti-NXP2 (p140 or MJ) are the most commonly identified autoantibodies in Caucasian JDM patients (20--35 and 16--23%, respectively) ([@B28], [@B73]--[@B76]). Anti-TIF1 is associated with skin ulceration, photosensitive skin rashes, lipodystrophy, and edema ([@B24], [@B75]--[@B78]), whereas anti-NXP2 is associated with a severe disease course with more profound muscle involvement, calcinosis, gastrointestinal ulceration, joint contractures, and dysphonia ([@B75], [@B77], [@B79], [@B80]). A recently identified myositis specific autoantibody which is especially frequent in the Asian JDM population, is anti-MDA5 (CADM-140) ([@B81]). It is found in 33% of Asian JDM patients, compared to 7% of Caucasian patients ([@B8], [@B82]). Patients with anti-MDA5 have a higher risk of developing ILD than patients without these antibodies. This anti-MDA5 conferred risk is seen in both Asian and Caucasian JDM cohorts, although the risk difference appears to be more pronounced in Asian cohorts ([@B8], [@B83]). Common symptoms in Caucasian patients with anti-MDA5 antibodies include oral and cutaneous ulceration, arthritis, and milder muscle disease with fewer histologic abnormalities and a higher remission rate off medication after 2 years of follow-up ([@B76], [@B82], [@B84], [@B85]). Less frequently identified autoantibodies in the juvenile population include anti-Mi2 (4--10%) and anti-amino-acyl-tRNA synthetase antibodies such as anti-Jo-1 (1--3%) and anti-SAE (\<1%). Anti-SRP and anti-HMG-CoA-reductase (Anti-HMGCR) autoantibodies, both accounting for \<3% of juvenile myositis patients, are associated with a necrotizing type of myopathy with severe muscle weakness ([@B73], [@B76], [@B86], [@B87]). It remains unclear whether each MSA reflects a distinct pathologic process, influencing the type and severity of disease phenotype and tissue involvement. Notably, autoantibodies against Jo-1, TIF1, SRP, and Mi-2 are not only informative at disease onset, but their levels have been found to correlate with disease activity during follow-up in the context of rituximab treatment ([@B88]). This highlights that perhaps autoantibodies should be measured during or soon after the first clinic visit as their levels may decline and become undetectable in remission. A last and different (not myositis-specific) category of autoantibodies identified in JDM comprises autoantibodies against components of endothelial cells, which are thought to contribute to capillary loss. These anti-endothelial cell autoantibodies (AECA) were detected in 76% of JDM patients, as opposed to 30% of control patients ([@B49]). Twenty-two candidate target autoantigens for AECA were identified in JDM plasma, 17 of which were proteins associated with antigen processing and protein trafficking ([@B50]). Identification of autoantibody targets may provide novel insights into the auto-immune process and self-antigens involved in JDM. ### Biomarkers for Systemic Inflammation and Muscle Disease Activity Reliable assessment of disease activity during follow-up can be aided by laboratory markers that represent systemic and/or local inflammation. Especially for detection of low-grade inflammation and for differentiation between various causes of muscle weakness, laboratory investigation can be a helpful or even necessary tool. So far, reliable and validated laboratory markers for disease activity and tissue involvement in JDM are still lacking. A large number of proteins in plasma, serum, and urine as well as circulating immune cell subsets have been investigated as potential biomarkers for (tissue-specific) disease activity in patients with JDM (Tables [1](#T1){ref-type="table"}, [2](#T2){ref-type="table"}). In theory, every biological parameter that can be measured, could serve as a biomarker. To be suited for use in clinical practice however, a biomarker has to meet additional criteria, such as being reliable, robust, relatively stable and easy to measure. In the following paragraphs we highlight all biological markers that have been associated with disease activity in JDM, regardless of their suitability for use in clinical practice, as some of these identified markers may still contribute to the understanding of the immunopathogenesis of JDM. However, it is important to note that due to the rarity of the disease, many of these studies were carried out in small cohorts of \<30 patients (as outlined in Tables [1](#T1){ref-type="table"}, [2](#T2){ref-type="table"}). Insights based on such small numbers have limitations in a heterogeneous disease like JDM. Therefore, validation of identified markers in larger cohorts is crucial before implementation into clinical practice. ###### Biomarkers for disease activity in JDM cohorts. **Biomarker** **Global disease activity** **Muscle disease activity** **Other activity measures** **Patients** **Material & technique** **Cohort** **References** -------------------------------------------------------------- ------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------------------------------------- --------------------------------------------------------- ---------------------------------------------------------------------- ---------------------------------------------- -------------------------- **Interferon related biomarkers** MxA ++++[^\*\*^](#TN2){ref-type="table-fn"} (DAS, O), +++[^\*^](#TN1){ref-type="table-fn"} (DAS, FU) NS (skin DAS) 14 act JDM: 7 untreated, 7 treated PBMC, qRT-PCR USA O\'Connor [@B89] IFNα activity \#\#\#[^\*^](#TN1){ref-type="table-fn"} (DAS, off therapy at 36 months) NS (DAS) \#\#\#[^\*\*^](#TN2){ref-type="table-fn"} (skin DAS, off therapy at 36 months), [^\*\*^](#TN2){ref-type="table-fn"} (vsHC) 39 JDM and 19 ped HC Serum, Functional reporter assay USA Niewold [@B90] IFN gene score r~p~: NS (DAS) r~p~: NS (DAS) 27 JDM Whole blood, qRT-PCR USA Baechler [@B91] IFN chemokine score r~p~: ++[^\*\*^](#TN2){ref-type="table-fn"} (DAS) r~p~: ++[^\*^](#TN1){ref-type="table-fn"} (DAS) 29 JDM Eotaxin \+[^\*\*^](#TN2){ref-type="table-fn"} (DAS) NS (DAS) \+[^\*\*^](#TN2){ref-type="table-fn"} (skin DAS), [^\*^](#TN1){ref-type="table-fn"} (vsHC) 54 JDM Serum, Luminex Norway Sanner [@B92] MCP-1 \+ [^\*^](#TN1){ref-type="table-fn"} (DAS) NS (DAS) NS (skin DAS), [^\*\*^](#TN2){ref-type="table-fn"} (vsHC) 54 age+sex matched controls IP-10 NS (DAS) NS (DAS) NS (skin DAS), [^\*^](#TN1){ref-type="table-fn"} (vsHC) Median time 16.8 yrs after onset IP-10 +++[^\*\*\*^](#TN3){ref-type="table-fn"} (PGA) \#\#\#[^\*\*\*^](#TN3){ref-type="table-fn"} (CMAS) 2014: 25 JDM (18 act, 19 rem), 14 ped HC, 8 NIMD Plasma and serum, Luminex NL Enders [@B93], [@B94] TNFR2 +++[^\*\*\*^](#TN3){ref-type="table-fn"} (PGA) NS (CMAS) Galectin-9 +++[^\*\*\*^](#TN3){ref-type="table-fn"} (PGA) \#\#[^\*\*^](#TN2){ref-type="table-fn"} (CMAS) 2015: 3 refractory JDM (pre and post aSCT) Soluble IL-2R [^\*\*^](#TN2){ref-type="table-fn"} (diagnosis vs. rem) 7 JDM: 7 at diagnosis, 7 in rem Serum, ELISA & HPLC Japan Kobayashi [@B95] Neopterin Higher in act than rem Neopterin +++[^\*\*\*^](#TN3){ref-type="table-fn"} (act), ++++[^\*^](#TN1){ref-type="table-fn"} (FU 3 pts) (both with study-specific DAS) 15 JDM (21 samples: 12 act, 9 rem) Serum, radioimmunoassay Italy De Benedetti [@B96] Urine neopterin ++[^\*\*^](#TN2){ref-type="table-fn"} (PGA) \#\#\#[^\*^](#TN1){ref-type="table-fn"} (MMT), \#\#[^\*\*^](#TN2){ref-type="table-fn"} (CMAS) ++[^\*\*^](#TN2){ref-type="table-fn"} (skin VAS), ++[^\*\*^](#TN2){ref-type="table-fn"} (CHAQ), ++[^\*\*^](#TN2){ref-type="table-fn"} (MRI) 39 JDM, 3 JDM with overlap CTD, 3 JPM Urine and plasma, ELISA, HPLC, gas chromatographic mass spectrometry USA Rider [@B97] Urine quinolonic acid ++[^\*\*^](#TN2){ref-type="table-fn"} (PGA) \#\#\#[^\*^](#TN1){ref-type="table-fn"} (MMT), \#\#[^\*\*\*^](#TN3){ref-type="table-fn"} (CMAS) ++[^\*\*\*^](#TN3){ref-type="table-fn"} (CHAQ), ++[^\*\*^](#TN2){ref-type="table-fn"} (MRI) Plasma neopterin/quinolonic acid NS (PGA) NS (CMAS, MMT) **OTHER MARKERS OF INFLAMMATION** MRP8/14 +++[^\*\*\*^](#TN3){ref-type="table-fn"} (PGA) \#\#[^\*\*^](#TN2){ref-type="table-fn"} (CMAS) NS (CHAQ) 56 JDM Serum, ELISA UK Nistala [@B98] CRP Low during relapse in 4 patients 9 JDM: 4 during relapse and 3 rem Serum UK Haas [@B99] **IMMUNE CELL SUBSETS** Changes in %CD19+ cells ++[^\*^](#TN1){ref-type="table-fn"} (DAS) PBMC, flow cytometry USA Eisenstein [@B100] T cell subsets NS (DAS) T cell activation (CD25, HLA-DR) NS (DAS) T cell recognition of human Hsp60 Higher in rem than act 22 JDM: 6 new-onset, 6 act, 10 rem PBMC, ^3^H-thymidine assay NL Elst [@B101] Th1 within CXCR5+ CD4 T cells Higher in rem than act[^\*\*\*^](#TN3){ref-type="table-fn"} 45 JDM (52 samples): 26 act, 26 rem, 43 ped HC PBMC, Flow cytometry USA Morita [@B102] Ratio (Th2+Th17)/Th1 in CXCR5+ CD4 T cells Higher in act than rem[^\*\*\*^](#TN3){ref-type="table-fn"} \% Plasmablasts (CD19+CD20--CD27+CD38++) Higher in act than rem[^\*\*\*^](#TN3){ref-type="table-fn"} Change in % CD3+CD69+ T cells ++[^\*^](#TN1){ref-type="table-fn"} 24 JDM PBMC, Flow cytometry USA Ernste [@B103] Change in HLA-DR- CD11c+ mDC ++[^\*^](#TN1){ref-type="table-fn"} (extra) Change in HLA-DR- CD123+ pDC \#\#[^\*^](#TN1){ref-type="table-fn"} \% FOXP3+ Tregs NS (CMAS) 48 JDM: 21 act, 27 rem Muscle biopsies, immunohistochemistry NL Vercoulen [@B104] Defective suppressive function of Tregs In 4/11 active pts vs. 0/9 in remission Flow cytometry, ^3^H-thymidine incorporation RORC [^\*^](#TN1){ref-type="table-fn"} [^\*^](#TN1){ref-type="table-fn"} NS (extra) 26 JDM new-onset Whole blood, qRT-PCR USA Lopez de Padilla [@B105] IL-17F NS [^\*^](#TN1){ref-type="table-fn"} NS (extra) GATA3 NS [^\*^](#TN1){ref-type="table-fn"} NS (extra) STAT4 [^\*\*\*^](#TN3){ref-type="table-fn"} [^\*\*\*^](#TN3){ref-type="table-fn"} NS (extra) Changes in STAT6 NS NS [^\*^](#TN1){ref-type="table-fn"} (extra) Changes in IL-17D NS NS [^\*\*^](#TN2){ref-type="table-fn"} (extra) Changes in BCL6 NS NS [^\*\*^](#TN2){ref-type="table-fn"} (extra) \% Immature transitional B cells +++[^\*\*\*^](#TN3){ref-type="table-fn"} (PGA) 68 JDM (113 samples): 20 pre-treatment, 93 on treatment PBMC, Flow cytometry UK Piper [@B106] Absolute number immature transitional B cells +++[^\*\*\*^](#TN3){ref-type="table-fn"} (PGA) **MARKERS RELATED TO ENDOTHELIAL ACTIVATION OR DYSFUNCTION** vWF Sens 0.85; Spec 0.45 (for flare) 16 JDM, prospective Serum CA Guzman [@B107] vWF Sens 0.40 (6/15 act had high vWF) NS (muscle strength) NS (skin rash, calcinosis) 15 JDM Serum USA Bloom [@B108] C3d Elevated in 6/7 pts with act 15 JDM: 7 act, 5 mild disease, 3 rem, 15 ped HC Plasma, radioimmuno assayand rocket immuno-elektrophoresis USA Scott [@B109] Fibrinopeptide A [^\*^](#TN1){ref-type="table-fn"} (vsHC) Factor VIII-related antigen [^\*\*^](#TN2){ref-type="table-fn"} (vsHC) MiRNA-10a NS (DAS) NS (DAS) NS (skin DAS) 15 untreated JDM Muscle boipsies, RT-PCR USA Xu [@B110] EPC number NS (DAS) NS (skin DAS) 34 JDM: 6 untreated, 19 act on med, 9 rem PBMC, Flow cytometry USA Xu [@B111] **LIPID METABOLISM** HDL NS (PGA) ++[^\*^](#TN1){ref-type="table-fn"} (CMAS), NS (MMT) NS (Skin, CHAQ) 16 JDM, 1 JPM Serum USA Coyle [@B112] LDL r~p~: ++[^\*^](#TN1){ref-type="table-fn"} (DAS) r~p~: \#\#[^\*^](#TN1){ref-type="table-fn"} (CMAS) r~p~: ++[^\*\*^](#TN2){ref-type="table-fn"} (MYOACT) 25 JDM Serum Brazil Kozu [@B113] Triglycerides All r~p~: +++[^\*\*^](#TN2){ref-type="table-fn"} (DAS), ++[^\*\*^](#TN2){ref-type="table-fn"} (MITAX) All r~p~: \#\#[^\*\*^](#TN2){ref-type="table-fn"} (CMAS), \#\#[^\*\*^](#TN2){ref-type="table-fn"}(MMT) r~p~: +++[^\*\*^](#TN2){ref-type="table-fn"} (MYOACT) IL-6 NS \#[^\*^](#TN1){ref-type="table-fn"} NS (extra) 26 JDM Whole blood, qRT-PCR USA Olazagasti [@B114] Resistin ++[^\*\*\*^](#TN3){ref-type="table-fn"} ++[^\*\*\*^](#TN3){ref-type="table-fn"} \+[^\*^](#TN1){ref-type="table-fn"} (extra) Spearman correlations (r~s~) of biomarkers with global/muscle/skin/extraskeletal VAS are shown unless otherwise specified. +:r~s~ ≥0.2, ++:r~s~ ≥0.4, +++:r~s~ ≥0.6, ++++:r~s~ ≥0.8, \#:r~s~ ≤ −0.2, \#\#:r~s~ ≤ −0.4, \#\#\#:r~s~ ≤ −0.6, \#\#\#\#: r~s~ ≤ −0.8. r~p~: Pearson correlation. Statistical significance: *P \< 0.05*, *P \< 0.01*, *P \< 0.001, NS, not significant. Sens, sensitivity; Spec, specificity. Abbreviations biomarkers: IFN, interferon; MCP-1, CCL2; IP-10, CXCL10; TNFR2, Tumor necrosis factor receptor 2; IL-2R, Interleukin-2 receptor; MRP8/14, myeloid related protein 8/14 (S100A8/9); CRP, C-reactive protein; Hsp60, heat shock protein 60; Th, T helper; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; Treg, Regulatory T cell; IL, interleukin; vWF, von Willebrand factor; EPC, endothelial progenitor cell; HDL, high density lipoprotein; 25(OH)D, Vitamin D. Abbreviations disease activity: DAS, disease activity score; VAS, visual analog scale; PGA, physician\'s global activity VAS; MyoAct, Myositis disease activity assessment visual analog scales; MITAX, myositis intention to treat activity index; MMT, manual muscle testing; CMAS, childhood myositis assessment scale; vsHC, compared to healthy controls; CHAQ, childhood healthy assessment questionnaire; MRI, magnetic resonance imaging; ANA, anti-nuclear antibody; extra, extraskeletal/extramuscular symptoms. Abbreviations patients: JDM, juvenile dermatomyositis; JPM, juvenile polymyositis; HC, healthy control; ped, pediatric; act, active; rem, remission/asymptomatic/inactive disease; yrs, years; NIMD, non-inflammatory muscle disease; aSCT, autologous stem cell transplantation; CTD, connective tissue disease; O, onset of disease; FU, follow-up. Abbreviations material & technique: ELISA, enzyme-linked immuno sorbent assay; HPLC, high-performance liquid chromatography; PBMC, peripheral blood mononuclear cells; qRT-PCR, quantitative real time polymerase chain reaction*. ###### Biomarkers for disease activity in mixed cohorts containing patients with JDM. **Biomarker** **Global disease activity** **Muscle disease activity** **Other activity measures** **Patients (samples)** **Material & technique** **Cohort** **References** ----------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------ -------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------- ---------------------------------------------------- ------------------------- -------------------------- **Interferon related biomarkers** Type I IFN signature NS 2 JDM, 10 DM, 15 ad HC Whole blood, microarray USA Baechler [@B115] IP-10 NS Serum, Luminex ITAC NS MCP-1 ++[^\*^](#TN4){ref-type="table-fn"} MCP-2 +++[^\*\*^](#TN5){ref-type="table-fn"} IFN gene score ++[^\*\*^](#TN5){ref-type="table-fn"} ++[^\*\*^](#TN5){ref-type="table-fn"} (VAS), \#\#[^\*\*^](#TN5){ref-type="table-fn"} (MMT) ++[^\*\*^](#TN5){ref-type="table-fn"} (skin), +[^\*^](#TN4){ref-type="table-fn"} (extra) 19 JDM, 37 DM, 20 ad HC Whole blood, qRT-PCR USA Bilgic [@B116] IP-10 +++[^\*\*\*\*^](#TN7){ref-type="table-fn"} Serum, multiplexed sandwich immunoassay I-TAC +++[^\*\*\*\*^](#TN7){ref-type="table-fn"} MCP-1 ++[^\*\*\*^](#TN6){ref-type="table-fn"} MCP-2 ++[^\*\*\*^](#TN6){ref-type="table-fn"} MIP-1α ++[^\*\*\*^](#TN6){ref-type="table-fn"} IL-6 ++[^\*\*\*^](#TN6){ref-type="table-fn"} \+[^\*\*^](#TN5){ref-type="table-fn"} (VAS), \#\#[^\*\*^](#TN5){ref-type="table-fn"} (MMT) \+[^\*^](#TN4){ref-type="table-fn"} (skin), ++[^\*\*^](#TN5){ref-type="table-fn"} (extra) IL-10 \+[^\*^](#TN4){ref-type="table-fn"} TNFα \+[^\*^](#TN4){ref-type="table-fn"} TNFR1 \+[^\*^](#TN4){ref-type="table-fn"} *MIG, MIP-1β, IL-8* NS Type I IFN chemokine score (Summarization of ITAC, IP-10, MCP-1, and MCP-2) ++[^\*^](#TN4){ref-type="table-fn"} (JDM), +++[^\*\*\*\*^](#TN7){ref-type="table-fn"} (mixed) ++[^\*\*\*^](#TN6){ref-type="table-fn"} (VAS, mixed), \#\#[^\*\*^](#TN5){ref-type="table-fn"} (MMT, mixed) \+[^\*^](#TN4){ref-type="table-fn"} (skin), ++[^\*\*^](#TN5){ref-type="table-fn"} (extra) Type I IFN gene score \+[^\*^](#TN4){ref-type="table-fn"} ++[^\*\*^](#TN5){ref-type="table-fn"} NS (extra) 21 JDM (each active and remission sample), 30 DM (each active and remission sample) Whole blood, qRT-PCR USA Reed [@B117] Type I IFN chemokine score ++[^\*\*\*^](#TN6){ref-type="table-fn"} ++[^\*\*\*^](#TN6){ref-type="table-fn"} ++[^\*\*\*^](#TN6){ref-type="table-fn"} (extra) Serum, multiplexed sandwich immunoassay IP-10 ++[^\*\*\*^](#TN6){ref-type="table-fn"} ++[^\*\*^](#TN5){ref-type="table-fn"} ++[^\*\*\*^](#TN6){ref-type="table-fn"} (extra) ITAC ++[^\*\*^](#TN5){ref-type="table-fn"} ++[^\*\*^](#TN5){ref-type="table-fn"} ++[^\*\*^](#TN5){ref-type="table-fn"} (extra) MCP-1 ++[^\*\*^](#TN5){ref-type="table-fn"} ++[^\*\*^](#TN5){ref-type="table-fn"} ++[^\*\*^](#TN5){ref-type="table-fn"} (extra) MCP-2 NS ++[^\*\*\*^](#TN6){ref-type="table-fn"} NS (extra) IL-6 ++[^\*\*\*^](#TN6){ref-type="table-fn"} ++[^\*\*\*^](#TN6){ref-type="table-fn"} \+[^\*^](#TN4){ref-type="table-fn"} (extra) IL-8 \+[^\*^](#TN4){ref-type="table-fn"} \+[^\*^](#TN4){ref-type="table-fn"} NS (extra) TNFα \+[^\*\*^](#TN5){ref-type="table-fn"} ++[^\*\*\*^](#TN6){ref-type="table-fn"} \+[^\*^](#TN4){ref-type="table-fn"} (extra) **OTHER MARKERS OF INFLAMMATION** IL-1Ra High in act than rem ++[^\*^](#TN4){ref-type="table-fn"} (CK) [^\*\*\*^](#TN6){ref-type="table-fn"} (vsHC) 2 JDM, 5 DM, 2 caDM, 4 PM, 2 OM, 12 HC Serum, ELISA Switzerland Gabay [@B118] sTNFR75 (sTNFR2) ++[^\*^](#TN4){ref-type="table-fn"} (CK) BAFF \+[^\*\*\*^](#TN6){ref-type="table-fn"} (CK, mixed) 49 DM (of which ≥1 JDM), 44 PM, 6 IBM, 30 HC Serum, ELISA Sweden & Czech Republic Krystufkova [@B119] BAFF \+[^\*\*\*^](#TN6){ref-type="table-fn"} (mixed) \+[^\*^](#TN4){ref-type="table-fn"} (mixed) \+[^\*\*\*^](#TN6){ref-type="table-fn"} (extra, mixed) 20 JDM, 45 DM, 26 PM, 7 IBM, 21 HC PBMC, qRT-PCR USA Lopez de Padilla [@B120] ΔBAFF (downregulates BAFF activity) ++[^\*\*\*^](#TN6){ref-type="table-fn"} (mixed) \+[^\*\*^](#TN5){ref-type="table-fn"} (mixed) ++[^\*\*\*^](#TN6){ref-type="table-fn"} (extra, mixed) Anti-Jo1 LMM: ++[^\*\*\*^](#TN6){ref-type="table-fn"} LMM: \#\#[^\*\*\*^](#TN6){ref-type="table-fn"} (MMT), +++[^\*\*\*^](#TN6){ref-type="table-fn"} (ME) LMM: +[^\*\*^](#TN5){ref-type="table-fn"} (extra), ++[^\*\*\*^](#TN6){ref-type="table-fn"} (HAQ) Refractory pts: 48 JDM, 76 DM, 76 PM (all analyses in mixed cohort) Serum, ELISA & RNA and protein immunoprecipitation USA Aggarwal [@B88] Anti-TIF1γ LMM: ++[^\*\*^](#TN5){ref-type="table-fn"} LMM: \#\#\#[^\*\*\*^](#TN6){ref-type="table-fn"} (MMT), NS (ME) LMM: +++[^\*\*\*^](#TN6){ref-type="table-fn"} (HAQ), NS (extra) Anti-SRP LMM: NS LMM: NS (MMT), +[^\*\*^](#TN5){ref-type="table-fn"} (ME) LMM: NS (extra, HAQ) Anti-Mi2 LMM: +++[^\*\*\*^](#TN6){ref-type="table-fn"} LMM: \#\#[^\*\*\*^](#TN6){ref-type="table-fn"} (MMT), ++[^\*\*^](#TN5){ref-type="table-fn"} (ME) LMM: +[^\*^](#TN4){ref-type="table-fn"} (extra), NS (HAQ) **IMMUNE CELL SUBSETS** \% CD3+ cells Higher in rem than act[^\*^](#TN4){ref-type="table-fn"} (DM, not JDM) 14 JDM, 24 DM, 17 ad HC, 9 ped HC PBMC, Flow cytometry Japan Ishida [@B121] \% CD8+ cells Higher in rem than act[^\*^](#TN4){ref-type="table-fn"} (DM, not JDM) \% CD20+ cells Higher in act than rem[^\*^](#TN4){ref-type="table-fn"} (DM, not JDM) \% CD3+ cells Higher in rem than act[^\*^](#TN4){ref-type="table-fn"} (DM) 29 DM act (of which ≥1 JDM), 20 DM rem, 13 PM act, 37 PM rem, 32 ad HC PBMC, Flow cytometry Hungary Aleksza [@B122] \% CD8+ cells Higher in rem than act[^\*^](#TN4){ref-type="table-fn"} (DM) \% IFNγ+ of CD4 T cells Higher in rem than act[^\*\*^](#TN5){ref-type="table-fn"} (DM) \% IFNγ+ of CD8 T cells Higher in rem than act[^\*\*^](#TN5){ref-type="table-fn"} (DM) \% CD19+ cells Higher in act than rem[^\*^](#TN4){ref-type="table-fn"} (DM) \% IL-4+ of CD4+ T cells Higher in act than rem[^\*^](#TN4){ref-type="table-fn"} (DM) **MARKERS RELATED TO ENDOTHELIAL ACTIVATION OR DYSFUNCTION** sVCAM-1 NS (CK, mixed) NS (skin, mixed) 5 JDM, 27 DM, 4 PM, 25 HC Serum, ELISA Japan Kubo [@B123] sE-selectin [^\*^](#TN4){ref-type="table-fn"} (CK, mixed) sICAM Higher in act than rem[^\*^](#TN4){ref-type="table-fn"} (mixed) 4 JDM, 2 ped MCTD, 8 ped SLE, 4 ped Vasculitis Serum, ELISA USA Bloom [@B124] sICAM-3, sVCAM-1, sL-selectin, sE-selectin NS (mixed) Spearman correlations (r~s~) of biomarkers with global/muscle/skin/extraskeletal VAS are shown unless otherwise specified. +:r~s~ ≥ 0.2, ++:r~s~ ≥ 0.4, +++:r~s~ ≥ 0.6, ++++:r~s~ ≥ 0.8, \#:r~s~ ≤ −0.2, \#\#:r~s~ ≤ −0.4, \#\#\#:r~s~ ≤ −0.6, \#\#\#\#:r~s~ ≤ −0.8. r:~p~: Pearson correlation, LMM, linear mixed model. Statistical significance: *P \< 0.05*, *P \< 0.01*, *P \< 0.001*, *P \< 0.0001, NS, not significant. Abbreviations biomarkers: IFN, interferon; MCP-1, CCL2; MCP-2, CCL8; IP-10, CXCL10; ITAC, CXCL11; MIP-1α, CCL3; IL, interleukin; TNF, Tumor necrosis factor; TNFR1 /2 = TNF receptor 1/2, MIG, CXCL9; MIP-1β, CCL4; IL-1Ra, IL-1 receptor alpha; BAFF, B cell activating factor. Abbreviations disease activity: CK, creatine kinase; ME, muscle enzymes; VAS, visual analog scale; MMT, manual muscle testing; HAQ, health assessment questionnaire; extra, extraskeletal/extramuscular symptoms. Abbreviations patients: JDM juvenile dermatomyositis; JPM, juvenile polymyositis; DM, adult dermatomyositis; caDM, cancer-associated DM; PM, adult polymyositis; OM, overlap myositis; IBM, inclusion body myositis; SPA, spondylartropathy; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; MCTD, mixed connective tissue disease; HC, healthy control; ped, pediatric; ad, adult; act, active; rem, remission/asymptomatic/inactive disease. Abbreviations material & technique: ELISA, enzyme-linked immuno sorbent assay; PBMC, peripheral blood mononuclear cells; qRT-PCR, quantitative real time polymerase chain reaction*. #### Currently used laboratory markers The markers that are currently used in clinical practice, AST, ALT, LDH, aldolase and in particular creatine kinase activity (CK), do not correlate as well with disease activity in JDM as in DM ([@B125]--[@B127]). At diagnosis, any one muscle enzyme was only elevated in 80--86% of patients with JDM and CK was found to be elevated in only 61--64% of patients ([@B125], [@B128]). In almost 20% of patients the most abnormal measurement of CK was not elevated above normal values ([@B28]). Low muscle enzymes at first presentation may be associated with delayed diagnosis ([@B129]). During follow-up, CK may underestimate disease activity due to suppressed release by corticosteroids, circulating inhibitors of CK activity, or loss of muscle mass ([@B127], [@B130]--[@B132]). On the other hand, CK and aldolase can be elevated in steroid myopathy and are therefore not reliable as markers for disease activity requiring more potent immunosuppression ([@B133]). However, according to recent consensus guidelines, these muscle enzymes are still regarded as an important monitoring tool ([@B134], [@B135]). #### Markers related to the interferon signature An important group of investigated biomarkers is related to the type 1 interferon (IFN) signature, which has been demonstrated in the peripheral blood and muscle biopsies of JDM patients ([@B136], [@B137]). Activated plasmacytoid dendritic cells (pDC) are generally thought to be the main producers of the type 1 IFNs (IFNα and IFNβ) in JDM. This notion may be challenged by a recent study measuring circulating IFNα with a highly sensitive assay and investigating the cellular source of IFNα in several systemic inflammatory diseases. JDM patients had higher levels of circulating IFNα than patients with systemic lupus erythematosus (SLE), but lower levels than patients with monogenic interferonopathies. However, neither isolated circulating pDC nor other circulating immune cell subsets from JDM patients expressed more IFNα than cells from healthy controls, suggesting that a non-circulating cellular source may be responsible for IFNα production in JDM ([@B138]). Due to the lack of available methods to measure circulating IFNα and IFNβ until recently, the type 1 IFN signature, consisting of genes upregulated in response to IFNα or IFNβ stimulation, was used as a surrogate marker of type 1 IFN levels. The type 1 IFN signature in whole blood of three mixed DM and JDM cohorts correlated weakly to moderately with global disease activity \[spearman *r* (*r*~s~) = 0.33--0.44\] and muscle activity (*r*~s~ = 0.44--0.47), while single IFN signature related serum chemokines MCP-1, IP-10 (CXCL10) and ITAC (CXCL11) had moderate to strong correlations with global (*r*~s~ = 0.42--0.66), muscle (*r*~s~ = 0.44--0.50), and extraskeletal disease activity (*r*~s~ = 0.42--0.55) ([@B115]-- [@B117]). MxA expression in PBMC, also used as a surrogate for the IFN signature, had a very strong correlation with muscle disease activity of JDM patients (*r*~s~ = 0.80) at disease onset, but not with skin disease activity ([@B89]). IFNα activity measured by a functional reporter assay was also higher in JDM patients than controls ([@B90]). Recently, IP-10, TNF receptor 2 (TNFR2) and galectin-9 were found to strongly correlate with global disease activity (*r* = 0.60--0.75) in two studies by Enders et al. ([@B93], [@B94]) IP-10, together with MCP-1 and eotaxin, was also higher in 54 JDM patients a median of 17 years after disease onset than matched healthy controls ([@B92]). TNFR2 correlated with CK in a mixed IIM cohort (*r*~s~ = 0.55) ([@B118]). Galectin-9 was recently identified as a biomarker for the IFN signature in SLE and anti-phospholipid syndrome ([@B139]). IP-10, TNFR2 and galectin-9 are promising biomarkers for disease activity, as they can potently discriminate between active disease and remission even during treatment ([@B93], [@B94]). After stem cell transplantation and concomitant eradication of circulating immune cells, their levels stayed high over several months, which suggests that these proteins are not primarily produced by circulating immune cells, but rather by non-circulating immune or tissue cells, just as IFNα ([@B94], [@B138]). IP-10 and galectin-9 are currently being validated as biomarkers for disease activity in two large international JDM cohorts. One of the best investigated biomarkers so far in JDM is neopterin, a catabolic product of guanosine triphosphate, which was previously shown to be a marker of immune activation that can be induced by stimulation with IFNγ ([@B140]). In the first study identifying serum neopterin as a biomarker for JDM, neopterin levels correlated strongly with muscle strength impairment in 15 JDM patients (*r*~s~ = 0.68) ([@B96]). Elevated serum neopterin levels at diagnosis compared to remission were confirmed in an independent cohort ([@B95]). In a juvenile myositis validation cohort, plasma neopterin (*n* = 13), and quinolonic acid (*n* = 24), however, did not correlate with myositis disease activity measures ([@B97]). Urine neopterin (*n* = 45) moderately correlated with global (*r*~s~ = 0.42), muscle (*r*~s~ = 0.50--0.62) and skin activity (*r*~s~ = 0.49), and edema on MRI (*r*~s~ = 0.55). Urine quinolonic acid also correlated with global and muscle activity and edema on MRI (*r*~s~ = 0.45--0.61) ([@B97]). Despite these efforts of validation, neopterin has not been widely implemented into clinical practice as a biomarker for disease activity in JDM. #### Other inflammatory mediators Next to type 1 IFN-related markers, other inflammatory mediators have been studied as biomarkers for JDM. The innate TLR4 ligand myeloid related protein 8/14 (MRP8/14 or S100A8/9), originally found to be elevated in patients with systemic-onset juvenile idiopathic arthritis (JIA), correlated moderately to strongly with global and muscle disease activity in a large cohort of 56 JDM patients (*r*~s~ = 0.55--0.65) ([@B98], [@B141]). Another marker adopted from studies in JIA, the soluble IL-2 receptor, was elevated at disease onset compared to remission ([@B95], [@B142]). Serum/plasma levels of the more conventional pro-inflammatory cytokines IL-6, IL-8, and TNFα also moderately correlated with global (*r*~s~ = 0.19--0.46) and muscle disease activity (*r*~s~ = 0.35--0.52) in three mixed JDM and DM cohorts ([@B116], [@B117]). Remarkably, CRP levels did not increase during disease flares ([@B99]). BAFF and especially its antagonistic non-cleavable form ΔBAFF, both important for survival and maturation of B cells, moderately correlated with global, muscle and extraskeletal VAS (*r*~s~ = 0.27--0.54), and CK (*r*~s~ = 0.37) in two mixed IIM cohorts ([@B119], [@B120]). #### Markers related to vasculopathy and cardiovascular risk Due to the vasculopathic component of JDM, markers related to endothelial activation and dysfunction were explored for their association with disease activity. Von Willebrand factor (vWF) was increased during most periods of active disease in a prospective cohort study, but did not reliably predict disease flares in another study ([@B107], [@B108]). sICAM-1, a marker of endothelial activation, was higher during active disease than remission in a combined cohort of juvenile patients with various systemic autoimmune diseases. VCAM-1, sICAM-3, and L-selectin did not correlate with disease activity, although expression of MiRNA-10a in JDM muscle, which is negatively associated with VCAM-1 expression, showed a correlative trend with muscle and global DAS \[Pearson *r* (*r*~p~) = −0.45\] ([@B110], [@B123], [@B124]). C3d and fibrinopeptide A, which are related to vasculopathic changes, were higher in JDM patients with active disease than in remission ([@B109]). Endothelial progenitor cell numbers did not differ between JDM patients and controls and did not correlate with disease activity ([@B111]). In view of the increased cardiovascular risk in JDM patients, the lipid profile has been investigated in relation to disease activity ([@B41]). Serum HDL negatively correlated with muscle activity (*r*~s~ = −0.54), but not global or skin activity ([@B112]). Triglyceride levels correlated strongly with global disease activity assessed by DAS (*r*~s~ = 0.61) and LDL was higher in patients with a higher disease activity ([@B113]). Gene expression of the adipokine resistin in PBMC was also upregulated in JDM patients compared to controls and moderately correlated with global and muscle disease activity (*r*~s~ = 0.51 and *r*~s~ = 0.50, respectively) ([@B114]). These results indicate that the cardiovascular risk profile is more pronounced in JDM patients with active disease. #### Circulating immune cell subsets as biomarkers for disease activity Among the circulating immune cell subsets, T cells and B cells have been studied most extensively in relation to disease activity in JDM. In two mixed cohorts of JDM and DM patients, the frequency of T cells, and especially CD8+ and IFNγ-producing T cells, was decreased during active disease, while the frequency of B cells and IL-4 producing CD4+ T cells was increased compared to remission ([@B121], [@B122]). This may suggest a shifted balance toward a T helper 2 (Th2) type immune response. In cohorts with only JDM patients, total B cell numbers were also increased compared to controls and changes in B cell frequencies accompanied changes in disease activity (*r*~s~ = 0.47) ([@B100], [@B106]). Within the B cell compartment, numbers and frequencies of circulating immature transitional B cells correlated strongly with global disease activity (*r*~s~ = 0.69--0.71). Compared to healthy pediatric controls, these specialized B cells were highly proliferative, had a prominent IFN signature and produced less of their regulatory signature cytokine IL-10 ([@B106]). Plasmablast frequencies were also increased during active disease compared to remission ([@B102]). Several T cell subsets have been studied in JDM. In 26 new-onset JDM patients the blood gene expression of Th17-related genes, such as RORC and IL-17F, Th1-related genes, including STAT4, and Th2-related genes, including GATA3 and STAT6, was studied in relation to disease activity. RORC, IL-17F, STAT4, and GATA3 positively correlated with muscle activity and RORC and STAT4 correlated with global activity. This would suggest that the immune response is not specifically skewed toward a certain T helper response. However, at baseline, JDM patients had higher gene expression of Th17 related cytokines IL-23, IL-17F, IL-6, and IL-21 than DM patients, indicating that the Th17 pathway may play a more prominent role in the pathogenesis of JDM than DM. Changes in BCL6, a transcription factor for follicular helper T cells, correlated negatively with a change in extramuscular activity ([@B105]). Within CXCR5+ follicular helper T cells, the Th1 subset was decreased in active JDM compared to remission and controls, and Th2 and Th17 subsets were increased in JDM compared to controls ([@B102]). Regulatory T cell frequencies in muscle biopsies did not correlate with muscle activity, but suppressive activity of circulating Tregs may be impaired during active disease ([@B104]). Finally, global disease activity correlated moderately with the activation status of circulating T cells assessed by CD69 expression (*r*~s~ = 0.43), but not with CD25 and HLA-DR expression ([@B100], [@B103]). The expansion and functional alteration of particular B cell and CD4+ T cell subsets, coinciding with changes in disease activity, hints toward the involvement of these cell subsets in the pathogenesis of JDM. In conclusion, many circulating, either soluble or cellular, markers have been studied for their relation with muscle and global disease activity. Correlations with disease activity were only moderate for most markers, and some of these molecules are relatively unstable in blood samples or complicated to measure, rendering them unsuited for use in clinical practice. The highest correlations with disease activity were found for markers related to the IFN signature, the lipid profile, for MRP8/14, and immature transitional B cells. However, most of these biomarkers were identified in small patient cohorts and except for neopterin, so far none have been reproduced or thoroughly validated in independent and large JDM cohorts. Neopterin was investigated in a validation cohort, but its correlation with disease activity could only be confirmed in urine, not in plasma. Galectin-9 and IP-10 are currently being validated in two international cohorts and are promising biomarkers for implementation in clinical practice due to their high sensitivity and stability in serum. ### Biomarkers for Extramuscular Disease Activity Next to markers for global and muscle disease activity, biomarkers for involvement of specific tissues and organs have been investigated. Four studies by Kobayashi et al. have focused on biomarkers for ILD, and specifically the rapid progressive (RP-ILD) and chronic ILD type, in a Japanese JDM cohort. Not only the presence, but also the level of anti-MDA5 was a sensitive and specific marker for ILD, with the highest levels found in patients with RP-ILD ([@B8], [@B143], [@B144]). In addition, BAFF, APRIL, KL-6, and IL-18 levels were higher in patients with RP-ILD compared to chronic ILD and JDM patients without ILD ([@B145]). KL-6 was prognostic for ILD, as it stayed high in patients with persistent damage on HRCT ([@B144]). Biomarkers for cardiac involvement were tested in a Norwegian JDM cohort, a median of 17 years after diagnosis. Eotaxin and MCP-1 were elevated in patients with cardiac dysfunction and correlated moderately to strongly with systolic and diastolic dysfunction especially in patients with persistently active disease (*r*~s~ = 0.45--0.65) ([@B146]). In the same cohort, a reduced heart rate variability, which is an indicator of cardiac disease, correlated moderately with ESR, hsCRP, and also MCP-1 and eotaxin levels (*r*~s~ = 0.29--0.47) ([@B147]). Next to the autoantibody NXP2, which is prognostic for the development of calcinosis, phosphorylated matrix Gla protein was shown to be higher in patients with calcinosis than without calcinosis ([@B79], [@B148]). Reduced osteocalcin levels were found to be predictive of reduced bone mass, even before start of steroids ([@B149]). The presence of the TNFα-308A allele is associated with a more severe disease in JDM. However, apparent associations with this allele are likely to reflect the association with ancestral haplotype 8.1 due to linkage disequilibrium and should be interpreted with this in mind ([@B150]). Patients with this genotype are reported to show prolonged symptoms requiring ≥36 months of immunosuppressive therapy, a higher incidence of pathologic calcifications, increased production of TNFα by peripheral blood mononuclear cells *in vitro* and JDM muscle fibers *in vivo*, a higher IFNα activity and a higher rate of complications arising from occlusion of capillaries. Vascular occlusion has been linked to higher levels of the anti-angiogenic thrombospondin-1 ([@B90], [@B151]--[@B154]). In summary, a number of potential biomarkers for extramuscular disease activity has been identified, and especially for ILD and cardiac dysfunction the biomarkers seem promising. Validation in independent cohorts will have to confirm their potential as biomarkers for these extramuscular symptoms. Histopathology of Muscle and Skin Biopsies ------------------------------------------ The diagnostic criteria for JDM by Peter and Bohan encompass histopathological findings consistent with DM: "necrosis of myofibers, phagocytosis, regeneration with basophils, large vesicular sarcolemmal nuclei, and prominent nucleoli, atrophy in a perifascicular distribution, variation in fiber size and an inflammatory exudate, often perivascular" ([@B155], [@B156]). For a long time, muscle biopsies were therefore taken as part of routine diagnostic workup. However, with evolving diagnostic options and more specialized trained pediatric rheumatologists muscle biopsies are currently not always considered a necessity for diagnosis ([@B135]). One of the main problems hindering standardized evaluation of muscle biopsies was the lack of an internationally agreed upon scoring tool. An international consensus group of pediatric rheumatologists and pathologists developed such a tool, which encompasses 4 histopathological scoring domains: inflammatory, vascular, muscle fiber and connective tissue changes ([@B157]). The scoring tool has now been validated in an independent cohort consisting of 55 patients and was found to correlate with clinical measures of disease activity, including CMAS, PGA, and MMT-8 (*r*~s~ = 0.40--0.62) ([@B45]). Muscle biopsy scores may also have prognostic potential: in combination with MSA group, these scores were found to predict the risk of remaining on treatment over time, based on analysis of muscle biopsies from 101 JDM patients ([@B158]). The most common findings in muscle biopsy specimens in JDM compared to healthy individuals or patients with non-inflammatory muscle diseases, are profound upregulation of MHC I expression on muscle fibers, increased expression of integrins and complement and membrane attack complex deposition on capillaries and perimysial large vessels, a type 1 IFN signature and immune cell infiltrates consisting mostly of mature pDC, memory CD4+ T cells, and B cells ([@B48], [@B52], [@B159]--[@B169]). (Figure [1](#F1){ref-type="fig"}) The IFN signature, measured by expression of MxA, correlated with muscle disease activity ([@B166]). In skin biopsies similar features are found, with the additional presence of diffuse mast cell infiltration ([@B164]). ![Histopathological features and biomarkers in JDM. JDM is characterized by vasculopathic changes in the tissues, with loss and dysfunction of endothelial cells, leading to capillary dropout and subsequent atrophy of muscle fibers. The exact chain of events leading to loss of blood vessels and muscle fibers is not known, but it is thought that both overexpression of MHC-I (and MHC-II) on myocytes and endothelial damage are early events in the cascade ([@B159], [@B170]). They result in the first attraction of immune cells to the tissue, probably by a stress response of the myocytes and endothelial cells, leading to a first production of chemoattractants. The immune cell infiltrates, which can be organized in lymphoid structures, consist mostly of CD4+ and CD8+ memory T cells, B cells, mature plasmacytoid dendritic cells (pDC) and monocytes. CD4+ and CD8+ T cells are considered responsible for direct killing of muscle cells. pDC are considered the main producers of type I interferons (IFNs), which explains the IFN-I signature that is found in the muscles of JDM patients. Some typical IFN-inducible chemokines, CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (ITAC), are known for their angiostatic properties. The receptor for these cytokines, CXCR3, is upregulated on endothelial cells in JDM muscle, which may be one of the factors contributing to endothelial dysfunction ([@B137]). Other factors include anti-endothelial circulating antibodies (AECA), complement and membrane attack complex (MAC) deposition on endothelial cells. Endothelial cells in muscle also express high levels of ICAM-1 and VCAM-1, which further enables extravasation of immune cells into the tissues and promotes a positive feedback loop resulting in further tissue damage. Not only immune cells in the tissues, but also circulating immune cells show a type I IFN signature and increased IFNα activity. Various circulating markers reflecting immune activation and endothelial activation or distress are increased during active disease in JDM and can potentially be used as biomarkers for disease activity.](fimmu-09-02951-g0001){#F1} Several studies have suggested associations between histopathological findings in muscle biopsies and disease duration before the biopsy or disease severity at a later time point. Biopsy specimens taken after a short duration of untreated disease (\<2 months), showed higher expression of VCAM-1 (which correlated with higher serum soluble VCAM-1) and expression of genes involved in stress response and protein turnover, whereas biopsies taken after more than 2 months of untreated disease had more pDC infiltration, higher expression of genes involved in the immune response and vascular remodeling and more apoptosis-related markers ([@B171]--[@B173]). Thus, it should be taken into account that histological findings can depend on the disease duration before the biopsy. In addition, these findings may indicate that endothelial activation is an early feature of JDM, which precedes immune cell infiltration and vasculopathy. The degree of vasculopathy and vascular injury (as defined by marked capillary dropout, increased direct immunofluorescent arterial staining and lymphocytic vasculitis, amongst others) was associated with a more severe and chronic disease, with severe or persistent weakness, low remission rates at 12 months requiring additional treatment, subcutaneous edema, and chronic ulcerative disease of the skin and gastrointestinal tract ([@B21], [@B55], [@B165]). The degree of vasculopathy was also correlated with the expression of angiostatic chemokines MIG, IP-10 and ITAC ([@B137]). This indicates that the degree of vascular injury may be one of the most important factors determining long-term disease outcomes and that it is related to the IFN signature. Not only the type of immune cell infiltration, but also the organization of immune cells in the muscle is of significance in JDM. Organization of immune infiltrates in lymphocytic aggregates or lymphoid follicle--like structures with dendritic cells and T cells, as compared to diffuse infiltrates, was associated with a more severe disease course and less response to treatment ([@B174]). MHC I expression, one of the most prominent and early histological features in JDM, did not correlate with clinical features of the disease ([@B159], [@B160], [@B175]). The importance of thorough and standardized assessment of tissue involvement is underlined by the fact that even in cases with amyopathic DM, with normal EMG and MRI findings, the muscle biopsy can show focal endomysial lymphocyte and macrophage aggregates and 90% positivity for HLA class I in the sarcolemma ([@B176]). Unrecognized, low-grade muscle inflammation may be undertreated, resulting in a larger risk of long term damage. However, muscle biopsy is not routinely performed for children with JDM in all centers and therefore in future, biomarkers which are measureable in blood and correlate with biopsy features would represent a major advance. Immunopathogenic Implications: Interferons and Vasculopathy {#s4} =========================================================== From the biological research conducted in JDM so far, it has become clear that IFNs and their signature play an important role in the immunopathogenesis of JDM (Figure [1](#F1){ref-type="fig"}). The IFN signature is detectable in muscle fibers, myogenic precursor cells, endothelial cells, skin and several circulating cell subsets of patients with JDM and could point toward a viral etiology ([@B89], [@B106], [@B167]). Although it has never been demonstrated definitively, several studies suggest that infections may be more common before onset of JDM ([@B177]--[@B180]). Not only are IFNs potent drivers of (auto)inflammation, they may also be anti-angiogenic factors that could directly or indirectly contribute to endothelial damage and loss in JDM: directly by inhibiting angiogenesis and disrupting the vascular network organization and indirectly by inducing several other angiostatic factors such as galectin-9, IP-10, and ITAC ([@B137], [@B181]--[@B186]). In addition, type 1 IFNs inhibit the generation of myotubes and induce atrophy-associated genes in differentiated myotubes. Human skeletal muscle cells can also produce large quantities of IP-10 upon stimulation with IFNγ and TNFα ([@B186], [@B187]). Rather than being produced by circulating immune cells, IFNs are probably mainly produced within inflamed tissues. Satellite cells, active myogenic cells and endothelial cells in JDM muscle strongly express IFNβ ([@B167]). The notion that non-circulating cells within tissues are responsible for IFN production also fits observations by Rodero et al. ([@B138]). In particular within muscle of JDM patients the dysbalance between angiogenic and angiostatic factors can contribute to endothelial loss ([@B137], [@B188]). Endothelial cells in JDM muscle downregulate genes related to vessel development, cell adhesion and migration, which are essential for angiogenesis ([@B167]). Downregulation of these genes is likely a key event in the development of vasculopathy. Next to being a target of the inflammation, the endothelium may also play an active role in the inflammatory process. In biopsies from JDM patients endothelial cells express inflammatory features, such as high levels of adhesion molecules ICAM-1 and VCAM-1, and produce cytokines and chemokines ([@B161]). These can facilitate the attraction and invasion of immune cells into tissues, thereby supporting the inflammatory process and subsequent damage. IP-10 and ITAC were the most highly upregulated genes in endothelial cells from JDM muscle and correlated with the degree of vasculopathy ([@B137], [@B167]). Endothelium-derived IP-10 can even stabilize the interaction between T cells and endothelial cells, thereby possibly contributing to the chronicity of T cell infiltration ([@B189]). Recently, a new function has been ascribed to endothelial cells as "semi-professional" antigen presenting cells, which act as sentinels for antigens, and possibly self-antigens, in tissues and facilitate T cell trafficking into these tissues ([@B190], [@B191]). The high expression of MHC molecules on endothelial cells in JDM muscle may support the notion that this process is involved in JDM ([@B160], [@B175]). Although the exact mechanisms of interaction between immune cells and endothelial cells in JDM are still elusive, they may be more elaborate than so far recognized. Conclusions and Future Perspectives for Biomarker Research {#s5} ========================================================== JDM is a multisystem disease. Not only the skin and skeletal muscles are affected, but also other organ systems and tissues such as the lungs, heart and intestines are frequently (subclinically) involved and may be under-evaluated. Vasculopathy due to loss and dysfunction of endothelial cells as a result of the inflammatory process is thought to underlie the symptoms in most of these organs and tissues. Monitoring of disease activity and damage in all of these affected tissues is important during clinical follow-up, as these are key determinants for the long-term outcomes of patients. Tools for monitoring of tissue activity and damage include histopathological investigation of biopsies, and laboratory testing of blood for specific biomarkers as well as several imaging methods. Each of these methods has their strengths and weaknesses and can be of value for specific diagnostic questions at disease onset or during follow-up, as outlined in the consensus-based recommendations for the management of JDM ([@B135], [@B192]). There is still a need for minimally invasive, but at the same time sensitive and specific diagnostic methods that correlate well with clinical symptoms or reflect low-grade, local inflammation. Tissue-specific biomarkers can therefore be of great value as a monitoring tool. To be able to identify sensitive, robust and reliable biomarkers or develop monitoring tools, it is of key importance to set up well-defined and large prospective patient cohorts, with a thorough longitudinal collection of a standardized clinical dataset assessing disease activity and organ involvement, paired with collection of patient material ([@B193]). Such a dataset is required to ensure a strict definition of active and inactive disease \[e.g., as proposed by Almeida et al. ([@B72])\]. An important consideration for a successful biomarker study is the timing of data and sample collection: depending on the purpose of the biomarker, time points before start of immunosuppressive treatment, before each adjustment of medication, during flares, at paired time points during active and inactive disease or even at regular intervals of max 3--4 months may be crucial to reliably investigate the potency of a biomarker. Next to the "classical" statistical approach, comparing patients with active disease and patients in remission (cross-sectionally or in paired samples), new computational approaches providing analysis methods that can integrate longitudinal data from multiple patients and multiple (bio)markers or scoring tools should be considered. These methods take into account the fluctuating nature of a relapsing-remitting disease such as JDM and are therefore better suited to test the reliability of a tool that will be used for longitudinal follow-up in clinical practice ([@B194], [@B195]). To achieve implementation of a marker or tool into clinical practice, both clinical and technical validation in independent cohorts is of utmost importance. Only few markers prove to be stable, reliable and easy to measure, which are key features for a marker or tool to be suited for implementation into clinical practice. Also the invasiveness of the method should be taken into account. Ideally, a period of experimental implementation can demonstrate the added value and feasibility of a marker or tool in clinical practice. To achieve all this in a large group of JDM patients to ensure sufficient statistical power, international networks with well-established collaborations are fundamental. Eventually, monitoring of disease activity with a reliable tool can be used to guide treatment and thereby facilitate precision medicine, with high dose therapy when indicated but also preventing overtreatment. This may reduce both the duration of active disease and thereby the disease-inflicted damage, and medication side effects, which will benefit the long-term outcomes on various domains, such as muscle weakness, organ damage, cardiopulmonary fitness, and quality of life. Next to facilitating personalized treatment strategies, newly identified biomarkers may also provide insights into the immunopathogenesis of JDM and provide new treatment targets. For instance, new treatment strategies targeting the IFN signature, such as anti-IFN antibodies (sifalimumab) or JAK-inhibition (ruxolitinib) have been shown to reduce the IFN signature in blood and muscle of adult dermatomyositis patients, and may therefore be promising new strategies for patients with JDM ([@B186], [@B196], [@B197]). Several studies discussed in this review suggest a strong link between the IFN signature and vasculopathy; and vasculopathy has been related to disease severity. Targeting the IFN signature may thus benefit vascularization in JDM and thereby improve outcomes. Author Contributions {#s6} ==================== JW collected literature and wrote the manuscript draft. FvW and AvR-K supervised JW, outlined the manuscript focus and revised the manuscript. CD and LW critically revised the manuscript. Conflict of Interest Statement ------------------------------ The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. **Funding.** JW is funded by the Bas Stichting, the Princess Beatrix Muscle Foundation and Innovatiefonds Zorgverzekeraars. LW and CD are supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital and by grants from Arthritis Research UK (21953), Cure-JM, and The Myositis Association. [^1]: Edited by: Ann Marie Reed, Duke University, United States [^2]: Reviewed by: David A. Hafler, Yale University, United States; Hanna Kim, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), United States [^3]: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

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Civilization VI is Turning Into a Competitive Esport I know, Civilization VI being an Esport sounds weird, but bear with me for a moment. Just this past weekend, competitive Esports team Team Liquid announced that they had just recruited their first pro Civ player, and were looking to build a full team of Civ players, with Stephen ‘MrGameTheory’ Takowsky leading them. ‘MrGameTheory is a former world champion Civilization player who achieved the rank of #1 on the Civilization Revolution leader board, Civilization IV international league, and Civilization V international league. He holds the records for most 1v2, 1v3, 1v4, and 1v5 ladder victories in Civilization IV. He is commonly referred to by members of the competitive community as a the “God” or “Legend” of Civilization. Civilization provides the perfect platform for players to showcase their gaming intellect and we feel that Firaxis is on the cusp of bringing the franchise to a competitive esports level. It is inevitable that Civilization will take its place alongside the top esports in the world.’ While I can’t disagree with the comparisons drawn between Civ and chess, I can’t imagine that a competitive game of Civilizavion VI will be very interesting to watch. Still, it should be fun to see how this develops.

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Western Airways Western Airways was an airline based in Weston-super-Mare, Somerset, England between 1932 and 1978. Before World War II, for a short period it was the world's busiest airline. It survived WWII by using its aircraft engineering expertise. History Origins and development On 26 September 1932, Norman Wallace George Edgar started a twice-daily passenger service between Bristol (Whitchurch) Airport and Cardiff (Splott) Airport – a 20-minute trip in the De Havilland Fox Moth of his company, Norman Edgar & Co. At that time a road journey between Bristol and Cardiff meant either crossing the Severn by the Aust Ferry, or a long detour upstream via Gloucester. Business boomed, and Edgar formed a new company, Norman Edgar (Western Airways) Ltd at Whitchurch, with a larger aircraft, a De Havilland Dragon. New routes were added, across the English Channel to Le Touquet and Paris, and also to Cardiff and Bournemouth (Christchurch), as that airport's first airline service. Further Dragons were added to the fleet, and Edgar decided to look for a new base. In January 1933 Edgar approached the council of Weston-super-Mare to finance the construction of a new airfield. Convinced, the council bought the land and construction started in February 1936. Edgar's company started two new ventures: Western Air Transport whose role was 'to operate airlines', and Airways Union, to 'establish lines of aerial connection'. Airways Union appears to have been a holding company for all of the planned activities. Western Airways was to manage the new airport for a fee that would help to mitigate the landing and per-passenger fees charged by the council to recover its large investment. In May, the new airport was licensed for De Havilland Dragon flights and, to Edgar's dismay, Railway Air Services started flights on two routes the same month, one to Cardiff and Whitchurch, and another via Cardiff and Haldon, Devon, to Plymouth (Roborough) Airport. With the help of good publicity, Edgar soon responded with the Weston to Cardiff 'air ferry', another between Weston and Whitchurch, and a route to Birmingham (Castle Bromwich). By the end of July 1936 the company had relocated to Weston and the fleet had expanded to four Dragons, plus two De Havilland Puss Moths and a Gipsy Moth available for charter and pleasure flights. To Edgar's great relief, Railway Air Services withdrew all its services from Weston on 12 September, leaving his company with no competition. In 1937 the company started Western Airways Aero Club, teaching many pupils to fly. Edgar also gained a contract with the Army for night flying for anti-aircraft practice. This meant equipping Weston Airport with lighting, including floodlights, and a control tower. Many of the company's aircraft were fitted with radios, and operations got under way by the end of April. At first, aircraft engineering and maintenance had been performed by outside contractors in a hangar at Weston. With the growth of activity, it was decided to do this work in-house and in October 1937 an ex British Airways chief engineer, Freddy Jeans, was hired to oversee this work. An Air Training School was started by Western Airways to train engineers to work there. Up to now, despite all its activity, the airline had failed to make a profit. On 10 July 1937, Louis Strange, a director of Straight Corporation, diverted to Weston during the annual air race from London (Heston) to Cardiff (Pengam Moors, which had been renamed from Splott). Seeing all the activity at Weston may have had an influence on the Straight management, who intended to get into the airline business, and in January 1938 the Straight Corporation bought a controlling share in Norman Edgar (Western Airways) Ltd, renaming it Western Airways Ltd. It was then operating the highest frequency of flights of any airline in the world: 58 services a day. At the same time, Western Air Transport was renamed Straghtways Ltd. On 10 August 1938, Norman Edgar left the company in some acrimony after he alleged that some of its pilots were flying while drunk. An unfair dismissal claim ran on into 1940. With airport lighting in place for the Army contract, the airline wanted to start night passenger operations, principally for the Cardiff air ferry route. The Air Ministry demanded further work, mainly the lighting of nearby electricity pylons and the cables between them. All four runways were also lengthened, and once the work at Weston and Pengam Moors had been approved, the first British commercial night service began. The event, on 2 October 1938, was covered live by BBC reporters, and famous aviators Arthur Whitten Brown and Jim Mollison were at Cardiff to meet the incoming Rapide. Routes in 1938 Weston – Cardiff (Pengam Moors Airport) Bristol – Cardiff – Swansea (Jersey Marine Airport) Swansea – Barnstaple – Newquay (Trebelzue airfield) – Penzance Swansea – Weston Weston – Bristol – Birmingham (Castle Bromwich) – Manchester (Barton airport, moving to Ringway) Weston – Le Touquet – Paris (Le Bourget) Routes in 1939 Weston – Cardiff – Swansea: Until 30 April, four times weekly. Weston – Cardiff: Until 4 March, five times daily; 5 March to 15 April, six times daily; 16 to 30 April, seven times daily; 1 to 31 May, twenty-eight times daily; 1 to 30 June, twenty-five times daily; from 1 July, twenty-six times daily. Bristol – Cardiff – Swansea: From 1 May, five times daily. Swansea – Barnstaple: From 8 May, twice daily. Swansea – Barnstaple – Newquay – Penzance: From 8 May, once daily. Weston – Bristol – Birmingham (Elmdon) – Manchester (Ringway): From 17 June, three times daily. To service these routes, a DH.86 Express and two Percival Q.6 airliners were acquired, offering greater capacity and, with the Q6s, greater speed, than the airline's existing fleet. World War II On 3 September 1939, war with Germany was declared and the National Air Communications (NAC) organisation came into action. All British aerodromes and civil transport aircraft were requisitioned and most of the aircraft were flown to RAF bases. Western's DH.86 Express had been parked through lack of spares, but was overhauled and soon converted to an air ambulance. The NAC was persuaded to allow the Weston – Cardiff air shuttle to resume, but it only operated, on an hourly schedule, from 25 November until 30 March 1940. This was the last day of Western Airways' pre-war airline operations, but not the end of the company itself. The maintenance facilities were expanding rapidly with work to repair, maintain and modify a wide range of aircraft, ranging from Miles Magisters to Curtiss Tomahawks, Avro Ansons and Fairey Battles. This work continued until the end of the war, during which time the airfield had been greatly expanded, hard runways laid, and the Bristol Aeroplane Company had established a huge presence at Weston Airport. Post-war diversification Western Airways had done subcontracting work for Bristol, and after the war was producing components for their aircraft, such as for the Type 170 Freighter. It already had a contract for Royal Canadian Air Force Canadair Sabres, and to this was added component work on the Britannia airliner. They also refurbished a wide range of military vehicles, many for export, and Slingsby gliders, which led to them being appointed dealers for Slingsby Sailplanes and Percival Aircraft, a business that lasted into the early 1950s. Another post-war activity was the conversion of military aircraft for civilian use. At first the aircraft were from the old Straight Corporation fleet which had been impressed for war service; these were restored to their old registrations and sold on. A wide range of aircraft types were then worked on, including Avro Tutor, Supermarine Walrus, Percival Petrel (military Q6), Taylorcraft and Miles. Eight Ansons were converted for the corporation's Straight Aviation Training. Two were retained as civilian conversions with seven passenger seats and used for communications and charter work. Other Ansons were converted for other, mainly military, customers. Western Airways' airline operations restarted in July 1946, when the Ministry of Civil Aviation permitted services on the Weston – Cardiff air ferry route. At first Western operated the route alone, but the following year the ministry dictated that it had to be operated in conjunction with Cambrian Airways. Western used its Avro Ansons, while Cambrian used Rapides which they had acquired specially for the route. The service only lasted until the end of the 1949 holiday season, when Western withdrew, Cambrian carrying on for a few weeks, finally stopping on 29 October. Western Airways then again concentrated on its parts manufacturing operations. Starting with orders for components for the Westland Wyvern and De Havilland Vampire, they started on parts for the Bristol 170 Freighter. This soon led to a Freighter production line being created in one of Western Airways' hangars. The first one was rolled out on 28 September 1953, the last on 23 March 1958. In total, 31 were built by Western Airways. With many Freighters used for intense English Channel car ferry operations, stresses on the airframe were high, and Western Airways got considerable business replacing components in the wing's main spar for many years after production finished. More work was obtained for Bristol, the next major project being completion of the Britannia, two of which could just be squeezed into Western's hangar. Again Western Airlines got further repair and parts replacement work from that aircraft. Other work also came in, and during the 1960s work on Concorde and the Rolls Royce RB211 engine was done. However, the company had already started to diversify, and in 1958 a hangar was taken over by a company soon to be called Barber Weston Ltd, whose director, Arthur A Barber, became a director of Western Airways and its holding company, Airways Union. Barber manufactured a range of products including conveyor systems, wheelchairs, vending machines, and prefabricated steel-frame buildings, many of which were bought by the Little Chef restaurant chain. Another subsidiary was created, Straghtaways Ltd, taking its name from the Straight Corporation's pre-war house magazine. On the Weston Airport site it made prams and push-chairs for Mothercare along with chicken cages and electrically heated clothes driers. In the early 1970s, Western Airways had a contract to weld the fuselages of autogyros to be produced for Campbell Aircraft, and were contracted to build the prototype of a new version, the Campbell Cougar. It was completed in 1973 and flight testing went well. However, Campbell's funding ran out and the whole project was abandoned, the Cougar moving to The Helicopter Museum, built on the site of Weston Airport's control tower. Western Airways continued to operate Weston Airport, and serviced and maintained a number of private aircraft. Pleasure flights were still popular, and for a short while in the 1976 season, famous ATA pilot Jackie Moggridge was employed as a pilot. However, during the 1970s the level of activity was declining, and the runway was in need of costly resurfacing. Airways Union decided to relinquish the airport's licence at the end of 1978, and the remaining staff were made redundant. Fleet list (pre-war airline use only) After takeover by the Straight Corporation, aircraft were moved between their different airlines, airport operating companies and flying clubs as the need arose. Therefore aircraft listed here probably didn't spend their entire career with Western before disposal, and some Straight Corporation aircraft not listed here may have operated for Western Airways. References: De Havilland DH.83 Fox Moth G-ABYO Norman Edgar from 5 January 1933 to 16 June 1934 (crashed) De Havilland DH.84 Dragon G-ACAO from 8 July 1938, impressed 2 April 1940 as N9398 G-ACJT from 26 August 1933 to 20 December 1939 (crashed) G-ACLE from 18 May 1939, impressed 2 April 1940 as X9397 G-ACMJ from 1 July 1938, impressed 2 April 1940 as X9396 G-ACPX from 23 July 1938, impressed 2 April 1940 as X9399 G-AECZ from 1 February 1937, impressed 8 May 1940 as AV982 De Havilland DH.86B Express G-AETM from 18 April 1939 to 31 January 1940 De Havilland DH.89 Dragon Rapide G-ACTU from 14 July 1937, impressed 8 June 1940 as AW115 G-ADBV from 31 May 1937, impressed 2 March 1940 as N8511 G-ADDD from 8 July 1937, impressed 4 June 1940 as AW116 G-AFSO (DH.89A) from 21 May 1939, impressed 23 January 1940 as W6457 De Havilland DH.90 Dragonfly G-ADNA from 27 January 1939, impressed 17 April 1940 as X9452 G-AEDH from 25 September 1937, impressed 10 May 1940 as AV987 General Aircraft ST-6 Monospar G-ACGI from 6 November 1936, impressed 6 May 1940 as AV979 Percival Q.6 G-AFIX from April 1939, impressed 2 April 1940 as X9406 G-AFVC from 30 June 1939, impressed 10 May 1940 as AX860 Short S.16 Scion G-ADDV from 22 May 1936, impressed 11 April 1940 as X9456 G-ADDX from 15 May 1936, impressed 3 April 1940 as X9430 Spartan Cruiser II G-ACBM from 28 July 1937 to August 1937 (scrapped} Aircraft production Bristol Type 170 Freighter Mk 31 (1953–1958) F-VNAR Air Vietnam G-APLH Dan-Air ZK-BVM Safe Air Total = 3 Mk 31M (1954–1957) S4408 Royal Pakistan Air Force (RPAF) S4410 RPAF S4413 RPAF S4415 RPAF S4417 RPAF S4419 RPAF S4421 RPAF S4422 RPAF S4424 RPAF S4426 RPAF S4427 RPAF S4429 RPAF S4430 RPAF S4432 RPAF S4433 RPAF S4435 RPAF S4437 RPAF S4438 RPAF 9850 Royal Canadian Air Force Total = 19 Mk 32 Superfreighter (1956–1957) G-ANWJ Silver City G-APAU Air Charter G-AOUU Air Charter G-AOUV Air Charter G-ANWK Silver City G-ANWL Silver City G-ANWM Silver City G-ANWN Air Charter Total = 9 Total Freighter production = 31 Campbell Cougar G-BAPS. first flight 20 April 1973 Accidents and incidents On 16 June 1934 De Havilland Fox Moth G-ABYO of Norman Edgar & Co was on a business charter flight from Llanvair, near Caerwent in Wales to Glasgow when the aircraft crashed near Llanfair and caught fire. The pilot, Douglas Brecknell, was thrown clear and rescued his two trapped passengers. One of the passengers, Godfrey Jones, survived with injuries, but the other, Arthur Turner, aged 41, died later of his injuries. On 20 December 1939 De Havilland Dragon G-ACJT registered to Southern Airways (part of the Straight Corporation) crashed on take-off at Weston Airport on a flight to Cardiff. It is thought the pilot, Leslie Ivor Arnott, aged 35, the sole occupant, had become incapacitated. He died in hospital of his injuries. Footnotes References Category: Defunct airlines of the United Kingdom Category: Airlines established in 1932

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Hatch set forth the goals of tax reform as: "Fairness, efficiency, simplicity and American competiveness." He offered three reasons to move forward on tax reform. Hatch continued, "American families, individuals, and businesses collectively spend hundreds of billions of dollars a yearnot to mention countless hourssimply trying to comply with the tax code. Tepid growth rates for the U.S. economy have seemingly become the new normal for some. America's multinational businesses find it difficult to compete abroad and are often targets for acquisition by foreign companies." Wyden also set forth his hopes for tax reform. He noted, "What is needed is bipartisan tax reform that focuses on progressivity, helping the middle class, cleaning out flagrant tax loopholes, fiscal responsibility and giving everybody in America the chance to get ahead. In short, bipartisan tax reform would build on key principles that brought Democrats and Republicans together for major bipartisan tax reforms slightly more than three decades ago." Witnesses before the Senate Finance Committee were four former Assistant Secretaries of the Treasury for Tax Policy. They held diverse opinions, but generally supported fairness for middle class taxpayers and strengthening the economy. House Hearing on Tax Reform On July 19 the House Ways and Means Tax Policy Subcommittee held a hearing on tax reform. Subcommittee Chairman Peter Roskam (R-IL) opened the hearing and stated, "As a committee, we now have a choice. We can accept high tax rates and a confusing code or we can grow the economy, lower taxes for everyone and create a fair system that Americans can trust. I think the choice is clear." Former Chairman of the House Ways and Means Committee Bill Archer highlighted the goals of tax simplification and improving the economy. Archer noted, "I commend the efforts of this committee and particularly Chairman Kevin Brady for taking the lead to advance the indisputable goal of simplifying the code and helping to make the United States a leader in the world in terms of having a tax code that gives our country a competitive edge in the marketplaces of the world." Archer explained that when he was Chairman of the Ways and Means Committee, he felt that as the chief taxwriter in America he should also prepare his personal return. Archer explained that he prepared his tax returns, "Because I believed that I had to experience the same process as every other taxpayer. I would lock myself in my office to struggle through the entire effortusing paper and pencilnot a computer program. It was a multi-day effort!" Archer concluded his testimony by approving the effort to enable "the vast majority of Americans" to file a tax return on a postcard. The House Budget Committee also passed an appropriations bill this week that will be submitted to the full House. The bill creates an October 6 deadline for creation of a tax bill by the House Ways and Means Committee. Chairman Kevin Brady (R-TX) indicated that this deadline will be met. He noted that they will prepare a bill with "permanent tax reform that balances within the budget so we can deliver the certainty and economic growth Americans deserve." The budget committee also envisioned a revenue neutral tax bill. IRS Review of Syndicated Conservation Easements On July 13 IRS Commissioner John Koskinen sent a report on syndicated conservation easements to Senate Finance Committee Ranking Member Ron Wyden (D-OR). In the letter, Koskinen explained the IRS analysis of 40 disclosures of syndicated conservation easement transactions. These disclosures were in compliance with IRS Notice 2017-10. This Notice classified certain syndicated conservation easement transactions as "listed transactions." Koskinen noted the 40 reported transactions included both the investment amounts and the claimed charitable deductions. The aggregate charitable deductions were $217 million and the investment amounts were approximately one-ninth this amount. Executive Vice President Wendy Jackson of the Land Trust Alliance commented on the Koskinen letter. She noted, "The preliminary data show for 40 specific transactions that happened since 2010, people bought the equivalent of $9 of tax deductions for $1, on average. It is clear that in these instances, the deductions significantly exceeded the limit established by the IRS." The Land Trust Alliance previously warned their 1,000 members to "steer clear" of syndicated conservation easement transactions. Jackson continued, "In the vast majority of cases, conservation easement donors are philanthropic heroes working with nonprofit land trusts that are above reproach, and we cannot let the actions of those focused on material greed undermine a program that benefits all Americans." Editor's Note: The House Budget Committee passed a bill that directs the IRS to not regulate syndicated conservation easement transactions. Senate Finance Committee Chairman Orrin Hatch (R-UT) and Ranking Member Ron Wyden (D-OR) are researching and reviewing IRS actions with respect to syndicated conservation easements. The Land Trust Alliance's support of the IRS may be a factor in their future decisions. The IRS has announced the Applicable Federal Rate (AFR) for August of 2017. The AFR under Section 7520 for the month of August will be 2.4%. The rates for July of 2.2% or June of 2.4% also may be used. The highest AFR is beneficial for charitable deductions of remainder interests. The lowest AFR is best for lead trusts and life estate reserved agreements. With a gift annuity, if the annuitant desires greater tax-free payments the lowest AFR is preferable. During 2017, pooled income funds in existence less than three tax years must use a 1.2% deemed rate of return. Federal rates are available by clicking here.

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BLOG 24th July, 2019By April In episode 244 of Semantic Mastery's weekly Hump Day Hangouts, one viewer asked if the team has any case studies that RYS stacks benefit authority sites in broad niches. The exact question was: I am building out an authority site in the health niche. It seems that RYS stacks are geared towards local GMB assets. Do you have any case studies that RYS stacks benefit authority sites in broad niches?

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Hyland's Residence Window and Door PanelShown here is the back addition with a custom wood door and window panel opening out to a back deck and garden. As a south facing door and window panel the transoms over the doors work well to bring light into the interior of the house

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Thelymitra imbricata Thelymitra imbricata, commonly called the broad sun orchid, is a species of orchid that is endemic to Tasmania. It has a single erect, channelled leaf and up to fifteen or more pale to dark or purplish blue, relatively large flowers. Description Thelymitra imbricata is a tuberous, perennial herb with a single erect, fleshy, channelled, light green, linear to lance-shaped leaf long and wide with a purplish base. Between three and fifteen or more pale to dark or purplish blue flowers wide are arranged on a flowering stem tall. The sepals and petals are long and wide. The column is white, bluish or pinkish, long and wide. The lobe on the top of the anther is about long and wide, brown or orange brown with a narrow blue band, gently curved with an inflated hood and a V-shaped notch. The side lobes are finger-like and have dense, toothbrush-like tufts of white hairs. Flowering occurs from late October to early December. The flowers are long-lasting, insect pollinated and open on warm sunny days. Taxonomy and naming Thelymitra imbricata was first formally described in 1998 by David Jones and the description was published in Australian Orchid Research. The name replaced the synonym Thelymitra nuda var. grandiflora Lindl.. The specific epithet (imbricata) is a Latin word meaning "overlapping like roofing-tiles and shingles". Distribution and habitat The broad sun orchid usually grows in a range of habitats including open forest, scrubland, grassland and heath in the Tasmanian midlands. References External links imbricata Category:Endemic orchids of Australia Category:Orchids of Tasmania Category:Plants described in 1998

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Silencing non-SMC chromosome-associated polypeptide G inhibits proliferation and induces apoptosis in hepatocellular carcinoma cells. The present study was designed to investigate the significance of non-structural maintenance of chromosomes (non-SMC) chromosome-associated polypeptide G (NCAPG), a subunit of condensin complex I, in the development of hepatocellular carcinoma (HCC). NCAPG protein expression in human HCC and paracancerous hepatic tissues were examined using immunohistochemistry, and NCAPG mRNA expression in HCC cell lines were quantified using quantitative RT-PCR. Lentivirus-mediated RNA interference was used to silence NCAPG in HCC cells. Cell proliferation was monitored by MTT assay. Cell colony-forming capacity was measured by colony formation assay. Apoptosis was determined by flow cytometry. The results showed that increased protein expression of NCAPG was found in HCC tissues compared with the matched paracancerous hepatic tissues. At the mRNA level, increased expression of NCAPG was found in HCC cells as opposed to the normal hepatocytes. Silencing of NCAPG in BEL-7404 and SMMC-7721 cells led to decreased cell proliferation and increased apoptosis. These changes were associated with increased mRNA expressions of P53, P27, and Bad, but decreased mRNA expression of EGFR, Akt, survivin, and JNK. NCAPG might play an oncogenic role in the development of liver cancer. Further studies to clarify its role and underlying mechanisms in the development of liver cancer are warranted.

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IRT Perundurai Medical College The IRT Perundurai Medical College is one of the Premier Government Medical institutions in the state affiliated to The Tamil Nadu Dr. M.G.R Medical University, Chennai. The school includes a medical college and a hospital. The school falls under the auspices of the Tamil Nadu State Transport Corporation. History On the suggestion of Lord Willington (then Viceroy of India) in 1930 a district committee to combat tuberculosis was formed in Coimbatore and the decision to start a tuberculosis sanatorium in Perundurai was made. The foundation stone was laid by Sir K.V.Reddy Naidu on 1 July 1936. The sanatorium was declared open by Sri.C.Rajagopalachari. It was renamed Ramalingam Tuberculosis Sanatorium in 1952. In 1986 the government of Tamil Nadu attached a medical college with the sanatorium. The college has 600 beds and started functioning in 1992. In 2017, the strength of the Medical College was increased from 60 students to 100 students. In 2004, doctors' quarters were added. A school of nursing was started in 2008. Graduation day ceremony (VIDAI 2018) for 2012 batch students (Dravagonz) was conducted in the newly built auditorium on 25 April 2018. The chief guests were 1. The Honourable Vice-chancellor of Tamilnadu Dr.MGR Medical University, Dr. S.Geethalakshmi MD PHD; and 2. The Honourable Erode district collector, Dr. S.Prabakar IAS. Other notable guests include Dr. T.Ramaprasad MD, Thiru Thoppu N.D.Venkatachalam MLA, Thiru V.Shanmugam Chairman of Nanda educational trust. Government to takeover the College from 2019-2020 Classes and years of entry Every class of MBBS students has assigned to itself an (unofficial) name denoting the year of their entry into the medical school. The recent batches (with their culturals name) 1995 Maestros 1997 Trendsetters 2001 Challengers [Swasam] 2002 Vibrant Victors [Mithz] 2003 Stalwarts [Inferno] 2004 Kosmocraterz [Revenant] 2005 Racing Rampantz [Hedonic] 2006 Hurricanz [Xtonant] 2007 Tantalizers [Ewiganz] 2008 Invinciblz [Xperanza] 2009 Salvadorz [Extemus] 2010 Spangblattens [Nakshatra] 2011 Xanthronz [Ignitron] 2012 Dravagonz [Festino] 2013 Xentinelz [Inceptra] 2014 Facidianz [Maghizhazhi / மகிழாழி] 2015 STRATONZ [ oliyum oliyum 19/ ஒளியும் ஒலியும் 19 ] 2016 Krenoviantz 2017 Indominerz 2018 Exustardianz 2019 Zephyrianz References External links http://irtpmc.ac.in/ Category:Medical colleges in Tamil Nadu Category:Universities and colleges in Erode district

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A site that encourages smokers to quit and provides tips to friends and family on how to motivate a smoker to quit without nagging, shaming or blaming. Also check out my website with several videos on becoming smoke-free at: www.VJSleight.com and connect with me on LinkedIn at :www.linkedin.com/in/vjsleight . Friday, July 25, 2014 What is a Tobacco Treatment Specialist and how can you help me quit smoking? Can't I just quit smoking on my own? A Tobacco Treatment Specialist (TTS) is a person who has been specially trained in the treatment of nicotine addiction. I was trained at the Mayo Clinic. I also belong to a professional organization: The Association for the Treatment of Tobacco Use and Dependence(ATTUD). A TTS will use evidence based material (proven strategies) to help a smoker become smoke-free. One guideline that is used is the The Clinical Practice Guideline: Treating Tobacco Use and Dependence. This publication has delved into all of the research into tobacco treatment and has complied the best practices. Methods are rated A, B, C. A = This method has been proven to work on a consistent basis. B = These methods have conflicting information. C = No clinical controlled trials to show efficacy. Many smokers do quit on their own, just like other addictions such as alcohol, cocaine and heroin. But many need help to kick their addiction, especially nicotine. I have had former heroin addicts tell me that heroin and/or alcohol were easier to quit than smoking. Have you ever talked to a former smoker and asked what helped them to quit? They can tell you the long trial and error process they used and what ultimately worked for them. It doesn't mean that it will work for you. Working with a professional will shorten your learning curve in what will help you quit and stay quit. Here is what you can expect when working with a professional Tobacco Treatment Specialist: A detailed personal history. Every smoker is different. There is no one-size-fits-all when it comes to tobacco treatment, not even a one-size-fits-most. You will be asked about how much you smoke, for how long, your previous quit attempts, your medical and mental health history, previous or current substance use, your common triggers, assessment of your nicotine dependence and your perceived obstacles to quitting. From your detailed history, an individualized treatment plan is developed. It will include information of what medications may help and what practical counseling skills are needed for your particular situation including: emotional cues, dealing with stress, weight gain, handling withdrawals with or without medications, being around other smokers, and relapse prevention. Motivation when times are tough. Some days you will feel that nothing can ever drag you back to smoking and other days you will feel that nothing will help except a cigarette. Explanations for any questions or myths related to smoking. I have had many clients whose doctors have told them that if they quit they would: breathe better, have lower cholesterol, their neuropathy will improve etc. yet they didn't believe their doctors. Why? Because their doctors didn't take the time to fully explain what smoking is doing to their body and how the body heals itself when you quit. Someone who understands how difficult it is to become smoke-free. While I am a former smoker having quit 9 separate times for at least 3 months and I personally know how hard it is, many TTS's have never smoked but with their specialized training and after working with countless smokers, they don't need to know what it is like. Just as an OB/GYN doctor doesn't need to know how it feels to be pregnant to deliver a baby. Signs that it is time to use a TTS instead of trying to quit on your own: You have quit multiple times, only to relapse back to smoking. Have a history of other substance abuse and/or addiction, or a history of mental illness. A sense of shame or guilt that you are still smoking. Shame is when you feel there is something wrong with you that you can't quit. Guilt is when you feel you should quit and want to quit, but are still smoking. These are normal emotions that a TTS can help you work through instead of letting these emotions stop you from moving forward. You've tried everything and nothing works. A TTS will help you cut through the "noise" of quitting, helping you focus on what will work. Too often a smoker relies on the latest fad or gimmick to quit instead of what will work, or will rely on just one tool instead of developing several coping strategies. A TTS will focus on the process of quitting, not just the method, since every method will work for some smokers, NO method will work for every smoker. Call me today at 760-333-1270 for a FREE 15 minute counseling session to see how I can help you. 1 comment: O my God....I can't see this any-more. Please spread message for avoiding smoking and drugs to the whole nation. People are damn dumb to get goad for smoking without thinking about their horrible death story. Thank you so much for sharing this valuable information. My younger brother was also addicted to smoking but now my parents are trying to relieve him from smoking cessation with hypnosis . May God help us VJ Sleight, Queen of Quitting Send me a message with your questions. Subscribe to My Blog One on One Coaching Now Available I believe that EVERY smoker can become smoke-free with my help. No matter how many times your have tried, no matter how many different products you have used, no matter if you think it is hopeless, I can help you. Call me today for a FREE 15 minute coaching session at 760-333-1270 or email me for more information. As a former smoker I know how difficult it is to quit but also how rewarding it can be once you achieve your goal. Let me help you walk through the process of going from a long-time smoker to becoming smoke-free. Change is hard but you CAN do it, and I will show you how.

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1. Field of the Invention The present disclosure relates generally to a method of applying a graphic image on a substrate. More particularly, the invention relates to the use of a liquid release coating formulated to form a durable first film wherein the transferred graphic material is superimposed on a print film and sandwiched between a primer coat on the one hand and a top coat of the target substrate on the other hand. 2. Description of the Related Art There are a myriad of methods of applying graphic images to a substrate. However the known methods have achieved limited success in applying complex multi colored high resolution graphic images to certain substrates, such as for example leather. Known methods of applying graphics to substrates, in particular, leather use adhesives or other material that often compromise the supple feel of the leather and don't protect the graphic from wear. Thus, many luxurious materials in which the texture of the material is paramount are often offered in monochromatic colors only. The prior art discloses equipment and methods that teach printing graphic images directly on a substrate, such as leather. Direct printing on a substrate is slow and expensive. It is additionally disadvantageous because the inks used contain hazardous ingredients and the graphic image remains unprotected and is subject to damage from wear. The prior art teaches various methods for transferring digitally created images to a target surface via heat and/or pressure. In particular, U.S. Pat. Pub. No. 2008/0043087 A1 (to Cowan) teaches a method for creating and transferring digitally created images on a film to a target surface via heat and/or pressure transfer using a modified large-format digital printer. The method generally comprises the steps of modifying a large format digital printer to convert it from heat fused toner printing to cold toner printing, preparing a transfer film, creating a digital image, applying a release layer onto the transfer film, printing the image onto the release layer on the transfer film in a reverse mirror-image manner, applying an adhesive overtop said image, and pressure transferring the image onto the target substrate and peeling away the transfer film to selectively leave the image on the target substrate. U.S. Pat. Pub. No. 2002/0131333 A1 (to Sofer et al.) discloses a method using a personal computer to create designs and or images. The design is first created on the computer and then printed onto a heat transfer sheet. The printed design on the heat transfer sheet is then heat pressed onto the leather (cow hide, calf, pig, goat, kid, sheep) material. The design may also be an image such as a picture created using a digital camera or manual camera. U.S. Pat. No. 7,699,458 B2 (to Mabbott) teaches a method of providing a surface of a material with an image, including applying to the surface an image sheet comprising (i) a flexible layer of a shape memory polymer, and (ii) an image bonded to said layer by means of an image key coat. The image sheet is bonded to the surface by means of an adhesive and a process that involves heating of the shape memory polymer to a temperature above its Glass Transition Temperature. U.S. Pat. No. 7,025,451 B2 (to Mabbott) discloses a method for transferring an image onto a non-planar surface in which an image transfer sheet comprising a shape memory polymer or like substance is used to transfer said image. U.S. Pat. No. 6,039,822 (Heyworth et al.) discusses a process of applying decals to products having rough textured surfaces, such as products made from thermoplastic resins, leather, or synthetic leather. The decals applied to the products contain detailed multicolor graphic images made from a four color printing process. The decal applying process includes applying a first clear ink layer directly to the substrate surface, applying a water-release slide-off decal on top of the first clear ink layer, and applying a second clear ink layer over the applied decal to firmly bond the decal to the substrate surface. The two ink layers encapsulate the decal on the substrate surface, maintaining the integrity of the decal. It is desirable to introduce an improved method of applying bright and complex multi graphics to a substrate, in particular luxury materials, such as for example fine leather, without altering the intrinsic nature and pliability of the leather or other substrate the graphic is adhered to and without damaging the material due to excessive heat or pressure used in the application process, while also protecting the graphic against normal wear and tear.

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Java-based client spreads Skype far and wide Why should smartphone and 3 Skypephone users have all the fun? Skype has finally released a client written for mobile Java, enabling the ubiquitous VoIP pipe to be used on a wide, wide variety of phones (Skype says they've tested it on about 50, but it's likely to work on far more than that). Though it's naturally scaled down a bit to fit in its tiny target footprint, the client still manages to pack in support for Skype-to-Skype and SkypeOut calls, chat, group chat, and your buddy list -- pretty much everything you need to make it functional. If you're going to have a go at it, just make sure you're on a sufficiently generous data plan, k? [Thanks to everyone who sent this in] Update: Turns out the data plan doesn't have to be that generous. Straight from Skype: "Tom has 20 Skype contacts and signs in twice a day for a total of 90 minutes. He IMs for about 25 minutes each day and makes 20 minutes of Skype calls. Tom would use just under 1 MB of data in one month." Thanks, everyone!

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Friday, April 21, 2017 Canada’s Fundamental Science Review: Good News for Basic Research! —Heidi Engelhardt, FAUW Board of Directors A comprehensive look at research in Canada The report “Strengthening the Foundations of Canadian Research”, released April 10, 2017, is the culmination of a thorough look at the federal research ‘ecosystem’ in Canada. There is a lot to like here for the entire research community. Although the report was submitted to the Minister of Science, it goes well beyond STEM disciplines. Indeed, research was defined to include both science and non-science (‘scholarly inquiry’). For this undertaking, the more important distinction was between investigator-led research focused on knowledge generation, versus ‘priority-driven’ research. The latter was defined as research with a tightly defined area of focus, oriented primarily to partnerships (with government, industry, business), or promoting knowledge translation, innovation, and commercialization. The primary focus was on investigator-led research supported by the three granting councils plus CFI, referred to as the four funding agencies. The advisory panel A nine-member Advisory Panel appointed in June 2016 consisted of six academics from diverse disciplines across Canada, the Chief Scientist of Quebec, an expat Canadian now the Silverman Professor of Physics and Public Policy at UC Berkeley and Mike Lazaridis. There were meetings with 230 researchers at different career stages, 1,275 written submissions and roundtables in five cities (Toronto, Montreal, Calgary, Ottawa, Halifax). The 280 page report is surprisingly readable. Their mandate was captured by two broad questions: Are there any overall program gaps in Canada’s fundamental research funding ecosystem that need to be addressed? Are there elements or programming features in other countries that could provide a useful example for the Government of Canada in addressing these gaps? Challenges identified It will surprise no one that one of their findings was that Canada’s research competitiveness had eroded in recent years, in association with flat-lined federal spending and redirection of funding to priority-driven and partnership oriented research. Coordination and collaboration among the four agencies was found to be suboptimal, and variability in practices was evident across these agencies beyond what could be explained by disciplinary differences. Lack of ‘life cycle’ support for both researchers and equipment/infrastructure was discussed at length. With respect to researcher support, the panel believed that the CRC program was no longer meeting its aim to “attract and retain the world’s most accomplished and promising minds”. A substantial (and rising) number of chairs are awarded to researchers already in-house or recruited from other Canadian universities; 10-15% of chairs are empty at any given time. At least part of this may be due to the fact that the funding levels of these positions have been unchanged for the past 17 years. Even more concern was expressed about the CERC (Canada Excellence Research Chairs) program, hence the recommendation that retooling the CRC program was the more sustainable strategy. With respect to trainees, levels of funding and numbers of awards for students and postdoctoral fellows have not kept pace, variously, with inflation, peer nations, or the number of applicants. The panel recommended that doctoral scholarship and PDF programs be reinvigorated, and harmonized across the tri-councils to achieve more consistency. They also recommended elimination of barriers to international portability. The growth in programs requiring cost-sharing or matching support was flagged as problematic in some jurisdictions and inappropriate for many disciplines. It was recommended that when the intent is to support independent research, matching should be used sparingly and in a coordinated and targeted manner. Highlights of recommendations Overall, 35 specific recommendations were made. Highlights include: creation of an independent National Advisory Council on Research and Innovation (NACRI) that would work closely with the soon-to-be appointed Chief Science Advisor wide ranging improvements in oversight and governance of all four agencies more money! … significant reinvestment on a multi-year basis spread across … investigator-led grants (highest priority) enhanced personnel support for researchers and trainees at different career stages targeted spending on infrastructure-related operating costs for small equipment and Big Science facilities improved coverage of the institutional costs of research Inevitably, this boils down to the reality of dollars. Carrying out these recommendations was estimated to increase annual spending across the four agencies from approximately $3.5 billion to $4.8 billion, requiring redirection of an additional 0.4% of the Government of Canada’s annual budget. While most of this funding would go to the granting councils’ core programs, a portion would be channelled to investigator-led projects involving international collaborations, multidisciplinary work, high-risk, high-reward (‘HR2’) ventures and projects requiring rapid response. Other valuable information In addition to its potential impact on national science policy, this document is a rich source of information on many topics, including: trends in research funding among select G7 nations, key east Asian countries and small peer nations (Chapter 3) a comparison of funding levels by the three granting agencies (an eye opener for some; Chapters 4, 5, 7) of particular relevance to Waterloo - Canada’s World Share in Emerging Research Areas, many of which are considered to be strengths of our institution (nanotech, bioinformatics, computer science, quantum computing, robotics and mechatronics, et al.; Appendix 1) Overall, this undertaking and its report – an impressive output in less than a year – is good news for Canadian research. It is unlikely that there will ever be enough funding to support all researchers at all institutions in a style to which they would like to become accustomed. And “reasonable people will disagree unreasonably about where the funds flow”. However, this report outlines many steps, large and small, in the right direction. The question now is whether, and when these recommendations will be implemented.

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Q: Insert Into with Case on whole entry I'm creating a script to run which will take all the stock in an old system and insert into the new system. However the old system has 1000's of erroneous part number data that I want to ignore on the import. I've tried encapsulating the whole select in a case statement and iterations on that theme. It's quite a large set of data so for simplicity sake I've taken the vital information into the below code. INSERT INTO [LOT_TBL] ( Part_No Total_Stock ) --Ignore an insert if Part_No_Old NOT IN (SELECT Part_No from PART_TBL) SELECT Part_No_Old Total_Stock FROM OLD_ERP WHERE Total_Stock > 0 The PART_TBL in the new system has a list of all the valid parts, so if any on the import don't match, ignore and move on to the next one. A: You can filter with exists: insert into [lot_tbl] (part_no, total_stock) select part_no_old, total_stock from old_erp o where total_stock > 0 and exists ( select 1 from part_tbl p where p.part_no = o.part_no_old ) Or, if part_nos are unique in part_tbl, you can use a join: insert into [lot_tbl] (part_no, total_stock) select o.part_no_old, o.total_stock from old_erp o inner join part_tbl p on p.part_no = o.part_no_old where o.total_stock > 0

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Q: Replacing a pattern with awk or sed I have a file with patterns like below 12345343|559|-2,0,-200000,-20|20161108000000|FL|62,859,1439,1956|0,0,21300,0|S 3434344|-100000|20161108000000|GL|135|0|S 45454545|214|-2000,-2,0,0,-20|20161108000001||21,62,859,969,1956|77440,0,0,0,0|S Here I need to replace all the , values and get the first value in the sub set Required output: 12345343|559|-2|20161108000000|FL|62|0|S 3434344|-100000|20161108000000|GL|135|0|S 45454545|214|-200000|20161108000001||21|77440|S I have tried sed 's/\,*|//' but didnt work A: Okay, simplest of all: $ sed 's/,[^|]*//g' ip.txt 12345343|559|-2|20161108000000|FL|62|0|S 3434344|-100000|20161108000000|GL|135|0|S 45454545|214|-2000|20161108000001||21|77440|S Just replace , followed by non| characters with nothing Same with perl $ perl -pe 's/,[^|]*//g' ip.txt 12345343|559|-2|20161108000000|FL|62|0|S 3434344|-100000|20161108000000|GL|135|0|S 45454545|214|-2000|20161108000001||21|77440|S With awk, courtesy @JamesBrown $ awk '{gsub(/,[^|]*/,"")} 1' ip.txt 12345343|559|-2|20161108000000|FL|62|0|S 3434344|-100000|20161108000000|GL|135|0|S 45454545|214|-2000|20161108000001||21|77440|S or $ awk 'gsub(/,[^|]*/,"")+1' ip.txt 12345343|559|-2|20161108000000|FL|62|0|S 3434344|-100000|20161108000000|GL|135|0|S 45454545|214|-2000|20161108000001||21|77440|S

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I used bitcoin-iterate and gnumeric to render the current bitcoin blocksizes, and here are the results. My First Graph: A Moment of Panic This is block sizes up to yesterday; I’ve asked gnumeric to derive an exponential trend line from the data (in black; the red one is linear) That trend line hits 1000000 at block 363845.5, which we’d expect in about 32 days time! This is what is freaking out so many denizens of the Bitcoin Subreddit. I also just saw a similar inaccurate [correction: misleading] graph reshared by Mike Hearn on G+ :( But Wait A Minute That trend line says we’re on 800k blocks today, and we’re clearly not. Let’s add a 6 hour moving average: In fact, if we cluster into 36 blocks (ie. 6 hours worth), we can see how misleading the terrible exponential fit is: Clearer Graphs: 1 week Moving Average So, not time to panic just yet, though we’re clearly growing, and in unpredictable bursts.

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--- abstract: 'This paper proposes a representational model for grid cells. In this model, the 2D self-position of the agent is represented by a high-dimensional vector, and the 2D self-motion or displacement of the agent is represented by a matrix that transforms the vector. Each component of the vector is a unit or a cell. The model consists of the following three sub-models. (1) Vector-matrix multiplication. The movement from the current position to the next position is modeled by matrix-vector multiplication, i.e., the vector of the next position is obtained by multiplying the matrix of the motion to the vector of the current position. (2) Magnified local isometry. The angle between two nearby vectors equals the Euclidean distance between the two corresponding positions multiplied by a magnifying factor. (3) Global adjacency kernel. The inner product between two vectors measures the adjacency between the two corresponding positions, which is defined by a kernel function of the Euclidean distance between the two positions. Our representational model has explicit algebra and geometry. It can learn hexagon patterns of grid cells, and it is capable of error correction, path integral and path planning.' author: - | Ruiqi Gao$^{1}$[^1], Jianwen Xie$^{2}$, Song-Chun Zhu$^{1}$ & Ying Nian Wu$^{1}$\ $^{1}$University of California, Los Angeles, USA\ $^{2}$Hikvision Research Institute, Santa Clara, USA\ `{ruiqigao, jianwen}@ucla.edu`, `{sczhu, ywu}@stat.ucla.edu`\ bibliography: - 'grid.bib' title: 'Learning Grid Cells as Vector Representation of Self-Position Coupled with Matrix Representation of Self-Motion' --- Introduction ============ Imagine you are walking in your living room in the dark at night without any visual cues. Purely based on your self-motion, you know where you are while you are walking simply by integrating your self-motion. This is called path integral ([@hafting2005microstructure; @fiete2008grid; @mcnaughton2006path]). You can also plan your path to the light switch or to the door. This is called path planning ([@fiete2008grid; @erdem2012goal; @bush2015using]). You need to thank your grid cells for performing such navigation tasks. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ![Place cells and grid cells. (a) The rat is moving within a square region. (b) The activity of a neuron is recorded. (c) When the rat moves around (the curve is the trajectory), each place cell fires at a particular location, but each grid cell fires at multiple locations that form a hexagon grid. (d) The place cells and grid cells exist in the brains of both rat and human. (Source of pictures: internet)[]{data-label="fig:g1"}](./FIG/g1.png "fig:"){height=".15\linewidth"} ![Place cells and grid cells. (a) The rat is moving within a square region. (b) The activity of a neuron is recorded. (c) When the rat moves around (the curve is the trajectory), each place cell fires at a particular location, but each grid cell fires at multiple locations that form a hexagon grid. (d) The place cells and grid cells exist in the brains of both rat and human. (Source of pictures: internet)[]{data-label="fig:g1"}](./FIG/g0.png "fig:"){height=".15\linewidth"} ![Place cells and grid cells. (a) The rat is moving within a square region. (b) The activity of a neuron is recorded. (c) When the rat moves around (the curve is the trajectory), each place cell fires at a particular location, but each grid cell fires at multiple locations that form a hexagon grid. (d) The place cells and grid cells exist in the brains of both rat and human. (Source of pictures: internet)[]{data-label="fig:g1"}](./FIG/g2.png "fig:"){height=".15\linewidth"} ![Place cells and grid cells. (a) The rat is moving within a square region. (b) The activity of a neuron is recorded. (c) When the rat moves around (the curve is the trajectory), each place cell fires at a particular location, but each grid cell fires at multiple locations that form a hexagon grid. (d) The place cells and grid cells exist in the brains of both rat and human. (Source of pictures: internet)[]{data-label="fig:g1"}](./FIG/g4.png "fig:"){height=".15\linewidth"} (a) (b) (c) (d) ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Figure \[fig:g1\](a) shows Dr. May-Britt Moser, who together with Dr. Edvard Moser, won the 2014 Nobel Prize for Physiology or Medicine, for their discovery of the grid cells ([@hafting2005microstructure; @fyhn2008grid; @yartsev2011grid; @killian2012map; @jacobs2013direct; @doeller2010evidence]) in 2005. Their thesis advisor, Dr. John O’keefe, shared the prize for his discovery of the place cells ([@o1979review]). Both the place cells and grid cells are used for navigation. The discoveries of these cells were made by recording the activities of the neurons of the rat when it moves within a square region. See Figure \[fig:g1\](b). Some neurons in the Hippocampus area are place cells. Each place cell fires when the rat moves to a particular location, and different place cells fire at different locations. The whole collection of place cells cover the whole square region. The discovery of grid cells was much more surprising and unexpected. The grid cells exist in the Entorhinal cortex. Each grid cell fires at multiple locations, and these locations form a regular hexagon grid. See Figure \[fig:g1\](c). The grid cells have been discovered across mammalian species, including human. See Figure \[fig:g1\](d). In this paper, we propose a representational model to explain the hexagon patterns of the grid cells, and to explain how the grid cells perform path integral and path planning. We shall show that the grid cells are capable of error correction, which provides a justification for the grid cells. ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ![Grid cells form a high-dimensional vector representation of 2D self-position. Three sub-models: (1) Local motion is modeled by vector-matrix multiplication. (2) Angle between two nearby vectors magnifies the Euclidean distance. (3) Inner product between any two vectors measures the adjacency which is a kernel function of the Euclidean distance. []{data-label="fig:g2"}](./FIG/v1.pdf "fig:"){height=".11\linewidth"} ![Grid cells form a high-dimensional vector representation of 2D self-position. Three sub-models: (1) Local motion is modeled by vector-matrix multiplication. (2) Angle between two nearby vectors magnifies the Euclidean distance. (3) Inner product between any two vectors measures the adjacency which is a kernel function of the Euclidean distance. []{data-label="fig:g2"}](./FIG/v2.pdf "fig:"){height=".11\linewidth"} ![Grid cells form a high-dimensional vector representation of 2D self-position. Three sub-models: (1) Local motion is modeled by vector-matrix multiplication. (2) Angle between two nearby vectors magnifies the Euclidean distance. (3) Inner product between any two vectors measures the adjacency which is a kernel function of the Euclidean distance. []{data-label="fig:g2"}](./FIG/v3.pdf "fig:"){height=".14\linewidth"} \(1) Vector-matrix multiplication \(2) Magnified local isometry \(3) Global adjacency kernel ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Figure \[fig:g2\] illustrates our model. The 2D self-position of the agent is represented by a high-dimensional vector, and the 2D self-motion or displacement of the agent is represented by a matrix that acts on the vector. Each component of the vector is a unit or a cell. In Figure \[fig:g2\], $x$ denotes the 2D self-position, $v(x)$ is the high-dimensional vector representation of the 2D $x$. $\Delta x$ is the self-motion or one-step displacement. $M(\Delta x)$ is the matrix representation of $\Delta x$. The model consists of the following three sub-models. (1) Vector-matrix multiplication. The movement from the current position $x$ to the next position $x+\Delta x$ is modeled by matrix-vector multiplication, i.e., the vector of the next position $v(x+\Delta x)$ is obtained by multiplying the matrix of the motion, $M(\Delta x)$, to the vector of the current position $v(x)$. (2) Magnified local isometry. The angle between two nearby vectors equals the Euclidean distance $|\Delta x|$ between the two corresponding positions multiplied by a magnifying factor. (3) Global adjacency kernel. The inner product between two vectors $\langle v(x), v(y)\rangle$ measures the adjacency between the two corresponding positions, which is defined by a kernel function $f$ of the Euclidean distance $|x-y|$ between the two positions $x$ and $y$. One additional feature is that the whole vector $v(x)$ is partitioned into multiple sub-vectors, and each sub-vector is driven by an associated sub-matrix. The whole system is like a multi-arm clock, with each arm rotating at a magnified speed and spanning a 2D sub-manifold on a high-dimensional sphere. Our experiments show that sub-models (1) and (2) are sufficient for the emergence of the hexagon grid patterns of the grid cells. Sub-model (2) makes the vector representation robust to noises or errors due to the magnification of the distance. Sub-model (3) enables unique decoding of the position from the vector, because $f$ is unimodal and peaked at 0, and it may serve as the link between the grid cells and place cells. Together with sub-model (1), sub-model (3) enables path integral and path planning, because the adjacency $\langle v(x), v(y)\rangle$ informs the Euclidean distance $|x-y|$. All the three sub-models can be implemented by one-layer neural networks. Contributions and related work ============================== The following are the contributions of our work. (1) We propose a representational model for grid cells, where the self-position is represented by a vector and the self-motion is represented by a matrix that acts on the vector. (2) We show that our model can learn hexagon grid patterns. (3) We show our model is capable of path integral, path planning, and error correction. Many mathematical and computational models ([@burak2009accurate; @sreenivasan2011grid; @blair2007scale; @de2009input]) have been proposed to explain the formation and function of grid cells. Compared to previous computational models on grid cells, our model only makes very generic assumptions about the algebra and geometry of the representational scheme, without assuming Fourier plane waves or clock arithmetics. Recently, deep learning models ([@banino2018vector; @cueva2018emergence]) have been proposed to learn the grid-like units for navigation. Our work was inspired by them. Compared with these models, our model has explicit algebra and geometry. In terms of algebra, our model has explicit matrix representation of self-motion, and the change of self-position is modeled by vector-matrix multiplication. In terms of geometry, our model assumes that the vector rotates while the agent moves, and our model assumes magnified local isometry and global adjacency kernel based on the angles between the vectors. Expressing the adjacency kernel as the inner product between the vectors is related to the kernel trick ([@cortes1995support]), random Fourier basis ([@ng2002spectral]), and spectral clustering ([@ng2002spectral]). Representational model of grid cells ==================================== Consider an agent navigating within a domain $D = [0, 1] \times [0, 1]$ (actually the shape does not matter, and it can be $\R^2$). We can discretize $D$ into an $N \times N$ lattice. $N = 40$ in our experiments. Let $x = (x_1, x_2) \in D$ be the self-position of the agent. $x$ is 2D. Suppose the agent wants to represent its self-position by a $d$-dimensional hidden vector $v(x)$. We introduce the following three sub-models. Sub-model 1 about motion algebra: vector-matrix multiplication -------------------------------------------------------------- Suppose at a position $x$, the self-motion or one-step displacement is $\Delta x$, so that the agent moves to $x + \Delta x$ after one step. We assume that $$\begin{aligned} v(x+\Delta x) = M(\Delta x) v(x), \label{eq: motion}\end{aligned}$$ where $M(\Delta x)$ is a $d \times d$ matrix that depends on $\Delta x$. While $v(x)$ is the vector representation of the self-position $x$, $M(\Delta x)$ is the matrix representation of the self-motion $\Delta x$. We can illustrate the motion model by the following diagram: $$\begin{aligned} \begin{array}[c]{cccc} {\rm Motion:} & x_t & \stackrel{ + \Delta x}{\xrightarrow{\hspace*{1cm}}}& x_{t + 1} \\ & \downarrow& \downarrow &\downarrow\\ & v(x_t) &\stackrel{ M(\Delta x) \times }{\xrightarrow{\hspace*{1cm}}} & v(x_{t+1}) \end{array} \label{eq:diagram}\end{aligned}$$ See Figure \[fig:g2\](1). Both $v(x)$ and $M(\Delta x)$ are to be learned. We can discretize $\Delta x$, and learn a motion matrix $M$ for each $\Delta x$. We can also learn a parametric model for $M$. To this end, we can further parametrize $ M = I + \tilde{M}(\Delta x) $ such that each element of $\tilde{M}(\Delta x)$ is a quadratic (or polynomial) function of $\Delta x = (\Delta x_1, \Delta x_2)$: $$\begin{aligned} \tilde{M}_{ij}(\Delta x) = \beta_{ij}^{(1)} \Delta x_1 + \beta_{ij}^{(2)} \Delta x_2 + \beta_{ij}^{(11)} \Delta x_1^2 + \beta_{ij}^{(22)} \Delta x_2^2 + \beta_{ij}^{(12)} \Delta x_1 \Delta x_2, \label{eqn: param}\end{aligned}$$ where the coefficients $\beta$ are to be learned. The above may be considered a second-order Taylor expansion which is expected to be accurate for small $\Delta x \in \Delta$, where $\Delta$ is the allowed collection of one-step displacements, e.g., $\pm 3$ grid points in each direction on the $40 \times 40$ grid. The motion model can be considered a linear recurrent neural network (RNN). However, if we are to interpret $M$ as the weight matrix, then the weight matrix is dynamic because it depends on the motion $\Delta x$. One may implement it by discretizing $\Delta x$, so that we have a finite set of $\Delta x$, and thus a finite set of $M(\Delta x)$. Then at each time step, the RNN switches between the finite set of motion matrices. This is like the gearing operation of a multi-speed bicycle. Disentangled blocks or modules ------------------------------ For the sake of estimation accuracy and computational efficiency, we further assume that $M(\Delta x)$ is block diagonal, i.e., we can divide $v$ into $K$ blocks of sub-vectors, $v = (v^{(k)}, k = 1, ..., K)$, and $ v^{(k)}(x+\Delta x) = M^{(k)}(\Delta x) v^{(k)}(x). $ That is, the vector $v$ consists of sub-vectors, each of which rotates in its own subspace, so that the dynamics of the sub-vectors are disentangled. The assumption of disentangled blocks in our model is related to the modular organization of grid cells in neuroscience ([@stensola2012entorhinal]), where a module refers to a region of grid cells where all cells share similar grid scales and orientations. Sub-model 2 about local geometry: magnified local isometry ---------------------------------------------------------- The above motion algebra alone is not sufficient for learning the vector matrix representations, because a trivial solution is that all the $v(x)$ are the same, and the matrix $M(\Delta x)$ is always identity. We need to properly displace the vectors $v(x)$. So we shall model $\langle v(x), v(y)\rangle$ both locally and globally. Let $d$ be the dimensionality of $v^{(k)}$, i.e., the number of grid cells within the $k$-th block. For the local geometry, we assume that for each block, $$\begin{aligned} \langle v^{(k)}(x), v^{(k)}(x+\Delta x)\rangle = d(1 - \alpha_k |\Delta x|^2), \label{eq:isometry}\end{aligned}$$ for all $x$ and $\Delta x$ such that $\alpha_k |\Delta x|^2 \leq c$, i.e., $\Delta x \in \Delta({\alpha_k}) = \{\Delta x: \alpha_k |\Delta x|^2 \leq c\}$. In our experiments, we take $c = 1.5$. $\alpha_k$ can be either designed or learned. Based on sub-model (\[eq:isometry\]), $\|v^{(k)}(x)\|^2 = d$ for every $x$. The inner product on the left hand side is $d \cos(\Delta \theta)$ where $\Delta \theta$ is the angle between $v^{(k)}(x)$ and $v^{(k)}(x+\Delta x)$. $1 - \alpha_k |\Delta x|^2$ on the right hand side may be considered a second order Taylor expansion of a function $f(r)$ such that $f(0) = 1$, $f'(0) = 0$, i.e., $0$ is the maximum, and $f''(0) = -2 \alpha_k$. It is also an approximation to $\cos(\sqrt{2\alpha_k} |\Delta x|)$. Let $\omega_k = \sqrt{2\alpha_k}$, we have $$\begin{aligned} \mbox{Magnified local isometry}: \Delta \theta = \omega_k |\Delta x|,\end{aligned}$$ i.e., the angle between $v(x)$ and $v(x+\Delta x)$ magnifies the distance $|\Delta x|$ by a factor of $\omega_k$ uniformly for all $x$. See Figure \[fig:g2\](2). The factor $\omega_k$ defines the metric of block $k$. Rotation and projection ----------------------- Since $\|v^{(k)}(x)\|$ is a constant for all $x$, $M^{(k)}(\Delta x)$ is an orthogonal matrix, and the self-motion is represented by a rotation in the $d$-dimensional space. $\omega_k |\Delta x|$ is the angular speed of rotation of the sub-vector $k$. $(v^{(k)}(x), \forall x)$ forms a 2D sub-manifold on the sphere in the $d$-dimensional space. $v^{(k)}$ is like an arm of a clock except that the clock is not a 1D circle, but a 2D sub-manifold. This 2D sub-manifold becomes a local codebook for the 2D positions within a local neighborhood. For a vector $v^{(k)}$, we can decode its position by projecting it onto the 2D sub-manifold, to get $\hat{x} = \arg\max_x \langle v^{(k)}, v^{(k)}(x)\rangle$ where the maximization is within the local neighborhood. Error correction ---------------- The neurons are intrinsically noisy and error prone. For $\omega_k = \sqrt{2\alpha_k} \gg 1$, the magnification offers error correction because $v^{(k)}(x)$ and $v^{(k)}(x+\Delta x)$ are far apart, which is resistant to noises or corruptions. That is, projection to the 2D sub-manifold codebook removes the noises. Specifically, suppose we have a vector $u = v^{(k)}(x) + \epsilon$, where $\epsilon \sim {\rm N}(0, s^2 I_d)$, and $I_d$ is the $d$-dimensional identity matrix. We can decode $x$ from $u$ based on the codebook by maximizing $\langle u, v^{(k)}(y)\rangle = \langle v^{(k)}(x), v^{(k)}(y)\rangle + \langle \epsilon, v^{(k)}(y)\rangle = d(1 - \alpha_k |y-x|^2) + \sqrt{d} s Z$ over $y$ that is within a local neighborhood of $x$, where $Z \sim {\rm N}(0, 1)$. The optimal $y$ will be close to $x$ because if $y$ deviates from $x$ by $\Delta x$, then the first term will drop by $d \alpha_k |\Delta x|^2$, which cannot be made up by the second term $\sqrt{d} s Z$ due to noises, unless the noise level $s$ is extremely large. From the above analysis, we can also see that the larger $d$ is, the more resistant the system is to noise, because the first term is of order $d$ and the second term is of order $\sqrt{d}$. In addition to additive noises, the system is also resistant to multiplicative noises including dropout errors, i.e., multiplicative Bernoulli 0/1 errors. The dropout errors may occur due to noises, aging, or diseases. They may also be related to the asynchronous nature of the neuron activities in computing. Hexagon grid patterns {#sect: analytical} --------------------- While the magnified local isometry enables error correction, it also causes global periodicity. Because the angle between nearby $v^{(k)}(x)$ and $v^{(k)}(x+\Delta x)$ is magnified, when we vary $x$, the vector $v^{(k)}(x)$ will rotate at a magnified speed $\omega_k |\Delta x|$, so that it quickly rotates back to itself, like an arm of a clock. Thus each unit of $v^{(k)}(x)$ is periodic with $\omega_k$ determining the periodicity. Our experiments show that sub-models (1) and (2) are sufficient for the emergence of hexagon grid patterns. In fact, we have the following analytical solution (see Appendix for a proof): \[thm: 1\] Let $e(x) = (e^{i \langle a_j, x\rangle}, j = 1, 2, 3)^\top$, and $a_1$, $a_2$, $a_3$ are three 2D vectors so that the angle between $a_i$ and $a_j$ is $2\pi/3$ for $\forall i \neq j$ and $|a_j| = 2\sqrt{\alpha}$ for $\forall j$. Let $C$ be a random $3 \times 3$ complex matrix such that $C^*C = I$. Then $v(x) = C e(x)$, $M(\Delta x) = C {\rm diag}(e(\Delta x))C^*$ satisfy equation \[eq: motion\] and equation \[eq:isometry\] approximately for all $x$ and small $\Delta x$. $v(x)$ amounts to a $6$-dimensional real vector. Since the angle between $a_i$ and $a_j$ is $2\pi/3$ for $\forall i \neq j$, patterns of $v(x)$ over $x$ have hexagon periodicity. Moreover, the scale of the patterns is controlled by the length of $a_j$, i.e., the scaling parameter $\alpha$. We want to emphasize that sub-models (1) and (2) are about local $\Delta x$, where we do not make any assumptions about global patterns, such as Fourier basis. In contrast, the solution in the above theorem is global. That is, our model assumes much less than the solution in the theorem. Our experiments show that the hexagon patterns will emerge as long as the number of units is greater than or equal to 6. Sub-model 3 about global geometry: adjacency kernel {#sect: localization} --------------------------------------------------- Because of the periodicity, each block $(v^{(k)}(x), \forall x)$ does not form a global codebook of 2D positions, i.e., there can be $x \neq y$, but $v^{(k)}(x) = v^{(k)}(y)$, i.e., $v^{(k)}$ does not encode $x$ uniquely. We can combine multiple blocks to resolve the global ambiguity. Specifically, let $v(x) = (v^{(k)}(x), k = 1, ..., K)$ be the whole vector, we assume the following global adjacency sub-model for the whole vector: $$\begin{aligned} \langle v(x), v(y)\rangle = \sum_{k=1}^{K} \langle v^{(k)}(x), v^{(k)}(y)\rangle = (K d) f(|x-y|), \label{eqn: localization}\end{aligned}$$ where $(v(x), M(\Delta x), \alpha_k, \forall x, \Delta x, k)$ are to be learned. Recall $d$ is the number of grid cells in each block, and $K$ is the number of blocks. $f(r)$ is the adjacency kernel that decreases monotonically as the Euclidean distance $r = |x-y|$ increases. One example of $f$ is the Gaussian kernel ${ f(r) = \exp\left(- {r^2}/{2\sigma^2}\right). }$ Another example is the exponential kernel ${ f(r) = \exp\left(- {r}/{\sigma}\right). }$ As a matter of normalization, we assume $f(0) = 1$, which is the maximum of $f(r)$. Since ${f(0) = 1}$, $\|v(x)\|^2 = Kd$ for any $x$, and $\langle v(x), v(y)\rangle = (Kd) \cos \theta$, where $\theta$ is the angle between $v(x)$ and $v(y)$, and we have $$\begin{aligned} \mbox{Global adjacency}: \cos \theta = f(|x-y|).\end{aligned}$$ The angle between any two vectors is always less than $\pi/2$. See Figure \[fig:g2\](3). By fitting the multiple sub-vectors together, we still retain the error correction capacity due to magnified local isometry, meanwhile we eliminate the ambiguity by letting $\langle v^{(k)}(x), v^{(k)}(y)\rangle$ for different $k$ cancel each other out by destructive interference as $y$ moves away from $x$, so that we obtain unique decoding of positions. Let $C = \{v(x), x \in D\}$ be the codebook sub-manifold, error correction of a vector $u$ is obtained by projection onto $C$: $\arg\max_{v \in C} \langle u, v\rangle$. The whole vector $v$ is like a $K$-arm clock, with each $v^{(k)}$ being an arm rotating at a speed $\omega_k |\Delta x| = \sqrt{2\alpha_k} |\Delta x|$. Localization and heat map ------------------------- $(v(x), \forall x)$ forms a global codebook for $x$. It is a 2D sub-manifold on the sphere in the $(Kd)$-dimensional space. For a vector $v$, we can decode its position by its projection on the codebook manifold. Since $f(r)$ is monotonically decreasing, ${h(x) = \langle v, v(x)\rangle}$ gives us the heat map to decode the position of $v$ uniquely. Let the decoded position be $\hat{x}$, then ${ \hat{x} = \arg \max_x \langle v, v(x)\rangle. }$ We can obtain the one-hot representation $\delta_{\hat{x}}$ of $\hat{x}$ by non-maximum suppression on the heat map $h(x)$. Let $V = (v(x), \forall x)$ be the $(Kd) \times N^2$ matrix (recall the domain $D = [0, 1]^2$ is discretized into an $N \times N$ lattice), where each column is a $v(x)$. We can write the heat map $h(x) = \langle v, v(x)\rangle$ as a $N^2$-dimensional vector $h = V^\top v$, which serves to decode the position $x$ encoded by $v$. Conversely, for a one-hot representation of a position $x$, i.e., $\delta_x$, which is a one-hot $N^2$-dimensional vector, we can encode it by $v = V \delta_x$. Both the encoder and decoder can be implemented by a linear neural network with connection weights $V$ and $V^\top$ respectively, as illustrated by the following diagram: $$\begin{aligned} \begin{array}[c]{ccccc} {\rm Localization:} & v &\stackrel{ V^\top \times }{\xrightarrow{\hspace*{1cm}}} & h & (\mbox{heat map and decoding to $\delta_x$})\\ & \delta_x &\stackrel{ V \times }{\xrightarrow{\hspace*{1cm}}} & v(x) & (\mbox{encoding}) \end{array} \label{eq:diagram}\end{aligned}$$ Note that in decoding $v \rightarrow h(x) \rightarrow \delta_x$ and encoding $\delta_x \rightarrow v$, we do not represent or operate on the 2D coordinate $x$ explicitly, i.e., $x$ itself is never explicitly represented, although we may use the notation $x$ in the description of the experiments. Path integral ------------- Path integral (also referred to as dead-reckoning) is the task of inferring the self-position based on self-motion (e.g., imagine walking in a dark room). Specifically, the input to path integral is a previously determined initial position $x_0$ and motion sequences $\{\Delta x_1, ..., \Delta x_T\}$, and the output is the prediction of one’s current position $x_T$. We first encode the initial position $x_0$ as $v(x_0)$. Then, by the motion model, the hidden vector $v(x_T)$ at time $T$ can be predicted as: $$\begin{aligned} v(x_T) = \prod\nolimits_{t=T}^{1} M(\Delta x_t) v(x_0). \end{aligned}$$ We can then decode $x_T$ from $v(x_T)$. Path planning ------------- Our representation system can plan direct path from the starting position $x_0$ to the target position $y$ by steepest ascent on the inner product $\langle v(x), v(y)\rangle$, i.e., let $v_0 = v(x_0)$, the algorithm iterates $$\begin{aligned} && \Delta x_t = \arg \max_{\Delta x \in \Delta}\langle v(y), M(\Delta x) v_{t-1}\rangle, \\ && v_t = M(\Delta x_t) v_{t-1}, \end{aligned}$$ where $\Delta$ is the set of allowable displacements $\Delta x$. When a rat does path planning, even if it is not moving, its grid cells are expected to be active. This may be explained by the above algorithm. In path planning, the rat can also fantasize bigger step sizes that are beyond its physical capacity, by letting $\Delta$ include physically impossible large steps. In general, our representation scheme $(v(x), M(\Delta x), f(|x-y|))$ mirrors $(x, \Delta x, |x-y|)$. Thus the learned representation is capable of implementing existing path planning algorithms in robotics ([@siegwart2011introduction]) even though our system does not have explicit coordinates in 2D (i.e., the 2D coordinates $x$ are never explicitly represented by two neurons). Place cells and scale --------------------- For each $x$, we may interpret $\langle v(x), v(y)\rangle /(Kd) = f(|x-y|)$ as a place cell whose response is $f(|x-y|)$ if the agent is at $y$, or at least, we may consider $f(|x-y|)$ as an internal input to the place cell based on self-motion, in addition to external visual cues. For the Gaussian kernel $f(r) = \exp(-r^2/2\sigma^2)$, the choice of $\sigma$ determines the scale. In path integral, for accurate decoding of the position $x$ from the vector $v$ in the presence of noises, we want $\sigma$ to be small so that $f(r)$ drops to zero quickly. However, in path planning, for a vector $v$, we also want to know the Euclidean distance between its position $x$ to a target position $y$, which may be far away from $x$. The distance is $|x-y| = f^{-1}(\langle v, v(y)\rangle/(Kd))$. For accurate estimation of long distance in the presence of noises, we need $\sigma$ to be large, so that the slope of $f^{-1}$ is not too big. Perhaps we need multiple $f(r)$ with different $\sigma$, and for each $f(r)$ we have $(Kd) f(r) = \sum_{k=1}^{K} \gamma_k \langle v^{(k)}(x), v^{(k)}(y)\rangle$, where different $f(r)$ have different coefficients $(\gamma_k)$ while sharing the same $(v^{(k)}(x))$. We shall study this issue in future work. Group representation in motor cortex ------------------------------------ Where does the self-motion $\Delta x$ come from? It comes from the movements of head and legs, i.e., each step of navigation involves a whole process of path integral and path planning of the movements of head and legs (as well as arms). In general, we can use the same system we have developed for the movements of head, legs, arms, fingers, etc. Their movements form groups of actions. In navigation, the movements belong to 2D Euclidean group. In body movements, the movements belong to various Lie groups. Our method can be used to learn the representational systems of these groups, and such representations may exist in motor cortex. We leave this problem to future investigation. Learning representation ======================= The square domain $D$ is discretized into a $40 \times 40$ lattice, and the agent is only allowed to move on the lattice. We can learn $(v(x), \forall x)$ and $(M(\Delta x), \forall \Delta x)$ (or the $\beta$ coefficients that parametrize $M$) by minimizing the following loss functions. For sub-model (1) on vector-matrix multiplication, the loss function is $$\begin{aligned} L_1 = \E_{x, \Delta x} \left[ \|v(x+\Delta x) - {M}(\Delta x) v(x)\|^2\right], \end{aligned}$$ where $x$ is sampled from the uniform distribution on $D = [0, 1]^2$, and $\Delta x$ is sampled from the uniform distribution within a certain range $\Delta_1$ (3 grid points in each direction in our experiments). The above motion loss is a single-step loss. It can be generalized to multi-step loss $$\begin{aligned} L_{1, T} = \E_{x, \Delta x_{1}, ...\Delta x_{T}} \left[ \|v(x+\Delta x_1 + ... + \Delta x_T) - M(\Delta x_T) ... {M}(\Delta x_1) v(x)\|^2\right], \label{eqn: multi-step} \end{aligned}$$ where $(\Delta x_t, t = 1, ..., T)$ is a sequence of $T$ steps of displacements, i.e., a simulated trajectory. For sub-model (2) on magnified local isometry, the loss function is $$\begin{aligned} L_{2, k} = \E_{x, \Delta x} \left[(\langle v^{(k)}(x), v^{(k)}(x+\Delta x)\rangle - (d(1- \alpha_k |\Delta x |^2))^2\right], \end{aligned}$$ where for fixed $\alpha_k$, $\Delta x$ is sampled uniformly within the range $\Delta_{2}(\alpha_k)= \{\Delta x: \alpha_k |\Delta x|^2 \leq c\}$ ($c = 1.5$ in our experiments). We can define $L_2 = \sum_{k=1}^{K} L_{2, k}$. For sub-model (3) on global adjacency kernel, the loss function is $$\begin{aligned} L_3 = \E_{x, y} \left[((Kd) f(|x-y|) - \langle v(x), v(y)\rangle)^2\right], \end{aligned}$$ where both $x$ and $y$ are sampled uniformly from $D$. Let $v(x) = (v_i(x), i = 1, ..., Kd)$, we also impose a regularization loss $ L_0 = \sum_{i=1}^{Kd} (\E_x[v_i(x)^2] - 1)^2, $ to enforce uniform energy among the grid cell. It also helps to break the symmetry caused by the fact that the loss function is invariant under the transformation $v(x) \rightarrow Q v(x), \forall x$, where $Q$ is an arbitrary orthogonal matrix. This loss is not crucial though, so we will make it implicit for the rest of the paper. Fixing the magnitude of $\E_x[v_i(x)]$ within a certain range is biologically plausible, because $v_i(x)$ is a single cell. For mathematical and computational convenience, we can also normalize $v(x)$ so that $\|v(x)\|^2 = 1$, $\langle v(x), v(y)\rangle = f(|x-y|)$, $\langle v^{(k)}(x), v^{(k)}(x+\Delta x)\rangle = (1-\alpha_k |\Delta x|^2)/K$, and $\E_x[v_i(x)^2] = 1/(Kd)$. When learning a single block, we can normalize $v^{(k)}(x)$ so that $\|v^{(k)}(x)\|^2 = 1$, $\langle v^{(k)}(x), v^{(k)}(x+\Delta x)\rangle = 1-\alpha_k |\Delta x|^2$ and $\E_x[v_i(x)^2] = 1/d$. The total loss function is a linear combination of the above losses, where the weights for combining the losses are chosen so that the weighted losses are of the same order of magnitude. The loss function is minimized by Adam optimizer ([@kingma2014adam]) (lr $= 0.03$) for $6,000$ iterations. A batch of $30,000$ examples, i.e., $(x, \Delta x_t, t = 1, ..., T))$ for $L_1$, $(x, \Delta x)$ for $L_2$, and $(x, y)$ for $L_3$ are sampled at each learning iteration as the input to the loss function. In the later stage of learning ($\geq 4,000$ iterations), $\|v(x)\| = 1$ is enforced by projected gradient descent, i.e., normalizing each $v(x)$ after the gradient descent step. Experiments =========== Learning single blocks: hexagon patterns and metrics {#sect: single} ---------------------------------------------------- [C[.15]{}C[.75]{}]{} [$\alpha = 18$]{} & ![Learned units of a single block with fixed $\alpha$. (a) Learned single block with $6$ units. Every row shows the learned units with a given $\alpha$. (b) Learned single block with $100$ units and $\alpha = 72$.[]{data-label="fig: single units"}](./FIG/units_single_block/alpha18 "fig:"){width=".75\textwidth"}\ [$\alpha = 36$]{} & ![Learned units of a single block with fixed $\alpha$. (a) Learned single block with $6$ units. Every row shows the learned units with a given $\alpha$. (b) Learned single block with $100$ units and $\alpha = 72$.[]{data-label="fig: single units"}](./FIG/units_single_block/alpha36 "fig:"){width=".75\textwidth"}\ [$\alpha = 72$]{} & ![Learned units of a single block with fixed $\alpha$. (a) Learned single block with $6$ units. Every row shows the learned units with a given $\alpha$. (b) Learned single block with $100$ units and $\alpha = 72$.[]{data-label="fig: single units"}](./FIG/units_single_block/alpha72 "fig:"){width=".75\textwidth"}\ [$\alpha = 108$]{} & ![Learned units of a single block with fixed $\alpha$. (a) Learned single block with $6$ units. Every row shows the learned units with a given $\alpha$. (b) Learned single block with $100$ units and $\alpha = 72$.[]{data-label="fig: single units"}](./FIG/units_single_block/alpha108 "fig:"){width=".75\textwidth"}\ [$\alpha = 144$]{} & ![Learned units of a single block with fixed $\alpha$. (a) Learned single block with $6$ units. Every row shows the learned units with a given $\alpha$. (b) Learned single block with $100$ units and $\alpha = 72$.[]{data-label="fig: single units"}](./FIG/units_single_block/alpha144 "fig:"){width=".75\textwidth"}\ [$\alpha = 180$]{} & ![Learned units of a single block with fixed $\alpha$. (a) Learned single block with $6$ units. Every row shows the learned units with a given $\alpha$. (b) Learned single block with $100$ units and $\alpha = 72$.[]{data-label="fig: single units"}](./FIG/units_single_block/alpha180 "fig:"){width=".75\textwidth"} [(a) Learned single block with $6$ units]{} ![Learned units of a single block with fixed $\alpha$. (a) Learned single block with $6$ units. Every row shows the learned units with a given $\alpha$. (b) Learned single block with $100$ units and $\alpha = 72$.[]{data-label="fig: single units"}](./FIG/units_single_block/blocksize100.png "fig:"){width="\textwidth"} [(b) Learned single block with $100$ units]{} We first learn a single block with fixed $\alpha_k$ by minimizing $L_1 + \lambda_2 L_{2, k}$ (we shall drop the subscript $k$ in this subsection for simplicity). Figure \[fig: single units\] shows the learned units over the $40 \times 40$ lattice of $x$. Figure \[fig: single units\](a) shows the learned results with $6$ units and different values of $\alpha$. The scale or metric of the lattice is controlled by $\alpha$. The units within a block have patterns with similar scale and arrangement, yet different phases. Figure \[fig: single units\](b) shows the learned results with $100$ units and $\alpha=72$, indicating that the grid-like patterns are stable and easy to learn even when the number of units is large. Learning multiple hexagon blocks and metrics -------------------------------------------- [C[.06]{}|C[.375]{}|C[.06]{}|C[.375]{}]{} [$\alpha_k$]{} & [Learned blocks]{} & [$\alpha_k$]{} & [Learned blocks]{}\ & & [$44.1$]{} &\ [$4.7$]{}&&[$56.3$]{}&\ [$11.9$]{}&&[$57.0$]{}&\ [$17.0$]{}&&[$61.7$]{}&\ [$17.3$]{}&&[$73.0$]{}&\ [$35.7$]{}&&[$85.7$]{}&\ [$39.1$]{}&&[$87.5$]{}&\ [$39.7$]{}&&[$94.7$]{}&\ \ ![(a) Response maps of learned units of the vector representation and learned scaling parameters $\alpha_k$. Block size equals 6 and each row shows the units belonging to the same block. (b) Illustration of block-wise activities of the units (where the activities are rectified to be positive).[]{data-label="fig: units"}](./FIG/units_multiple_blocks/group_illustration.png "fig:"){width="\textwidth"}\ [(b) Disentangled blocks]{} We learn multiple blocks by minimizing $L_1 + \lambda_2 L_2 + \lambda_3 L_3$. Instead of manually assigning $\alpha_k$, we learn $\alpha_k$ by gradient descent, simultaneously with $v$ and $M$. In Figure \[fig: units\](a), we show the learned units $v(x)$ over the $40 \times 40$ lattice of $x$ and the learned metrics $\alpha_k$. A Gaussian kernel with $\sigma = 0.08$ is used for the global adjacency measure $f(|x-y|)$. Block size is set to $6$ and each row shows the learned units belonging to the same block. The scales of the firing fields are controlled by the learned $\alpha_k$. Figure \[fig: units\](b) illustrates the combination of multiple blocks. For the localization model, given a vector $v$, the heat map of a single block $\langle v^{(k)}, v^{(k)}(x)\rangle$ has periodic firing fields and cannot determine a location uniquely. However, ambiguity disappears by combing the heat maps of multiple blocks, which have firing fields of multiple scales and phases that add up to a Gaussian kernel $\langle v, v(x)\rangle$. The Gaussian kernel informs the place cell, by which the location is determined uniquely. For a motion $\Delta x$, every block rotates in its own subspace with motion matrix $M^{(k)}(\Delta x)$, resulting in phase shifting in the heat map of each single block. In the subsequent experiments, we shall learn the grid cells by minimizing $L_1 + \lambda_3 L_3$ for simplicity. Path integral ------------- ![(a) Path integral prediction. The black line depicts the real path while red dotted line is the predicted path by the learned model. (b) Mean square error over time step. The error is average over $1,000$ episodes. The curves correspond to different numbers of steps used in the multi-step motion loss. (c) Mean square error performed by models with different block sizes and different kernel types. Error is measured by number of grids. []{data-label="fig: integral"}](./FIG/path_integral/path.png "fig:"){width="\textwidth"}\ [(a) Predicted path]{} ![(a) Path integral prediction. The black line depicts the real path while red dotted line is the predicted path by the learned model. (b) Mean square error over time step. The error is average over $1,000$ episodes. The curves correspond to different numbers of steps used in the multi-step motion loss. (c) Mean square error performed by models with different block sizes and different kernel types. Error is measured by number of grids. []{data-label="fig: integral"}](./FIG/path_integral/path_integral_err.png "fig:"){width="\textwidth"}\ [(b) MSE over time step]{} ![(a) Path integral prediction. The black line depicts the real path while red dotted line is the predicted path by the learned model. (b) Mean square error over time step. The error is average over $1,000$ episodes. The curves correspond to different numbers of steps used in the multi-step motion loss. (c) Mean square error performed by models with different block sizes and different kernel types. Error is measured by number of grids. []{data-label="fig: integral"}](./FIG/path_integral/path_integral_bk.png "fig:"){width="\textwidth"}\ [(c) Selection of block sizes and kernels]{} Figure \[fig: integral\](a) shows an example of path integral result (time duration $\tilde{T} = 40$), where we use single step motion loss $L_{1, T=1}$ in learning. Gaussian kernel with $\sigma = 0.08$ is used as the adjacency measure in $L_3$. We find single-step loss is sufficient for performing path integral. The mean square error remains small ($\sim1.2$ grid) even after $400$ steps of motions (figure \[fig: integral\](b)). The error is averaged over $1,000$ episodes. The motion loss can be generalized to multi-step $L_{1, T}$, as shown by equation \[eqn: multi-step\]. In Figure \[fig: integral\](b), we show that multi-step loss can improve the performance slightly. In Figure \[fig: integral\](c) we compare the learned models with fixed number of units (96) but different block sizes. We also compare the performance of models using Gaussian kernel ($\sigma=0.08$) and exponential kernel ($\sigma=0.3$) as the adjacency measure in the localization model. The result shows that models with Gaussian kernel and block size $\geq 3$, and with exponential kernel and block size $\geq 4$ have performances comparable to the model learned without block-diagonal assumption (block size $=96$). Path planning {#sect:pp} ------------- For path planning, we assume continuous $x$ and $\Delta x$. First, we design the set of allowable motions $\Delta$. For a small length $r$, we evenly divide $[0, 2\pi]$ into $n$ directions $\{\theta_i, i=1,...,n\}$, resulting in $n$ candidate motions $\Delta = \{\Delta x_i = (r \cos(\theta_i), r\sin(\theta_i)), i=1,...,n\}$. These $n$ small motions serve as motion basis. Larger motion can be further added to $\Delta$ by estimating the motion matrix $M(k \Delta x_i) = M^k(\Delta x_i)$. The starting position and destination can also be any continuous values, where the encoding to the latent vector is approximated by bilinear interpolation of nearest neighbors on the lattice. In the experiments, we choose $r=0.05$ and $n=100$, and add another set of motions with length $0.025$ to enable accurate planning. The system is learned with exponential kernel ($\sigma = 0.3$) as global adjacency to encourage connection of long distance. Figure \[fig: planning\](a) shows planning examples with six settings of motion ranges $\Delta$. Including larger motions accelerates the planning process so that it finishes with less steps. We define one episode to be a success if the distance between the end position and the destination is less than 0.025. We achieve a success rate of $>99\%$ over $1,000$ episodes for all the six settings. ![(a) Planning examples with different motion ranges. Red star represents the destination $y$ and green dots represent the planned position $\{x_0 + \sum_{i=1}^t \Delta x_i\}$. (b) Planning examples with a dot obstacle. Left figure shows the effect of changing scaling parameter $a$, while right figure shows the effect of changing annealing parameter $b$. (c) Planning examples with obstacles mimicking walls, large objects and simple mazes.[]{data-label="fig: planning"}](./FIG/path_planning/plain/path_multiple_speed_crop.png "fig:"){width="\textwidth"}\ [(a) Simple planning]{} ![(a) Planning examples with different motion ranges. Red star represents the destination $y$ and green dots represent the planned position $\{x_0 + \sum_{i=1}^t \Delta x_i\}$. (b) Planning examples with a dot obstacle. Left figure shows the effect of changing scaling parameter $a$, while right figure shows the effect of changing annealing parameter $b$. (c) Planning examples with obstacles mimicking walls, large objects and simple mazes.[]{data-label="fig: planning"}](./FIG/path_planning/obstacle/change_a_crop.png "fig:"){width=".48\textwidth"} ![(a) Planning examples with different motion ranges. Red star represents the destination $y$ and green dots represent the planned position $\{x_0 + \sum_{i=1}^t \Delta x_i\}$. (b) Planning examples with a dot obstacle. Left figure shows the effect of changing scaling parameter $a$, while right figure shows the effect of changing annealing parameter $b$. (c) Planning examples with obstacles mimicking walls, large objects and simple mazes.[]{data-label="fig: planning"}](./FIG/path_planning/obstacle/change_b_crop.png "fig:"){width=".48\textwidth"}\ [(b) Planning with dot obstacle]{} ![(a) Planning examples with different motion ranges. Red star represents the destination $y$ and green dots represent the planned position $\{x_0 + \sum_{i=1}^t \Delta x_i\}$. (b) Planning examples with a dot obstacle. Left figure shows the effect of changing scaling parameter $a$, while right figure shows the effect of changing annealing parameter $b$. (c) Planning examples with obstacles mimicking walls, large objects and simple mazes.[]{data-label="fig: planning"}](./FIG/path_planning/obstacle/line2_crop.png "fig:"){width=".465\textwidth"} ![(a) Planning examples with different motion ranges. Red star represents the destination $y$ and green dots represent the planned position $\{x_0 + \sum_{i=1}^t \Delta x_i\}$. (b) Planning examples with a dot obstacle. Left figure shows the effect of changing scaling parameter $a$, while right figure shows the effect of changing annealing parameter $b$. (c) Planning examples with obstacles mimicking walls, large objects and simple mazes.[]{data-label="fig: planning"}](./FIG/path_planning/obstacle/rectangular1_crop.png "fig:"){width=".465\textwidth"}\ ![(a) Planning examples with different motion ranges. Red star represents the destination $y$ and green dots represent the planned position $\{x_0 + \sum_{i=1}^t \Delta x_i\}$. (b) Planning examples with a dot obstacle. Left figure shows the effect of changing scaling parameter $a$, while right figure shows the effect of changing annealing parameter $b$. (c) Planning examples with obstacles mimicking walls, large objects and simple mazes.[]{data-label="fig: planning"}](./FIG/path_planning/obstacle/maze3_crop.png "fig:"){width=".465\textwidth"} ![(a) Planning examples with different motion ranges. Red star represents the destination $y$ and green dots represent the planned position $\{x_0 + \sum_{i=1}^t \Delta x_i\}$. (b) Planning examples with a dot obstacle. Left figure shows the effect of changing scaling parameter $a$, while right figure shows the effect of changing annealing parameter $b$. (c) Planning examples with obstacles mimicking walls, large objects and simple mazes.[]{data-label="fig: planning"}](./FIG/path_planning/obstacle/maze7.png "fig:"){width=".465\textwidth"}\ [(c) Various obstacles]{} The learned system can also perform planning with obstacles, where the global adjacency between the agent’s current position and an obstacle serves as a repulsive forces. Specifically, suppose $z$ is an obstacle to avoid, the agent can choose the motion $\Delta x_t$ at time $t$ by $$\begin{aligned} \label{eqn: planning_obs} \Delta x_t = \arg \max_{\Delta x \in \Delta} \left[\langle v(y), M(\Delta x) v_t\rangle - a\langle v(z), M(\Delta x)v_t\rangle^b\right], \end{aligned}$$ where $a$ and $b$ are the scaling and annealing parameters. Figure \[fig: planning\](b) shows the planning result with a dot obstacle laid on the direct path between the starting position and destination, with tuning of $a$ and $b$. We choose $a = 0.5$ and $b = 6$ in subsequent experiments. Now suppose we have more complicated obstacles $\{z_i\}_{i=1}^m$. They can be included by summing over the kernels of every obstacle $\{a\langle v(z_i), M(\Delta x) v_t\rangle^b\}_{i=1}^m$ and choosing $\Delta x_t$ at time $t$ by $\Delta x_t = \arg \max_{\Delta x \in \Delta} \left[\langle v(y), M(\Delta x) v_t\rangle - \sum\nolimits_{i=1}^m a\langle v(z_i), M(\Delta x) v_t\rangle^b\right]$. Figure \[fig: planning\](c) shows some examples, where the obstacles mimicking walls, large objects and simple mazes. The above method is related to the potential field method in robotics ([@siegwart2011introduction]). Discussion: rotationist-connectionist model? ============================================ In terms of general modeling methodology, a typical recurrent network is of the form $v_t = \tanh(W(v_{t-1}, \delta_t))$, where $v_t$ is the latent vector, $\delta_t$ is the input change or action. $v_{t-1}$ and $\delta_t$ are concatenated and linearly mixed by $W$, followed by coordinate-wise tanh non-linearity. We replace it by a model of the form $v_t = M(\delta_t) v_{t-1}$, where $M(\delta_t)$ is a matrix that is non-linear in $\delta_t$. $M(\delta_t)$ is a matrix representation of $\delta_t$. $v_t$ can be interpreted as neuron activities. We can discretize the value of $\delta_t$ into a finite set $\{\delta\}$, and each $M(\delta)$ can be stored as synaptic connection weights that drive the neuron activities. In prediction, the input $\delta_t$ activates $M(\delta_t)$. In planning or control, all the $\{M(\delta)\}$ are activated, and among them the optimal $\delta$ is chosen. The matrix representation of the above model is inspired by the group representation theory, where the group elements are represented by matrices acting on the vectors ([@fulton2013representation]). It underlies much of modern mathematics and holds the key to the quantum theory ([@zee2016group]). Perhaps it also underlies the visual and motor cortex, where neurons form rotating sub-vectors driven by matrices representing groups of transformations. One may call it a rotationist-connectionist model. Project page {#project-page .unnumbered} ============ [<http://www.stat.ucla.edu/~ruiqigao/gridcell/main.html>]{} Acknowledgement {#acknowledgement .unnumbered} =============== We thank the three reviewers for their insightful comments and suggestions. Part of the work was done while Ruiqi Gao was an intern at Hikvision Research Institute during the summer of 2018. She thanks Director Jane Chen for her help and guidance. We also thank Jiayu Wu for her help with experiments and Zilong Zheng for his help with visualization. The work is supported by DARPA XAI project N66001-17-2-4029; ARO project W911NF1810296; ONR MURI project N00014-16-1-2007; and a Hikvision gift to UCLA. We gratefully acknowledge the support of NVIDIA Corporation with the donation of the Titan Xp GPU used for this research. Proof for section \[sect: analytical\] {#sect: app1.1} ====================================== $(a_j, j = 1, 2, 3)$ forms a tight frame in the 2D space, in that for any vector $x$ in 2D, $\sum_{j=1}^{3} \langle x, a_j\rangle^2 \propto |x|^2$. Since $C^*C = I$, we have $$\begin{aligned} \langle v(x), v(y)\rangle &=& v(x)^* v(y) \\ &=& e(x)^* C^* C e(y) \\ &=&\sum_{j=1}^{3} e^{i \langle a_j, y-x\rangle}. \end{aligned}$$ Then we have $$\begin{aligned} {\rm RE}(\langle v(x), v(x+\Delta x)\rangle) &=& \sum_{j=1}^{3} \cos(\langle a_j, \Delta x\rangle) \\ &\approx& \sum_{j=1}^{3} (1 - \langle a_j, \Delta x \rangle^2/2)\\ &=& 3 - \sum_{j=1}^{3} \langle a_j, \Delta x \rangle^2/2\\ &=& 3(1 - \alpha|\Delta x|^2), \end{aligned}$$ where $ |a_j| = 2\sqrt{\alpha}$. The self motion from $v(x)$ to $v(x+\Delta x)$ is $$\begin{aligned} v(x+\Delta x) &=& C e(x+\Delta x) \\ &=& C D(\Delta x) e(x) \\ &=& C D(\Delta x) C^{*} v(x) \\ &=& M(\Delta x) v(x), \end{aligned}$$ where $D(\Delta x) = {\rm diag}(e^{ i \langle a_j, \Delta x\rangle}, j = 1, 2, 3)$. If $K > 1$ and block size $=6$, we can fit the multiple blocks together by a Fourier expansion of the kernel function $$\begin{aligned} f(|x-y|) &=& \langle v(x), v(y) \rangle \\ &\approx& \sum_{k=1}^{K} \sum_{j=1}^{3} e^{i \langle a_{kj}, y-x\rangle}\\ &=& \sum_{k=1}^{K} \langle v^{(k)}(x), v^{(k)}(y)\rangle. \end{aligned}$$ Hexagon grid patterns and metrics ================================= Simulated input data -------------------- We obtain input data for learning the model by simulating agent trajectories with the number of steps equal to $\tilde{T}$ in the square domain $D$. $D$ is discretized into a $40 \times 40$ lattice and the agent is only allowed to move on the lattice. The agent starts at a random location $x_0$. At each time step $t$, a small motion $\Delta x_t$ ($\leq 3$ grids in each direction) is randomly sampled with the restriction of not leading the agent outside the boundary, resulting in a simulated trajectory $\{x_0 + \sum_{i=1}^t \Delta x_i\}_{t=1}^{\tilde{T}}$. $\tilde{T}$ is set to $1,000$ to obtain trajectories that are uniformly distributed over the whole area. Although the trajectories used for training are restricted to the lattice and with small motions, in Section \[sect:pp\] we show that the learned model can be easily generalized to handle continuous positions and large motions. In training, pairs of locations $(x, y)$ are randomly sampled from each trajectory as the input to the adjacency loss $L_3$, while consecutive position sequences $(x, \Delta x_t, t = 1, ..., T)$ are randomly sampled as the input to the motion loss $L_1$, with length specified by $T$ (which is usually much smaller than the whole length of the trajectory $\tilde{T}$). Learned single block units with different block sizes {#app: 2Dunits} ----------------------------------------------------- In ([@blair2007scale]), the grid cell response is modeled by three cosine gratings with different orientations and phases. In our model, we learn such patterns of different scales without inserting artificial assumptions. ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize2.png "fig:"){width=".2\textwidth"}\ [(a) Block size = 2]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize3.png "fig:"){width=".3\textwidth"}\ [(b) Block size = 3]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize4.png "fig:"){width=".4\textwidth"}\ [(c) Block size = 4]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize5.png "fig:"){width=".5\textwidth"}\ [(d) Block size = 5]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize7.png "fig:"){width=".7\textwidth"}\ [(e) Block size = 7]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize8.png "fig:"){width=".8\textwidth"}\ [(f) Block size = 8]{} ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize9.png "fig:"){width=".9\textwidth"}\ [(g) Block size = 9]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize10.png "fig:"){width="\textwidth"}\ [(h) Block size = 10]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize20.png "fig:"){width="\textwidth"}\ [(i) Block size = 20]{}\ ![Response maps of learned single block units with different block sizes[]{data-label="fig: app_units_single"}](./FIG/units_single_block/blocksize40.png "fig:"){width="\textwidth"}\ [(j) Block size = 40]{}\ Figure \[fig: app\_units\_single\] displays the response maps of the learned single block units with different block sizes. For block sizes 4 and 5, the learned maps show square lattice patterns. For block sizes greater than or equal to 6, the learned maps show hexagon lattice patterns. Learned multiple block units and metrics {#app: 2Dunits_multiple} ---------------------------------------- ### With different block sizes [C[20pt]{}|C[37pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$7.7$]{}&\ [$10.4$]{}&\ [$10.7$]{}&\ [$11.6$]{}&\ [$12.7$]{}&\ [$18.0$]{}&\ [$31.2$]{}&\ [$31.2$]{}&\ [$37.8$]{}&\ [$56.0$]{}&\ [$68.0$]{}&\ [$73.5$]{}&\ [$74.3$]{}&\ [$86.5$]{}&\ [$92.5$]{}&\ \ [C[20pt]{}|C[54pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$6.7$]{}&\ [$10.6$]{}&\ [$11.0$]{}&\ [$13.9$]{}&\ [$23.4$]{}&\ [$31.3$]{}&\ [$38.9$]{}&\ [$39.3$]{}&\ [$56.7$]{}&\ [$64.5$]{}&\ [$72.3$]{}&\ [$75.4$]{}&\ [$80.5$]{}&\ [$84.4$]{}&\ [$93.0$]{}&\ \ [C[20pt]{}|C[70.5pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$6.9$]{}&\ [$12.3$]{}&\ [$18.7$]{}&\ [$19.5$]{}&\ [$25.7$]{}&\ [$28.9$]{}&\ [$39.7$]{}&\ [$41.9$]{}&\ [$52.3$]{}&\ [$55.1$]{}&\ [$61.1$]{}&\ [$66.3$]{}&\ [$67.7$]{}&\ [$70.6$]{}&\ [$88.3$]{}&\ \ [C[20pt]{}|C[88pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$9.1$]{}&\ [$12.4$]{}&\ [$18.5$]{}&\ [$28.6$]{}&\ [$32.8$]{}&\ [$41.9$]{}&\ [$48.6$]{}&\ [$49.9$]{}&\ [$58.0$]{}&\ [$64.5$]{}&\ [$73.0$]{}&\ [$74.9$]{}&\ [$77.8$]{}&\ [$81.7$]{}&\ [$97.1$]{}&\ \ [C[20pt]{}|C[121pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$6.8$]{}&\ [$10.3$]{}&\ [$11.7$]{}&\ [$14.6$]{}&\ [$21.1$]{}&\ [$21.9$]{}&\ [$24.1$]{}&\ [$25.8$]{}&\ [$45.1$]{}&\ [$56.4$]{}&\ [$65.3$]{}&\ [$66.1$]{}&\ [$67.7$]{}&\ [$72.6$]{}&\ [$93.2$]{}&\ \ [C[20pt]{}|C[137.5pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$7.2$]{}&\ [$8.5$]{}&\ [$14.5$]{}&\ [$18.5$]{}&\ [$19.5$]{}&\ [$28.1$]{}&\ [$46.9$]{}&\ [$47.8$]{}&\ [$56.2$]{}&\ [$60.4$]{}&\ [$62.3$]{}&\ [$77.3$]{}&\ [$84.9$]{}&\ [$86.3$]{}&\ [$95.4$]{}&\ \ [C[20pt]{}|C[132pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$6.4$]{}&\ [$6.6$]{}&\ [$15.4$]{}&\ [$16.2$]{}&\ [$20.5$]{}&\ [$21.0$]{}&\ [$32.1$]{}&\ [$38.2$]{}&\ [$40.2$]{}&\ [$65.2$]{}&\ [$65.2$]{}&\ [$67.5$]{}&\ [$74.5$]{}&\ [$75.8$]{}&\ [$76.2$]{}&\ \ [C[20pt]{}|C[147.8pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$8.8$]{}&\ [$9.3$]{}&\ [$10.5$]{}&\ [$13.9$]{}&\ [$19.3$]{}&\ [$20.4$]{}&\ [$20.9$]{}&\ [$31.6$]{}&\ [$34.9$]{}&\ [$35.7$]{}&\ [$57.5$]{}&\ [$61.3$]{}&\ [$67.5$]{}&\ [$78.7$]{}&\ [$80.0$]{}&\ \ Figure \[fig: app\_units\_multiple\] displays the response maps of the multiple block units with different block sizes. The metrics of the multiple blocks are learned automatically. ### With different shapes of area [C[20pt]{}|C[102pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$5.9$]{}&\ [$10.2$]{}&\ [$12.0$]{}&\ [$12.6$]{}&\ [$18.3$]{}&\ [$22.5$]{}&\ [$23.9$]{}&\ [$26.3$]{}&\ [$31.7$]{}&\ [$37.9$]{}&\ [$60.2$]{}&\ [$71.8$]{}&\ [$72.0$]{}&\ [$93.7$]{}&\ [$94.4$]{}&\ \ [C[20pt]{}|C[102pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$6.5$]{}&\ [$10.8$]{}&\ [$13.4$]{}&\ [$16.0$]{}&\ [$18.7$]{}&\ [$19.9$]{}&\ [$20.6$]{}&\ [$26.1$]{}&\ [$36.5$]{}&\ [$37.5$]{}&\ [$54.4$]{}&\ [$59.5$]{}&\ [$62.3$]{}&\ [$83.8$]{}&\ [$85.4$]{}&\ \ Figure \[fig: app\_units\_shape\] displays the response maps of the multiple block units with different shapes of the area, such as circle and triangle. Quantitative analysis of spatial activity {#app: gridness} ----------------------------------------- We assess the spatial activity of the learned units quantitatively using measures adopted from the neuroscience literature. Specifically, we quantify the hexagonal regularity of the grid-like patterns using the gridness score ([@langston2010development; @sargolini2006conjunctive]). The measure is derived from the spatial autocorrelogram of each unit’s response map. A unit is classified as a grid cell if its gridness score is larger than $0$. For those units that are classified as grid cells, grid scale and orientation can be further derived from the autocorrelogram following [@sargolini2006conjunctive]. Figure \[fig: app\_gridness\](a) summarizes the results. $76$ out of $96$ learned units are classified as grid cells. Most units with large learned $\alpha_k$ are classified as grid cells, while those units with small $\alpha_k$ are not due to the lack of a full period of hexagonal patterns. The grid scales and orientations vary among units, while remaining similar within each block. We show the histograms of the grid orientations and scales in Figure \[fig: app\_gridness\](b) and \[fig: app\_gridness\](c) respectively. Moreover, we average the grid scales within each block and make the scatter plot of the averaged grid scales and the learned $1/\sqrt{\alpha_k}$ in figure \[fig: app\_gridness\](d). Interestingly, the grid scale is nicely proportional to the learned $1/\sqrt{\alpha_k}$. [C[20pt]{}|C[170pt]{}|C[20pt]{}|C[170pt]{}]{} [$\alpha_k$]{} & [Autocorrelograms of the learned units’s spatial rate maps]{} & [$\alpha_k$]{} & [Autocorrelograms of the learned units]{}\ & & [$44.1$]{} &\ [$4.7$]{}&&[$56.3$]{}&\ [$11.9$]{}&&[$57.0$]{}&\ [$17.0$]{}&&[$61.7$]{}&\ [$17.3$]{}&&[$73.0$]{}&\ [$35.7$]{}&&[$85.7$]{}&\ [$39.1$]{}&&[$87.5$]{}&\ [$39.7$]{}&&[$94.7$]{}&\ \ \ ![(a) Autocorrelograms of the learned units’ response maps. Gridness scores are calculated based on the autocorrelograms. A unit is classified as a grid cell if the gridness score is larger than $0$. The gridness score is shown in red color if a unit fails to be classified as a grid cell. For those units that are classified as grid cells, gridness score, scale and orientation are listed sequentially in black color. Orientation is computed using a camera-fixed reference line ($0^{\circ}$) and in counterclockwise direction. (b) Histogram of grid orientations. (c) Histogram of grid scales. (d) Scatter plot of averaged grid scales within each block versus the corresponding learned $1/\sqrt{\alpha_k}$. []{data-label="fig: app_gridness"}](./FIG/units_multiple_blocks/orientation_hist.png "fig:"){width="\textwidth"}\ [(b) Histogram of grid orientations]{} ![(a) Autocorrelograms of the learned units’ response maps. Gridness scores are calculated based on the autocorrelograms. A unit is classified as a grid cell if the gridness score is larger than $0$. The gridness score is shown in red color if a unit fails to be classified as a grid cell. For those units that are classified as grid cells, gridness score, scale and orientation are listed sequentially in black color. Orientation is computed using a camera-fixed reference line ($0^{\circ}$) and in counterclockwise direction. (b) Histogram of grid orientations. (c) Histogram of grid scales. (d) Scatter plot of averaged grid scales within each block versus the corresponding learned $1/\sqrt{\alpha_k}$. []{data-label="fig: app_gridness"}](./FIG/units_multiple_blocks/scale_hist.png "fig:"){width="\textwidth"}\ [(c) Histogram of grid scales]{} ![(a) Autocorrelograms of the learned units’ response maps. Gridness scores are calculated based on the autocorrelograms. A unit is classified as a grid cell if the gridness score is larger than $0$. The gridness score is shown in red color if a unit fails to be classified as a grid cell. For those units that are classified as grid cells, gridness score, scale and orientation are listed sequentially in black color. Orientation is computed using a camera-fixed reference line ($0^{\circ}$) and in counterclockwise direction. (b) Histogram of grid orientations. (c) Histogram of grid scales. (d) Scatter plot of averaged grid scales within each block versus the corresponding learned $1/\sqrt{\alpha_k}$. []{data-label="fig: app_gridness"}](./FIG/units_multiple_blocks/scatter.png "fig:"){width="\textwidth"}\ [(d) Scatter plot of grid scales and learned $1/\sqrt{\alpha_k}$]{} Ablation studies {#sect: ablation} ---------------- We conduct ablation studies to assess various assumptions in our model. ### Loss terms ![Ablation study of the components in the training loss. (a) Learn the model using only the localization loss with global adjacency. (b) Learn the model using only the localization loss with local adjacency. (c) Using global adjacency and motion loss, leaving out local adjacency. []{data-label="fig: ablation2"}](./FIG/units_multiple_blocks/loss1.png "fig:"){width=".9\textwidth"}\ [(a) $L_3$ only.]{} ![Ablation study of the components in the training loss. (a) Learn the model using only the localization loss with global adjacency. (b) Learn the model using only the localization loss with local adjacency. (c) Using global adjacency and motion loss, leaving out local adjacency. []{data-label="fig: ablation2"}](./FIG/units_multiple_blocks/loss3.png "fig:"){width=".9\textwidth"}\ [(b) $L_2$ only.]{} ![Ablation study of the components in the training loss. (a) Learn the model using only the localization loss with global adjacency. (b) Learn the model using only the localization loss with local adjacency. (c) Using global adjacency and motion loss, leaving out local adjacency. []{data-label="fig: ablation2"}](./FIG/units_multiple_blocks/loss1andloss2.png "fig:"){width=".9\textwidth"}\ [(c) $L_1 + \lambda_3 L_3$, without $L_2$.]{} We learn $v$ and $M$ with multiple blocks by minimizing $L_1 + \lambda_2 L_2 + \lambda_3 L_3$, which consists of (1) a motion loss $L_1$, (2) a local isometry loss $L_2$, and (3) a global adjacency loss $L_3$. Figure \[fig: ablation2\] shows the learned units when using only some of the components. Grid-like patterns do not emerge if using only the adjacency loss $L_3$, or only the isometry loss $L_2$. If using only the motion loss, the motion equation is approximately satisfied at the beginning of training, since both $v$ and $M$ are initialized from small values that are close to $0$. The system cannot be learned without an extra term to push $v(x)$ apart from each other. Figure \[fig: ablation2\](c) shows the learned units using the adjacency loss and the motion loss, leaving out the isometry loss. Grid-like patterns still emerge (also some strip-like patterns), although less obvious than the ones learned using the full loss. ### Assumptions of motion matrix {#app: discrete} ![Learned units by dropping the parametrization and the block diagonal assumption of the motion matrix $M(\Delta x)$.[]{data-label="fig: ablation"}](./FIG/units_single_block/discrete_blocksize2.png "fig:"){width=".2\textwidth"}\ [block size = 2]{}\ ![Learned units by dropping the parametrization and the block diagonal assumption of the motion matrix $M(\Delta x)$.[]{data-label="fig: ablation"}](./FIG/units_single_block/discrete_blocksize4.png "fig:"){width=".4\textwidth"}\ [block size = 4]{}\ ![Learned units by dropping the parametrization and the block diagonal assumption of the motion matrix $M(\Delta x)$.[]{data-label="fig: ablation"}](./FIG/units_single_block/discrete_blocksize6.png "fig:"){width=".6\textwidth"}\ [block size = 6]{}\ ![Learned units by dropping the parametrization and the block diagonal assumption of the motion matrix $M(\Delta x)$.[]{data-label="fig: ablation"}](./FIG/units_single_block/discrete_blocksize8.png "fig:"){width=".8\textwidth"}\ [block size = 8]{}\ ![Learned units by dropping the parametrization and the block diagonal assumption of the motion matrix $M(\Delta x)$.[]{data-label="fig: ablation"}](./FIG/units_single_block/discrete_blocksize10.png "fig:"){width="\textwidth"} [block size = 10]{}\ ![Learned units by dropping the parametrization and the block diagonal assumption of the motion matrix $M(\Delta x)$.[]{data-label="fig: ablation"}](./FIG/units_single_block/discrete_blocksize100.png "fig:"){width=".8\textwidth"}\ [block size = 100]{} \ [(a) With local isometry $L_2$: scaling parameter $\alpha = 72$]{}\ ![Learned units by dropping the parametrization and the block diagonal assumption of the motion matrix $M(\Delta x)$.[]{data-label="fig: ablation"}](./FIG/units_single_block/discrete_global_kernel_cut.png "fig:"){width=".85\textwidth"}\ [(b) With global adjacency $L_3$: Gaussian kernel with $\sigma = 0.08$]{} In another ablation study, we drop the quadratic parametrization by $\beta$ coefficients and the block diagonal assumption of the motion matrix. A separate motion matrix $M(\Delta x)$ is learned for each displacement $\Delta x$, and $v(x)$ is assumed to be a single block. We use either the local isometry loss $L_2$ or the global adjacency loss $L_3$ in addition to the motion loss $L_1$. The results are shown in Figure \[fig: ablation\]. With the isometry loss, the setting is similar to the one of learning single block, except that the parametrization of $M(\Delta x)$ is dropped. As shown in figure \[fig: ablation\](a), the learned units resemble the ones learned with parametrized $M(\Delta x)$, but when the block size is large, the grid-like patterns are less obvious. With the adjacency loss, grid-like patterns do not emerge any more. Modeling egocentric motion {#sect: egocentric} ========================== The model can be generalized to handle egocentric motion that involves head direction. Coupling two grid systems ------------------------- The egocentric motion consists of angular velocity in the change of head direction and the spatial velocity along the current head direction. We couple two grid systems, one for head direction and the other for the spatial position. For notational simplicity, we put the “hat” notation on top of $v$ and $M$ notation to denote the vector and matrix for the head direction. Specifically, the agent has a head direction $\theta$, which may change over time. The agent moves along its head direction with scalar motion. We can discretize the range of $\theta$, $[0, 2\pi]$, into $\hat{N}$ equally spaced values $\{\theta_{i}, i=1,...,\hat{N}\}$, and introduce a vector representation of self-direction. That is, the agent represents its self-direction by a $\hat{d}$-dimensional hidden vector $\hat{v}(\theta)$. ### Motion sub-model Suppose at a position $x$, the agent has a head direction $\theta$. The self-motion is decomposed into (1) a scalar motion $\delta$ along the head direction $\theta$ and then (2) a head direction rotation $\Delta \theta$. The self-motion $\Delta x = (\delta \cos\theta, \delta \sin\theta)$. We assume $$\begin{aligned} \hat{v}(\theta+\Delta\theta) &=& \hat{M}(\Delta \theta) \hat{v}(\theta),\\ v(x + \Delta x) &=& M(\delta, \hat{v}(\theta)) v(x), \end{aligned}$$ where $\hat{M}(\Delta \theta)$ is a $\hat{d} \times \hat{d}$ matrix that depends on $\Delta \theta$, and $M(\Delta \theta, \hat{v}(\theta))$ is a $d \times d$ matrix that depends on $\delta$ and $\hat{v}(\theta)$. $\hat{M}(\Delta \theta)$ is the matrix representation of the head direction rotation $\Delta \theta$, while $M(\delta, \hat{v}(\theta))$ is the matrix representation of scalar motion $\delta$ along the direction $\theta$. We can model $M(\delta, \hat{v}(\theta))$ by an attention (or selection) mechanism: $$\begin{aligned} && p_{i} = \frac{\langle \hat{v}(\theta), \hat{v}(\theta_{i}\rangle^b} {\sum\nolimits_{i=1}^{\hat{N}}\langle \hat{v}(\theta), \hat{v}(\theta_{i})\rangle^b},\\ && M(\delta, \hat{v}(\theta)) = \sum\nolimits_{i=1}^{\hat{N}} p_{i} M^{(i)}(\delta),\end{aligned}$$ where $M^{(i)}(\delta)$ is the matrix representation of scalar motion $\delta$ given the head direction $\theta_{i}$. The inner product $\langle \hat{v}(\theta), \hat{v}(\theta_{i}) \rangle$, that informs the angular distance between $\theta$ and $\theta_{i}$, serves as the attention weight. $b$ is an annealing (inverse temperature) parameter. If $b \rightarrow \infty$, $p = (p_i, i = 1, ..., \hat{N})$ becomes a one-hot vector for selection. We can further assume that $\hat{M}(\Delta \theta)$ and $M^{(i)}(\delta)$ are block diagonal, and learn a parametric model for each of them by the second order Taylor expansion at $\Delta \theta$ and $\delta$ respectively. ### Localization sub-model For the localization sub-model, we define the adjacency measures of self-direction and self-position separately. Let $\hat{f}(|\theta_1-\theta_2|)$ be the adjacency measure between two directions $\theta_1$ and $\theta_2$ . We use von Mises kernel $\hat{f}(r) = \exp((\cos(r)-1)/\sigma^2)$, where $\hat{f}(0) = 1$. For adjacency measure between self-positions $x$ and $y$, we keep it the same as described in section \[sect: localization\]. ### Loss function for learning For learning the system, we can first learn $\hat{v}$ and $\hat{M}$ (or the coefficients that parametrize $\hat{M}$) by minimizing $$\begin{aligned} \E_{\theta_1, \theta_2} \left[(\hat{f}(|\theta_1-\theta_2|) - \langle \hat{v}(\theta_1), \hat{v}(\theta_2)\rangle)^2\right] + \lambda \E_{\theta, \Delta \theta} \left[ \|\hat{v}(\theta+\Delta \theta) - {\hat{M}}(\Delta \theta) \hat{v}(\theta)\|^2\right], \end{aligned}$$ and then we learn $v$ and $M$ (or the coefficients that parametrize $M$) as before. Learned units for self-direction and self-position -------------------------------------------------- Figure \[fig: egocentric\] shows a result of learning such an egocentric motion model by displaying the response curves of the learned units in the head direction system, $\hat{v}(\theta)$, for $\theta \in [0, 2\pi]$, as well as the response maps of the learned multiple block units in the self-position system, $v(x)$, for $x \in [0, 1]^2$. ![(a) Response curves of learned units in the head direction model, $\hat{v}(\theta)$. Each block shows the units belonging to the same sub-vector in the model. The horizontal axis represents the angle within a range of \[0, 2$\pi$\], while the vertical axis indicates the values of responses. (b) Response maps of the learned multiple block units of the self-position model, $v(x)$, for $x \in [0, 1]^2$.[]{data-label="fig: egocentric"}](./FIG/egocentric/head_weights_5999.png){width="110pt"} [C[20pt]{}|C[101pt]{}]{} [$\alpha_k$]{} & [Learned blocks]{}\ &\ [$6.6$]{}&\ [$8.4$]{}&\ [$14.9$]{}&\ [$21.2$]{}&\ [$26.3$]{}&\ [$33.5$]{}&\ [$43.2$]{}&\ [$43.4$]{}&\ [$46.0$]{}&\ [$59.0$]{}&\ [$61.2$]{}&\ [$72.5$]{}&\ [$80.5$]{}&\ [$82.5$]{}&\ [$85.3$]{}&\ \ Clock and timestamp {#sect: 1D} ------------------- We may re-purpose the head direction system as a clock, by interpreting $\theta \in [0, 2\pi]$ as the time on a clock, and $\hat{v}(\theta)$ as a timestamp for events happening over time. This may be related to the recent neuroscience observations in [@tsao2018integrating]. Errors ====== Error correction {#app: error} ---------------- Unlike commonly used embedding in machine learning, here we embed a 2D position into a high-dimensional space, and the embedding is a highly distributed representation or population code. The advantage of such a redundant code lies in its tolerance to errors. We show that the learned system is tolerant to various sources of errors. Specifically, in both path integral and path planning tasks, at every time step $t$, we randomly add (1) Gaussian noises or (2) dropout masks to the hidden units and see if the system can still perform the tasks well. We find that the decoding-encoding process (DE) is important for error correction. That is, at each time step $t$, given the noisy hidden vector ${v}_t$, we decode it to $x_t = \arg\max_x \langle v_t, v(x)\rangle$ and then re-encode it to the hidden vector $v(x_t)$. Actually the whole process can be accomplished by projection to the codebook sub-manifold without explicit decoding, by obtaining the vector: $\arg\max_{v \in C} \langle v_t, v\rangle$, where $C = \{v(x), x \in [0, 1]^2\}$. Table \[tab: err\] shows the error correction results tested on path integral and path planning tasks. Each number is averaged over $1,000$ episodes. We compute the overall standard deviation of $\{v(x)\}$ for all $x$ and treat it as the reference standard deviation ($s$) for the Gaussian noise. For dropout noise, we set a percentage to drop at each time step. With the decoding-encoding process, the system is quite robust to the Gaussian noise and dropout error, and the system still works even if $70\%$ units are silenced at each step. Noisy self-motion input ----------------------- Besides adding noises to the hidden units, we also experiment with adding noises to the self-motion $\Delta x$, and compare the performance of path integral with the one performed in the original 2D coordinates. Specifically, at each time step, we add Gaussian noises to the self-motion $\Delta x$. For path integral, we compute the mean square error between the predicted locations and ground truth locations. Besides, we also compute the predicted locations using the 2D coordinates with the noisy self-motions. Its mean square error serves as the reference error. Table \[tab: err2\] shows the result, indicating that the error of the learned system is close to the error in the original 2D coordinates, i.e., our system does not blow up the noise. 3D environment and 1D time {#app: 3Dstart} ========================== The system can be generalized to 3D environments. Specifically, we assume the agent navigates within a domain $D = [0, 1] \times [0, 1] \times [0, 1]$, which is discretized into a $40 \times 40 \times 40$ lattice. We learn a parametric model for motion matrix $M$ in a residual form $M = I + \tilde{M}(\Delta x)$, where $\tilde{M}(\Delta x)$ is approximated by the second order Taylor expansion of $\Delta x$. We first learn a single block with fixed $\alpha_k$ by minimizing $L_1 + \lambda _2 L_{2, k}$. A batch of 500,000 examples of $(x, y)$ and $(x, \Delta x_t, t = 1, ..., T)$ is sampled online at every iteration for training. Figure \[fig: 3D\] shows the learned units. [C[.07]{}C[.93]{}]{} [$\alpha = 18$]{} & ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_0.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_1.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_2.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_3.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_4.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_5.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_6.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/18-2/heatmap_7.png "fig:"){width=".11\textwidth"}\ [$\alpha = 36$]{} & ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_0.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_1.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_2.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_3.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_4.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_5.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_6.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/36/heatmap_7.png "fig:"){width=".11\textwidth"}\ [$\alpha = 72$]{} & ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_0.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_1.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_2.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_3.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_4.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_5.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_6.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/72/heatmap_7.png "fig:"){width=".11\textwidth"}\ [$\alpha = 108$]{} & ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_0.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_1.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_2.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_3.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_4.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_5.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_6.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/108-2/heatmap_7.png "fig:"){width=".11\textwidth"}\ [$\alpha = 144$]{} & ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_0.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_1.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_2.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_3.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_4.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_5.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_6.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/144-2/heatmap_7.png "fig:"){width=".11\textwidth"}\ [$\alpha = 180$]{} & ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_0.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_1.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_2.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_3.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_4.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_5.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_6.png "fig:"){width=".11\textwidth"} ![Learned units of a single block with fixed $\alpha$ in 3D environment. Every row shows the learned units with a given $\alpha$.[]{data-label="fig: 3D"}](./FIG/iclr_new_results/3d_units/180/heatmap_7.png "fig:"){width=".11\textwidth"} Next we learn multiple blocks by minimizing $L_1 + \lambda_3 L_3$, and use the learned models to perform 3D path integral and path planning. For simplicity, we remove $L_2$. We use $8$ blocks of units with block size $8$ and exponential kernel ($\sigma = 0.3$) for path planning. A batch of 200,000 examples is sampled online at every iteration for training. 3D path integral ---------------- Figure \[fig: 3d\_path\_integral\_app\] shows some results of 3D path integral with duration $\tilde{T} = 30$. Gaussian Kernel ($\sigma = 0.08$) is used as the adjacency measure. ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_2.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_8.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_17.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_19.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_29.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_31.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_33.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_66.png "fig:"){width="32.00000%"} ![Examples of 3D path integral with duration $\tilde{T}=30$.[]{data-label="fig: 3d_path_integral_app"}](./FIG/iclr_new_results/3d_path_integral_testing/None_id_71.png "fig:"){width="32.00000%"} 3D path planning ---------------- Figure \[fig: 3d\_planning\_app\] shows some results of 3D simple path planning. Exponential kernel ($\sigma = 0.3$) is used as the adjacency measure. We design a set of allowable motions $\Delta$: $m$ lengths of radius $r$ are used, and for each $r$, we evenly divide the inclination $\theta \in [0, \pi]$ and the arimuth $\alpha \in [0, 2\pi]$ into $n$ directions, which results in a motion pool with $mn^2$ candidate motions $\Delta = \{(r \sin(\theta) \cos(\alpha), r \sin(\theta) \sin(\alpha), r \cos(\theta) )\}$. We use $m = 2, n = 90$ in this experiment. ![Examples of 3D simple path planning, where the agent is capable of planning a direct trajectory.[]{data-label="fig: 3d_planning_app"}](./FIG/iclr_new_results/3d_path_planning/test00.png "fig:"){width="32.00000%"} ![Examples of 3D simple path planning, where the agent is capable of planning a direct trajectory.[]{data-label="fig: 3d_planning_app"}](./FIG/iclr_new_results/3d_path_planning/test02.png "fig:"){width="32.00000%"} ![Examples of 3D simple path planning, where the agent is capable of planning a direct trajectory.[]{data-label="fig: 3d_planning_app"}](./FIG/iclr_new_results/3d_path_planning/test08.png "fig:"){width="32.00000%"} ![Examples of 3D simple path planning, where the agent is capable of planning a direct trajectory.[]{data-label="fig: 3d_planning_app"}](./FIG/iclr_new_results/3d_path_planning/test05.png "fig:"){width="32.00000%"} ![Examples of 3D simple path planning, where the agent is capable of planning a direct trajectory.[]{data-label="fig: 3d_planning_app"}](./FIG/iclr_new_results/3d_path_planning/test23.png "fig:"){width="32.00000%"} ![Examples of 3D simple path planning, where the agent is capable of planning a direct trajectory.[]{data-label="fig: 3d_planning_app"}](./FIG/iclr_new_results/3d_path_planning/test13.png "fig:"){width="32.00000%"} 3D path planning with obstacles ------------------------------- Figure \[fig: 3d\_path\_planning\_obstacle\] shows some examples of 3D path planning with a cuboid obstacle. $a = 38$ and $b = 24$ in equation \[eqn: planning\_obs\]. ![Examples of 3D path planning with a cuboid obstacle.[]{data-label="fig: 3d_path_planning_obstacle"}](./FIG/iclr_new_results/3d_path_planning_obstacle/test00.png "fig:"){width="32.00000%"} ![Examples of 3D path planning with a cuboid obstacle.[]{data-label="fig: 3d_path_planning_obstacle"}](./FIG/iclr_new_results/3d_path_planning_obstacle/test03.png "fig:"){width="32.00000%"} ![Examples of 3D path planning with a cuboid obstacle.[]{data-label="fig: 3d_path_planning_obstacle"}](./FIG/iclr_new_results/3d_path_planning_obstacle/test05.png "fig:"){width="32.00000%"} ![Examples of 3D path planning with a cuboid obstacle.[]{data-label="fig: 3d_path_planning_obstacle"}](./FIG/iclr_new_results/3d_path_planning_obstacle/test08.png "fig:"){width="32.00000%"} ![Examples of 3D path planning with a cuboid obstacle.[]{data-label="fig: 3d_path_planning_obstacle"}](./FIG/iclr_new_results/3d_path_planning_obstacle/test10.png "fig:"){width="32.00000%"} ![Examples of 3D path planning with a cuboid obstacle.[]{data-label="fig: 3d_path_planning_obstacle"}](./FIG/iclr_new_results/3d_path_planning_obstacle/test07.png "fig:"){width="32.00000%"} Learning in 1D {#sect:1D} -------------- The system can also be applied to 1D. Inspired by [@tsao2018integrating], the learned system in 1D may serve as a timestamp of events. We assume domain $D = [0, 1]$ and discretize it into $100$ time points. A parametric $M$ is learned by a residual form $M = I + \tilde{M}(\Delta t)$, where each element of $\tilde{M}(\Delta t)$ is parametrized as a function of $(\Delta t, \Delta t^2)$. $16$ blocks of hidden units with block size $6$ are used. Figure \[fig:1D\] visualizes the learned units over the $100$ time points. The response wave of every unit shows strong periodicity of a specific scale or frequency. Within each block, the response waves of units have similar patterns, with different phases. ![Response curves of learned units in 1D. Each block shows the units belonging to the same sub-vector in the motion model. The horizontal axis represents the time points, while the vertical axis indicates the value of responses. []{data-label="fig:1D"}](./FIG/units_1D.png){width=".7\textwidth"} [^1]: Equal contributions.

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minipile

NaturalLanguage

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Search form A Big GOP Tax Loophole Winner: Donald Trump Kevin Lamarque By Michael Rainey December 6, 2017 MOST POPULAR Commercial real estate is one of the clear winners in the Republican tax plan, according to The New York Times: “House and Senate Republicans, in their divergent bills, both offered steeply reduced rates to corporate giants, partnerships and family-owned firms across the board. But when it came time to eliminate special breaks or impose tighter standards, real estate was generally excused from the room.” Coincidentally or not, President Trump and his family stand to gain considerably from the new rules. Real estate investors will be able to use a more favorable depreciation schedule on their properties, and rental income will be taxed at a lower rate. Real estate investment trusts also do exceptionally well in the bill, and the Trump Organization has substantial deals with several REITS, including Vornado Realty Trust in New York. Income from REIT investments will be taxed at the new, lower pass-through rate, giving Trump big savings while creating what tax lawyer Steven M. Rosenthal called “giant new tax shelters” for investors. Those and other loopholes are raising plenty of eyebrows, both in shock and in eager anticipation. Rather than simplifying the tax code, the Republican plan seems to be creating more nooks and crannies that can be exploited by clever tax layers. Adam Looney of the Brookings Institution told the Times, “Suddenly, there are a dozen different tax rates that apply to different businesses, in different industries, and to different investments.” Experts expect to see a wave of restructurings and asset shifting as businesses and wealthy investors maneuver to take advantage of every new tax break in the code.

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Mets infielder Jose Reyes said Sunday that there was no excuse for teammate Matt Harvey to go MIA from a game the day before. “Injuries are injuries. What happened to Harvey, that’s a different ballgame,” Reyes said without elaborating. “You’re an employee, you have to understand you need to show up for your work. That’s the rules that the team has since spring training. As a grown man, you’ve got a job to do. You have to understand: If you don’t show up, you’re going to pay the consequence.” Harvey claimed to Mets higher-ups that a “migraine” kept him from the game, Fox Sports reported. Reyes said that even if the pitcher wasn’t supposed to play, his presence was missed. “I mean, we know. When you don’t see somebody, there’s only 25 guys in the locker room,” Reyes said. “If you don’t see somebody the whole day, you’re going to say, ‘Man, what’s going on?’ ”

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Home entertainment networks are becoming popular and allow media stored on or accessible by a computer to be presented on more traditional presentation devices, such as a television, in a separate room from the computer. In order for a television to present such media, it is often connected with a media rendering device, which in turn is connected with the computer over a home entertainment network. These media rendering devices often have limited functionality for providing “trick” playback capabilities such as scan forward or reverse, seek, or pause. The limited capabilities of the media rendering devices often stem from a lack of sufficient memory and/or memory buffers to store the media stream locally, which are generally required to provide the dynamic playback functions. Even if a media rendering device is equipped with appropriate memory, transmission of all of the media content required to provide dynamic playback functionality at the media rendering device may consume significant bandwidth on the home entertainment network. Excessive bandwidth consumption may impact the ability of the network to provide content to other devices on the network or provide the requisite content to the particular media rendering device within the necessary time constraints to perform the requested function.

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British national Samia Shahid was asphyxiated, says forensic report LAHORE: A British woman whose husband alleges she was killed for marrying him against her parents’ wishes was murdered, police said on Wednesday. The case attracted attention because it came just days after the high-profile “honour killing” of outspoken social media star Qandeel Baloch, whose brother confessed to the crime and has been arrested. Samia Shahid, 28, a beautician from Bradford who had gone to visit her family in Pakistan, died last month in the village of Pandori in northern Punjab, the political power base of Prime Minister Nawaz Sharif. No arrests have been made so far, but Shahid’s father and a cousin have been questioned by police. Mukhtar, her second husband, told media last week that the couple had received death threats from her family in the past. He also said her family was angered that Shahid converted from the majority Sunni to the minority Shia sect of Islam after the couple married. Some 500 women are killed each year in Pakistan by relatives who feel their family has been shamed by a daughter or sister fraternising with men, eloping or otherwise infringing conservative demands on women. Last month’s murder of Qandeel Baloch, who had divided opinion in the society by regularly posting risqué photos on social media, led the government to announce that it would pass long-delayed legislation outlawing honour killing within weeks.

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Introduction {#s1} ============ Extra-pair paternity (EPP) is a widespread phenomenon in birds: it has been found in three quarter of the socially monogamous bird species studied [@pone.0012006-Griffith1]. There is also striking interspecific variation in the rate of EPP, which seems to be related to ecological and social factors, which in turn are also correlated with phylogeny [@pone.0012006-Griffith1], [@pone.0012006-Petrie1], [@pone.0012006-Westneat1]. For example, species or populations with high breeding densities appear to have higher rates of EPP than those with low breeding densities [@pone.0012006-Gowaty1], [@pone.0012006-Mller1], [@pone.0012006-Westneat2], presumably because there are more opportunities for extra-pair matings in high than in low density populations. Consequently, the social system may also influence the rate of EPP, and indeed, the highest rates of EPP are found in group-living and cooperatively breeding Superb Fairy-wrens (*Malurus cyaneus*) where 72% of all offspring are extra-pair offspring and almost all broods contain extra-pair offspring [@pone.0012006-Double1], [@pone.0012006-Mulder1]. Another important factor that may affect the rate of EPP is the amount of paternal care provided. The larger the investment of the male is, the greater is the fitness loss faced by unfaithful females if their mates abandon the brood after detecting EPP of their female. Consequently, EPP rates should be lower in species where males provide parental care [@pone.0012006-Bennet1], [@pone.0012006-HoiLeitner1], [@pone.0012006-Mller2]. Siberian Jays (*Perisoreus infaustus*) are long-lived (on average 4.9 years for breeders and up to 16 years), socially monogamous birds that live in family groups consisting of the breeding pair, so-called retained offspring and additional individuals that are unrelated to the breeding pair [@pone.0012006-Blomgren1], [@pone.0012006-Ekman1]. Pair-bonds are stable and divorces occur rarely, if ever [@pone.0012006-Blomgren1], [@pone.0012006-Lillandt1]. While both retained offspring and unrelated individuals are tolerated within the territory, retained offspring are treated favourably by the parents [@pone.0012006-Griesser1], [@pone.0012006-Griesser2]. In this system with stable pair-bonds and 'prolonged brood care' [@pone.0012006-Ekman1], [@pone.0012006-Slepkovych1], females engaging in extra-pair matings would be expected to pay high costs of infidelity since raising a brood on her own or finding a new partner are likely to incur high fitness costs. Also limited possibilities of finding an extra-pair mate can be important as population densities are low (0.1--2 ind/km^2^) and territories are large, 1--4 km^2^ [@pone.0012006-Lillandt1], [@pone.0012006-Lillandt2], [@pone.0012006-Visnen1]. A female would thus have to travel several kilometers only to sample a reasonable number of potential extra-pair mates. On the other hand, unrelated group members provide candidates for extra-pair matings. Here we analysed a large data set from a long-term study of a Finnish Siberian jay population with over 1000 individuals genotyped at up to 21 microsatellites to test for evidence for extra-pair paternity in this species. Methods {#s2} ======= Study species and area {#s2a} ---------------------- Siberian jays (*P. infaustus*) are comparably small (ca. 80 g) corvids inhabiting boreal forests from Fennoscandia to Siberia. After becoming independent in early summer, juveniles have three options. They either (i) leave their natal family group to join another family group, (ii) establish a territory of their own, or (iii) stay within the natal family group as retained offspring [@pone.0012006-Blomgren1], [@pone.0012006-Ekman1]. Groups consist of the breeding pair and up to four additional individuals that are retained offspring or unrelated individuals [@pone.0012006-Ekman1], [@pone.0012006-Lillandt2], [@pone.0012006-Ekman2], but neither retained offspring nor do the unrelated group-members help at the nest [@pone.0012006-Ekman1]. The study area is located in Ostrobothnia (SW-Finland), near Kristiinankaupunki (62°22′N, 21°30′E). Annual monitoring of the Siberian jay population started in 1974 in a 120 km^2^ sized forest area. Subsequently, the study area has been enlarged and now covers about 1000 km^2^ divided into seven sub-areas with a maximum N-S and E-W distances of about 75 km and 50 km, respectively ([Fig. 1](#pone-0012006-g001){ref-type="fig"}). The number of breeding pairs in the area has varied from five in the early years to 50 in later years. For a more detailed description of the study area and fieldwork procedures see [@pone.0012006-Lillandt1], [@pone.0012006-Lillandt2]. Briefly, during late summer and autumn (July--October) birds are caught at feeding stations, measured, blood sampled (since 1997) and ringed with aluminium and colour rings. In some years additional observations in spring were done. All birds included in this analysis were sexed using molecular markers [@pone.0012006-Fridolfsson1]. ![Schematic map of the study area.\ Dark grey areas indicate open land (mainly arable fields). The study area is indicated by medium gray, with darker medium gray indicating areas where monitoring started in 1992 and earlier. Lighter medium gray indicates areas where monitoring started in 1998 and later. Areas outside the study area are shown in light gray. The inset map shows the location of the study area within Finland.](pone.0012006.g001){#pone-0012006-g001} Capturing and ringing of birds was approved by the institution that coordinates ringing activity in Finland (Finnish Museum of Natural History), based on the regulation by the Ministry of the Environment (No. 17/5713/2002). Procedures for blood and DNA sampling were approved by the ethical license board of University of Helsinki (No. HY 133-06). Paternity analysis and pedigree construction {#s2b} -------------------------------------------- The original pedigree for this study-population was constructed based on field observations and microsatellite markers [@pone.0012006-Lillandt3], [@pone.0012006-Lillandt4]. In short, identities of breeding partners were inferred from observations at feeding stations, and the genotypes of all offspring born in a given year were manually matched against all breeding pairs in the same year [@pone.0012006-Lillandt2], [@pone.0012006-Lillandt4]. Based on the improved genotypic data (see below) and parentage analysis using Cervus 3.0 [@pone.0012006-Kalinowski1], we re-constructed the pedigree. This was done separately per birth year to avoid the possibility that an individual\'s offspring could become assigned as its parent. We used Delta-scores, the difference in the logarithms of the likelihood ratios (LOD) of the most likely and the second most likely candidate pair, as a criterion for the confidence of the parentage assignment. Because the number of candidate parents differed between years, critical Delta-scores were calculated on an annual basis using the simulation option in Cervus. We set the proportion of the population sampled to the average annual recapture probability \[0.90±0.02, [@pone.0012006-Bergholm1]\]. The genotyping error was assumed to be 1%. This is a conservative estimate since all samples were run twice, read blindly and the resulting genotypes only accepted if the two runs gave identical results. If the results differed the sample was re-ran and re-scored. To test how sensitive our results were to this parameter, we re-run a subsample using genotyping errors of 0.1% and 2%, respectively. No qualitative differences in the assigned parentages were found. All individuals genotyped at less than six (1974--79), less than eight (1980--96) and less than nine loci (1997--2006), respectively, were excluded from the analysis. The threshold values for exclusion differed between periods because the average number of loci typed per individual differed: Initially only individuals after 2005 were genotyped for 21 markers. Not all other individuals could be successfully typed for the new markers due to different sample types (feathers vs. blood). All parents that were (possibly) alive in the given birth year were included as candidate parents in the separate runs. The most likely candidate parents as identified by Cervus were assigned as 'true' parents if they were observed as a breeding pair in the individual\'s birth year. When the most likely candidate parents were not observed as a breeding pair, but the second or third most likely candidate pair was observed as a breeding pair, the latter were assigned as parents. However, in all these cases the Delta-score was small, and no candidate pair could be assigned with 95% confidence. If none of the candidate pairs had a positive LOD-score or were observed together as a breeding pair, no parents were assigned to the individual. Normally, nests were not located and visited because of the amount of work involved with finding the nests, but also to minimise the disturbance which can increase the risk of nest predation [@pone.0012006-Armstrong1], [@pone.0012006-Sandvik1]. However, in total 37 broods were ringed in the nest. Of these, 40 offspring from 23 broods could be included in the paternity analysis. In three cases no DNA-sample from the social mother was available, but they were included regardless. Paternity analysis was carried out using Cervus assuming the social mother was the 'true' mother. Again, paternity assignments were carried out with the known genetic mothers separately per birth year since the number of candidate fathers differed between years. We used the same values for proportion of the population sampled and genotyping error as in the parentage analysis. Genetic samples were obtained from blood samples and for the early years from the tip of collected tail feathers. DNA was extracted using DNeasy Blood & Tissue kit according to the manufacturers\' instructions (Qiagen). The individuals were genotyped for 21 previously reported markers ([Table 1](#pone-0012006-t001){ref-type="table"}). Briefly, the markers were divided into groups (panels) of 3--4 markers based on the size of the PCR products and the labels used. PCR amplification was carried out in similar conditions (2 pmol of each primer, 1× Qiagen multiplex mastermix, 0.5× Q-Solution, and approximately 30 ng of DNA in a total volume of 10µl) and the same cycling profile (15 min at 95°C, followed by 30 cycles 30 s at 94°C, 90 s at 56°C and 60 s at 72°C and a final extension for 10 min) for all markers, using a commercial multiplex PCR kit (Qiagen). The PCR products were diluted 1∶750 with MQ-water and mixed with Et-ROX 400 standard (GE Healthcare, Life Sciences) according to the manufacturer\'s instructions and resolved in a MegaBace 1000 capillary sequencer (GE Healthcare, Life Sciences). Genotypes were scored with the Fragment Profiler 1.2 program (GE Healthcare, Life Sciences). Not all birds could be scored for all markers due to low quality and low concentration of DNA. This was mainly the case for the old feather samples. 10.1371/journal.pone.0012006.t001 ###### Microsatellite loci used for pedigree re-construction and extra-pair paternity analyses. ![](pone.0012006.t001){#pone-0012006-t001-1} Locus A n H~O~ H~E~ PIC N-Excl~1~ N-Excl~2~ Ref. -------- ---- ------ ------- ------- ------- ----------- ----------- ------------------------------ SJ103 18 929 0.872 0.895 0.885 0.3507 0.2121 [@pone.0012006-Fridolfsson1] SJ104 6 950 0.323 0.322 0.307 0.9458 0.8208 [@pone.0012006-Fridolfsson1] SJ105 5 909 0.482 0.503 0.408 0.8730 0.7776 [@pone.0012006-Fridolfsson1] SJ106 8 953 0.787 0.802 0.774 0.5650 0.3876 [@pone.0012006-Fridolfsson1] SJ107 10 951 0.693 0.698 0.653 0.7084 0.5346 [@pone.0012006-Fridolfsson1] SJ109 9 926 0.726 0.755 0.715 0.6450 0.4682 [@pone.0012006-Fridolfsson1] SJ110 4 934 0.668 0.653 0.587 0.7706 0.6176 [@pone.0012006-Fridolfsson1] SJ111 5 921 0.562 0.587 0.523 0.8218 0.6758 [@pone.0012006-Fridolfsson1] SJ112 4 895 0.191 0.302 0.257 0.9544 0.8706 [@pone.0012006-Fridolfsson1] SJ114 5 888 0.498 0.505 0.410 0.8718 0.7754 [@pone.0012006-Fridolfsson1] SJ116 3 861 0.48 0.482 0.379 0.8841 0.8032 [@pone.0012006-Fridolfsson1] SJ115 4 872 0.429 0.505 0.432 0.8724 0.7536 [@pone.0012006-Fridolfsson1] MJG1 2 1034 0.414 0.405 0.323 0.9179 0.8384 [@pone.0012006-Griesser3] PER1 7 1034 0.538 0.539 0.490 0.8438 0.6916 [@pone.0012006-Griesser3] Ppi1 4 1008 0.57 0.543 0.485 0.8494 0.7050 [@pone.0012006-Griesser3] PPi2 5 1029 0.747 0.728 0.681 0.6910 0.5158 [@pone.0012006-Griesser3] LTML7 3 1007 0.367 0.37 0.302 0.9316 0.8488 [@pone.0012006-Griesser3] LTML8 13 1022 0.86 0.848 0.831 0.4643 0.3000 [@pone.0012006-Griesser3] CK1B5D 2 1003 0.5 0.495 0.373 0.8774 0.8137 [@pone.0012006-Griesser3] CK2A5A 16 1033 0.803 0.807 0.787 0.5295 0.3557 [@pone.0012006-Griesser3] CKL5 12 1010 0.82 0.815 0.792 0.5296 0.3558 [@pone.0012006-Griesser3] Number of alleles (A) and number of individuals genotyped (n), observed (H~O~) and expected (H~E~) heterozygosity, non-exclusion probability for first (N-Excl~1~) and second (N-Excl~2~) parent (with first parent assigned) per locus. Ref. = reference for original publication describing the loci. Results {#s3} ======= A total of 1029 genotyped offspring could be included in the parentage analysis. In 177 cases (17.2%) no candidate parents with positive LOD scores were found and these individuals were hence regarded as immigrants into the study area. In the majority of the remaining cases (71%) the most likely candidate pair was observed as a breeding pair, and hence, assigned as parents. In 118 (11.5%) cases the most likely candidate parents had a positive LOD scores but were not observed as an actual breeding pair, but were breeding in different territories with other partners. These are thus possible cases of extra-pair paternity. However, for 76 of these the LOD and the Delta scores were so low that none of the candidate pairs could be assigned for parentage at the 95% confidence level. In the remaining 36 (3.5%) cases, the candidate pairs could be assigned at the 95% confidence level but there are several reasons why we think that none of them provides good evidence for extra-pair paternity. 1) In eight cases one or both candidate parents could already have died, because they were observed in the years before but not in the year when the individual in question was born. 2) In the majority of cases, the male or female would have had to travel quite far (mean = 14.7 km, range = 1.6--41.3 km) to seek the extra-pair mating, further than the average natal dispersal distance (mean = 5.0 km (males), 5.9 km (females), [@pone.0012006-Gienapp1]) and also further than the neighbouring territories. 3) In none of these cases social mother would have been the genetic mother, and the offspring in question were never observed in the assumed natal territory. This means that all extra-pair offspring would have dispersed in their first summer, which seems very unlikely given that a half to two thirds of the fledglings stay with their parents [@pone.0012006-Ekman2]. It becomes even more unlikely when one considers that extra-pair offspring should be of higher quality [@pone.0012006-Hasselquist1] and that it is the low-quality, sub-dominant offspring which are more likely to disperse during the first summer [@pone.0012006-Ekman2]. Four out of 40 offspring with known social father could have been EPP-offspring. However, in the years when three of these offspring hatched critical LOD and Delta-scores were low ([Table 2](#pone-0012006-t002){ref-type="table"}). This was because not all individuals could successfully be genotyped for 21 markers and the number of candidate fathers was small. This was true even for strict (95%) confidence, which means that almost all candidate fathers were possible 'true' fathers. It would hence be difficult to assign any extra-pair father as 'true' father with any confidence and consequently there is no good evidence for these three offspring really being EPP-offspring. In 2002 and 2003 critical LOD and Delta scores were reasonably high to distinguish between likely and unlikely candidates ([Table 2](#pone-0012006-t002){ref-type="table"}). 19 nestlings from eight broods in these years could be included in the analysis and in only one case an extra-pair candidate father was the most likely father. However, both this candidate father as well as the social father mismatched at one locus with the offspring and neither of them would have been likely father if tested on their own without knowledge of the social mother\'s genotype. 10.1371/journal.pone.0012006.t002 ###### Minimum number of loci for inclusion in analysis, median number of loci typed per individual, number of candidate fathers and critical LOD-scores and Delta-values (95% confidence) of the paternity analysis of offspring with known social parents, i.e. being ringed in the nest, separately per year. ![](pone.0012006.t002){#pone-0012006-t002-2} Father alone Father given known mother ------ --- ------ ----- -------------- --------------------------- ------- ------ 1976 6 10.4 17 1.15 0.25 −4.50 0.00 1980 6 13.5 15 0.27 0.16 −4.50 0.00 1984 8 12.4 6 −4.00 0.00 −9.00 0.00 1987 8 16.1 12 −1.00 0.00 −6.00 0.00 1990 8 17.3 24 1.81 0.77 −3.00 0.00 1991 8 18.5 29 2.85 1.08 −2.75 0.00 1992 8 19.2 25 2.00 0.84 −3.50 0.00 1993 8 19.1 36 3.53 1.48 −1.88 0.00 1994 8 18.8 41 3.57 1.72 −1.13 0.00 2002 8 20.8 116 5.54 2.57 2.19 1.01 2003 8 20.8 112 5.90 2.41 2.74 0.85 Locating nests did not belong to the standard field work procedure and was done only in some years. Discussion {#s4} ========== We found no evidence for extra-pair paternity (EPP) in our study population despite the fact that data set covered over 30 years and more than 1000 offspring genotyped for up to 21 microsatellite markers. This concurs with an earlier study of the same population [@pone.0012006-Lillandt4] and the results of an analysis of a smaller data set of five large families (349 individuals) genotyped for 117 microsatellite loci from the same population [@pone.0012006-Jaari1] that did not find a single case of EPP. Likewise, in a Swedish study of Siberian jays, no evidence for extra-pair paternity was found [@pone.0012006-Ekman3]. Hence, our results -- together with similar evidence from earlier studies -- provide little evidence to support the possibility that extra-pair paternity in Siberian jays would be common, or in matter of fact, occurring at all. Of course, we cannot strictly rule out the possibility that single cases of extra-pair paternity may have gone undetected. Yet, even if extra-pair paternity in Siberian jays would occur, its frequency must be very low. Due to the limited number of loci typed and the small number of candidate fathers included in extra-pair paternity analysis, critical LOD- and Delta-scores -- and thereby our ability to detect extra-pair paternity -- were low for several years. However, even in years when critical these scores were reasonably high to distinguish in between likely and unlikely candidates, little evidence for extra-pair paternity was found. Another reason why our analyses might underestimate the rate off EPP in Siberian jays is that most of the offspring were sampled after they had left the nest. This means that young that died or dispersed outside the study area before sampling were not available for analyses, and reduces the likelihood of detecting EPP. However, focussing on those 23 broods ringed in the nest and available to analyses, this possible bias could be eliminated: none of those offspring were very likely EPP-young. Hence, if some EPP young were missed due to early mortality or dispersal, their frequency is likely to have been low. If extra-pair paternity in Siberian jays is so rare as our data and earlier analyses suggest, possible reasons for this become of interest. Phylogeny explains over 50% of the among species variation in extra-pair paternity [@pone.0012006-Griffith1]. Although it is not clear whether this is due to ecological similarity of related species or an actual phylogenetic constraint, it is interesting to note that our result of no extra-pair paternity in Siberian jays is in line with the generally low rates of extra-pair paternity in other corvids \[0--1.4% extra--pair offspring, [@pone.0012006-Hall1]\]. Providing 'prolonged brood care' is beneficial in Siberian jays since retained offspring have improved survival prospects [@pone.0012006-Griesser3] and higher life-time reproductive success as compared to dispersing offspring [@pone.0012006-Gienapp1], [@pone.0012006-Ekman3]. Successful 'prolonged brood care' requires both parents and an unfaithful female being deserted by its male may face brood loss and consequently high fitness costs. While the generally low breeding densities in Siberian jays should reduce the 'availability' of extra-pair mates, this may be counteracted by the presence of unrelated males within the group. However, unrelated individuals within a family group have been forced to leave their natal family by dominant siblings [@pone.0012006-Ekman2]. Since they are therefore likely to be of low 'quality' (phenotypic or genetic), they may be unattractive candidates for extra-pair matings. Furthermore, most of the unrelated group-members will leave the group in spring to attempt to establish their own territories. The observed absence or very low frequency of EPP in Siberian jays could hence be easily explained by the high costs of EPP due to their breeding system and the reduced choice of extra-pair partners. Bo-Göran Lillandt is thanked for the field-work and access to the data. Thanks are also due to Marika Karjalainen and Sonja Jaari for help in the lab, as well as Karen Bouwman, Meng-Hua Li and an anonymous reviewer for reading and commenting on the manuscript. **Competing Interests:**The authors have declared that no competing interests exist. **Funding:**This work was funded by research grants from the Academy of Finland to PG and JM, from the Kone Foundation to PG and the Maj and Tor Nessling Foundation to JM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. [^1]: Analyzed the data: PG. Contributed reagents/materials/analysis tools: JM. Wrote the paper: PG JM.

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Dave Nalle is better known for designing roleplaying games like the groundbreaking Ysgarth RPG, but during the 1970s and 1980s he designed a number of small budget but interesting board games and then in the 1990s he designed the much higher budget collectible card game Quest for the Grail. He primarily makes his living as a font designer at (see http://www.fontcraft.com ) and many of his fonts are featured on popular boardgames from other designers. He has designed several technical fonts specifically for game design. Rumor is that he has new games in development from a new company Hanged Man Games (http://www.hangedmangames.com ).

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The Wall Street Journal reports that YouTube is deep in discussions with the movie studios to offer both paid (likely $3.99) and ad-supported movie rentals. This would include new releases, which would be new to YouTube. Lion's Gate, Sony and Warner Bros are all reportedly discussing such a service with Google (who owns YouTube), although details are thin. Negotiations are still ongoing, so a lot of major issues (will downloads be available? Which films would be ad-supported versus a flat fee? What about TV shows?) are still unresolved. But if YouTube could get a solid, competitive system going, they'd have a fair chance at competing with Hulu, iTunes and Crackle and maybe even turn a profit one of these days. [WSJ]

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The husband of an American missionary diagnosed with the deadly Ebola virus has ended his quarantine in North Carolina and visited his wife Sunday at an isolation room at Emory University Hospital in Atlanta, a Christian missionary group announced Monday. David Writebol, who was quarantined as a precautionary measure after returning from Liberia, said his wife, Nancy, was continuing to improve. Nancy Writebol, 59, and a missionary doctor, Ken Brantly, 33, were flown from Liberia earlier this month for treatment at Emory’s special containment unit, one of just four in the country. "I have had the great joy to be able to look through the isolation room glass and see my beautiful wife again,’’ David Writebol said in a statement Monday. "We both placed our hands on opposite sides of the glass, moved with tears to look at each other again." Writebol has not had contact with his wife since she was diagnosed with Ebola in Liberia on July 26. Nancy Writebol, wearing a full-body white protective suit, was flown to Atlanta on a specially-outfitted private plane on Aug. 5. David Writebol said he had no symptoms of Ebola and was cleared by doctors to leave quarantine Sunday to visit his wife. "She was standing with her radiant smile, happy beyond words," David Writebol said of Sunday’s meeting. "She is continuing to slowly gain strength, eager for the day when the barriers separating us are set aside, and we can simply hold each other." David Writebol AP David Writebol, seen here during an interview last week in Charlotte, N.C., was able to visit his wife, who remains in an isolation ward. David Writebol, seen here during an interview last week in Charlotte, N.C., was able to visit his wife, who remains in an isolation ward. (AP) He added: "We prayed together over the intercom." "My family and I look forward to her speedy restoration, and we give thanks for continued prayers on her behalf," Writebol said. Ebola has infected at least 2,100 people and killed 1,145 in Liberia, Sierra Leone, Guinea and Nigeria, according to the World Health Organization. Two other doctors with the Charlotte-based missionary group SIM also were placed in precautionary quarantine on SIM’s campus in Charlotte, N.C., on Aug. 10. The doctors, whose names have not been released, have not been diagnosed with Ebola. Palmer Holt, a spokesman for SIM, declined to say Monday whether the two doctors were still in quarantine. Both Nancy Writebol and Brantly have been treated with the experimental drug Zmapp, which contains a mixture of antibodies. There is no effective vaccine for Ebola, but patients are given fluids and other treatments in hopes of stabilizing them long enough for their immune systems to eventually fight off the virus. In the worst Ebola outbreak in Africa since the virus first appeared in 1976, as many as 90% of those diagnosed have died, according to the WHO. The virus is spread through contact with bodily fluids. On Friday, Brantly released a statement from his isolation room at the Atlanta hospital, saying his condition continued to improve. "I am growing stronger every day," Brantly said. Brantly said he traveled to Liberia not to fight Ebola but to treat patients at a SIM-run missionary hospital in Monrovia on behalf of a North-Carolina based Christian charity, Samaritan’s Purse. But as Ebola swept through West Africa, he began treating Ebola patients, he said. "I witnessed the horror first-hand, and I can still remember every face and name," he said. He added: "As you continue to pray for Nancy and me, yes, please pray for our recovery. More importantly, pray that we would be faithful to God’s call on our lives in these new circumstances."

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Non-iterative method for phase retrieval and coherence characterization by focus variation using a fixed star-shaped mask. A novel non-iterative phase retrieval method is proposed and demonstrated with a proof-of-principle experiment. The method uses a fixed specially designed mask and through-focus intensity measurements. It is demonstrated that this method is robust to spatial partial coherence in the illumination, making it suitable for coherent diffractive imaging using spatially partially coherent light, as well as for coherence characterization.

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The effect of repeated applanation on subsequent IOP measurements. In studies aimed at assessing the accuracy and repeatability of non-contact tonometers, the order in which these tonometers and the Goldmann tonometer are used is usually randomised despite studies in the literature that demonstrate an ocular massage effect that occurs post-applanation but not after non-contact tonometry. The purpose of this study was to investigate the effect of repeated corneal applanation on subsequent assessments of IOP. Data were obtained from 65 left eyes of 65 young, oculovisual normals. Three sets of IOP measurements were obtained, one set with the Goldmann applanation tonometer and two with the Topcon CT80 non-contact tonometer (one set each before and after applanation with the Goldmann tonometer), in each one of two separate measurement sessions, one week apart. The average (and SD) IOP measured with the Goldmann tonometer in the first session (14.8+/-2.9 mmHg) did not vary significantly from the IOP measured with the non-contact tonometer (pre-applanation) in both sessions or with the average Goldmann IOP in the second session. The bias (mean difference +/- SD) between methods was 0.3+/-1.4 mmHg and 0.4+/-1.4 mmHg, respectively, for the first and second sessions, with the CT80 (pre-applanation) recording the higher IOP in both sessions. The within-session repeatability coefficients were +/-2.3 mmHg, +/-2.6 mmHg, +/-2.1 mmHg and +/-2.0 mmHg for the CT80 (pre-applanation) in the first and second sessions, and the Goldmann tonometer in the first and second sessions, respectively. Test-retest repeatability coefficients were +/-2.8 mmHg and +/-2.5 mmHg for the CT80 (pre-applanation) and the Goldmann tonometer respectively. Post-applanation with the Goldmann tonometer, there was a statistically significant (p<0.05) reduction (1.5+/-1.2 mmHg in session 1) in the IOP measured with the non-contact tonometer in both sessions. These results suggest that repeated corneal applanation leads to a statistically significant reduction in IOP on subsequent measurements.

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Summary and Info Subterranean Rodents presents achievements from recent years of research on these rodents, divided into five sections: ecophysiology; sensory ecology; life histories, behavioural ecology and demography; environmental and economical impact; molecular ecology and evolution. It is a must for all researchers working in this field and will be of interest to zoologists, physiologists, morphologists, ecologists, and evolutionary biologists.

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Institutions like Harvard, Massachusetts Institute of Technology and Stanford, among others, are developing ethics and data courses to fill tech industry demand for students who can consider the implications of inappropriate information handling or software development that unfairly targets certain users. Course topics include privacy policy pitfalls, social media responsibility and business models developing around ethical data science. Garlin Gilchrist, executive director of the University of Michigan's School of Information Center for Social Media Responsibility, said in an experts advisory statement that institutions have a unique role in providing a platform where prospective tech industry employees can learn hard data skills and the social implications around them, noting "It will take a collective effort" of higher ed researchersand "policymakers, media companies and users to establish new norms, better understand roles, and create real accountability mechanisms for all parties." Dive Insight: As more major tech companies like Facebook face public scrutiny over their handling of user data, there grows a need for graduates to know the societal implications of the software they develop. Erik Gordon, clinical assistant professor at the Ross School of Business at the University of Michigan, said Facebook is not the only company dealing with these types of privacy scandals and recognizing that its revenue model could be disrupted. "The data scandal means that Facebook has to consider a new model in which it is responsible for content. That is a costly model. It's a model that will lose posters and viewers," said Gordon in the experts advisory. "Facebook is not the only company facing threats. Twitter could be hurt even more because it may gather a higher proportion of its revenue from data than at Facebook." Subsequently, greater numbers of colleges and universities are recognizing the business case for creating blended data and ethics courses, as students become attracted to such offerings that help them stand out within the labor pool for lucrative tech jobs. For example, Dustin Loeffler, associate professor of cyber security and information systems at Maryville University, told Education Dive his institution started offering these interdisciplinary courses because of student demand. He added Maryville combined ethics and philosophy courses with technical courses because "students wanted this, they wanted to be more well-rounded." "In the last presidential election we really saw the outcomes that technology can drive. Students I've worked with have really had their eyes opened up during this time more than they ever had, and this request for this ethical component embedded in the technical curriculum has turned into a sort of organic movement," said Loeffler.

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[Long-term results of the surgical treatment of hiatal hernia using the Boerema technic]. The authors analyse the results of the surgical treatment of "symptomatic hiatus hernia" by the Boerema anterior gastropexy, in 69 patients. As compared to other techniques, the observed mortality and morbidity rates are similar. The postoperative delay is greater than 2 years in 95% of the patients and 83% of them are satisfied with the treatment. Better results are actually obtained with other techniques. Nevertheless, anterior gastropexy which remains the easiest and fastest technique, may still be used in elderly or high risk patients. The Nissen fundoplication is recommended for the majority of the patients suffering from "symptomatic hiatus hernia", especially when ulcerative reflux esophagitis is present.

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Co-culture of healthy human keratinocytes and T-cells promotes keratinocyte chemokine production and RORγt-positive IL-17 producing T-cell populations. Both keratinocytes and T-cells are crucial players in cutaneous immune responses. We hypothesized that direct interactions between keratinocytes and T-cell subsets could shape the nature or strength of the local immune response. We investigated direct interactions between keratinocytes and T-cell subsets, focused on keratinocyte chemokine production and T-cell phenotype and cytokine production. A newly developed in vitro serum free co-culture model using primary keratinocytes and T-cells subsets from healthy human donors was used. Keratinocyte chemokine production was analyzed with luminex, T-cell phenotype and cytokine production were analyzed with flow cytometry. Our data show that upon co-culture with CD4(pos) or CD8(pos) T-cells primary human keratinocytes increased production of functionally active chemokines CCL2, CCL20 and CXCL10 and that regulatory T-cells did not regulate keratinocyte chemokine production. Next to that, we found that keratinocytes skewed CD4(pos) and CD8(pos) T-cell populations toward an IL-17(pos) CCR6(pos) RORγt(pos) phenotype in a cell-cell contact independent manner, and that Treg were able to decrease the absolute number of IL-17 producing T-cells in keratinocyte/T-cell co-cultures. Correspondingly, freshly isolated skin-derived T-cell populations contained relatively high percentages of IL-17(pos) cells. We provide evidence that keratinocyte/T-cell communication may regulate leukocyte influx in the skin, and that keratinocytes enrich T-cell populations for Th17/Tc17 cells. Accumulation of Th17/Tc17 cells, but not chemokine production, appears under the control of regulatory T-cells. Dysregulation of these processes may well contribute to the pathophysiology of inflammatory skin diseases.

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Just a few quick personal thoughts on a third year of blogging about Kenya from the U.S. *The first two years of this blog have coincided with my wife’s graduate school program–she graduated in December (proud smile!) so I will need to be especially aware of evening and weekend time reading and writing about Africa. As I have mentioned, this blog has been in significant part a tool of my own education, so there is a symmetry here. *At the same time, 2012 is a huge year for Kenya, and the natural opportunity for the fulfillment of the hopes and aspirations of so many of us who were involved in some way in the 2007-08 election fiasco, so I will do my best to stay highly engaged. Likewise, we once again have a simultaneous presidential campaign in the U.S., which will just makes things that much more interesting. *Regardless, I do want to take advantage at present of my literal “distance” to observe and comment on larger themes and not get too sucked into the daily cycle of purported Kenyan campaign news. I learned quickly during the last campaign that every day brings big announcements breathlessly covered by the competitive Kenyan media–and of course this is available to us globally through modern ICT (and a real aspect of the campaign since the votes and especially contributions of the diaspora will be important)–but most of them are of little lasting significance. *My distance from Washington will also, I hope, let me have something of a “bird’s eye view” on what is similar and what is different in the approach of the U.S. government and U.S. politicians and other actors to the Kenyan campaign and other events. Continue Reading American lawyer. Took leave from corporate career to “assist” democracy in East Africa. After stolen '07 election in Kenya and violent aftermath I have tried to bring out truth of events for those who care in hope we can learn and do better.

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News Wisconsin, Edwin Witte and Social Security: A History Lesson for Ron Johnson and Paul Ryan Republicans On 75th Anniversary (8/13/10) Posted August 12, 2010 MADISON - Following is the statement of Democratic Party of Wisconsin Chair Mike Tate on the 75th Anniversary of the Social Security Act and the "Father of Social Security," Wisconsin's Edwin Witte: "Seventy-five years ago today, a Wisconsin farm boy named Edwin Witte helped enact a program made necessary by the excesses of Wall Street. At the time, poverty ran rampant amid the elderly as a direct consequence of the greedy speculation of forces far removed from the Dairy State. As an advisor to President Roosevelt, Witte took with him the example of hard work and humility learned here in Wisconsin and sought to fight back the forces conspiring against our nation's working families. Now 75 years later, Paul Ryan and Ron Johnson, who grew up privileged in Wisconsin and Minnesota respectively, have drawn some very different conclusions about the safety net woven for our seniors. In an irony that would not have escaped Witte, Ryan and Johnson, as they seek glory for themselves, now want to hand over Social Security to the very Wall Street forces that threw us into the Great Depression and that caused the economic crisis we face today. Other Wisconsin Republicans, like Scott Walker and Congressional candidate Sean Duffy, have endorsed the Ryan plan, equally blind to the irony. As we celebrate the 75th anniversary of the Social Security Act, brought into being by our own Ed Witte, we promise we will not bend to Wall Street as Ron Johnson, and Paul Ryan would have us. We will protect our seniors."

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It is a common advertising and promotional technique to place coupons, discount cards, prizes or other promotional materials into containers such as cartons for breakfast cereal or snack items or into bagged products such as potato chips. The coupon is highly visible to the consumer who can then use the coupon for the intended purpose, such as for discounts on future purchases or rebates. The coupon itself may also contain a prize or other premium, often a molded plastic figure or other piece. Accordingly, the term “coupon” used herein includes any type of insert, coupon, card, sheet, receipt, warranty, prize, premium, or other part that can be advantageously handled in accordance with the invention hereinafter described. Similarly, the terms “container” and “receiving product” are used in the broadest possible context to include containers such as boxes, tubs, cans, and vessels of all kinds as well as other coupon receiving objects that can be advantageously used with the present invention, such as the fill tube of a form, fill, and seal packaging machine. Placing coupons by hand is very expensive as it is labor intensive and human hands cannot always keep up with the speed of modern automated packaging equipment. Thus, packaging equipment manufacturers have developed a variety of automated coupon inserter machines for placing coupons on or into products. Typically, coupon inserting devices operate by discharging or positioning a single coupon in each container rapidly moving along a conveyor system or into a chute or tube of some other type of product handling system. There are several methods and apparatus for placing single coupons. One requires a stack of pre-cut coupons that are individually dispensed from a downwardly sloping channel, such as the system shown in Prewer, U.S. Pat. No. 4,530,200. In that system, pusher elements and advancing rollers coact to withdraw the forwardmost coupon from the pre-cut stack. The coupon is then drawn into the downwardly sloping channel to a dispensing location. In another apparatus, shown in Gallimore, U.S. Pat. No. 4,197,113, a reciprocal vacuum head picks a coupon from a stack of pre-cut coupons and places the coupon on a conveyor system, which in turn transports the coupons to the containers. Another system, shown in Lewis et al., U.S. Pat. No. 4,354,894, requires the use of a mechanical cutting device to separate each coupon from a continuous web. Once separated, the coupons are dispensed to the containers using a conveyor system. In yet another system, a device separates a single coupon from a continuous web of coupons using a bursting technique and places the coupon into the container or places the coupon into the fill tube of a form-fill-seal packaging system. Such devices are disclosed in U.S. Pat. Nos. 5,845,462 and 6,082,079, respectively, which are assigned to the assignee of the present invention. While such systems are generally effective with flat coupons, they have not been found to be entirely effective for use in connection with thick or bulky coupons such as overwrapped plastic prizes or parts (such coupons shall be referred to herein generally as “three-dimensional coupons”). This invention relates to an improved coupon delivery system as compared to the systems described above and to solutions to some of the problems raised or not solved thereby.

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1. Field of the Invention The present invention relates to a head used for thermally-assisted magnetic recording in which a light propagating through a waveguide is converted into near-field light (NF-light), a magnetic recording medium is irradiated with the NF-light, thereby anisotropic magnetic field of the medium is lowered, thus data can be written. Further, the present invention relates to a magnetic recording apparatus provided with the head. 2. Description of the Related Art As the recording densities of magnetic recording apparatuses become higher, as represented by magnetic disk apparatuses, further improvement has been required in the performance of thin-film magnetic heads and magnetic recording media. To improve the recording densities, it is necessary to decrease the size of magnetic grains that constitute a magnetic recording layer of the medium and to reduce irregularity in the boundary of record bit, thus to form minute record bits reliably. However, the decrease in size of the magnetic grains raises a problem of degradation in thermal stability of the magnetization due to the decrease in volume. As a measure against the thermal stability problem, it may be possible to increase magnetic anisotropy energy KU of the magnetic grains. However, the increase in energy KU causes the increase in anisotropic magnetic field (coercive force) of the magnetic recording medium. As a result, the head cannot write data to the magnetic recording medium when the anisotropic magnetic field (coercive force) of the medium exceeds the write field limit. Recently, as a method for solving the problem of thermal stability, so-called a thermally-assisted magnetic recording technique is proposed. In the technique, a magnetic recording medium formed of a magnetic material with a large magnetic anisotropy energy KU is used so as to stabilize the magnetization; anisotropic magnetic field of the medium is reduced by applying heat to a portion of the medium where data is to be written; just after that, writing is performed by applying write magnetic field (write field) to the heated portion. In the thermally-assisted magnetic recording, a technique is well known, which utilizes a near-field optical device (NF-optical device) as a metal piece that generates NF-light from plasmon excited by irradiated laser light, so-called plasmon antenna. For example, U.S. Pat. Nos. 6,768,556 and 6,649,894 disclose a technique in which NF-light is generated by irradiating a metal scatterer with light and by matching the frequency of the light with the resonant frequency of plasmon excited in the metal. As described above, various kinds of thermally-assisted magnetic recording systems with NF-optical devices have been proposed. Meanwhile, the present inventors have devised a NF-optical device in which laser light is coupled with the NF-optical device in a surface plasmon mode to cause excited surface plasmon to propagate to the opposed-to-medium surface, thereby providing NF-light, instead of directly applying laser light to a NF-optical device. The NF-optical device is hereinafter referred to as a surface plasmon generator. In the surface plasmon generator, its temperature does not excessively rise because laser light is not directly applied to the surface plasmon generator. As a result, there can be avoided a situation in which the end of a read head element, which reaches the opposed-to-medium surface, becomes relatively far apart from the magnetic recording medium due to the thermal expansion of the NF-optical device, which makes it difficult to properly read servo signals. In addition, there can also be avoided a situation in which the light use efficiency is degraded because thermal fluctuation of free electrons increases in the NF light generator. Here, the light use efficiency is a ratio of the intensity of NF-light emitted from the NF-optical device relative to the intensity of laser light incident to the waveguide. In a near-field light generating (NFL-generating) optical system that includes the surface plasmon generator devised by the present inventors and a waveguide through which laser light propagates, it is important to improve the light use efficiency descried above. Here, the surface plasmon generator includes a portion where the generator is coupled with the waveguide light in a surface plasmon mode. Specifically, a surface plasmon mode is induced in the portion by coupling between evanescent light that is equivalent to waveguide light seeping from the waveguide and fluctuations in charge excited on the surface of the surface plasmon generator, thereby exciting surface plasmon. Accordingly, in order to increase the light use efficiency of the NFL-generating optical system described above, it is important to enable the evanescent light to well reach a desired location in the surface plasmon generator. To that end, some artifices are needed not only in the structure of the surface plasmon generator but also in the configuration of the NFL-generating optical system including the waveguide.

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Several proposals expand the existing JavaScript class syntax with new functionality. This article explains the new public class fields syntax in V8 v7.2 and Chrome 72, as well as the upcoming private class fields syntax. Here’s a code example that creates an instance of a class named IncreasingCounter:

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The present invention relates to a RJ modular connector, and more particularly to a RJ modular connector having a substrate provided therein to balance electrical couplings between terminals. RJ modular connector has been widely used in telecommunication system since it was firstly created. A so-called RJ45 modular connector has been widely used in the network system. The RJ45 modular connector includes totally eight terminals. Resulting from miniaturization of the computer, all corresponding components, including connectors, have to be reduced for their dimension and size. One of the negative consequences or problem created from miniaturization is electrical coupling between terminals. When the RJ connector is used in low speed signal transmission, the couplings between adjacent terminals can be ignored in light of its effect. However, when the RJ connector is used for high speed signal transmission, the couplings between adjacent terminals create a great problem. Unless the electrical coupling can be effectively controlled within an accepted level, it is unlikely that the RJ45 modular connector can be used in the high-speed signal transmission. One of the approaches is to select a pair of terminals as a differential pair. In the differential pair, two terminals transmit the same signal but with inverted phase. By this arrangement, the couplings coupled thereto can be finally subtracted in a data processing unit. As shown in the catalog from The Siemon Company which will be submitted later with IDS, there are at least eight different patterns in selecting terminals as differential pair, i.e. T568A, T568B, USOC 4-pair, USOC 1-, 2- or 3-pair, 10BASE-T (802.3), Token Ring (802.5), 3-pair (MMJ), and TP-PMD (X3T9.5) and ATM. In each implementation, two terminals are selected as a pair in which some are close to each other, while some are apart from each other. Each pattern has its own uniqueness, while each also carries a coupling issue need to be solved. Among those patterns, T568A and T568B are widely used and in T568A, terminals 1,2 configure 3rd pair, terminals 3,6 configure 2nd pair, terminals 4,5 configure 1st pair, while terminals 7,8 configure 4th pair. In T568B, terminals 1,2 configure 2nd pair, terminals 3,6 configure 3rd pair, terminals 4,5 configure 1st pair, while terminals 7,8 configure 4th pair. Since those eight terminals are equally spaced, electrical couplings between terminals will surely create some problems, i.e. coupling or cross-talk. For example, if we take terminal 3 into consideration, terminal 3 will naturally pick up energy coupled from terminals 2, and 4 which are close to terminal 3. On the other hand, terminal 6, which carries signal having inverted phase of the signal carried by terminal 3, will also pick up energy coupled from terminals 5 and 7. However, energy coupled into terminals 3,6 from terminals 2 and 7 can not be suitably eliminated because terminals 3,6 is unlikely to establish couplings between terminals 1 and terminals 8 to balance the couplings between terminals 2,3 and 6,7. Accordingly, signals transmitted by terminals 3,6 carry noises generated by their adjacent terminals 2,7. In addition, terminals 3 and 6 will also carry noises coupled thereto from terminals 4,5 and which couplings should be also carefully taken to avoid certain noises. In order to decrease the effects of electrical coupling between the (3rd, 4th) and (3rd, 2nd) terminals, and (6th, 5th) and (6th, 7th) terminals, many approaches have been provided, such as creating electrical couplings between 3rd and 1st terminals and 3rd and 5th terminals, to balance the electrical coupling between the 3rd and 2nd terminals and 3rd and 4th terminals, and creating electrical coupling between 6th and 8th terminals and 6th and 5th terminals to balance the electrical couplings between the 6th and 7th terminals and 6th and 4th terminals. However, as mentioned above, those eight terminals are arranged in a common plane, it is impossible to create those balancing electrical couplings, i.e. (1st, 3rd), (3rd, 5th), and (4th, 6th), (6th, 8th) terminals when all terminals are located in the same level, it is unlikely to create any electrical channels therebetween to create those electrical couplings accordingly. The Siemon Company, a U.S. company, discloses a solution posted on the Internet, http://www.siemon.com/white papers/99-08-30-through-hole.asp. A hard copy thereof will be submitted with IDS for reference. As clearly shown in FIG. 4 of that reference, 6th and 2nd terminals are arranged in the first layer, while 8th, 5th, 4th, and 1st terminals are arranged in the second layer, and 7th and 3rd terminals are arranged in the third layer. The 6th terminal in the first layer has a rectangular loop having its longitudinal sides aligned with terminals 4th and 8th located in the second layer, while terminal 3 in the third layer also has a rectangular loop having its longitudinal sides aligned with terminals 5th and 1st located in the second layer. In addition, the right longitudinal loop side of the terminal 6th further includes a square corresponding to a square formed in terminal 4th. The left longitudinal loop side of the terminal 3 includes also a square with respect to the square formed on terminal 8th. Arrangements suggested by Siemon are to increase the couplings between (1st, 3rd) (3rd, 5th) and (4th, 6th), (6th, 8th) terminals thereby helping to balance electrical couplings of the terminals. However, those eight or four set sets of terminals are arranged in three different layers, and each set of terminals are separately divided by an insulative sheet material. This will no doubt increase the complexity of the connector. In addition, there are five different shapes and configurations among those eight terminals. Each terminal has its own shape which is different from each other, especially the 3rd and 6th terminals, each including the rectangular loop portion which overlap to corresponding terminals to create wanted electrical couplings. Each loop further forms the square to increase the electrical couplings with corresponding terminals having the square. The electrical couplings created can help to meet higher system requirement. The eight different configuration of the terminals will surely increase the difficulty and complexity in production. There are some other approaches that including routing terminal tails of those 3rd, 6th and 4th, 5th terminals to alter their position and affect couplings between 3rd, 2nd and 3rd, 4th; and 6th, 5th, and 6th, 7th terminals. However routing terminal tails will inevitably increase the manufacturing cost. U.S. Pat. No. 6,120,329 issued to Steinman on Sep. 19, 2000, discloses another approach to solve the above-addressed problem. Again, terminals are configured with different shapes and dimensions making the production complex. U.S. Pat. No. 5,069,641 issued to Sakamoto et al. discloses a suggestion of using printed circuit board in the RJ modular housing, however, it addresses to different issues. It is an object of this invention to provide an RJ modular connector, and more particularly to a RJ modular connector having a substrate with conductive traces provided therein to balance electrical couplings between terminals. It is still an object of this invention to provide a RJ modular connector which can be easily manufactured. In order to achieve the objective set forth, an RJ modular connector in accordance with the present invention comprises a housing defining a plug receiving section, and a terminal core receiving section. A terminal core is received in the terminal core receiving section and includes a plurality of terminals. A substrate is provided having conductive trace thereon. The terminals are securely mounted onto the substrate. An electrical connection is established between a first terminal and the conductive trace, and a portion of the conductive trace is arranged to create a first electrical coupling between the first terminal and a third terminal thereby balancing a second electrical coupling between the first terminal and a second terminal arranged between the first and third terminals.

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Q: Spring JPA query findByNameAndType returns null I have an interface public interface IAllAccountsRepo extends CrudRepository and a method in that like below @Query(value = "SELECT * FROM account a where a.id in :id AND a.accountType = :accountType", nativeQuery=true) public AccountEntity findByIdAndAccountType(@Param("id") String id, @Param("accountType") String accountType); When i call this method in a helper class, where I will get a list of ids and I loop through them and pass in a filter value to the above method, but i have issues when there is no record matching the query in the database. It just stops by saying null(when there is no record in db). I do not want to through exception, need to ignore and proceed if i can do that. Is there anyway i can code it to ignore the null and proceed? or do i need criteria query or any other? for (String id : accountIdList) { accountEntityTemp = iAllAccountsRepo.findByIdAndAccounttype(id, accounttype); System.out.println("bs" + accountEntityTemp.getId()); if (accountEntityTemp != null) { accountsEntityList.add(accountEntityTemp); } } accountEntityTemp = null for one id and accounttype and i'm getting the below error. 2015-12-10 14:20:03.784 WARN 10524 --- [nio-8080-exec-1] .m.m.a.ExceptionHandlerExceptionResolver : Handler execution resulted in exception: null Thanks. A: Uhm... First of all please.. @Query(value = "SELECT * FROM account a where a.id =:id AND a.accountType = :accountType", nativeQuery=true) public AccountEntity findByIdAndAccountType(@Param("id") String id, @Param("accountType") String accountType); That being said... Just.. why? You're extending crudrepository, so you could as well just write AccountEntity findByIdAndAccountType(String id, String accountType) IF your attributes on AccountEntity bean are named Id AccountType or change id to Integer, as I don't know its type.. plus man, some care of potential NPE.. you told us it's possible no accountentity is found... yet you do accountEntityTemp = iAllAccountsRepo.findByIdAndAccounttype(id, accounttype); System.out.println("bs" + accountEntityTemp.getId()); /// Null pointer here potentially... if (accountEntityTemp != null) { accountsEntityList.add(accountEntityTemp); } at most change it to accountEntityTemp = iAllAccountsRepo.findByIdAndAccounttype(id, accounttype); if (accountEntityTemp != null) { System.out.println("bs" + accountEntityTemp.getId()); accountsEntityList.add(accountEntityTemp); }

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Q: expanding and collapsing menu items I have a menu made of divs containers and when I mouse over the menu item i want to exand the next element that has a class called container the thing I want to know is when they are expand and I go back to the previous div like back two divs I want the others to contract there widths so if three divs are open and i go back to the first div container the last or others in front contract there width to 0 except the next div cos it displays the next menu items how do do this any examples would be appreciated. <div class="container> <div class="menu"> <div>Menu Item 1</div> <div>Menu Item 2</div> <div>Menu Item 3</div> <div>Menu Item 4</div> </div> </div> <div class="container> <div class="menu"> <div>Menu Item 5</div> <div>Menu Item 6</div> <div>Menu Item 7</div> <div>Menu Item 8</div> </div> </div> <div class="container> <div class="menu"> <div>Menu Item 9</div> <div>Menu Item 10</div> <div>Menu Item 11</div> <div>Menu Item 12</div> </div> </div> $('.container .menu .menu-item').mousenter(function() { $(this).closest('.container').next('.container').css('width' 200); }); A: Wow, that was a long sentence...please use punctuation (and run grammar check). In answer to your question, you could set all the containers' widths to 0 before running the next line of your code, like this: $('.container').css('width': 0); $(this).closest('.container').next('.container').css('width' 200); If you use this method you should probably also save $('.container') in a variable for better performance. Is that what you wanted to do? If not, please explain your question a little more clearly.

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Category: India East Godavari District, Andhra Pradesh, India (2nd May 2010) While India is known for its sweet tooth and a range of tasty sweet foods, I have seldom seen how they are actually made. Fortunately, I got this opportunity rather unexpectedly while travelling through the villages of East Godavari district in the Southern Indian state of... Continue Reading →

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Q: Qt の GridLayout にて、予め指定したグリッド数でカラムを分割したい Qt上のグリッドレイアウトで悩んでいますいくつかのカラム数に分割してラベルを配置したいのですがあらかじめ縦横の分割数を設定することは可能でしょうか lblDummyMainUpLeft = new QLabel(); lblDummyMainBottomRight = new QLabel(); //左上 lblDummyMainUpLeft->setText("topleft(0,0)"); lblDummyMainUpLeft->setStyleSheet("border:2px solid red;"); //右下(4,5)のところに配置したい lblDummyMainBottomRight->setText("bottomright(4,5)"); lblDummyMainBottomRight->setStyleSheet("border:2px solid red;"); //QGridLayout上に配置 gridmain->addWidget(lblDummyMainUpLeft,0,0,1,1); gridmain->addWidget(lblDummyMainBottomRight, 4, 5 , 1 , 1); //●Y=1,X=1に配置されてしまう本当は細かく分割した箱があって、2個目のラベルを右下に配置したいのですが、2分割しかされませんでしたあらかじめ縦横の分割数を決定しておくことは可能でしょうか・・・まあ、透明なラベルを個数分敷き詰めれば上手く行くと言えば行くのですがちょっとスマートじゃないな・・と・・ A: ありがとうございます。複数の解像度で動作して、基本は等間隔で並ぶのでカラムごとに最小、最大を一々求めるのは上手く行かなかったですとりあえず、あらかじめダミーのラベル(この場合は横に5列、縦に4列)のからのラベルを敷き詰めてそれから本命のパーツをはめ込んで上手く行ったのでそれで解決としました

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Extra Credits Extra Credits is a video lesson series currently presented by James Portnow, narrator Matt Krol, and artists David "D" Hueso, Lilienne "Lil" Chan, Scott DeWitt, Nick DeWitt, and Dan Jones. The series of videos discuss issues pertinent to video games and game studies, particularly discussing issues concerning video game development, addressing the legitimacy of video games as art, and creating intellectual discourse on important issues in gaming culture. The series was developed directly from a series of lecture videos by animator Daniel Floyd, informally known as "Video Games And...", which ran sporadically from February 17, 2008 to April 16, 2010 with certain episodes written by Portnow. The series originally aired on The Escapist from July 28, 2010 to August 10, 2011, before being split off over a financial dispute. Between September 7, 2011 and December 31, 2013, the show aired on PATV, a distribution channel hosted by Penny Arcade, whose downsizing of partner services after the latter date was cited as the reason for the show's subsequent "move" to YouTube, where the show is currently aired. In addition, the episodes have been syndicated on many websites, including ScrewAttack. History 2008-2011: Beginnings The series has its roots in 2008 when co-creator Daniel Floyd created two video presentations for his respective art history and media theory classes at Savannah College of Art and Design. Floyd states that the style of his presentations was "loosely modeled" after Zero Punctuation. The assignment had a time limit of ten minutes, so Floyd sped up his voice by 10% to meet that limit, an effect that continued in subsequent episodes. He put it on YouTube just to see if anyone had interest and to his surprise the videos viewers hits grew very large very quickly. James Portnow had been referenced in these early videos and decided to contact Floyd about the possibility of working together to make more videos. Portnow wanted Dan to continue using his original created format of videos with animated Dan giving lectures at the podium about articles that would be written by Portnow. These were not part of an officially-named series, though this early collection eventually went by "Video Games and...". A blog maintained by creator Floyd for the videos used the secondary title "Talking About These", and certain videos also went by "Game Design Corner". One episode also features journalist Leigh Alexander from Gamasutra in a discussion about video games and their female audience. In July 2010, an announcement was made that the series would be a featured series for The Escapist, where weekly episodes of the series began, as well as the introduction of the new title, Extra Credits. Since Floyd had started working at Pixar Canada at the time, Portnow also enlisted colleague Allison Theus to handle the art. The first episode, "Bad Writing", debuted on July 28 and would since be on The Escapist for the next year. In May 2011, The Escapist and the show's creators hosted the Extra Credits Innovation Awards at LOGIN 2011, which was meant to praise developers who were willing to take risks and push the boundaries of video games as a medium. Awards were intentionally nonstandard compared to other awards frequently presented, focusing on ingenuity rather than success, including the categories: Innovation in Game Design, Innovation in Narrative Delivery, Most Unbelievable Awesome Fun, Genre Buster Award, Positive Impact Innovator, and LOGIN Special Award for Innovation in Multiplayer. 2011-2016: Dispute and revival On June 28, 2011, Portnow announced through the show's Twitter account that Theus had a radial tear in her shoulder (likely a separated shoulder) that could potentially end her career. A two-month crowdfund project on RocketHub was created with a goal of $15,000, which eventually raised around $104,000. The crew, overwhelmed at the response, decided to start an independent game publisher with the excess profits. Around the end of July, The Escapist privately contacted Portnow with a disputing claim for the funds. Alexander Macris, then-content director for The Escapist, led the claim and stated the money should have been used to create more episodes of Extra Credits and to compensate parent company Themis Media for donation incentives, such as premium memberships and T-shirts. As a result, Extra Credits broke ties with The Escapist, and after a brief four-week stint posting directly to YouTube, the show was picked up by Penny Arcades PATV network. The indie fund would ultimately be created under Extra Credits LLC, which was started on November 18, 2011 and holds the show's unregistered IP rights. Starting with episode 100, Elisa "LeeLee" Scaldaferri (creator of former Escapist webcomic Name Game) became an official staff artist for the show, to rotate episode productions with Theus. Later, Theus departed from the series to work full-time at Retro Studios (though she still contributes to spin-off mini-series) and was replaced by webcomic artist Scott DeWitt. In December 2013, Penny Arcade announced the downsizing of its services, including the detachment of Extra Credits and other partner shows from PATV. The crew announced that their official YouTube channel, which was previously intended to be an outlet for syndication, would become the official release outlet starting at the beginning of 2014. The first videos officially released since then were a previously-broadcast live Q&A video and the episode "The Good We Do". 2017-present: New team and departures On 2017 the show's Twitch channel was relaunched, with nightly hosts including Echo Diaz and Will Overgard. On May 23, 2018, in the episode "Choice Paralysis - Too Much Of A Good Thing", Daniel Floyd announced that he and Carrie would be leaving Extra Credits, and that Matt Krol would take over as new narrator and showrunner. Krol was a television producer and podcast host who frequently guest hosts with Portnow on the show's Twitch channel. A series of Extra History and a spinoff called Extra Politics were completed ahead of the announcement and aired throughout June of that year. On October 30, 2019, however, in the episode "The Perfect Horror Protagonist - Writing a Character for Fun & Terror", Krol mentioned that James Portnow, the only member of the original lineup, is leaving Extra Credits after 10 years of being the show's writer, even though his scripts will be used for future episodes. Members Controversy Will Overgard was laid off after a harassment claim was privately reported, though the exact events are disputed. On June 9, 2018, former media director Soraya Een Hajji went public on Twitter about leaving the show due to growing tensions with Portnow after their romantic relationship had ended. Extra Credits responded with a statement on their website in which they confirmed there had been a complaint but stated that an investigation "found no evidence of improprieties with regards to the claims of workplace harassment." Format The show is presented in the style of a lecture hall, and addresses the topic of the week with illustrations and random imagery from various sources on the internet, with a strong focus on visual puns. The tone is generally light-hearted and often humorous, but always didactic, intended to educate the audience and encourage discussions on the presented subject. Generally, the show's topics target the perspective of a game designer rather than average gamers. The opening song, "Penguin Cap" by CarboHydroM, is a cover of the "Slide" music cue from Super Mario 64. Ending songs vary between episodes, but are typically sourced from OverClocked ReMix, where Floyd was a former contributor. Notably, Floyd hinted occasionally about another arrangement from CarboHydroM that he wanted to use as his departing outro song, which was revealed to be a cover of the end credits music from Super Mario Kart called "Secret 1000cc Mode" on his final Extra Credits episode in May 2018. Extra Credits for most of its history was produced and narrated by Floyd, who used pitch-shifting to create a unique, high-pitched voice. Portnow is credited for writing episode scripts, which are refined by Floyd or Krol for recording. Floyd was also responsible for editing videos, but later assigned these duties to his wife, Carrie. Original art was drawn by Theus in the first years of the show, but episodes were split between Scaldaferri and DeWitt. Since October 2014, episodes have been split between Dan Jones and DeWitt. Occasionally, guest artists have been invited during production droughts and spin-off series, most notably webcomic artist Erin Siegel, who had made repeated appearances. While Extra Credits discusses new topics every week as they apply to video games, there are some topics which are more frequently addressed than others, including: poor narrative creation, level design, gamification, tangential learning, sexuality and gender discrimination both within games and in the gaming community, and diversity in games (including gender, sexuality, and racial diversity). The show is also frequently critical of the triple-A video game industry. Extra Credits is also a big proponent of independent developers, although it has been frequently stated that they don't want to see only "art house" games either. "No one on this show wants every game to try to be gaming's Ulysses or even gaming's Blood Meridian. But we really would like to see a few more Mass Effects, Portals, Bioshocks, even Call of Duty 4s." Business operations have been handled by Kate Donaldson until the end of 2013, and have been handled from then until 2018 by Soraya Een Hajji, who is also a volunteer director for GaymerX. Een Hajji also began writing Extra History in 2017 to assist Portnow in scheduling. Community July 1, 2011 marked the creation of a fan-operated community surrounding Extra Credits with a Steam group indirectly started in response to Theus' injury, and which was supported by Portnow. Group chat sessions ultimately led to the creation of a web forum, Extra Curricular, during the night of the 15th. The forum was publicly acknowledged by Portnow on July 21 and August 25, and was re-launched on a new official domain for the show around January 10, 2012. Meant for PAX East 2012, a tribute video to Extra Credits was also made featuring some fans and colleagues of the crew. This was the basis for an independent testimonial program. After Extra Credits had established its home on YouTube, on January 12, 2016, plans were announced to shut down the official website, including the Extra Curricular forum. The forum was independently spun off as Bonus Points, while a semi-official Discord server was established to fill the community gap and a new official website was launched in late 2017. On August 6, 2018 Extra Credits announced their first game jam hosted on itch.io, running from August 16 - August 18. The jam hosted 1,158 participants, and finished with 328 entries, a little over 28% participation (an average game jam has approximately 25% participation). In a blog post following the jam, Extra Credits indicated they would like to host more events like the jam and "By hosting more opportunities in the future for people to creatively collaborate, we hope that more people are enabled to make cooler things--because learning matters." Serials Since partnering with PATV, all official episodes have been re-categorized into seasons of 26 each for technical constraints on their site. The only videos to not follow this format are the pre-Escapist videos, which are exclusively held by Floyd but have each been eventually replaced by updated official episodes. Mini-series and spin-offs During the show's run, the creators have been occasionally requested to create game-specific mini-series based on Extra Credits. The first one was Extra Credits: Firefall, which spanned 5 episodes and was requested by Red 5 Studios to help reinforce the game design decisions in their video game Firefall. After moving to YouTube, the team decided to make use of their space to expand their channel with new series running on different days of the week. First announced on March 24, 2013 and debuted 4 days later, James Recommends is an extension of previous "Games You Might Not Have Tried" episodes of the main series, and features Portnow discussing the merits of less-popular games which he finds unique. The following week, Floyd announced Extra Remix, which features spotlights on promising members of the video game music community, namely through OverClocked ReMix. Portnow also brought in colleague Dan Emmons to run Design Club, a series supplemented by live streams in which Emmons discusses the merits of design as they pertain to specific games or levels. Extra Frames is a series of videos produced by Floyd in which he discusses video game animation, which has since rebranded to New Frames Plus(see PlayFrame below). A new series began in late 2017 titled Extra Sci-Fi, which examines works of science-fiction and their cultural impact. Another spin-off, titled Extra Mythology, began in early 2018, examining myths from different early religions. On June 4, 2018, Extra Credits launched an 8-episode mini-series named Extra Politics that exploring the United States political system from a game design perspective. Extra HistoryExtra History is a spin-off on the main channel focused on topics in history. It started out as a mini-series requested by Creative Assembly to deal with the Punic Wars, in which their video game Total War: Rome II was set. On August 23, 2014, the crew announced a campaign through Patreon to fund the continuation of Extra History full-time. This campaign gained over $2,500 within a 24-hour period, and as of June 2018 lists over $15,000 in monthly pledges. Topics are chosen by a monthly poll seeded with suggestions made by Patreon supporters. The show has its own dedicated staff, including art by David Hueso, Lilienne Chan, and Nick DeWitt, and music by Dean and Sean Kiner. Twitch channel The show's official Twitch channel was launched in 2013 as a live supplement on certain weekdays. It originally ran with Design Club Live and Allison's Art Corner, hosted by Dan Emmons and Allison Theus respectively. Emmons departed within a few years, and the channel went dormant. It was relaunched in 2017 with the hiring of professional streamer Will Overgard to be production lead for the channel. Overgard frequently streamed video games on the channel until his removal in April 2018. Various gameplay and discussion streams have since been aired by Echo Diaz, David Hueso, James Portnow, and Matt Krol. PlayFrame Extra Credits launched a sister channel called Extra Play on December 14, 2014, but it did not become active until October 2015, when Side Quest, a Let's Play series of Dark Souls with Floyd and Portnow, was moved from the main channel to Extra Play. The purpose of this channel is to provide a place for the team to post more casual, less-scripted videos that wouldn't fit on Extra Credits. Besides Side Quest, the channel runs several other let's play series. In Guest Play, Floyd brings in people who also work in the gaming industry to discuss design elements in video games, which often features other members of the Extra Credits team. Floyd also started an unnamed series of videos discussing animation in video games, which has since been named Extra Frames and moved to Extra Credits on May 5, 2016. Portnow has started Destiny Whaaat? and Tea & Hearthstone. He discusses questionable design choices in Destiny in the former and analyzes aspects of Hearthstone in the latter. Dan Jones, one of the artists of Extra Credits has started a Pokémon Nuzlocke Challenge of Pokémon Diamond. Since leaving Extra Credits, Floyd took personal ownership of the channel (as well as Extra Frames series, see Mini-series and spin-offs above) and renamed it PlayFrame''''', with future content to be announced. References External links Official site Category:2008 web series debuts Category:Non-fiction web series Category:American web series Category:Internet properties established in 2010 Category:2010 web series debuts Category:Online edutainment Category:Gaming-related YouTube channels Category:Video game critics

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Introduction ============ Pregnancy involves a greater risk of malaria[@B01]. The prevalence and severity of gestational malaria (GM) that occurs during pregnancy has been studied in Africa, Latin America, Oceania and Asia[@B02]. What is known about GM and placental malaria (PM) relates to *Plasmodium falciparum* and very little is known about the role of *P. vivax* [@B03]. Gestational malaria patients usually present with anemia[@B04]. A review of seven Latin American studies on GM confirms the clinical effects of the infection with *P. falciparum* as the main causing species[@B05]. During a normal pregnancy the immune response undergoes specific changes to allow successful implanting and development of the fetus. Therefore, a Th2 profile is observed in successful pregnancies, while presence of a Th1 cytokine (pro- inflammatory) profile results in spontaneous abortion due to direct cytotoxic effects on the trophoblast. *Plasmodium* infection in the mother changes the protective cytokines balance and increases the Th1 responses leading to complications such as anemia, abortion, stillbirth, low birth weight, among other. The normal anti-inflammatory status observed in the uninfected placenta is mediated by the increased production of cytokines, such as interleukin (IL)-10, and transforming growth factor β (TGFβ) which probably suppress the immune response mediated by cells. During GM-PM, this type of response is required to control symptoms, while the parasite is cleared by other mechanisms [@B06]. The most studied cytokines in the physiopathology of *P. falciparum* GM are tumor necrosis factor (TNF), gamma interferon (IFNγ) and IL- 10, but other cytokines and chemokines have also been explored[@B07]. Many cytokines changes during GM-PM might be involved in the pathogenesis of gestational malaria resulting in low birth weight, intrauterine growth restriction, and preterm delivery. During placental infection, increased production of TNF and IFNγ results in injury of the villous trophoblast[@B08]. Furthermore, macrophage inflammatory protein 1-beta (MIP-1β), TNF and IL-8 have been associated with low birth weight and intrauterine growth restriction; and Interleukin 1β, IL-6, IL-8 and TNF have all been involved in pre-term delivery[@B09] ^,^ [@B10]. Accumulation of inflammatory cells, particularly macrophages and monocytes, in the inter-villous space, results after increased MIP-1β. Consequently, both the trophoblastic morphology and placental cytokine production are affected [@B11]. About 25% of women with GM have placental monocyte infiltrates at the time of delivery and this has been identified as a key factor and predictor of low birth weight. It has been suggested that infiltrating monocytes represent a significant source of pro-inflammatory cytokines in the infected placenta[@B12]. Currently, no reports have been made on the immune balance during GM-PM by *P. vivax*, a species highly endemic in Asia and America. The aim of this research was to describe the expression profile of the pro-inflammatory cytokines TNF, IFNγ, IL-1β, the anti-inflammatory cytokines IL-10, IL-6, TGF-β and the chemokines IL-8 (CXCL8), MIP-1 β (CCL4) and MCP-1 (CCL2), in pregnant women and placentas infected with *P. vivax* at the time of delivery as well as to describe the association with clinical and epidemiological characteristics. Materials and methods {#s1} ===================== Study site {#s1a} ---------- The study was carried out in north-west Colombia in the locality of Puerto Libertador (Cordoba department). Between Antioquia and Cordoba departments lays the malaria endemic region known as Uraba-Altos Sinu/San Jorge-Bajo Cauca, which has an estimated area of 43,506 km2 and a malaria at-risk population of 2.5 million distributed in 35 municipalities. This large region generates over 60% of malarial cases in Colombia: 18% in Córdoba and 42% in Antioquia. *P. vivax* predominates over *P. falciparum* malaria in approximately a 2:1 ratio[@B13]. In 2006-2007, Antioquia and Córdoba contributed, on average, 61,458 cases of malaria, or 60.2% of the total for Colombia. Those two departments during the same years contributed 72.1% of the cases of *P. vivax*, 34.4% of the cases of *P. falcpiarum*, and 45.7% of the cases by both especies[@B14]. Subjects for the current study were recruited at the local hospital and the antenatal clinic of \"CAMU Divino Niño\", in Puerto Libertador. Study type, design and sample size {#s1b} ---------------------------------- Volunteers were enrolled as part of a descriptive, prospective and transversal study, between June 2010 and June 2012. The sample size was defined by convenience and the lengthy period of recruitment was the result of severe and prolonged political turmoil in the region, which also jeopardized a random inclusion of subjects. Therefore, recruitment took place in a sequential fashion until the sample size for the study was reached. Subjects were grouped as follows: a) parturient women with *P. vivax* GM at delivery (GM+); b) healthy pregnant women without GM during pregnancy and at childbirth (GM-). Recruitment took place regardless on the presence clinical signs of malaria infection at the time of diagnosis. Thirty-five pregnant participants were enrolled: 15 with GM at delivery (GM+), and 20 without GM at the antenatal clinic or at delivery (GM-). Criteria for inclusion and exclusion {#s1c} ------------------------------------ Inclusion criteria were\>1 year residency in the study region, general good health and no history of serious disease, signature of the voluntary consent form, hospital delivery and attendance to at least three antenatal check-ups. Exclusion criteria were withdrawal of the voluntary consent and the finding of a PCR positive for *P. falciparum* infection. Collection of clinical data {#s1d} --------------------------- Clinical data were collected after review of the antenatal clinical records and delivery charts. Information on mother´s age, weeks of gestation, parity, mother´s hemoglobin and newborn weight, was recorded. Sample collection and preparation {#s1e} --------------------------------- Whole blood samples from mother´s peripheral blood and placenta were obtained at delivery rooms in the local hospitals of Puerto Libertador. The mother\`s sample was obtained by finger prick and placental blood was obtained from the lake formed following a wash with saline (0.9%) and removal of a 3x3x3 cm section in the area of the cord\'s insertion on the maternal side of the organ. These samples were used to perform thick and thin smear examination and PCR as detailed below. In addition, 4ml of maternal peripheral blood were collected and immediately stored in liquid nitrogen, this and a RNA later^(r)^ preserved tissue fragment obtained from the placenta, were processed for expression of cytokines and chemokines. Diagnosis of Plasmodium infection {#s1f} --------------------------------- The presence of *Plasmodium vivax* was confirmed in maternal and placental blood by thick smear and a nested polymerase chain reaction (PCR) according to standard published methods[@B15] ^,^ [@B16]. Diagnosis by microscopy was carried out in the field site by a trained technician with certified experience in malaria diagnosis. Parasitaemia was calculated after observation of fields corresponding to 200 leukocytes and a constant of 8,000 leucocytes/μL. A sample was considered negative after observation of 500 high power fields. Diagnosis of infection by PCR was performed to whole blood samples collected onto Whatman 3MM filter paper, from which DNA was extracted using Chelex100^(r)^ (Sigma(tm)). Amplification was carried out using a nested PCR assay to detect the 18 s rRNA gene of *P. vivax*, according to previously published procedures[@B16]. The positive reaction control consisted of DNA from a well characterized field isolate of *P. vivax*. Amplification products were resolved in a 2% agarose gel using ethidium bromide and visualized under UV light. Samples were processed once as long as controls were confirmed to operate in optimal conditions, otherwise, the assay was repeated until successful performance of controls. For the GM+ group, at least one positive test was required for allocation and all tests were required negative for the GMC- group. Term definitions {#s1g} ---------------- The following definitions were applied: A) Low birth weight: \<2,500 grams. B) Preterm delivery: a pregnancy concluded before 37 weeks. F) Maternal anaemia: haemoglobin \<11 g/dL, G) Full term pregnancy: \>38 weeks. H) Gestational or pregnancy malaria: plasmodial infection diagnosed in a pregnant woman after examination of maternal peripheral blood. I) Placental malaria: plasmodial infection diagnosed in placenta after examination of placental blood. Cytokines and chemokines expression analysis {#s1h} -------------------------------------------- Relative quantitation for expression analysis was performed using a reverse-transcription real time PCR assay (RT-PCR). Total RNA was extracted using QIAamp RNA Blood Mini^(r)^ (QIAGEN) and cDNA was synthesized using First Strand cDNA Synthesis^(r)^ (Fermentas). The quality of the cDNA was confirmed by using a conventional PCR for the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene. The reaction was set up in an Applied Biosystems Step One Plus system using TaqMan^(r)^. Results were read at 530 nm. the following genes were analyzed for expression: TNF, IFNγ, IL-1β , IL-10, IL-6, TGF-β, IL-8, MIP-1 and MCP-1 . The efficiency of the PCR reactions was determined based on mRNA extracted from a stimulated BeWo cell culture or peripheral mononuclear cells from a donor. cDNA was serially diluted and expression of β-actin was used to normalize the assays using the delta delta CT method (ΔΔCt). The reaction was performed in a final volume of 10 uL containing 1 uL DNA, 5ul TaqMan(r) master mix (Applied Biosystems), and 0.5 uL of 20X TaqMan assay mix (primers and probes for each cytokine/chemokine). All primers were supplied by Applied Biosystems. Reactions were performed at Laboratory of Tropical Diseases of the University of New Mexico, USA. Statistical analyses {#s1i} -------------------- Data were analyzed using SPSS 10.0 (SPSS IBM, Armonk, NY). Proportions and medians were obtained. Significance was established at p\<0.05%. The analysis included comparisons with using Mann-Whitney U test. Bivariate linear correlations were analyzed using Spearman´s rho coefficient. Ethical issues {#s1j} -------------- The study protocol was reviewed and approved by Ethics Committee of Instituto de Investigaciones Medicas, Universidad de Antioquia (acta 012: project Colciencias code 111549326134, contract 611 de 2009). Volunteers were recruited in accordance with national guidelines (Resolution No. 008430 of October 4, 1993, Republic of Colombia, Ministry of Health), as well as international guidelines (Declaration of Helsinki and its amendments, World Medical Association (WMA), Edinburgh, Scotland, October 2000). Subjects were assigned a code which was known only by the researchers. Results {#s2} ======= Characteristics of the population studied. {#s2a} ------------------------------------------ A total 35 pregnant women were included in the study, 15 were allocated to the GM+ group and 20 to the GM-. . No significant differences were observed in the clinical and epidemiological variables between the two groups ([Table 1](#t01){ref-type="table"}). In both groups, there was a significant linear correlation between age and parity (rho = 0.868, p = 0.000) and parity and birth weight (rho = 0.628, p = 0.000). Pre-term delivery was observed in the GM+ group and absent in the GM- group. Table 1Characteristics of the study groups with and without gestational malaria Expression of pro-inflamatory/anti-inflamatory cytokines and chemokines in placental tissue and maternal peripheral blood. {#s2b} -------------------------------------------------------------------------------------------------------------------------- When comparing the expression of pro-inflammatory and anti-inflammatory cytokines in placental tissue in the GM+ and GM- groups, an increase in the levels of pro-inflammatory cytokines (TNF, IFNg and IL1β) was observed in the former. Significance in this finding was confirmed for TNF. Regarding the anti-inflammatory cytokines, these were lower in the GM+ group *versus* the GM- group; however, no significance could be confirmed in this result. Similarly, the chemokine MCP-1 was observed high in the GM+, but no significant difference was confirmed ([Table 2](#t02){ref-type="table"}). Table 2Levels of cytokine and chemokine expression in the placental tissue of pregnant women with malaria by P. vivax at delivery (P+) and without it at delivery or during prenatal care (PC-). In maternal blood, all changes were not statistically significant. However, pro-inflammatory cytokines (TNF, IFNg and IL-1β) were higher in the GM+ group with respect to the GM- group. In addition, all anti-inflammatory cytokines, but TGF-β, were increased in the GM+ group when compared to GM-. As for the chemokines, IL-8 and MIP-1 were lower, and MCP-1 higher, in the GM+ group when compared to GM-. Table 3Levels of cytokine and chemokine expression in maternal peripheral blood of pregnant women with malaria by P. vivax at childbirth (GMP+) and without it at birth or during prenatal care (GMP-C-). Discussion ========== This reports for the first time on the status of cytokines and chemokines in women with GM in a *P. vivax* endemic region of America. The technique used to measure the expression of immune mediators is precise and sensitive. Volunteers were selected from the general population, particularly those regularly attending the hospital facilities in Puerto Libertador. Therefore, the study represents the typical population which seeks health services in the region. An obvious limitation in this work is the reduced number of women with GM, which is the result of the current socio-political instability in the area. Despite the small sample size, the results obtained are consistent and suggest a clear trend. The study contributes to outline the epidemiology of malarial infection during pregnancy in a highly endemic region of the country, since it includes subjects whose peripheral and placental blood was monitored for *P. vivax* infection using standard microscopy and contributes with the evidence, so far gathered, on the deleterious effects of this species [@B17]. Other authors have reported on the particular predisposition to acquire malaria, regardless of the species, according to mother´s age, parity and gestational age [@B18]. In the current study, women in the GM+ group were younger, with less parity and fewer weeks of pregnancy than those in the GM- group. Others have also reported on *P. vivax* as responsible of low birth weight, maternal anemia and preterm delivery[@B17]. In this study, no significant differences were observed on mother´s haemoglobin levels or the newborn´s weight. However, children born from mothers with GM+ had a mean 215g less weight. In addition, preterm delivery occurred in high proportion (18%) in the same group. Preterm delivery is a recognized cause of neonatal mortality [@B09] ^,^ [@B19]. Pro-inflammatory and anti-inflammatory cytokines and chemokines were found altered during GM by *P. falciparum* and this was associated with abortion, stillbirth, preterm delivery, intrauterine growth restriction, low birth weight and maternal anemia[@B04] ^,^ [@B20]. However, for *P. vivax* there is no report on this matter. We found an increased expression of all pro-inflammatory cytokines studied, both in maternal peripheral blood and in placental tissue. Although differences between the groups were not significant, the probability values observed strongly suggest that the sample size might have influenced this outcome. Similar to the findings herein reported, studies with *P. falciparum* GM also showed increased expression of TNF and IL1β but not IFNγ [@B21] ^,^ [@B22] ~.~In other reports on *P. falciparum* GM, increased TNF has been associated with fetal growth restriction, spontaneous abortion and maternal anemia [@B22] ^,^ [@B23]. Likewise, the increase in IL-10 has been associated with preterm delivery and increased IFNγ with spontaneous abortion. The beta chemokine MCP-1 has also been reported to increase in GM and PM by *P. falciparum* [@B24] ^,^ [@B25] and it has been associated with immune cell recruitment in the placenta, specifically monocyte. This chemokine might also be involved in mononuclear recruitment in *P. vivax* infected placentas. Moreover, a rise on IL-8 has been reported in placentas with active *P. falciparum*infection [@B10] ^,^ [@B26]. In the current study, monocytes-macrophages infiltrates (data not shown) were observed in infected placentas and the concomitant finding of high IL-8 might explain this observation. Alternatively, other have implicated hemozoin or parasite´s persistence in the immune alterations observed in the placenta during malaria infection [@B27]. In summary, in women with GM at delivery pro-inflammatory cytokines tend to be elevated both in maternal blood and placental tissue, anti-inflammatory cytokines were high in the mother and low in the placenta and the chemokines were reduced in both compartments, but MCP-1 which was observed high in placenta and mother. The results seemed to be strongly affected by the relative small number of women with GM by *P. vivax* at the time of delivery. To consolidate these findings it is necessary to carry out additional studies with more women both in this region and elsewhere in the country. The authors are grateful to the staff and directives of the Puerto Libertador local hospital, to the patients for their participation and to Zac Karim and Prakasha Kempaiah of University of New Mexico for their assistance in performing some diagnostic procedures. Funding Sources: Universidad de Antioquia-Estrategia Sostenibilidad 2013-2014; Colciencias (project 111549326134). [^1]: **Conflict of interest:**The authors declare that there are no conflicts of interest.

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Q: How to edit my query SQL Server to get result faster I tried a query on SQL Server using Java like this SELECT * FROM DATA1 WHERE Project NOT IN (SELECT DISTINCT Project FROM DATA1 WHERE Resource = 'I-FINAL') ORDER BY RECORDID DESC It runs slowly for about 1 minutes. But when I ran it with this query SELECT * FROM DATA1 ORDER BY RECORDID DESC It was really fast about 100 ms. I guess my problem is NOT IN caused it. I do not know to make new query to get result faster. A: You can try an exclusion join: SELECT d.* FROM DATA1 d LEFT JOIN ( SELECT DISTINCT Project FROM DATA1 WHERE Resource = 'I-FINAL' ) d0 ON d0.Project = d.Project WHERE d0.Resource IS NULL ORDER BY d.RECORDID DESC or NOT EXISTS SELECT * FROM DATA1 d WHERE NOT EXISTS (SELECT 1 FROM DATA1 d0 WHERE d0.Project = d.PROJECT AND d0.Resource = 'I-FINAL') ORDER BY d.RECORDID DESC Neither has any guarantee to run faster. The thing that is most likely to be effective is evaluating indexes on the table, but we don't have enough info in the question to tell you what to change.

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Pages Monday, May 14, 2012 The Foreign Bride (1964) Iran This poster is part of a lot I obtained from an eBay seller years ago. It is safe to say this poster is scarce, because that is true of most Iranian film posters. In any case it was a chance acquisition, one of a very small number of film posters I have from Iran. It was made to advertise a film released during the time of the late shah of Iran. The film itself was not one of the ones that are shown to people who study Persian in American universities, I assume because it was not perceived to have any social significance. For a collector it could be part of a topical collection of posters for films about strange brides. Socially significant or not, according to Iranian film encyclopedist Jamal Omid the film found some commercial and critical success. In 1964 Iranian films that showed signs of religious piety were not nearly as common as they are now, and this one was praised by a Muslim cleric because of a scene in which its protagonist finds a quiet corner to pray. When published this praise helped bring audiences to theaters. It also received a letter of commendation from the Ministry of the Interior Exhibition Commission, the third Delfan Bronze Medal in the international division at the First Ministry of Education International Film Festival as well as the Second Golden Lion Medal. The film was shown at the First Tashkent Festival and was popular with audiences in the Soviet Union. It was also popular with the public in Tehran. The film tells the story of taxi driver Hoseyn who is unable to marry his fiance because of financial problems and is working overtime. He gets involved with a foreign girl named Maria, who soon decides she wants to marry him. After a few incidents the taxi driver decides he prefers to marry his fiance.

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Recent findings suggest that a significant proportion of the genetic variance in complex psychiatric disorders can be explained by a collection of individually rare, highly penetrant genetic variants. Each of these copy number variants (CNVs) may be a risk factor for disease, and many are non-recurrent and sporadic. Optimally, the identification of specific mutations would result in personalized treatment interventions tailored to the underlying biology of the mutation. We have identified a complex structural rearrangement at 9p24.1 that segregates with psychosis in one family. One gene in the rearranged region, glycine decarboxylase (GLDC), is involved in the degradation of glycine in glia cells and is triplicated in mutation carriers. Glycine is a co-agonist for the N-methyl-D-aspartate receptor (NMDAR). Carriers of the GLDC triplication would be expected to have low levels of brain glycine, resulting in NMDAR-mediated hypofunction, which has been strongly implicated in the pathophysiology of schizophrenia. The carriers of this mutation are strong candidates to benefit from glycine augmentation of their psychotropic drug regimens. One aim of this R21 application is to carry out a proof-of-principle double-blind placebo-controlled glycin augmentation trial in carriers of this mutation and to assess changes in clinical symptoms and neurocognitive function. We also propose to carry out targeted neurobiological follow-up of mutation carriers and non-carriers in the same family in order to characterize the brain structural, functional and neurochemical properties of this mutation. These studies will probe glycine homeostasis using proton magnetic resonance spectroscopy, assess the relationship between brain and plasma glycine levels following an acute oral dose of glycine, and examine brain pathways (magnocellular) implicated in dysregulation of NMDA-mediated neurotransmission. The same procedures (except for the glycine loading scans) will be re-administered to carriers after six weeks of open label glycine augmentation. The results will significantly enhance our understanding of the neurobiology of rare CNVs associated with psychosis and their relevance to disease pathophysiology. More importantly, the results will, for the first time, link pathophysiology and a medically actionable treatment intervention to underlying genetics, with potential benefit to other patients with neuropsychiatric disease who have mutations in either the same gene or in other genes/pathways that are impacted by the same or related aberrant biological processes.

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Former president Pervez Musharraf knew that Osama bin Laden was hiding in the garrison town of Abbottabad and the Pakistani intelligence itself had made the safe house that sheltered him, a former...... Former PCB chairman Ijaz Butt has welcomed the planned revival of bilateral cricket ties with India, but has asked the BCCI to compensate it financially for the cancelled series of 2009. Butt, who...... Former PCB chairman Ijaz Butt has said that the BCCI's top brass has assured him that the Pakistan players will be allowed to play in the next edition of the Indian Premier League in 2013. Butt met......

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Function Definition Specifies the mapping of the near clipping plane to window coordinates. The initial value is 0. farVal Specifies the mapping of the far clipping plane to window coordinates. The initial value is 1. Description After clipping and division by w, depth coordinates range from -1 to 1, corresponding to the near and far clipping planes. glDepthRange specifies a linear mapping of the normalized depth coordinates in this range to window depth coordinates. Regardless of the actual depth buffer implementation, window coordinate depth values are treated as though they range from 0 through 1 (like color components). Thus, the values accepted by glDepthRange are both clamped to this range before they are accepted. The setting of (0,1) maps the near plane to 0 and the far plane to 1. With this mapping, the depth buffer range is fully utilized. Notes It is not necessary that nearVal be less than farVal. Reverse mappings such as nearVal = 1, and farVal = 0 are acceptable. The type of the nearVal and farVal parameters was changed from GLclampf to GLfloat for glDepthRangef and from GLclampd to GLdouble for glDepthRange. This change is transparent to user code.

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Britons will work for 149 days to pay their taxes in 2011, according to respected free-market think tank the Adam Smith Institute. Every penny earned in the UK between January 1 and May 29 will be taken by the taxman to support government expenditure. This means that Tax Freedom Day, the day when people stop working for the government and start working for themselves, will come on May 30 in 2011. The most up to date government statistics suggest that Tax Freedom Day came on May 27 in 2010. This means that Britons will spend three extra days working to pay their taxes in 2011, compared with the year before. The main reason for this is that the government has raised VAT, in order to help reduce the UK’s record budget deficit. “As well as hitting every household in the country, the VAT hike is going to dent consumer confidence and put a dampener on our economic recovery – as the Office of Budget Responsibility has already pointed out.” He added: “The government is right to give priority to cutting spending and plugging the deficit. But as Tax Freedom Day shows, Britons are still desperately overtaxed. The fact that we spend almost five months working for the State – and only seven months working for ourselves and our families – is a shocking indictment of big, wasteful government.” Dr Eamonn Butler, director of the Institute, added: “The coalition should examine the possibility of making targeted tax cuts now to encourage economic growth. But in the long term, they need to fundamentally overhaul the entire tax system. Lower, simpler, flatter taxes would be fairer for individuals, and better for the economy.”

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INTRODUCTION {#sec1-1} ============ Delayed childbearing, voluntary or involuntary, is a common feature in couples visiting fertility clinics. Majority of the fertility clinics perform ovarian reserve tests (ORTs) as part of the evaluation of women with infertility prior to *In Vitro* fertilization. Diminishing ovarian reserve is a phenomenon noted in women during mid to late thirties and at times earlier, reflecting the declining follicular pool and oocyte quality.\[[@ref1]\] This age-related decline of follicles in the human ovary is believed to more than double when numbers fall below a critical figure of 25,000 at \~37.5 years of age.\[[@ref2]\] Assuming fixed time differences between reproductive milestones, fertility will not be lost completely for 4 years, on average, following the onset of this phase.\[[@ref3]\] ORTs provide an indirect estimate of a woman\'s remaining follicular pool. An ideal ORT should be easy to perform, reproducible, and the decisions based on their results should help differentiate women with a normal and poor ovarian response. This should in turn help identify and counsel couples with negligible chance of conception against any expensive and repeated treatment. However, the availability of multiple ovarian reserve markers suggests that none is ideal. Largely, these tests have been used in subfertile women prior to the first IVF attempt to predict a poor ovarian response. More recently, their value in predicting hyper-response and thus using safe stimulation regimes to prevent OHSS is also explored.\[[@ref4][@ref5]\] Their role in the assessment of ovarian reserve in subfertile women not necessarily undergoing IVF or in general population, to identify those at the risk of diminished ovarian reserve, is still poorly understood. The initial evidence suggested that various ORTs have a good predictive value for pregnancy.\[[@ref6]\] However, in the recent years it has been understood that these tests are effective in predicting the ovarian response to stimulation and not for the prediction of pregnancy or its outcome.\[[@ref7]\] The interpretation of the results is further complicated by the lack of uniform definitions for poor or hyper-responders and uniform threshold values to identify abnormal results. Biological (age), biochemical, biophysical, and histological tests have been used to identify ovarian reserve \[[Figure 1](#F1){ref-type="fig"}\]. ![Types of ovarian reserve tests](JHRS-4-108-g001){#F1} A literature search was made using the key words "ovarian reserve" and "ovarian reserve tests," using MEDLINE (1966--2011). A total of 308 articles were found. Further searches were made for individual ORTs using their titles as key words. Appropriate cross-references were manually searched. Age {#sec2-1} --- It is long established that ovarian reserve reduces progressively with age.\[[@ref8]\] Fecundity in both natural and stimulated ovarian cycles declines with maternal age, beginning in the late 20s and becoming more abrupt in the late 30s \[[Figure 2](#F2){ref-type="fig"}\]. This decline has been observed in population-based studies,\[[@ref9]\] and in women undergoing ovulation induction or IVF.\[[@ref10]\] Even though fertility does not decline uniformly in women, age is known to be the most important factor determining the pregnancy potential in regularly cycling women.\[[@ref11]--[@ref13]\] However, chronological age alone has a limited value in predicting individual ovarian responses.\[[@ref14]--[@ref17]\] This has led to the development and use of various biochemical and biophysical markers of ovarian reserve. ![Quantitative (solid line) and qualitative (dotted line) decline of the ovarian follicle pool, which is assumed to dictate the onset of the important reproductive events (reproduced and adapted with permission from\[[@ref8]\]).](JHRS-4-108-g002){#F2} Basal follicle stimulating hormone {#sec2-2} ---------------------------------- Basal follicle stimulating hormone (FSH) levels measured on day 3 of the menstrual cycle is the most widely used ORT to assess the ovarian response to stimulation, for over two decades now.\[[@ref14]\] An increase in FSH levels occurs due to follicle depletion. The measurement of FSH is easy, and inexpensive. However, it is known to have diurnal, intra- and intercycle variability.\[[@ref18][@ref19]\] There is no universally accepted cut-off value to identify a poor response. A wide range in threshold values up to 25 IU/L has been used to define abnormal levels of basal FSH. Meta-analysis and systematic reviews have failed to identify any combination of specificity and sensitivity for basal FSH as a test of poor response or prediction of non pregnancy. In regularly cycling women, FSH can predict a poor response adequately only at very high levels, and hence will be helpful only to a small number of women as a screening test, for counselling purposes.\[[@ref20][@ref21]\] It is understood that the ovarian aging begins several years before any elevation in FSH levels is noted and hence a normal test cannot rule out a poor ovarian response in some women. Combined with other markers it can be used to counsel couples regarding a poor response but should not be used to exclude regularly cycling women from ART. The usefulness of basal FSH in a general subfertile population or elevated levels in young, regularly cycling women is unclear.\[[@ref22]\] Anti-Mullerian hormone {#sec2-3} ---------------------- Anti-Mullerian hormone (AMH) is a dimeric glycoprotein exclusively produced by granulosa cells of preantral (primary and secondary) and small antral follicles (AFs) in the ovary. The production of AMH starts following follicular transition from the primordial to the primary stage, and it continues until the follicles reach the antral stages, with diameters of 2-6 mm.\[[@ref23]--[@ref25]\] The number of the small AFs is related to the size of the primordial follicle pool. With the decrease in the number of the AFs with age, AMH production appears to diminish and become undetectable at and after menopause.\[[@ref26]\] AMH levels strongly correlate with basal antral follicle count (AFC) measured by transvaginal ultrasonography.\[[@ref5]\] Unlike other biochemical markers, it can be measured on any day of the cycle\[[@ref27][@ref28]\] and does not exhibit intercycle variability.\[[@ref29]\] Various threshold values, 0.2--1.26 ng/ml, have been used to identify poor responders with 80--87% sensitivity and 64--93% specificity.\[[@ref30]--[@ref32]\] With better understanding of its clinical implications, AMH is now known to have the ability to predict a hyper-response as well.\[[@ref5][@ref33]\] The use of nomograms identifies the age-related physiological decline in the AMH levels and thus ovarian reserve, and abnormal deviations can be used for counselling couples wishing to delay childbirth.\[[@ref34][@ref35]\] Available evidence does not suggest that serum AMH can be used as a marker to predict pregnancy.\[[@ref36][@ref37]\] However, the evaluation of follicular fluid AMH has shown that oocytes obtained from follicles with higher levels of AMH have a better fertility potential compared to those with lower AMH levels.\[[@ref38]\] Longitudinal studies in fertile women have shown a clear decline in AMH levels with age and it is the earliest marker to show a decline longitudinally in young women\[[@ref39][@ref40]\] offering the probability of a screening test for women wishing to delay childbirth. It is considered that at levels 0.5--1.26 ng/ml, AMH indicates perimenopausal transition within 3--5 years.\[[@ref41]\] Levels within this range still suggest favorable results with ART. Of all the ORTs available, AMH has a unique place in that it may be applicable as a screening test in a general subfertile population.\[[@ref41]\] Inhibin B {#sec2-4} --------- Inhibin B is a heterodimeric glycoprotein released by the granulosa cells of the follicle. Women with a low day 3 inhibin B concentration (\<45 pg/ml) have a poor response to superovulation for IVF and are less likely to conceive a clinical pregnancy.\[[@ref42]\] It is also noted that a decrease in inhibin B probably precedes the increase in the FSH concentration.\[[@ref43]\] However, other investigators have failed to show any added predictive value for inhibin B as a measure of ovarian reserve\[[@ref44][@ref45]\] and nonoccurrence of pregnancy.\[[@ref42]\] At very low threshold levels, the accuracy in the prediction of a poor response and nonpregnancy is only modest\[[@ref19]\] and hence its routine use cannot be recommended. An exaggerated inhibin B response to exogenous FSH ORT has been found to be a predictor of hyper-response in a subsequent cycle.\[[@ref46]\] Basal estradiol {#sec2-5} --------------- Basal estradiol (E2) has been evaluated as a marker of ovarian reserve in women, prior to IVF. An elevated basal E2 level may mask abnormal FSH levels and hence, FSH levels alone may not be predictable of the ovarian response in such women. Initial studies did show an association between an elevated basal E2 level and a poor ovarian response,\[[@ref47]--[@ref49]\] using different values to define elevated estradiol. A large study showed that a poor ovarian response was more commonly seen in those with \<20 or \>80 pg/ml of estradiol but did not show any correlation to the pregnancy rate.\[[@ref50]\] A meta-analysis concluded that as basal E2 does not add to the predictive value of other commonly used ORTs, its routine use in clinical practice is not recommended.\[[@ref21]\] Clomiphene citrate challenge test {#sec2-6} --------------------------------- Clomiphene citrate challenge test (CCCT) is a dynamic test involving the administration of 100 mg of clomiphene citrate from the fifth day of the cycle for 5 days. Basal FSH is estimated on day 3 of the cycle and stimulated FSH levels on day 10. Abnormal values on day 3 or day 10, or on addition of the two, is considered as a predictor of a poor ovarian response. However, a meta-analysis has shown that CCCT is no better than basal FSH in predicting a clinical pregnancy.\[[@ref51]\] In addition, it has the drawback shared by all dynamic tests in that it is expensive, more invasive, more time consuming, and associated with the possible side effects of administered drugs.\[[@ref52]\] Exogenous follicle stimulating hormone ovarian reserve test {#sec2-7} ----------------------------------------------------------- This dynamic test involves the measurement of basal FSH and estradiol followed by the administration of 300 IU FSH on day 3 of the cycle. The serum estradiol concentration is determined 24 h later. It is found to be better than CCCT in predicting hyper-responders and inferior to the latter in predicting a poor response. But, in view of the high rate of false positives, the authors did not recommend this test alone for the identification of hyper-responders.\[[@ref4]\] Gonadotrophin releasing hormone agonist stimulation test {#sec2-8} -------------------------------------------------------- It involves the assessment of serum estradiol on day 2 of the cycle followed by the subcutaneous administration of GnRHa (Triptorelin) 100 μg. A change in estradiol levels is noted by repeating the test 24 h later on day 3. A rise in estradiol is considered to be indicative of good ovarian reserve. It is found to have a good ability for the prediction of poor ovarian reserve but is not superior to inhibin B or AFC in this regard.\[[@ref53]\] ULTRASOUND PARAMETERS {#sec1-2} ===================== Antral follicle count {#sec2-9} --------------------- AFs are measured by transvaginal ultrasonography in the early follicular phase, by taking the mean of two perpendicular measurements. The numbers of follicles in both ovaries are added for the total AFC. AFC has long been used as a marker of ovarian reserve.\[[@ref30][@ref40]\] A count of 8--10 is considered as a predictor of a normal response. Different diameters are used to define AFs -- those measuring 2--6 and 7--10 mm. There is no consensus regarding the size of AFs which truly represent ovarian reserve. It is found that the number of AFs 2--6 mm in size declines with age and correlates with other markers such as FSH and CCCT but that of 7--10 mm sized remains constant\[[@ref54]\] and hence, the former appears to be a more reliable marker of ovarian reserve. Repeated measurements have shown that there is only a limited intercycle variability.\[[@ref55]\] AFC is considered to have the best discriminating potential for a poor ovarian response compared to the total ovarian volume and basal serum levels of FSH, E2, and inhibin B on day 3 of the cycle but lacks the sensitivity and specificity to predict the nonoccurrence of pregnancy.\[[@ref52][@ref56]\] More than 14 AFs are considered to be a good predictor of hyper-response.\[[@ref57]\] 3D ultrasound does not have any advantage over 2D ultrasound in the assessment of ovarian reserve.\[[@ref58]\] Ovarian volume {#sec2-10} -------------- The ovarian volume is measured by transvaginal ultrasonography applying the formula for an ellipsoid (D1 × D2 × D3 × π/6). The volume of each ovary is calculated by measuring in three perpendicular directions. The volumes of both ovaries are added for the total basal ovarian volume (BOV). The ovarian volume remains unchanged till the perimenopausal period and does not add to the predictive value of AFC.\[[@ref56][@ref57]\] A decline in the ovarian volume is a late event noticed in women \>40 years.\[[@ref59]\] Ovarian vascularity {#sec2-11} ------------------- The observation of the ovarian Doppler flow during ovarian stimulation has been studied in IVF cycles. The increase in the Doppler flow noted during stimulation is considered not to provide additional information to AFC.\[[@ref60]\] Ovarian biopsy {#sec2-12} -------------- Ovarian biopsy done at laparoscopy or laparotomy has shown that the follicular density reduces with age and is correlated with the ovarian volume in women \>35 years of age.\[[@ref61]\] Also, women with unexplained infertility have fewer follicles than those with tubal factor infertility. However, the distribution of follicles is not uniform within the ovary and hence the biopsy may not represent the true follicular density.\[[@ref62]\] It is understood that an invasive ovarian biopsy does not add to the information available through noninvasive modalities and it is not recommended to be used as an ORT.\[[@ref63]\] DISCUSSION {#sec1-3} ========== Women in their mid to late 30s and early 40s constitute an important part of the infertile population and many of them require expensive treatments including assisted reproductive technologies. Performing an ORT is an effort toward estimating the primordial follicle pool. It is well understood that the ovarian follicular pool and hence fertility declines with age. However, there is a large individual variation in its onset.\[[@ref1]\] The ideal parameter to estimate ovarian reserve would be easily measurable, minimally invasive, inexpensive, and have good predictive value for the outcome being assessed. Majority of the ORTs available are not expensive but need very high threshold levels to identify majority of poor responders.\[[@ref21]\] Even though ORTs primarily have been used to identify poor responders, and counsel such women to avoid repeated ineffective treatment, it is now known that some of them are able to predict a hyper-response. This helps avoid maximal ovarian stimulation in such women and minimize the risk of life-threatening OHSS without compromising the pregnancy rate.\[[@ref33]\] Majority of the ORTs, including the most widely used basal FSH levels, show abnormal values late in a woman\'s reproductive life to be of practical help.\[[@ref20][@ref21]\] Abnormal results indicate a much compromised ovarian reserve, implicating that all interventions would be ineffective which is compounded by a huge emotional and financial burden to such couples. Basal E2 and inhibin B are not found to be any better predictive value than FSH. Though FSH induced increase in the inhibin B level may be useful in predicting hyper-response, AMH and AFC are the basal markers found to predict the ovarian response, both poor and hyper, with a high sensitivity and specificity and are comparable in this regard.\[[@ref5]\] Serum AMH levels show minimal intra- and intercycle fluctuations and thus can be performed at any stage of the menstrual cycle. They show distinct age-related declines at a very young age, much earlier than other markers including AFC.\[[@ref40][@ref64]\] Nomograms have been developed for AMH for infertile women which should help identify those with diminishing ovarian reserve at any given time in the general subfertile population and thus providing an opportunity to counsel couples appropriately regarding reproductive performance. This would also enable them to go through effective modalities of treatment when the chances of achieving a pregnancy are reasonably good.\[[@ref34][@ref35][@ref65]\] AMH is the only ORT found to be useful in evaluating the residual ovarian reserve in young women treated for malignancies with chemotherapy or radiotherapy.\[[@ref66]\] Dynamic tests do not add to the value of baseline tests and hence cannot be recommended as a diagnostic tool with the available evidence.\[[@ref67]\] Attempts to improve the predictive value of ORTs by using multiple markers instead of single basal marker have not been found to be beneficial.\[[@ref30][@ref68][@ref69]\] It is clear from the current evidence that ORTs cannot be used as diagnostic tests for a poor ovarian reserve but should be used as screening tests, and the first IVF attempt remains the diagnostic tool to identify a poor response.\[[@ref21]\] AFC and AMH can be used as diagnostic tools to identify hyper-responders and treatment strategy modified accordingly to minimize OHSS.\[[@ref5][@ref33]\] Despite the multitude of ORTs available, age remains the best predictor of pregnancy. A poor predictive value of ORTs in this regard may be due to the fact that chance of pregnancy after IVF depends on many other factors than ovarian reserve alone and that the pregnancy outcome after an ORT is usually assessed in the first IVF cycle alone which may not adequately represent a woman\'s true reproductive potential.\[[@ref21]\] CONCLUSIONS {#sec1-4} =========== ORTs do have a moderate ability to predict poor and hyperresponse.The information can influence the treatment protocol to be chosen for IVF but should not be used to exclude anyone from first attempt at IVF.The present evidence shows that AFC and AMH appear to be the most useful markers of ovarian reserve in addition to chronological age. In addition AMH has the ability to be applied to the general population for identification of diminishing ovarian reserve before it reaches a critical level below which no effective treatment can be offered.This may help women who wish to delay pregnancy to make an informed decision. **Source of Support:** Nil, **Conflict of Interest:** None declared.

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Q: Table Alignment (Making the word from 1 row into 2 row) Would like to adjust the table in better looking, tried both methods, not working. Make the first column letter into 2 row. Make all the content to left-hand side All the column around same length \documentclass[12pt,oneside]{book} \usepackage{showframe} \renewcommand\ShowFrameLinethickness{0.15pt} \renewcommand*\ShowFrameColor{\color{red}} \usepackage{makecell,siunitx} \usepackage{booktabs} \usepackage{tabulary,siunitx} \usepackage{makecell, multirow, tabularx} %for table multirow %for table multirow \begin{document} \renewcommand\theadfont{\small\bfseries} \begin{table}[!ht] \centering \begin{tabularx}{\textwidth}{>{\raggedright\arraybackslash}Xcclc} \toprule \thead[l]{} & & \thead{Value Label} & \thead{N} \\ \midrule \multirow{2}{*}{\textbf{Example}} & 1 & Example Example Example & 20\\ \cline{2-4} & 2 & Example Example Example Example & 20 \\ \cline{1-4} \multirow{2}{*}{\textbf{Example Example Example}} & 1 & AM & 20\\ \cline{2-4} & 2 & FM & 20 \\ \bottomrule \end{tabularx} \end{table} \setlength\extrarowheight{1pt} \renewcommand{\arraystretch}{1.2} \begin{table}[h!] \centering \begin{tabularx}{\textwidth}{@{}Y*{3}{W}@{}} \toprule & & \small {\textbf{Value Label}} & \small {\textbf{N}} \\ \midrule \multirow{2}{*}{\textbf{Example}} & 1 & Example Example Example & 20\\ \cline{2-4} & 2 & Example Example Example Example & 20 \\ \cline{1-4} \multirow{2}{*}{\textbf{Example Example Example}} & 1 & AM & 20\\ \cline{2-4} & 2 & FM & 20 \\ \bottomrule \end{tabularx} \end{table} \end{document} A: Changing {*} to {=} fixes the linebreak in multirows when you change first and third column to a left aligned X column. To reduce typing, I defined such column as a new columntype. In addition, by using array's new w column, you can fix both width and alignment. I fixed the width to 2 cm, but change those values if you prefer wider or narrower second and fourth column. Example 1 Since you cannot use a new version of array, I changed the second and fourth column to a fixed width p-column, with contents centred. For readability, I defined a new columntype V. In addition, I limited the width of the whole tabular to 0.7\linewidth. I also chosed fontsize \small. \documentclass[12pt,oneside]{book} \usepackage{showframe} \renewcommand\ShowFrameLinethickness{0.15pt} \renewcommand*\ShowFrameColor{\color{red}} \usepackage{makecell,siunitx} \usepackage{booktabs, array} \usepackage{tabulary,siunitx} \usepackage{makecell, multirow, tabularx} %for table multirow %for table multirow \begin{document} \setlength\extrarowheight{1pt} \renewcommand{\arraystretch}{1.2} \newcolumntype{Y}{>{\raggedright\arraybackslash}X} \newcolumntype{V}{>{\centering\arraybackslash}p{1cm}} % Centred fix width column \begin{table} \small \centering \begin{tabularx}{0.7\textwidth}{@{}YVYV@{}} % Limit the width of the tabular \toprule & & \small {\textbf{Value Label}} & \small {\textbf{N}} \\ \midrule \multirow{2}{*}{\textbf{Example}} & 1 & Example Example Example & 20\\ \cmidrule{2-4} & 2 & Example Example Example Example & 20 \\ \cmidrule{1-4} \multirow{2}{=}{\textbf{Example Example\newline Example}} & 1 & AM & 20\\ \cmidrule{2-4} & 2 & FM & 20 \\ \bottomrule \end{tabularx} \end{table} \end{document} Example 2 \documentclass[12pt,oneside]{book} \usepackage{showframe} \renewcommand\ShowFrameLinethickness{0.15pt} \renewcommand*\ShowFrameColor{\color{red}} \usepackage{makecell,siunitx} \usepackage{booktabs, array} \usepackage{tabulary,siunitx} \usepackage{makecell, multirow, tabularx} %for table multirow %for table multirow \begin{document} \setlength\extrarowheight{1pt} \renewcommand{\arraystretch}{1.2} \newcolumntype{Y}{>{\raggedright\arraybackslash}X} \begin{table} \centering \begin{tabularx}{\textwidth}{@{}Yw{c}{2cm}Yw{c}{2cm}@{}} \toprule & & \small {\textbf{Value Label}} & \small {\textbf{N}} \\ \midrule \multirow{2}{*}{\textbf{Example}} & 1 & Example Example Example & 20\\ \cmidrule{2-4} & 2 & Example Example Example Example & 20 \\ \cmidrule{1-4} \multirow{2}{=}{\textbf{Example Example\newline Example}} & 1 & AM & 20\\ \cmidrule{2-4} & 2 & FM & 20 \\ \bottomrule \end{tabularx} \end{table} \end{document}

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Two things came to light in the past couple of days. The Cleveland Browns brought on former Washington Redskins offensive coordinator Kyle Shanahan to run their offense, and word got loose that Shanahan “loves” his former pupil, Kirk Cousins. With Shanny junior now in Cleveland and Cousins already making it known that he’s open to a trade, the dust could end up settling in such a fashion that could land Cousins in Cleveland. Cleveland seems intent on separating itself from failed first round experiment Brandon Weeden, while Jason Campbell is a cut candidate. The only other quarterback on the roster is Brian Hoyer and the Browns are also expected to be in the mix for a quarterback in the first round of this year’s draft. The likes of Johnny Manziel, Teddy Bridgewater and Blake Bortles have had their name brought up in draft rumors involving the Browns. However, is the Cleveland brass agree with Shanahan and are high on Cousins, perhaps they’d pass up spending a first rounder on a quarterback and trade a mid-round pick to get their guy in Cousins. It could end up matching up, but solely banking on Cousins still seems to be a reach. A former fourth round pick, Cousins has flashed starter ability, but doesn’t have elite arm strength and has been inconsistent in his starts. On the plus side, he knows Shanahan’s offense and has the intelligence and skill-set to succeed in the right situation. That being said, Cousins is a safe option that wouldn’t involved much risk and arguably doesn’t carry a ton of upside. Drafting a quarterback high in the 2014 NFL Draft clearly carries risk, but all of this year’s top passers all carry solid potential – specifically Manziel and Bortles. Cleveland seemed to be exercising the safe route by trading away Trent Richardson for a second first round draft choice last season, but at some point they need to land difference-makers on offense. They have two in Josh Gordon and Jordan Cameron already, but adding a true star under center has to be the next move to take their team to the next level. Swinging a trade for Cousins probably won’t accomplish that.

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As the proprietor of a bed & breakfast in Oaxaca, Mexico, I frequently field inquiries from travelers with plans to visit the city who are intent upon bringing the family dog or cat along for the vacation. They initially ask if pets are permitted in our guest level, and then after receiving a reply in the negative, in a second email ask for names of alternate hotels or other accommodations which do accept pets. The advice is always the same, but the inquiries keep coming. This pet lover and owner of a brindle boxer is not a pet psychologist, nor professes to intimately know whats right or wrong when it comes to decisions about the family dog or cat (or ones children for that matter lord knows weve made and will continue to make mistakes raising our daughter), nor the impact that leaving a pet behind could have on the mutt or his parents or siblings. However, there are certain factors which ought to at least be considered prior to deciding definitively to take Fido or Tabby along for the trip. Yes, Some Hotels and Bed & Breakfasts in Oaxaca Do Accept Pets, Including Dogs and Cats Of course virtually every major tourist city in the civilized world includes the odd hotel, guest house or bed & breakfast which accepts pets, at minimum dogs and cats. Oaxaca is no exception. For example, a couple of members of the Oaxaca Bed & Breakfast Association are happy to extend invitations to the four legged. But most shun the thought of even the possibility of a cat meowing or dog barking, and therefore having to contend with complaints from pet-less guests. Certainly there are exceptions; but what might it reveal about the quality of lodging if the owner is struggling to rent out rooms to the extent that he feels compelled to accept dogs, cats, rats, parrots, snakes and lizards? Your choice of lodging is dramatically reduced by restricting the selection to accommodations in Oaxaca which accept pets. Is the vacation for the Homo sapiens in the family, or for the canines and felines? But Think of the Poor Pet, No Matter How Attached You Insist He is To the Family Believe it or not, family pets are in fact different from the human members of the family, no matter how much we might treat them the same as we treat ourselves, no matter that they sleep with us in our beds, no matter they might pick up on our emotions and even thoughts. After the first couple of hours of the road trip to Oaxaca, will the pet not be less patient than the children? Is he capable of playing board games in the car? Would he be happier being cared for in a quality facility back home where he can frolic with his own kind? When we vacation we board Tito with a dog trainer. Now, seven years later, whenever we begin to gather up his food and water bowls, and leash and choke chain for the ride, he becomes unimaginably excited, sensing that hes off once again to the country club. Pet Owners with a Dog or Cat Accompaniment in Oaxaca are Otherwise Restricted Many ruins and cultural sights do not permit pets, leashed or otherwise. Yes, the dog or cat can be left in the car, windows left slightly ajar. But do you want to run the risk of returning to the parking lot and finding Fido has fled the coup with the help of a Oaxacan anxious to turn the catch into coin? Do you want to constantly be obsessing about that possibility rather than expending all of your energies enjoying Monte Albán, Mitla or a marketplace? Bringing the pet will on balance dramatically restrict your ability to enjoy a number of priority tourist sights. If Still Not Convinced, Consider Boarding the Pet in Oaxaca, and Compare Costs True enough, boarding costs in the US and Canada are prohibitive for most of us. Accordingly, as a last ditch effort to convert the otherwise committed, consider boarding the beast here in Oaxaca. The advantages of doing so include: The cost is about a quarter of what it costs back home. Your vacation will have no restrictions in terms of the sights which you can see. You hopefully will not be constantly obsessing about how your dog or cat is doing; and you wont have to incur long distance calls to assure yourself. Your pet can still enjoy spending quality time with the rest of the family driving through the American mid-West. You can drop by to see him daily and exchange stories about how the day went. Most boarding facilities have posted visiting hours. Hell be having the vacation of a lifetime, and perhaps even pick up a bit of Pet-Spanish. You wont have any such restrictions on selecting a hotel or B & B, and accordingly your vacation in Oaxaca will be that much more relaxing and enjoyable. Since pet boarding facilities in Mexico invariably have dog psychologists on staff, you can kill the proverbial two birds with one stone use the first half hour for the dog to deal with his stress, and the other half hour for yourself. Together with his wife Arlene, Alvin Starkman operates Casa Machaya Oaxaca Bed & Breakfast (http://www.oaxacadream.com ). Alvin has written over 200 articles about life and culture in Oaxaca, assists tourists in planning their visit to Oaxaca and tour of its central valleys, and with Chef Pilar Cabrera arranges culinary tours of Oaxaca (http://www.oaxacaculinarytours.com).

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GCR Class 8B GCR Class 8B was a class of 25 two-cylinder steam locomotives of the 4-4-2 wheel arrangement built between 1903 and 1906 for the Great Central Railway. They were nicknamed "Jersey Lillies" after the famous music star Lillie Langtry. GCR era Facing a potential rise in passenger traffic, the Great Central Railway placed an order for 2 pairs of different locomotives - one pair being the 4-6-0 GCR Class 8C, the other pair being this 4-4-2 locomotive. The two locomotives shared as many common components as possible to allow easy conversion of the 8Bs to the 4-6-0 configuration - and both designs borrowed heavily from John G. Robinson's earlier GCR Class 8. However, due to a much smaller than anticipated traffic increase, no further Class 8Cs were built, and instead a further 25 Class 8Bs were ordered and built between 1904 and 1906 - built with larger fireboxes as there was no longer a need to convert the locomotives to a 4-6-0 configuration. In 1909 and 1910, the original locomotives also received this larger firebox. Despite Robinson commencing the conversion to superheaters in 1912, the conversion was not actually completed until 1936. At the same time, any locomotive requiring cylinder replacement saw both larger cylinders and piston valves being fitted - 20 of the class would eventually receive this modification. From 1921, the Ramsbottom safety valves were phased out and removed, to be replaced by Ross pop safety valves. Experimental locomotive Following a high-speed incident that caused severe damage to its frame and cylinders, No. 1090 was rebuilt with 3 simple expansion cylinders in 1908, as a comparison to the GCR Classes 8D and 8E. These cylinders had their Stephenson valve gear replaced with Walschaerts valve gear, which was the only application of this valve gear, excluding railcars, on a GCR locomotive. The experiment was reverted in 1922 when No. 1090 was rebuilt, with the original 2 cylinders and Stephenson valve gear being refitted. Post-Merger Following the merger of the GCR into the London & North Eastern Railway, the class became known as the LNER Class C4. In 1925, several C4s were fitted with the LNER's trademark "Flowerpot" chimney, with one locomotive, No. 6085, also modified to fit the LNER composite gauge - a modification that the remainder of the class underwent between 1936 and 1939. In 1929, a further LNER classification change was made - the non-superheated locomotives were designated Class C4/1, those fitted with superheaters but still utilized slide valves Class C4/2, and those with both superheaters and piston valves became Class C4/3. By 1932, the re-gauged No. 6085 had been given the designation Class C4/4 - which became more populated as Class C4/3s were cut down. By 1939, all Class C4/1s and Class C4/3s had been redesignated as either Class C4/2s or Class C4/4s - by this time all locomotives were both superheated and had also been cut down to the LNER composite gauge. Withdrawal Following an accident at Banbury in 1939, the first locomotive, No. 6090 (the same engine as No. 1090, which had already been modified after a previous accident), was withdrawn from service. The rest of the class began being withdrawn from 1945, although 20 locomotives made it into British Rail hands following the nationalisation of the British railways. The last locomotive was withdrawn in 1950, and none survived into preservation. References External links The Robinson C4 (GCR Class 8B) 4-4-2 Atlantics 08B Category:4-4-2 locomotives Category:Railway locomotives introduced in 1905 Category:Scrapped locomotives Category:Standard gauge steam locomotives of Great Britain Category:2′B1′ n2 locomotives Category:2′B1′ h2 locomotives

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Q: How does the container get passed to a fragment? I'm attempting to understand someone else's code. They are using fragments (which I'm rather hazy on). I know that a fragment starts up with onCreateView(LayoutInflater inflater, ViewGroup container, Bundle savedInstanceState .. but I can't fathom where the "container" was set up. where should I look? A: container is handled by the Android framework, it typically refers to View passed by id in methods like FragmentTransaction's add(int containerViewId, Fragment fragment) or replace(int containerViewId, Fragment fragment). For example, this is from the Developer's Guide: ExampleFragment fragment = new ExampleFragment(); fragmentTransaction.add(R.id.fragment_container, fragment); fragmentTransaction.commit();

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Q: Django : Access model data in template using Class-based generic views I'm trying to display the model data in the template. When I don't have any filtering, it works fine! class UserLogList(ListView): context_object_name = 'data' queryset = UserLog.objects.all().values('user_id__username','event_id','time') But if I want to have some filtering, example if I want to get the details based on the user_id where user_id = 1. I can get the user id from the request object or self.request object. So to achieve this, I did the following in my views.py class DisplayUserActivity(ListView): template_name = 'user_activity.html' uid = self.request.user.id def get_object(self): uid = self.request.user.id object = super(DisplayUserActivity,self).get_object() object.data = UserLog.objects.filter(user_id = uid).values('user_id__username','event_id','time') return object and my template file: {% block content %} <h2> Logs </h2> <table border="1" style="width:50%"> <tr> <th> User Name </th> <th> Description </th> <th> Time </th> </tr> {% for user in data %} <tr> <td> {{user.user_id__username}}</td> <td> {{user.event_id}}</td> <td> {{user.time}} </td> {% endfor %} </tr> </table> {% endblock %} What am I missing? A: I think you need a method called get_queryset instead of get_object when extending the generic ListView. EDIT: Regarding your edit, theres an issue with your template {% for user in data %} should be {% for user in object_list %} But I suspect there are deeper problems here which are hard to decipher. My advice is to look through your code and the Django documentation more carefully, and possibly switch to a custom written view until you are more comfortable. :)

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Welcome to the WHO/Europe Health Economic Assessment Tool (HEAT). 29 October 2014 New dates for free online trainings in English and German Thanks to support from the Swiss Federal Office for Public Health and the collaboration with the European Cyclists’ Federation we are pleased to announce the continuation of the free live online trainings in English and German on how to use HEAT. Please see here for the new dates and registration: Introduction This tool is designed to help you conduct an economic assessment of the health benefits of walking or cycling by estimating the value of reduced mortality that results from specified amounts of walking or cycling. The tool can be used in a number of different situations, for example: when planning a new piece of cycling or walking infrastructure. HEAT attaches a value to the estimated level of cycling or walking when the new infrastructure is in place. This can be compared to the costs of implementing different interventions to produce a benefit–cost ratio (and help to make the case for investment) to value the reduced mortality from past and/or current levels of cycling or walking, such as to a specific workplace, across a city or in a country. It can also be used to illustrate economic consequences from a potential future change in levels of cycling or walking. to provide input into more comprehensive economic appraisal exercises, or prospective health impact assessments. For example, to estimate the mortality benefits from achieving targets to increase cycling or walking, or from the results of an intervention project.

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~HEATTORNEY GENERAL OF TEXAS Aus- 11.- letter of ikke 15th reqw8t4 cur Q&aklon Qn the ~Bhbm we lm?intly rwd#ed a#.!don 0-907 coastruiy the mlldity 8nd eonrtfttitlawllty of H.l% 20!5passed by the Fort~-1slxth Legirlatw, we enelow a eog;r of mid oginlen fez your oonridwtioA. The plaia provirAoA or th8 ZWWAtly enaated strtutr (a.23, would give aa afilcnr the right to one-harf of hi8 oosts the amviot laid out hlr fine arg oomE5 without labor, Ike ~aflmr the eff8etSve date of the bill. ‘Artiale lOfj& The county &all not be liable te the 0rne aad witabss bav* ooetr in a ai*aaaor a8e wh8re defeadant p8yr hi8 fina and costs. !rhe eotlaty 8hall be limb10 r0r 0nr-holr of the fee8 of the offioerr Of th*OOW%, WhW thOt%mAdSmt fad tOpqhi8 riA8 8Ad lays his fina out la the aounty jail or diW.!h8X3&~8 the saw by - of rorklng au& tine out on the uounty mN.ds or QA any uouaty p?ojbut. AAd to puy such half of oortr the aouaty alerIc shall Issue hlr warrent on tb8 Cou& Yreaurer IA hvDr of BuOh of?ioU to be pald OIPtofthej(Dd8ndBrLdgemAdaro~r rundraot 0therwl.w approprmed,” ‘prurtin(c tha abova Urtirhctori~ UtSWrS y0U.V qW8tiOA, Ip- mws m truly &22OlWiU(upIIRIIWTRXkE

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Commensurate CO2 Capture, and Shape Selectivity for HCCH over H2CCH2, in Zigzag Channels of a Robust Cu(I)(CN)(L) Metal-Organic Framework. A novel copper(I) metal-organic framework (MOF), {[Cu(I)2(py-pzpypz)2(μ-CN)2]·MeCN}n (1·MeCN), with an unusual topology is shown to be robust, retaining crystallinity during desolvation to give 1, which has also been structurally characterized [py-pzpypz is 4-(4-pyridyl)-2,5-dipyrazylpyridine)]. Zigzag-shaped channels, which in 1·MeCN were occupied by disordered MeCN molecules, run along the c axis of 1, resulting in a significant solvent-accessible void space (9.6% of the unit cell volume). These tight zigzags, bordered by (Cu(I)CN)n chains, make 1 an ideal candidate for investigations into shape-based selectivity. MOF 1 shows a moderate enthalpy of adsorption for binding CO2 (-32 kJ mol(-1) at moderate loadings), which results in a good selectivity for CO2 over N2 of 4.8:1 under real-world operating conditions of a 15:85 CO2/N2 mixture at 1 bar. Furthermore, 1 was investigated for shape-based selectivity of small hydrocarbons, revealing preferential uptake of linear acetylene gas over ethylene and methane, partially due to kinetic trapping of the guests with larger kinetic diameters.

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Q: weighted cross entropy for imbalanced dataset - multiclass classification I am trying to classify images to more then a 100 classes, of different sizes ranged from 300 to 4000 (mean size 1500 with std 600). I am using a pretty standard CNN where the last layer outputs a vector of length number of classes, and using pytorch's loss function CrossEntropyLoss. I tried to use $weights = \frac{max(sizes)}{sizes}$ for the cross entropy loss which improved the unweighted version, not by much. I also thought about duplicating images such that all classes ends up to be of the same size as the larges one. Is there any standard way of handling this sort of imbalance? A: If you are looking for just an alternative loss function: Focal Loss has been shown on imagenet to help with this problem indeed. Focal loss adds a modulating factor to cross entropy loss ensuring that the negative/majority class/easy decisions not over whelm the loss due to the minority/hard classes. I would look into using that is it seems to be really promising. Link To Focal Loss Paper: https://arxiv.org/pdf/1708.02002.pdf A: To handle class imbalance, do nothing -- use the ordinary cross-entropy loss, which handles class imbalance about as well as can be done. Make sure you have enough instances of each class in the training set, otherwise the neural network might not be able to learn: neural networks often need a lot of data. Assuming you care about global accuracy (rather than the average of the accuracy on each individual class, say), I wouldn't bother with a weighted cross-entropy loss or duplicating images. Your training sounds rather small. To deal with that, you might try starting from an existing pre-trained model and fine-tune the last few layers. Also use image augmentation.

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1. Field of the Invention The present invention relates to an auto telephone answering apparatus for recording an incoming message (to be referred to as an ICM hereinafter) while the called telephone is unattended. 2. Description of the Prior Art In a conventional auto telephone answering apparatus, a recorded outgoing message (to be referred to as an OGM hereinafter) stating that the called party is out and that an ICM will be recorded is played back and sent to the calling party upon reception of a call, and an ICM is then recorded. A conventional auto telephone answering apparatus of this type has a selector switch for selecting an auto answer mode or a listen mode. When a user or subscriber is leaving the phone unattended, the selector switch is set in the auto answer mode. For example, U.S. Pat. No. 4,421,954 describes an auto telephone answering apparatus using a 1MD (One Mechanical Deck) system in which a single tape can sequentially record an OGM and a plurality of ICMs. When the auto telephone answering apparatus is being set in the auto answer mode, an OGM is first played to make certain that the OGM is properly recorded in a predetermined tape format. After the OGM is played, the tape is rewound to the beginning of the OGM and is ready for an incoming call. When the first incoming call is received, the OGM is played and sent to the calling party, and an ICM is recorded on the tape. When recording of the ICM is completed, the tape is rewound to the beginning of the OGM and is ready for the next incoming call. When the second incoming call is received, the OGM is played and sent to the calling party. Then, the tape is fast forwarded to skip the first ICM, and the second ICM is recorded after the first ICM. After the second ICM is recorded, the tape is again rewound to the beginning of the OGM and is ready for the next call. The same operation is repeated automatically to sequentially record a plurality of ICMs. When the recorded ICMs are to be played back, the user sets the switch to select the listen mode and depresses a play button. The ICMs are played sequentially starting from the first recorded ICM. When the ICMs are being played back, a conventional auto telephone answering apparatus normally goes into a stop mode when all ICMs have been played back or when ICM playback is manually interrupted to permit the user to attend to some other urgent business. If the user again leaves the telephone unattended while the apparatus is in the stop mode, he may forget to set the switch in the auto answer mode, thus resulting in the failure to record subsequently received ICMs. In another conventional auto telephone answering apparatus, the auto answer mode is cancelled when a tape cassette is inserted or ejected with the apparatus in its auto answer mode. When a plurality of tapes with different OGMs are prepared and used for different purposes, the user must set the switch to establish the auto answer mode each time he replaces one tape with another, thus inconveniencing the user. Furthermore, since only the beginning of an OGM need be checked to determine the OGM content, the user often interrupts OGM playback before completion thereof. To do this, the user depresses the stop button or sets the selector switch in the auto answer mode. If the stop button is depressed for that purpose, the selector switch must be thereafter set in the auto answer mode to ensure that incoming messages will be recorded. However, the user often forgets to do this, resulting in the failure to record ICMs.

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Comments (2) WOW! This is both beautiful and touching. Perhaps I should have passed by this LO without blowing it up and reading it. But I did. Today is January 19th...tomorrow is my 34th birthday. I should be happy...but my birthdays are bitter sweet. Tomorrow will mark the 18th anniversary of me learning I lost my first baby...I don't call it her (long story why I say "her") birthday because the remains were delivered later...and she died a bit before I began to "miscarry", exactly how long be for I'm not sure. I remember that birthday...it was supposed to be my "Sweet 16". It was anything but. First, I woke up bleeding that morning...spent 1/2 the morning at the ER, the other half of the day at an OB/GYN, the night on bed rest. At the OB's office, first they could find no heartbeat. Then, what the ultrasound showed still haunts me...there was part of a baby, only a skull with eye sockets, a nose indention, the form of closed lips......where did the rest of her go I wondered. I found out the answer to that question on January 24th. Gestational Trophoblastic Tumor...my oncologist told me, "Your baby saved your life. The cancer killed her before it began killing you. Had the baby not been forming you would not have the chance of survival that you do." They disected her "remains" and ran MANY tests. Only my OB and onco refered to the baby as "her", everyone else just called her "it". But, I named her anyways, my own coping mechanism..November Nicole...my precious angel. WOW! This is sooooo beautiful and sad at the same time. It touched my heart. I know the feeling. On March 1989 I lost a baby on my 13 week of pregnancy. He had an extra chromosome on the 13th pair. I got to know it was a boy so I named him Alan. I had another boy a year later, I have 3 kids but my youngest is not the third, he will always be the fourth. Alan is my third kid. It never goes away. I will always remember him sucking his thumb in the sonogram. Thanks for sharing this, you did a great job.

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Tag Robert A. Burt Robert A. Burt— The judicial task is not mechanistic but properly and necessarily involves judgment. In particular, judges must understand themselves as ultimately promoting equal deliberation among conflicting parties rather than imposing their own calculus of equality on the parties. This understanding is not alien to the judicial function; it About The Blog The Yale Press Log is the official blog of Yale University Press. Founded in 2005, the Log has since chronicled updates and breaking news about authors, books, publishing, museums, awards, contests, events, podcasts, book trailers, and reading.

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Eldon Piper Birth Name Eldon Piper Titles Lord of Pinkmaiden Gender Male Date Of Birth 3rd of the 12 Moon of 69 AC Culture Andal Religion Faith of the Seven Physical Information Build Muscular Height 6'2 Weight 190 Relations Father Robin Piper Mother Cyrenna Piper nee Toyne Spouse(s) Sarra Piper nee Vance Children Kylar Piper (7) Grover Piper (6) Siblings Lynora Piper (Deceased) Moriah Piper (26) Marla Piper (25) Forrest Piper (24) Liege Agnes Tully Heir Kylar Piper META Player Username /u/GrimmFury Name on Discord Grimm Auxiliary Character Forrest Piper Alternative Characters Clyve Caron, Corwin Caron, and Wyndylyn Manderly Lord Eldon Piper is the second-born son of Lord Robin Piper and Cyrenna Piper. A brash and arrogant man, he became known throughout the realm for his prowess in combat, even making a name for himself in Myr for a short time. After the death of his father and older brother, Lord Robin Piper and Ser Harwood Piper, he found himself the ruling Lord of Pinkmaiden. He now works to build up his lordship alongside his younger brother, Forrest. Appearance and Character Edit Eldon stands moderately tall and is built of lean muscle due to the vigorous training that he commits himself to. While hints of red can still be seen in his hair, his mother's Toyne blood can be seen as well through his hazel eyes and darker hair color. He often dresses in black tunics as opposed to his house colors as he views wearing one's banner as naive and foolish in times of both peace and war; he would much rather simply be another face in the crowd. In terms of Eldon's personality, Eldon gradually became known for his boisterous antics from a very young age. His older brother, Harwood, excelled greatly at nearly any task that he was given, and made a habit of displaying his greatness to his siblings. Although their mother would take him aside and scold him mildly, his father did not ever seem to mind it. Because of this, Eldon found that misbehavior was the only manner in which he could receive any sort of attention and found himself in less than ideal situations throughout his upbringing. History Edit Born inside of Pinkmaiden Castle in 69 AC, Eldon was merely the second of seven siblings that his parents would bring into the world. He spent the first ten years of his life being a general annoyance to his siblings, especially Harwood, and attempting to "explore" the exciting world that he would always gaze out at longingly. During a feast held for the realm, he took a particular liking to the Peacock sigil of House Serretts of Silverhill. Running in between the different areas of the feast, Eldon left behind all decorum and found himself laughing and playing with the children of Lord Otho Serrett, especially Daryn and Oscar. Because of this taking place, their father decided it to be the perfect opportunity to push Eldon onto another family. This was only more emphasized by Lord Piper when he heard of the strict nature in which Lord Otho Serrett did pretty much everything. It was at Silverhill that Eldon was trained in swordsmanship as well as commanding those in times of war, and he find a fierce rival in Daryn Serrett. The heir to Silverhill treated much of his family as Harwood treated the rest of the Pipers. This rivalry pushed Eldon to become more adept at his sparring skills while Daryn became more familiar with the art of warfare. Endless hours of sparring against both Daryn as well as other knights left Eldon with a keen eye for exploiting weaknesses in an enemy's defenses; a tactic that he often utilized in order to introduce any foe to the ground scrambling after being disarmed. That being considered, this rivalry also finally allowed Eldon to feel connected to someone else in the forms of Victaria and Oscar Serrett. Both members of the family in which he served as a ward felt the neglect of love from their father, and became good friends of Eldon on nights where Daryn and Otto were spending their nights with nobility. In a strange way, Eldon became an older brother figure to Oscar. His constant antics attempting to break the sober-faced "winter child" of the ridicule and neglect that he faced by those that shared his same blood. A few moons before his seventeenth nameday, the solemn maester of House Serrett shuffled into his cramped quarters and handed him a short missive. His brother was to be wed to Selyse Bywater, and a tourney would be held in their honor. Eldon was invited to come and stay back at Pinkmaiden to participate in the tourney in order to assess whether or not he had become the man that Robin wanted him to be. Eldon wished Oscar and Victaria the best wishes and invited them to come. An invitation that Otto would sadly decline on their behalf. At the tourney, he displayed his expertise swordsmanship, much to the dismay and awe of Harwood. For some reason, it took this display for his father and older brother to finally recognize him; recognition that Eldon was not able to wholly accept, but he appreciated it nonetheless. Coming in second place at his first tourney, his father appointed him a scout commander and knighted him at the feast held after the event. It was also after this event that he first laid eyes on his beloved, Sarra Vance. With one look, his heart was hers to command, and they maintained a mischievous tryst while also courting one another. It was two years later that they would wed, and she would give birth to their first child, Kylar Piper. A mere year later, she would fall ill with Grover Piper. A chill having taken her, she gave birth in constant pain and passed out unconscious throughout her delivery of the sickly boy. It was only after an hour of her not waking back up that the handmaidens realized she had died of exhaustion just after giving birth. Not a week later, he read the missive that told him of his sister, Lynora Piper, had passed away while at Atranta. Two losses that Eldon thought himself not strong enough to take both hit him harder than he could have ever prepared himself for. Despite his attempts to comfort, Lord Robin was not able to convince the son he had given up all those years ago that things would turn out alright, and this led Eldon to follow a dream that he had always held. A dream of exploration. Through a small missive left to his skilled steward of a brother, Forrest, Eldon rode east to Maidenpool and used a sizable amount of Pinkmaiden's treasury to sail for Myr. A city that had been fabled to him throughout his childhood. There, he bought a small hovel and began to learn his way around the city and sold his sword for whatever noble may have needed protection. Jobs connected to contacts and before he knew it, he found himself working under another man from his home. After three months of protecting petty lords seeking trade deals, he began to lead men under Albar Vance, and quickly worked his way up the ranks; even to the point where his own son, Accalon, became another rival of his. It was also in Myr that he began to learn the technique of weaving daggers into one's combat. Small strikes that could debilitate an enemy if done correctly. His second-in-command became a close friend as well. Qosh hailed from the scummy underbelly of Myr and mainly dispatched those that the various magisters found troublesome. Through months of training, Qosh passed on his main method of killing them quickly, and Eldon seemed to be a natural at utilizing poisons against any who would stand against them in Myr. On the evening of the eleventh moon in 92 AC, Eldon was leading men under the orders of Albar and Accalon. Eldon, in his haste to dispatch the vagabonds on the outskirts of town, ignored the advice of Accalon and charged directly into the den of vipers thinking them to not be a threat. Despite his prowess, the ambush was more than Qosh as well as any of his other men could take. It seemed that the vagabonds had actually been sellswords in the employ of an opposing magister vying for influence in the region. Rumors of them being simply primarily thieves had simply been the product of his subversion. Once again, Eldon turned his back and decided that facing the lessons of his failures was a burden too weighty for him to ever bear. Having barely escaped with his life and knowing he had failed his commander, he set sail back to King's Landing in the hopes that he might fight respite back home amongst the family that he had forsaken. Upon landing in the capital, Eldon received the grave news of the King's comments toward the realm and could feel the tension of the Rosegold building. When he arrived home, he was imprisoned by his father in a passionate rage. The family argued for seven days and seven nights while Forrest sent little Kylar and Grover to meet their neglectful father in his cell. It was only after Eldon asked to play outside with his children that Cyrenna convinced Robin to allow Eldon freedom to father his children. But times of peace would not last for long, and Eldon knew he had to protect his family that had forgiven him for so much. During the initial stages of the Rosegold Rebellion, he found himself a sworn sword in the employ of his liege at Riverrun. In the midst of the night, he would stare out and wonder what ever became of the Serretts, knowing fully that he might have to stand against Daryn or even worse...Oscar if they ever marched so far north. It was only later that he would come to know that it was not the Serretts, but a Lannister that had cut down both his father as well as his older brother in the Battle of Tumbler's Fall; a memory that burned itself into his mind since that very night. Despite the loss and grief, Eldon made his way back to Pinkmaiden and worked alongside his sisters and brother to fortify and defend their home from any Western advance. And soon after, news came that peace had been restored. The deaths of his father and his brother, both men that he had never been able to truly reconnect with, took place simply because of a drunken king's comments. These truths burrowed themselves within his heart, and continue to motivate him to this very day as he leads the remaining members of his family toward more influence, power, wealth, and protection. Still seemingly a stranger to his many siblings, he enjoys spending time with the sisters that he barely spent any precious moments with throughout his upbringing. Ambivalent in most of his actions, Eldon seeks to use his skills both to bring his House more prestige and to bolster the influence of the Riverlands over its enemies. Family Tree Edit http://www.familyecho.com/?p=START&c=smyhm9yyz7&f=165458493399838980

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Five known melanosome-specific proteins currently serve as immune targets for melanoma, i.e. TYR, TRP1/gp75, TRP2/Dct, Pmel17/gp100 and MART1. Host cellular and humoral immune responses play important roles in autoimmune pigmentary diseases (e.g. vitiligo) but are usually unable to control the growth of primary melanomas or their metastases. We are attempting to identify novel melanocyte-specific proteins expressed by less differentiated melanocytic cells that should provide more immune targets for diagnosis and/or therapy of melanoma. We are also looking at approaches to regulating the expression of genes in melanocytic cells which modulate their growth, and are mapping loci that are closely linked to the growth and metastases of melanomas in various locations on the body. Molecular approaches to clone pigment-related genes have been highly successful, but despite that only 50% of the >200 known pigment-related genes have been cloned leaving many potential melanocyte-specific targets to be identified. Tissue microarray and proteomics approaches to define markers of melanoma progression have also identified useful tumor markers. We have used a more direct approach, i.e. to purify melanosomes and use mass spec microsequencing to identify their protein constituents. We identified 1,500 proteins in melanosomes of all stages of maturation, with 600 in any given stage;they include 16 homologous to mouse coat color genes and many associated with human pigmentary diseases. As a result, we successfully published online the first global proteome database, an early gold standard for future proteomics studies on melanosomes. This project is now focused on identifying novel and specific melanosomal proteins that may prove to be useful targets for the immunodiagnosis and/or immunotherapy of melanoma. We are examining differences in proteins expressed in various stages of melanosomes produced by pigmented and/or by amelanotic melanoma cells. Special emphasis will be made to identify new markers potentially suitable to identify amelanotic melanomas, which are difficult to detect and are highly aggressive. We have also identified the processing and trafficking of GPNMB as another potential marker for melanoma cells. Our research has focused on one of the most frequent causes for failure to detect highly aggressive melanomas, which is the lost expression of melanoma antigens. We have found that melanoma cells lose expression of critical melanoma antigens such as Pmel17/gp100. Further, our work has revealed that Pmel17 expression and processing is tightly linked to the growth of melanoma cells via other critical intracellular signaling intermediates. We have identified SOX9 as a critical transcription factor involved in regulating melanocyte function and proliferation, which is down-regulated in a large number of melanoma cells. Up-regulation of SOX9 expression in melanoma cells is an effective way to inhibit their growth and to decrease their metastatic potential. We have identified approaches to up-regulate SOX9 expression using existing pharmaceutical agents that not only increases SOX9 expression, but increases the sensitivity of melanoma cells to retinoic acid, which might prove to be an effective way to target tumors in melanoma patients. We have also recently identified NUAK2 as an important factor associated with the growth and metastasis of acral melanomas. We are collaborating with Dr. Gottesman's MDR group to define yet another unexpected function of melanosomes, which involves the specific expression of an MDR protein (ABCB5) in melanocytes and its localization in melanosomes. MDR mechanisms underlying the intractability of melanomas to chemotherapy remain largely unknown but are a critical therapeutic challenge. We found that MDR (at least in some melanomas) involves the sequestration of cytotoxic drugs within subcellular organelles (including melanosomes), which significantly reduces their nuclear localization and efficacy. Our study provides evidence that melanosomes contribute to the refractory nature of melanoma cells by sequestering cytotoxic drugs and increasing melanosome-mediated export of drugs. Preventing sequestration of cytotoxic drugs by inhibiting the functions of melanosomes may have great potential as an approach to improve the chemosensitivity of melanoma tumors. We hypothesize that ABCB5 plays an important role in normal melanosomes to ensure that cytotoxic intermediates of melanin synthesis remain within that organelle, which are eventually lost by desquamation of the skin or growth of hair, and we are testing that hypothesis. Regarding our studies of pigmentary disorders, mutations in the TYR gene result in OCA1, the most dramatic and severe form of that disease, where little or no melanin is produced in the hair, skin or eyes. Mutations in the gene encoding TYRP1 affect its interactions with TYR, and result in the hypopigmented phenotype of OCA3. Mutations in Tyr or Tyrp1 elicit the retention of TYR in the ER and its degradation by proteasomes, revealing that OCA1 and OCA3 are in fact ER-processing diseases. OCA2 and OCA4 are relatively severe forms of OCA which arise from mutations in the P and MATP loci, respectively. Both encode highly similar proteins with 12 transmembrane motifs. We found that both OCA2 and OCA4 result from altered trafficking of TYR after processing in the ER and Golgi en route to melanosomes, which reduces pigmentation despite the presence of functionally active TYR. We are testing the hypothesis that P and MATP affect the pH of sorting vesicles leading to disrupted trafficking of TYR to melanosomes. Our studies on the disrupted processing and sorting of TYR in OCA2 and in OCA4 melanocytes explains their hypopigmented phenotypes will provide new insights into the involvement of transporters in the normal physiology of melanocytes. Mutations in sorting determinants also result in a hypopigmentary disease known as HPS, which is due to the misrouting of many cellular components (including melanocyte-specific proteins) and thus has effects on other types of tissues as well as pigmented ones. We are characterizing novel forms of HPS mutations and the mechanisms of disrupted trafficking in mouse melanocyte models and are in the process of characterizing the functions of P and MATP.

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The present invention relates to disc brakes for vehicles, and in particular to brake pads in disc brakes, such as air-operated disc brakes utilized on commercial vehicles. An example of a commercial vehicle air-operated disc brake is shown in FIG. 1. In the FIG. 1 embodiment the disc brake 1 includes a brake disk 2 which rotates in direction A about its rotation axis B. A brake caliper 3 straddling the brake disk 2 is affixed to a carrier mount 4 which in turn is fixed to a vehicle axle, typically via a torque plate or a brake spider (not illustrated). In this embodiment the carrier mount 4 receives and supports both the caliper 3 and the brake pads 6. The caliper 3 is actuated in this embodiment by a pneumatic actuator (not illustrated) mounted at the actuator mounting face 5 of the caliper. The actuator acts upon a brake pad application mechanism contained within caliper 3 to press the brake pads 6 against the brake disk 2 to slow the vehicle. The present invention is not restricted to a particular type of brake actuator, for example, a pneumatic actuator or an electrically-driven actuator may be used. Nor is the invention limited to a particular type of brake caliper mount arrangement. For example, the brake caliper may be mounted in a fixed manner on a carrier or may be a sliding caliper. In disc brake applications such as commercial vehicle disc brakes the brake pads typically have had a generally rectangular shape, in part due to the limitations on the size and configuration of the disc brake components (the disc brake having to exist within a highly-space constrained envelope provided by wheel rims), and in part due to cost and structural limitations discussed further below. An example of such a previous brake pad is shown in FIG. 4. A common feature of a previous brake pad 20 is their having essentially parallel lateral sides 22, 23, i.e., the brake pad sides facing in the circumferential direction of the brake disc toward adjacent brake pad abutment surfaces are parallel to one another. The generally rectangular shape may include radially inner and radially outer sides of the brake pad 24, 25 that are slightly curved to generally follow the curvature of the brake disc as shown in FIG. 4, or in the case of the radially outer side, follow the shape of an adjacent outer region of the brake caliper (not illustrated). The use of parallel lateral sides of the brake pad has in part been the de facto standard in commercial vehicle disc brakes in part due to practical manufacturing considerations (for example, less costly machining of brake pad abutment surfaces and parallel-sided brake pad backing plates) and in part due to structural reasons to ensure adequate brake pad abutment strength, wear, and braking force absorption performance. With their generally rectangular shape, the previous commercial vehicle disc brake pads have presented to the brake disc essentially constant width and height profiles from one lateral side of the brake pad to the other. Such brake pad shapes have several disadvantages during brake operation. Among these is the fact that the specific braking energy transfer from the brake disc to the brake pad is not constant across the radial height of the brake pad. Instead, the energy transfer varies as a function of radial height relative to the rotation axis of the brake disc (i.e., braking torque varying as a function of the distance from the brake disc rotation axis, where force×distance=torque), and as a function of the length of the friction surface of the brake pad friction material at different radial heights. As a result, the energy transfer to the brake pad, and the resulting localized wear of the brake pad, is inconsistent across the face of the brake pad friction material. This can lead to premature wear of the friction material in some areas of the brake pad and thereby shorten the time before the brake pad must be replaced. The present invention addresses this and other problems by providing a brake pad with more efficient and even braking energy transfer distribution across the face of the brake pad lining material. The approach of the present invention provides for more even pad lining material wear, thereby extending service life of the brake pad. The improved brake pad performance also enables reduction in overall brake size by allowing the use of smaller brake pads while still providing satisfactory braking performance. In an embodiment of the present invention, the brake pad lining material, and preferably the brake pad backing plate carrying the lining material, has a generally arc-shaped profile, with the radially outer portion of the lining material having a width in the circumferential direction that is longer than the width of the lining material at the radially inner portion of the brake pad. Preferably, the width of the brake pad lining material as a function of radial distance from the brake disc rotation axis is established by generally aligning the lateral sides of the lining material along radial lines that intersect at or near the rotation axis of the brake disc. The lateral sides of the brake pad need not be exactly aligned with the radial lines from the rotation axis; rather the present invention contemplates the greatest lining material width at the radially outer region of the brake pad, while the width is smaller at the radially inner region of the lining material. The closer the intersection is to the center of the brake disc rotor, the more efficient the energy distribution at the pad-disc interface. Another further advantage of the present invention is that the reduced width in the radially inner region of the brake pad permits the abutment faces of the brake pad carrier and the lateral sides of the brake pad to meet along a line that is more nearly perpendicular to a radius from the rotation axis. This arrangement allows the transfer braking forces between the lateral side of the brake pad and pad abutment surface of the pad carrier at or nearly normal to the abutment line. This provides for more uniform distribution of the abutment forces over the abutment surface, i.e., more even (and thus lower) contact pressures, helping minimize brake pad vibrations and associated brake noise, improved fatigue life performance and reduce component wear. In addition, the arrangements can help in reducing the effects of “pad kick,” an in-place rotation of the brake pad that can generate undesired brake application noise due to pad vibrations, increase fatigue damage to typical brake pad retaining hardware (e.g., over-pad leaf springs) and increase wear and damage to the brake pad and/or brake caliper mounting structure. An illustration of pad kick is provided in FIG. 4. When a brake pad 101 is applied against a friction surface of a brake disk (not illustrated) which is rotating in direction DR, the brake disk's rotation induces motion and reaction forces between the brake pad 101 and its adjacent mount abutment surfaces (not illustrated). At the leading edge 102 of the brake pad the brake pad attempts to move upward in direction LU in response to the friction forces along the face of the brake pad (illustrated here by force arrows across the face of brake pad 101). At the trailing edge 103 of the brake pad, the brake pad attempts to move downward in direction TD. However, because the brake pad 101 is constrained by adjacent mount abutment surfaces, the overall motion of the brake pad is generally a rotation about an axis parallel to the brake disk rotation axis. This motion may be unilateral during the brake application, or may manifest itself as a moderate-to-severe oscillation of the brake pad in its mount, significantly increasing wear of the abutting brake pad and mount surfaces. One of ordinary skill in the art will recognize that the brake pad support function may be provided by a brake caliper mount designed to support the brake pads, or by a brake pad carrier which is separate from the caliper mounting structure. For convenience in this description, the terms caliper carrier, caliper mount and brake pad carrier may be interchanged without intending to limit the brake par supporting structure to any specific brake pad and brake caliper carrying structure. A further advantage of the present invention is that the reduced width in the radially inner region of the brake pad permits brake pad retention features, such as those disclosed in co-pending application Ser. No. 14/640,152, to be moved closer together to enable further reduction in the size of the disc brake components while maintaining a desired level of braking performance and/or or increasing braking performance by increasing brake pad lining surface area while still keeping overall brake size within the space-constrained envelope of the wheel rim and other nearby components. Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings.

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We're about: Meet other atheists, agnostics, and people with different religious backgrounds in Korea. We share ideas mostly about atheism and rational thought, debunk superstitions, and discuss morality and what it means to be human.

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ShortLink v2.5 is a Premium URL Shortner ASP.Net Project. They have a url shortner that help you most to short your link easily and provides a plateform where anyone can short their url. for more information about this script please click On Demo Button. DemoDownload

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Two weekly sessions of combined aerobic and resistance exercise are sufficient to provide beneficial effects in subjects with Type 2 diabetes mellitus and metabolic syndrome. This study was performed to establish whether only 2 sessions per week of combined aerobic and resistance exercise are enough to reduce glycated hemoglobin (HbA(1c)) and to induce changes in skeletal muscle gene expression in Type 2 diabetes mellitus (DM2) subjects with metabolic syndrome. Eight DM2 subjects underwent a 1-yr exercise program consisting of 2 weekly sessions of 140 min that combined aerobic [at 55-70% of maximal oxygen uptake (VO(2max))] and resistance circuit training [at 60-80% of 1 repetition maximum (RM)]. The training significantly improved VO(2max) (from 33.5+/-3.8 ml/kg/min to 38.2+/-3.5 ml/kg/min, p=0.0085) and muscle strength (p<0.05). Changes over baseline were significant for HbA(1c), reduced by 0.45% (p=0.0084), fasting blood glucose (from 8.8+/-1.5 to 6.9+/-2.2 mmol/l, p=0.0132), waist circumference (from 98.9+/-4.8 to 95.9+/-4.6 cm, p=0.0054), body weight (from 87.5+/-10.7 to 85.7+/-10.1 kg, p=0.0375), systolic blood pressure (from 137+/-15 to 126+/-8 mmHg, p=0.0455), total cholesterol (from 220+/-24 to 184+/-13 mg/dl, p=0.0057), and LDL-cholesterol (from 150+/-16 to 105+/-15 mg/dl, p=0.0004). Mitochondrial DNA/nuclear DNA ratio at 6 and 12 months did not change. There was a significant increase of mRNA of peroxisome proliferator- activated receptor (PPAR)-gamma after 6 months of train - ing (p=0.024); PPARalpha mRNA levels were significantly increased at 6 (p=0.035) and 12 months (p=0.044). The mRNA quantification of other genes measured [mitochondrially encoded cytochrome c oxidase subunit II (MTCO2), cytochrome c oxidase subunit Vb (COX5b), PPARgamma coactivator 1alpha (PGC- 1alpha), glucose transporter 4 (GLUT 4), forkhead transcription factor BOX O1 (FOXO-1), carnitine palmitoyltransferase 1 (CPT-1), lipoprotein lipase (LPL), and insulin receptor substrate 1 (IRS-1)] did not show significant changes at 6 and 12 months. This study suggests that a twice-per-week frequency of exercise is sufficient to improve glucose control and the expression of skeletal muscle PPARgamma and PPARalpha in DM2 subjects with metabolic syndrome.

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This is a blog dedicated to highlight the issue of Christian Persecution in India. The posts here in contain information about Christian Persecution in India from various sources with links and some exclusive to us. No Copyright infringement is intended. This is only for the purpose of spreading awareness about the ongoing Christian persecution in India. We have no political affiliations. We hope for a nation where all could live in peace with each other. Sunday, October 29, 2006 NEW DELHI, October 27 (Compass Direct News) - Ostracized by their village for the past year, two converts of a church in Madhya Pradesh state's Shahdol district have been beaten for their refusal to return to the Hindu fold. Santu Prasad Barmaia and Kunjan Prasad Barmaia, both farmers and members of a Gospel for Asia church in Paralia village, were attacked by a group of 12 villagers on October 19. The attack took place in the morning, when the two were on their way to their fields, a local Christian requesting anonymity told Compass. Both men suffered internal injuries. Police have not arrested the culprits, the source said, in spite of the fact that the victims named them in a complaint filed at the Amarkantak police station. Police officials could not be reached for comment. The source explained that villagers were angry with the Christians for declining to participate in Hindu rituals since receiving Christ four years ago. "The villagers had been persistently putting pressure on them to 'reconvert' to Hinduism," he said. He added that in the past year villagers have refused to allow the two men, the only Christians in the village, to take water from the hamlet's common well to pressure them to return to Hinduism. In spite of their limited resources, the Christians dug their own well. "Earlier, some miscreants vandalized a Hindu temple in the village and the blame fell on the Christians," the source said. "Later, however, police investigation revealed that they had not done it. Yet the villagers continued to treat them with contempt." Beaten Pastor Jailed In Barghat village in Madhya Pradesh's Seoni district, Pastor Haroon Jonathan continues to languish in jail after police officials failed to fulfill a promise to release him on bail. Jonathan faced charges of "hurting religious sentiments" and "forced conversion" after he was attacked by Hindu extremists in September. Still recovering from his injuries, he turned himself in to police on October 15 after officers promised that he would be bailed out the following day. But submission of formal charges is a prerequisite for obtaining bail, and police did not file them before courts shut down for Diwali (Hindu festival) from October 18 to October 26, said another local source. At press time it was not clear when the charges would be formally filed. Jonathan and several other Christian family members were arrested on September 10 after some 70 Hindu extremists allegedly belonging to the Jagran Dharma Seva ("Service to Awaken Faith") burst into the house church and attacked the congregation. (See Compass Direct News, "More Christians Attacked in Madhya Pradesh, India," September 15). They dragged Jonathan and his wife Anita out of the house, along with in-laws Sunil Prem and his wife Sunita. The four were detained for hurting religious sentiments, promoting religious animosity and forced conversion under the Indian Penal Code and Sections 3 and 4 of the Madhya Pradesh Freedom of Religion Act, or "anti-conversion law." Police claimed to have a tape recording of Jonathan urging people to get rid of any idols or pictures of Hindu deities. The Christians were released on bail, but two more cases were filed against Jonathan, and he was declared as "absconding." On October 18, about 600 local Christians held a rally in Seoni district to protest the increasing attacks in Madhya Pradesh. Jonathan was supposed to have been one of the leaders of the rally. Local police under intense pressure to file charges against owner of prayer meeting home. MUMBAI, India, October 26 (Compass Direct News) - Police this morning arrested a recent convert in Mayapuri, Madhya Pradesh state for the second time in three days in an apparent attempt to pressure him to give evidence that his pastor forcibly converted him. By nightfall in India, the new believer was charged with "insulting religious beliefs." Dewas Gate police again detained Ramesh Thakur, 37, at 9 a.m. after having arrested him on Tuesday (October 24) and releasing him the next day after intense questioning. The pastor of his church in the Mayapuri area of Ujjain district, Jagdish Bharti, had been arrested last June on charges of "insulting religious beliefs" and is still fighting those charges, with his next hearing set for Monday (October 30). R.R. Malvi, police in-charge of the Dewas Gate police station, told Compass that Thakur would continue to be detained while investigations are underway. When Thakur, his pastor and others were arrested on June 4, he was released the same day on bail after four hours of interrogation without being charged. The church holds Sunday prayer meetings at the home of Thakur. "On Tuesday the police barged into Ramesh Thakur's house and ordered him to produce all house documents," Pastor Bharti of the Bethel Fellowship Church told Compass. "However, since he did not have any papers on hand, they took him to the police station, where he was threatened with dire consequences if he were shielding me." The pastor added that police officials inquired, in an intimidating manner, whether Thakur was given the house as an allurement to become Christian. Though Thakur has not yet been baptized, he received Jesus as savior six months ago and has been praying and worshiping at the Bethel Fellowship Church since then. Bharti told Compass that since their arrest on June 4, the Hindu extremist Rashtriya Swayamsevak Sangh (RSS) and its youth wing, the Bajrang Dal, have subjected them to insults, abusive language and threats. Political Pressure to Charge Christians Dilip Akodiya of the Bethel church told Compass that officer Malvi informed him that he was under tremendous political pressure to charge Thakur. Viju Varghese, Global Council of Indian Christians coordinator in Madhya Pradesh, told Compass that the RSS had offered Thakur 25,000 rupees (US$552) to implicate Pastor Bharti in a charge of "allurement" to convert. Indira Iyengar, a former member of the Madhya Pradesh State Minorities Commission, told Compass "The harassment of the Christians just keeps spiraling upwards. Pastor Jagdish and Ramesh Thakur have been continuously harassed by the police, as well as by the Bajrang Dal." Bharti and 15 other Christians had been arrested on June 4 after a mob of Hindu extremists stormed their home prayer meeting in Mayapuri and dragged them to a nearby temple to force them to bow before local gods. Saturday, October 21, 2006 The Chhattisgarh government is targeting a Catholic voluntary health service in Ambikapur diocese after some people charged it with illegal conversion activities, a Church official has said. Since 1995, the Raigarh-Ambikapur Health Association has been functioning from Pathalgoan. The government of undivided Madhya Pradesh state had entrusted it with its Integrated Child Development Services program in one of the 19 Blocks in the district of Surguja. "It has functioned wonderfully well. So much so in the years 1999-2000 this NGO had received state's Birsa Munda award. Satisfied with its works, the MP government had decided to entrust it with yet another Block namely, Odgi Block in Surguja, the same responsibility," a diocesan official said. But "the picture is totally different" now because of motivated allegations of some fanatic groups that accuse the voluntary group of "conversion activities" in the villages where it works. "Inquiries were made from Raipur and even from central government. But their report was in our favor. Accusations of conversions were proved baseless," the Church official said. However, the state government has taken some steps against the organization, the officials said. Since April 2006 some 340 employees were denied of their salary. There are two Religious Sisters belonging to St. Joseph of Lyons Congregation working for of the program, appointed by the government. Seventeen supervisors work under them, who are in charge of 327 workers and co-workers spread out in villages.The government has taken steps to terminate the two religious sisters and 17 supervisors saying that they are improperly appointed. However, the 327 village workers will not be removed from their job, diocesan officials said. The diocese of Ambikapur was erected on December 14, 1977 by dividing Raigarh-Ambikapur diocese. The diocese is co-extensive with the present civil districts of Surguja and Korea in the northern part of the State of Chhattisgarh. Friday, October 06, 2006 Disinformation Campaign against Christians in Jaunpur, UPThe Times of India (Lucknow) reported on 5 Oct 2006 at 0257 hrs on its online internet edition that “Over 300 villagers adopt Christianity” in Belhara village in Jaunpur district, Uttar Pradesh. The report further went on to mention that 350 men and women embraced Christianity in a conversation ceremony held on Oct 3rd. There could not be a worse misrepresentation of facts here. The only iota of truth in the entire news report was that a gathering of a large number of people had taken place on the 3rd, in the home of Sanjay Singh. Some were Christians and some non-Christians who had voluntarily assembled from the nearby villages in Kudupur, who had come together for prayer. Some of them may have been first generation converts, but none of them had embraced Christianity that day in that particular prayer meeting held in the home of Sanjay Singh.Distorted versions of similar news have been featuring everyday in the local edition of the Hindi newspaper, Dainik Jagran since October 3rd. This is inciting the radical Hindutva outfits such as the Vishva Hindu Parishad to take up the issue and with the help of the local authorities bully the local Christian leaders. On October 4, a large team of 70 people including police and VHP personnel barged into Sanjay Singh’s home in order to question him and his involvement in the alleged ‘conversion’ meeting. Apart from the evangelist, Rajendra Chouhan who was leading the prayer meeting on the 3rd, Sanjay Singh was perceived as the ‘co-accused’ since the prayer meeting was being held in his home. They went on to take Sanjay to the police station known as the Kotwali Line Bazaar. He was questioned extensively regarding the prayer meeting and his willful conversion to Christianity was raised up as a big issue. The officials threatened him to go back to the faith of his fore-fathers, and if he didn’t he may have to face ugly consequences. Further, bribe was demanded of him if he wanted to leave the police station that night. The next day on October 5, another team of investigating officers landed up at Sanjay Singh’s home. They alleged to have proof regarding his involvement in forceful conversion of villagers of the area, and that they would check the water well since sources had tipped them off that statues and idols of Hindu gods had been thrown into the well. A thorough investigation by the police team revealed no idol in the well. Incensed at not finding anything, the VHP people present along with the investigating officers broke down portions of the wall of Sanjay Singh’s house. The fact of the matter is that due to rash and biased reporting by a national daily, the lives of many Christians in Jaunpur district are in danger. There are several Christians who have been have been taken in for questioning on October 6, in an unjust manner in Badlapur Police Station, also in Jaunpur district. The four men: Rajesh, Sangram, Rajpath and Lalman were beaten up and interrogated as if they were hardened criminals. The only thing against them is that they are Christians who were present for the meeting on the 3rd at Sanjay Singh’s home.At this moment, Sanjay Singh and his home need protection from Hindutva radical forces. Sanjay Singh was taken in for questioning again today, October 6th, and still hasn’t been released by the authorities.At this moment evangelist, Rajendra Chauhan needs protection for his regular prayer meetings held on Saturdays (10 am – 4 pm) and on Sundays (10 am – 2 pm) held in Kudupur - Bagcha, of Jaunpur district. The VHP people have warned the Christians that they will carry out a re-conversion ceremony on October 8th, and bring back all the converted Christians residing in the area, back to the Hindu fold. Vijayesh LalAssociate CoordinatorCenter for Human RightsEvangelical Fellowship of India

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Estradiol-17 beta has a biphasic effect on oxytocin secretion by bovine granulosa cells. The peptide hormone oxytocin (OT) and its mRNA are synthesized by bovine granulosa cells. Bovine granulosa cells isolated before the preovulatory LH/FSH surge secrete low amounts of OT and respond to gonadotropins with an increase in OT secretion. After the LH/FSH surge, basal OT secretion increases 20-fold. At the same time, dramatic changes in steroidogenesis occur in the preovulatory follicle. Estradiol-17 beta production is high before and declines after the LH surge. The objective of this study was to determine whether steroid hormones, particularly estradiol-17 beta, influence OT secretion by bovine granulosa cells. Heifers (n = 5) were injected with prostaglandin F2 alpha (PGF2 alpha) on Day 7 of the estrous cycle to induce luteolysis. Preovulatory follicles were obtained during the ensuing follicular phase, 24 h after PGF2 alpha injection (about 24-36 h before the expected time of the preovulatory LH/FSH surge). Granulosa cells were isolated and cultured for 5 days in defined medium containing graded doses (0, 0.001, 0.01, 0.1, 1, 10 micrograms/ml) of estradiol-17 beta, testosterone, or progesterone. Media were collected daily and assayed for OT by radioimmunoassay. Addition of 0.001 or 0.01 micrograms estradiol-17 beta/ml stimulated OT secretion by granulosa cells by about 75% during the last 2 days of culture (p < 0.01). In contrast, estradiol-17 beta at high doses (1 and 10 micrograms/ml) inhibited OT secretion by 45-85% (p < 0.01). Therefore, estradiol-17 beta had a biphasic effect on OT secretion by granulosa cells.(ABSTRACT TRUNCATED AT 250 WORDS)

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blog I was jointly commissioned by Jinju International Music Festival and Ensemble Opus to write a piano quartet to be performed in Jinju. The Music Festival that has been going on in Jinju is to commemorate Lee Sang Geun, a composer I was jointly commissioned by Jinju International Music Festival and Ensemble Opus to write a piano quartet to be performed in Jinju. The Music Festival that has been going on in Jinju is to commemorate Lee Sang Geun, a composer Changak contemporary music society hosted its annual exchange performance with composers from Xian, China. My work for geomungo and classical guitar was performed again by two great performers, Eun-ja Yoon(윤은자) and Jung-Ryul Kim(김정열). The link contains their premiere in Changak contemporary music society hosted its annual exchange performance with composers from Xian, China. My work for geomungo and classical guitar was performed again by two great performers, Eun-ja Yoon(윤은자) and Jung-Ryul Kim(김정열). The link contains their premiere in Works by Yamamoto Tetsuya, Francesco Filidei, Sirin Nah, Eunkung Park, Sangbong Nam and Jee Soo Shin were performed in February 2014 in Seoul Citizens Hall. Preparation for the event, especially for the performance of Filidei was a rather peculiar sight Works by Yamamoto Tetsuya, Francesco Filidei, Sirin Nah, Eunkung Park, Sangbong Nam and Jee Soo Shin were performed in February 2014 in Seoul Citizens Hall. Preparation for the event, especially for the performance of Filidei was a rather peculiar sight It was an honour to have my work presented alongside with works of Brahms and Penderecki at the winter season of Seoul International Music Festival which took in the week of 16.-20.December 2013 My piano quartet was performed on It was an honour to have my work presented alongside with works of Brahms and Penderecki at the winter season of Seoul International Music Festival which took in the week of 16.-20.December 2013 My piano quartet was performed on impressions@nokha from ulkat films on Vimeo. At this performance, the performers reacted to certain behavioural patterns of the audience, who were given the freedom to wander around the tiny courtyard of a hanok(traditional Korean house) while the performers played impressions@nokha from ulkat films on Vimeo. At this performance, the performers reacted to certain behavioural patterns of the audience, who were given the freedom to wander around the tiny courtyard of a hanok(traditional Korean house) while the performers played

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Since Present Franklin Delano Roosevelt met with King Ibn Saud on Valentine's Day 1945, the U.S. and Saudi Arabia have maintained a close relationship. For decades, however, critics have warned that this relationship is a fundamentally dysfunctional — and destructive — one. Advertisement: Although a brutally repressive theocratic absolute monarchy that imprisons, tortures and beheads peaceful pro-democracy activists, Saudi Arabia provides its Western allies with a stable, cheap and plentiful oil source and is one of the biggest purchaser of Western weapons. In turn, however, the Saudi regime uses its gargantuan oil revenue to spread its Wahhabi religious fundamentalism throughout the world, and even funnels weapons and supplies to extremist Islamist groups. Peace activists in the U.S. are hoping to change the U.S. relationship with the Saudi regime. In Washington, D.C., on March 5 and 6, approximately 250 activists, human rights experts and scholars gathered for what may have been the first international summit to challenge the U.S. relationship with the theocratic dictatorship in Saudi Arabia. Advertisement: The 2016 Summit on Saudi Arabia was organized by the peace group CODEPINK. It was co-sponsored by a panoply of other organizations, including the Institute for Policy Studies, the Institute for Gulf Affairs, Just Foreign Policy, the D.C. branch of the Women's International League for Peace and Freedom and even the Nation magazine. An important co-sponsor was the Coalition to End the U.S.-Saudi Alliance, a new advocacy group that is pushing for the U.S. to cut its ties with the Middle Eastern monarchy over its brutal human rights violations. The 2016 Summit on Saudi Arabia featured a Who's Who of Saudi dissidents and specialists, along with representatives from the rights organizations Amnesty International, Human Rights Watch and Reprieve. Advertisement: Salon attended the summit, which was filmed and archived by Baltimore-based independent media outlet the Real News. CODEPINK co-founder Medea Benjamin noted that her organization invited supporters of the Saudi regime to appear at the summit, offering them an opportunity to give their side of the story. "We begged members of the Saudi embassy to speak," she said, but no one agreed to do so. Advertisement: Ray McGovern, a former longtime CIA analyst turned anti-war activist, also attended. "Why do American politicians become incontinent when someone mentions the words 'Saudi Arabia'?" he joked. Saudi activist Mohammed al-Nimr spoke at the summit. Mohammed is the son of Sheikh Nimr al-Nimr, a prominent leader in the kingdom's Shia Muslim minority community whom the Saudi regime arrested and executed for leading a peaceful uprising in 2011 and 2012. Salon obtained an exclusive interview with Mohammed, which will be published separately. Renowned scholar Vijay Prashad, a leading expert on foreign policy and international affairs, was the keynote speaker. Advertisement: Prashad detailed what he called "the foreign policy of the 1 percent" — the foreign policy practiced today, one that is based on control of natural resources like oil, the opening of new markets for multinational corporations, expansion of U.S. influence, and an increase in arms sales and militarism. Warning of "suicidal death pact between the U.S. and Saudi Arabia," Prashad proposed the possibility of a foreign policy of the 99 percent, which would be based on respect for human rights, democracy and diplomacy. Salon also sat down with Prashad to discuss the disastrous U.S.-backed wars in Libya, Iraq and Syria. This interview will be published separately. Advertisement: Ali al-Ahmed, a renowned Saudi analyst and the founder of the independent think tank the Institute for Gulf Affairs, kicked off the summit, lamenting that the royal family has "hijacked our country, hijacked our religion." Stressing that it is important to distinguish the Saudi regime from the Saudi people, al-Ahmed said "I am dedicating my life to ending the Saudi monarchy, and any absolute monarchy we have in the region." Al-Ahmed pointed out the irony that the U.S., which was founded in a revolution that challenged the British absolute monarchy, has for decades propped up the Saudi monarchy. "The largest concentration of absolute monarchies in the world are in the Gulf," he noted, and these oil-rich countries, especially Saudi Arabia, have a big influence on Western politics. Advertisement: He noted that the Saudi regime has given tens of millions of dollars to the Clinton Foundation, the Carter Center and the Bush family, while funding prestigious schools like Yale, Harvard and Georgetown. More personally, as a Muslim, al-Ahmed stressed that he is particularly disgusted by what the Saudi monarchy does in the name of Islam. "Saudi Islam is not Islam; it's an Islam of an absolute monarchy," he said. The Saudi scholar argued that the monarchy had "hijacked Islam" and used it as a tool "I am a Muslim, and in my religion monarchies are forbidden," he said. "Islam forbids monarchy. Anyone who tells you otherwise is lying to you." Even in the U.S., al-Ahmed says he has faced some repression for his outspoken activism. Several years ago, he says he was quietly placed on a U.S. government no-fly list, and effectively banned from travel. Al-Ahmed says he threatened to make this public and protested, and was eventually given his travel documents. Advertisement: He warned fellow Americans that the close U.S. relationship with the Saudi regime is harming them too. "The Saudi oil war is hurting the United States," al-Ahmed said. He argued the U.S. reliance on Gulf oil is preventing a move toward alternative, renewable energy sources and is damaging the environment. Al-Ahmed additionally emphasized that the Saudi regime is supporting extremism throughout the world. "Without removing the Saudi monarchy from power, the terrorism will continue," he said. He implored Americans to speak out against their government's policies. "It's really important that you support us, because you are freer. You can speak out; we can't," he said. Advertisement: "We are killing for speaking out," al-Ahmed added, noting the "thousands of political prisoners" languishing in Saudi dungeons. "We need to liberate our people from the Saudi monarchy." Abdulaziz al-Hussan, a Saudi human rights lawyer, also spoke of the plight of reformists in the kingdom. "If you support democracy in Saudi, you will be considered a terrorist," he lamented. Al-Hussan said the 47 people executed by the Saudi regime in January were killed "without due process." Although state-sponsored sectarianism is a big problem in Saudi Arabia, al-Hussan said, at the end of the day, nobody in Saudi absolute monarchy, outside of the royal family, has rights, regardless of whether they are Sunni or Shia. When he worked as a human rights lobbyist in Europe, al-Hussan recalled being "depressed by how nobody wanted to say anything about human rights in Saudi, because of all the money." He criticized "hypocrite governments in the West, who support the violation of human rights for business interests. Al-Hussan said he has seen how the regime's brutality and torture radicalizes people. "You created them, through violence, state violence," he declared. "To stop the violence, we must stop the injustice." He added, "I will never be on the side of the oppressor; I will always be on the side of the oppressed." Saudi journalist Ebtihal Mubarak headed a panel on women's rights in Saudi Arabia. She spoke of the "gender apartheid" that exists in the kingdom. She recalled using this term once on CNN to describe the Saudi regime, "and it upset them," Mubarak said. "Reality should upset them," she added. In Saudi society, women are essentially second-class citizens. They are banned from driving, can only travel when accompanied by a male guardian and face severe legal restrictions. Mubarak was joined by Kristine Beckerle, a fellow at Human Rights Watch, who specializes in Saudi Arabia. Beckerle emphasized that the Saudi regime's male guardianship system is the biggest impediment to women's rights. The "imposition on women's movement goes far behind driving," Beckerle noted. It is illegal for Saudi women to travel abroad without approval of a male guardian, for instance. And the laws for male guardianship are so strange that a 44-year-old mother's 23-year-old son can be considered her legal guardian and could have complete control over her. Male guardians can file legal claims against women in court for "disobedience." In cases where women try to take legal action against male guardians for abuse, then, Beckerle explained, their male legal guardians can file counter-claims for disobedience, and send the woman to prison. "The very fact that male guardianship exists is a huge violation of human rights," Beckerle said. Women getting punished for the crime of their male assailants is not uncommon in Saudi Arabia. Mubarak also pointed out that even Saudi rape survivors have been imprisoned and sentenced to public lashings. There is no civil society in Saudi Arabia. There are no non-governmental organizations, no independent groups and no dissenting political parties. Women face large political, systemic barriers, then, in their fight for equality and justice. Mubarak lamented that the problem that gets the most attention in the West is the Saudi ban on women driving, "but there are much more catastrophic problems that women face," she said. Saudi men "have all this power in their hands," Mubarak said. But this is not necessarily because they are uniquely patriarchal, she stressed — women in Western countries face structural impediments to equality too — but rather because Saudi men are given this much power in an autocratic regime. The Saudi regime's "favorite narrative" is that the Saudi people are very conservative, but the monarchy is a progressive force that can balance these supposed widespread views, Mubarak explained. But she said this argument is false. "There are certain things the government could do tomorrow that could really help women's lives," Beckerle noted. She also pointed out that coverage of the Saudi regime in the Western media is often very euphemistic. Reports will applaud minor developments as a "small steps for Saudi women" while ignoring the much larger structural oppression Saudi women face in a regime strongly backed by Western governments. Experts from leading human rights organizations also spoke of the Saudi regime's egregious record. Julianne Hill, of Reprieve, discussed the widespread use of executions and torture in Saudi Arabia. Seventy-two percent of people on death row were on for non-violent offenses, mostly involving drugs or dissent, she explained. Sixty-nine people of those executed by the Saudi regime were killed for non-violent offenses. Saudi courts are political, not impartial, Hill explained, and torture is frequently used to extract confessions from people who were arrested. In most cases, confessions are the primary basis for sentencing. Hill recalled an incident in which a young man who was imprisoned and tortured by the Saudi regime signed a blank sheet of paper as a "confession." Text was later put on the paper he signed, although he never even saw the text. Foreign nationals who do not speak Arabic are often forced to sign confessions they don't understand, Hill explained, and these kinds of confessions have been used to justify executions. The Saudi regime also often arrests and sentences to death juveniles. Saudi Arabia is a signatory on Convention on the Rights of the Child human rights treaty, however, so it waits until the minors it sentenced to death become adults; then it kills them. Sharat Lin, an expert on the exploitation of migrant labor in Saudi Arabia, also spoke about the plight of mostly South Asian immigrants in the Saudi regime. Lin worked in Saudi Arabia for several years, but was eventually expelled from the country for reporting on corruption in his job. Gulf regimes frequently rely heavy on migrant workers, whom they intensely exploit, sometimes in slave-like conditions. In Saudi Arabia, migrant workers are paid significantly less, and Saudi nationals are preferentially treated throughout the economy. Blasting "the totalitarian government which is controlled by the royal family," Lin noted that "corporate America played a role in creating a highly discriminatory" environment in Saudi Arabia. Sunjeev Bery, advocacy director for Middle East North Africa issues at Amnesty International USA, criticized the U.S. for its hypocrisy on the Saudi regime. Islamophobic pundits in the West frequently ask "Where are the Islamic reformers?," Bery noted, but "a major U.S. ally has put them in prison." Bery explained that all public gatherings in Saudi Arabia are essentially prohibited, unless they receive approval by the regime. He also pointed out that the rights of other minority groups — such as the religious rights of Filipino Christian workers — are not at all respected. The Amnesty official expressed special concerns about the brutal war Saudi Arabia has been leading in Yemen since March 2015. A coalition led by Saudi Arabia has relentlessly bombed civilian areas in Yemen for approximately a year. The Saudi-led coalition has targeted hospitals, residential homes, refugee camps and even an Oxfam humanitarian aid warehouse. It has even dropped widely banned cluster munitions on civilian areas. Human rights organizations and the U.N. have accused the U.S.-backed, Saudi-led coalition of war crimes. Bery said the Saudi regime declared an entire province in Yemen to be a legitimate military target, with no differentiation between military and civilian, in violation of the laws of war. "From Amnesty International's perspective, there is no legal basis" for the U.S. support for the Saudi regime in its war on Yemen, Bery said. "There is no legal justification." He pointed out that, because the U.S. media has barely reported on the U.S.-backed war in Yemen, "most people don't even know." The Amnesty official also pointed out that Saudi Arabia's "reckless mass bombardment of Yemen is expanding the operating space of al-Qaida and ISIS — that is a fact." There were several more panels at the summit. Institute for Policy Studies analyst Phyllis Bennis spoke of the history of the U.S.-Saudi relationship. She detailed how Saudi Arabia's position as an oil giant emerged, with the company Aramco, and argued the U.S.-Saudi oil pact "was not only about access; it was more about control." In the Cold War, Bennis recalled that the Saudi regime was a reliable opponent of leftist and Arab nationalist movements, which the U.S. opposed. Describing U.S. foreign policy in the Middle East in its fight against communism, Bennis quoted President Dwight D. Eisenhower, who quietly insisted to White House staff "we should do everything possible to stress the 'holy war' aspect." Activist and writer Raed Jarrar spoke of the overall disastrous U.S. policy in the Middle East, describing it as a source of instability, death and destruction. The U.S. should "stop being accomplices to and supporters of crimes committed in the region," he argued. William Hartung, the director of the Arms and Security Project at the Center for International Policy, detailed how the U.S. has ramped up enormous arms sales to Saudi Arabia in recent years. Likening the Obama Doctrine to the Nixon Doctrine, Hartung noted that there have been at least $195 billion arms sales under Obama, more than any administration since WWII, and that much of this has gone to the Saudi regime. The war in Yemen, which he called "the silent war," "is essentially one big war crime, wrapped into one campaign," Hartung said. Scholar Robert Vitalis argued analysts should look beyond just oil at other reasons the U.S. maintains a close relationship with the Saudi regime. Bahraini politician and human rights activist Matar Matar spoke of Saudi influence over Bahrain, and the U.S.-backed invasion of Saudi troops in order to quell the 2011 pro-democracy uprising. He recalled Bahraini activist Ali Sager, who was imprisoned by the Western-allied regime and tortured to death. Matar also criticized U.S. imperialism in his country, and spoke of the "de-democratization of Bahrain" after it became home to the U.S. Navy Fifth Fleet. Activist Mohammed al-Shami also spoke of Saudi war in Yemen and the history of Saudi influence over the impoverished country in the southern Arabian Peninsula. Jamal Abdi, of the National Iranian American Council, spoke of how the Saudi regime tried to jeopardize the U.S. nuclear deal with Iran. Abdi criticized the visa restrictions the U.S. imposed on Iranians and Iranian dual nationals. He also spoke of how the U.S. is essentially "renting" the Saudi army to carry out the war in Yemen, and potentially even Syria. Daniel Arshack, the lawyer for the imprisoned Saudi attorney and human rights activist Waleed Abu al-Khair, blasted the hypocrisy of the U.S., a country founded on opposition to monarchism, propping up the most oppressive absolute monarchy on the planet. Sanam Naraghi-Anderlini, the executive director of the International Civil Society Network, wrapped up the summit with a reflection on the Saudi regime's egregious human rights record and large influence in the U.S. Naraghi-Anderlini noted that Saudi Arabia spends at least $240,000 per month on PR firms in Washington, D.C. alone, and works with lobbying powerhouses like the Podesta Group. She accused the Saudi regime of spreading "stealth sectarianism," of framing its political conflict with Iran "as a sectarian issue," while simultaneously "spreading Wahhabi sectarianism." "We need to stop thinking that being against something is enough," Naraghi-Anderlini said, and called for further political action. The growing conversation around challenging the close U.S. relationship with Saudi Arabia, she added, is "the most important foreign policy discussion having right now, and it's not on TV."

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Dairy Farm Business Strategic Review results in $3.65 million in new investment Rural Business Support’s highly successful Dairy Farm Business Strategic Review has assisted more than 50 dairy family businesses in the past two years, contributing to more than $3.65 million in new investment by the program’s participants. The pilot program in 2016 was funded by a grant from the South Australian Government through PIRSA. The rollout in 2017 was funded by DairySA, the SA Dairy Industry Fund and PIRSA. RBS also acknowledges the support of the dairy industry at state and national level. This is what some of the dairy families had to say about the program. “Absolute necessity” “I was sceptical – but it’s useful and full of fresh ideas” “Great way to evaluate where your business is at and where you are heading” “We have greater understanding of our farm productivity and profitability” “Very helpful for assessing future investment plans” “It is not intimidating – the facilitators are respectful and knowledgeable” “Great that it is a specific and tailored plan for every farm” “The program gives you goals, deadlines and the confidence to move forward” “Well organised and to the point” “Definitely do it!” “As a participant in the pilot I recommend this to all dairy families” – John Hunt SADA Building on its success in the dairy industry, the Farm Business Strategic Review has also been piloted with 10 pork families. In 2018 the Grains Industry Farm Business Strategic Review will be rolled out – find out more here.

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Our location on the south shore of Lady Bird Lake, in the heart of the new Lakeshore District, puts us just minutes from everywhere you want to be in Austin. And we mean minutes. By car, by bike - or with your own running shoes - you can get where you’re going without the hassles of traffic and wasted time. With rents significantly lower than downtown, and transportation costs - including cab fares - far lower than what you’ll rack up further out, you’ll have extra money in your pocket. That’s freedom to have an extra drink at Liberty bar, catch another show at Emo's, or even head to the airport for a weekend getaway.

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--- author: - 'Nathan Musoke,' - Richard Easther bibliography: - 'bib.bib' - 'autobib.bib' title: 'Expectations for Inflationary Observables: Simple or Natural?' --- Introduction {#sec:introduction} ============ Inflation has been part of the conventional cosmological narrative of the evolving universe since the early 1980s [@Guth:1980zm; @Linde:1981mu; @Albrecht:1982wi] and can account for key observations, including the overall flatness, isotropy, homogeneity of the universe, and the nearly scale-invariant spectrum of perturbations. However, there is no clear and compelling “standard model” of inflation, making it difficult to formulate conclusive tests of the overall paradigm. There are two broad approaches to establishing generic properties of the inflationary phase within the framework of slow-roll inflation driven by a single scalar field with a canonical kinetic term. The first stipulates that the inflationary potential is algebraically [*simple*]{}, with monotonic derivatives and an elementary algebraic form [@Boyle:2005ug; @Bird:2008cp; @Boyle:2008ri; @Ijjas:2013vea]; the quadratic and quartic potentials are the canonical examples. For simple scenarios the tensor to scalar ratio $r$ is typically $r \gtrsim 0.1$, while values of $r\lesssim 0.01$ appear fine-tuned. However, relatively large values of $r$ suggest that the inflaton field makes a super-Planckian excursion during the course of inflation [@Lyth:1996im]. At large VEVs generic Planck scale operators contribute significantly to the potential; these contributions must be fine-tuned if the potential is smooth and flat over a trans-Planckian field range, a violation of technical [*naturalness*]{}. From this perspective, a very small ($r\ll10^{-3}$) tensor background is the more likely outcome. As a consequence, [*simple*]{} and [*natural*]{} are far from synonymous in the context of inflation. The tension between these viewpoints is resolved if a symmetry suppresses Planck-scale and other very high energy corrections to the potential. Within string theory, this approach leads to the identification of scenarios such as monodromy inflation [@Baumann:2014nda; @Silverstein:2008sg; @McAllister:2008hb; @Flauger:2009ab] which generate a significant tensor spectrum in a framework whose stability against ultraviolet corrections can be directly assessed. Likewise, an effective single-field model can arise as a cooperative effect among many individual fields, each of which makes a sub-Planckian excursion [@Liddle:1998jc; @Copeland:1999cs; @Kanti:1999vt; @Kanti:1999ie; @Dimopoulos:2005ac; @Easther:2005zr]. The status of inflationary models is usefully discussed from a Bayesian standpoint [@Easther:2011yq; @Planck:2013jfk; @Martin:2013nzq; @Ade:2015lrj]. Rather than performing parameter estimation for empirical observables associated with the primordial perturbations such as $n_s$ (spectral index), $r$, $A_s$ (amplitude), $\alpha_s$ (running) or $f_{NL}$ (non-Gaussianity), candidate inflationary models can be defined by the [*prior*]{} specifying the functional form of the model and the distributions from which its free parameters are drawn. In many cases a natural measure on the inflationary parameter space map to highly non-uniform and strongly correlated distributions for $n_s$, $r$ and $\alpha_s$ [@Easther:2011yq; @Adshead:2010mc]. Furthermore, Bayesian methodology addresses the inflationary model selection problem via the [*evidence*]{} for each identified inflationary scenario. For a model with an $m$-dimensional parameter vector $\bar a$ drawn from a joint distribution $P(\bar a)$ the evidence is $$\label{eq:evidence} E= \int da^m P(\bar a) {\cal L}(\bar a)$$ where ${\cal L}(\bar a) $ is the likelihood derived from a specified set of observations and $P(\bar a)$ is normalised to unity [@Jenkins:2011va; @Easther:2011yq; @Planck:2013jfk; @Martin:2013nzq; @Ade:2015lrj]. If two models $M_1$ and $M_2$ are [*a priori*]{} equally likely, $E_1/E_2$ is the odds ratio for the two scenarios; if the relative prior likelihood of $M_1$ and $M_2$ is $P(M_1) / P(M_2)$ then the odds ratio becomes $E_1 P(M_1)/E_2 P(M_2)$. Quantitative treatments of inflationary model selection typically assume that the $P(M_j)$ are equal, where $j$ labels the models under consideration. The statement that a model is fine-tuned can reflect external knowledge regarding the model’s physical origin, resulting in a stipulation that the corresponding $P(M_i)$ is small. Alternatively, fine-tuning may become apparent when parameter estimation reveals that the posteriors of one or more free parameters differ greatly from a physically motivated prior. In some cases this tuning, and thus the impact on $P(M_j)$, can be quantified. For example, given a “new physics scale” $\Lambda$ it is well-known that the effective mass $m^2$ of a scalar field with bare mass $m^2_b$ is $$m^2 = m^2_b + f_2 \Lambda^2$$ where $f_2$ is expected to be of order unity [@Baumann:2014nda]. With $\Lambda \sim {\ensuremath M_\text{Pl}}$, a uniform distribution for $f_2$, and in the absence of an underlying symmetry controlling $f_2$ it can appear that $P(M_{\tiny \rm quad }) \sim 10^{-11}$ since successful quadratic inflation requires $m^2 \sim 10^{-11} {\ensuremath M_\text{Pl}}^2$. While attempts to identify truly canonical attributes of the inflationary paradigm have been largely futile, the accuracy and precision of measurements of the primordial perturbations has improved dramatically over the last 25 years [@Adam:2015rua; @Ade:2015xua; @Ade:2015lrj]. In particular, current constraints on $n_s$ and $r$ barely with overlap the region of parameter space open to the quadratic model, while the quartic potential has been disfavoured by observations since the first WMAP data release [@Peiris:2003ff]. It is thus unlikely that very simple implementations of the inflationary paradigm are consistent with observational constraints. In Bayesian terms, this allows us to update inflationary priors in light of data. Consequently, although we cannot draw inferences about the detailed structure of high energy physics, we can state with increasing confidence that (for example) it is unlikely our universe underwent a period of inflation driven by a potential that is quadratic or steeper. The immediate goal of this paper is to fully assess the possible observable consequences of inflation due to a single scalar field with a 4-th order polynomial. This is the most general renormalizable potential for a minimally coupled scalar field. Moreover, this is the simplest polynomial that supports inflection point inflation [@Okada:2016ssd; @Allahverdi:2006iq; @Lyth:2006ec; @BuenoSanchez:2006rze; @Martin:2013nzq] while being bounded below, so it yields both large field and small field inflation [@Dodelson:1997hr]. Clearly this is not a new model; to our knowledge this scenario was first explicitly analysed in 1990 [@Hodges:1989dw; @Hodges:1990bf], with a focus on its ability to support designer scenarios with broken scale invariance in the large-field regime. In addition, Ref. [@Bird:2008cp] gives a Monte Carlo sampling of the parameter space, Ref. [@Destri:2007pv] presents an analysis of possible observable outcomes with constraints from early WMAP data, Ref. [@Aslanyan:2015hmi] provides up-to-date constraints on potential parameters, and Ref. [@Fowlie:2016jlx] performs a Bayesian analysis in the context of the hierarchy problem. Our treatment adds to previous discussions by a) presenting a more complete analysis of the possible observables including the spectral running; b) stating clear “inflationary priors” that will facilitate parameter estimation and model selection calculations; c) treating these model specifications as hyperpriors for a generative model [@Price:2015qqb] of the spectrum and computing distributions for the usual spectral parameters, showing that these are highly nonuniform; d) providing a qualitative analysis of the extent to which these inflationary priors can be updated with reference to present-day data, and e) showing that data from plausible future experiments could potentially rule out [*all*]{} inflationary scenarios based on the single-field 4-th order potential. In particular, although the catalog of inflationary behaviours available to a 4-th order polynomial potential populates a substantial subset of the $\{n_s,r,\alpha_s\}$ parameter-space, a significant fraction of this region is revealed to be incompatible with the potential and near-future experiments will have the ability to exclude the full parameter space. This is a key result of this paper: the 4-th order polynomial – the most complex potential compatible with the tree-level action of a single, renormalizable, minimally coupled scalar field – can be falsified by experiments that are part of the current roadmap for experimental cosmology. The physical basis of this result is that parameter combinations that predict smaller values of $r$ tend to have larger values of $\alpha_s$ [@Boyle:2008ri; @Adshead:2010mc; @Munoz:2016owz]. We do not find scenarios where both parameters are vanishingly small and $n_s$ lies inside its currently permitted range, so even null results for both $r$ and $\alpha_s$ could rule out a 4-th order potential. This analysis sets the stage for a broader discussion of the status of fine-tuning in inflationary cosmology. Our results allow us to construct priors based on a variety of physically motivated expectations for values of parameters in the potential, from which we derive distributions for $n_s$, $r$ and $\alpha_s$. These are typically highly non-uniform and effectively quantify the degree of tuning associated with different values of the empirical spectral parameters. Furthermore, in some regions of parameter space the pre-inflationary initial conditions must themselves be chosen carefully in order for inflation to begin, further heightening the degree of tuning these models require. The prospect of all putatively simple models being ruled out by observations forces a closer evaluation of the naturalness of these scenarios. Given that even simple potentials are more plausible when embedded in more complex theories we argue that this development need not immediately undermine confidence in the overall inflationary paradigm. However, if the simplest potentials are ruled out, arguments that inflation is natural must increasingly be framed within the context of more general discussions about the properties and nature of ultra-high energy physics. Inflationary Dynamics {#sec:the_model} ===================== A minimally coupled scalar field with a canonical kinetic term and potential $V(\phi)$ obeys the Klein-Gordon equation, $$\ddot{\phi}+3H\dot{\phi}+V'(\phi) = 0\,,$$ where $H$ is the Hubble parameter. The scale factor $a(t)$ is described by the usual Friedman equation $$H^2 = \left(\frac{\dot{a}}{a}\right)^2 = \frac{1}{3{\ensuremath M_\text{Pl}}^2}\left[\frac{1}{2}\dot{\phi}^2 + V(\phi)\right]\, ,$$ where ${\ensuremath M_\text{Pl}}$ is the (reduced) Planck mass. Our analysis is based on the generic quartic potential, the most complicated renomalizable tree-level action a single scalar field can possess $$V(\phi) = \sum_{i=0}^4 c_i \phi^i\, .$$ We require that the potential has a global, stable minimum at $\phi_\text{min}$ with $V(\phi_\text{min}) = 0$; a linear shift can always give $\phi_\text{min} = 0$. As a consequence of these criteria we fix $c_0 = c_1 = 0$, $c_2 > 0$ and $c_4 >0$ so $$\label{eq:v_phi} V(\phi) = \frac{m^2}{2} \phi^2 - \frac{g}{3} \phi^3 + \frac{\lambda}{4} \phi^4$$ with $\lambda > 0$. We also choose $g \ge 0$ without loss of generality since the underlying theory is invariant under $\phi \rightarrow -\phi$ if $g \rightarrow -g$. Inflationary observables may be characterised by the potential slow roll parameters [@Liddle:1994dx] $$\begin{aligned} \label{eq:epsilon_approx} \epsilon &= \frac{{\ensuremath M_\text{Pl}}^{2}}{2} \left( \frac{V'}{V} \right)^2 \, , \\ \label{eq:eta} \eta &= {\ensuremath M_\text{Pl}}^{2} \frac{V''}{V} \, , \\ \label{eq:xi} \xi &= {\ensuremath M_\text{Pl}}^{4} \frac{V'}{V} \frac{V'''}{V} \, .\end{aligned}$$ Inflation occurs when $\epsilon \lesssim 1$. The slow roll parameters specify the inflationary observables, $$\begin{aligned} \label{eq:n_s} n_s - 1 &\approx -6 \epsilon + 2 \eta \, , \\ r &\approx 16 \epsilon \, , \\ \alpha_s &\approx 16 \epsilon \eta - 24 \epsilon^2 - 2 \xi \, .\end{aligned}$$ These quantities are evaluated at the field value ${\ensuremath \phi_{N}}$ corresponding to the instant at which the corresponding mode leaves the horizon, $N$ $e$-folds before the end of inflation, with $$\label{eq:N_integral} N = \frac{1}{{\ensuremath M_\text{Pl}}^2} \int_{\phi_{end}}^{{\ensuremath \phi_{N}}} \frac{V(\phi)}{V'(\phi)} d \phi .$$ A 4th-order potential can have up to three local extrema. Given that $\lambda > 0$, $V(\phi)$ may have either two local minima (including a global minimum) and a local maximum, a global minimum and a saddle point, or a single, global minimum. The ratio $M_{Pl} V'/V$ goes to zero at large $\phi$ so this potential certainly supports inflation at very large field values. However, the potential can have an inflection point at arbitrary values of $\phi$, in the vicinity of which $V'/V$ is small enough to support inflation. Consequently, there are two distinct inflationary regimes – the large-field case and a possible small field case around an inflection point – and we analyse them separately. Small Field: Observables From Inflection Point Inflation {#sec:analysis} ======================================================== Inflection point potentials have been studied in many contexts. Some are motivated by particle physics, e.g. an inflection point added to monomial chaotic models through radiative corrections [@Ballesteros:2015noa], Higgs potentials [@Okada:2016ssd], the minimal supersymmetric standard model (MSSM) [@Allahverdi:2006iq; @Lyth:2006ec; @BuenoSanchez:2006rze; @Martin:2013nzq], D-brane inflation [@Baumann:2007np; @Baumann:2007ah], or loop inflection-point inflation [@Dimopoulos:2017xox]. The 4-th order model looked at here is discussed by Martin, Ringeval and Vennin [@Martin:2013tda], who dub it Renormalizable Inflection Point Inflation.[^1] We begin by noting that the potential has an exact saddle point at $\phi = g/2\lambda$ when $m^2 = \frac{g^2}{4 \lambda}$ and reparameterize via $$m^2 = \frac{g^2}{4 \lambda} (1 + \delta) \, . \label{eqn:mmpert}$$ If the dimensionless parameter $\delta$ is negative we have a trapping potential[^2] and $\delta =0$ is the saddle point limit. Our first task is to determine the overall inflationary region inside the potential. The slope $V'$ is minimized at $$\phi_\text{inf} = \frac{g \bigl( 2 \pm \sqrt{1-3\delta} \bigr)}{6 \lambda} \, . \label{}$$ The positive root coincides with the saddle location when $\delta=0$ and this inflection point only exists if $\delta<1/3$. We will see that a realistic inflationary phase requires $\delta \ll 1/3$, so we write $$\phi_\text{inf} \approx \frac{g}{2 \lambda} \Bigl(1 - \frac{\delta}{2}\Bigr) = M \Bigl(1 - \frac{\delta}{2}\Bigr) \label{}$$ and make the identification $g = 2 \lambda M$. Changing variables to $\psi = \phi - \phi_\text{inf}$ and dropping terms beyond first order in $\delta$ gives $$V(\psi) = \frac{\lambda}{12} \left[ M^{4} (1 + 6 \delta) + 12 M^{3} \delta \psi + 2 M \psi^{3} \left(- 3 \delta + 2\right) + 3 \psi^{4} \right] . \label{potential_psi}$$ Note that the quadratic term would be proportional to $\delta^2$ and is thus absent in this approximation. The overall minimum lies at exactly $\psi=-M$ with $V(-M)=0$. The shape of the potential is determined by the parameters $M$ and $\delta$, while its overall scale is fixed by $\lambda$. Since inflation occurs when $\phi \approx M$ the total field excursion is of order $M$. In this section we assume $M \le {\ensuremath M_\text{Pl}}$, i.e. small field inflation. The $\psi^4$ term in equation (\[potential\_psi\]) ensures the potential is bounded below. During a viable inflationary phase $V'/V$ and $V''/V$ are both small. Dropping higher order terms in $\delta$ and noting that $V$ changes much more slowly than $V'$ and $V''$ near $\psi=0$, we approximate the slow roll parameters as $$\begin{aligned} \label{eq:epsilon_approx_inf} \epsilon & \approx \frac{72 {\ensuremath M_\text{Pl}}^{2}}{M^2} \left( \delta + \frac{\psi^2}{M^2} \left( 1 - \frac{3}{2} \delta \right)\right)^{2} \\ \label{eq:eta_inf} \eta & \approx 12 \frac{{\ensuremath M_\text{Pl}}^{2} \psi }{M^{3}} \left(2 - 3 \delta\right) \\ \label{eq:xi_inf} \xi & \approx 288 \delta \frac{{\ensuremath M_\text{Pl}}^{4}}{M^{4}} \left(1 + 3 \frac{\psi}{M}\right) \,.\end{aligned}$$ To have any inflation at all we need $\epsilon<1$ at $\psi=0$, so $$\label{eq:delta_max} \delta \lesssim \frac{\sqrt{2}}{12} \frac{M}{{\ensuremath M_\text{Pl}}} \equiv \delta_{\text{max}}\, .$$ If $M \lesssim {\ensuremath M_\text{Pl}}$ this immediately implies $\delta \lesssim 0.1$, justifying our decision to retain only terms first order in $\delta$. We also need the higher order slow roll parameters to be small. By definition, $V''=0$ at an inflection point, so $\eta=0$ when $\psi=0$ and we do not find a new constraint. However, writing $\delta = c\delta_{\text{max}}$ and substituting into $\xi$ we find $$\xi \approx +c \frac{24 \sqrt{2} {\ensuremath M_\text{Pl}}^3}{M^3} \, .$$ The full hierarchy of slow roll equations (in either the potential or Hubble slow roll formalism [@Liddle:1994dx]) shows that $d \epsilon /d N$ and $d \eta /d N$ are large if $\xi \ge 1$ so the inflationary region of the potential is very narrow and the number of $e$-folds $N$ less than unity. Consequently, $N$ and $\alpha_s$ are correlated in generic slow roll models [@Easther:2006tv]; current observational bounds on $\alpha_s$ and ensuring $N \gtrsim 30$ both require $|\xi| \lesssim 0.01$ at $\psi=0$, or $$c \lesssim \frac{0.01}{24 \sqrt{2}} \left(\frac{M}{{\ensuremath M_\text{Pl}}}\right)^3 \, .$$ Since $\delta = c \delta_{\text{max}}$, combining with equation yields $$\label{eq:delta_max2} \delta \lesssim \frac{0.01}{288} \left(\frac{M}{{\ensuremath M_\text{Pl}}}\right)^4 \,;$$ decreasing $M$ by an order of magnitude decreases this upper bound on $\delta$ by four orders of magnitude. If $M \sim 10^{-2} {\ensuremath M_\text{Pl}}$ the cubic term is tuned to parts in $10^{12}$, independently of the constraint on $\lambda$ required to produce a suitable amplitude for the perturbation spectrum. This relationship is illustrated in Figure \[fig:N\_total\]. Similar tuning requirements have been seen in the analysis of other models with inflection points, including MSSM motivated potentials [@BuenoSanchez:2006rze] and accidental inflation [@Linde:2007jn]. This fine tuning can be reduced by adding a constant term to the potential , decreasing $V'/V$ and effectively flattening the potential [@Enqvist:2010vd; @Hotchkiss:2011am]. The trade-off is that $V(\phi_{\text{min}}) > 0$, making the model unrealistic in the absence of a mechanism to subsequently ensure that the vacuum energy becomes vanishingly small. ![ The total number of $e$-folds of inflation $N$ as function of $\delta$ for representative values of $M$, found by numerically integrating . The value of $\delta$ required for a fixed number of $e$-foldings scales as $(M/{\ensuremath M_\text{Pl}})^4$, consistent with the constraint . []{data-label="fig:N_total"}](N_total){width="0.8\linewidth"} To compute $N$ note that inflation begins and ends when $\epsilon \approx 1$, or $$\begin{aligned} \label{eq:psi_end_sq} {\ensuremath \psi_{\text{end}}}^{2} &\approx \frac{M^2}{1 - \frac{3}{2}\delta} \left( -\delta \pm \frac{\sqrt{2}}{12} \frac{M}{{\ensuremath M_\text{Pl}}} (1+6\delta) \right) \, . \end{aligned}$$ Since $\delta \ll \delta_\text{max}$, inflation ends at $$\begin{aligned} \label{eq:psi_end} {\ensuremath \psi_{\text{end}}}&\approx - \frac{2^{\frac{1}{4}} \sqrt{3}}{6} M \sqrt{\frac{M}{{\ensuremath M_\text{Pl}}}} .\end{aligned}$$ When expressed as a function of $\psi$ the minimum of the potential is at $\psi=-M$; the relative width of the inflationary saddle scales as $\sqrt{M/{\ensuremath M_\text{Pl}}}$ and $\psi_{\text{begin}} \approx - {\ensuremath \psi_{\text{end}}}$. We can now evaluate the integral in ; if $\delta=0$ it is formally divergent for ${\ensuremath \psi_{N}}\ge 0$, and $N$ is apparently infinite. For $\delta \ne 0$ can be solved approximately by setting $V= V(0)$ and taking only the two lowest order terms in $V'$: $$\begin{aligned} N &\approx \frac{1}{12} \frac{M^3}{{\ensuremath M_\text{Pl}}^2} \int_{{\ensuremath \psi_{\text{end}}}}^{{\ensuremath \psi_{N}}} \frac{ 1 }{ M^{2} \delta + \psi^{2} } d \psi \\ &= \label{eq:N_integral_soln} \begin{cases} \frac{1}{12} \left(\frac{M}{{\ensuremath M_\text{Pl}}}\right)^2 \frac{1}{\sqrt{\delta}} \arctan\left( \frac{1}{\sqrt{\delta}} \frac{\psi}{M} \right) \bigg|_{{\ensuremath \psi_{\text{end}}}}^{{\ensuremath \psi_{N}}} & \delta \ne 0 \\ - \frac{1}{12} \frac{M^{3}}{{\ensuremath M_\text{Pl}}^2} \frac{1}{\psi} \bigg|_{{\ensuremath \psi_{\text{end}}}}^{{\ensuremath \psi_{N}}} & \delta = 0 \end{cases} \,.\end{aligned}$$ These expressions apparently disagree in the limit $\delta\to0$ but the identity $\arctan(x) = -\arctan(1/x) - \pi/2$ makes their overlap manifest when ${\ensuremath \psi_{N}}$ has the same sign as ${\ensuremath \psi_{\text{end}}}$: $$\begin{aligned} N &\approx - \frac{1}{12} \left(\frac{M}{{\ensuremath M_\text{Pl}}}\right)^2 \frac{1}{\sqrt{\delta}} \arctan\left( \sqrt{\delta} \frac{M}{\psi} \right) \bigg|_{{\ensuremath \psi_{\text{end}}}}^{{\ensuremath \psi_{N}}} \\ &\approx - \frac{M^{3}}{12 M_{pl}^{2} \psi} + \frac{\delta}{36} \frac{M^{5}}{{\ensuremath M_\text{Pl}}^{2} \psi^{3}} \qquad \text{for} \qquad 0 \leq \frac{\sqrt{\delta} M}{{\ensuremath \psi_{N}}} \ll 1 \,.\end{aligned}$$ Consequently, when $\delta \rightarrow 0$ and $M < {\ensuremath M_\text{Pl}}$ the field value at the pivot scale is approximately $$\label{eq:psi_n_approx} {\ensuremath \psi_{N}}\approx - \frac{1}{12} \frac{M^3}{{\ensuremath M_\text{Pl}}^2} \frac{1}{N} .$$ We need $\delta \ll 1$ for successful inflation but equation (\[eq:psi\_n\_approx\]) is valid only when $\delta$ is smaller than the bound in eq. : as this bound becomes saturated the inflationary phase is relatively short and the pivot scales leaves the horizon when $\psi_N>0$. In this case $\eta$ changes sign during the observationally relevant phase of inflation and when $\eta$ is positive $n_s$ can exceed unity. However, for fixed $N$ there is a lower limit on $n_s$. This behaviour can be deduced from a slow roll analysis, and is apparent in the plots of $n_s$ and $r$ shown in Ref. [@Bird:2008cp] for the spectral parameters 60 $e$-folds before the end of inflation. Similar behaviour is also seen in the related model studied in Ref. [@BuenoSanchez:2006rze]; for a given $r$ there is sharp lower bound on $n_s$, and no clear upper bound. The matching equation connects present-day scales to the inflationary era [@Liddle:2003as; @Adshead:2008vn; @Adshead:2010mc]; assuming instant thermalization after inflation it is $$\begin{aligned} N &= 56.12 + \frac{1}{4} \log \frac{2}{3} + \log\left(\frac{V_N^{1/4}}{V_\text{end}^{1/4}}\right) + \log\left(\frac{V_N^{1/4}}{10^{16} \text{~GeV}}\right) \\ \label{eq:matchin_equation_with_subs} &\approx 61 + \frac{1}{4} \log \lambda + \frac{1}{4} \log\left( \frac{ \bigl[ M^4 + 12 M^3 \delta {\ensuremath \psi_{N}}]^{1/2} }{ {\ensuremath M_\text{Pl}}\bigl[ M^4 + 12 M^3 \delta {\ensuremath \psi_{\text{end}}}]^{1/4} } \right) .\end{aligned}$$ ![ Spectral parameters for three values of $M$, varying $\delta$ across its permissible range. The values of $\lambda$ and $N$ are fixed by simultaneously matching the amplitude to the observed value of $A_s$ and solving the matching equation assuming instant reheating. We include indicative bounds on $n_s$ (blue) and $\alpha_s$ (red); 68% confidence level results from Planck [@Ade:2015lrj]. The points at the ends of the lines in the top left figure denote $\delta=0$. []{data-label="fig:spectrum_N_matching"}](inflection_point_spectrum-matching_N){width="0.95\linewidth"} Finally, the parameter $\lambda$ is fixed by the amplitude of the scalar perturbations: $$\begin{aligned} \label{eq:scalar_amplitude} A_s &= \frac{1}{12 \pi^2 {\ensuremath M_\text{Pl}}^6} \frac{V^3}{V'^2} = \frac{\lambda}{20736 \pi^{2}} \frac{ M^7 \left(M + 12 {\ensuremath \psi_{N}}\delta \right)^{3} }{ {\ensuremath M_\text{Pl}}^{6} \left(M^{2} \delta + {\ensuremath \psi_{N}}^{2} \right)^{2} } \, .\end{aligned}$$ The value of $A_s$ is well-measured [@Ade:2015xua]; in our numerical examples we take $A_s = 2.2 \times 10^{-9}$. In the limit $\delta \rightarrow 0$ equations and give an expectation for the height of the potential: $$\lambda = \pi^2 A_s \left(\frac{M}{{\ensuremath M_\text{Pl}}}\right)^2 \frac{1}{N^4} \, . \label{eq:lambda_small_field}$$ In Figure \[fig:spectrum\_N\_matching\] we show spectral parameters as a function of $\delta$ computed self-consistently from the matching equation along with current bounds on these parameters.[^3] For any sub-Planckian $M$ the scalar-tensor ratio $r$ is very small, with $r\sim 10^{-14}$ for $M=0.1 {\ensuremath M_\text{Pl}}$. Moreover, when $\delta \rightarrow 0$, $n_s$ is below the observationally allowed range, $n_s \lesssim 0.93$ vs $n_s = 0.9677\pm0.0060$. However, $n_s$ increases as $\delta$ approaches the bound in equation and so this model is consistent with current data. ![ We plot spectral parameters for three values of $M$ and two values for $N$, while varying $\delta$ across its permissible range. As in Figure \[fig:spectrum\_N\_matching\] we have plotted current constraints on $n_s$ (blue) and $\alpha_s$ (red), and $\delta$ varies along each of the curves. Note that the curves for $\alpha_s$ vs $n_s$ coincide. []{data-label="fig:spectrum_N_fixed"}](inflection_point_spectrum-fixed_N){width="0.95\linewidth"} Interestingly, $|\alpha_s|$ also increases with $\delta$, providing leverage to test the model as constraints on the spectrum improve. CMB-S4 in the microwave background “roadmap” aims to measure the running with an uncertainty of $0.002$ to $0.003$ [@Abazajian:2016yjj; @Munoz:2016owz], while the Square Kilometer Array (SKA) may reduce the 1-$\sigma$ bounds on $\alpha_s$ to $0.0018$ (SKA1) or $0.00092$ (SKA2) [@Pritchard:2015fia]; combining data from CMB-S4 and SKA2 would put even tighter constraints on $\alpha_s$ [@Munoz:2016owz]. Consequently, planned future observations could conclusively falsify this model. These conclusions would not change significantly if we drop the assumption of instant thermalization; Figure \[fig:spectrum\_N\_fixed\] shows the spectral parameters as a function of $N$. In the $\delta =0$ limit, increasing $N$ pushes $n_s$ closer to the observationally allowed range. Physically, this would require a post-inflationary phase where the equation of state $w > 1/3$, which is technically feasible but has little motivation. Even then the $\delta =0$ limit cannot easily be made consistent with the data. Conversely, if thermalization is preceded by a substantial matter dominated phase, $n_s$ is moved further away from unity. Likewise, the running $\alpha_s$ depends on $N$, but $\left| \alpha_s \right|$ remains above $10^{-3}$ for any reasonable configuration. This analysis takes place in the slow roll limit. This amounts to a constraint on the initial conditions since, if the inflaton arrives at the plateau with a significant kinetic energy, it will experience “ultra slow-roll” and “overshoot” before inflation can commence [@Itzhaki:2007nk; @Dimopoulos:2017ged]. To show this we make the simplifying assumptions that $\ddot{\phi} + 3H \dot{\phi} \approx 0$ and $\dot{\phi}^2 \approx V$ as the field-point approaches the inflationary plateau; the latter condition is equivalent to requiring that $\rho + 3p \approx 0$, which is the condition for the onset of inflation [@Lidsey:1995np]. In this limit, the field velocity is approximately $\dot{\phi}_0 \exp{(-3 H t)}$ where $\dot{\phi}_0$ is the velocity at a given initial time. Via equation (\[eq:psi\_end\_sq\]) the total width of the inflationary plateau is roughly $M \sqrt{M/{\ensuremath M_\text{Pl}}}$. Putting all this together (and recalling that $H \sim \sqrt{V}/{\ensuremath M_\text{Pl}}$) we see that $3H\Delta t \sim (M/{\ensuremath M_\text{Pl}})^{3/2}$ so for $M<{\ensuremath M_\text{Pl}}$ the field velocity will not change dramatically as it evolves through the region containing the inflection point. Consequently, inflation cannot commence unless $\dot{\phi}^2 \ll V(\phi)$ initially. Imposing this condition is strong tuning unless the model is embedded inside a larger dynamical system in which this situation occurs naturally – a stipulation that undercuts any claim to simplicity. Large Field Inflation ===================== We now turn our attention to the large field limit. As previously, there is no minimum other than the origin if $g \le 2 \sqrt{\lambda} m$. When $M\lesssim {\ensuremath M_\text{Pl}}$ and $\phi \sim M$, inflation requires $\delta \ll 1$; when $M \gtrsim {\ensuremath M_\text{Pl}}$ and $\phi \gtrsim {\ensuremath M_\text{Pl}}$ inflation will occur whether or not the potential possesses an inflection point. Moreover, negative values of $g$ are consistent with inflation in this regime; in that case all nontrivial derivatives of the potential are positive. We will find it convenient to define $g= 2 \sqrt{\lambda} m \Delta$ and again use $M = g/2\lambda$ to write $$\begin{aligned} \label{eq:} m &= \sqrt{\lambda} M \, , \\ g &= 2 \lambda M \Delta \, .\end{aligned}$$ This allows us to express $V(\phi)$ as $$\label{eq:potential_large_field} V(\phi) = \lambda \left( \frac{M^2}{2} \phi^2 - \frac{2}{3}\Delta M \phi^3 + \frac{1}{4}\phi^4 \right) \, .$$ and we have not dropped any terms from the potential. The contribution of the cubic term, $\frac{2}{3}\Delta M \phi^3 / V(\phi)$, is maximized at $\phi=\sqrt{2} M$ so the transition from a quadratic to quartic potential occurs when $\phi \sim M $ even if $V'$ increases monotonically. In the near-saddle point limit $\Delta \sim 1/\sqrt{1+\delta}$, where $\delta$ is the expansion parameter from the small field case. Large field inflation occurs for any value of $\Delta$, although $\Delta \le 1$ is needed to avoid a trapping potential. As in the small field case, $\lambda$ sets the amplitude of the perturbations but does not influence the inflationary dynamics. We restrict our attention to scenarios where the velocity is consistent with slow roll; additional possibilities arise if we allow transient velocities but have little physical motivation. The $\{M,\Delta\}$ parameter space contains a number of distinguishable large field scenarios, which we now enumerate: - [*Effective Quadratic Potential*]{} If $M\gg 10 {\ensuremath M_\text{Pl}}$, the potential is effectively quadratic throughout the cosmologically relevant phase of inflation. - [*Effective Cubic Potential*]{} If $\Delta \gg 1$ and $M \gtrsim {\cal{O}}(\text{few}){\ensuremath M_\text{Pl}}$, the potential is effectively cubic during the cosmologically relevant phase of inflation. - [*Effective Quartic Inflation*]{} If $M \lesssim {\ensuremath M_\text{Pl}}$ the potential is effectively quartic for $\phi \gtrsim {\ensuremath M_\text{Pl}}$ and the resulting spectrum will be incompatible with the data [@Peiris:2003ff; @Adam:2015rua; @Ade:2015xua; @Ade:2015lrj]. - [*Exact Saddle Point: Eternal Inflation*]{} Here $\Delta = 1$ and $M \gtrsim 2{\ensuremath M_\text{Pl}}$. If $\phi$ is initially larger than $M$, the field dynamics have an attractor solution with $\phi\rightarrow M$ as $t \rightarrow \infty$ and inflation never ends. In the slow roll limit, $$\begin{aligned} &3 H \dot{\psi} + \lambda M \psi^2 \approx 0 & \label{hpsi}\\ \Rightarrow & \psi \approx \frac{M}{2 {\ensuremath M_\text{Pl}}\sqrt{\lambda}} \frac{1}{t}\end{aligned}$$ where again $\phi = \psi+M$ and $H$ is effectively constant. The neglected terms in equation (\[hpsi\]) all scale as $t^{-2}$ or beyond as $\psi \rightarrow 0$ so this solution has a non-trivial basin of attraction establishing that slow roll remains valid even as $V'$ vanishes identically. Consequently this configuration supports eternal inflation and semiclassical evolution must begin with $\phi < M$, both from the perspective of the field configuration in the primordial universe and in numerical treatments of the inflationary dynamics. - [*Large Field Saddle Point Inflation*]{} The most complex possibility is a saddle point lying in the cosmologically relevant segment of the potential, e.g. with $M \sim {\cal{O}}(\text{few}){\ensuremath M_\text{Pl}}$ and $0 \lesssim \Delta < 1$. In the large-field regime, $V'/V$ is necessarily small but is further suppressed in the vicinity of a (near)-saddle point. The perturbation amplitude scales as $V^3/V'$ so when $V'$ passes through a local minimum there is a corresponding feature in the spectrum. The height of the feature is correlated with its width (as a function of comoving wavenumber, $k$) since $N \sim V/V'$, “stretching” the feature over a larger range of $k$-values if $V'$ approaches zero. As explored below, this scenario produces a range of outcomes including the counterintuitive possibility that the scalar amplitude is reduced relative to a comparable monomial case at the same energy density. - [*Punctuated Inflation*]{} If ${\ensuremath M_\text{Pl}}\lesssim M \lesssim 2{\ensuremath M_\text{Pl}}$ and $\Delta \approx 1$ a punctuated inflationary scenario is possible [@Jain:2008dw; @Jain:2009pm], as illustrated in Figure \[fig:traj\]. These solutions arise when $\Delta$ is very close to unity and in the exact $\Delta=1$ limit. When ${\ensuremath M_\text{Pl}}\lesssim M \lesssim 2{\ensuremath M_\text{Pl}}$ the $\Delta = 1$ limit is far enough from perfect slow roll to evade the eternal inflation solution above. ![ Spectral parameters $r$ and $n_s$ as a function of $\Delta$ and $N$, the number of $e$-folds before the end of inflation. In each case $M=8{\ensuremath M_\text{Pl}}$. []{data-label="fig:large-M-N_Delta-M010"}](surface-M=8-r.png "fig:"){width="0.9\linewidth"} ![ Spectral parameters $r$ and $n_s$ as a function of $\Delta$ and $N$, the number of $e$-folds before the end of inflation. In each case $M=8{\ensuremath M_\text{Pl}}$. []{data-label="fig:large-M-N_Delta-M010"}](surface-M=8-n_s.png "fig:"){width="0.9\linewidth"} - [*Hilltop Inflation*]{} If $\Delta>1$ hilltop inflation results; hilltop inflation yields a relatively large value of $r$ unless the quadratic term in the Taylor expansion vanishes almost exactly [@Kinney:1995ki; @Easther:2006qu], a situation that cannot occur for this potential. ![ The tensor to scalar ratio $r$ is plotted for three models, quadratic (blue), quartic (orange) and $M=8{\ensuremath M_\text{Pl}}$ and $\Delta = 0.75$ (green); data computed with ModeCode assuming instant preheating with $\lambda$ chosen to reproduce the observed density perturbation amplitude. The tensor amplitude of the inflection point scenario can exceed that of either monomial scenario. []{data-label="fig:r_values"}](compare-r){width="0.7\linewidth"} ![ Trajectory for a set of parameters ($M=8 {\ensuremath M_\text{Pl}}$, $\Delta=0.935$, $\lambda = 1.6 \times 10^{-11}$) yielding a large tensor-scalar ratio $r = 0.8$ when $N$ is fixed at $55$. []{data-label="fig:large-r-traj"}](traj-large-r-M=008){width="0.7\linewidth"} Some of these scenarios are limited to a narrow region of the $\{M,\Delta\}$ parameter space but unlike the small-field regime there is no need for tuning to ensure that inflation takes place. In most cases the power spectrum can be well-understood in the slow-roll limit, but there are regions of parameter space for which this approach would be inadequate and we have implemented both the small field and large field scenarios in ModeCode [@Price:2014xpa], which we use to generate the results shown here.[^4] ![ The parameter $\epsilon_{H}$, $N$ $e$-folds before the end of inflation; $\epsilon_{H} < 1$ if the expansion of the universe is accelerating. Each plot is with $\Delta = 0.9999$. For small $M$, the inflaton rolls through the inflection point without inflation resuming; inflation is effectively quartic. For $1.06 {\ensuremath M_\text{Pl}}\lesssim M \lesssim 2.04{\ensuremath M_\text{Pl}}$ inflation pauses briefly. For larger $M$ all of the observationally relevant portion of inflation occurs in the vicinity of the inflection point. []{data-label="fig:traj"}](traj-punctuated){width="0.95\linewidth"} ![ The top plot is of $n_s$ and $r$ as functions of $\Delta$ when $M = 4 {\ensuremath M_\text{Pl}}$. The lower plot shows that large values of $r$ are accompanied by a higher energy scale at horizon crossing as $\lambda$ must increase to match the observed perturbation amplitude when $V/V'$ decreases. []{data-label="fig:large-M-Delta-cut-M=004"}](vary-Delta-cut-M=004){width="0.95\linewidth"} The most interesting scenarios from our perspective are those with $0\le\Delta\le1$ and ${\ensuremath M_\text{Pl}}<M \lesssim 20 {\ensuremath M_\text{Pl}}$. Figure \[fig:large-M-N\_Delta-M010\] shows the astrophysical observables $n_s$ and $r$ as a function of $\Delta$ and $N$, the number of remaining e-folds. These plots show that $n_s$ varies significantly thanks to the “feature” in the potential. However, for these scenarios $r$ can be counter-intuitively large: the cubic term reduces both $V$ and $V'$ but the impact on $V$ is larger than that on $V'$, increasing $\epsilon$ and thus $r$ relative to values seen with monomial potentials. A representative scenario is shown in Figure \[fig:r\_values\]. Given the observational constraints on $r$ this significantly reduces the area of the $\{M,\Delta\}$ plane that yields observables compatible with current data, and runs contrary to the naive expectation that a flatter potential necessarily leads to a lower value of $r$. As illustrated by Figure \[fig:large-r-traj\], models with a large $r$ are those where the inflaton is approaching the plateau in the potential as astrophysical modes leave the horizon. In these cases $\epsilon$ and thus $r$ is significantly scale dependent. Models with large $r$ are now primarily of academic interest, but note that the tensor amplitude is proportional to $V$ and thus slowly decreasing; the rapidly increasing scalar amplitude drives the scale-dependence of $r$. The punctuated inflation scenarios can be understood as extreme versions of this situation. Recalling that $$\epsilon_H = \frac{1}{2} \frac{1}{{\ensuremath M_\text{Pl}}^2} \left(\frac{d \phi}{d N}\right)^2$$ is exactly unity when accelerated expansion ends, Figure \[fig:traj\] shows several punctuated scenarios in which inflation pauses briefly before resuming. Interestingly, these scenarios only exist when $M\gtrsim{\ensuremath M_\text{Pl}}$. For smaller values of $M$ the field rolls past the plateau before inflation can resume, further demonstrating the “ultra slow-roll” and “overshoot problem” faced by the small field models. For any model the specific value of $\lambda$ can be obtained by self-consistently solving the matching equation for $N$ and matching to the observed spectral amplitude. Given this constraint, a large value of $r$ implies that the energy density during inflation is higher than that in the low $r$ configurations. The height of the potential at the pivot scale is shown as a function of $\Delta$ in Figure \[fig:large-M-Delta-cut-M=004\], assuming instant thermalisation. In Figure \[fig:large-M-vary-Delta-spectrum-MultiModeCode\] we show $n_s$ and $r$ measured at the pivot scale for a range of $M$ and $\Delta$. The limit $\Delta\rightarrow1$ is a saddle point model with the field rolling away from a plateau toward the global minimum; in these cases $r$ can be very small and $n_s$ lies below the observationally permitted range. A preference for relatively large values of the running (as compared to typical single-term potentials [@Adshead:2010mc]) is clear, and we we also see that models in which the running is small typically have large values of $r$, an observation we explore in detail in the following Section. ![ In the top two panels $\Delta$ runs from $[0, 1]$ values of $n_s$ and $r$ consistent with current data are shown in blue and green. The lower two rows show trajectories for fixed $\Delta$ and $0.1 {\ensuremath M_\text{Pl}}< M < 100 {\ensuremath M_\text{Pl}}$. The inflationary phase is at large $\phi$ and we assume instant preheating with $\lambda$ chosen to reproduce the observed amplitude at the pivot. The small discontinuity at $M \sim ~1$ corresponds to the transition between the first and second cases of Figure \[fig:traj\]. []{data-label="fig:constraints"}](vary-Delta-spectrum "fig:"){width="0.8\linewidth"} ![ In the top two panels $\Delta$ runs from $[0, 1]$ values of $n_s$ and $r$ consistent with current data are shown in blue and green. The lower two rows show trajectories for fixed $\Delta$ and $0.1 {\ensuremath M_\text{Pl}}< M < 100 {\ensuremath M_\text{Pl}}$. The inflationary phase is at large $\phi$ and we assume instant preheating with $\lambda$ chosen to reproduce the observed amplitude at the pivot. The small discontinuity at $M \sim ~1$ corresponds to the transition between the first and second cases of Figure \[fig:traj\]. []{data-label="fig:constraints"}](vary-M-spectrum "fig:"){width="0.99\linewidth"} \[fig:large-M-vary-Delta-spectrum-MultiModeCode\] Fine-tuning, Priors and Testability =================================== The preceding Sections catalog the wide range of inflationary dynamics associated with the quartic polynomial potential. We now use these analyses to specify priors for these scenarios that will facilitate parameter estimation and model selection calculations. In principle, one can work with a generic quartic potential with priors specified in terms of the slow roll parameters[^5] but here we build on the analysis of the previous sections to parametrize these inflationary scenarios.[^6] In particular, these priors will facilitate parameter estimation and model selection calculations, see e.g. [@Peiris:2006ug; @Mortonson:2010er; @Easther:2011yq; @Planck:2013jfk; @Martin:2013nzq; @Ade:2015lrj], for these scenarios. Specifying the distributions from which the parameters are drawn is a necessarily qualitative process. However, the choices made when constructing these distributions weight the evidence integrals (via equation ) and this issue can be particularly pressing for multiparameter models. Approaches to specifying “maximal entropy” priors for inflationary models were examined carefully in Ref. [@Easther:2011yq]. Here the overall amplitude of the spectrum is set by a multiplicative parameter in front of the potential in both the large and small field regimes. In the small field case we can estimate the likely value of $\lambda$ (via equation (\[eq:lambda\_small\_field\])) but in the large field case we have to allow a large enough range of $\lambda$ to account for scenarios like those in Figure \[fig:large-M-Delta-cut-M=004\]. We also apply a further cut – any parameter choice for which the spectral amplitude does not satisfy $10^{-11} \le A_s \le 10^{-7}$ is excluded from the prior volume. This will have no impact on the posterior distributions but protects against a “volume effect” when calculating evidence [@Easther:2011yq], a task we will pursue in a followup publication. Small Field ----------- To handle the small field case we first make the following parameterization $$\begin{aligned} \delta &=& \frac{\tilde{\delta}}{288} \left( \frac{M}{{\ensuremath M_\text{Pl}}} \right)^4\\ \lambda &=& 10^{-9} \pi^2 \tilde{\lambda} \left(\frac{M}{{\ensuremath M_\text{Pl}}}\right)^2 \frac{1}{50^4} \, .\end{aligned}$$ Inflationary solutions in this regime need an almost-exact inflection point for which the potential is described by equation (\[potential\_psi\]). In this setting, $M$ is an unknown energy scale and by assumption $M\le{\ensuremath M_\text{Pl}}$. The lower bound $M_{\rm min}$ is less clear; in principle it could be as low as the TeV scale, the minimal energy at which we can reasonably expect to see new physics, but in this limit the required tuning would be extreme. - [*Small field, log prior:* ]{} If $M$ corresponds to an unknown scale it is appropriate to draw it from a logarithmic or Jeffries prior: $$\begin{aligned} &\log_{10}{\left(\frac{M_{\rm min}}{{\ensuremath M_\text{Pl}}}\right)} \le \log_{10}{\left(\frac{M}{{\ensuremath M_\text{Pl}}}\right)} \le 0 \, ,& \nonumber \\ & 0 \le \tilde \delta \le 1 \, , &\\ &-5 \le \log_{10}(\tilde \lambda) \le 5 \nonumber \, .&\end{aligned}$$ - [*Small field, uniform prior:* ]{} If $M$ is assumed to be associated with an intrinsically high scale it is self-consistently drawn from a uniform prior, or $$\begin{aligned} &\frac{M_{\rm min}}{{\ensuremath M_\text{Pl}}} \le \frac{M}{{\ensuremath M_\text{Pl}}} \le 1 \, ,& \nonumber \\ & 0 \le \tilde \delta \le 1 \, , &\\ &-5 \le \log_{10}(\tilde \lambda) \le 5 \nonumber \, .&\end{aligned}$$ Inflationary models typically require a “small parameter” to ensure that the perturbation amplitude matches observation. However, this potential requires not one but two small parameters – $\lambda$ to set the overall scale of the potential and fix the perturbation amplitude, and $\delta$ to quantify the departure of the inflection point at $\psi=0$ from an exact saddle. As we saw in Section 3, inflation will only occur when $\delta \lesssim (M/{\ensuremath M_\text{Pl}})^4$. Given current constraints on $n_s$ the limit $\delta \equiv 0$ is excluded by the data, as illustrated by Figures \[fig:spectrum\_N\_matching\] and \[fig:spectrum\_N\_fixed\]. Consequently, the posterior for $\tilde{\delta}$ will differ substantially from the prior. If a symmetry is responsible for generating the saddle point it must be weakly broken by higher order contributions,[^7] but these corrections must be exceptionally small to prevent the inflection point phase from being completely destabilized. Moreover, beyond the tuned parameters and the “overshoot” problem analysed in Section 3, models in which inflation is supported by a narrow range of field values typically need highly homogeneous initial field configurations [@Goldwirth:1989pr; @East:2015ggf; @Clough:2016ymm], partially undermining the explanatory power of inflation. These problems could be ameliorated if small field inflation is preceded by a tunnelling event [@Allahverdi:2008bt] but extra structure would need to be added to the theory to permit this, undercutting any claim to simplicity. We have not attempted to “score” the dynamical tunings when constructing the priors, but these are more pronounced at lower values of $M$ which are disfavoured in the uniform prior relative to the log prior. Large Field ----------- We now consider the large field case for which relevant values of $M$ lie between ${\ensuremath M_\text{Pl}}$ and (generously) $50 {\ensuremath M_\text{Pl}}$ – beyond this we are in the quadratic limit of the theory and increasing $M$ will have little impact on observables; given this relatively limited range we draw $M$ from a uniform distribution. Conversely, we can draw $|1-\Delta|$ from either a logarithmic or a uniform distribution, depending on whether we understand the inflection point as arising from a (near) symmetry or an accidental cancellation, respectively. Further, $\Delta-1$ can have either sign and these cases are physically distinct, since $\Delta>1$ yields a local maximum with a trapping potential for which the onset of inflation and associated initial conditions problem differs significantly from the case where field values can be arbitrarily large.[^8] - [*Large field, log prior:* ]{} This scenario is appropriate if it is assumed that a near-saddle point is required by the symmetries of some underlying theory. $$\begin{aligned} &{\ensuremath M_\text{Pl}}\le M \le 50 {\ensuremath M_\text{Pl}}\, , &\nonumber \\ & -6 \le \log_{10}(|\Delta -1|) \le 0 \, , &\\ &-15 \le \log_{10}( \lambda) \le -5 \nonumber \, .&\end{aligned}$$ - [*Large field, uniform prior:* ]{} This scenario is appropriate if the near-inflection point arises from an “accidental” cancellation of terms. $$\begin{aligned} &{\ensuremath M_\text{Pl}}\le M \le 50 {\ensuremath M_\text{Pl}}\, ,& \nonumber \\ & 0< |\Delta-1| \le 2 \, ,&\\ &-15 \le \log_{10}( \lambda) \le -5 \nonumber \, .&\end{aligned}$$ The ranges of some free parameters (e.g. the upper bound on $M$) cannot be inferred from fundamental principles and so we set the endpoints such that further extending the range would not introduce new possible combinations of empirical observables. ![The prior probabilities for the empirical spectral variables derived for the log (top) and uniform hyperpriors (bottom) describing large field inflection point models. []{data-label="fig:derived_priors"}](logprior.png "fig:"){width="0.95\linewidth"} ![The prior probabilities for the empirical spectral variables derived for the log (top) and uniform hyperpriors (bottom) describing large field inflection point models. []{data-label="fig:derived_priors"}](uniformprior.png "fig:"){width="0.95\linewidth"} \ ![ Joint distributions for the large field, log prior inflection point scenario, measured $N=55$ $e$-foldings before the end of inflation, with observables computed in the slow roll approximation. The top plot shows the joint distribution of $r$ and $n_s$; the lower plots show $r$ and $\alpha_s$ – the left hand plot is restricted to parameter combinations for which $.9<n_s<1.1$ while the right hand plot shows only those with $0.95<n_s<0.97$. []{data-label="fig:joint_distro"}](cut1.png "fig:"){width="0.49\linewidth"} ![ Joint distributions for the large field, log prior inflection point scenario, measured $N=55$ $e$-foldings before the end of inflation, with observables computed in the slow roll approximation. The top plot shows the joint distribution of $r$ and $n_s$; the lower plots show $r$ and $\alpha_s$ – the left hand plot is restricted to parameter combinations for which $.9<n_s<1.1$ while the right hand plot shows only those with $0.95<n_s<0.97$. []{data-label="fig:joint_distro"}](cut2.png "fig:"){width="0.49\linewidth"} These models can viewed as hyperpriors for hyperparameters $\Delta$ and $M$ in a Bayesian network that defines a generative model yielding $n_s$, $r$ and $\alpha_s$ [@Price:2015qqb]. If the running is large the scale dependence of $\alpha_s$ may also be nontrivial; however these scenarios are generically also those for which $r$ is much larger than observationally permitted. In what follows we will assume instant reheating and that the spectrum can be fully described by $r$, $\alpha_s$ and $n_s$. The resulting distributions of spectral variables for large field inflection point scenarios are shown in Figure \[fig:derived\_priors\] and they are anything but uniform. For both scenarios there is considerable support for models with $r<0.1$. Figure \[fig:joint\_distro\] shows joint distributions for the spectral parameters generated from the logarithmic large field prior. The degree of fine-tuning required to produce any given set of observables can be inferred from these plots, relative to the specified hyperprior. This distribution is peaked at $n\approx 0.963$, $r\approx0.14$, a pairing broadly consistent with quadratic inflation. However, the distribution of $r$ in Figure \[fig:derived\_priors\] reveals that there is an overall preference for $r<0.1$ with the logarithmic prior. The distribution for $r$ derived from a uniform prior on $\Delta$ has a similar peak but favours larger values of $r$ relative to the logarithmic case. These results can be contrasted with the tuning criterion advocated by Boyle, Steinhardt and Turok [@Boyle:2005ug] for which the “least tuned” region of the $\{n_s,r\}$ plane is larger than the peak found here, while ascribing a high level of tuning to regions of parameter space that are not strongly disfavoured by this Bayesian analysis.[^9] A second noteworthy feature of the joint distributions is that some combinations of parameters cannot be produced by any configuration of the 4-th order potential, so future observations could comprehensively falsify the overall scenario. “Excluded regions” exist in both the $\{n_s,r\}$ and $\{\alpha_s,r\}$ planes. For example, if $n_s$ and $r$ had been accurately measured to be $0.93$ and $0.1$ respectively all 4-th order potentials would be ruled out; however $n_s$ is now known to be larger than this limit.[^10] However, the permitted pairings of $\{\alpha_s,r\}$ are restricted by limits on $n_s$ so we can update these priors in the light of observational evidence, as illustrated by Figure \[fig:joint\_distro\]. Looking again at Figure \[fig:joint\_distro\] we see that small values of $r$ are correlated with relatively “large” values of $\alpha_s$, in contrast to most widely studied, simple models of single field inflation for which the running is typically $\alpha_s \sim -{\cal{O}}(\text{few}) 10^{-4}$ [@Adshead:2010mc]. Likewise, the distributions for $\alpha$ shown in Figure \[fig:derived\_priors\] peak at $|\alpha_s| < 10^{-3}$. Projections suggest that SKA2 will be able to measure $\alpha_s$ to a precision of $0.001$ [@Pritchard:2015fia] and Stage-IV CMB experiments likewise hope to measure $r$ to a precision of $0.001$ [@Abazajian:2016yjj Table 6-2]. Consequently, even if future high-precision cosmological measurements only put tight upper bounds on the running and the tensor amplitude this would suffice to rule out all possible inflationary scenarios built upon a single minimally coupled field with a 4-th order polynomial potential.[^11] Figures \[fig:derived\_priors\] and \[fig:joint\_distro\] were obtained using the slow roll approximation with a fixed number of $e$-folds, rather than a self-consistent solution of the matching equation. For an extreme post-inflationary equation of state the pivot scale may be pushed to larger values of $N$, which typically reduces the running. However, Figure \[fig:squares\] shows the allowed regions of parameter space for two specified sets of bounds on the spectral parameters obtained from self-consistent solutions to the matching equation. These results are consistent with Figure \[fig:joint\_distro\] – if $\alpha \approx -0.002$ and $r<0.001$ a nontrivial region of parameter space (if $1-\Delta$ is drawn from a logarithmic prior) would be consistent with these observations, but if $|\alpha| \approx 0.001$ the overall model space is excluded. ![ Contours in the $M$-$\Delta$ plane corresponding to the assumption that $\delta_{\alpha_s} < 0.001$ and $r<0.001.$ Measurements of this precision are consistent with SKA2 [@Pritchard:2015fia] and Stage-IV CMB experiments [@Abazajian:2016yjj Table 6-2]. []{data-label="fig:squares"}](contour-future-alpha=-2e-3 "fig:"){width="0.8\linewidth"} ![ Contours in the $M$-$\Delta$ plane corresponding to the assumption that $\delta_{\alpha_s} < 0.001$ and $r<0.001.$ Measurements of this precision are consistent with SKA2 [@Pritchard:2015fia] and Stage-IV CMB experiments [@Abazajian:2016yjj Table 6-2]. []{data-label="fig:squares"}](contour-future-alpha=0.pdf "fig:"){width="0.8\linewidth"} In contrast to the small field case, the large field scenarios are likely to need no significant tuning of their initial conditions. Matching the overall amplitude of the perturbations will constrain $\lambda$ but inflation occurs for generic values of $\Delta$ and $M$. Discussion {#sec:discussion} ========== We have reviewed the inflationary scenarios generated by a 4-th order polynomial potential. This topic was first addressed in 1990 [@Hodges:1989dw; @Hodges:1990bf] and has been the subject of numerous subsequent analyses. Our treatment is based on a parametrization of $V(\phi)$ which makes it easy to identify the inflationary regimes the potential supports and adds to previous discussions by including the spectral running among the possible observables. The simplest potentials, both of which are at odds with observations, are the quadratic and quartic models. The 4-th order polynomial is the next-most-simple scenario that is bounded below. It also marks a critical threshold in the inflationary model space as it is the most complex potential consistent with a renormalizable scalar field theory. This potential has far richer phenomenology than the simplest models – we catalogued eight different supported inflationary regimes (including the small field case). However, this scenario is not arbitrarily complex and many combinations of the spectral parameters $n_s$, $r$ and $\alpha_s$ cannot be generated by any configuration of the potential. Interestingly, the 4-th order model has previously been used to explore questions of tuning and naturalness in inflationary models [@Boyle:2005ug; @Bird:2008cp; @Boyle:2008ri; @Ijjas:2013vea]. Our treatment allows us to give a quantitative and fully Bayesian assessment for the naturalness of any combinations of cosmological observables this potential can produce. As part of our analysis we have written down priors that describe the distributions of free parameters in the 4-th order scenario, looking at both the large field and small field regimes. The free parameters in the potential can be viewed as hyperparameters in a generative model for the spectral parameters and the resulting prior distributions are computed in Section 5.2, with examples plotted in Figures \[fig:derived\_priors\] and \[fig:joint\_distro\]. In the large field scenarios the joint distributions for $n_s$ and $r$ are sharply peaked around the values expected from quadratic inflation but a wide range of tensor amplitudes can be generated within these scenarios. This is clearly true for the large field log prior example but even with a uniform prior case there is still non-zero support for small values of $r$; these cases are somewhat disfavoured relative to those with $r\gtrsim 0.1$ but the level of tuning involved to produce a tensor amplitude in the range $0.001 \lesssim r \lesssim 0.1$ would not be outlandish from this perspective. Conversely, this analysis has shown that there are combinations of $n_s$, $r$ and $\alpha_s$ which cannot be produced by a 4-th order potential for any choice of parameter values. In particular, given current limits on $n_s$, if $r$ and $\alpha_s$ are simultaneously constrained to have magnitudes smaller than $10^{-3}$ no scenarios we have identified within this potential would survive. Such a result that would represent a significant threshold in the understanding of inflationary phenomenology, and thus provides a target for the designers of future experiments. It is worth considering what we would learn if future experiments do rule out the 4-th order potential. Clearly, if algebraic simplicity is held to be synonymous with naturalness this would diminish the credibility of the inflationary paradigm. However, the only small-field (i.e. $\phi \lesssim {\ensuremath M_\text{Pl}}$ at all times) scenario that the 4th-order potential supports is the inflection point scenario described in Section 3, for which the parameters in the potential and the initial field configuration are both highly tuned. Conversely, potentials with a higher degree of algebraic complexity can support inflation at lower scales (and thus smaller field excursions) without fine-tuned initial conditions [@East:2015ggf]. These potentials typically have large plateau, which can be a consequence of possible symmetries in the underlying theory of high energy particle physics but cannot be constructed from a quartic polynomial. If natural models are those where the inflationary dynamics is the consequence of a fundamental symmetry rather than happenstance, the most natural small-field scenarios are [*necessarily*]{} more complex than the 4-th order polynomial, and metrics based on naturalness as opposed to simplicity will yield contradictory conclusions about the likelihood of inflation. Conversely, the 4-th order potential supports large-field inflation without needing dramatic tunings to either the potential parameters or initial state. However, the robustness of this potential against corrections from Planck-scale operators is again a question of high energy physics rather than the simplicity of its algebraic form [@Lyth:1996im; @Baumann:2014nda]. Consequently, the one inference we can draw is that in all cases the naturalness or prior likelihood of an inflationary scenario is best assessed in terms of the theory or theories of fundamental physics that are hypothesised to give rise to its potential, rather than the form of the potential itself. We thank Shaun Hotchkiss, Kei-ichi Maeda, Mason Ng, and Hiranya Peiris for useful conversations on this topic. Part of this work was completed during a visit to the Centro de Ciencias de Benasque Pedro Pascual \[RE\]. We made use of Matplotlib, NumPy and SymPy [@Hunter:2007ouj; @vanderWalt:2011bqk; @Meurer:2017yhf]. [^1]: Section 4.18 of Ref [@Martin:2013tda] treats the $\delta=0$ case (in our notation) while Section 5.7 discusses the general $\delta\ne0$ case; we give a unified account of both situations and our conclusions regarding the tuning required for inflation and the overall falsifiability of the scenario are new. [^2]: Such a potential would support hilltop inflation but this possibility does not change any of our conclusions as it yields an $n_s$ even more inconsistent with observations – see for example [@Martin:2013tda Section 5.7, Figure 125]. [^3]: We do not plot joint probability distributions on $r$, $n_s$ and $\alpha_s$; as we will see later, $\alpha_s$ may be strongly scale dependent for some parameter choices and direct observational constraints on this potential will be obtained in a forthcoming analysis. [^4]: ModeCode was modified to add the potential ; the initial conditions must be chosen with some finesse and the stopping condition must account for the possibility of punctuated inflation. [^5]: As done in [@Aslanyan:2015hmi] for potential slow roll parameters, or [@Norena:2012rs] for a three parameter Hubble Slow Roll analysis; in the latter case the potential is not strictly a quartic polynomial. [^6]: In the context of Bayesian model selection, two “models” with the same algebraic specification and which differ only in the joint distribution from which their parameters are drawn and are viewed as distinct scenarios, since the evidence integral will be weighted differently for each case. [^7]: We justified the choice of a 4-th order polynomial, in part, by appealing to renomalization requirements but the actual inflaton dynamics will be controlled by the semi-classical potential which includes all loop corrections to the tree-level action. [^8]: In principle we could have also considered a small-field hilltop scenario but it cannot yield physically reasonable spectra. [^9]: This statement is, to some extent, dependent on the choice of upper bound on $M$ in the priors – if the upper bound becomes arbitrarily large the joint distributions will become more peaked at the values associated with purely quadratic inflation. However, simply doubling this bound (to $100{\ensuremath M_\text{Pl}}$) would not materially change our conclusions. [^10]: The same structure in the $\{n_s,r\}$ plane is visible in the plots of Refs [@Boyle:2005ug; @Bird:2008cp]. [^11]: A similar correlation between $r$ and $\alpha_s$ is observed in Ref. [@Boyle:2008ri] in the context of the Hubble Slow Roll approximation, in which the Hubble parameter $H$ is represented as a finite order polynomial in $\phi$.

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NOT RECOMMENDED FOR FULL-TEXT PUBLICATION File Name: 12a0928n.06 FILED Nos. 11-5550, 11-5609, 11-5664 Aug 21, 2012 UNITED STATES COURT OF APPEALS LEONARD GREEN, Clerk FOR THE SIXTH CIRCUIT UNITED STATES OF AMERICA, Plaintiff-Appellee, v. ON APPEAL FROM THE UNITED STATES DISTRICT COURT FOR RODNEY EDWARD MOORE, THE WESTERN DISTRICT OF JAMES LAMONT DUNBAR, and KENTUCKY DWAYNE MICHAEL JOSEPH JR., Defendants-Appellants. / Before: GUY, and CLAY, Circuit Court Judges; HOOD, District Court Judge.* DENISE PAGE HOOD, District Court Judge. Defendants James Dunbar, Rodney Moore, and Dwayne Joseph, Jr. were charged in a five-count, twenty-one defendant indictment for conspiracy to distribute more than fifty grams of cocaine base in violation of 21 U.S.C. §§ 841(a)(1), (b)(1)(A) and 846. All three Defendants proceeded to trial. Defendants now make several evidentiary and constitutional challenges to the district court’s sentence and also argue that the Fair Sentencing Act should apply to their pre-Act offenses. For the reasons stated below, the district court is AFFIRMED in part and the cases are REMANDED back to the district court for sentencing pursuant to Dorsey v. United States, Nos. 11-583 and 11-5721, 2012 U.S. LEXIS 4664 (June 21, 2012). * The Honorable Denise Page Hood, United States District Judge for the Eastern District of Michigan, sitting by designation. Nos. 11-5550, 11-5609, 11-5664 I. BACKGROUND In June 2007, based on information received from a confidential informant, the Drug Enforcement Agency (DEA) began investigating a drug trafficking conspiracy in Christian County, Kentucky. In July 2009, the grand jury returned a five-count indictment against 21 individuals, including Defendants Dunbar, Moore, and Joseph. Dunbar, Moore, and Joseph were all charged with conspiracy to distribute more than 50 grams of cocaine base in violation of 21 U.S.C. §§ 841(a)(1), (b)(1)(A) and 846 and a forfeiture count. The indictment alleged that the conspiracy took place from June 2007 until June 2009. Moore was also charged with being a felon in possession of a firearm in violation of 18 U.S.C. §§ 922(g)(1) and 924(a)(2). Trial began on January 11, 2011. The jury returned guilty verdicts for Dunbar, Moore, and Joseph on January 18, 2011 for conspiracy to distribute 50 or more grams of cocaine base. A. James Dunbar In June 2010, the government filed a Rule 404(b) notice of its intent to use evidence of Dunbar selling crack cocaine on September 11 and 12, 2008. The government noted that it was not required to file a Rule 404(b) notice because the instances “happened during the period of the conspiracy and [were] relevant to and directly probative of conspiratorial intent.” The government admitted evidence of a third transaction, which took place on October 15, 2008, but it did not file a 404(b) notice. The government also filed its intent to seek life imprisonment given Dunbar’s two prior felony drug convictions. 2 Nos. 11-5550, 11-5609, 11-5664 Dunbar requested that the district court exclude evidence of his prior convictions and criminal activities.1 The district court found that evidence of Dunbar selling crack cocaine in September 2008 was probative of intent and direct evidence of Dunbar’s participation in the conspiracy. At trial, co-conspirator Demetrius Williams identified Dunbar’s voice on telephone conversations. He testified that Dunbar purchased crack cocaine from Williams during the period of 2007 until 2008. Dunbar was sentenced on April 28, 2011. Dunbar argued that the Fair Sentencing Act should be applied retroactively and the imposition of a mandatory life sentence was cruel and unusual punishment in violation of the Eighth Amendment. The district court rejected Dunbar’s arguments finding that the holding in United States v. Carradine, 621 F.3d 575 (6th Cir. 2010), precluded the district court from applying the Fair Sentencing Act retroactively. The district court also rejected Dunbar’s cruel and unusual argument. B. Rodney Moore At trial, Williams testified that Moore “cooked” crack cocaine for him, which is the process used to turn powder cocaine into crack cocaine. On cross-examination by co-defendant Dunbar, DEA Agent Daren Atkins testified that the confidential informant identified Moore as a “crack cook.” The government did not call the confidential informant to testify. A task force officer also testified that, when arrested, Moore admitted that he was involved with the distribution of a small amount of crack cocaine and had the ability to cook powder cocaine into crack cocaine. A search 1 The district court granted the motion in part by excluding Dunbar’s past convictions for trafficking cocaine because sufficient notice was not provided. 3 Nos. 11-5550, 11-5609, 11-5664 of Moore’s residence revealed a baggie of cocaine, which Moore admitted was his. There was also other testimony that Moore had cooked crack cocaine on different occasions. Moore moved for a new trial on the basis of the hearsay statements solicited from Agent Atkins. Specifically, Moore argued that his Sixth Amendment right to confrontation had been violated when the government failed to call the confidential informant as a witness. The district court denied the motion finding that the statement was not introduced for the truth of the matter asserted but rather to bolster the confidential informant’s credibility. The district court also noted that if there was an error it was harmless given the evidence against Moore. Moore was sentenced on April 27, 2011. Moore argued that the Fair Sentencing Act should apply retroactively. After finding that the Fair Sentencing Act was not retroactive, the district court sentenced Moore to a term of life imprisonment. C. Dwayne Joseph At trial, Williams identified Joseph’s voice on a series of recorded telephone conversations and indicated that the two were discussing a drug deal. The evidence showed that Joseph purchased crack cocaine from Williams on several occasions between 2007 and 2008. During the testimony of co-defendant Alvin Quarles, the government asked whether Quarles remembered telling the government that he had observed Joseph cook crack cocaine. Joseph objected to the questioning as being beyond the scope of direct and cross examination. The district court allowed it, noting that the court had allowed all counsel to go beyond the scope of examination. The government then called Agent Atkins to testify to the statement Quarles made. The government argued that the 4 Nos. 11-5550, 11-5609, 11-5664 statement was a prior inconsistent statement that was only offered to impeach Quarles’ testimony. The district court allowed it over objection. II. ANALYSIS A. Fair Sentencing Act Dunbar, Joseph, and Moore all argue that the Fair Sentencing Act, which took effect on August 3, 2010, should be applied retroactively because they were sentenced after the Act was passed. The Supreme Court in Dorsey v. United States, in considering whether the Fair Sentencing Act should apply retroactively, determined that there were six reasons that weighed in favor of applying the Act retroactively. 2012 U.S. LEXIS 4664 (2012). First, the savings statute allows Congress to apply the Act to pre-Act offenders without the Act expressly stating so. Id. at *24. Second, the Sentencing Reform Act requires that defendants are sentenced based on the Guidelines in effect when they are sentenced and not when the offense was committed. Id. at *26. Third, the language requiring that the Act take effect as soon as possible shows Congress’ intent to apply the Sentencing Reform Act’s principle of sentencing defendants based on the Guidelines in effect when the defendant is sentenced and not when the offense was committed. Id. at *27. Fourth, the inability to apply the Act to pre-Act offenders would create a sentencing disparity that Congress intended to prevent, namely that two individuals in possession of either crack or powder cocaine would receive “radically different sentences.” Id. at *29. Fifth, failing to apply Act Guidelines to pre-Act defendants would exacerbate the problem by creating new anomalies, i.e., disproportionate sentences. Id. at *30. Finally, the Supreme Court found that there were no strong reasons against applying the Act to pre-Act offenders. Id. at *34. In consideration of the above, the Supreme Court 5 Nos. 11-5550, 11-5609, 11-5664 concluded that “Congress intended the Fair Sentencing Act’s new, lower mandatory minimums to apply to the post-Act sentencing of pre-Act offenders.” Id. at *36. In light of Dorsey, the district court erred when failing to apply the Act sentencing guidelines to Joseph, Moore, and Dunbar. Their cases must be remanded back to the district for resentencing in line with Dorsey. B. Dunbar 1. 404(b) Evidence Dunbar argues that the district court erred in admitting the September 11 and 12, 2008 Rule 404(b) evidence and not giving a cautionary instruction to the jury. Dunbar also takes issue with the district court’s admission of evidence of a related transaction on October 15, 2008. A prior Rule 404(b) notice was filed for the September acts, but not the October act. Dunbar contends that the applicable standard of review should be abuse of discretion because the district court had reason to be aware of the need to give cautionary instructions. Dunbar further argues that he did not have sufficient notice to make a contemporaneous objection to the admission of the evidence. The government asserts that the plain error standard of review applies because Dunbar failed to make a contemporaneous objection. In United States v. Davis, this Court considered a conspiring defendant’s objection to the admission of prior act evidence. 547 F.3d 520, 526 (6th Cir. 2008). The defendant objected to the admission of prior acts evidence and was overruled. Id. The Davis court noted that plain error review was not appropriate under the circumstances because, although the defendant did not make a contemporaneous objection to the admission, the defendant had brought the issue to the district 6 Nos. 11-5550, 11-5609, 11-5664 court’s attention, by motion in limine, before the evidence was admitted. Id. at 528. Although Dunbar failed to make a contemporaneous objection to the admission of the evidence, he objected to the Rule 404(b) notice in advance of trial. The district court was put on notice that something could be wrong. The Court will examine the admission of evidence under abuse of discretion. United States v. Davis, 514 F.3d 596, 611 (6th Cir. 2008). A district court’s decision to admit evidence “should remain undisturbed unless (we are) left with the definite and firm conviction that the district court clearly erred in its judgment after weighing the relevant factors, improperly applied the correct law, or inappropriately used the wrong legal standard.” Tisdale v. Fed. Express Corp., 415 F.3d 516, 535 (6th Cir. 2005) (quoting Shanklin v. Norfolk So. Ry. Co., 369 F.3d 978, 988 (6th Cir. 2004) (internal alterations omitted)). This Court applies the harmless error rule to evidentiary errors. United States v. Baker, 458 F.3d 513, 520 (6th Cir. 2006). This Court must determine whether “it was more probable than not that the error materially affected the verdict.” Id. (quoting United States v. Pugh, 405 F.3d 390, 401 (6th Cir. 2005)). Federal Rule of Evidence 404(b) precludes the admission of extrinsic evidence of prior bad acts to prove the defendant’s criminal propensity. However, such evidence is admissible to prove motive, opportunity, intent, preparation, plan, knowledge, identity, or absence of mistake or accident, provided the government gives reasonable notice in advance of trial. Fed. R. Evid. 404(b)(2). Admission of 404(b) evidence requires the district court to first determine if there is sufficient evidence “that the act occurred and that the defendant was the actor.” Huddleston v. United States, 485 U.S. 681, 689 (1988); United States v. Gessa, 971 F.2d 1257, 1261- 62 (6th Cir. 1992). The next inquiry is whether the evidence is probative of a material issue. Huddleston, 485 U.S. at 686. 7 Nos. 11-5550, 11-5609, 11-5664 The district court must then determine whether the relevant matter is actually “in issue.” United States v. Feinman, 930 F.2d 495, 499 (6th Cir. 1991). The evidence “must deal with conduct substantially similar and reasonably near in time to the offenses” for which the defendant is tried. Id. Finally, the court must consider the probative value of the evidence and whether it is substantially outweighed by the danger of unfair prejudice, confusion, or misleading the jury. Fed. R. Evid. 403; also Feinman, 903 F.2d at 499. However, this inquiry is irrelevant and Rule 404(b) is not implicated when prior acts evidence “is part of a continuing pattern of illegal activity.” United States v. Barnes, 49 F.3d 1144, 1149 (6th Cir. 1995). Dunbar contends that the trial testimony directly contradicted the district court’s finding that the September 11 and 12, 2008 drug buys were direct evidence of the conspiracy. Dunbar notes that the ATF agent admitted that the September drug buys were part of a separate investigation. The government counters that no Rule 404(b) cautionary instructions were required because the drug sales were evidence of a continuing pattern of criminal activity. The September drug buys being part of a separate investigation is irrelevant to whether they were direct evidence of the conspiracy itself or probative of intent. The drug buys occurred during the conspiracy in question and are of the same type of conduct that was at issue in the conspiracy. Regardless of whether the September drug buys were direct evidence of the conspiracy itself, they were probative of intent. The district court did not abuse its discretion by admitting the evidence of the September drug buys. Dunbar contends that the district court erred in allowing the introduction of evidence of the October 15, 2008 drug buy. The government did not provide a 404(b) notice of the October drug buy as it had done with the September drug buys. However, the October drug buy with the 8 Nos. 11-5550, 11-5609, 11-5664 September drug buys could all be properly admitted as direct evidence of the conspiracy. As with the September drug buys, evidence of the October incident was also properly admitted as evidence of intent and, therefore, notice was not required. Introduction of that evidence was harmless. Finally, Dunbar argues that the district court should have provided a cautionary instruction for the 404(b) evidence. Dunbar failed to make a contemporaneous objection to the district court’s failure therefore the Court will apply plain error review. Davis, 547 F.3d at 528. Because the September and October drug buys were direct evidence of the conspiracy itself as evidence of a “continuing pattern” of the same nature and type of criminal conduct, the district court was not required to give a cautionary instruction. There was no error. 2. Eighth Amendment Dunbar argues that a mandatory life sentence for conspiracy to distribute 50 grams or more of cocaine is cruel and unusual punishment in violation of the Eighth Amendment when the charged offense was nonviolent and his prior convictions were also nonviolent. The Court must review constitutional challenges to a sentence de novo. United States v. Graham, 622 F.3d 445, 552 (6th Cir. 2010). A severe mandatory life sentence may be cruel but is not necessarily unusual in a constitutional sense. See Harmelin v. Michigan, 501 U.S. 957, 994 (1980). Case law is overwhelmingly against Dunbar’s argument. See Graham, 622 F.3d at 452 - 53 (listing cases that have rejected such Eighth Amendment claims). However, in light of the recent holding in Dorsey v. United States, Dunbar’s argument is moot. 9 Nos. 11-5550, 11-5609, 11-5664 C. Joseph 1. Right to Fair Trial Joseph contends that the district court abused its discretion and violated his right to due process and a fair trial by allowing the government to ask co-defendant Alvin Quarles a question beyond the scope of direct or cross examination and then permitting the government to call Agent Atkins to impeach this prior testimony, eliciting prejudicial hearsay. Specifically, on re-direct the government asked Quarles whether he had observed Joseph cooking crack cocaine even though Quarles had not been asked about Joseph on direct or re-direct. Quarles denied having observed Joseph so engaged, and the government asked whether he remembered telling the government that he had observed such activity. Joseph objected. Quarles did not answer the question. The government then called Agent Atkins to impeach Quarles by testifying that Quarles had stated that he observed Joseph cook crack cocaine. Joseph declined the district court’s offer to give the jury a limiting instruction. The admission of evidence is reviewed under the abuse of discretion standard. Gibson v. United States, 271 F.3d 247, 254 (6th Cir. 2001). However, “[t]o the extent that [a defendant’s] claims sound in due process, we review them de novo.” United States v. Moncivais, 492 F.3d 652, 658 (6th Cir. 2007). Joseph argues that the government offered Quarles’ testimony as “mere subterfuge” to get otherwise inadmissible hearsay admitted as a prior inconsistent statement. Federal Rule of Evidence 613(b) allows a party to admit extrinsic evidence of a prior inconsistent statement “if the witness is given an opportunity to explain or deny the statement and an adverse party is given an opportunity 10 Nos. 11-5550, 11-5609, 11-5664 to examine the witness about it.” Fed. R. Evid. 613(b). The prosecution cannot impeach a witness that it knows will give adverse testimony merely to get in evidence that would be otherwise inadmissible. See Apanovitch v. Houk, 466 F.3d 460, 485 (6th Cir. 2006); United States v. Morlang, 531 F.2d 183, 189 (4th Cir. 1975). The record does not support a finding that the impeachment testimony was provided merely to get in otherwise inadmissible evidence. Joseph has not offered any evidence that the government knew that Quarles would recant his story. Once Quarles testified that he had not said that he observed Joseph cook crack cocaine, the government could call Agent Atkins to testify to Quarles’ prior inconsistent statement. This evidence was offered to impeach the witness and not as substantive evidence against Joseph. The district court offered to give the jury a limiting instruction, but Joseph declined the offer. Nor does the admission of the evidence violate Joseph’s right to due process and a fair trial. Joseph cites United States v. Shoupe, to support his proposition. 548 F.2d 636 (6th Cir. 1977). The Shoupe court held that “the recitation by the prosecutor of the entire substance of a witness’s disavowed, unsworn prior statements, which, if credited by the jury, would be sufficient to sustain a conviction, abridged defendants’ right to a fair trial.” Id. at 643. The Shoupe court noted that the district court failed to provide any protections for the defendants in light of the evidence solicited. Id. at 644 (noting that one prior “trial court protected the rights of the accused by limiting the scope of impeachment” and another “determined in advance, through independent evidence, that the statements were reliable”). Shoupe is distinct from the present case. Here, the district court attempted to limit the scope of the impeachment evidence but Joseph declined the offer to provide a limiting instruction to the jury. Furthermore, the government used Agent Adkin’s testimony to 11 Nos. 11-5550, 11-5609, 11-5664 impeach Quarles inconsistent testimony as opposed to attempting to testify for Quarles on the basis of a prior inconsistent statement, knowing that Quarles would give an inconsistent response. The statement that the witness observed Joseph cooking crack cocaine alone would not have sustained the conspiracy conviction. The Court does not find that Joseph’s due process rights were violated. 2. Variance Joseph argues for the first time on appeal that there was a variance because the evidence offered at trial was substantially different than the evidence charged in the indictment. In the alternative, Joseph contends that the indictment was constructively amended. “A variance to the indictment occurs when the charging terms of the indictment are unchanged, but the evidence at trial proves facts materially different from those alleged in the indictment.” United States v. Caver, 470 F.3d 220, 235 (6th Cir. 2006); see United States v. Blackwell, 459 F.3d 739, 762 (6th Cir. 2006) (“A variance occurs when an indictment alleges one large conspiracy but the evidence at trial establishes multiple conspiracies”). “[A] variance rises to the level of a constructive amendment when the terms of the indictment are in effect altered by presentation of evidence and jury instructions which so modify essential elements of the offense charged that there is a substantial likelihood that the defendant may have been convicted of an offense other than that charged in the indictment.” United States v. Barrow, 118 F.3d 482, 488 (6th Cir. 1997) (quoting United States v. Hathaway, 798 F.2d 902, 910 (6th Cir. 1986)). The Court reviews the record de novo to determine if there was a variance. Caver, 470 F.3d at 235. However, the Court will review the record for plain error if the issue of variance was not raised in the district court. Id. A variance is not reversible error unless the substantial rights of the defendant were 12 Nos. 11-5550, 11-5609, 11-5664 affected; but, a constructive amendment is per se prejudicial. United States v. Solorio, 337 F.3d 580, 590 (6th Cir. 2003). The substantial rights of a defendant are affected if the defendant was convicted based on a conspiracy that he did not participate in. Blackwell, 459 F.3d at 762. Joseph bases his contention on the testimony of Trey Galbraith who testified that Joseph engaged in powder cocaine transactions in Clarksville, Tennessee. Joseph contends that he was surprised by the testimony because it was not alleged to be part of the conspiracy to distribute crack cocaine alleged in the indictment. The majority of the evidence presented against Joseph involved his participation in transactions involving powder cocaine, but there was evidence showing that powder cocaine is cooked into crack cocaine. Williams testified that he sold crack cocaine to Joseph and identified Joseph’s voice on an audio recording requesting more crack cocaine. This evidence, coupled with other evidence presented at trial showing that Joseph was involved in the selling of powder cocaine in order to make crack cocaine, was sufficient to connect Joseph to the conspiracy absent Galbraith’s testimony. The instructions asked the jury to determine whether there was a conspiracy in terms of cocaine base or crack cocaine. The evidence presented at trial was consistent with the evidence charged in the indictment. Joseph’s substantial rights were not violated. D. Moore Moore argues that the district court erred in denying his motion for a new trial based on his claim that his Sixth Amendment right to confrontation was violated when the hearsay statement that Moore was a “crack cook” was offered to prove the truth of the matter asserted. The Court usually reviews the district court’s denial of a motion for a new trial for abuse of discretion. United States v. Pierce, 62 F.3d 818, 823 (6th Cir. 1995). However, given that Moore did not make a 13 Nos. 11-5550, 11-5609, 11-5664 contemporaneous objection to the complained of error, the Court will apply plain error review. United States v. Koeberlein, 161 F.3d 946, 949 (6th Cir. 1998). In Crawford v. Washington, 541 U.S. 36, 53 - 54 (2004), the Supreme Court held that the Confrontation Clause of the Sixth Amendment does not allow the “admission of testimonial statements of a witness who did not appear at trial unless he was unavailable to testify, and the defendant had had a prior opportunity for cross-examination.” The statements of a confidential informant are testimonial and, therefore, may not be offered to establish the truth of the matter asserted unless the accused has an opportunity to cross examine the speaker. United States v. Cromer, 389 F.3d 662, 670 - 71 (6th Cir. 2004). The confidential informant was not called to testify. However, Moore’s co-defendant Dunbar attacked the confidential informant’s credibility when he asked Agent Atkins whether she had provided information regarding the Defendant’s connection to crack cocaine. Agent Atkins responded that the confidential informant had stated that Moore cooked crack cocaine. This statement appears to have been offered to show that the confidential informant gave reliable information and was in response to defense counsel’s own questioning. The statement, however, could be viewed as testimonial and, therefore, raise a Crawford issue. Regardless, any potential error was harmless in light of the other evidence, including Moore’s own admission, establishing that Moore was connected to the conspiracy as a cook. See United States v. Hayes, 218 F.3d 615, 623 (6th Cir. 2000)(citing Delaware v. Van Ardsdall, 475 U.S. 673, 684 (1986)). 14 Nos. 11-5550, 11-5609, 11-5664 III. CONCLUSION AFFIRMED IN PART and REMANDED back to the district court for resentencing. 15

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Q: what is BOOL WINAPI return type I came across a function definition in c++ as follows: (source) BOOL WINAPI GetProcessMemoryInfo( _In_ HANDLE Process, _Out_ PPROCESS_MEMORY_COUNTERS ppsmemCounters, _In_ DWORD cb ); What is the return type here. Is it BOOL WINAPI or BOOL? Where is this type defined? A: BOOL is a typedef for int. WINAPI is a macro specifying the calling convention (__stdcall, __cdecl etc.) of the function. typedef int BOOL; #define WINAPI __stdcall See MSDN for details. It's basically equivalent to: int __stdcall ...

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Cairo offices torched as Egypt death toll mounts Published duration 15 August 2013 media caption James Reynolds in Cairo: "[Wednesday] was one of the most violent days in Egypt's recent history" Hundreds of Muslim Brotherhood supporters have set fire to a government building in Giza, near the Egyptian capital, Cairo. The move comes a day after security forces broke up the Brotherhood's protest camps, leaving hundreds dead. Brotherhood members had been protesting for weeks about the army's overthrow of President Mohammed Morsi in July. The government says 525 died nationwide on Wednesday, but the final toll is likely to be significantly higher. Scores of bodies have not been registered, because the official count only includes bodies which have passed through hospitals. The BBC's Khaled Ezzelarab has reported seeing at least 140 bodies wrapped in shrouds at the Eman mosque, close to the main protest camp at Rabaa al-Adawiya Square. These will not have been counted in the official toll. The Muslim Brotherhood insists that more than 2,000 people died. It says 300 bodies were taken to the Eman mosque, and other bodies were taken to sports halls. Reports speak of disputes between bereaved relatives and officials entrusted with documenting the causes of death. The Muslim Brotherhood, the main source of Mr Morsi's support, had called for marches on Thursday, both in Cairo and Egypt's second city, Alexandria, to protest against Wednesday's deaths. After attempting to storm the building housing the local government in Giza - Cairo's twin city on the west bank of the Nile - the protesters were repelled by police, according to state television. Local TV footage showed two buildings burning, and firefighters evacuating employees. State-run Nile News TV also reported clashes between Muslim Brotherhood members and residents in a suburb of Alexandria. 'Serious massacre' Armoured bulldozers had moved into the two protest camps in Cairo shortly after dawn on Wednesday morning. The smaller of the two protest camps, at Nahda Square, was cleared quickly but clashes raged for several hours in and around the main encampment at Rabaa al-Adawiya. The mosque of the same name was damaged by fire. Mobs later carried out reprisal attacks on government buildings and police stations as well as churches belonging to the country's Coptic Christian minority. In a televised address on Wednesday evening, Egyptian interim Prime Minister Hazem Beblawi defended the operation, saying the authorities had to restore security. He declared a state of emergency, but said this would be lifted as soon as possible. Many countries have condemned the Egyptian security forces' actions. Navi Pillay, the UN High Commissioner for Human Rights, has demanded an independent, impartial inquiry into what happened on Wednesday. "The number of people killed or injured, even according to the government's figures, point to an excessive, even extreme, use of force against demonstrators," Ms Pillay said in a statement. Turkish Prime Minister Recep Tayyip Erdogan described the events as a "very serious massacre". US President Barack Obama is due to give a statement on the issue soon. Mr Morsi, Egypt's first democratically elected president, was ousted by the military on 3 July.

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IN THE COMMONWEALTH COURT OF PENNSYLVANIA Lallie Robinson, : Petitioner : : v. : : Workers' Compensation Appeal : Board (Service Plus Delivery : Systems, Inc. and State Workers' : Insurance Fund), : No. 2013 C.D. 2014 Respondents : Argued: October 5, 2015 BEFORE: HONORABLE BERNARD L. McGINLEY, Judge HONORABLE MARY HANNAH LEAVITT, Judge1 HONORABLE ROCHELLE S. FRIEDMAN, Senior Judge OPINION NOT REPORTED MEMORANDUM OPINION BY JUDGE McGINLEY FILED: January 8, 2016 Lallie Robinson (Petitioner/Claimant) petitions for review from an order of the Workers’ Compensation Appeal Board (Board) that affirmed Workers’ Compensation Judge Lawrence C. Beck’s (WCJ Beck) grant of Service Plus Delivery Systems, Inc.’s (Employer) and the State Workers’ Insurance Fund’s (SWIF) (collectively, Respondents) petition to review compensation benefits offset (review petition). I. WCJ Beck’s Decision The parties agree that “[t]he facts are not genuinely in dispute on the issues pertaining to the present appeal.” Brief for Petitioner at 16. 1 This case was assigned to the opinion writer before January 4, 2016, when Judge Leavitt became President Judge. WCJ Beck made the following pertinent findings of fact: 1. On July 6, 2010, Workers’ Compensation Judge Christina Barbieri circulated a decision granting Claimant’s Claim Petition and Penalty Petition.[2] (Emphasis added.) 2. Judge Barbieri found that, on March 10, 2006, Claimant suffered a large eccentric disc herniation at C7- C8, which impinged the C7-C8 nerve root, causing cervical radiculopathy at C7-C8 and 1, exacerbation of pre-existing but symptomatic bilateral acromioclavicular arthropathy, bilateral post-traumatic shoulder impingement syndrome, exacerbation of a pre-existing mildly symptomatic cervical spondylosis, exacerbation of cervical radiculopathy and clinical evidence of right neurogenic thoracic outlet syndrome. Claimant suffered his injuries as the result of a motor vehicle accident.[3] 3. In support of its Review Petition, Employer submitted the March 29, 2011 deposition of James Jordon, Esquire. (Emphasis added.) This Judge has reviewed Mr. Jordan’s testimony and summarizes it as follows: a. Mr. Jordon is assistant counsel for the State Workers’ Insurance Fund (SWIF). In his capacity as assistant counsel, Mr. Jordon is point of contact with counsel for claimant’s [sic] in third-party actions . . . . In this role, Mr. Jordon has access to SWIF’s payment records with regard to a claimant’s medical and indemnity benefits. 2 Petitioner filed a claim petition and alleged that he was totally disabled since March 10, 2006. Petitioner also filed a penalty petition and alleged numerous violations of the Workers’ Compensation Act (Act), Act of June 2, 1915, P.L. 736, as amended, 77 P.S. §§ 1-1041.4, 2501- 2708, which included failure to investigate. Petitioner requested fifty percent in penalties, unreasonable contest fees and workers’ compensation benefits with statutory interest. Employer and SWIF denied the allegations of the claim and penalty petitions. 3 On March 10, 2006, Petitioner was operating a van for Employer when his vehicle was rear-ended by one vehicle which forced his vehicle into another vehicle. Brief of Respondents (Service Plus Delivery Systems, Inc. and State Workers’ Insurance Fund) at 7. 2 b. Mr. Jordon is familiar with Claimant’s subrogation file. As part of Claimant’s subrogation file, a Notice of Subrogation was sent to Claimant and Claimant’s third party counsel, Lowenthal & Abrams, on February 21, 2008. (Emphasis added.) c. Despite the claim being originally denied, medical benefits in the amount of $17,494.83 were paid as of November 21, 2008. Mr. [James B.] Mogul [Petitioner’s attorney] had discussed third party recovery with John Aris, Esquire, of Lowenthal & Abrams in 2008. (Emphasis added.) d. On February 12, 2009, SWIF received a check for $9,494.70 from Lowenthal & Abrams. (Emphasis added.) e. On June 24, 2009, SWIF received a check for $1,663.22 from Lowenthal & Abrams. (Emphasis added.) f. Mr. Jordon believed these amounts were for reimbursement of SWIF’s medical lien at the time. There were no other liens at that time. Mr. Jordon did not deem SWIF’s receipt of these amounts to be a waiver of SWIF’s future lien. (Emphasis added.) g. Mr. Jordon did not sign any agreement waiving SWIF’s future subrogation rights against Claimant’s third party recovery. To Mr. Jordon’s knowledge, no one else at SWIF agreed to waive SWIF’s subrogation rights. h. Claimant first began receiving indemnity benefits, pursuant to Judge Barbieri’s July 6, 2010 decision, on August 10, 2010. i. As of November 1, 2010, SWIF had paid Claimant $97,151.55 in indemnity benefits. (Emphasis added.) j. As of November 1, 2010, SWIF had paid Claimant $27,468.36; however, $8,044.09 in litigation costs was incorrectly included in that amount. This amount ($19,424.27) is the net amount of benefits paid after the 3 $9,494.70 and $1,663.22 payments from Lowenthal & Abrams were previously deducted. k. As of March 29, 2011, SWIF had paid $134,736.42 in indemnity and medical benefits. (Emphasis added.) 4. In opposition to Employer’s Review Petition, Claimant submitted the September 8, 2011 deposition testimony of John Aris, Esquire. This Judge has reviewed Mr. Aris’ testimony and summarizes as follows: a. Mr. Aris is an associate attorney for Lowenthal & Abrams and represented Claimant in the third party and under-insured motorist (UIM) claims arising out of the March 10, 2006 motor vehicle accident. b. Mr. Aris explained that the third party recovery against Sharon Merriweather, the driver of the vehicle which struck Claimant’s vehicle, settled for $15,000.00. These represented the policy limits of Ms. Merriweather’s automobile insurance. The matter settled in or about December 2008. c. On February 6, 2009, Lowenthal & Abrams forwarded to SWIF a check for $9,494.70. A second check in the amount of $1,663.22 was sent on March 25, 2010; as of June 10, 2010, it had not been cashed. d. Mr. Aris believed that SWIF’s lien, at the time, had been satisfied in full. He did not ask SWIF to compromise its lien. (Emphasis added.) e. Mr. Aris had no conversations with Mr. Jordon regarding any potential future payments or the waiver of any future lien. (Emphasis added.) f. Following the settlement of Claimant’s third party claim, Mr. Aris instituted a civil action against United States Fire Insurance Company for UIM benefits. g. On March 23, 2010, Claimant and United States Fire Insurance Company engaged in binding arbitration . . . [t]he arbitrator determined the value of Claimant’s case 4 to be $110,000.00. As $15,000.00 had already been tendered to Claimant through the third party settlement, United States Fire Insurance Company was liable for $95,500.00. (Emphasis added.) 5. Mr. Aris’ cost incurred in prosecution of Claimant’s UIM claim was $7,056.34. 6. Mr. Aris’ contingent attorney fee for the prosecution of Claimant’s UIM claim was 1/3 ($31,666.66), pursuant to the representation of Claimant’s counsel at the January 11, 2011 hearing on this matter. 7. The schedule of distribution for the recovery of Claimant’s third party claim included a $5,000.00 contingent attorney fee and $505.30 in litigation costs and expenses. WCJ Beck’s Decision, January 7, 2013, Findings of Fact (F.F.) Nos. 1-7 at 3-5; Reproduced Record (R.R.) at 135a-37a. WCJ Beck granted Respondents’ review petition and concluded: 2. Employer’s right to subrogation against Claimant’s third party and UIM benefits is absolute and has not been waived. (Emphasis added.) 3. Employer’s reimbursement rate on future compensation liability is 40.2%. 4. Employer is responsible for 40.2% of any future weekly benefits and medical benefits until it recovers $91,809.78. 5. Following the recovery of $91,809.78, Employer shall be responsible for 100% of any compensation liability. (Emphasis added.) 6. Employer’s contest has been reasonable at all times. 5 WCJ Beck’s Decision, Conclusions of Law (C.L.) Nos. 2-6 at 6; R.R. at 138a. The Board affirmed and concluded that “[a]lthough the UIM (Under Insured Motorist) settlement occurred in March of 2013 and at that time, a decision had not been rendered finding Defendant [Employer] liable for workers’ compensation benefits, Defendant [Employer] was still entitled to recover its lien.” Board’s Opinion, October 9, 2014, at 4. “Therefore, because subrogation is mandatory and the purpose of subrogation would not be served if we were to find that Defendant [Employer] was not entitled to subrogation in these circumstances, we see no error in the Judge granting Defendant’s [Employer’s] Review Offset Petition.” Board’s Opinion, October 9, 2014, at 4-5. II. Issues A. Whether WCJ Beck Failed To Issue A Reasoned Decision? Initially, Petitioner contends4 that WCJ Beck failed to render a reasoned decision because his decision did not provide for meaningful appellate review. Specifically, Petitioner asserts that WCJ Beck devoted only one sentence that could be considered a legal analysis of the case. WCJ Beck did not address the real issue. Petitioner asserts that WCJ Beck failed to provide adequate reasons for what evidence he rejected and what evidence he accepted “in order to ensure that a legally erroneous basis will not lie undiscovered and will allow meaningful appellate review of possible legal error.” Brief for Petitioner at 22. Petitioner contends that WCJ Beck failed to render credibility determinations and never indicated what testimony he accepted and what testimony he rejected. 4 This Court’s review is limited to a determination of whether an error of law was committed, whether necessary findings of fact are supported by substantial evidence, or whether constitutional rights were violated. Vinglinsky v. Workmen’s Compensation Appeal Board (Penn Installation), 589 A.2d 291 (Pa. Cmwlth. 1991). 6 Respondents counter that Petitioner waived the issue of whether WCJ Beck issued a reasoned decision because he failed to raise this issue on appeal to the Board. In Wheeler v. Workers’ Compensation Appeal Board (Reading Hospital and Medical Center), 829 A.2d 730, 734 (Pa. Cmwlth. 2003), this Court addressed the criteria necessary to determine whether an issue was waived: It is well established that an issue is waived unless it is preserved at every stage of the proceeding. Nabisco Brands, Inc. v. Workers’ Compensation Appeal Board (Tropello), 763 A.2d 555 (Pa. Cmwlth. 2000). The strict doctrine of waiver applies to a workers’ compensation proceeding. Hinkle v. Workers’ Compensation Appeal Board (General Electric Co.), 808 A.2d 1036 (Pa. Cmwlth. 2002) . . . . The purpose of the waiver doctrine is to ensure that the WCJ is presented with all cognizable issues so that the ‘integrity, efficiency, and orderly administration of the workmen’s compensation scheme of redressed for work-related injury’ is preserved . . . . (Citations omitted and emphasis added.) Here, the record reveals that after WCJ Beck granted Respondents’ review petition, Petitioner appealed to the Board and alleged the following errors: Conclusion of Law No. 2. Judge Beck committed a reversible error of law when his Honor found that the right of subrogation is absolute and can be abrogated only by choice. Claimant satisfied the third-party lien that was in existence at the time of the settlement of the third-party case. There was no other existing lien at the time that claimant’s third party case was settled . . . . Judge Beck erred in finding that the issue is whether or not State Workers’ Insurance Fund had waived its third- party lien. Claimant never argued or asserted that State Workers’ Insurance Fund had waived its third-party lien . . . . Claimant never had any established entitlement to 7 any workers’ compensation benefits, until the Judge granted the claim petition and awarded benefits. None of that existed at the time that the third-party case was settled. Defendants had no lien in addition to the lien already satisfied in full when the third-party case was settled. Therefore, Judge Beck committed a reversible error of law. Judge Beck did not address the critical issues in this case at all. (Emphasis added.) Appeal from Judge’s Findings of Fact and Conclusions of Law, January 22, 2013, at 1 and 3; R.R. at 130a and 132a.5 Clearly, Petitioner failed to raise the issue that WCJ Beck’s decision was unreasonable before the Board. Pa. R.A.P. 1551(a) provides that “[r]eview of quasijudicial orders shall be conducted by the court on the record made before the government unit . . . [n]o question shall be heard or considered by the court which was not raised before the government unit . . . .” (Emphasis added.) Therefore, this issue is waived on appeal to this Court. B. Whether The Board Erred As A Matter Of Law Because “Only A Lien On A Third-Party Case That Actually Exists In Fact And Not In Theory Can Be Satisfied?”6 5 Petitioner responded: This allegation could not be further from the truth. Petitioner did raise this issue with the . . . Board. Petitioner argued to the . . . Board and to this Honorable Commonwealth Court . . . that [WCJ Beck] issued an unreasoned decision because he failed to address the genuine issue in this case. . . . This argument formed the core of petitioner’s appeal to the . . . Board and the appeal to this . . . Court . . . . Reply Brief for Petitioner at 1-2. This Court must disagree. Petitioner’s allegation of error was that WCJ Beck failed to address the genuine issue in the present matter, not that he failed to issue a reasoned decision. 6 Brief for Petitioner, Statement of Questions Involved at 2. 8 Petitioner next contends that he did not contest the issue of whether Respondents have a right to subrogation. Specifically, Petitioner contends that when he received the third-party award, WCJ Barbieri did not rule on his claim petition. Petitioner states that the existing subrogation lien of $11,157.92 was paid in full at the time of the third party settlement. Petitioner concludes that SWIF failed to establish legal entitlement to a future reimbursement of a lien which did not exist at the time of the third-party settlement. Respondents counter that this Court has previously recognized that employers have an absolute right to immediate payment of a past-due lien from the recovery fund after payment of attorneys’ fees and litigation expenses. Respondents state that at no time did it either explicitly or impliedly waive its future right to subrogation with respect to Petitioner’s still-pending workers’ compensation claim. Respondents pose that Petitioner could have choosen not to pursue the workers’ compensation claim to its conclusion and just accepted the third party settlement and arbitration award. As a result of the compensation award by WCJ Barbieri, Respondents’ subrogation lien increased. Respondents caution that to allow Petitioner to keep the entire third party settlement/award after it paid a total of $134,736.42 in indemnity and medical benefits would result in a double recovery. Section 319 of the Act, 77 P.S. § 671, provides: Where the compensable injury is caused in whole or in part by the act or omission of a third party, the employer shall be subrogated to the right of the employe . . . against such third party to the extent of the compensation payable under this article by the employer; reasonable attorney’s fees and other proper disbursements incurred in obtaining a recovery or in effecting a compromise 9 settlement shall be prorated between the employer and employe . . . . The employer shall pay that portion of the attorney’s fees and other proper disbursements that the amount of compensation paid or payable at the time of recovery or settlement bears to the total recovery or settlement bears to the total recovery or settlement. Any recovery against such third person in excess of the compensation theretofore paid by the employer shall be paid forthwith to the employe . . . and shall be treated as an advance payment by the employer on account of any future installments of compensation. In Murphy v. Workers’ Compensation Appeal Board (City of Philadelphia), 871 A.2d 312 (Pa. Cmwlth. 2005), this Court reiterated the employer’s absolute right to subrogation: The rationale underlying the right to subrogation is threefold. First, it prevents double recovery for the same injury by the claimant. Second, it prevents the employer from having to make compensation payments which resulted from the negligence of a third party. Finally, it prevents a third party from escaping liability for his negligence. (Emphasis added.) Id. at 317. This Court concurs with the Board’s analysis that Respondents were entitled to subrogation: In the instant case, the Judge found that despite the fact that the claim had been originally denied, medical benefits in the amount of $17,494.83 had been paid by defendant [Respondents] as of November 21, 2008 (Finding of Fact No.3(c)). In December 2008, Claimant settled a third-party claim against the driver involved in his vehicular accident for $15,000.00 (Finding of Fact No. 4(b)). On February 12, 2009, Defendant [Respondents] received a check in the amount of 10 $9,494.70 from Claimant’s Counsel and on June 24, 2010, Defendant [Respondents] received a check in the amount of $1,663.22 from Counsel (Finding of Fact No. 3(d) & (e)). It was believed that these checks were for the reimbursement of Defendant’s [Respondents’] medical lien at the time (Finding of Fact No. 4(f)). On July 6, 2010, Judge Barbieri issued the Decision granting the Claim Petition and Claimant began receiving benefits pursuant to that Decision on August 10, 2010 (Findings of Fact Nos. 1 & 3(h)). As of November 1, 2010, Defendant [Respondents] had paid $97,151.55 in benefits (Finding of Fact No. 3(i)). As of March 29, 2011, Defendant [Respondents] had paid $134,736.42 in indemnity and medical benefits (Finding of Fact No. 3(k)). While Claimant’s Claim Petition was pending, on March 23, 2010, Claimant and United States Fire Insurance Company engaged in binding arbitration and pursuant to that determination, Claimant settled his UMI [Under Insured Motorist] claim for $95,000.00 (Finding of Fact No. 4(g)). (Emphasis added.) The Judge determined that defendant [Respondents] did not expressly or impliedly waive its right to subrogation (Discussion). As a result, he found that Defendant [Respondents] was entitled to a recovery of $91,809.78 and it was responsible for 40.2% of any future weekly benefits and medical expenses until it recovers $91,809.78. We observe no error in this conclusion. (Emphasis added.) Although the UMI settlement occurred in March of 2013 and at that time, a decision had not been rendered finding Defendant [Respondents] liable for workers’ compensation benefits, Defendant [Respondents] was still entitled to recover its lien. Defendant did subsequently make payment to claimant for workers’ compensation benefits. Pursuant to Section 319 of the Act, the right to subrogation is ‘absolute’ and just because Claimant settled his UMI claim prior to his workers’ compensation claim, does not render 11 Defendant’s right to subrogation invalid. Subrogation prevents double recovery for the same injury and relieves the employer of liability occasioned by the negligence of a third party. Since Defendant [Respondents] was eventually found liable for workers’ compensation benefits and did make payment for those benefits, disallowing subrogation in these circumstances where a lien had not been asserted because the party had not yet been found liable at the time of the settlement would be in direct contradiction to the mandatory language contained in Section 319. . . . (Emphasis added.) Board’s Opinion at 3-5. Accordingly, this Court affirms the WCJ’s grant of Respondents’ review offset petition. ____________________________ BERNARD L. McGINLEY, Judge 12 IN THE COMMONWEALTH COURT OF PENNSYLVANIA Lallie Robinson, : Petitioner : : v. : : Workers' Compensation Appeal : Board (Service Plus Delivery : Systems, Inc. and State Workers' : Insurance Fund), : No. 2013 C.D. 2014 Respondents : ORDER AND NOW, this 8th day of January, 2016, the order of the Workers’ Compensation Appeal Board in the above-captioned matter is affirmed. ____________________________ BERNARD L. McGINLEY, Judge

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#Thu Sep 28 22:00:15 CEST 2017

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Kevin Kelly (politician) Kevin Kelly (born August 18, 1953) is an American politician from Maryland and a member of the Democratic Party. He served in the Maryland House of Delegates, representing District 1B in Allegany County for six terms, from 1987 until 1995, and again from 1999 until 2015. Kelly was a member of the Judiciary Committee and its Civil Law and Procedure Subcommittee. Background Kelly was born in Cumberland, Maryland on August 18, 1953. He graduated from Bishop Walsh School in 1971. After high school he attended Frostburg State University where he got his B.S. in Political Science. After Frostburg he attended the University of Baltimore School of Law where he attained his J.D. in 1978. Kelly was admitted to the Maryland bar in 1980. Education Kevin Kelly received his education from the following institutions: JD, University of Baltimore School of Law, 1978 BS, Political Science, Frostburg State College, 1975 Political experience Kevin Kelly has had the following political experience: Delegate, Maryland State House of Delegates, 1999-2015 Delegate, Maryland State House of Delegates, 1987-1995 Current legislative committees Kevin Kelly has been a member of the following committees: Judiciary, Member Subcommittee on Civil Law and Procedure, Member In the legislature Kelly was first elected to the General Assembly in 1986, serving through 1994, and was re-elected in 1998. Kelly was defeated in the 2014 Maryland general election after serving 20 years in the Maryland House of Delegates. Election 2014 general election Voters to choose one: {| class="wikitable" !Name !Votes !Percent !Outcome |- |- |Kevin Kelly, Dem. |4,623 |40.9% |Lost |- |- |Jason C. Buckel, Rep. |6,664 |58.9% |Won |} 2010 general election Voters to choose one: {| class="wikitable" |- !Name !Votes !Percent !Outcome |- |- |Kevin Kelly, Dem. |6,226 | 51.26% | Won |- |- |Mary Beth Pirolozzi, Rep |5,908 | 48.64% | Lost |} 2006 general election Voters to choose one: {| class="wikitable" |- !Name !Votes !Percent !Outcome |- |- |Kevin Kelly, Dem. |6,489 | 55.7% | Won |- |- |Mark A. Fisher, Rep. |5,151 | 44.2% | Lost |} 2002 general election Voters to choose one: {| class="wikitable" |- !Name !Votes !Percent !Outcome |- |- |Kevin Kelly, Dem. |6,654 | 55.7% | Won |- |- |Tricia Wolfe, Rep. |5,286 | 44.3% | Lost |- |Other |4 | 0.0% | Lost |} 1998 general election Voters to choose one: {| class="wikitable" |- !Name !Votes !Percent !Outcome |- |- |Kevin Kelly, Dem. |5,232 | 51% | Won |- |- |Tricia Wolfe, Rep. |4,991 | 49% | Lost |} 1990 general election Voters to choose two: {| class="wikitable" |- !Name !Votes !Percent !Outcome |- |- |Kevin Kelly, Dem. |11,579 | 41% | Won |- |- |Betty Workman, Dem. |11,413 | 40% | Won |- |- |Dolores Chase Morgan, Rep. |5,321 | 19% | Lost |} 1986 general election Voters to choose two: {| class="wikitable" |- !Name !Votes !Percent !Outcome |- |- |Betty Workman, Dem. |8,195 | 29% | Won |- |- |Kevin Kelly, Dem. |7,858 | 28% | Won |- |- |Robert M. Hutcheson, Rep. |6,151 | 22% | Lost |- |- |William R. Davis, Rep. |5,984 | 21% | Lost |} References Notes Category:Members of the Maryland House of Delegates Category:Living people Category:1953 births Category:People from Cumberland, Maryland Category:Maryland Democrats Category:Frostburg State University alumni Category:University of Baltimore School of Law alumni Category:21st-century American politicians

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India's Got Talent 5 - High on emotions and Outstanding! A multitude of talent is on display in this show of skill, perseverance and aptitude. While the daredevil stunts leave you gaping in wonder; some of the acts make you go all teary eyed bringing a lump to your throat! India's Got Talent 5 is a reality show for common people from India who have unusual skills and who come over to highlight their talent. There is no age limit and people from all over India in solo or group can perform and compete to win the title and the prize. What works - The contestants! They are the best amongst the lot of reality shows we see on air these days. These is a farmer, tailor, teacher, accountant, hospital attendant, students, make-up artist amongst many others who want to do excel in something other than their profession and are making the most of this opportunity. Maybe because there is a plethora of shows on Indian Television which focus only song and dance but here we have singing, dancing and other creative skills along with stunts on display. The back story of many of the contestants too is quite interesting and pulls at your heart strings when we see it on screen. So along with a cute, fat boy in the first episode dancing to Salman Khan numbers we also have the stuntbaaz Balram who set his body on fire before jumping off in a swimming pool along with Bhawna, the sensuous dancer from Tollywood who did a sensational pole dance. The show has now had six episodes on air and along with superb solo acts there has been an excellent team effort in various unusual group performances too. The most impressive performances till now have been that of the ever hopeful one legged Shubrit Kaur's dance, the 3 year old chhota packet Sarika Bijli's performance, Sanjay Kumar the farmer who did a remixed MJ version, the magician Hassan Rizvi, the balloon act by Sarvanna, the UV act from Silver Steppers, the stunt man by Sunil Kumar, the Star Guides group of blind boys from Victoria Memorial blind school in the category 5 - 17 years of age who did the pole Mal-Khamb amongst many others. We also like all the three judges who appear to be fair and sweet to the contestants and have uniformity while making the decision. Malaika Arora Khan comes across as the yummy mummy who understands what it means to have little kids practice and perform, Karan Johar is forever encouraging while Kirron Kher who has been in a judge in all the previous seasons of the show is the best amongst the lot! She is visibly scared and upset while watching some of the dare devil performances but that does not hamper her judgement as she excitedly claps her hands or frankly says no' when the need be! The hosts Mantra and Bharti Singh have excellent comic timings which suit the show. While we have always seen the funny side of Bharti, here even she is biting her nails and gets emotional when she sees any unusual performances. We also like the last bit in the show which has the uncut version of what the judges are doing when not shooting. It is just raw footage of couple of minutes wherein they are singing or generally pulling each other's leg but it is fun to see them do so! What doesn't work - Actually, nothing but since the show is all about talent they should try to keep the sympathy factor a little low so that there is equality between all contestants. In fact in almost all the talent based reality shows we have disabled contestants which is a good way to boost their morale but with no offense meant if there are so many of them then someone should have a separate show for such contestants. Many shows need the Bollywood touch which works for the films getting promoted as well as for the show and here too we saw celebs like Madhuri Dixit, Remo Fernandes and others coming in but even without them the show can leave a distinguished mark. Our take - The show has been getting good ratings on the TRP meter and is popular with the mass audience. We are still watching the auditions wherein the judges are giving them a yes or no for the next round and given the nature of contestants the final rounds are going to be nail biting. As it is when we watch some of the performers it is not unusual to get goosebumps and tears in the eyes to see all the struggle that these people go through. It brings to fore exclusive talent from small towns of India, people from humble backgrounds who despite all odds and difficulties manage to pursue their passion to reach this stage. This is one show you can watch with your family and feel proud of each and every contestant. In fact, children from metros who get all things easily and are becoming increasingly lazy as they engage in inane activities need to watch this show just to see the real India and the confident talent that lies within it! Like the judges have said time and again on the show seeing the struggle of some of the contestants will make each one of us a better person. Disclaimer: All Logos and Pictures of various Channels, Shows, Artistes, Media Houses, Companies, Brands etc. belong to their respective owners, and are used to merely visually identify the Channels, Shows, Companies, Brands, etc. to the viewer. Incase of any issue please contact the webmaster.

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A PILOT sparked an armed response after accidentally triggering the hijack alarm on board a plane. Dutch military police were called to a suspicious situation on board a plane at Schiphol airport, Amsterdam. 2 A suspected hijacking has been reported at Schiphol Airport in Amsterdam Credit: Twitter / @vikasjournolko 2 Dutch police were seen milling around after the threat was worked out to be an error Credit: AP:Associated Press Reports on Twitter earlier suggested that three men armed with knives were trying to take control of an outbound Air Europe flight to Madrid. "There is a suspicious situation and that's all I can say," a spokesman for the military police said. However the airline later confirmed that the hijack alarm was triggered by mistake, adding that "nothing has happened". Images showed crowds of people in the airport and armed police behind a cordon. Schiphol Airport's official Twitter account tweeted: "The Royal Netherlands Marechaussee is currently investigating a situation on board of a plane at Amsterdam Airport Schiphol. We keep you posted."

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Reviews from a small country Dead And Breathing, Theatre Review. Unity Theatre, Liverpool. Liverpool Sound and Vision Rating * * * * * Cast: Lizan Mitchell, Kim Tatum. Aside from yourself and your loved ones being healthy and happy, all that you can ever hope for in life is either being part of history, having your name linked to the times you live and have your name roll off the extensive tongue as if attached to a medieval proclamation, complete with booming voice reading out your virtues and perhaps a heroic deed or two; or seeing history made, knowing you were alive when the Earth shattering, the amazing or the downright incredible happened and perhaps seeing someone else have their moment in your company…being witness to the most awesome of performances. Whichever way you see history, it comes at the most unexpected of times, it hits you between the eyes and reminds you of what it means to be alive and in Chisa Hutchinson’s play Dead and Breathing, that feeling is intensified, brutally chiselled into a statue and giving absolute reverence; for in Lizan Mitchell’s performance as Carolyn, a woman living with stage three cancer and the bitterness of death having had the temerity not to have claimed her crotchety old and cantankerous soul yet, one of the most outstanding moments in Liverpool theatre, certainly in the last ten years, opened up before the Unity Theatre’s audience’s eyes. Whilst in a very different play, it could not helped be thought that Ms. Mitchell, aided beautifully by Kim Tatum in this particular two hander, had the air of the late, great Jessica Tandy in Driving Miss Daisy, the assuredness of spite, the grip of fear and the tongue of a devil were heartbreakingly brilliant, the soft squeal of excited panache as the play unfolded, this is award winning presence, and to witness it is to hopefully understand the joy of living. Dead and Breathing, perhaps something in which we all cling too, just barely surfacing above the waterline, taking in life but not living it, forgetting that seize the day is not just some mantra spoken by a comic genius, but is the most honest and yet destructive force, the most studious of pursuits that we can achieve and it often takes the nudge from the person we would least like to be around to fulfil that affirmation of life. A play of incredible depth, of the passion that beats between life and death and of looking kindness in the face, no matter what clothes it wears; Dead and Breathing is breath-taking.

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When using ProGuard, you should be aware of a few technical issues, all of which are easily avoided or resolved: - For best results, ProGuard's optimization algorithms assume that the processed code never **intentionally throws NullPointerExceptions** or ArrayIndexOutOfBoundsExceptions, or even OutOfMemoryErrors or StackOverflowErrors, in order to achieve something useful. For instance, it may remove a method call `myObject.myMethod()` if that call wouldn't have any effect. It ignores the possibility that `myObject` might be null, causing a NullPointerException. In some way this is a good thing: optimized code may throw fewer exceptions. Should this entire assumption be false, you'll have to switch off optimization using the `-dontoptimize` option. - ProGuard's optimization algorithms currently also assume that the processed code never creates **busy-waiting loops** without at least testing on a volatile field. Again, it may remove such loops. Should this assumption be false, you'll have to switch off optimization using the `-dontoptimize` option. - When obfuscating, ProGuard writes out class files named "`a.class`", "`b.class`", etc. If a package contains a large number of classes, ProGuard may also write out **"`aux.class`"**. Inconveniently, Windows refuses to create files with this reserved name (among a few other names). It's generally better to write the output to a jar, in order to avoid such problems. Alternatively, you can use the Uniform Naming Convention (UNC) for your Windows paths, which doesn't suffer from the constraint.

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