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Liquid Facelift
Facial Rejuvenation without surgery! The liquid facelift is a non-invasive procedure that utilizes various injectable treatments to minimize the appearance of fine lines and wrinkles, and address the volume loss that is so common with aging. At our clinic, Dr. Recasens can create a liquid face lift treatment plan to meet your specific needs.
Crow’s Feet
Forehead Creases
Nasolabial Folds
Frown Lines
Bunny Lines
Hollow Cheeks
Under Eye Hollows
Hollow Temples
Thin Lips
A variety of treatment modalities will be used to achieve optimal results.
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Background
==========
Medullary thyroid carcinoma (MTC) metastasizes very early lymphogenously.
The presence of initial lymph node metastases in non-screening patients is generally reported to be higher than 50%, often as high as 75-80% \[[@B1],[@B2]\]. Even bilateral lateral lymph node involvement is quite frequent (\>25%) \[[@B2]\] and has been shown to be associated with distant metastases \[[@B3]\]. In these advanced cases, biochemical cure, i.e. normalization of posttherapeutical calcitonin levels, is extremely rare \[[@B4]\].
It has been shown that the presence of lymph node metastases in general is associated with a worse outcome \[[@B5]\]. Interestingly, it has less clearly been shown that lymphadenectomy improves the outcome in patients with MTC \[[@B5]\]. What has been shown is that, depending on patient selection, biochemical cure can be achieved in about 30-40% of patients with regional lymph node metastases \[[@B4],[@B6]\] which, however, is a significantly lower rate than that for patients without lymph node metastases (90-100%) \[[@B1],[@B6]\]. Biochemical cure itself has been shown to correlate with a better outcome \[[@B7]-[@B9]\] but late recurrence has been shown.
That the extent of lymph node dissection is part of ongoing discussion has apart from the unknown benefit in a specific patient in part to do with the possible complications that are accompanied with this procedure, mainly hypoparathyroidism and nerve injury \[[@B10]\]. In addition, in the presence of advanced disease, t.ex. distant metastases, the benefit of lymph node dissection is even more questionable.
ATA guidelines regarding lymphadenectomy
========================================
The guidelines published by the American Thyroid Association (ATA) \[[@B11]\] contain various recommendations dealing with the extent of lymphadenectomy.
Clinically evident or highly suspected MTC
------------------------------------------
According to the guidelines, patients having MTC or those where MTC is highly likely should undergo total thyroidectomy and prophylactic central compartment (level VI) neck dissection both with and without evidence of cervical lymph node metastases in the absence of advanced local invasion and distant metastases (recommendation 61 & 62). The lateral compartment (level II-V) should be included in the case of ultrasound-confirmed lateral lymph node metastases (recommendation 63). Preoperative ultrasound is therefore indicated in all patients prior to surgery (recommendation 19).
Some members of the task force recommended prophylactic inclusion of the lateral compartment recommended in the presence of central compartment lymph node metastases (recommendation 62). This recommendation is based on the finding that the involvement of the ipsilateral cervicolateral compartment correlates with the number of lymph node metastases in the central compartment \[[@B12]\].
Advanced disease
----------------
In general, a less aggressive approach is advised in the presence of advanced local and/or distant metastases while maintaining locoregional disease control to prevent central neck morbidity (recommendation 64 & 65). In patients with distant metastases, removal of small asymptomatic and nonthreatening lymph node metastases (\<1 cm) is of unknown benefit and such lymph nodes may be observed (recommendation 81).
Primary incomplete surgery
--------------------------
Following primary incomplete surgery, reoperation including the central lymph node compartment is recommended when neck US is suspicious for persistent local disease in the central or lateral neck compartment (recommendation 71) or when the basal serum calcitonin level is above the normal reference range (recommendation 72).
If not previously performed, node dissection in both the central and lateral compartment should be compartment-oriented. Removal of only grossly metastatic lymph nodes, or other limited procedures, should be avoided in these instances (recommendation 77). This recommendation is based on the fact that removal of only grossly metastatic lymph nodes correlates with a lower calcitonin normalization rate, a higher reoperation rate and a lower survival rate \[[@B13]\].
In view of the ATA guidelines, central lymph node dissection remains controversial if primary surgery only consisted of total thyroidectomy in patients with continuously elevated calcitonin levels in the absence of radiographic findings (recommendation 78). It is explained in the guidelines that controversy also exist due to the increased risk of harm. It is obvious that the surgical experience and expertise plays an important role in this regard. Of note, it must be primarily assumed that continuously elevated calcitonin levels following thyroidectomy mainly are due to lymph node metastases left *in situ*. Calcitonin normalization has in selected patients been observed in up to 35-40% even after reoperation \[[@B14],[@B15]\] and may actually be as low as 6% if one waits for radiographic positive findings \[[@B16]\]. Thus the recommendation to wait for positive imaging as suggested by the ATA guidelines is questionable.
Hereditary MTC
--------------
In patients with hereditary MTC, early identification of patients, e.g. through family screening, may enable to limit the extent of surgery to the thyroid gland since lymph node metastases may be very unlikely if preoperative calcitonin levels are normal \[[@B17],[@B18]\]. Besides patient's age, primary tumor size and calcitonin levels may be helpful in determining the surgical extent. The ATA guidelines give some recommendations in this regard (recommendations 33, 35, 40-43). Since this review is focusing on clinically evident MTC, these recommendations will not be discussed in detail here.
Further comments
================
In general, lymph node dissection should be very restrictive in the presence of advanced local and/or distant disease. This is justified by the very low chance to cure those patients \[[@B6]\] where no benefit might be gained from the lymph node dissection. In these instances, the calcitonin doubling-times may be of help assessing patient's prognosis where doubling-tomes less than 6 months are very unfavourable \[[@B19]\].
Clinically evident or highly suspected lymph node metastases
------------------------------------------------------------
Taken the above into account, dissection is almost always indicated in the presence of cervical lymph nodes metastases. Clinically, the presence of lymph node metastases is most often assumed in the presence of enlarged lymph nodes. Fine-needle aspiration is rarely performed. However, lymph node metastases in MTC are typically rather small in size and, thus, normal lymph node size does not exclude the presence of metastases.
Unknown lymph node status
-------------------------
If no enlarged lymph nodes are present, the extent of lymph node dissection is much more difficult to assess. This situation, however, is very common.
Most surgeons would recommend central lymphadenectomy (defined as dissection of level VI) in all patients with sporadic MTC and in all screening patients with elevated calcitonin levels at the time thyroidectomy is performed due to the high likelhood of the presence of positive lymph nodes \[[@B20]\]. The exception are screening patients with normal calcitonin levels that probably have an extremely low risk that lymph node metastases exist \[[@B17],[@B18]\]. These patients may therefore forego lymphadenectomy. As mentioned before, one reason to avoid cervical lymphadenectomy is the observed higher rate of complications \[[@B10]\]. The reason to perform central lymphadenectomy synchronous with thyroidectomy is that metachronous lymphadenectomy confers an even higher risk of complications. This does not apply to the lateral compartments (level II-V) that are not touched if the previous operation consist of thyroidectomy both with and without central lymphadenectomy.
Since the ipsilateral cervicolateral compartment contains almost as often lymph node metastases as the central compartment \[[@B21]\], some surgeons would recommend performing both central and lateral lymphadenactomy synchronous with thyroidectomy. Others have recommended lateral lymph node dissection "on demand", i.e. in the setting of measurable postoperative bCT and/or sCT levels indicating LN metastasis \[[@B22]\]. In the case of contralateral positive lymph nodes, the chance of biochemical cure decreases dramatically \[[@B21]\] and no beneficial outcome has been shown if lymphadenectomy is performed in these patients.
Assessing the lymph node status
-------------------------------
The question is how the extent of lymph node metastases can be assessed pre- or at the latest intraoperatively in MTC patients.
### Imaging techniques
The accuracy of computed tomography and ultrasonography for evaluating cervical lymph node metastases in patients with papillary thyroid carcinoma is not very high, 74% vs. 68 resp. \[[@B23]\]. Since it is known that lymph mode metastases in MTC are often rather small as compared to papillary thyroid carcinoma, the accuracy is expected to be lower which has indeed been shown \[[@B24]\]. Both, somatostatin receptor scintigraphy and, in particular, FDG-PET have been used with some success in detecting lymph node metastaes preoperatively but the reported series are small \[[@B24]-[@B28]\].
In reoperative cases, a variety of imaging techniques (ultrasound, computed tomography, FDG-PET) seems to have a low sensitivity (56%, 42%, and 32%, respectively).
Thus, currently available imaging techniques are of minor value identifying small lymph node metastases. Ultrasound, which is readily available, is the investigation of choice and should always be performed first.
### Venous sampling
In reoperative cases, it has been shown that pentagastrin-stimulated intravenous calcitonin sampling followed by targeted surgery may be beneficial in the diagnostic work-up of MTC after thyroidectomy \[[@B29]\]. However, the number of reported cases is low and the real value is not known yet.
### Primary tumor size
Even small tumors (\<1 cm) inherit a risk for lymph node metastases that increases with tumor size \[[@B30]\]. Patients having a primary tumor of less than 5 mm in size have a risk of having lymph node metastases between 13-20% if sporadic and between 6-14% if hereditary. The biochemical cure rates at these early stages are 69-85% and 80-96%, respectively. Concerning tumors smaller than 1 cm in size, lymph node metastases are found in 5-31% and the biochemical cure ranges from 71% to 100% (reviewed in \[[@B30]\]). Thus, even at these early stages, lymph node metastases are not uncommon \[[@B31]\].
Thus, lymph node metastases are not uncommon even in small primary tumors. The tumor size is, hence, of less value in assessing the presence of lymph node metastases in patients with MTC.
### Lymph node metastases in the central compartment
Studies have shown that the involvement of the ipsilateral cervicolateral compartment correlates with the number of lymph node metastases in the central compartment. If more than 3 lymph nodes in the cervicocentral compartment were involved, almost all patients had lateral lymph node metastases in one study \[[@B12]\]. This "marker", however, is of less use in the clinical setting in the absence of macroscopically enlarged lymph nodes since it is not possible to determine the numbers of central lymph node metastases within a decent time period intraoperatively so far. Of note, lateral lymph node metastases were found in about 10% even in the absence of central lymph node metastases. This finding, i.e. the presence of cervicolateral lymph node metastases without cervicocentral compartment involvement, often referred to as skip metastases \[[@B32]\], has even been found in up to 35% by others \[[@B33]\].
### Calcitonin levels
Concerning microMTC (\<1 cm), calcitonin levels cannot distinguish between patients with and without lymph node metastases \[[@B22]\]. This is also true for patients with larger primary tumors even though higher basal calcitonin levels correlate better than pentagastrin stimulated calcitonin levels with lymph node involvement \[[@B20]\]. In the latter study, both central and ipsilateral lateral lymph node metastases were present in about 10% of the patients already at a basal level of 20 pg/mL. In patients higher than 200 pg/mL, contralateral lateral lymph node involvement was observed in at least 12% of the patients.
One study showed that intraoperative stimulated calcitonin levels following thyroidectomy and central lymph node dissection correlated well with the presence of lateral lymph node metastases \[[@B34]\]. The intraoperative usefulness of this technique would require quick calcitonin assays. Currently, the analysis takes several hours.
### Age
While age plays an important role assessing timing and extent in patients with hereditary MTC \[[@B35]\], it does not seem to play a role in sporadic MTC.
### Other "markers"
Beside these more traditional markers, other markers are sought after.
Of interest, one such "marker" has been cervical pain. In one study, the authors reported that roughly 80% of their patients with MTC presented with neck pain (defined as any subjective complaint of anterior neck discomfort, ache, pressure, or sharp, throbbing, or dull sensations in the region of the thyroid gland, with or without palpation) as opposed to only 6% of their patients with papillary thyroid carcinoma \[[@B36]\]. However, even 36% of those without pain had lymph node metastases.
Desmoplastic stromal reaction is one of those intraoperative markers that appear to have more clinical value. In one study analyzing 120 MTCs, it was shown that desmoplastic stromal reaction, which can be assessed intraoperatively, has a low (38%) sensitivity of predicting N0 but a very high (100%) specificity. The authors therefore recommend avoiding lymph node dissection in the absence of desmoplastic stromal reaction \[[@B37]\]. The results where later shown to be reproducible by other pathologists \[[@B38]\] but larger prospective studies are missing yet.
Conclusions
===========
If advanced disease is absent, central lymph node dissection is almost always indicated at the initial operation in patients with clinically evident MTC. Synchronous inclusion of the ipsilateral lateral compartment is recommended by some but might probably also be done "on demand" if postoperative calcitonin levels remain elevated.
In reoperative cases, the extent of lymph node dissection depends primarily on the extent of previous operation(s). Compartments that have not been operated on in a systematic way, i.e. dissection of all lymph node and the connective tissue *"en bloc"*, should be operated in this manner. Node picking should be reserved to those compartments that have been operated on systematically. I these cases, positive imaging is required. This approach, however, has not been proven to be of any benefit for the patient.
Future research has to concentrate on improving preoperative imaging and on the identification of intraoperative measurable markers that correlate with the presence or absence of lymph node metastases with a high accuracy.
Competing interests
===================
The author declares no competing interests.
Declarations
============
This article has been published as part of *Thyroid Research* Volume 6 Supplement 1, 2013: European comments on Medullary Thyroid Cancer Management Guidelines of the American Thyroid Association. The full contents of the supplement are available online at <http://www.thyroidresearchjournal.com/supplements/6/S1>. Publication of this supplement has been supported by the European Thyroid Association-Cancer Research Network.
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Q:
redirect to html page using jsf
I can't figure out why this code doesn't redirect me correctly to the html page that i want. This is the code that i'm using:
String url = "Start.xhtml";
FacesContext fc = FacesContext.getCurrentInstance();
ExternalContext ec = fc.getExternalContext();
try {
ec.redirect(url);
}catch (IOException ex) {
ex.printStackTrace();
}
It seems to be redirecting the page, but nothing appears, even though i have something in the html file. How should i put the string of the xhtml file?
THANK YOU for your help
A:
You have to consider the context root of your application. In most cases it is something like this:
String url = "/ApplicationName/faces/Start.jsf";
try {
FacesContext.getCurrentInstance().getExternalContext.redirect(url);
} catch (IOException e) {
// error handling
}
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Isolating RNA from whole blood--the dawn of RNA-based diagnosis?
A novel cationic surfactant solution is used to lyse blood cells and precipitate RNA and DNA. The RNA is recovered by extracting the pellet with a small volume of guanidinium isothiocyanate or formamide.
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Oscar Pedersen (politician)
Oscar Adolf Pedersen (14 September 1885 – 1939) was a Norwegian newspaper editor and politician for the Labour and Social Democratic Labour Labour parties.
He was born in Haugesund. He was a subeditor in Arbeidet in 1908. In 1910 he was tried in the Supreme Court of Norway for conscientious objection. The sentence of 90 days prison was upheld. Later in 1910 he was called in for military service again; objected again and was sentenced to another 90 days. He appealed for pardon, but this was rejected. In 1911 he objected yet again, was sentenced for the third time, but was this time pardoned.
From 1912 to 1919 he managed Arbeidernes Pressekontor. He resigned after being forced to fire a correspondent who was perceived as too rightist by the majority in the Labour Party. Pedersen edited the newspaper Arbeider-Politikken from 1921 to 1923, a newspaper for the right wing in the Labour Party. He was one of the first to suggest that a new party be formed as a split from the Labour Party, and he joined the Social Democratic Labour Party when it was formed in 1921. He represented the party in Oslo city council from 1923 to 1925.
He also edited Riksmålsbladet from 1926 to 1933, as a secretary in the Riksmål Society from 1920. He also chaired the Norwegian Union of Journalists and was a board member of the Norwegian Press Association. He died in 1939.
References
Category:1885 births
Category:1939 deaths
Category:People from Haugesund
Category:Norwegian newspaper editors
Category:Labour Party (Norway) politicians
Category:Social Democratic Labour Party of Norway politicians
Category:Politicians from Oslo
Category:Norwegian trade unionists
Category:Conscientious objectors
Category:Norwegian prisoners and detainees
Category:Prisoners and detainees of Norway
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This proposal is for molecular genetic assessment of SNCA in alpha-synucleinopathy. Our data shows alpha-synuclein overexpression is sufficient to give rise to a spectrum of Parkinsonism disorders, including Parkinson's disease, parkinsonism and dementia, dementia with Lewy bodies and multiple system atrophy; alpha-synuclein is undoubtedly a central component in sporadic and familial disease. Our aims are to: 1) identify genetic variability in the SNCA locus and determine what contribution it has to these phenotypes; 2) molecularly, clinically and pathologically characterize SNCA multiplication mutations;, 3) quantify SNCA gene expression in normal aging and disease, and; 4) functionally assess genetic variability within the gene and its promoter. Furthermore, we are to examine the transcriptional consequence of alpha-synuclein over-expression, in model systems, in human brain tissue from cases with SNCA multiplication. Our objective is to provide meaningful molecular diagnoses to reclassify this heterogeneous group of diseases, into distinct groups, for further longitudinal and pathological assessment. As alpha-synuclein has an extended half-life (approximately 30hrs), thus our work is focused on characterizing SNCA genetic variability, transcriptional regulation and mRNA expression. We posit reduction in alpha-synuclein expression may provide a powerful therapeutic strategy to prevent alpha-synucleinopathy or halt its progression.
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Equestrian at the 1952 Summer Olympics
The equestrian events at the 1952 Helsinki Summer Olympics included dressage, eventing, and show jumping. All three disciplines had both individual and team competitions and were held from 28 July to 3 August 1952.
One of the biggest changes at the 1952 Olympics was the demographics of competitors. Before this, most of the riders were officers (41 of 44 starters at the 1948 Olympics were riding in uniform), whereas the Helsinki Games saw over 50% of competitors from the civilian ranks. Additionally, women were now allowed to compete for the first time in equestrian events. At the 1952 Games, they were permitted in the dressage competition, although prohibited from the jumping (per a ruling in 1951) and most definitely not in eventing which was considered too dangerous. A total of 4 women competed out of 138 riders.
25 nations competed: Argentina, Brazil, Bulgaria, Canada, Chile, Denmark, Egypt, Finland, France, Federal Republic of Germany, Great Britain, Ireland, Italy, Japan, Korea, Mexico, the Netherlands, Norway, Portugal, Romania, Soviet Union, Spain, Sweden, Switzerland, and the USA. This was the first appearance for Canada, Egypt, Korea, and the Soviet Union. Russia had sent riders to the 1912 Games, but had not competed since. The youngest participant was Walter Staley (19) from the United States, while the oldest rider was the Danish Kristian Jensen (63).
Disciplines
Show jumping
52 riders from 20 nations competed at the 1952 Games. For the first time, individual and team medals were awarded based on a two-round Prix des Nations (Nations Cup). 16 teams rode around Björn Strandell's 786 meter course with a 1 min 57.2 second time allowed and fences up to 1.60 meters in height and a 5-meter water jump. The individual gold was won by the French rider Pierre d'Oriola, aboard the gelding, Ali Baba. D'Oriola would repeat the feat in 1964 and remains the only rider to win two gold medals in this discipline. The team event was won by Great Britain, anchored by a clear round for Harry Llewellyn and Foxhunter. This gold medal, attained on the last day of competition, was Great Britain's only gold of the 1952 Games. They remain the only nation to have won gold medals in every Summer Olympics since 1896.
Dressage
27 riders, including for the first time 4 women, from 10 nations rode in the dressage competition. One of these women was Denmark's Lis Hartel, who in 1944, at age 23, had been paralyzed by polio. She gradually regained muscle function but remained paralyzed below the knee. Amazingly, despite not being able to mount or dismount unassisted, she won individual silver.
5 judges were present at the test, with the lowest and highest scores of the panel being dropped (the only time in Olympic dressage history this method was used). The test reintroduction of the piaffe and passage, and was 15 minutes in length.
Eventing
The eventing competition was slightly harder in 1952 than in 1948. Phase A was 7 km at 240m/min, Phase B (steeplechase) was 4 km at 600m/min, Phase C 15 km at 240 m/min, Phase D (cross-country) was 9 km at 450 m/min with jumping efforts up to 1.20 meters, followed by the final phase which was a 2 km "gallop" at 333m/min. The final stadium jumping round also had fences up to 1.20 meters.
59 riders from 21 countries competed, forming 19 teams. 13 of those teams were strictly officers, while 2 were a mix of officers and civilians (Great Britain and Ireland) and four had civilian-only teams (Canada, Germany, the Netherlands, and the USA). Of the 12 medals awarded between the individual and team competitions, 7 went to civilians.
Medal summary
Medal table
References
International Olympic Committee medal database
Category:1952 Summer Olympics events
1952
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Prostaglandin specific binding in hamster myometrial low speed supernatant.
A charcoal adsorption method was developed to measure specific prostaglandin binding in low speed supernates of hamster myometrial homogenates. This method was used to characterize and quantitate PGE-1-specific binding. The equilibrium binding constants and the concentration of specific PGE-1 binding sites were determined during the hamster estrous cycle. The apparent association constant for 12 different preparations was 1.16 plus or minus 0.08 times 10-9M-1. The concentration of PGE-1 specific binding sites was significantly higher on days 2 and 3 of the estrous cycle that it was on days 1 or 4. The competition for PGE-1 binding sites by PGE-2, PGF-2alpha, tpga-1 and various PGE-1 metabolites and derivatives was measured in hamster myometrial homogenates. Relative affinities of the natural prostaglandins for the PGE-1 binding sites, calculated by parallel line assay, were: PGE-2 greater than PGE-1 greater than PGA-1 greater than PGF-2alpha. For PGE-1 metabolites the relative affinities were: PGE-1 greater than 13,14-dihydro-PGE-1 greater than 13,14-dihydro-15-keto-PGE-1 greater than 15-keto-PGE-1. For the analogs and derivatives the compounds tested ranked as: 16,16-dimethyl-PGE-1 greater than PGE-1 methyl ester greater than 17-phenyl-18,19,20-trinor-PGE-1 greater than 15(S) 15-methyl-PGE-1 methyl ester. Arachidonic acid, bis-homo-gamma-linolenic acid and 7-oxa-13 prostynoic acid had relative affinities greater than 0.1 compared to PGE-1 equal 100. Indomethacin had a relative affinity of 0.4 compared to PGE-1.
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Lower limb movements and urologic function in fetuses with neural tube and other central nervous system defects.
Lower limb movements and urologic systems were evaluated by prenatal ultrasound in 120 fetuses with either neural tube defects or intracranial anomalies. Despite anticipated major lower extremity and bladder dysfunction, lower limb movements were seen in 100% of the fetuses with anencephaly and encephaloceles, 93% with isolated spina bifida, 60% with complex spina bifida and 90% with abnormal intracranial findings. In all the cases except those with cloacal exstrophy, fetal bladder and collecting systems appeared normal. Therefore, fetal lower limb movements and urinary tract integrity appear to have no diagnostic or prognostic value in fetuses with neural tube defects or other central nervous system anomalies. These diagnoses can only be made by direct ultrasound observation of the lesion itself.
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Introduction {#s1}
============
Class I Major Histocompatability Complex (MHC-I) molecules present peptides generated by proteasomal degradation in the cytosol and transport into the endoplasmic reticulum, or by cross-presentation of endo/phagocytosed material [@pone.0022936-Kloetzel1], [@pone.0022936-Vyas1]. During infection, MHC-I antigen presentation is responsible for the activation and expansion of specific CD8^+^ T-cells, and is involved in the immune response to diverse intracellular pathogens, including viruses, bacteria, and microbial eukaryotes [@pone.0022936-Wong1], [@pone.0022936-Harty1]. CD8^+^ T-cells are required for the control of the protozoan parasite *Toxoplasma gondii* during its acutely lytic 'tachyzoite' stage, and (directly or indirectly) during the chronic 'bradyzoite' stage characterized by latent cysts in the muscle, brain and other tissues [@pone.0022936-Parker1], [@pone.0022936-Gazzinelli1]. Activated T-cells recognize and destroy both *T. gondii* parasites and parasite-infected cells, and also produce IFN-γ, activating reactive oxygen pathways [@pone.0022936-Denkers1]--[@pone.0022936-Khan2].
The route by which *T. gondii* antigens reach the endoplasmic reticulum for loading onto MHC-I is not fully understood, as these parasites reside within a specialized intracellular 'parasitophorous vacuole' (PV) distinct from the phagocytic/endocytic pathway and the host cell cytoplasm. Presentation is dependent on host cell immunoproteasomes, TAP, and ERAAP [@pone.0022936-Tu1]--[@pone.0022936-Blanchard1], indicating that parasite antigens must reach the host cell cytosol, and several pathways have been proposed, including cross-presentation of phagocytosed parasite material, degradation of the PV membrane, secretion of parasite proteins outside of the PV, and fusion of the PV with the host cell ER [@pone.0022936-John1]--[@pone.0022936-Ling1]. Various immunogenic *T. gondii* antigens are known, including proteins secreted from the dense granules and rhoptries, but responses are often both parasite and host strain-specific [@pone.0022936-Khan2], [@pone.0022936-Blanchard1], [@pone.0022936-Frickel1], [@pone.0022936-Wilson1]. In order to address the route of *T. gondii* antigen entry into the MHC-I presentation pathway, we have examined CD8^+^ T-cell activation following infection with parasites engineered to target the well-characterized antigen ovalbumin to various locations, including the parasite cytoplasm, mitochondrion, inner membrane complex, plasma membrane, and the parasitophorous vacuolar space.
Results {#s2}
=======
Generation of transgenic parasite expressing organelle specific OVA antigen {#s2a}
---------------------------------------------------------------------------
To explore whether antigen access to the MHC-I presentation pathway is affected by subcellular location of antigen within *T. gondii*, RH strain *T. gondii* was engineered to stably express the model antigen OVA (amino acids 140--386), fused to various organelle-targeting sequences as described under Methods. The rationale behind these experiments was to help distinguish between cross-presentation of phagocytosed antigen, *versus* translocation of antigen across the parasitophorous vacuole where intracellular *T. gondii* parasites reside (a compartment distinct from the endophagocytic system; [@pone.0022936-Mordue1]). As shown in [Fig. 1A](#pone-0022936-g001){ref-type="fig"} (top row), expression of ovalbumin without additional targeting signals results in cytoplasmic localization (Cyto-OVA), while fusion to a signal sequence results in secretion into the parasitophorous vacuole (P30-OVA), as previously described by Pepper *et al* [@pone.0022936-Pepper1]. Co-localization of additional OVA fusion proteins with well-characterized markers showed proper targeting to the inner membrane complex (IMC-OVA, row 2), the mitochondrion (HSP-OVA, row 3), or the cell surface, using a GPI anchor (GPI-OVA, row 4). Antibodies to OVA label the surface of non-permeabilized, extracellular GPI-OVA parasites, indicating targeting to the parasite membrane (row 4); permeabilization prior to staining also reveals OVA associated with internal secretory organelles (ER, Golgi, vesicles), presumably *en route* to the plasma membrane (row 5).
{#pone-0022936-g001}
As antigen load is known to be important during infection [@pone.0022936-Wherry1], OVA levels were assessed by immunoblotting of parasites ([Fig. 1B](#pone-0022936-g001){ref-type="fig"}) and infected culture supernatants ([Fig. 1C](#pone-0022936-g001){ref-type="fig"}). Levels of OVA produced by individual parasite strains ranged from 4.5 to 21 ng/10^6^ parasites. Secreted antigen was detected only in P30-OVA and GPI-OVA culture supernatants ([Fig. 1C](#pone-0022936-g001){ref-type="fig"}). We presume that significant quantities of GPI-OVA protein are shed from the parasite surface during parasite gliding motility, as has been reported for the endogenous P30 protein [@pone.0022936-Hakansson1]. No secreted antigen was detected in culture supernatants following HSP-OVA or IMC-OVA infection. Cyto-OVA was not included on this Western blot, but no secreted OVA was detected in Pru Cyto-OVA transgenics (not shown), and note that no secreted antigen is visible in [Fig. 1A](#pone-0022936-g001){ref-type="fig"} (top left). *In vitro* assays indicate similar rates of replication for all of the transgenics described in this report, and preliminary real-time PCR analysis of liver and spleen samples from infected mice indicates \<1.5-fold difference in parasite burden (data not shown).
Antigen presentation and T-cell activation *in vitro* correlate with antigen secretion {#s2b}
--------------------------------------------------------------------------------------
The ability of OVA transgenic lines to induce MHC-I antigen presentation *in vitro* was determined using the 'B3Z' CD8^+^ T-cell hybridoma line [@pone.0022936-Shastri1]. Recognition of the OVA antigenic epitope 'SIINFEKL' in the context of the H-2K^b^ restricted MHC-I mouse background causes activation of these cells to produce ß-galactosidase, which is readily detected by conversion of CPRG to a purple reaction product. Activated (IFN-γ treated) bone marrow-derived macrophages were able to present antigen (activate B3Z cells) when infected with *T. gondii* parasites secreting OVA (P30-OVA and GPI-OVA transgenics), but not parasites harboring intracellular OVA antigen (Cyto-OVA, HSP-OVA, IMC-OVA), as shown in [Fig. 2A](#pone-0022936-g002){ref-type="fig"}. Significant activation was also seen in bone marrow-derived dendritic cells following infection with P30-OVA transgenics ([Fig. 2B](#pone-0022936-g002){ref-type="fig"}); an increase was observed in GPI-OVA-infected dendritic cells as well, although this failed to achieve statistical significance at *P*\<0.05. The lower levels of activity observed using GPI-OVA transgenics likely reflect the lower levels of OVA secreted by this parasite line ([Fig. 1C](#pone-0022936-g001){ref-type="fig"}). T-cell activation was strictly dependent on the presence of live *T. gondii* parasites: heat-killed parasites were readily taken up by activated macrophages, but these effectors failed to activate B3Z cells (data not shown).
{ref-type="fig"}), and co-cultivated with B3Z T-cells in medium containing the ß-galactosidase substrate CPRG. Absorbance at 565 nm is represented relative to controls treated with media alone (average of three replicate assays). Results shown are representative of three independent experiments. Asterisks indicate *p*\<0.05 (\*) or *p*\<0.005 (\*\*), based on the students T-test statistic.](pone.0022936.g002){#pone-0022936-g002}
Activation of naïve OT-I cells *in vivo* correlates with OVA secretion {#s2c}
----------------------------------------------------------------------
In order to determine whether the activation of B3Z T-cells by *T. gondii*-expressed OVA antigen *in vitro* reflects T-cell activation *in vivo*, non-activated OVA specific CD8^+^ T-cells (OT-I cells) were labeled with carboxy-fluoresceine succinimidyl ester (CFSE) and transferred into naïve mice. Five days after infection with *T. gondii* transgenics expressing OVA or wild-type controls, cells from the peritoneum, parathymic lymph node, and spleen were assayed for CFSE dilution and T-cell activation markers, as shown in [Figure 3](#pone-0022936-g003){ref-type="fig"}.
{#pone-0022936-g003}
OT-I cells from uninfected animals, or mice infected with wild-type RH strain *T. gondii*, showed no diminution of CFSE levels, indicating that the T-cells were not activated by parasite infection *per se* over the course of this experiment ([Fig. 3A](#pone-0022936-g003){ref-type="fig"}, light shading). All mice infected with either of the parasite lines secreting OVA (P30-OVA, GPI-OVA) displayed marked dilution of CFSE ([Fig. 3A](#pone-0022936-g003){ref-type="fig"} upper left, intermediate and dark shading). The kinetics of CFSE dilution in P30-OVA and GPI-OVA differed, however ([Fig. 3A](#pone-0022936-g003){ref-type="fig"}, right-hand panels): P30-OVA parasites activated T-cell proliferation as early as 3 days post-infection in all three compartments (peritoneal exudate (PECs), lymph node, spleen), and by day 4 essentially all OT-I cells displayed reduced CFSE levels. In contrast, T-cell activation by GPI-OVA parasites was first observed at day 4 and while all OT-I cells had divided by day 5, CFSE dilution still lagged slightly behind that observed following P30-OVA parasite infection (upper left). This delay likely reflects slower accumulation of antigen due the slow release of GPI-anchored OVA from the parasite cell surface. Further indication of OT-I cell activation during infection is provided by the down-regulation of CD62L and up-regulation of CD44 ([Fig. 3B](#pone-0022936-g003){ref-type="fig"}) and CD69 (not shown). Time-course assays indicate similar kinetics of OT-I cell activation, whether measured by CFSE dilution or activation markers (compare the right-hand panels of [Fig. 3A](#pone-0022936-g003){ref-type="fig"} with [Fig. 3B](#pone-0022936-g003){ref-type="fig"}). Note that while mean fluorescence levels shows a significant lag in CD44 up-regulation by GPI-OVA parasites ([Fig. 3B](#pone-0022936-g003){ref-type="fig"}, bottom right), the histogram (bottom left) indicates that the spectrum of CD44 expression in the GPI-OVA sample is closer to the P30-OVA sample than the wild-type control.
In contrast to the B3Z assay ([Fig. 2](#pone-0022936-g002){ref-type="fig"}), which showed no detectable activation of T-cells by intracellular OVA, the more sensitive *in vivo* system shows low levels of OT-I cell activation by these parasites ([Fig. 3A](#pone-0022936-g003){ref-type="fig"}, lower left). At 5 days post infection, 50% of OT-I cells showed a history of proliferation in the IMC-OVA sample, based on reduced CFSE levels (note, however that this reflects proliferation of \<50% of the starting population, as cell numbers double with each division). These proliferating cells also displayed up-regulation of CD44 and CD69, and lower levels of surface CD62L (not shown). 30% of OT-I cells in the HSP-OVA sample showed evidence of proliferation, while 15% showed evidence of proliferation in response to Cyto-OVA; proliferation was observed in only 9% of OT-I cells in response to wild-type parasite infection. These results confirm that *T. gondii* antigens secreted into the parasitophorous vacuole are readily presented on MHC-I. Intracellular antigens are far less prone to MHC-I presentation (and may derive from phagocytosis and cross-presentation of dead parasites and parasite debris; see below for further discussion).
Discussion {#s3}
==========
Activation of CD8^+^ T-cells is known to be critical for the control of *T. gondii* infection [@pone.0022936-Parker1], [@pone.0022936-Suzuki1]. In order to further clarify the basis of MHC-I antigen presentation during infection, OVA was expressed in various subcellular compartments ([Fig. 1](#pone-0022936-g001){ref-type="fig"}), including three locales within the parasite (the cytoplasm, inner membrane complex, and mitochondrion) and two external locales (anchored to the plasma membrane via a GPI anchor, and secreted into the parasitophorous vacuole). Efforts to stably express OVA antigen in the rhoptries and micronemes were unsuccessful (see Methods); while we (and others) have successfully targeted various reporters into these organelles in transient transfectants, stable transgenics are often more difficult to obtain, and these proteins typically fail to secrete [@pone.0022936-Striepen1]. Our results demonstrate that subcellular localization of antigen matters: surface and secreted antigen is readily presented, while internal antigen is not ([Figs. 2](#pone-0022936-g002){ref-type="fig"} & [3](#pone-0022936-g003){ref-type="fig"}). While surface antigens may be released at low levels from parasites prior to invasion by either dense granule secretion or protein shedding [@pone.0022936-Hakansson1], [@pone.0022936-Sibley1], [@pone.0022936-Seeber1], the failure to present OVA from internal compartments, and the requirement for living parasites, indicates that biologically relevant antigen loading occurs only during active infection, rather than by phagocytosis of parasites or parasite debris from lysed host cells. These results support previous observations with parasites secreting OVA or β-galactosidase [@pone.0022936-Gubbels1], [@pone.0022936-Dzierszinski1], [@pone.0022936-Kwok1], although evidence for cross-presentation by uninfected dendritic cells has also been reported during Prugniaud P30-OVA infection [@pone.0022936-John1].
Activation of OT-I cells induced by presentation of OVA antigen secreted into the parasitophorous vacuole occurs as early as day 3 post-infection. These data are consistent with previous reports that CD8 responses against pathogens (including *T. gondii*) are initiated within 3 days of infection [@pone.0022936-John1], [@pone.0022936-Williams1]. By 5 days post-infection, antigen-specific OT-I cells had proliferated extensively in response to secreted OVA, while responses to intracellular OVA were just getting underway ([Fig. 3](#pone-0022936-g003){ref-type="fig"}).
Although OVA is not a native parasite antigen, previous studies have highlighted the importance of secreted *T. gondii* proteins in CD8^+^ T-cell responses to infection with various parasite strains (P30/SAG1 [@pone.0022936-Khan1], [@pone.0022936-Khan2], [@pone.0022936-Kasper1], GRA6 [@pone.0022936-Blanchard1], GRA4 & ROP7 [@pone.0022936-Frickel1], TGD057 [@pone.0022936-Wilson1]). In addition to secreted antigens, the observed CD8^+^ T-cell response to GPI-OVA, while slightly lower than responses to P30-OVA ([Fig. 3](#pone-0022936-g003){ref-type="fig"}), suggests the possible importance of the large SAG/SRS family [@pone.0022936-Jung1] as subdominant epitopes in *Toxoplasma* infection. These findings are also consistent with observations on other intracellular pathogens: antigens secreted by either bacteria (*Listeria monocytogenes*) or protozoa (*Leishmania major*, *Trypanosoma cruzi*) are more effective in activating CD8^+^ T-cells than intracellular antigen [@pone.0022936-Shen1]--[@pone.0022936-Garg1]. In the *Listeria* system, it has also been shown that T-cells stimulated by intracellular antigen are limited in their ability to lyse infected cells, presumably because intracellular antigens are unlikely to be presented by infected target cells [@pone.0022936-Shen1].
Both *Listeria* and *T. cruzi* live within the host cell cytoplasm, but *T. gondii* is found within the 'parasitophorous vacuole', a specialized intracellular compartment distinct from the endo-phagocytic pathway [@pone.0022936-Mordue1]. The fact that secreted OVA is presented by infected cells therefore implies that this antigen must escape from the parasitophorous vacuole into the cytoplasm. The mechanism by which OVA reaches the host cell cytoplasm is uncertain, but there is ample precedent for traffic out of the parasitophorous vacuole [@pone.0022936-Gubbels1], [@pone.0022936-Peixoto1]--[@pone.0022936-Taylor1]. Previous studies have shown that presentation of secreted OVA is dependent on TAP [@pone.0022936-Gubbels1], [@pone.0022936-Dzierszinski1], which mediates transport from the cytoplasm into the endoplasmic reticulum [@pone.0022936-Suh1]; additional work suggests that the parasitophorous vacuole may sometimes fuse directly with the endoplasmic reticulum [@pone.0022936-Goldszmid1]. Yet another possible model for antigen escape from the parasitophorous vacuole involves vacuolar membrane breakdown by IFN-γ inducible p47 GTPase induced autophagic mediated mechanisms releasing vacuolar proteins into the host cell cytoplasm [@pone.0022936-Ling1], [@pone.0022936-Zhao1].
The use of antigen-specific reagents, including endogenous T-cell tetramers and T-cell specific mice [@pone.0022936-Blanchard1], [@pone.0022936-Frickel1], [@pone.0022936-Wilson1], [@pone.0022936-Kirak1] should provide answers to questions that have been difficult to interpret using model antigen systems, including: the differences in T-cell responses to multiple *T. gondii* strains, the role of changing antigen availability during parasite differentiation, and the generation of memory precursors. It will still be necessary to examine each antigen individually, however, as different antigens can yield different T-cells responses, based not only on their protein sequence but also subcellular location, perhaps influencing the clonality of the immune response. Further studies will be necessary to understand how secreted antigens become accessible to the MHC-I pathway, despite their apparent confinement to the parasitophorous vacuole, and such work is likely to offer new insights into the activation of CD8^+^ T-cells during *T. gondii* infection.
Materials and Methods {#s4}
=====================
Ethics statement {#s4a}
----------------
Mouse studies were conducted in accord with all relevant national and international guidelines, as approved by the University of Pennsylvania Institutional Animal Care and Use Committee (protocol 801344).
Parasites and cell cultures {#s4b}
---------------------------
RH ΔUPRT ΔHXPGRT strain *T. gondii* parasites were maintained by serial passage in human foreskin fibroblast (HFF) monolayers, cultivated in Eagle\'s Minimal Essential Medium (Gibco) containing 1% fetal bovine serum (FBS), as previously described [@pone.0022936-Roos1]. Extracellular tachyzoites were purified by filtration through 3.0 µm filters (Nuclepore), and washed in phosphate buffered saline.
Molecular methods {#s4c}
-----------------
Expression vectors were based on the Bluescript pKS(+)-derived plasmids *tub*P30OVA*dhfr* and *tub*CATOVA*dhfr* described previously by Pepper *et al*, in which the parasite\'s major surface antigen (P30, encoded by the *SAG1* gene), lacking the C-terminal glycophosphatidyl inositol (GPI) addition signal, is fused to amino acids 140--386 of *Gallus gallus* ovalbumin (OVA) [@pone.0022936-Pepper1]. Transcriptional regulatory sequences were provided by the *T. gondii* tubulin 1 promoter (*tub*) and dihydrofolate reductase 3′ untranslated region (*dhfr*). Plasmids employed in this report substituted the following sequences in place of P30 (between *tub* and OVA, flanked by *Bgl II* and *Avr* II sites): IMC1 (amino acids 1--608) for targeting to the inner membrane complex [@pone.0022936-Hu1], heat shock protein 60 (HSP 60) for mitochondrial targeting (amino acids 1--55) [@pone.0022936-Nishi1], ROP1 for rhoptry targeting (amino acids 1--396) [@pone.0022936-Striepen2], or MIC3 for microneme targeting (amino acids 1--358) [@pone.0022936-Dzierszinski2]. Retention of P30-OVA in the plasma membrane was achieved by adding the P30 GPI anchor motif (AAGTASHVSIFAMVIGLIGSIAACVA; flanked by *Nhe* I and *Afl* II sites) to the C-terminus of OVA. All plasmids also included a *sag*CAT*sag* cassette downstream of the OVA reporter gene for selecting stable transgenic parasites. 10^7^ freshly harvested extracellular tachyzoites were transfected with 50 µg linearized plasmid DNA (2 mm gap cuvettes, 1.5 kEV pulse, 24Ω), inoculated into HFF cell monolayers in 20 µM chloramphenicol, and incubated through three passages prior to cloning in 96 well plates by limiting dilution [@pone.0022936-Kim1].
Immunofluorescence Assays and Microscopy {#s4d}
----------------------------------------
Confluent HFF monolayers grown on glass coverslips were inoculated with clonal parasite lines expressing OVA, incubated for various times, fixed in 4% formaldehyde (in PBS), permeabilized in 0.2% TritonX-100, blocked in 10% fetal bovine serum, and stained with rabbit anti-chicken ovalbumin (Bethyl Laboratories; Montgomery, Texas), followed by ALEXA 448-conjugated goat anti-rabbit antibodies (Molecular Probes/Invitrogen), as described previously [@pone.0022936-Pepper1]. For co-localization, parasites were stained with mouse anti-P30 or anti-IMC1 (kindly provided by Drs. David Sibley, Washington University School of Medicine, and Gary Ward, University of Vermont, respectively), followed by ALEXA 594-conjugated goat anti-mouse antibodies (Molecular Probes/Invitrogen). Mitotracker was used for mitochondrial detection, and 10 µM DAPI for nuclear labeling. Images were captured using a Leica inverted epifluorescence microscope fitted with a 100 W Hg lamp and appropriate filter sets.
Western Blots {#s4e}
-------------
Free *T. gondii* tachyzoites (2×10^6^) were filtered through a 3 µM Nuclepore filter, pelleted by centrifugation, washed with PBS, and treated 30 min with DNAse I (0.2 U/µl) at 37°C. Parasite samples and OVA standards (Worthington Biochemical; Lakewood NJ), were boiled in reducing agent and loading buffer and separated on a 4--12% bis-tris gel (Nupage; Invitrogen) in MES, in parallel with protein standards (MagicMark; Invitrogen), and transferred to nitrocellulose membranes using a semi-dry system (BioRad). After probing with rabbit anti-OVA (Bethyl Laboratories; 1∶2000) or anti-*Tg*DHFR [@pone.0022936-Reynolds1] and horseradish peroxidase-conjugated goat anti-rabbit antibodies (Jackson ImmunoResearch; 1∶3000), chemiluminescence was detected with Immobilon Chemiluminescent HRP Substrate (Millipore; Billerica MA) and exposed to Kodak MR X-ray film. OVA production levels were determined using a standard curve generated from purified OVA dilutions run in parallel with parasite samples, and analyzed using Image J software.
B3Z assays {#s4f}
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Macrophages (MØ) and dendritic cells (DC) were prepared as described previously [@pone.0022936-Caamano1], [@pone.0022936-Lutz1]. Briefly, bone marrow was extracted from C57Bl/6 female mice, and cultivated 8--9 d in uncoated plastic dishes containing RPMI medium, 10% FBS (Gibco), and either 30% L929 culture supernatant (for MØs), or 20 ng/ml GM-CSF (PeproTech, for DCs). Cells were inoculated into 96 well flat bottom plates at 10^5^ per well, incubated overnight at 37°C, supplemented with medium +/− recombinant mouse interferon-γ (100 U/ml), and incubated for 4 hr. Triplicate wells were inoculated with live (MOI = 0.5) or heat-killed (MOI = 5) tachyzoites, recombinant OVA (500 µg/ml; Worthington, Lakewood NJ), or OT-I peptide (50 ng/ml SIINFEKL; CHI Scientific, Maynard MA), and incubated 12 hr in RPMI+10% FBS, followed by the addition of B3Z T-cell hybridoma cells (10^5^ / well), and a 12 hr further incubation in RPMI without phenol red. Finally, cultures were supplemented with 100 µM chlorophenol red ß-D-galactopyranoside (CPRG; Calbiochem), incubated 12 hr, and ß-galactosidase activity assessed by spectrophotometric determination of absorbance at 565 nm. All experiments were conducted in triplicate, averaged, and normalized with reference to controls exposed to neither parasites nor OVA.
*In vivo* assays {#s4g}
----------------
C57Bl/6 and Thy1.1 C57Bl/6 mice were obtained from NCI Production and Jackson Labs, respectively; Thy1.2 OT-I TCR transgenics were bred in an SPF facility at the University of Pennsylvania. Thy 1.2 OT-I T-cells from pooled spleens and lymph nodes of naïve C57Bl/6 female mice were purified on CD3/CD28 columns, labeled 9 min in 5 µM carboxy fluoresceine succinimidyl ester (CFSE; Molecular Probes/Invitrogen) and transferred into congenic Thy 1.1 C57Bl/6 females animals (5×10^5^ cells/mouse). After 24 hr, these animals were infected with 10^4^ *T. gondii* parasites (RH strain or RH-OVA transgenics) with 3 mice per group. CFSE levels were determined by flow cytometry (FACs Canto, Becton-Dickinson) at d3, 4 and 5 post-infection, in order to assess the proliferation of OT-I cells. CD8^+^ T-cell activation was determined in parallel using antibodies against CD62L (eBiosciences clone Mel-14), CD44 (eBioscience clone IM7), and CD69 (eBiosciences clone H1.2F3). Data collection and analysis was carried out using DIVA and FlowJo software. *In vivo* parasite burden was tested using real-time PCR as described previously [@pone.0022936-Wilson2]. Briefly, parasite genomic DNA was isolated using the High Pure PCR Purification Kit (Roche) and real-time analysis conducted using B1 primers on a 7500 Fast Real-Time PCR System.
Statistical analysis {#s4h}
--------------------
Student\'s T tests were completed for the B3Z and flow cytometry assays using GraphPad Prism software. P values\<0.05 (\*) or \<0.005 (\*\*) are indicated.
We wish to thank Dr. Dan Beiting and other members of the Roos and Hunter laboratories for helpful discussions.
**Competing Interests:**The authors have declared that no competing interests exist.
**Funding:**This work was supported by grants AI28724, AI071302, and AI 42334 from the National Institutes of Health (NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
[^1]: Conceived and designed the experiments: BG FD ET KAJ CAH DSR. Performed the experiments: BG . Analyzed the data: BG. Wrote the paper: BG DSR.
[^2]: Current address: Institute of Parasitology, McGill University, Ste-Anne-de-Bellevue, Québec, Canada
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If hired, Jeff Hornacek will face same challenges as Tyrone Corbin
Assistant Coach Jeff Hornacek and Head Coach Tyrone Corbin at the Zion's Bank Basketball Center in Salt Lake City on Sunday, June 19, 2011.
Mike Terry, Deseret News
Summary
Current Jazz coach is off to a better career start than Hall of Fame coach Jerry Sloan.
SALT LAKE CITY — Judging by the reaction to my column last month, that said Tyrone Corbin deserves another year, I might as well have been endorsing Edward John Smith.
Smith was the captain of the Titanic who failed his original navigation test, years before the famous 1912 shipwreck. Likewise, a lot of NBA teams could use some navigation help. There could be as many as 10 new coaches next season.
Although Corbin’s name hasn’t arisen in connection with any of those vacancies, here’s one that has: Jeff Hornacek. The Jazz assistant has reportedly been scheduled for interviews with Charlotte, Phoenix and Philadelphia, with more to come.
Whether Hornacek gets any of the jobs remains to be seen, but Arizona Republic columnist Bob Young wrote this: “Hey Ryan McDonough, congratulations on your new gig as Suns general manager. Here’s what I suggest for your first move. Hire Jeff Hornacek as the club’s new coach before somebody, such as the 76ers or Bobcats, beat you to him.”
Is this the same unassuming Hornacek that can be seen lobbing lead passes to Gordon Hayward during practice? The guy whose job is to keep the head coach from getting technical fouls? The very same.
But he’s not going to be under the radar much longer.
As Lady Gaga once said, “I’ve always been famous, it’s just no one knew it yet.”
Hornacek’s name is everywhere lately, and in some ways it’s not a surprise. He was a wonderful player, and has been able to translate that skill into coaching. Remember, this guy actually improved Andrei Kirilenko’s 3-point shooting. He is a calming influence to players in close games.
Now he is getting close to having his own team. It’s bound to eventually happen. Yet he still has little overall experience. Curiously, teams such as Milwaukee, Charlotte and Philadelphia have shown interest in Jerry Sloan, who was a head coach for 26 years and is in the Hall of Fame, but at the same time those teams also considered Hornacek.
That’s not to say Hornacek won’t become a fine head coach. But if hired, he’ll be on an even steeper learning curve than Corbin. And he’s likely to have the same problems. Corbin was an assistant under Jerry Sloan for seven years before getting the top spot; Hornacek has been a full-time assistant for less than three full seasons.
As early as 2004, Chicago and Phoenix interviewed Hornacek and even the Boston Celtics considered hiring him, despite having zero coaching experience. Boston’s interest made sense, considering president Danny Ainge was hired to coach the Suns in 1996, after being an assistant for just eight games.
Magic Johnson was hired without coaching experience, but only lasted 16 games before quitting in disgust. Larry Bird was hired without experience and won 147 games in three seasons in Indiana. Mark Jackson was hired without experience to coach the Golden State Warriors, but was just 23-43 in his first season, following the lockout. This year he led his team to the Western Conference semifinals.
Occasionally experience doesn’t matter, but more often it does.
Truth is that Corbin hasn’t been perfect, but he hasn’t been terrible, considering his personnel. There wasn’t an All-Star on the team this year.
If Hornacek is hired as a head coach, he’ll go through the same things. He’ll waffle with substitutions and misuse a few timeouts. He’ll butt heads with players, the way Corbin did with Raja Bell. He’ll sometimes have legendary coaches like San Antonio’s Gregg Popovich and Denver’s George Karl make him look bad.
This isn’t a condemnation, just a reminder that Hornacek will have his growing period, same as Corbin. Some have suggested Hornacek become the Jazz’s coach instead of Corbin, or have the Jazz swap Corbin for Sloan. Yet Sloan was fired by Chicago halfway through his third season as a head coach, with a 94-121 record (.438). Corbin is 87-89 (.494) at roughly the same place in his career.
Moral to the story: You never know when a “failure” will end up in the Hall of Fame.
Hornacek has a bright future; one day he’ll be a winning head coach.
The same could be said for Corbin, who has two winning seasons in his three years. The only non-winning year was in 2011 when he took over midstream.
Popular Comments
I disagree. Corbin has been horrible. Corbin failed to make basic game time
moves that even I as a non-coach can see. It took him over a season to
recognize that he needed to make offense/defense subsitutions down the stretch.
It took him over a
More..
5:22 p.m. May 18, 2013
Top comment
dumprake
Washington, UT
Hire Popovich, he get more out of less talent than any coach in the NBA...and
how many NBA titles has he won? he could get another this year, no Lakers, no
Celtics, no team who is going to dominate the Spurs.
"otters done quit making beavers", old man Sharp used to say and he is
still right. Every Coach makes mistakes. My problem with Corbin is he don't
seem to learn from his. Comparing win loss records is no way to judge a Coach.
Look at
More..
Brad Rock, a.k.a. "Rockmonster," has been a sports columnist at the Deseret News since 1994. Prior to that he worked as a beat writer, covering the Utah Jazz (1990-94). He has covered the Super Bowl, NCAA Final Four, NBA more ..
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In true DCEU fashion, where there is smoke, there is most definitely a fire. After months of rumors suggesting that Ben Affleck was out of Matt Reeves' The Batman project, it now appears to be true. A new report released today pointed to a quote from Reeves implying that The Batman is a standalone movie and that it will take place outside of the DCEU. The reporter, Kim Masters, who Reeves relayed the information to, was also the same reporter that broke the initial story about Ben Affleck bailing on the project.
And in another interesting turn of events, Warner Bros. and DC announced yet another Joker movie, but this time with Harley Quinn. Buried in The Hollywood Reporter article announcing the new Joker/Quinn movie is a very interesting piece of information that echoes the rumors that have been swirling for months: Ben Affleck will not be portraying the Caped Crusader in Matt Reeves' The Batman. The article explains.
"Matt Reeves' The Batman, for example, is intended to not be connected to the Justice League universe but to be set in a different time period and star another actor."
This is all starting to make sense, but at the same time, what the hell is going on over there? Ben Affleck was seen at Comic-Con telling the world that he would be playing Batman for as long as the studio wanted him to do so. While that was a pretty vague answer, it all makes sense now. Even Casey Affleck's recent brotherly love "joke" concerning his brother and The Batman appears to have been true as well. There has been a whirlwind of craziness surrounding Warner Bros. and DC lately, but now they've thrown an earthquake wrapped in a hurricane nestled in a box of tsunamis at all of us. Have Warners and DC officially jumped the shark?
The new line, or label, whatever DC and Warner Bros. are going to call it is about to make some movies outside of the DCEU timeline and The Batman will be one of those movies alongside the recently announced Joker origin story movie. This leads to a bunch of new questions concerning who will be the new Batman in Reeves' version of the story. Also, will Jeffrey Dean Morgan get a shot at playing the Dark Knight in the recently announced Flashpoint movie? It sure seems that anything is possible at the current time.
DC and Warner Bros. are either geniuses or they're playing fast and loose with some of the most beloved comic book heroes in history. Either way, if you though things were confusing before, they're about to get even more confusing. We could possibly see three new actors portraying Batman in the next few years. Flashpoint Batman, Justice League Batman, and finally the version that we'll see in Matt Reeves' The Batman. For those keeping track, Affleck signed on to direct, write, and star in The Batman and now, one by one, he's fallen off the project entirely. Let the arguments begin.
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Both Sertoli and peritubular cells respond to androgens with increased expression of an androgen response element reporter.
To explore the ability of androgens to affect gene expression in Sertoli and peritubular cells in vitro, constitutively expressed pSV2-Luc and a regulated reporter containing an androgen response element (MMTV-Luc) were transiently transfected into these cells. Reporter expression was markedly affected by cell density and maturational age. Mibolerone-stimulated MMTV-Luc expression increased in Sertoli cells with animal age between 15 and 25 days, consistent with the developmental increase in androgen receptor concentration, but was not markedly age-dependent in peritubular cells. The antiandrogen hydroxyflutamide inhibited stimulation of MMTV-Luc expression by 1 and 10 nM testosterone in both Sertoli and peritubular cells, consistent with an androgen receptor-mediated event. In contrast, dexamethasone at 1 and 10 nM elicited no effect in Sertoli cells, but stimulated MMTV-Luc expression in peritubular cells. In this study, the androgen receptor/glucocorticoid receptor ratio was 2.4 and 0.06 in Sertoli and peritubular cells, respectively. Cotransfection of Sertoli and peritubular cells with a plasmid expressing the rat androgen receptor further increased the androgen-stimulated expression of MMTV-Luc. These data demonstrate the functionality of the androgen receptors in both Sertoli and peritubular cells in culture. Receptor expression appears to be a limiting factor in the response. The data are consistent with potential roles for both Sertoli and peritubular cells in androgen-mediated transcriptional events in the testis.
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Triplet States of Tetrazoles, Nitrenes, and Carbenes from Matrix Photolysis of Tetrazoles, and Phenylcyanamide as a Source of Phenylnitrene.
Photolysis of 1- and 5-aryltetrazoles at 5-10 K using a 266 nm laser immediately generates their triplet excited states, which are characterized by their electron spin resonance (ESR) spectra with zero-field splitting parameters D = 0.12-0.13 cm-1 and E = 0.002-0.008 cm-1. Further photolysis of all of the aryltetrazoles affords arylnitrenes ( D ≅ 1 cm-1), and in the case of 5-aryltetrazoles also arylcarbenes ( D ≅ 0.5 cm-1). The formation of arylnitrenes from 5-aryltetrazoles, where no aryl-N bond is present, is explained by the photochemical rearrangement of initially formed nitrile imines ArCN+N-R to carbodiimides. The monosubstituted carbodiimide PhN═C═NH isomerizes to phenylcyanamide, PhNH-CN, and photolysis of the latter causes rapid elimination of HCN and formation of phenylnitrene. When N-methyl groups are present in the tetrazoles, methylnitrene, CH3-N, is formed too. In the case of 5-phenyltetrazole, additional hydrogen shift and fragmentation afford cyano- and isocyanonitrenes, NCN and CNN.
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James Harold Seley
James Harold "Hal" Seley (April 19, 1906 – September 22, 1994) was an American businessman.
In 1947, when owner Dan Reeves relocated his National Football League Cleveland Rams to Los Angeles, Seley acquired an interest in the team.
In 1957, he established Seley Ranches, a citrus farm in Southern California's Anza-Borrego Valley. Best known for its "Seley Reds" brand of grapefruit, the business remains in family hands.
Thoroughbred horse racing
Hal Seley and his wife owned a stable of Thoroughbred racehorses. Among their successes, their colt Trackmaster won the 1955 California Derby and the 1956 Santa Anita Maturity. They had two horses compete in the Kentucky Derby. Duplicator, who won the California Breeders' Champion Stakes, finished eighth in the 1949 Derby and Trackmaster's son, Field Master, finished thirteenth in the 1967 edition.
References
Seley Ranches
St. Louis Rams history
Category:1906 births
Category:1994 deaths
Category:American orchardists
Category:American racehorse owners and breeders
Category:Los Angeles Rams owners
Category:National Football League owners
Category:20th-century American businesspeople
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Summer sucks. It’s hot, sweaty, stinky, and worst of all, there’s no good hockey news out. Oh, sure, if you’re big on legal shenanigans, you’re probably in heaven: we’ve got the never-ending Kovalchuk saga and the can of worms that could potentially open, Khabibulin’s DUI, the Blackhawks’ cap crunch, Tom Hicks’ financial woes, and if you’re really feeling nostalgic for 2009, some more Phoenix Coyotes ownership malarkey. For those of us who hate the business end of the game, though, it’s been another dreary summer. So, I decided to take some time out and write an article or two about the history of the game, and for my first topic, I naturally picked a subject near and dear to my heart: the Edmonton Oilers. Or at least, that’s what I had intended.
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See, when I started writing this article many weeks ago, I thought it would be interesting to trace back the history of the dynasty Oilers, not so much through the NHL period – everyone knows that story – but in their origins with the World Hockey Association and more specifically, the profound influence of the Winnipeg Jets of the latter half of the 1970s. But as I was writing it up, I kept coming back to not just the specific details of the Jets and their dominance, but the way the WHA did business as a whole, and how it planted the seeds for the way the NHL does business today. Many of the changes wrought in the NHL through the ‘70s, ‘80s, and early ‘90s had their origins in things the WHA did to try to get an edge on the NHL (or later, blackmail them into a merger deal), with the 1980s Oilers being the most prominent symbol of those changes. So, I’ve refocused a bit on the larger story of the World Hockey Association, and how a small, crazy, but determined league, with more dollars than sense (and not that many dollars to begin with) managed to change professional hockey forever.
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The Golden Jet
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The WHA was borne out of the same era that gave us the American Football League and the American Basketball Association, two rebel leagues that changed the faces of their respective sports through the 1960s and early 1970s. In fact, the WHA was founded by some of the same businessmen who had founded the ABA some years earlier, with a similar goal in mind. The problem was, they didn’t know a hell of a lot about hockey, and didn’t have many contacts in the hockey world. Enter “Wild Bill†Hunter, a junior hockey owner in Edmonton who’d made his reputation as an anti-authoritarian by founding the Western Canada Hockey League (now the WHL) in the late ‘60s against the express wishes of the Canadian Amateur Hockey Association, stealing the best teams from Alberta, Saskatchewan, and Manitoba out of their respective provincial junior leagues in order to provide better overall competition for Western teams1. Hunter helped put league brass in touch with a number of other hockey men, many of them NHL expansion rejectees or old buddies from the WCHL, and the WHA was set to drop the puck with a slate of twelve teams in the fall of 1972.
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In the beginning, it was pretty easy to sign players. NHLers and AHLers alike were woefully underpaid compared to their brethren in other sports, thanks to a couple of unfortunate circumstances of that period. One was their weak union, led by the conniving and thieving Alan Eagleson, who posed as the players’ best friend while acting as the NHL’s puppet ruler. The other was to the reserve clause, a restrictive and illegal bit of language that allowed NHL teams to keep their players in perpetuity, and intimidate anyone who got uppity with the threat of being traded to a league also-ran or simply shipped down to the minors. The WHA used this to their advantage, deciding early on that they would not use the reserve clause, and offering two to three times more money than whatever the player had previously been making. For minor leaguers in particular, this was a pretty sweet deal: $12,000 per year in the AHL, or $30,000 in the WHA? Not much of a choice.
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But while the new league had money and ideals, they didn’t have a marquee player, a legitimate star who would lend them instant credibility. After considering and dismissing recently retired Detroit star Gordie Howe – who’d eventually spend six years in the WHA with Houston and New England – they settled on Chicago ’s Bobby Hull, and decided that the Winnipeg Jets, one of the more well-heeled teams in the new league, should sign him. His contract was up in 1972, which was perfectly timed, and he’d recently come off a bitter public feud with Bill Wirtz and the Black Hawks organization over that same deal. The Jets made their first overtures in the fall of 1971, and were greeted with a polite thanks-but-no-thanks. Hull ’s agent was intrigued, though, and kept pushing for a deal. Eventually, Hull said he’d agree to play in Winnipeg for a million dollars – “to get rid of them,†he’d later admit – but despite the absurdity of his demand, the Jets came through. In the summer of ‘72, Bobby Hull became the Golden Jet, the face of the WHA, signing for five years and $2.75M, which included that crazy $1M signing bonus.
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The NHL had not taken the WHA very seriously to this point, and with good reason: the new league had already seen five franchise relocations before a game had even been played, and hadn’t really signed away anyone of consequence. In response, the NHL expanded to Long Island and Atlanta for ’72 and announced plans for more expansion in ’74, to cut off potential expansion sites for the WHA, and also declined the new league’s challenge for the Stanley Cup2. Moreover, there were two WHA teams – the New England Whalers in Boston and the Raiders in New York – challenging long-established NHL teams (and the most recent Stanley Cup finalists) in their own buildings! Little wonder, then, that NHL president Clarence Campbell wasn’t convinced that the newcomers posed a real long-term threat: the whole thing read like a flash in the pan, a bunch of crazy moves to drum up publicity based around an unsustainable financial model. By signing Hull , however, the WHA had crossed the line: they’d not only signed away one of the NHL’s best players, but in the weeks that followed, dozens more NHLers, this time of a somewhat higher calibre than before. Boston , Toronto , Chicago , California , and the expansion Islanders had been particularly hard-hit, and many other teams, most notably the Rangers, had to pay through the nose, relatively speaking, to keep their stars in the fold.
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The NHL’s response this time was swift and predictable: they filed injunctions against Bobby Hull and every NHLer who had followed him. While all the other injunctions were thrown out immediately, the NHL won the one that mattered, against Hull in Chicago , setting up an appeal that would drag into the WHA’s inaugural season. Fortunately for the Jets and the WHA, however, the appeals judge was not terribly impressed by the NHL’s arguments citing the reserve clause: he slammed the NHL’s business practices as monopolistic, conspiratorial, and illegal, struck down the injunction, and made it clear that any future injunctions based on the reserve clause would be stillborn, essentially killing that, too. Of all the crazy moves they made in their early years, it was the WHA’s craziest move of all that changed everything. Not only were Hull and the others to play in the WHA, but the foundation had also been laid for the modern free-agency system, though thanks again to Eagleson and his intentionally toothless NHLPA, true unrestricted free agency didn’t come to the NHL until the 1990s.
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European Invasion
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Of course, the new league may have had Bobby Hull, and later Gordie Howe, but that was really about it. Even the NHLers who followed Hull , capable as they were, weren’t the sort of players that put bums in seats, and there were a lot of has-beens and never-weres in the mix, thanks to those rich contracts to minor-leaguers. Hull was getting frustrated with the lack of help, and was on the verge of retirement. To placate the league’s meal ticket, the Jets made one of the most forward-thinking and unusual moves in hockey to that date: since they weren’t exactly going to be plucking Stan Mikita out of Chicago for Hull to play with, they decided to try their luck overseas3. Through a friend of chief scout Billy Robinson, they got in touch with winger Anders Hedberg and centre Ulf Nilsson, who would join Hull in forming the greatest line in WHA history, the Hot Line. With them came smooth-skating defenceman and future captain Lars-Erik Sjöberg, whose skillset reads not unlike that of Scott Niedermayer.
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When the three Swedes signed in the summer of ’74, they agreed that they would try to influence the Jets towards a more European style of play. This meant much more east-west movement and changing of positions as holes opened up, as opposed to the traditional north-south, stay-in-your-lanes game that the NHL and WHA had played to that point. It was a beautiful, flowing game that would require significant skill, great skating, and above-average hockey sense, but all three could bring it, and most importantly, Hull had been keen to play in that style since before leaving Chicago . After just one practice, the Hot Line was ready to take the league by storm, which is precisely what they did. That first year, Hull set the WHA record at 77 goals, while Nilsson finished second in assists with 94. Granted, the Jets still missed the playoffs in 1975, but it wasn’t due to any failings on the part of their Europeans, who now numbered seven or eight, and included a couple of Finns in addition to the many Swedes they’d recruited. In fact, the Jets found their Canadians to typically be the ones lacking, and turfed some of them in favour of more Swedes!
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As you might expect, the Jets’ European contingent proved to be popular targets, especially the two on the Hull line. Euros were “soft,†and easy to intimidate, so the theory went: scare off the Swedes, lock down Hull , and call it a night. Problem was the Swedes didn’t scare that easily. They took their lumps, played through the abuse, and frustrated their opponents by dominating them, anyway, particularly on the many power plays they earned. From 1975-79, the Jets played in all four Avco Cup Finals, winning three of them; they beat the Soviet Red Army 5-3, two years after the Habs tied them, with the Hot Line outscoring the Kharlamov line 5-04; they even challenged the Canadiens to an exhibition series, which was sadly never played. They were the dynasty of the WHA, and there didn’t seem to be much anyone could do to stop them. WHA veteran Dennis Sobchuk summarizes the experience of “defending†against Hull , Nilsson, and Hedberg:
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“They’d do all these criss-crosses and drop passes, and the puck would just be sitting there between the dots while you took your man to the net. Then you’d look up and see Bobby going a hundred miles an hour with his stick over his head. You’d just close your eyes and you wouldn’t open them until you heard the puck hit the glass or the crowd react to the goal. It was one of the scariest sights you could imagine.â€
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Slats and Gretz
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The nigh-unstoppability of the Jets was a source of frustration for most, but for journeyman winger Glen Sather, in the twilight of his career as captain of the Edmonton Oilers in 1976-77, they were a source of inspiration. Sather saw the magic up close and personal, playing twelve games against the Jets and seeing his team go 4-8 (0-6 in Winnipeg ) and get outscored 72-33, including 61-15 in the eight losses. No, that’s not a typo. He witnessed firsthand how they frustrated defences, and realized that understanding and emulating them would be the key to beating them (or at least staunching the bleeding). So, when head coach Bep Guidolin stepped down late in the season and handed the reins of the team to his captain, Slats immediately changed the game plan. Amazingly, the Oilers, who had gone 11 games under .500 to that point, finished the year 9-7-2 and snuck into a playoff berth on the final weekend of the year. They followed that up with a one-game-below-.500 performance the next season and another low playoff seed. Granted, they got pasted 4-1 in the playoffs both years by league powers Houston and New England , respectively, but it was a step in the right direction, which the fans appreciated, if nothing else. Still, Sather wanted to challenge the Jets, and in order to do that, the Oilers would need a major infusion of talent, which serendipity would provide in 1978.
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To give a bit of background, during the ‘70s, the NHL draft age was 20, meaning that no matter how talented you were, you weren’t making the NHL until at least then. The WHA felt this, too, was an unfair and illegal practice, and eventually got the courts to see their way on this topic, as well.5 After merger talks fell through in 1977 thanks to three of the old-guard owners the WHA had wronged five years earlier – in Toronto, Boston, and Chicago – the rebel league decided to step up the pace on signing kids, reasoning that eventually, the NHL would have to accept a merger, just to gain the rights to those players. Among the players who got their start in the WHA as teenagers were longtime NHLers Ken Linseman, Rick Vaive, Craig Hartsburg, Rob Ramage, and Michel Goulet, as well as future Hall of Famers Mark Messier and Mike Gartner. The biggest prize of all, though, was the 17-year-old kid from Brantford who’d just lit junior hockey on fire, scoring three points per game and setting an OHA record with 70 goals as a 16-year-old in 1977-78, leaving little to prove at that level despite not being draft-eligible until 1981. Wayne Gretzky was ready to turn pro; the only question was, with whom.
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It turns out that it wasn’t originally supposed to be with Edmonton : while he’d later be the perfect cornerstone for Glen Sather’s European-by-way-of-Winnipeg system, he was first courted by the Birmingham Bulls at the 1978 World Juniors, declining then because his father insisted that he finish his junior season. By the time Gretzky came available, the Bulls had no room for him, opening the door for Nelson Skalbania, former Oilers owner and future Flames owner, to sign him as the star attraction of his revitalized Indianapolis Racers, much as Sidney Crosby would be in Pittsburgh more than 25 years later. Unfortunately, Indy didn’t have the hockey history or appetite that the Steel City did, and moreover, the pressure seemed to be getting to the young prodigy, who had failed to impress in his early games. He finally broke out of his slump and showed his phenomenal gifts during a home game against the Oilers, scoring his first two professional goals against Sather’s club that night in a mere eight seconds, no doubt leaving an impression on the young bench boss. When Skalbania decided the experiment was over and started shopping Gretzky to make ends meet, it became a match made in heaven. While the Jets themselves made a competitive offer, they couldn’t afford to match Peter Pocklington’s pure-cash deal6. Gretzky, Peter Driscoll, and Eddie Mio became Oilers for $850,000, giving the Oilers the foundation for a dynasty; Indy, despite the cash infusion, bled out before Christmas.
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Wayne flourished in his new environment, surrounded by veterans who could show him the ropes and support him through his early growing pains, and placed into a system that gave him free reign to take offensive chances when he saw the opportunity. Even at 17, he was making those signature two-moves-ahead plays that left opponents wondering just how he knew a guy would be there, or how he found the back of the net. He finished third in league scoring, won rookie of the year in what one would assume to be a landslide, and then paced the Oilers with 15 points en route to a seven-game victory over the Whalers in the semi-finals. Waiting for them in the Avco Cup Finals was their old nemesis, the Winnipeg Jets, setting up a showdown between master and apprentice. On paper, the Oilers were the superior team, having finished in first place by a double-digit point total while Winnipeg barely managed .5007, but when the teams hit the ice, the result rather resembled that of the initial meeting between Luke Skywalker and Darth Vader: disaster for the upstarts. The Jets had now lost the Hot Line to the NHL and retirement, but found scoring from all over the roster, and were able to hold Gretzky off the scoresheet in the opening set in Edmonton, stealing a 2-0 series lead and all but ending things right there. While the Oilers would win a couple of blowouts, and outscore Winnipeg in the series altogether, it was the Jets who emerged victorious in game six, the last game in WHA history, by a 7-3 tally, with a late and meaningless Dave Semenko goal serving as the league’s last.
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The Legacy of the WHA
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It can be fairly said that the WHA is to some degree responsible for hockey being the high-stakes business it is today. Gretzky and company were a big hit even playing out of remote Edmonton in the ‘80s; having Gretzky in L.A. and Messier et al. in New York in the early ‘90s, though, was a massive coup for the NHL. The former grew the game in non-traditional markets, paving the way for the Pacific and Southeast Divisions to, well, exist, while the latter brought the Cup to the NHL’s biggest media market for the first time since World War II, ending the longest drought in League history. While the lockout and the trap era sapped a lot of the NHL’s momentum from that period, the impact of those moves is unquestionably felt to this day: the WHA itself may have brought hockey to Arizona and Texas 20-plus years before the NHL did, but it was WHA alumnus Wayne Gretzky and his profile in the Sun Belt that made it possible for it to survive. It’s all very ironic, really, coming from a league that lived paycheque to paycheque for much of its existence: WHA history is littered with league cash calls, franchises moving in the middle of the night and folding mid-season, of missed paydays and envelopes of cash being divvied into stipends by coaches on airplanes. Even before all of that, though, the pressure the WHA put on the NHL forced salaries upward, firmly into the six-figure range for high-end players, and the death of the reserve clause made life at least a little easier on players, in terms of free agency, especially during the WHA period, when they had the leverage of another league to play in. Even after that, contract holdouts – which could almost never happen before – were now enough of a weapon that players could finally be well-compensated. The money Bruce McNall gave Gretzky in 1988 probably didn’t hurt that upward trend at all, either.
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The WHA also brought a stylistic change to the game of hockey: the bubble-hockey game of yesteryear was on its way out, thanks in large part to the dominance of the Oilers, and the tendency of others to mimic their successful formula just as surely as the Oilers had imitated the Jets years earlier. Today, the North American and European games have hybridized each other to a degree: while there are still some clear stylistic differences, owing to different rules and rink dimensions, European hockey is much more North American in style than it was 30 years ago, and vice versa. The WHA also pioneered making European players integral to the roster of a North American team: Lars-Erik Sjöberg was the first European captain of a WHA and NHL team with the Jets, and was the first European captain to hoist a North American pro hockey trophy, in the 1976 and 1978 Avco Cups. The 1970s Jets were, at their peak, about half-European and half-North American, well before the Red Wings enjoyed success with the Russian Five in the ‘90s, or their ample complement of Swedes in the 2000s.
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The other underrated impact of the WHA was the reintroduction of the 18-year-old draft. Steve Stamkos scored 51 goals in his 19-year-old season this past year: in the old system, he’d still be in Sarnia . Steve Yzerman scored 176 points his first two seasons, years he would’ve spent in Peterborough otherwise. I could go on down the list of high selections and see guys who’ve made immediate impacts in the NHL who wouldn’t have even been considered prior to 1979. Of lesser note, but still worth mentioning, is that the new Entry Draft – replacing the Amateur Draft of years past – allowed teams to select draft-aged pros. While it was targeted at allowing the NHL to snag 18- and 19-year-olds who had played in the WHA, it also allowed, for example, Boston to choose Sergei Samsonov out of the IHL in 1997.
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Most immediately, though, there are the teams. Unfortunately, Quebec, Winnipeg, and Hartford all wound up finding new homes, as the fall of the dollar and the rise of the large market – as noted above, another indirect WHA legacy – took their toll through the ‘90s, and Edmonton was only saved by some last-minute intervention on the part of a massive number of local businessmen. Then again, former WHA teams account for eight Stanley Cups and eleven Finals appearances since the merger in 1979. Gretzky’s Oilers, of course, went on that legendary run in the ‘80s, while Colorado ( Quebec ) was a League power through the late ‘90s and early 2000s, winning two Cups, and Carolina ( Hartford ) won the first post-lockout Cup, and the first all-WHA Final, against Edmonton in 2006. Former WHA teams have made a tremendous impact on the League, but the funny thing is, none of them might have been there at all if not for Canada ’s love of beer.
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Epilogue: The Beer Boycott
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The WHA always was a little…different. Aside from the perpetual off-ice eye-poking of the NHL, there were a lot of things that happened in the WHA that you’d never have seen in the senior loop: the short-lived blue puck, rat-killing competitions in musty old dressing rooms, players smuggled out of road cities in equipment bags, guys jumping into hotel pools in full gear, drunken fans challenging entire dressing rooms to a brawl (and subsequently being chased down by a dozen half- or fully-naked hockey players, fresh from the showers), and so on. So it’s only appropriate that things ended the way they did.
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Back in 1977, the proposed merger would’ve seen six WHA teams – the four ultimate survivors, plus Cincinnati and Houston – join the NHL intact and play in their own division, slowly integrating with the rest of the League over the course of five years. With the defeat of that merger, and the subsequent collapse of several more teams, the NHL mostly had the WHA over a barrel. Despite their bravado, the WHA was forced to sign the terms of their surrender in 1979: the four surviving clubs would be allowed to protect just two skaters and two goalies, with the rest either reclaimed by their NHL clubs or sent to the draft pool8; the other two teams, Cincinnati and Birmingham, would be paid by the survivors to go away; and the WHA teams selected from the bottom of the draft, instead of the top, as most expansion teams would. Oh, and they each had to pay a $6M expansion fee for the privilege. Great deal.
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Despite the overwhelmingly pro-NHL terms, the hardliners held strong, and defeated the measure by only voting 12-5 in favour, with LA, Boston , and the three Canadian teams in dissent. (One presumes that they didn’t want to lose half of their Hockey Night in Canada royalties to the three new Canadian teams.) That might have been it, but for Canadian beer drinkers. The Montreal Canadiens, then as now, were owned by the Molson family, of Molson Breweries. The people of Edmonton , Winnipeg , and Quebec City started a boycott of Molson products and, in short order, made their message heard: the Habs and Canucks changed their votes, allowing the WHA merger to go through, much to the fury of Maple Leafs owner Harold Ballard (pissing him off was a side benefit of the whole affair). The course of hockey history was changed, and the WHA’s legacy was preserved, all because of beer, which really goes to show that the stereotypes are, to some degree, true: we may love our brews up here, but nothing, not even beer, will come between us and our hockey teams.
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Special thanks to Ed Willes, whose marvelous book The Rebel League: The Short and Unruly Life of the World Hockey Association furnished many of the facts, quotes, and stories in this essay, and Oilers blogger Bruce McCurdy, who held season tickets from 1977-93, and shared his first-hand observations of those late-‘70s and early-‘80s teams with me.
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1 Hunter would take one more opportunity to piss off the Establishment in 1983, when he attempted to buy the St. Louis Blues and move them to Saskatoon . Not surprisingly, the NHL kicked up a fuss and blocked the bid at the end of the season. For more on that situation, including how the Blues missed the 1983 draft because of it, check out this great post on St. Louis Game Time: it’s a story worth reading. Given Hunter’s life and contributions to the sport – the creation of the WHL, the creation of the WHA and the Oilers, and the long-reaching effects of those manoeuvres – it boggles my mind that he’s not in the Hockey Hall of Fame as a builder.
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2 While the challenge format was effectively terminated in 1915, in favour of various pre-arranged interleague (and later, NHL-only) series and tournaments, the Stanley Cup is still technically a challenge trophy. The initial rules set forward by the Trustees of the Cup in 1893 specify that the Cup defaults to the champion of the previous winner’s League, and that any challenges from there would have to come from the champion of another “senior hockey association,†which in the modern understanding, could conceivably have included the WHA. However, the NHL was granted the authority to determine the conditions of Stanley Cup competition and qualification of future challengers in a 1947 agreement with the Trustees of the Cup: because of this, the Trustees have rejected all challenges since its inception, even in 2005, when the NHL wasn’t actually playing for it. In 2006, an Ontario Superior Court judge ruled that, should the same thing happen again, the Cup could be awarded to a non-NHL team.
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3 Of course, this wasn’t an entirely unusual move for the WHA. The Calgary Broncos, before closing up shop and moving to Cleveland , had drafted a large number of Eastern Europeans, including future Summit Series stars Valeri Kharlamov and Alexander Maltsev. The Toronto Toros signed Vaclav Nedomansky out of Czechoslovakia around the same time the Jets went shopping in Scandinavia . Hell, even the NHL was getting in on the act, with the Leafs signing Börje Salming and Inge Hammarström out of Sweden in 1973. Still, the Jets were far and away the most aggressive and successful participants in the first wave of European recruitment.
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4 Strangely enough, the games between WHA teams and international all-star teams counted in the standings during the league’s last couple of years. This was done primarily to make teams and fans alike take the game seriously, rather than treat it as an exhibition, though I suspect it may have been done in part to paper over holes created in the schedule by the numerous franchise collapses in that later period. If nothing else, it gave the hybrid-style teams, Winnipeg and Edmonton , loads of practice against European squads.
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5 I don’t know if this was their intent, but they certainly got this by barring Ken Linseman from playing as an underager in Birmingham in 1977, despite signing away other underagers in prior years; Linseman filed an injunction and won the right to play. If that really was their gambit, it worked out brilliantly.
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6 No truth to the rumour that a game of backgammon actually decided the thing: the Jets offered less money and a stake in the franchise, and with no guarantee of an NHL merger and the Racers losing money at an alarming rate, the Oilers’ up-front cash was the obvious choice. A game was, in fact, offered but ultimately rejected.
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7 A point worth making regarding the matchup is that Sjöberg missed most of the regular season with injury. Certainly, one would think that with their Niedermayer healthy for the whole year, the Jets would’ve finished much better than they did.
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8 The reclamation draft was a disaster for the WHA clubs, with most of the good players from that league being spread throughout the NHL, forcing the WHA teams to pay through the nose in a trade or burn expansion-draft picks in order to keep more than a couple of them. Even when the WHA teams played by the rules, they got screwed: the Oilers initially claimed Wayne Gretzky and Bengt-Åke Gustafsson as their two protected skaters, but lost Gustafsson to the Capitals anyway, and likely only kept Gretzky because he’d signed a 21-year personal services contract with Peter Pocklington directly.
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As It Happened: BJP to hold rallies in favor of land bill
Written By kom nampultig on Sabtu, 04 April 2015 | 08.20
BJP's national executive meeting has begun in Bengaluru today. Among the key issues, BJP plans to make the land bill a people's issue and fight the perception "created by the opposition" that it is 'anti-farmer'.
01:23 PM
BJP to hold nationwide rallies in support of land bill, 1st rally to be held in Ranchi on May 6
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Summary
The FLC gene encodes a MADS box repressor of flowering that is the main cause of the late-flowering phenotype of many Arabidopsis ecotypes. Expression of FLC is repressed by vernalization; maintenance of this repression is associated with the deposition of histone 3 K27 trimethylation (H3K27me3) at the FLC locus. However, whether this increased H3K27me3 is a consequence of reduced FLC transcription or the cause of transcriptional repression is not well defined. In this study we investigate the effect of changes in transcription rate on the abundance of H3K27me3 in the FLC gene body, a chromatin region that includes sequences required to maintain FLC repression following vernalization. We show that H3K27me3 is inversely correlated with transcription across the FLC gene body in a range of ecotypes and mutants with different flowering times. We demonstrate that the FLC gene body becomes marked with H3K27me3 in the absence of transcription. When transcription of the gene body is directed by an inducible promoter, H3K27me3 is removed following activation of transcription and H3K27me3 is added after transcription is decreased. The rate of addition of H3K27me3 to the FLC transgene following inactivation of transcription is similar to that observed in the FLC gene body following vernalization. Our data suggest that reduction of FLC transcription during vernalization leads to an increase of H3K27me3 levels in the FLC gene body that in turn maintains FLC repression.
Figure S3. Kinetics of H3K27me3 addition after vernalization and following decreased transcription of tFLC are similar. H3K27me3 ChIP at amplicon 7 (normalised to FUS3 H3K27me3) plotted against time after removal from dexamethasone for flc-2 pOp6:tFLC plants and time after removal from cold for the endogenous FLC gene in ColFRI. Linear regression lines and R2 co-efficients are shown on the plot.
Table S1. Oligonucleotide sequences. Primer sets 3a and 10a amplify longer (approximately 200 nt) products than 3b and 10b (approximately 100 nt). The ‘a’ and ‘b’ primer sets gave the same relative differences between samples when tested on the same ChIP DNA. Primer sets 5a and 5b amplify at a similar location, 5a gives non-specific products in the absence of the target region in flc-2, but is specific in the presence of FLC, 5b does not amplify from flc-2.
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Please note: Wiley-Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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Marvel at the works of Yasujiro Ozu and Hirokazu Kore-eda in Bangor with Pontio's Tokyo Tales season
MASTERWORKS by two of cinema's most humane auteurs will receive a welcome homecoming to the silver screen in Bangor this week.
A season of 'Tokyo Tales' by Japanese film pioneer Yasujiro Ozu and modern master Hirokazu Kore-eda begins on Thursday, June 13, with four unforgettable films sure to reaffirm Pontio's outstanding reputation for offering the most inspired of international programmes on the North Wales coast.
As Tokyo comes into the spotlight this autumn with the Rugby World cup followed by the 2020 Olympics, this season is the perfect primer to the almost impenetrable megalopolis, as well as the incomprehensibly under-appreciated legacy of Japanese cinema.
Beginning with a welcome return of Kore-eda's triumphant Cannes 2018 Palme d'Or winner Shoplifters - on Thursday at 8.15pm following a first screening earlier this year - the season starts with the perfect opportunity to dip a toe into the deep running waters of this incredible film maker's tenderly felt vision of home and an unconventional, impoverished family unit.
Cinema is famous for being an art form obsessed with innovation, always advancing and looking forward but sometimes great film makers can remind us that we, as people and families, aren’t so easy to update and improve.
This has perhaps never been more definitively stated than in Ozu's towering 1953 film Tokyo Story, a heart wrenching tale of generations and working life regularly voted among the best films ever made which screens on Saturday, June 15 at 8.15pm.
Subtle, sensitive and each a crowning achievement of what cinema can achieve, these movies bookend the rich history of Japan's unique perspective on the human condition.
While it would be grossly understating Kore-eda's darkly comic talent to suggest he is merely updating Ozu's work, the films presented here show how, from the early days of cinema, the passing of time can accentuate rather than eradicate the similarities between people then and people now.
To further present this universal truth, Tokyo Tales will finish with a poetically selected double bill that looks forward into Ozu's utterly singular talent with An Autumn Afternoon on Wednesday 19 at 5.30pm, followed by a look back to Kore-eda's beginnings with his visually stunning 1996 debut Maborosi at 8.15pm.
Any self respecting cinephile simply must take this voyage through one of the richest cultural lineages of the past 100 years.
Tickets for each screening are £7.50, with concessions available. To book visit pontio.co.uk or call the box office on 01248 382828.
This website and associated newspapers adhere to the Independent Press Standards Organisation's Editors' Code of Practice. If you have a complaint about the editorial content which relates to inaccuracy or intrusion, then please contact the editor here. If you are dissatisfied with the response provided you can contact IPSO here
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UNITED STATES OF AMERICA
MERIT SYSTEMS PROTECTION BOARD
JOHN PAUL JONES, III, DOCKET NUMBERS
Appellant, DE-3330-15-0491-I-1
DE-3330-15-0465-I-1
v.
DEPARTMENT OF HEALTH AND
HUMAN SERVICES, DATE: April 6, 2016
Agency.
THIS FINAL ORDER IS NONPRECEDENTIAL ∗
John Paul Jones, III, Albuquerque, New Mexico, pro se.
Jaime I. Espinosa, Esquire, James E. Simpson, and Susan M. Andorfer,
Esquire, Washington, D.C., for the agency.
Robert E. Nerthling, II, Esquire, Atlanta, Georgia, for the agency.
BEFORE
Susan Tsui Grundmann, Chairman
Mark A. Robbins, Member
FINAL ORDER
¶1 The appellant has filed a petition for review of the initial decision, which
denied his request for corrective action under the Veterans Employment
∗
A nonprecedential order is one that the Board has determined does not add
significantly to the body of MSPB case law. Parties may cite nonprecedential orders,
but such orders have no precedential value; the Board and administrative judges are not
required to follow or distinguish them in any future decisions. In contrast, a
precedential decision issued as an Opinion and Order has been identified by the Board
as significantly contributing to the Board’s case law. See 5 C.F.R. § 1201.117(c).
2
Opportunities Act of 1998. Generally, we grant petitions such as this one only
when: the initial decision contains erroneous findings of material fact; the initial
decision is based on an erroneous interpretation of statute or regulation or the
erroneous application of the law to the facts of the case; the administrative
judge’s rulings during either the course of the appeal or the initial decision were
not consistent with required procedures or involved an abuse of discretion, and
the resulting error affected the outcome of the case; or new and material evidence
or legal argument is available that, despite the petitioner’s due diligence, was not
available when the record closed. See title 5 of the Code of Federal Regulations,
section 1201.115 (5 C.F.R. § 1201.115). After fully considering the filings in this
appeal, we conclude that the petitioner has not established any basis under
section 1201.115 for granting the petition for review. Therefore, we DENY the
petition for review and AFFIRM the initial decision, which is now the Board’s
final decision. 5 C.F.R. § 1201.113(b).
NOTICE TO THE APPELLANT REGARDING
YOUR FURTHER REVIEW RIGHTS
You have the right to request review of this final decision by the U.S.
Court of Appeals for the Federal Circuit. You must submit your request to the
court at the following address:
U.S. Court of Appeals
for the Federal Circuit
717 Madison Place, N.W.
Washington, DC 20439
The court must receive your request for review no later than 60 calendar days
after the date of this order. See 5 U.S.C. § 7703(b)(1)(A) (as rev. eff. Dec. 27,
2012). If you choose to file, be very careful to file on time. The court has held
that normally it does not have the authority to waive this statutory deadline and
that filings that do not comply with the deadline must be dismissed. See Pinat v.
Office of Personnel Management, 931 F.2d 1544 (Fed. Cir. 1991).
3
If you need further information about your right to appeal this decision to
court, you should refer to the Federal law that gives you this right. It is found in
title 5 of the U.S. Code, section 7703 (5 U.S.C. § 7703) (as rev. eff. Dec. 27,
2012). You may read this law as well as other sections of the U.S. Code, at our
website, http://www.mspb.gov/appeals/uscode.htm. Additional information is
available at the court’s website, www.cafc.uscourts.gov. Of particular relevance
is the court’s “Guide for Pro Se Petitioners and Appellants,” which is contained
within the court’s Rules of Practice, and Forms 5, 6, and 11.
If you are interested in securing pro bono representation for an appeal to
the U.S. Court of Appeals for the Federal Circuit, you may visit our website at
http://www.mspb.gov/probono for information regarding pro bono representation
for Merit Systems Protection Board appellants before the Federal Circuit. The
Merit Systems Protection Board neither endorses the services provided by any
attorney nor warrants that any attorney will accept representation in a given case.
FOR THE BOARD: ______________________________
William D. Spencer
Clerk of the Board
Washington, D.C.
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Introduction {#s1}
============
Status epilepticus (SE) refers to a seizure that lasts for over 30 min or repeated seizures, without returning to the normal state (Motamedi and Meador, [@B21]). Epilepsy is a paroxysmal neurological disorder, which is accompanied by a number of physiological and neurochemical changes, such as cognitive impairment, astrocyte activation, and neuronal necrosis (Motamedi and Meador, [@B21]; Rodriguez-Alvarez et al., [@B29]). It is reported that multiple interacting factors may affect cognitive function of epileptic patients (Motamedi and Meador, [@B21]). Hippocampus, which plays a key role in learning and memory, is the main region that neurological alterations occur (Rodriguez-Alvarez et al., [@B29]). Previous research demonstrated that neuronal loss and marked gliosis were associated with hippocampal sclerosis in patients with mesial temporal lobe epilepsy (MTLE) (Byeon et al., [@B4]). Pyramidal neuronal loss and degeneration are common in various regions of the hippocampus in a range of animal models of epilepsy (Elsharkawy et al., [@B9]; Pestana et al., [@B25]). Changes in the hippocampus, including reactive gliosis, are reported to be the cause of epilepsy-induced cognitive impairment (Swann, [@B33]; Jansson et al., [@B15]).
Astrocytes are the most common type of glial cells in the central nervous system. Besides providing trophic support for neurons, astrocytes sense brain microenvironment and interact with neurons, thus regulating neuronal function, plasticity, and signaling (de Lanerolle et al., [@B6]). They are thought to be of importance for the homeostasis of neurons (Ricci et al., [@B28]). In epileptic seizures, astrocytes are related to the heightened neuronal excitability and abnormal synchronization of discharge in the neuronal network (Agarwal et al., [@B1]). Astrogliosis is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from disease including neurodegenerative disease (Ricci et al., [@B28]; Peixoto-Santos et al., [@B24]). Astrogliosis is pathological hallmarks of the epileptic brain and thought to contribute to seizure generation in epilepsy (Ricci et al., [@B28]; Peixoto-Santos et al., [@B24]).
The calcineurin inhibitor FK506 is an effective immunosuppressant used in the clinic to prevent the allograft rejection (Malvezzi and Rostaing, [@B19]; Zou et al., [@B38]). It exerts its immunosuppressive action by binding to FK506 binding protein 12 (Wang et al., [@B35]; Vervliet et al., [@B34]). Recent studies demonstrated that FK506 played a role in both neuroprotection and neurotrophy (Kaminska et al., [@B17]; Nito et al., [@B22]). Despite the neuronal protective effect of FK506 observed in experimental cerebral ischemia and seizure models, the mechanism by which FK506 targets neurons remains unclear. It was reported that FK506 may protect neurons by preventing the sprouting of mossy fibers in the hippocampus in kainate-induced seizures (Gant et al., [@B11]).
In our present study, a lithium pilocarpine-induced SE rat model was used to examine the effect of FK506 on cognitive impairment after SE and its role in the modulation of reactive astrogliosis.
Materials and methods {#s2}
=====================
Experimental animals
--------------------
Adult male Wistar rats weighing 250--280 g were purchased from Experimental Animal Center of Shandong University, China. The rats were housed under controlled temperature and light conditions (12 h light; 12 h dark cycle, with lights on at 08:00 a.m.), with free access to food and water. The experimental procedures were approved by the ethics committee of Shandong University and performed in accordance with international standards for experiments on animals.
Pretreatment of animals
-----------------------
The rats were randomly divided into three groups (15 rats in each group, *n* = 45): the control group, the pilocarpine-treated group, and the FK506-treated group. The rats in the control group were injected with a single administration of 0.9% saline, intraperitoneally. The rats in the pilocarpine-treated group received a single administration of 0.9% pilocarpine, intraperitoneally. The rats in the FK506-treated group received an intraperitoneal injection of 2 mg/kg FK506 (Fujisawa, Japan) 24 h prior to the administration of pilocarpine, and another injection of 2 mg/kg FK506 were given 1 h before the administration of pilocarpine. The dose of pilocarpine in the FK506-treated group was the same as that in the pilocarpine-treated group.
Induction of seizures
---------------------
To prevent peripheral cholinergic effects on the central nervous system, lithium chloride (3 mEq/kg, intraperitoneal), which does not cross the blood--brain barrier, was administered 24 h prior to subcutaneous injection (s.c.) of 1 mg/kg scopolamine methyl nitrate, followed by the treatment of pilocarpine for 30 min. All efforts were made to reduce the number of animals used and minimize animal suffering. After 1 h, the rats developed convulsive seizures at stage 4 or 5 according to Racine as follows (Racine, [@B27]): stage 0, no spasm indicated; stage 1, facial myoclonus represented; stage 2, head nodding suggested; stage 3, forelimb clonus represented; stage 4, rearing along with severe forelimb clonus indicated; stage 5, rearing and falling together with severe forelimb clonus. SE was terminated by diazepam (10 mg/kg, intraperitoneal).
Morris water maze test
----------------------
After the induction of SE, the experimental animals put on black belts and were trained in a Morris water maze every day for 7 days to assess their spatial learning and memory abilities. The water maze consisted of a tank filling with opaque powdered milk (0.5--1.5%, 22--25°C). The tank with the diameter of 1.2 m and the height of 0.5 m was separated into four parts (marked as A--D) in the form of clockwise. A hidden rigid platform (12 cm in diameter) was placed 1 cm below the surface of the water in quadrant D. An automated video tracking system (Ethovision 2.0; Noldus, Wageningen, Netherlands) was used for synchronous tracking of the animals\' behavior. The Morris water maze tests included place navigation tests, which examine the ability of the rats to perform a specific location-based task, and spatial probe tests, which examine their ability to retain spatial memory (Pouzet et al., [@B26]). In the place navigation tests, the rats took part in four trials every day for 5 consecutive days. The escape latency (time from start point to reach the hidden platform) was used to assess the learning and memory performance of the rats. The platform is in quadrant D of the tank. The rats were placed in a determined start point and the longest escape latency was 120 s on each trial. The trial was terminated if the rats found a platform or the escape latency is over 120 s. If the rats failed to find the hidden platform within 120 s, they were allowed on the platform for a short time. In the experiment, we mainly selected the performance in the zone where the rat was released at the starting position farthest from the hidden platform was assessed. One day after place navigation tests, the hidden platform was removed. The rats were placed randomly in a determined start point to assess spatial memory. Each rat swam for 120 s. Swimming distance and trace in quadrant D and time spent in quadrant D were recorded to assess the cognitive ability of rats. The swimming speed was also recorded to find out whether the differences between escape latency and swimming distance resulted from different swimming abilities.
Hematoxylin-eosin (HE) staining
-------------------------------
The rats were anesthetized with chloral hydrate (500 mg/kg, i.p.) at 12 d post-seizure and perfused via the left cardiac ventricle with 4% paraformaldehyde in phosphate buffered saline (PBS). The brain was removed and placed in the same fixative at 4°C for at least 24 h. The cerebellum and olfactory bulbs were removed. The first 6 mm of the frontal cerebral hemispheres was removed, and the next 8 mm, which contained the hippocampus, was collected and fixed in paraffin. The brains were placed in a 20% sucrose solution in phosphate buffer at room temperature for 48 h and in a 30% sucrose solution for at least 48 h. The brains were positioned on a freezing microtome stage, cut to a nominal thickness of 10 μm in the horizontal direction, followed by preserving at −20°C. HE staining was performed later. Surviving cells were defined as those with nuclei that were round shaped, with an intact cytoplasmic membrane and no nuclear condensation or distortion. Live pyramidal cells distributed in the area of hippocampal CA3 were observed using high magnification (×400).
Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay
--------------------------------------------------------------------------
The One Step TUNEL Apoptosis Assay Kit (Beyotime Institute of Biotechnology, China) was used to detect the neuronal apoptosis. Continuous brain sections were dewaxed, hydrated, and incubated with proteinase K solution (20 μg/mL, without DNase) for 25 min at 37°C. Then, the sections were washed in PBS three times, 5 min each time. Next, DNA fragments were labeled by incubation with 50 μl TUNEL detection solution for 1 h at 37°C in a humidified chamber. The reaction was terminated by 2 × SSC termination solvent provided in the kit. After washed in PBS three times, the sections were mounted with anti-fluorescence quenching agent and examined under the fluorescence microscope.
Immunohistochemistry
--------------------
The 10-μm thick coronal sections were incubated with 3% H~2~O~2~ for 5 min to inhibit endogenous peroxidase activity and then rinsed in PBS for 5 min, followed by incubation with primary anti-glial fibrillary acidic protein (GFAP) antibody (Abcam, USA) diluted by 1:200 (glial fibrillary acidic protein) at 4°C overnight. Following incubation with species-specific biotinylated secondary antibody, the sections were incubated with peroxidase-labeled streptavidin, and the color was developed with diaminobenzene (Brusco et al., [@B3]). Finally, the sections were counterstained with hematoxylin. Negative controls were processed simultaneously by omitting the primary antibodies.
Western blot
------------
The dissected hippocampus tissues were washed with cold PBS, lysed in SDS lysis buffer and separated by SDS-PAGE. Then, the proteins were transferred to polyvinylidene difluoride membrane and immunoblotted with anti-GFAP primary antibody and horseradish peroxidase-conjugated secondary antibodies (all from Cell Signaling Technology, USA). Finally, detection was performed using the enhanced chemiluminescence reagents (Plus-ECL, PerkinElmer, MA, USA). β-actin was used as a control. The ImageJ software was used for the quantification of the bands.
Statistical analysis
--------------------
Statistical analyses were performed using SPSS version 19.0 (SPSS Inc., Chicago). The data were presented as the mean ± standard deviation (SD). Differences between two groups were determined using the *t*-Test. Differences among more than two groups were evaluated by one-way analysis of variance (ANOVA) followed by a Newman--Keuls *post-hoc* test. Chi-square test was applied to analyze the amount of subjects in stage 4 and 5 seizures. Differences were considered statistically significant at a *P* \< 0.05.
Results {#s3}
=======
FK506 ameliorated the course of pilocarpine-induced epilepsy
------------------------------------------------------------
Behavioral episodes induced by pilocarpine injections showed typical increases in their intensity and duration, gradually progressing toward SE. Compared with the pilocarpine-treated group, the FK506-treated group exhibited a longer latency period and a smaller percentage at stage V (Table [1](#T1){ref-type="table"}). Control animals did not exhibit any behavioral seizure activity.
######
Behavioral episodes of lithium-pilocarpine-induced status epilepticus rats after FK506 treatment.
**Groups** **Numbers** **The latency period to reaching stage IV--V ($\overline{x}$± s)** **The percentage of animals reaching stage IV (%)** **The percentage of animals reaching stage V (%)**
------------------- ------------- -------------------------------------------------------------------- ----------------------------------------------------- ----------------------------------------------------
Pilocarpine group 54 47.4 ± 9.1 42.6 57.4
FK506 group 54 67.5 ± 9.7[^\*^](#TN1){ref-type="table-fn"} 74.1[^\*^](#TN1){ref-type="table-fn"} 25.9[^\*^](#TN1){ref-type="table-fn"}
*The data are the mean ± SD*.
*p \< 0.05 vs. pilocarpine group*.
FK506 ameliorated the neuronal loss in the hippocampus after SE
---------------------------------------------------------------
HE staining was used to detect neuronal changes in the hippocampus. The results showed that dead neurons with pyknotic nuclei were mainly located at hippocampal CA3 zone. Different from dead neurons, the live cells have round and palely stained nuclei. Compared to the control group, the pilocarpine-treated group had fewer surviving cells. However, when FK506 was given before pilocarpine injection, more neurons survived after SE (Figure [1A](#F1){ref-type="fig"}). The results from TUNEL staining also showed that the number of apoptotic neurons in pilocarpine-treated group was higher than that in control group. FK506 treatment could decrease the number of apoptotic neurons after seizures (Figure [1B](#F1){ref-type="fig"}).
{#F1}
FK506 improved the learning and memory ability after SE
-------------------------------------------------------
As shown by the results obtained in the Morris water maze test, the FK506 treatment improved the learning and memory ability of the rats. In the place navigation tests, the escape latency was significantly prolonged in the pilocarpine-treated group compared to the control group. In contrast, the prolonged latency was significantly reduced in the FK506-treated group (Figure [2A](#F2){ref-type="fig"}). As shown in Figure [2B](#F2){ref-type="fig"}, in the spatial probe tests, there were no significant differences in the swimming speeds of the rats between the indicated groups. Compared with the control group, the swimming distance in target zone was significantly decreased in the pilocarpine-treated group, while the swimming distance of the FK506-treated rats in the target zone was longer than that of the pilocarpine-treated rats (Figure [2C](#F2){ref-type="fig"}). Consistently, the rats in the FK506-treated group spent more time in the target zone and made more crossings to the position of the former platform than pilocarpine-treated group (Figures [2D,E](#F2){ref-type="fig"}).
{#F2}
FK506 attenuated the GFAP expression and reactive astrogliosis after SE
-----------------------------------------------------------------------
GFAP, a cytoskeletal protein present in astroglial somata and projections, is used as a specific immunomarker of astrocytes. The immunohistochemistry analysis revealed that GFAP was expressed in cells 72 h after SE and that the number of GFAP-labeled cells increased 7 d after SE. As shown in Figure [3A](#F3){ref-type="fig"}, the GFAP expression was significantly increased in the pilocarpine-treated group compared with the control group, while the GFAP expression significantly decreased in the FK506-treated group when compared with the pilocarpine-treated group. Consistent with immunostaining data, the results from western blot showed that FK506 remarkably inhibited the increase of GFAP protein expression level after SE (Figure [3B](#F3){ref-type="fig"}). These results suggested that FK506 could significantly attenuate SE-induced reactive astrogliosis.
{#F3}
Discussion {#s4}
==========
So far the pathogenesis and treatment of SE still need to be studied more. In this study, the results showed that FK506 treatment could ameliorate the course of pilocarpine-induced epilepsy, ameliorate the neuronal loss in the hippocampus and improved learning and memory ability. Furthermore, the FK506 treatment attenuated the reactive astrogliosis in the hippocampus after SE. These data suggest a protective role of FK506 in cognitive impairment after SE and this protective effect may be achieved by inhibiting the reactive astrogliosis.
Many factors contribute to epileptogenesis. Recently, prof. Heinemann and his colleagues proposed a "cholinergic hypothesis of temporal lobe epilepsy (TLE)" (Friedman et al., [@B10]). They thought that cholinergic innervation played a key role in the normal control of neuronal excitability and in higher cognitive processes (Friedman et al., [@B10]). The changes in the expression of key cholinergic proteins and the associated cholinergic dysfunction are key factors in the basic mechanisms underlying TLE (Friedman et al., [@B10]). Here, we used the muscarinic agonist pilocarpine to develop a rat model of status epileptic. Status epileptic is characterized by considerable cell loss in some regions of the brain. Cognitive impairment in epilepsy has been attributed to neuronal loss, glial growth, and hippocampal circuit dysfunction at higher seizure frequencies (Jung et al., [@B16]). This study showed that the pilocarpine-treated rats had more apoptotic neurons than the normal control group and the neuron loss was mainly located in the hippocampal CA3 zone. Meanwhile, the results obtained in the Morris water maze test demonstrated that the learning and memory ability of the pilocarpine-treated rats was reduced when compared with that of the control rats. All these results suggested that SE induced cognitive impairment.
Besides the cholinergic hypothesis, Recent findings from several laboratories suggested an astrocytic basis for epilepsy (Seifert et al., [@B31]). Astrogliosis is a pathological hallmark of an epileptic brain. It may contribute to seizure generation in epilepsy (Binder and Steinhäuser, [@B2]; Haydon and Carmignoto, [@B12]) and subsequent recurrent spontaneous seizures (Miller, [@B20]). Researchers demonstrated that astrocytes could impair the homeostatic control of network excitability and abnormal discharge synchronization in epilepsy. Multiple underlying mechanisms are proposed, such as impaired spatial K+ buffering (Hinterkeuser et al., [@B13]), dysfunctional glutamate homeostasis (Eid et al., [@B8]), dysfunctional gap junctions (Rouach et al., [@B30]), and changes in calcium buffering and gliotransmitter release (Pascual et al., [@B23]). Thus, under epileptic conditions, astrocytes do not seem to be neuro-supportive (de Lanerolle et al., [@B6]). Instead, seizures-induced activation of astrocytes could release pro-inflammatory cytokines and free radicals, both of which accelerate neuron loss (de Lanerolle et al., [@B6]). In addition, the loss of neurons, growth of glial, and hippocampal circuit dysfunction lead to the impairment of cognition in epilepsy (Byeon et al., [@B4]; Gant et al., [@B11]). So it suggests the possibility of a role of astrocyte activation played in epileptogenesis and cognitive impairment in epilepsy. In the present study, the expression level of GFAP, an indicator of astrocytes, started to rise at 72 h after SE and increased remarkably at 7 days after SE. Meanwhile, the GFAP expression was significantly increased in the pilocarpine-treated group compared with the control group. These findings suggest that SE induced reactive astrogliosis, which was consistent with the previous studies (Damaye et al., [@B5]; Hong et al., [@B14]; Li et al., [@B18]; Sherafat et al., [@B32]). However, further studies are required to explore the exact role of astrocyte activation in cognitive impairment associated with SE.
As muscarinic receptor activation could increase intracellular Ca^2+^ (Egorov and Müller, [@B7]), the calcineurin inhibitor FK506 may be useful in the treatment of pilocarpine-induced epilepsy. Many studies suggested a role of FK506 in neuroprotection. In a rat model of middle cerebral artery occlusion, an intravenous injection of FK506 1 min after vascular occlusion reduced cortical lesions by 60--70% (Nito et al., [@B22]). In addition, FK506 exerted a neuroprotective effect in ischemia (Ricci et al., [@B28]; Gant et al., [@B11]; Malvezzi and Rostaing, [@B19]; Peixoto-Santos et al., [@B24]; Zou et al., [@B38]). FK506 protected hippocampal neurons from forebrain ischemia in the Mongolian gerbil (Nito et al., [@B22]). FK506 also prevented mossy fibers generation in the hippocampus and stimulation-induced epileptogenesis (Gant et al., [@B11]). In the present study, we observed that FK506 increased the latency period to seizures and decreased the maximal intensity of seizures. FK506 treatment could also greatly decrease the number of apoptotic neurons after seizures. In addition, FK506 reduced the escape latency and prolong the swimming distance in the Morris water maze test. Thus, we concluded that FK506 could improve impaired cognition after pilocarpine-induced SE in rats. On the other hand, we found that the FK506 treatment lessened the activation of astrocyte in the rats\' hippocampus after SE. In addition, FK506 treatment could markedly decrease the GFAP level, suggesting that FK506 attenuated reactive astrogliosis, which is in agreement with previous reports (Zawadzka and Kaminska, [@B37]; Yoshiyama et al., [@B36]). As FK506 is an immunosuppression, the risk of FK506 should be assessed in the further research.
In summary, the present study suggested that treatment with FK506 might improve cognitive impairment by preventing astrocyte activation after SE, suggesting that FK506 may be a promising agent for treatment of SE-induced cognitive impairment.
Author contributions {#s5}
====================
JL: performed the study, wrote the manuscript, and participated in designing of the study; ZS: performed the study and participated in writing the manuscript; SL: helped to perform the study and collected the data; ZH: collected the data and analyzed the data; YH and TZ: helped to perform the study; AW: conceived and designed the research; All authors read and approved the final 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.** This study was supported by grants from the Science and Technology Development Plan of Shandong Province, China (No. 2011GGB14095), the Medicine and Health Science Technology Development Program of Shandong Province, China (No. 2011HD009), the Traditional Chinese Medicine Science and Technology Development Program of Shandong Province, China (2011-194, 2017-163), and the Natural Science Foundation of Shandong Province, China (No. Y2007C168, No. ZR2011HL020, No. ZR2012HL28, No. ZR2015HL120, and No. ZR2016HP23).
[^1]: Edited by: Antonio Gambardella, Magna Græcia University, Italy
[^2]: Reviewed by: Hermona Soreq, Hebrew University of Jerusalem, Israel; Gourav Roy Choudhury, Texas Biomedical Research Institute, United States
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Animal models are used for the evaluation of acellular pertussis vaccine components before use in clinical trials and administration to humans. The aerosol challenge model provides a reproducible system for the study of virulence factors in immunity involved in respiratory infection and subsequent disease. We are evaluating purified antigens of B. pertussis for their ability to protect neonatal mice against lethal respiratory infection. Active immunization with the B oligomer of pertussis toxin, as well as with a genetically engineered non-toxic mutant of pertussis toxin elicits specific antibody in the serum and lungs of mice and protects neonatal mice against lethal respiratory infection. Monoclonal antibodies directed against the lipooligosaccharide of B. pertussis outer membrane protein protects against leukocytosis and death, as well as decreased bacterial infection when passively administered. Current studies are in progress to evaluate additional soluble and membrane-associated proteins protective ability and antigenicity.
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Tag: rabbit DNA
God’s Press Secretary announced yesterday what people have long feared—Michelle Duggar, Arkansas mother of 19, is a genetic monstrosity.
“Basically, we fucked up,” he said.
Duggar is the result of a whimsical experiment wherein God and his Creation Team spliced rabbit DNA into human DNA to potentially increase human reproduction.
“The first women we tried didn’t work very well,” reports the Archangel Gabriel, Head of Creation. “They just had big ears and buck teeth. The second batch had puffball tails and an insatiable sex drive, but were excessively twitchy and ate their weight in carrots every day.”
The Creation Team thought they’d achieved the perfect blend with Duggar. Born completely human in appearance, upon sexual maturity, she was found to be exceptionally fertile. She also possessed a pleasant docility, a vacuous stare and a seemingly endless capacity for indoctrination.
“At first, we were really pleased with the results,” says Gabriel, “but after she started homeschooling the offspring, we realized our experiment was misguided.” By then, says Gabriel, the damage couldn’t be reversed. To date, their experiment-gone-awry has resulted in twenty-two additional very fertile Independent Arkansan Baptists and a brain-numbingly horrible reality television show. God’s Press Secretary has issued a formal apology for these abominations.
God himself was reluctant to speak to reporters, but a source quoted him as grumbling, “What number are we on? Eighteen? Twenty-two? I mean, fuck.”
Michelle Duggar could not be reached for comment because a tiny Baptist was falling out of her vagina.
Out of all the gifts and donations received by the Duggars, strangely, none of them were these.
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Hong Kong Chief Executive CY Leung not to seek re-election
Chief Executive Leung Chun-ying has made a surprise announcement that he will not seek re-election due to family reasons.
“If I run my family will suffer an intolerable stress due to my electioneering,” he told a press briefing, which is still ongoing.
Leung had repeatedly told media “there was no message” yet when asked whether he would seek a second term in March.
During a trip to an Asia-Pacific Economic Cooperation meeting in Peru last month, Leung told the media that President Xi Jinping had approved of his work in office, but Leung later said people should not “over-interpret” the remarks as being any endorsement of further political ambitions.
On Thursday night, he was seen at Prince of Wales Hospital in Sha Tin, where his elder daughter Leung Chai-yan was rumoured to be receiving treatment.
Leung assumed office as Hong Kong’s fourth chief executive in 2012, succeeding Donald Tsang Yam-kuen. Leung was a member of te Executive Council from 1997 to 2011, prior to taking over the top spot.
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Image copyright Getty Images
There has been a remarkable global decline in the number of children women are having, say researchers.
Their report found fertility rate falls meant nearly half of countries were now facing a "baby bust" - meaning there are insufficient children to maintain their population size.
The researchers said the findings were a "huge surprise".
And there would be profound consequences for societies with "more grandparents than grandchildren".
How big has the fall been?
The study, published in the Lancet, followed trends in every country from 1950 to 2017.
In 1950, women were having an average of 4.7 children in their lifetime. The fertility rate all but halved to 2.4 children per woman by last year.
But that masks huge variation between nations.
The fertility rate in Niger, west Africa, is 7.1, but in the Mediterranean island of Cyprus women are having one child, on average.
In the UK, the rate is 1.7, similar to most Western European countries.
How high does the fertility rate have to be?
The total fertility rate is the average number of children a woman gives birth to in their lifetime (it's different to the birth rate which is the number of children born per thousand people each year).
Whenever a country's rate drops below approximately 2.1 then populations will eventually start to shrink (this "baby bust" figure is significantly higher in countries which have high rates of death in childhood).
At the start of the study, in 1950, there were zero nations in this position.
Prof Christopher Murray, the director of the Institute for Health Metrics and Evaluation at the University of Washington, told the BBC: "We've reached this watershed where half of countries have fertility rates below the replacement level, so if nothing happens the populations will decline in those countries.
"It's a remarkable transition.
"It's a surprise even to people like myself, the idea that it's half the countries in the world will be a huge surprise to people."
Which countries are affected?
More economically developed countries including most of Europe, the US, South Korea and Australia have lower fertility rates.
It does not mean the number of people living in these countries is falling, at least not yet as the size of a population is a mix of the fertility rate, death rate and migration.
It can also take a generation for changes in fertility rate to take hold.
But Prof Murray said: "We will soon be transitioning to a point where societies are grappling with a declining population."
Half the world's nations are still producing enough children to grow, but as more countries advance economically, more will have lower fertility rates.
'We'd rather give our daughter the best of everything'
Rachael Jacobs, 38, of Kent, had her first and only child seven years ago
I'd always focused on my career. When I was pregnant I was still focusing on my career.
I know now that we can survive on what we earn as a family and still go on holiday every year. If we had more than one child we couldn't go on holiday.
We'd rather give our daughter the best of everything than have multiple children that we can just about feed and clothe.
My partner and I are also thinking about the future. We want to be in a position where we can help her financially with university or housing. I don't want to ever have to say that she can't go to a party or have a new Christmas jumper.
Why is the fertility rate falling?
The fall in fertility rate is not down to sperm counts or any of the things that normally come to mind when thinking of fertility.
Instead it is being put down to three key factors:
Fewer deaths in childhood meaning women have fewer babies
Greater access to contraception
More women in education and work
In many ways, falling fertility rates are a success story.
What will the impact be?
Without migration, countries will face ageing and shrinking populations.
Dr George Leeson, director of the Oxford Institute of Population Ageing, says that does not have to be a bad thing, as long as the whole of society adjusts to the massive demographic change.
He told the BBC: "Demography impacts on every single aspect of our lives, just look out of your window at the people on the streets, the houses, the traffic, the consumption, it is all driven by demography.
"Everything we plan for is not just driven by the numbers in the population, but also the age structure and that is changing, so fundamentally we haven't got our heads around it."
He thinks workplaces are going to have to change and even the idea of retiring at 68, the current maximum in the UK, will be unsustainable.
The report, part of the Global Burden of Diseases analysis, says affected countries will need to consider increasing immigration, which can create its own problems, or introducing policies to encourage women to have more children, which often fail.
Report author Prof Murray argues: "On current trends there will be very few children and lots of people over the age of 65 and that's very difficult to sustain global society.
"Think of all the profound social and economic consequences of a society structured like that with more grandparents than grandchildren.
"I think Japan is very aware of this, they're facing declining populations, but I don't think it's hit many countries in the West, because low fertility has been compensated with migration.
"At a global level there is no migration solution," Prof Murray says.
But while the change may challenge societies, it may also have environmental benefits given the impact of our species.
What about China?
China has seen huge population growth since 1950, going from around half a billion inhabitants to 1.4 billion.
But it too is facing the challenge of fertility rates, which stood at only 1.5 in 2017, and has recently moved away from its famous one child policy.
The reason developed countries need a fertility rate of 2.1 is because not all children survive to adulthood and babies are ever so slightly more likely to be male than female.
But in China, the report shows for every 100 girls born there were 117 boys which "imply very substantial sex-selective abortion and even the possibility of female infanticide".
That means even more children need to be born to have a stable population.
Follow James on Twitter.
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This dissertation fits in the realm of the emerging scientific area named Experimental Software Engineering.
We propose and advocate the use of quantitative methods in Software Engineering where, traditionally,
qualitative-based approaches have been the rule. The quantitative emphasis has the objective aim of expressing
and assessing Software Quality.
The quantitative approaches p roposed herein are instantiated in the scope of the object-oriented paradigm and
targeted to the product quality. We formalize a set of software complexity metrics named MOOD (Metrics for
Object-oriented Design). These metrics, expressed with a formal specification language, OCL (Object
Constraint Language), are evaluated against several validation criteria, as those of Measurement Theory, and
are compared with other proposals in the literature. We demonstrate experimentally that is it possible to use
those metrics as explicative variables of software quality characteristics, such as reliability or maintainability.
To facilitate the construction of a versatile computational support to collect the design metrics, as required to
validate experimentally the hypothesis formulated herein, we have conceived a textual language to express
object-oriented designs, named GOODLY (a Generic Object-oriented Design Language? Yes!). This language is
used as an intermediate formalism in the MOODKit tool, whose architecture we present.
We approach the problem of software system modularization according to structural criteria, that is, guided by
cohesion and coupling among classes. We demonstrate that besides being possible to assess quantitatively the
modularity of a given system, we are able to suggest solutions that optimize it, given the adopted criteria. We
have verified experimentally that systems produced in several application domains are far from coping with the
desiderata of structural modularization as proclaimed in the Software Engineering literature.
To support the comparison, assessment and generation of optimized modularization architectures, we have
developed another tool named MOTTO (MOdularity Trial Tool for Object-oriented systems) that receives data
from MOODKit and interoperates with a statistical analysis tool to achieve the required purposes.
The most important outcome of this thesis is the proof of practicability of quantitative analysis applied to
software systems built according to the object-oriented paradigm. Several quantitative techniques originating
from Applied Statistics such as Multivariate Estimation and Cluster Analysis, as well as several types of
adherence and independence tests are applied. These techniques are commonly used in many fields of Science,
but their potential has not yet been fully realized by software engineers.
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Farlander wrote:id like to be a beta tester for this project especially since it's in glørous 2D been watching the project for a while, and figured that it would be fun to be a beta tester for it
Hi Farlander, welcome to the forums. I'll add you to the list, the next beta test round will start in a week or two hopefully. I'll contact everyone on these forums when it is ready, so keep a lookout.
YoungEnigma wrote:Oooh! I'd love to beta test this game! I've been watching it for a month or so, and I love 2D dogfighting games!
Hi YoungEnigma, I've added you to the beta testers groups. Please follow in the install instructions in the new Beta Testers forum you'll have access to (scroll all the way to the bottom). Look forward to hearing your feedback!
Hello everybody !I'd really love to be a bêta-tester of this game !Why ? Because I was looking for a game like this during a long time, and this one looks like to be THE 2D flight sim' I was looking for !Please accept me in the beta-testers !
Hello !I am interessed for beta-testing this game ! It looks awesome, and it is exactly the game I was looking for, during a long time ! A 2d realistic flight simulation game ! Yeah it looks really great.please accept me !
P.S. Sorry for my bad EnglishP.P.S. I don't know if I had already posted this message, but I sent an other message, and it is not dispayed on the forum...
Thanks mozillaf8. After quite a long time of relative inactivity, I'm managing to find time to work on this project again, hopefully I'll be able to release the initial WW1 game very soon. Please keep an eye on this forum to find out when.
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Support WGBH
Arts Ahead: Shadows, Pops and Merry Poppers
Olive Another as Maryand in the lastet production from Gold Dust Orphans.
BOSTON — Traditions take new and wild turns as a band of theater renegades reinterpret Mary Poppins, Tim Burton drops a vampire into 20th century Maine and the Boston Pops celebrate America's diverse music history with Steve Martin on banjo. Mary Poppers
Presented by the Gold Dust Orphans
At Machine (in the Fenway) through May 20th
Gold Dust Orphans give us another rollicking ride through the twisted imaginations of Boston's foremost comedic troupe with the musical parody they have been waiting a lifetime to present. "Mary Poppers" features Olive Another as Maryand other Orphan favorites: Ryan Landry, Penny Champayne, Bill Hough, Robin Banks and Delta Miles. The troupe is at their best with this show, which is fun and hits the heights of Orphan outrageousness.
Director Tim Burton's latest movie is a revival of the 1960s cult television classic, “Dark Shadows”.
In 1752 an family with a young son set sail to the new world to escape the mysterious curse that has plagued their family and they settle in Collinsport, Maine. Decades later, as the master of Collinwood Manor, the son, Barnabas, is rich, powerful and an inveterate playboy…until he makes the grave mistake of breaking the heart of Angelique Bouchard (Eva Green). A witch, in every sense of the word, Angelique dooms him to a fate worse than death: turning him into a vampire, and then burying him alive. Two centuries later, Barnabas is inadvertently freed from his tomb and emerges into the very changed world of 1972. He returns to Collinwood Manor to find that his once-grand estate has fallen into ruin and plenty of chaos ensues.
Burton has created a gothic comedy with an all-star cast, led by Johnny Depp, Michelle Pfeiffer and Helena Bonham Carter. It's delicious from start to finish
The Boston Pops led by conductor Keith Lockhart kicked off the 2012 season, “Visions of America”, with a gala opening night performance featuring Tony Award-winning icon Bernadette Peters. Celebrating the American musical traditions that weave together the imagination and spirit of our diverse nation, this season will feature the striking images of photo historian Joseph Sohm and his extraordinary photographs representing all 50 states. The season theme will culminate with the photos in a multi-media project, enhanced by the recorded narration of Clint Eastwood and featuring acclaimed vocalist Patti Austin.
During the 2012 spring season, catch comedian, author and musician Steve Martin and The Steep Canyon Rangers; John Williams will celebrates his 80th birthday by leading the Film Night; conductor Charles Floyd and the Boston Pops Gospel Choir give their 20th annual performance with American Idol’s Melinda Doolittle and gospel singer Crystal Aitkin and finally, don't miss a sports night complete with Fenway Franks as a special tribute to the 100th anniversary of Fenway Park.
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"Right, lads, we're going for 450 today." "Good thing, I could use the money." "Really, Jimmy?" "Tell me this, where does all that money go to?" "Down my neck." "What are you laughing at?" "Nothing." "Good." "Fill up that barrel and I'll show you how it's done." "How's the baby, Arthur?" "Aye, he's happy enough when he's fed." "He's a keeper!" "He's certainly a bawler." "Takes after his father, then..." "always complaining." "Is that right?" "Look who's talkin'!" "Alright, lads, let's get to it." "Yes, Mr McCann, sir!" "Good morning." "Good morning, sir." "I need someone to draw something for me." "Would you be free?" "Can I help you, Doctor Muir?" "Yes." "I need some drawings done in my lab." "I've asked Miss Silvestri to assist me." "I'm sure that can be arranged." "Great." "One hour." "Fine." "There's been a lock-out at Stokes Yard!" "Did yous hear that?" "Lads, there's a lock-out at Stokes Yard." "Stokes Yard must have locked out the union men." "Did you hear that, boys?" "Let's go." "What do we need them for?" "Confetti, son." "Belfast confetti." "You'll see." "Oi, you lot, get back to work!" "Keep going, boys!" "To the gates!" "Traitors, you're taking our jobs!" "Come on, lads!" "What are you doing?" "Traitors!" "You filthy scabs!" "I TOLD YOU TO CALM!" "LAY DOWN YOUR ARMS!" "It is NOT the men behind these gates who are your foe!" "Walk through these gates for justice and freedom." "You men... ..I know your minds." "I know what desperation, what needs, what false promises brought you here!" "But I say to you - lay down your tools." "They are the instruments of Judas." "There is no prize SO high that can merit the betrayal of your brothers!" "Lay down your tools and join our struggle." "Join us!" "Join us!" "Join us!" "Join us!" "Join us!" "Join us!" "Join us!" "Join us!" "Join us!" "Join us!" "Join us!" "Join us!" "Join us!" "About 300 men left their posts all in all." "Then send a message, Pirrie." "Gentlemen, I am under contract." "I can't afford long delays due either to mass firings or industrial action." "No, Pirrie, YOU have to show a strong hand." "I'll tell you what I'm doing - bolting the door to my coal yard." "And do you think that will help the situation?" "Well, no union man will cross my threshold." "Let them stay out 'til their bellies are empty and their wills are broken." "I'm afraid we can't afford that luxury, even if I were minded to do it!" "And there's a wider principle." "The time, perhaps, has come to realise that the working man will not always remain supine." "And if we provoke him..." "'Provoke him'?" "What are you talking about?" "I'm talking about locking him out of his place of work." "'His' place of work?" "I own that yard." "Hundreds went out, they say, Pitched battle." "Is Michael alright?" "Yes." "And Walter?" "Yes." "Seems to be." "Thank you for coming." "You alright?" "Yes, I'm fine." "Why shouldn't I be?" "Um, there's just...a lot of mayhem out there today." "Yeah." "It doesn't affect management, does it?" "No, I..." "I guess it doesn't." "At least it's all calm out there for now." "Yes." "Everyone back in their place." "That's not what I meant." "Um, I've nothing against a man making a stand." "Really?" "Would you like to have a look?" "Oh." "Mmm." "Come on." "Yes, um..." "Look down in there." "Here?" "Mmm-hmm." "Like this?" "May I?" "Oh!" "Do you see the image reflected in the glass?" "Yes." "What is it?" "Ferrite, pearlite and inclusions." "Oh!" "But what are they?" "Impurities, Miss Silvestri, in the steel." "And, and your job is to get rid of them?" "No, my job is to make the best of an imperfect substance." "Oh right." "I'll draw it so you can make the best of all our imperfections!" "Right, I'll leave you to it." "It was a good day." "We shouldn't assume it's a victory." "Just the first shots fired in a long war." "Now!" "I don't think anybody's talking about victory." "Not yet." "If the management want a war, that's what we should give them." "As long as there's lock-outs, use of scab labour, no injury compensation, we have to fight." "Do you mean a strike?" "Certainly that." "Withdrawal of labour is the chief weapon of the working man." "It's our strongest tool." "If there's gonna be strikes, we need to tighten our belts." "We're used to being hungry." "They're not." "I don't know how many men we'll get out at the yard." " Most of us have a pride in what we're building." " Then use it." "Use the symbol of that ship as YOUR power, not the management's." "Make Titanic YOUR issue, not theirs." "Remember our brothers in Russia." "It was on the battleship Potemkin that the movement arose." "This ship, this could be the site of your battle." "No plans for tonight, then, Doctor Muir?" "No." "Not for me." "Do you mind if I sit with you?" "Oh, please." "My husband told me about what happened at Stokes coal yard today." "Albert says there's Catholics at the base of all the trouble." "Is that what you think, Mrs Hatton?" "I really don't know about politics." "It's sad, though... ..in a way." "Isn't it?" "Yes." "All this strife." "Quite sad." "It must seem a little strange..." "if you're from the mainland." "Yeah." "Quite different from the mainland." "Do you think we're all mad?" "No, I don't." "To be honest, Doctor Muir... ..I sometimes think we are." "I've conducted examinations on the latest batch of steel plates and I believe there are serious grounds for concern." "I've tested the tensile strengths of the steel you use, and, as you can see, the steel cracks under quite modest stresses." "I have to tell you, Muir, this steel is sourced from a very reliable supplier." "That as it may be, it contains far too many impurities." "It's dangerously brittle." "'Dangerously?" "'" "Yes." "This is a very serious claim." "Yes, I'm aware." "Alright." "I'll take this matter up with Lord Pirrie and deal with it in due course." "And when will that be?" "This will be done as soon as I can." "Why don't I bring them now?" "Because I said this will be done as soon as possible." "I will decide when." "Muir, there are procedures in this office." "And I would remind you that I am Chief Designer on this project." "Trust I take this issue as seriously as you." "And it is very likely that this industrial action will spread... ..causing considerable shortages." "Stokes Yard remains closed and our coal supplies are threatened." "Electrical supplies are affected, as are transport facilities." "I shall need a precise inventory from everyone on the exact state of our supplies and our reserves." "Do we have any idea how long this 'business' is going to continue?" "No, Grey." "It's very difficult to predict." "I've spoken to other businesses but... ..both sides seem obdurate." "We may well be in for the long haul." "I cannot build my engines in time if I don't have coal." "And what do we do if our men go out?" "Yes." "Hello there, Doctor Muir." "How is it coming along?" "Remains to be seen." "Were my drawings not of some use?" "Er, they were great." "Oh." "Perfect, actually." "Whether the import of what they show is appreciated...we'll see." "Why is it so hard to communicate a simple truth?" "Tell me." "Because people don't listen." "Hmmm." "Why is that?" "Because they believe what they want to." "They don't hear what they don't want to or see what's in front of them." "Because people believe what they want to believe." "That's true." "Yeah." "It's human nature." "If you want to persuade, you have to take human nature into account." "I've never been very good at that." "That's because you are frustrated by it." "I am." "You're right." "So, what are the implications?" "Well... ..we don't know." "It does seem strange." "Well, if there IS something wrong with the steel..." "IF!" "But I mean, Cunard, Orient, in fact all our major competitors, use it and nobody's ship has fallen apart yet as far as I know." "What are we to do?" "Speak to the Board of Trade." "Let's bring the matter up with Carruthers." "Yeah, that sounds sensible, but it does bother me." "I mean, Muir wouldn't make this up, would he?" "I suppose not." "I know you don't like him." "Actually, that's not true." "Yes, he irritates me." "But he's young." "He speaks out of turn." "He's arrogant." "All youthful qualities." "He'll learn." "Watch your back!" "Watch the swing." "Bring it down, that's it." "Watch the swing." "Come on, lads, keep it going!" "Steady there, Jim!" "What's his problem?" "Ah, Jimmy's probably thirsty!" "You're not bloody wrong!" "Jesus!" "Heave!" "Jimmy!" "Is it bad?" "!" "You're alright." "Come on." "You're alright, it's not that bad." "Jack, away for the doctor!" "My family." "What am I gonna do?" "!" "What am I gonna do?" "!" "Don't worry about that." "Until you heal, we'll look after ye." "Promise." "♪ I wonder who's kissing her now?" "♪ I wonder who's teaching her how?" "♪ I wonder who's looking into her eyes?" "♪ Breathing sighs, telling lies." "♪ I wonder who's buying the wine?" "♪" "Muir, what do you say to a little wager?" "The length of the lake and back." "Ah, it's a bit cold for that, isn't it?" "It's just a bit of fun." "Oh, for God's sake, Ashley!" "You can have a head start if you need one." "No, don't need a head start." "Well, let's have it then." "Oh, come on, Muir!" "Oh, come on, Muir, what's the matter?" "Can't you swim?" "No, actually, I can't." "I'll have that guinea off you, Stokes." "Alright, Berkeley, you're on." "How very attractive." "I would have liked to have seen you at least prepare for the race." "Two!" "Three!" "Go!" "The problem with the British public schoolboy is that his emotional development is permanently arrested at the age of 18." "You didn't attend such an institution, I take it?" "No, I went to a local...grammar school." "I thought so." "You have something of the real world about you." "Shall I take that as a compliment?" "Oh certainly!" "Of course, I have made only infrequent trips to the real world and hardly know it at all." "The gilded cage has its advantages but the company one is obliged to keep is not always one of them." "Then you should get out of the cage." "I wonder if I'm brave enough?" "You don't strike me as the timid type." "In my own world, I am indeed quite courageous." "Yes." "I'm not sure I'd cope with poverty." "One must know one's limits." "Woo hoo!" "Come on!" "Don't let him win!" "Come on, Berkeley!" "Come on, Ashley!" "Come on!" "Come on!" "That's a guinea you owe me, Ashley!" "Are you good for it?" "Shut up!" "That's the man I'm meant to marry." "I would've beaten him if I hadn't got my foot stuck in a bloody weed." "Rank does have its privileges but... ..there's always a price to pay." "Do you pity me, Mark?" "Perhaps in that sense...yes." "Good book?" "Not bad." "Racy stuff!" "I'd like a wild love affair like this." "I'm sure you would!" "Papa will be marrying me off to some bloody Italian before long." "What about Michael?" "McCann?" "Mmm-hmm." "What about him?" "He likes you." "I know." "He is nice... ..but he's boring, isn't he?" "I think you can't marry someone who bores you." "And if you do, you'll never feel like this." "He kissed her, held her to his chest as the ocean swelled above them." "But, Violetta!" "What would Father Thomas say?" "Who do you think I got this from!" "Really?" "!" "No!" "Join the union!" "Stand united with your fellow workers!" "Support the locked-out men!" "Support the families of the striking workers!" "Join the union!" "Unite against scabbing!" "Join the National Union of Dock Labourers." "In togetherness, there is strength!" "Join a union!" "Join a union!" "Good morning." "The gates of these works will remain locked until every man and woman who works here renounces the union." "What's going on?" "Sounds like Hatton." "Calm down, calm down!" "Do I make myself clear?" "There will be no work here until everybody renounces the union." "Oh my God, it's a lock-out!" "What am I going to do?" "Go home or stay and protest." "You!" "Do you renounce the union?" "No, I do not!" "Away home with you then." "Enough is enough, I'm going to work!" "Away home with you." "Stop that man!" "Go home, Violetta." "Go!" "Go down." "We'd better get to work." "Another lock-out!" "Another attempt by those in management to intimidate the worker." "Denying the opportunities of employment, security." "Denying you your God given right to bargain." "But we will not suffer this tyranny!" "For we will stand up in demonstration of our steel, our might, our resolve!" "So, in solidarity with our brothers and sisters at Carlton Electric, with all those that have been locked out across this city, we will lay down our tools." "Who IS that man?" "I think his name's McCann." "Then you will see how management are forced to listen to our demands." "Mr McCann!" "Morning, sir." "Mr Andrews." "Are you the, er, the leader of these men, Mr McCann?" "Yes, I speak for them." "And what is your grievance?" "Sir, all across this city, workers are being denied their rights." "Even now, honest working men and women are being locked out on a whim." "Denied the basic sustenance of life, because they demand the right to representation." "And you fear the same may happen here?" "Will it?" "No." "You will not deny us the rights of union membership?" "No." "On the contrary, I welcome dialogue as long as it remains cordial, constructive and is conducted in a civilised manner." "All I ask is that you don't endanger the work we're doing here with any violent or precipitate action." "Come and speak with me." "My door is open." "Signor Pietro?" "Mmm?" "I think the time has come." "With your permission, I would like to ask for Sofia's hand in marriage." "Already?" "Is it too early?" "No, it's perfect." "You know, I could do with another man in the family!" "Thank you." "Big weight off my mind." "Something to celebrate." "Um...shhh." "Ahh!" "Salute!" "Salute!" "I have to tell you, sir, that I'm very worried about the way Mr Andrews brushes my concerns under the carpet." "I can assure you he doesn't." "He's raised all your concerns with me." "Well then, I'm surprised that you don't act." "My boy....." "I know you worked for the Royal Navy and I know the uncompromising standards they set, but ours is a business." "And we stay strictly within all maritime regulations that His Majesty's government sees fit to impose." "Do you know, Thomas Andrews has great experience in this yard?" "He hasn't risen because he's my nephew." "He started working here at the age of 16." "He's progressed through every level of the company." "There's no-one who knows shipbuilding better." "Hmm." "Including me." "Come on." "Daddy!" "When are you meeting him?" "Next week." "Just...be careful." "It could be a trap." "He, he could be stalling." "They're on a deadline with Titanic." "I know." "There's strategy to both sides of this." "Just need to be prepared." "That's all I'm saying." "Thanks, Ma." "Full house, eh?" "Conor!" "Hey, sis, you're looking well." "Would you look at who's come home!" "Ma." "Conor." "Good to see you." "I missed you." "Me too." "Look at you!" "Did the British Army not feed you at all?" "I'm alright." "Conor." "Michael." "And what way is that to greet your little brother?" "Ah, it's good to be home!" "How long are you home for?" "Till it's time to move off again, I guess." "So, what about the Army then?" "Did they let you go?" "In a way." "I did help with their decision by smacking my sergeant in the face, but they were quite nice about it." "Three months in the clink and a dishonourable discharge." "I'd say me and the Army parted on good terms!" "That's why no letters, then?" "They don't let you write from the clink." "You never wrote in the first place." "No need to write now." "Back in the bosom of my family, eh?" "Cheers." "Cheers." "Cheers." "It is my privilege to introduce a comrade in our great struggle." "She is a woman who has thrown away the shackles of her class and devoted herself to the plight of the working men and women throughout this island." "I ask you to welcome Constance Markievicz." "I take it as a GREAT compliment to appear here before you, the BOLD working people of Belfast." "But it is to the women I address myself most, for it is you who stand at the front of any revolution." "You who bear the brunt of oppression." "And yet a strong tide of liberty... ..is coming towards us carrying before it all the outposts that hold women enslaved and bearing them triumphantly into the life of the nation to which they belong." "So I say to you... ..don't trust your feminine charm and your capacity for getting on the soft side of men." "A consciousness of your own dignity and worth must be encouraged." "Get away from wrong ideals and false standards of womanhood." "Escape your domestic rut." "Be... ..as free as your dream of the future would have you." "Woo!" "Is this all I get?" "Times are hard." "We've little money coming in." "But with you out of work, I'm the only one who's earning." "It has to make do for all of us." "When's this nonsense gonna end?" "When Sir Henry opens the factory and those striking bastards see sense." "Albert!" "Your language!" "Well, they are!" "Anyway, we can last longer than they can." "We'll starve them out of it." "Sorry I'm late." "Very busy with work." "That's alright, Doctor Muir." "I'll give you your dinner." "Thank you." "Oh, this...came for you." "Oh." "Hmmm." "It's...from Lady Carlton." "Oh." "An invitation... ..to the races." "Get the man some dinner there, Edith." "Of course." "Oh come on!" "Can I go again?" "!" "Can I go again, please?" "!" "Oh no!" "Do it again!" "Hello, Kitty." "Hello, Doctor Muir." "Hello." "Hello." "So glad you could join us." "It was nice of your mother to invite me." "It was nice of me to ask her to!" "I need someone to talk to at these events." "I will never understand the attraction of this sport." "Over-bred nags and their over-bred owners hurtling pointlessly around in large circles." "Bores me to extinction." "Do it!" "My turn!" "Okay, one more." "Oh, good, just in time." "There she goes." "Caramel Nugget!" "Come on, Guinevere!" "Come on!" "Yes, Guinevere, come on!" "Yes!" "Come on, Caramel Nugget!" "COME ON!" "Doesn't Daddy look just perfectly absurd?" "Come on, Guinevere!" "Come on!" "He's obsessed." "He's more interested in the sex life of his horses than his own." "Come on, you beauty!" "Yes, come on!" "Come on!" "Go, Guinevere!" "Go!" "Move it!" "Come on!" "Keep going!" "COME ON!" "Woo hoo!" "Yes!" "Ahhh!" "I knew it!" "I told ya!" "You won something?" "A bob and a half." "Yay!" "Conor's rich!" "Ice creams are on you then!" "For everyone?" "I'll give you a hand." "Let me introduce you to Lady Guinevere." "Daddy wildly prefers her to mummy, you know." "He does?" "Yes." "There's a distinct physical resemblance, but Lady Guinevere wins on personality and general intellect." "Now this is Diamond Jim and this is Cleopatra." "She's mine." "She's beautiful." "Yes, I suppose." "Well, it looks like Lady Guinevere's not back yet." "So we'll just have to wait." "Hmm." "Well, come on." "Kiss me." "Don't you want to?" "Alright, miss?" "Oh!" "Liam!" "Let's go get a drink!" "What a nice day." "Are you happy?" "Yes." "Yes." "Listen." "I have something very important to ask you." "Sofia, I have known you for a little while now." "We have grown very fond of each other." "And I believe there's a good future for us." "Sofia Silvestri, I would like you to become my wife." "I find the best thing for a poorly back is the juice of one lemon mixed with salt, twice a day." "It really works." "I will give it a try." "Aye, you should." "No point suffering in silence!" "Well?" "Well, what?" "Where's Andrea?" "He's gone home." "Why?" "Because... ..for God's sake, Papa." "You know he asked me to marry him!" "And?" "And I told him I didn't want to." "Sofia, what are you saying?" "I turned him down." "You..?" "You..?" "What?" "!" "I will decide who I marry and when, if I want to get married at all!" "You have disgraced me!" "I have disgraced no-one!" "How can we be sure this talk isn't a device to keep us quiet?" "How do we know we're not being strung along?" "You don't." "It's a matter of trust and goodwill between both parties." "Can we trust you, Lord Pirrie?" "I hope so." "You realise we have the power to call our men out any time?" "Yes." "And we will, if the situation in this city does not improve." "I can't stop you, Mr McCann." "Though I would urge you to consider this:" "the prosperity of this city depends upon the prosperity of this yard." "Mr McCann, if we fail to complete the ship we're building, if we fail to deliver Titanic, this yard may very well be destroyed!" "You might destroy me and other employers, but also yourselves." "Wouldn't that be something of a Pyrrhic victory?" "Yes." "The phrase means a victory... ..that is self-defeating." "From King Pyrrhus of Epirus." "He beat the Romans, but destroyed himself in the process." "Quite!" "All we're asking for, my Lord, is the prosperity you speak of be more equitably spread." "Injury and death are commonplace in shipbuilding." "Shipwrights should receive realistic compensation for injuries sustained in the workplace, not just what management thinks is appropriate." "Make no mistake, an injury here can put an entire family in the poorhouse." "I got your note." "I never thought to see you back here." "Have you been hiding from me?" "No, son." "It's not as simple as that." "Look at you." "A fine man." "Why d'you come back?" "Er, they've offered me a job on the Titanic." "I'm a metallurgist." "I work with the steel." "A management position?" "Yeah." "Do they know you're a Catholic?" "No." "They don't." "You're in the belly of the beast, son." "I know it's a risk." "I've thought it through so..!" "I also thought I'd get a chance to see my old man." "Where are you living?" "How are you living?" "Are you okay?" "It's good to see you, son." "Yeah."
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How much to know about understound oil deposits? davidwilson1949/ Creative Commons
The U.S. consumes 19.1 million barrels of petroleum each day -- almost half of it in the form of gasoline, according to the U.S. Energy Information Administration. Thanks to its car culture, the U.S. is the top oil consuming country in the world, but with the economic recession, dependence has significantly wound down since peaking in 2005, the agency says. By 2035, U.S. total consumption per day is estimated to total 21.9 billion barrels.
So how far do we have to drill to get a hold of this black gold? Over the last six decades, it’s only gotten deeper. In 1949, the earliest year with data available, the average depth of oil wells drilled was 3,635 feet. By 2008, the most recent data available, we were drilling an average of 5,964 feet, a slight decrease from the 2007 at 6,064 feet.
What are the implications of drilling depth? Since oil takes millions of years to form, for all intents and purposes, it’s a finite resource. We’re drilling deeper because we’re literally running out of oil. But depth comes at a cost. Deep offshore drilling requires more money and energy, not to mention hazards for both the environment and workers. Let us explain some of the challenges:
Drilling on land is an undertaking on its own. How do you drill in lightless ocean depths and transport all that liquid, gas and solid petroleum back to the surface? How do you keep from polluting the ocean? And how do you do all of this, with tons of special equipment, in the middle of rough seas?
The process isn’t perfect, as demonstrated with the Deepwater Horizon oil spill in 2010 that devastated communities and wildlife. Even today, scientists say that oil in the Gulf of Mexico continues to poison wildlife and poses a public risk.
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Introduction {#Sec1}
============
Multiple Sclerosis (MS) is a complex, chronic, neurodegenerative autoimmune disorder that affects the central nervous system (CNS). MS manifests in the CNS through formation of inflammatory lesions in the white matter of the brain and spinal cord. The lesions represent an endpoint of repeated autoimmune attacks against endogenous myelin-associated antigens which lead to neuroaxonal degeneration, and death of myelin forming cells; the oligodendrocytes. This pathological process results in demyelinated plaques or astrocytic scars throughout the CNS perturbing neural networks^[@CR1]^. It is estimated that 2,221,188 individuals are living with MS worldwide, and global MS incidence is twice as many in females than in males^[@CR2]^. In Kuwait, MS prevalence has increased from 31.15 per 100,000 individual in 2009, to 104.88 per 100,000 individual in 2018 with a projected trend of further increases in the future^[@CR3],[@CR4]^. MS has been recognized and described 151 years ago but its underlying cause remains unknown. However, there is mounting evidence of several environmental and genetic risk factors associating with the disease^[@CR5],[@CR6]^. Environmental and genetic contributing factors to MS incidence are not exclusive but are thought to be synergistic as none of these factors fully explain causation alone, nor do they consistently associate with MS risk across different populations^[@CR7]^.
Among the strongest genetic susceptibility associations with MS is the major histocompatibility complex (MHC) genes region^[@CR8]^. The most significant associations were seen with polymorphisms in human leukocyte antigen (HLA) HLA-DR2 alleles, however their association was found variable across different MS populations^[@CR9],[@CR10]^. More MS risk associations were found with other HLA loci such as HLA-DR3, -DR4, -DQ2, -DQ6, and -DQ8 allelic variants^[@CR11]^. However, the associations found with HLA haplotypes are thought to explain only 25--60% of MS genetics. A large number of linkage analyses, genome wide association studies (GWAS) and candidate gene studies have been conducted to discover the missing genetics of MS. Association studies from Kuwait reporting MS genetic risk factors are sparse, and include positive association of polymorphisms in HLA class-II (DR4, DQ6, DQ7 and DQ8) genes^[@CR12]^, nitric oxide synthase (NOS) genes^[@CR13]^, vitamin D receptor gene^[@CR14]^, and leptin gene with MS risk^[@CR15]^. However, currently there are approximately more than 200 MS genetic risk factors reported so far and replication studies from Kuwait are lacking^[@CR16]^. Interestingly, the \~200 MS genetic risk factors include different susceptibility markers and modifier genes with inconsistent associations across different MS populations emphasizing ethnic, geo-epidemiological, and environmental factors associating with MS risk^[@CR17]^. To confirm the association of reported MS risk genetic factors, replication studies should be conducted across different MS populations to understand the influence of ethnic and geo-epidemiological factors on MS risk. Here, we report our findings from a replication study investigating non-HLA reported MS risk variants in a sampled Kuwaiti MS population. Our objective was to assess their association in a semi-ethnically homogeneous Kuwaiti cohort as these genetic risk factors were identified from multi-ethnic MS populations.
Results {#Sec2}
=======
Reported MS variants in arab exomes {#Sec3}
-----------------------------------
The demographics and clinical characteristics of Kuwaiti MS patients and healthy Arab controls included in the exome analysis are shown in Table [1](#Tab1){ref-type="table"}. Of the 96 selected variants 87 (90.6%) had variable detection frequency in SureSelect V5 library only, and 9 (10.4%) were not covered by our exome library. The final list of reported MS variants that had consistent detection across all exomes included 18 (20.7%) variants of acceptable detection frequencies across the two cohorts (Supplementary Table [1](#MOESM1){ref-type="media"}). Four variants had statistically significant different allele frequencies in MS exomes compared to healthy control exomes (Table [2](#Tab2){ref-type="table"}). These variants included; Ecotropic Viral Integration Site 5 (*EVI5*) rs11808092 (OR: 2.04, 95%CI: 1.4--2.9), TNF Receptor Superfamily Member 1 A (*TNFRSF1A*) rs1800693 (OR: 2.01, 95%CI: 1.45--2.75), Lymphocyte Function-Associated Antigen 3 (*CD58*) rs1414273 (OR: 2.2, 95%CI: 1.5--3.2), and a nominally significant and not clearly robust Methylenetetrahydrofolate Reductase (*MTHFR*) variant rs1801131 (OR: 1.4, 95%CI: 1.02--1.9). However, genotype frequencies were significantly different among the two cohorts for only three variants; *TNFRSF1A* rs1800693 (p = 0.0001), *MTHFR* rs1801131 (p = 0.024), and *CD58* rs1414273 (p = 0.0001). Since these variants showed risk association in Kuwaiti MS patients when compared to Arab healthy controls we further investigated their association with MS in an exclusively Kuwaiti nationality case-control population sample.Table 1Demographics and clinical characteristics of Kuwaiti MS (n = 113) and healthy control Arabs (n = 460) included in the investigative exome analysis.CriteriaMS patients (n = 113)Healthy Arab controls (n = 460)Sex (%)Male40 (35.4)229 (49.8)Female73 (64.6)231 (50.2)Age in years (Mean ±SD^a^)32.9 ± 9.440.7 ± 12.6MS type^b^ (%)---RRMS16 (14.2)SPMS93 (82.3)PPMS4 (3.5)Disease duration in years (Mean ±SD)6.77 ± 5.73---EDSS^c^ (Median, IQR^d^)2 (1.5--3.5)---^a^SD: Standard deviation; ^b^RRMS: Relapsing-remitting MS, SPMS: Secondary progressive MS, PPMS: Primary progressive MS; ^c^EDSS: Expanded disability status scale; ^d^IQR: Interquartile range.Table 2Statistically significant exome analysis results of reported variants associated with MS risk in this study's case-control exome cohorts.GeneSNPAllele frequency in Kuwaiti MS cases (%)Allele frequency in Arab healthy controls (%)P-value*CD58*rs1414273G: 158 (76)A: 50 (24)G: 722 (87.4)A: 104 (12.6)0.00007*EVI5*rs11808092C: 93 (63.3)A: 54 (36.7)C: 687 (77.9)A: 195 (22.1)0.00024*MTHFR*rs1801131T: 120 (57.1)G: 90 (42.9)T: 574 (65.1)G: 308 (34.9)0.038*TNFRSF1A*rs1800693T: 127 (60.5)C: 83 (39.5)T: 631 (75.5)C: 205 (24.5)0.00002Variant detection frequency was variable across the two exome cohorts and computed allele frequencies reflect the proportion of alleles divided by the total number of exomes in which the variant was detected.
Replication analysis of MS variants in kuwaiti samples {#Sec4}
------------------------------------------------------
The replication Kuwaiti population sample included 170 Kuwaiti MS patients and 311 healthy Kuwaitis. Replication cohorts' demographics and clinical characteristics are shown in Table [3](#Tab3){ref-type="table"}. Allelic and genotype frequencies for *TNFRSF1A* rs1800693, *EVI5* rs11808092, *CD58* rs1414273 and *MTHFR* rs1801131 are shown in Table [4](#Tab4){ref-type="table"}. *TNFRSF1A* rs1800693, *EVI5* rs11808092 and *MTHFR* rs1801131 genotype frequencies in healthy Kuwaiti controls were in Hardy-Weinberg equilibrium, except for *CD58* rs1414273 for which genotype frequencies were significantly different than those expected in European populations (p \< 0.0001). *TNFRSF1A* rs1800693C allele did not sustain significant association with MS risk (OR: 1.36, 95%CI: 1.04--1.78, p = 0.025) following adjustment for multiple testing. *TNFRSF1A* rs1800693 genotype distribution differed between the two cohorts (β = −0.106, 95%CI: −0.14- (−0.009), p = 0.027) after adjusting for sex and age albeit did not reach adjusted statistical significance. However, rs1800693CC+CT genotypes significantly associated with MS risk in an autosomal dominant inheritance model (OR: 1.7, 95%CI: 1.14--2.5, p = 0.008). No sex-specific MS risk or EDSS association was found for rs1800693, whereas genotype CC marginally associated with a younger age of MS onset (β = −0.169, 95%CI: −0.33 - (−0.001), p = 0.04) after adjusting for sex and disease duration.Table 3Demographics and clinical characteristics of the replication study's Kuwaiti case-control cohorts and their allelic and genotype frequencies for the associated MS risk variants.CriteriaKuwaiti MS patients (n = 170)Kuwaiti healthy controls (n = 311)**Sex (%)**Male58 (34.1)118 (37.9)Female112 (65.9)193 (62.1)Age in years (Mean ±SD)33 ± 8.7330.7 ± 8.47MS age of onset in years (Mean ±SD)27.06 ± 7.68MS type (%)---RRMS148 (87)SPMS14 (8.2)PPMS4 (2.4)Benign MS4 (2.4)Disease duration in years (Mean ±SD)5.6 ± 5.17---EDSS (Median, IQR)1.5 (1--3)---Table 4Replication cohorts' allelic and genotype distributions \[n (%)\] of the exome analysis resultant MS risk variants.VariantMS cohortHealthy controlsP-value(n = 170)(n = 311)*CD58* rs1414273A/G73 (21.5)/267 (78.5)137 (22)/485 (78)0.8AA7 (4.1)25 (8)0.11AG59 (34.7)87 (28)GG104 (61.2)199 (64)*EVI5* rs11808092A / C110 (32.4)/230 (67.6)141 (22.6)/481 (77.3)0.002AA20 (11.7)15 (4.8)0.003AC70 (41.2)111 (35.7)CC80 (47.1)185 (59.5)*MTHFR* rs1801131G / T149 (43.8)/191 (56.2)189 (30.4)/433 (69.6)0.00003GG31 (18.2)26 (8.4)0.0001GT87 (51.2)137 (44)TT52 (30.6)148 (47.6)*TNFRSF1A* rs1800693C / T143 (42)/197 (58)216 (34.7)/406 (65.3)0.025CC27 (15.9)42 (13.5)0.03CT89 (52.3)132 (42.4)TT54 (31.8)137 (44.1)
*EVI5* rs11808092A allele showed significant MS risk association in the Kuwaiti population sample (OR: 1.6, 95%CI: 1.19--2.16, p = 0.002). *EVI5* rs11808092 genotype distribution differed between the two cohorts (β = −0.195, 95%CI: −0.24- (−0.06), p = 0.001) when adjusted for age and sex. In addition, *EVI5* rs11808092 genotype association with female MS risk was stronger than in males (p = 0.007 in females vs. p = 0.042 in males). *EVI5* rs11808092 associated significantly with MS risk in both; autosomal dominant (OR: 1.65, 95%CI: 1.1--2.4, p = 0.009) and recessive (OR: 2.63, 95%CI: 1.32--5.2, p = 0.009) inheritance models. *MTHFR* rs1801131G allele significantly associated with MS risk (OR: 1.79, 95%CI: 1.3--2.36, p = 0.00003). *MTHFR* rs1801131 genotype distribution differed between the two cohorts (β = −0.23, 95%CI: −0.25- (−0.09), p = 0.0001) after adjusting for sex and age. *MTHFR* rs1801131 GG + GT strongly associated with MS risk in an autosomal dominant inheritance model (OR: 2.06, 95%CI: 1.39--3.1, p = 0.0003). Lastly, *CD58* rs1414273A allele did not show any MS risk association in the replication Kuwaiti only population sample. *CD58* rs1414273 genotypes were not significantly different with or without adjusting for sex (p = 0.69 and 0.38; respectively). *CD58* rs1414273 genotypes did not associate with MS risk in any of the inheritance models applied. None of the assessed variants associated with EDSS with or without adjusting for disease duration or/and sex.
Discussion {#Sec5}
==========
There are currently more than 200 reported MS genetic risk factors stemming from linkage analysis studies, GWAS studies, functional candidate gene approaches, exome sequencing association studies, and animal model and post mortem MS brain candidate gene studies. Only a handful of these genetic factors sustained MS risk association across different MS populations, and were linked to MS pathogenesis which provided valuable potential therapeutic targets. Here, we focused on reported non-HLA MS risk variants that might be captured in exome libraries available for clinical research. We noticed that exome coverage is not consistent across samples, and different libraries have variable exome coverage as well. Four candidate genetic factors were found to have statistically significant MS risk association in the Kuwaiti MS exome cohort when compared to Arab healthy controls. However, the Kuwaiti only replication cohorts; which adjusted for possible genetic background variation/bias in the exome study, highlighted the influence of ethnicity and genetic background in false positive results of genetic studies.
*TNFRSF1A* rs1800693, *EVI5* rs11808092, and *MTHFR* rs1801131 have been reported to associate with MS risk in mostly European Caucasian populations (Supplementary Table [2](#MOESM1){ref-type="media"}). However, the effect size of these associations is variable and is relatively small depending largely on the number of samples analyzed. TNFRSF1A is a membrane-bound and soluble receptor for tumor necrosis factor-alpha (TNFα) that plays a role in cellular survival, apoptosis and inflammation in the immune and nervous systems^[@CR18]^. *TNFRSF1A* rs1800693 is an intronic variant that has been shown to impact the splicing of *TNFRSF1A* mRNA resulting in a novel isoform that blocks the action of TNFα^[@CR19]^. Rs1800693 association with MS risk has been shown to have consistently a small effect size in different MS populations^[@CR20]^. It is possible that the marginal association of rs1800693 variant with an earlier age of MS onset seen in our study is the reason for the small effect size of this variant reported in other MS populations where younger age of MS onset cases were considerably well represented. Therefore, it is probable that due to the low representation of MS cases with younger age of MS onset in our replication MS cohort (17% with MS age of onset ≤20 years) rs1800693 association with MS risk did not reach statistical significance following adjustment for multiple testing.
*EVI5* rs11808092 variant lies in the 3′-end intron of *EVI5* gene that shares a similarity to an enhancer element and has been shown to act as a strong enhancer element on the promoter of an adjacent gene (*GFI1)* implicated in MS risk^[@CR21]^. Nevertheless, *EVI5* rs11808092 as well as other variants in *EVI5* have been reported to associate with MS risk and clinical characteristics^[@CR22],[@CR23]^. On the other hand, *MTHFR* rs1801131 had a nominal association with MS risk in our exome analysis, but later showed a robust association with MS risk in the Kuwaiti only cohorts. MTHFR is an enzyme involved in the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and the missense variant rs1801131 (E429A) has been shown to cause decreased MTHFR enzymatic function and is associated with impaired folate metabolism and mild increases in homocysteine levels (hyperhomocysteinemia) that is reported to occur in MS patients^[@CR24],[@CR25]^. Sustained elevated homocysteine levels associate with cardiovascular disturbances that are thought to predispose to MS pathogenesis and progression^[@CR26]^.
Lastly, *CD58* was first identified as an MS susceptibility factor by the association of its rs12044852 variant in a study of African American MS patients and further supported by evidence of altered expression in MS^[@CR27],[@CR28]^. A follow-up investigation provided two other *CD58* variants (rs2300747, rs1335532) associating with altered CD58 expression in MS^[@CR29]^. Structural analysis of *CD58* coding region revealed rs1414273 to be in strong linkage disequilibrium with the *CD58* MS-associated SNP rs1335532^[@CR30]^. A recent report highlighted the role of this variant in processing of the *CD58* transcript and associated microRNA in MS pathology^[@CR31]^. Our exome analysis did not detect any of the other *CD58* variants except for rs1414273 and initially an association with MS risk was found in the exome analysis. However, the association was later lost in the Kuwaiti only replication analysis. It should be noted that rs1414273A is the minor allele in Kuwaitis and has a lower frequency in Kuwaitis (0.2) compared to ExAc database (0.5) and 1000 genome database (0.43) frequencies. Therefore, it is plausible that rs1414273 allelic distribution is well-retained in the majority of Kuwait's genetic background, and rs1414273 reported linkage to rs1335532 may not be applicable to the Kuwaiti genetic background. Moreover, Qatar's patriotization laws are very flexible with an estimated 11.6% Arab Qataris contributing to the largely immigrant 2,723,003 Qatari population^[@CR32]^. Therefore, the association of rs1414273 with MS risk in our exome study was probably influenced by a non-uniform genetic background in the Qatari controls. Nevertheless, our replication study findings support the lack of rs1414273 association with MS risk in the Kuwaiti MS population but does not refute other *CD58* variants association with MS risk or CD58 altered expression in MS.
In conclusion, we have analyzed the association of a set of reported MS genetic risk variants in a semi-homogenous exome case-control study, and confirmed the results in a replication study of a homogenous genetic background. Population genetic analyses should strive to maintain genetic background uniformity to accurately ascertain population specific genetic risk susceptibilities. Our findings support the existing evidence on the roles of these genes in MS risk and pathogenesis providing further evidence into MS etiology and potential therapeutic targets.
Methods {#Sec6}
=======
Patient selection {#Sec7}
-----------------
Blood samples of 283 Kuwaiti MS patients were collected at Kuwait's Dasman Diabetes Institute (DDI), and 311 Kuwaiti healthy control volunteers were collected by word of mouth and social networks from the Kuwaiti population. Collection criteria for MS patients included; a complete clinical MS disease profile (demographics, age of onset, type of MS, disease duration, expanded disability status scale (EDSS) score, and history of MS treatments), being a Kuwaiti citizen, and agreement to provide a 4 mL blood sample. Exclusion criteria included; having an EDSS score of 0, and a disease duration of ≤1 year. Healthy controls' exclusion criteria included; being a non-Kuwaiti expatriate, having a family history of MS, and having a diagnosis of any complex disorder. All study protocols were approved by Kuwait's Health Sciences Center's Joint Committee for The Protection of Human Subjects and DDI's ethical review committee both of which adhere to declaration of Helsinki's Ethical Principles for Medical Research Involving Human Subjects' guidelines. All study information and protocols were fully explained to all participants prior to procurement of their informed written consent. Of the 283 MS patients collected, 113 were prioritized as most informative for exome sequencing to include equally distributed subgroups relevant to each of the following characteristics; EDSS score, disease duration, age group, and male to female ratio of \~1:2. Whereas 56 healthy control Kuwaiti samples were age and sex matched to selected MS samples and prioritized for exome sequencing.
DNA extraction {#Sec8}
--------------
Blood samples were collected from all 283 MS patients, while healthy controls' sample collection varied between blood and saliva samples. Blood samples were centrifuged at 2,500xg for 10 minutes at room temperature and three fractions were retrieved. Plasma fractions were stored at −80 °C, and white blood cells fractions (buffy coat) were subjected to DNA extraction using QIAamp DNA blood mini kit (Qiagen, CA, USA) according to manufacturer's standard protocol. For saliva samples the same kit was used with minor modifications. For every 1 mL saliva sample 4 mL of sterile phosphate buffer saline (PBS) were added, and samples were centrifuged at 1,800 × g for 5 minutes at room temperature. Resultant pellet was suspended in 180 µl of PBS and 20 µl of kit provided proteinase K was added. The following steps where according to manufacturer's standard kit protocol. DNA quality and quantity were assessed by a NanoDrop spectrophotometer.
Exome sequencing {#Sec9}
----------------
Exome sequencing of 113 Kuwaiti MS patients and 56 healthy Kuwaiti controls was performed on an Illumina HiSeq2000 platform using SureSelectXT v5 library preparation with target coverage of 50X (Illumina, CA, USA). Illumina raw paired-end reads, captured with Agilent exome library, were mapped to the human reference assembly (hg19) using Burrows wheeler aligner (BWA)^[@CR33]^. Sequence Alignment Map data with average of 50X coverage were then compiled and converted to a single compressed binary file, for each strain, using SAMtools^[@CR34]^. Picard software (<http://picard.sourceforge.net>) was used to flag PCR duplicate reads. Genome Analysis Toolkit (GATK) was used to (a) local realignment of a read that overlapped with an INDEL (b) recalibration of base quality (c) variants calling^[@CR35],[@CR36]^.
MS variant selection {#Sec10}
--------------------
A literature search was conducted using the following keywords "Multiple sclerosis genetics, Multiple sclerosis gene, multiple sclerosis polymorphism, multiple sclerosis variant, multiple sclerosis GWAS, multiple sclerosis exome sequencing, multiple sclerosis genome sequencing." In addition, variants included in the MSgene database (MSgene.org) were also retrieved. Collected variants were filtered according to the following criteria; being a single nucleotide variant, being within intronic gene sequence, being encoded in the nuclear genome, and being an MS risk factor. A total of 96 genetic MS risk factors were selected and used for mining exome data of MS patients and healthy controls (Supplementary Table [1](#MOESM1){ref-type="media"}). Two healthy control datasets were retrieved from publically available databases that are believed to share genetic background with Kuwaitis; Qatari and middle-eastern exome sequences. Selected Qatari and Middle Eastern (non-diabetic) individuals next generation sequencing data were obtained from the national center for biotechnology information (NCBI) sequence read archive with accessions; SRP060765, SRP061943 and SRP061463. Collectively, the case-control cohorts included 113 MS exomes and 460 healthy control exomes. A Fisher exact test was carried out for each variant, and variants were selected based on p-value of significance \<0.05.
Variant genotyping in replication cohorts {#Sec11}
-----------------------------------------
DNA from a replicate MS cohort of 170 MS patients and 311 healthy controls was used to genotype polymorphisms with p-values \< 0.05. Genotyping was performed using Taqman genotyping assays (Life Technologies, CA, USA) according to manufacturer's standard protocols and analyzed using ABI 7500 Fast Real-time PCR system (Life technologies, CA, USA). Genotype allelic discrimination was determined by SDS v1.4.1 software (Applied Biosystems, CA, USA).
Statistical analysis {#Sec12}
--------------------
Hardy-Weinberg equilibrium was assessed in the Kuwaiti healthy control cohort for the four replicated variants using allele frequencies of European ancestry as the majority of detected MS risk variants were reported from European populations. For genotype analysis Fisher's exact-test, chi-square test, and linear and logistic regression analyses were used. All statistical analyses were performed using SPSS v.25 (IBM, NY, USA). For the replication analysis, a multiple testing Bonferroni-adjusted p-value ≤ 0.0125 was considered significant.
Supplementary information
=========================
{#Sec13}
Supplementary Information.
**Publisher's note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
=========================
is available for this paper at 10.1038/s41598-020-64432-3.
This work was funded by KFAS grant 2012--1302--02.
M.D. performed the bioinformatics analyses, K.A. performed genotyping of selected variants, R.A.R. provided patients clinical data, and R.A.T. designed the study, collected samples and preformed DNA extractions, genetic analyses and drafted the manuscript. All authors approved the final manuscript.
The authors declare no competing interests.
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Q:
Updating textbox value, more then once in webform asp.net
I am trying to update a textbox with a string. The string will be concatenated then will update the textbox with a click event. I can do this in a windows app, but when I try to do this in a asp.net app, I can't get the result that I want.
public partial class WebForm3 : System.Web.UI.Page
{
public string string_punch;
protected void Page_Load(object sender, EventArgs e)
{
MultiView1.SetActiveView(View1);
txt_punch.MaxLength = 4;
txt_punch.Attributes.Add("OnChange", string_punch);
}
protected void btn_punch_7_Click(object sender, EventArgs e)
{
const string string_punch_Number_7 = "7";
string_punch = string_punch + string_punch_Number_7;
txt_punch.Attributes.Add("Value", string_punch);
}
protected void btn_punch_8_Click(object sender, EventArgs e)
{
const string string_punch_Number_8 = "8";
string_punch = string_punch + string_punch_Number_8;
txt_punch.Attributes.Add("Value", string_punch);
}
I want to be able to click btn_punch_7, then click btn_punch_8, and concatenate the string, and update the textbox with both numbers. Every time I click a button, the string gets set to null. Thanks for advance for the help.
A:
string_punch is lost between every PostBack and that is why it always equals null, because ASP.NET is stateless meaning it does not keep it state from post back to post back. Also use Text property of TextBox to assign/retrieve value of textbox.
Change your events accordingly to code below:
protected void btn_punch_7_Click(object sender, EventArgs e)
{
const string string_punch_Number_7 = "7";
var text = txt_punch.Text;
text += string_punch_Number_7
txt_punch.Text = text;
}
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Apart from socks that slide down, having a dress shirt that comes untucked constantly is one of the most annoying things in menswear. Today, we reveal the most important aspect of keeping a shirt tucked in all day.
You don’t want to tuck in your shirt 4 times a day at the office or even worse, having your shirt coming untucked during a meeting.
Some people come up with interesting techniques such as the military tuck which actually just helps to prevent the look of too much excess fabric on the sides if you get a shirt that is too wide. Or you can have the underwear tuck but ultimately, it’s not going to help you because the cause is actually a different one.
No, I’m not talking about shirt garters / shirt stays, you’ve watched different videos, you’ve probably seen them, little garters that are connected to your socks and they basically pull down your shirt when you move it up but ultimately, it’s just trying to fix the results of something, it does not go to the root cause.
Common Shirt Stays or Garters
Let’s compare the shirt getting untucked to a dripping faucet. You can either just put a little bucket underneath of it, or you can turn off the water of the main line every time you want to use it, or you can simply fix the faucet so it doesn’t drip anymore.Using sock and shirt garters or tucking in your shirt a certain way is the equivalent of putting a bucket underneath the dripping faucet.
Dress shirts are traditionally longer in the back and in the front but shorter on the sides
The biggest secret to getting a shirt that stays tucked in all day is to have a shirt that fits you properly. More specifically, you have to look at the following things.
1. Get Long Shirt Tails
Dress shirts are traditionally longer in the back and in the front but shorter on the sides so there’s not too much excess fabric. I suggest that the rear of your shirt covers your bum and has a same length on the front, that way, it won’t become untucked no matter if you wear your pants or your trousers on your natural waistline or lower on your hips.
The perfect fit will not constrict movement
2. Small Tight Armholes
The proper fit of an armhole is relatively tight; that means there’s not much excess fabric around your armpit and your shoulders. It fits very close. Now, most people think, when something is smaller, it is less comfortable, but in this case, it’s the opposite.
When I have a small armhole and I move up my shirt, the bottom part doesn’t move because nothing pulls on it. Let’s assume my armhole is slightly bigger, now the minute I pull up my arm, everything is pulled up and becomes untucked. The second I go down again, I have excess fabric being undone above my waistband.
A great fitting shirt will allow you to move around without getting untucked
Basically, whenever you buy a dress shirt, you should try it on and make sure that the armholes are as small as possible while still being comfortable. So if you have shirt and sock garters, they may pull the shirt back in but it’s not always perfect because once it has been pulled out, something may get caught and you can’t pull it right back in. Also if you have a thinner fabric, it shows in your pants. Let’s assume you’re on a date and you get to the crucial part and you have to take off something as ridiculous as your sock shirt garters; not only is that really unattractive but it may also kill the mood.
On the other hand, if you have a small armhole, you can move around, you can wave for a cab, you can say hi, you can shake hands, you can sit down, and your shirt will be tucked in all day and you won’t have to worry about it. Now of course, if you go climbing in a dress shirt, or if you workout, it will come untucked eventually but dress shirts are not meant for these kinds of activities and if you want to do something physical, get a t-shirt that’s flexible or a polo shirt.
A little bit of excess fabric goes a long way
3. Sleeves That Have Enough Room
Right now, it’s very popular to have slim sleeves and that’s okay but you should always make sure to have a little bit of fabric in the top part around your biceps because the minute you move forward or up, you need that extra room so your shirt does not come untucked. If it’s super tight, you are more likely to pull out your shirt by moving your arms around. If your shirt body is wider or slimmer, will it have a huge impact on the fact where it comes untucked or not? If it’s super wide, it may come untucked a little easier and you’ll also have more fabric hanging around in the first place. So if you don’t like your shirts coming untucked, try to get a trimmer fit that is based on your body. Avoid something that’s overly tight or you’ll get x-wrinkles because that’s unflattering as well.
If your shirt body is wider or slimmer, will it have a huge impact on the fact where it comes untucked or not? If it’s super wide, it may come untucked a little easier and you’ll also have more fabric hanging around in the first place. So if you don’t like your shirts coming untucked, try to get a trimmer fit that is based on your body. Avoid something that’s overly tight or you’ll get x-wrinkles because that’s unflattering as well.
wrinkling is definitely a sign of an improper fitting shirt
For classic evening shirts, back in the day, men wore a bib insert that was either starched or Marcella. They were quite stiff and so when people would sit or dance, they needed a little latch on the shirt that was able to be buttoned into the pants and that way, it would not move at all, all night. Unlike shirt garters, you can easily undo that very quickly, you don’t notice it and it really serves the proper purpose of not having your shirt come undone or move around because it’s connected to the pants. Again, for regular dress shirts, this is not necessary but it’s something specifically designed for evening shirts.
If you have a body that’s symmetrical or if you have issues with getting your shirt untucked, I suggest you invest in a custom shirt because you can really make sure that you get a tight armhole, that you can get a fitted shirt and you get the extra amount in your sleeve that is not too wide and that way, you’ll have a shirt that looks good on you, that flatters you, and won’t come untucked.
Still Thinking You Need Shirt Stays? Get these
Now, if you want shirt stays for nostalgic, vintage loving reasons or if you have a bunch of shirts with armholes that are too big but you cannot replace them at the moment, take a look at these shirts stays from sharp & dapper. Unlike most, they attach to your shirt at 3 points and they are more comfortable when you sit, even though we think nothing is as comfortable as a well-fitting custom shirt with tight armholes and no shirt stays or sock suspenders.
Some years ago I was told by the shirtmaker at Dunhills in London that the best way to secure the fit of a shirt was, after one was dressed, to put a hand (ones own) into the open trouser fly, to grab the bottom front end of the shirt on one side and to give it a firm tug down, and then to do the same with the shirt front on the other side. Sounds odd, but it works .. at least for custom made Dunhill shirts.
I tend to pull my shirt back down into my trousers by grabbing it and pulling down with my hands in my pockets – I find this works and looks better during the day than trying to stuff it back down past your belt
I see the problem is once the shirt is pulled out of the waist band it ain’t going back in. Perhaps a looser fitting waist band where the shirt can drop back down. Now to keep the pants from dropping at the wrong time, wear braces. Not sure if this would work 100% as the braces could cause the shirt to collect under them, stopping the shirt from returning to its proper place. My other weird idea is to attach the shirt to the elastic waist of the underwear. Hassle if you have to go to the mens room and could cause slight pain if you bent over too far. And women think we men have it easy!
Love your videos and I ask you to please please do one on (A) wearing the right size pant waist and (B) what it looks like when you don’t not to mention it makes your “pot belly” look larger and you heavier.
Thank you so much……I registered all the men in my family as recipients of your newsletter.
PS who checks you before your videos or during them? Check out your tie in the shirt video. Just a thought…during my past life, one of my tasks was to make sure my Chairman and CEO always appeared perfect on the videos…..credibility. Just a thought. You , 99% of the time DO!!!! Picky I know but you are all about PERFECT!!!!!
Hi Sven and all Gentlemen who follows the Gazette, Sorry for the late reply but other life priorities take precedence sometimes. I normally read and watch the Gazette for general knowledge and self style improvement. On this topic, I felt inclined to share my experience. Not so much about experiencing the “undone” or “untucked” shirt but more so the “mushroom” effect. For the gents who are unfamiliar with the term, this is when the shirt bulges out from the back like the mushroom discs spawning on tree trunks! As the vast majority of men, this is so common that colleagues and fellow gents almost except this fact as normal and have trained their eyes to ignore it as if it is invisible or just another normal fact of life. Nevertheless, the problem is there for the aware dappers. The problem always occurs when one is at a sitting position such as working at a desk and stands up afterwards. The long fabric part at the back of the shirt slips up from under the pant or waistcoat of a suit as in my case to accomodate the bend in the body position while sitting and when you straighten up at a standing position the excess fabric that was doing a great job covering your back and making sure your underwear is not showing becomes a burden and a sore to the eye! This lead me to relentless search for a solution which as Sven mentioned is not in shirt stays attached to the socks (being single band or tri-band). Underwear tucks makes the situation worse and strings … ?!? Finally, I came across a concept developed by a gent who had enough of this problem and decided to do something about it (good for him and all of us). His idea is a shirt stay of course but instead of hooking it up to your socks and risk loosing a date when you make it to the bedroom, it is simply attached to a band around your thigh. Each band has 3 straps to hold the shirt from the front, side and back virtually rendering it untuck-proof. The design is visually acceptable and not taxing on the eye should your date gets to the part of seeing it. What’s more, it is custom made to the measure of your thigh circumference and the straps are length adjustable to suit all body heights. And finally, it is available in 3 colours black, navy and tan or beige to avoid detection through lighter fabric! Please note that I am not running an ad to this company or its product nor I have any affiliation with it or its owner. The product is on Kickstarter and it has surpassed its funding target which says something about the product. Last email I received yesterday informed me that there are 3 days left till the funding period is over. Contributing towards a predetermined fund packages will buy you this product or multiple quantities of it at a discounted price from what it will be selling later on on their website. If you are interested even for looking it up, check out the S-Holder product by NV on Kickstarter. I cannot say yet if this product will surely resolve the long standing problem of untucked shirts until I give it a try. However, it looks as though it has the potential to do so. You may judge for yourself and be kind enough to share with us your opinion on this blog. Also, I would like to know what Sven think of it as a newly added necessity for the gentlemen wardrobe. Thank you for reading.
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('Recognized By Accident' music)
Greetings my beautiful lovelies. It's Emmy.
Welcome back to another episode of Fermented,
where I toy and experiment with things
that are fermented.
If you've missed the other episodes in the series,
I will put the link up above and down below to the playlist
where you can see other
bubbling, fizzing, things including kimchi,
and... what else have I made that's fermented? Oh!
Sourdough experiments...
But today I'm going to be making a beverage,
a beverage called kvass.
So kvass is a fermented drink and as a result of the fermentation process
alcohol is produced, but is produced in such small amounts,
it's about 0.5 to 1 percent alcohol.
It's kind of similar to drinks like kombucha where it is present,
but not high enough in amounts where it's considered alcoholic.
So kvass comes from the Slavic and Baltic regions of Central and Eastern Europe.
It's been produced and consumed for hundreds of years
all the way back to the Middle Ages.
Fermented drinks like kvass and beer were safer to drink
because they had undergone a fermentation process.
Also, the fermentation process often requires the water to be boiled,
killing many of the pathogens that were in the water.
So it's interesting to think that fermented drinks like beer and kvass
were safer means to get hydrated during the Middle Ages.
Brilliant, right? So, so interesting!
So today I'm gonna be making kvass, and the reason why I wanted to make it
is because it's super simple to make, and
it is made of only three ingredients:
water, sugar, and bread...bread!
So there are many different recipes and techniques to make kvass,
some use additional amounts of yeast with the bread,
some use fruits, some use this kind of flour paste
Lots of different recipes - some even use beets
Basically we need some kind of sugar that needs to be fermented,
we need a source of yeast, we can add additional
manufactured or commercial yeast
Or we can use naturally occurring yeast,
which exists everywhere kind of similar to sourdough
But today I'm going to use the simplest process,
I love the idea of just using
stale bread, water and sugar to make some kind of beverage
So stinking cool!
And in that sense
this is related to pruno which is
the prison hooch or prison wine that's made in prisons using some kinds of sugar,
kool-aid, ketchup, and the bread
mixed together with water, allow it to ferment,
and you got yourself some prison hooch
That is a prison recipe that I have not made -
if you're interested in seeing that one,
please comment down below
the recipe that I'm gonna be using today
I found from the Beets & Bones blog
and I will put a link down in the description
So the first thing you're gonna do
is take your bread
I'm using a very dark rye bread or pumpernickel bread
So place the bread on a rack and allow it to dry out
Some other recipes say that you can also toast this
to get a really dark color
that will also make your kvass a darker color
So, after a day
the bread was very very crisp and dry
and I cut it into small pieces
and we're gonna need two cups of that
So bring six to eight cups of water to a boil
and once it comes to a boil you're going to take about two cups of that and
add it to one cup of raw cane sugar
You're gonna stir this up until the sugar is completely dissolved
The sugar water needs to be at 130 degrees or less,
we don't want to add it immediately to
the bread because it will kill
the yeast
And the reason why we're using hot water is that the hot water will extract
more of the flavor from the bread
Once we've added the syrup,
we're just gonna close up the jar,
put it in a warm spot and allow it to ferment
anywhere from three to seven days
Every day or so you want to open the jar up
and allow it to burp a little bit
because carbon dioxide will build inside of
the jar
It's been six days for me and now we are ready to consume our kvass
So we're going to strain it
I should also mention, this is not the first time ever had kvass
I had my first tasting of it
I believe in my 'Emmy Eats Serbia' video
I also had the Estonian version of kvass and it's called kali,
and that was in my 'Emmy Eats Estonia' video
and I will put the links to those videos down below
So, let's see how mine compares:
open up my container
Ooh!
Can definitely smell the Rye
it smells a little bit anise-y,
kinda sweet
Alright, here we go
Now this soaked bread we can save
and actually use this as a starter for our next batch of kvass
Alright, I'm gonna have to get a second jar
Okay, I'm gonna seal this up
and place this in the refrigerator because kvass
is generally consumed cold
Doo doo doo!
Because this is not completely cold,
I put this in the refrigerator, but it's not completely chilled
I'm going to speed things up with a glass of ice
So, let's try it like that
(ice cracking)
I love that sound of cracking ice
It smells good,
you can definitely smell the rye in there.
Alright, let's give that a taste -
cheers!
Ooooh! Hmmmm!
That is interesting,
that tastes really different than what I remember
the kali and the kvass that I tasted in the cans
It's just slightly effervescent, just a little bit
Actually, the kali I tried
wasn't very effervescent at all, but it was much darker in color,
and as I remember it was called,
oftentimes, Estonian Coca Cola
Because this was the drink of choice before colas and Coca Cola
and sodas and soft drinks invaded
So it's slightly effervescent, there's a little bit of tanginess to it
You can definitely taste the bread
the rye flavor is in there,
it's a little bit anise-y,
a little bit kind of licorice
and it tastes of bread and there's a bit of sweetness to this,
that tastes kind of caramelized
but the color is really different than the kali that I tasted --
the kali was much much darker in color.
This is almost like a ginger-ale in color.
Hmm! Not bad!
I like it's actually really refreshing when you have it cold.
The kvass that I had in my Serbia video was also very dark in color,
and had a similar kind of bready flavor,
but it didn't taste as much like rye bread as this one.
And the glass that I had in the can I remember was much
fizzier than this one.
And I've read that you can make this fizzier by adding
just a pinch of commercial yeast to this
about a day before you're ready to
strain the bread out to give an extra little bit of carbonation.
But I kind of like it like this --
just barely barely a little bit of bubble in there.
This reminds me a little bit of kombucha,
it's not nearly as vinegar smelling or vinegar tasting as kombucha.
I love kombucha, by the way, if you haven't seen my kombucha video,
I have a very old video
on how to make it at home.
I'll put the link above and down below.
This reminds me of that a little bit because it has a little bit of a kind of a
slightly fruity flavor to it
But, it's more tangy rather than being
really kind of vinegar-ed
But this has a very strong rye bread flavor to it,
very interesting drink and when you iced it,
Very. Refreshing.
So, there you have it homemade kvass or
bread beer
If you've got some leftover pumpernickel or rye bread around
definitely try making this it's really fun
and I love the process of fermentation!
It's absolutely fascinating natural and alive
There's something about this energy that happens when something is fermenting,
you can hear it fizzing,
you can see the bubbles bubbling and gurgling,
it's just absolutely delightful
Alrighty, I hope you guys enjoyed that one,
I hope you guys learned something,
please share this video with your friends
Follow me on social media
check out the Fermented playlist
and...yeah!
Like this video, subscribe, and I shall see you in the next one!
Toodaloo! Take care! Byeee!
(giggles)
(Sprightly outro music)
('Recognized By Accident' music)
kvass kvass kvass kvass kvass KVASS!
(burp)
You knew it was coming!
(snare drum)
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INTRODUCTION
============
Despite the progress in the laboratory detection of acute myocardial infarction (AMI), medical history remains the most important diagnostic step in order to establish the diagnosis. Most patients with AMI describe a severe, pressure-type pain in the mid-sternum, often radiating to the left arm, neck or jaw \[[@R1]\]. The pain resembles angina, but it can be distinguished from it by its intensity, duration (\>30 min), and failure to resolve with nitroglycerin administration. The pain may also be accompanied by nausea, vomiting and diarrhea, especially when the infarction is located in the inferior wall \[[@R1]\]. Other symptoms include dyspnea, diaphoresis, dizziness, palpitations, cold perspiration, profound weakness and syncope \[[@R1],[@R2]\]. The diagnosis of AMI may be difficult when atypical symptoms occur, such as indigestion, unusual localization of the pain, agitation and altered mental status \[[@R1],[@R2]\]. Furthermore, AMI may be silent in more than 25% of cases, in which the infarction is not recognized by the patient and evidence of the infarction is provided by the electrocardiogram or post-mortem examination. Asymptomatic infarction occurs more frequently in elderly patients with hypertension, angina pectoris, and, mostly, diabetes mellitus, as a result of the polyneuropathy that accompanies long-standing and uncontrolled diabetes \[[@R1]\].
We describe a case presented with headache as the sole symptom of AMI.
CASE REPORT
===========
A 42-year-old male, with no history of coronary artery disease or any other risk factor, including hypertension, hyperlipidemia, smoking, and positive family history, presented to a primary health center, complaining for acute onset of severe headache beginning 4 h before. The headache was located mainly frontally and bitemporally and was constant with no periods of relief, even after taking analgesics. Since the physical examination and electrocardiogram were normal (Fig. **[1a](#F1){ref-type="fig"}**), no further evaluation was requested and the patient was discharged home. Two hours later, the patient was admitted to our emergency department complaining of persistent headache. On admission, he was conscious, well-orientated and the vital signs and physical examination were normal. The electrocardiogram showed a q wave with mild ST elevation (1.2 mm) and inverted T wave in the precordial leads V~2~-V~5~ (Fig. **[1b](#F1){ref-type="fig"}**). Laboratory examination revealed the following abnormal findings: serum glucose 382 mg/dl (70-110 mg/dl), CK 336 U/I (0-190 U/I), CK-MB 32 U/l (0-24 U/I), LDH 459 U/I (240-410 U/I) and troponin 0.19 ng/ml (normal\<0.03 ng/dl), whereas the rest hematological and biochemical parameters were normal. The chest X-ray was also normal. On the basis of the electocardiographic and cardiac enzyme findings (i.e. elevated troponin, CK-MB) the diagnosis of an AMI was established.
The patient was treated with loading dose of clopidogrel (600 mg), aspirin and heparin (5000 IU). Urgent coronary angiography was performed (10 h after the onset of the headache) which showed that the left anterior descending artery was totally occluded, whereas the rest coronary arteries were angiographically normal. Primary percutaneous coronary intervention (PCI) was performed in the culprit lesion followed by zotarolimus-eluting stent implantation. Of note, the headache was totally resolved during the PCI and the patient remained asymptomatic for the rest of his hospitalization. In the follow-up ECG the q waves were preserved, whereas the elevated ST segments and inverted T waves gradually returned to normal. Cardiac enzymes (CK-MB, troponin) followed a declining course. On the basis of elevated serum glucose and abnormal glucosylated hemoglobin (HbA1c = 12.6%) the diagnosis of diabetes mellitus was established and the patient was started on insulin treatment. An echocardiogram 7 days after the onset of the symptoms showed left ventricular dilatation with mildly impaired ejection fraction (45%), as well as anteroseptal wall and apex hypokinesis. The patient was discharged from the hospital in good clinical condition on the eighth day of hospitalization.
DISCUSSION
==========
The diagnosis of AMI is generally straightforward for most of the patients who present with typical chest pain. However, the diagnostic procedure becomes difficult when the patient complains for atypical symptoms. In most studies headache may co-exist with other typical symptoms. However, headache as a sole leading symptom of an AMI is extremely rare, as only a few reports exist in the literature which mostly refer to patients over 60 years old \[[@R3]-[@R6]\].
The presence of risk factors for cardiovascular disease, such as arterial hypertension, diabetes mellitus, hyperlipidemia, smoking, and positive family history increase the possibility of AMI, and therefore AMI should always be included in the differential diagnosis when evaluating such patients. In the current case, the patient was not aware of having diabetes mellitus. Undiagnosed, and therefore, long-standing diabetes mellitus and the subsequent diabetic polyneuropathy was likely associated with the absence of chest pain.
The fact that the patient was relieved from his severe headache immediately after the PCI suggests that the headache and cardiac ischemia may be closely correlated. Although the underlying pathophysiologic mechanism of headache is not well understood, one could speculate that an acute reduction of the cardiac output as a result of an AMI, especially in the presence of cerebral artery atherosclerosis, could result to the onset of neurological manifestations, such as headache. Alternatively, the headache in the setting of an acute cardiac event may be related to a generalized catecholaminemia-induced vasospastic disorder and subsequent increase of intracranial pressure \[[@R3],[@R8]\]. Another explanation of the headache in the setting of an AMI involves the perception of cardiac ischemic pain as headache due to the convergence - most likely at a thalamic level - of cardiac autonomic nerve fibers with somatic nerves originating from the head \[[@R3],[@R5],[@R7],[@R8]\]. Finally, it has been suggested that headache-eliciting mediators released during cardiac ischemia may also have a role in the manifestation of headache; however this issue is still under investigation \[[@R8]\].
In conclusion, we present an extremely rare case of an AMI presenting with headache as a sole symptom. Physicians should always consider headache as a presenting symptom of an acute coronary event, especially in patients at risk for cardiovascular disease. In a broader spectrum, physicians should consider the possibility of ischemic heart disease at every patient with recurrent headache on exertion, after the exclusion of intracranial pathology, especially in the presence of cardiovascular risk factors.
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Syrian rebels open new battlefront near Damascus
Damascus, March 13, 2013
Heavy fighting erupted in an area between Damascus and the Israeli-occupied Golan Heights on Wednesday in what could be a new battlefront between Syrian troops and rebels, opposition sources said.
Rebel fighters attacked an army barracks manned by elite Republican Guards and the Fourth Mechanised Division, headed by President Bashar al-Assad's brother Maher, in Khan Sheih, 6 km from the outskirts of Damascus, civilian activists and an opposition military source said.
An opposition campaigner in the nearby town of Jedeidet said troops stationed in hills overlooking Khan Sheih were attacking the area with multiple rocket launchers to try to dislodge rebels surrounding the barracks.
"I counted up to 20 explosions a minute on Khan Sheih," the activist, who uses the pseudonym of Abdo, told Reuters by phone.
A rebel commander in contact with the fighters said a force of some 1,000 insurgents had moved into Khan Sheih, which is 25 km from the Golan Heights, captured by Israel in 1967.
He said rebels had also attacked Syrian army positions in the town of Qunaitra, near the ceasefire line with Israel, and further south near the Golan, but those troops were well dug in.
"The aim is to cut supplies to Qunaitra," he said, adding that the Khan Sheih operations were also intended to relieve pressure on the southwestern Damascus suburb of Daraya, where a rebel pocket has been under army siege for two months.
The main front around Damascus has been in eastern suburbs and neighbourhoods and suburbs. Assad's forces have made incursions into Daraya on the highway to Jordan, but have not been able to retake it, opposition sources say.-Reuters
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This invention relates to a method and a system for processing molten slag and eventually for producing solidified slag which can be used as a construction material instead of natural gravel or the like.
Conventionally the slag which is discharged in great quantity from the refinery processes of a steel making plant is merely air-cooled so that the slag dusts or collapses or produces the yellow colored water which contains sulfur and hydrogen sulfide all of which lead to environmental pollution.
The conventional method for processing molten slag is called the "field method" wherein the molten slag is extensively spread onto a field and is air cooled for a long period. This method, however, has required a lengthy series of operations. Furthermore the solidified slag cuts deeply into the field or ground so that the thickness of the layer of the spread slag becomes irregular whereby the removing operation that is usually conducted after the slag has completely solidified becomes extremely difficult and produces a tremendous amount of dust leading to air pollution. The processed slag which is produced by this conventional method still contains the non-reacted lime or an unstable phosphorus material therein so that the slag collapses and the above mentioned yellow colored water is produced which necessitate difficult methods of treatment.
For the purpose of resolving the problems which afflict conventional methods, various improvements have been made wherein the slag in the molten stage is rapidly cooled by a desired means in order to prevent the occurrence of collapse of the slag and the production of yellow collored water.
The inventors of this application also have applied for a patent on a method for processing molten slag in Japan wherein the slag in the molten stage is spread extensively on a steel plate. However, the improved methods including the above mentioned inventors' method have proved unsuccessful from the practical point of view and have included various problems yet to be resolved.
It is an object of the present invention to provide a method and a system which can resolve the aforementioned defects of conventional methods and systems.
It is another object of the present invention to provide a method and system for processing molten slag which is characterized in that molten slag is first discharged onto the desired slag receiving means in a roofed slag processing factory and then is air and water cooled and finally is water-quenched so that the solidified slag of practical use which neither collapses nor produces dust.
It is still another object of the present invention to provide a method and a system for processing molten slag in a roofed slag processing factory without causing air pollution.
It is further an object of the present invention to provide a method and a system for processing molten slag which is characterized in that all the necessary devices for processing molten slag are arranged in a roofed slag processing factory systematically and compactly.
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The Obama administration calls its national security strategy “Countering Violent Extremism.” In the benighted times before January 20, 2009, we used to call it counter-terrorism.
Why does Obama insist on the more fuzzy “extremism”? Because “terror” has its roots in Islamic scripture. This fact ought to be undeniable, but Obama denies it -- and in Washington, he’s far from alone in that.
It is not just that the word terror appears several times in the Koran; it is that the word appears in a particular context: The duty of Muslims to act as Allah’s instrument to terrorize non-Muslims is a recurring scriptural theme. In Sura 3:151, to take one of several examples, Muslims are admonished:
Soon shall We cast terror into the hearts of the unbelievers.
Omar Abdel Rahman, the “Blind Sheikh” I prosecuted in the mid-'90s after his cell bombed the World Trade Center and planned similar strikes against other New York City landmarks, was a renowned scholar of Islamic jurisprudence. Indeed -- and this is worth pausing over -- his mastery of our enemy’s ideology was the sole source of his authority to approve jihadist attacks. Think about that: his blindness, and various other maladies, render Abdel Rahman unable to do anything useful for a terrorist network. He can’t build bombs, command forces on the battlefield, execute assassinations, and so on. But his authority is unquestioned because of his scholarship and rhetorical power in the scripture-based doctrine our president pretends is non-Islamic and of marginal importance.
Sheikh Abdel Rahman was adamant that terror is fundamental to Islamic doctrine:
Why do we fear the word terrorist? If the terrorist is the person who defends his right, so we are terrorists. And if the terrorist is the one who struggles for the sake of God, then we are terrorists. We ... have been ordered with terrorism because we must prepare what power we can to terrorize the enemy of Allah and your enemy. The Koran [said] “to strike terror.” Therefore, we don’t fear to be described with “terrorism.” ... They may say, “He is a terrorist, he uses violence, he uses force.” Let them say that. We are ordered to prepare whatever we can of power to terrorize the enemies of Islam.
Obama’s national security strategy is suicidal because it mulishly denies two unavoidable facts: (a) terrorism is rooted in Islamic supremacism’s literalist construction of scripture, and (b) even if Islamic supremacism is not the only way of interpreting Islam, it is a mainstream interpretation of Islam.
Islamic supremacism is not merely the creed of outlier “violent extremists,” but of hundreds of millions of Muslims, the ocean in which jihadists comfortably swim. A commander-in-chief who does not or will not come to terms with those facts is unfit for his most basic responsibilities. His stubbornness renders him incapable of protecting the nation.
That’s Obama. Understand: the president is not refusing to associate terror with Islam out of political correctness. His delusion is ideological. It informs his every decision. It is why the terrorist threat has so intensified, and why we are in more peril today than at any time since before the 9/11 attacks.
Don’t use training that is all “war stories,” which may rely too much on outdated information and overgeneralizations. Regaling an audience with a blow-by-blow account of a 2003 terrorism investigation does not address the changing nature of violent extremism we face today.
Obama believes the nature of terrorism is changing. This is absurd. The violence today is executed by jihadists. They are motivated by a scripture-based doctrinal command to impose sharia -- Islam’s societal framework and legal code, which is the necessary precondition to Islamicizing a society and, ultimately, establishing a caliphate. That is why they kill today, it is why they killed in 2003, in 1993, in 1800, in 1565, in 1064, in 732, and so on all the way back to the raids Muhammad himself led in the seventh century. The technology and tactics of violent jihadism have changed over time; the nature of it has been the same for nearly a millennium-and-a-half.
The Obama administration has thoroughly politicized national security (just as it has politicized law enforcement and most everything else), so I would not disappoint you by saying the president’s approach to “violent extremism” is all ideology and no cynicism. By bleaching out the ideological catalyst for mass-murder attacks and attributing them to “extremism” without acknowledging what the killers are extremeabout, Obama promotes an ugly moral equivalence between jihadists and his political opposition, whose members are habitually smeared as “extremists.” It is no surprise that, while unable to bring itself to concede that the Fort Hood massacre was a jihadist attack, the Obama administration was issuing Homeland Security Department memos that profiled conservatives and U.S. soldiers returning from war as potential violent extremists.
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Roles of lipid peroxidation and cytoplasmic droplets on in vitro fertilization capacity of sperm collected from bovine epididymides stored at 4 and 34 degrees C.
Sperm recovery from the cauda epididymis can be very advantageous, for example, in case of the unexpected death of a genetically highly valuable animal, for preserving endangered species, or when the collection of sperm by other means becomes impossible. Studies indicate that epididymides stored at cooler temperatures result in better quality sperm. One of the factors that could negatively affect sperm viability during storage is lipid peroxidation, in which the sperm membrane's ability to resist attacks by reactive oxygen species (ROS) plays an important role. Another factor is the presence of cytoplasmic droplets, which appear in high numbers in epididymal sperm, and are known to influence oxidative stress. The objectives of this study were: to determine whether the post-slaughter storage temperature of the epididymis would effect the sperm membrane's resistance to lipid peroxidation and/or the sperm cell's fertilizing capacity in vitro and to elucidate the role played by the cytoplasmic droplets. Forty-eight testicles with epididymides (24 bulls) were collected following slaughter, and divided into two groups. One testicle from each pair was stored at 4 degrees C, and the other at 34 degrees C, for 2h, after which sperm was collected from the caudae epididymides. Sperm concentration was measured, and an aliquot containing 10(8)sperm was subjected to induced lipid peroxidation with ferrous sulphate and ascorbate (37 degrees C, 2h). Subsequently, thiobarbituric acid reactive substances (TBARS), as an index of lipid peroxidation, were measured. A second aliquot of the same sample was used in a routine in vitro fertilization performed in duplicate. Sperm from caudae epididymides stored at 34 degrees C resulted in lower rates of total blastocyst formation and had a higher percentage of distal droplets, when compared to sperm from epididymides stored at 4 degrees C (21.2+/-2.42 and 71.8+/-4.7% versus 33.5+/-1.8 and 23.7+/-4.7%, respectively, P<0.05). Storage temperature had no effect on TBARS levels. For samples stored at 4 degrees C, TBARS were negatively correlated with distal droplets (r=-0.63, P<0.05) and positively correlated with proximal droplets (r=0.42, P<0.05). In conclusion, our results show that short-term storage of epididymides at 4 degrees C provided sperm of higher quality and in vitro fertilizing capacity than storage at 34 degrees C. Although resistance to oxidative stress could not be shown to directly influence these results, distal sperm droplets that appeared in high numbers in the cooled epididymal sperm samples, may have exerted an antioxidant effect. We hypothesize that this protection against ROS is one of the functions of distal sperm droplets in the epididymis.
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Kawara Museum
The (Omihachiman City Rooftile Museum) is a museum in Ōmihachiman, Shiga, Japan, devoted to Japanese-style roof tiles (kawara).
Buildings
The museum consists of ten buildings with roof tiles which form a whole pavilion. The new tiles on the roof of the museum were blackened to make them look older and thus fit in better with the other buildings in the neighborhood.
Exhibits
In the permanent exhibition room on the first floor objects are displayed to show the history of Omihachiman roof tiles and the process by which they are made. Images of the city of Omihachiman are displayed at the entrance, and there is a large 3-dimensional photograph of the roof tiles of the houses in Shinmachi street at the innermost corner of the exhibition room.
See also
Onigawara, a type of Japanese roof ornamentation
References
External links
Omihachiman City information
Category:Museums in Shiga Prefecture
Category:Ōmihachiman, Shiga
Category:Ceramics museums in Japan
Category:Museums established in 1995
Category:1995 establishments in Japan
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Q:
What is a fixed width binary data format?
What is fixed width binary data format and what's an example of it? If it's 8x8 fixed width binary, what does this mean and how much memory would it occupy in terms of bits?
I googled fixed width binary data format and searched stackoverflow. A different post on stackoverflow on how to handle fixed width binary (Ideal Field Type For Fixed Width Binary Data) wasn't helpful.
A:
There are two ways to store data : Variable length and fixed length. Variable length data format won't use max length every time while fixed one will use max provided fixed length every time. Fixed data format will use chunks/blocks of fixed size to store data.
Due to same, variable length uses less space but can't provide indexing while fixed length uses more space but you will get indexing as you can jump directly to the specified chunk.
Ex : In case of fixed n length data format. Data chunks of n length will be created and you can jump directly to X'th chunk by calculating memory index X*n .
For understanding : https://documentation.microfocus.com/help/index.jsp?topic=%2FGUID-0E0191D8-C39A-44D1-BA4C-D67107BAF784%2FBKFHFHORGSS014.html
As you have specified fixed width binary data format. So it is fixed length/width binary type format.
8x8 fixed width binary = 8 bytes fixed width data format = 64 bits fixed width data format .
It will store chunks/blocks of 64 continuous bits in memory.
Ex : In case of 8x8 fixed width binary type data format, you may try to store a data which requires 1 byte only but it will be stored in 8 bytes by padding 0's to make it fixed length.
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How to set the default font in Zimbra 5.0.18 for curent ant future users
The default font now when composing mail is Times new roman. I want to change this to Verdana. I open COS and change default font setting from Times new roman to Verdana but nothing happens.
I checked few mail accounts and their font settings and they were all set to Arial.
If you read my initial post you would noticed
I opened COS and change default font setting from Times new roman to Verdana but nothing happens.
I checked few mail accounts and their font settings and they were all set to Arial.
Is this some kind of bug, or did all my users choose Arial ?
But this doesn't have any effect. Obviously I need to flush cache which I didn't know and I'm gratefull to Saturdays and fyd to point this out.
1. I changed the setting in the COS (times new roman > verdana)
2. I ran "zmprov fc cos default"
3. I opened Zimbra web mail and checked Font setting under settings > composing and there is still Times new roman font selected. Well this makes me a sad panda
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Christmas gift ideas for a guy you just started dating
” My dad yells from the living room.“You got engaged at two months,” I yell back.“So?” I hear my father flipping channels.“So I don’t trust your timetable! ”My first boyfriend and I had been dating two months when Christmas came along.Based on inspiring true events, my God, Please Fix Me!trilogy will teach you how to be the woman that men pursue for a serious relationship.”“He’s watching The Godfather again,” my mom says, then: “You do care about-”“Don’t say the name! I’d planned his gift—a copy of Edward Albee’s Seascape and a gum wrapper necklace—for 90 days, and watching him open it, I knew I’d scored. Although strangely, I’m fine with giving hand-jobs. Not only do I try to keep hand-job references to a minimum with them, but I don’t believe past trauma excuses present dysfunction.When he broke up with me the next day, I pointed out that maybe he should have pulled the plug before I gave him a Christmas present, not to mention a hand-job. Still, my pathological reluctance to drop money at my beloved JCrew when they’re offering a whopping thirty percent off an obviously perfect gift is probably not normal.“It’s just that you keep making that keening sound.”“I just don’t think I can do it.”“Why the hell not?
So If you feel like you’re in a hopeless situation and you have no idea what to get for your new boyfriend or girlfriend, don’t freak out. Check out these 12 cute and affordable Christmas gifts for the person you just started dating. A Cool Mug Regardless of your partner’s preferences, you just can’t go wrong with a really cool mug. This is your chance to showcase how well you actually know your partner.There’s bound to be somewhere in your town that neither of you have yet to try, so why not make a night of it together?Plan ahead with reservations and make the night special with a meal that lingers, all the way from pre-dinner cocktails to dessert.This is especially perfect if your partner is a huge fan of puzzle games and brain teasers! A Netflix Subscription Image source: i Stock You just can’t go wrong with a Netflix subscription.Aside from the fact that it’s affordable, you’re practically giving your partner the gift of free movies and TV.
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MYP Blog
Evolve: End Violence Against Animals!
Mauritius has been creating international headlines recently not for their beautiful beaches and sunny climate, but for some dark and dirty secrets coming to the surface, all of them concerning animal treatment. The shocking news that this “Paradise Island” is amongst the last ones to export live monkeys to laboratories all over the world has created international stir and caused animal loving visitors to even cancel their island holidays. Now, as the stormy waters have calmed down a bit, an even more shocking film has been put online, showing the practices at a MSAW (Mauritius Society for Animal Welfare) “shelter”.
The footage shows incredible cruelty towards dogs. During the few minutes of footage, dogs of any age, size and build, some wearing collars, are beaten, kicked, thrown about, hosed down with high-pressure water and killed forcefully by injection, even a shy and friendly mother with small puppies. There is nothing orderly about the scenes, no vet in sight, just a bunch of crude-looking hateful men doing their dirty task with gusto. The last pictures show a big pile of lifeless bodies – a blood-chilling sight
To make bad turn into worse, the concerned minister stated in the Mauritian press that this activity is being done for national interests. It seems that he and the government of Mauritius fail to understand is that this absolutely not the case. On the contrary: not only numerous Mauritians, but also expats living in Mauritius and certainly the tourists are crying out against that kind of cruelty. Manifestations have taken place and petitions against the Government’s policies have been signed by people from all over the world. Animal rights organisations have called to boycott Mauritius as a tourism destination as long as the hellish conditions are not eliminated.
Local experts fear that the situation might escalate and weaken tourism, one of the pillars of Mauritian economy. In the meantime, animal welfare organisations such as PAWS have offered training and assistance, as evidently a sensible sterilisation-programme has proven to yield better results. So what will the government do? Whatever the outcome, those concerned have better consult the laws, as meanwhile the whole world is watching and ready to act on behalf of Mauritius animals’ rights.
I am a Switzerland-born producer of holistic nature products and journalist, living in Mauritius since 15 years. Having lived in exotic places around the world, such as Tahiti, New Zealand and Hawaii, I am especially interested in islands, their fascinating nature and plant life. As a result, I constantly cook up stories from the neighbourhood as well as inspired recipes from all that great stuff growing in my bio-garden.
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If you enjoy photography, radio controlled vehicles, or any other activity that requires you to keep multiple sets of rechargeable batteries on hand you know how much of a pain it can be if you get a dead battery mixed in with your charged batteries. This easy approach to managing your batteries while on location does not require fancy electronics, meters or anything else that might pop into mind, but rather simple stickers and storage.
The first set of labels get stuck on the battery, offering a green and red color code along with a number so its easy to keep track of which group of batteries go where and to catalog date / life. The second set of labels gets attached to your storage compartment, when a battery is charged, place it in the box so the positive end is facing the green on the storage label, and when its dead just flip it around.
While this mainly focuses on AA batteries (and even shows you how to make a simple but effective holder out of some elastic band and staples) this idea can be used with just about any type of battery for a quick glance to see where you stand on juice.
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Blue in colour, this handbag from the exclusive collection of Peperone will become your instant favourite. The PU (polyurethane) material of this handbag ensures durability. Exhibiting twin handles, a zippered pocket and a chic design, this handbag will be a worthy pick.
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Featured Shows
Weekday
Weekend
Can Trump's new chief of staff bring order to chaotic West Wing?
After over 200 days of reports that Trump's White House is chaotic and divided, can his new chief of staff John Kelly finally bring some calm? Zeke Miller & Anita Kumar react. ...moreDuration: {{video.duration.momentjs}}
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M.F.A. Graduate Lands Broadway Part
March 6, 2013
Paula Jon DeRose '10 joins the cast of Nora Ephron's Lucky Guy as an understudy for two of the play's female characters.
Little more than two years after receiving her master of fine arts degree from Brooklyn College, Paula Jon DeRose is making her mark on Broadway. Nora Ephron's Lucky Guy, which debuted for previews March 1 at the Broadhurst Theatre, features Academy Award winner Tom Hanks in the role of late New York Daily News writer Mike McAlary. DeRose is an understudy for two of the play's female characters, including McAlary's wife, Alice, who is being played by the film and television actress Maura Tierney.
"This is a dream come true," says DeRose, who grew up in New Jersey and often came to New York to see Broadway shows with her family. "I fell in love with the theater," she says, adding that this role is a huge opportunity for her. "Professionally, it opens doors."
Lucky Guy, directed George C. Wolfe, celebrates the life of McAlary, a charismatic columnist who won the Pulitzer Prize in 1998 for his coverage of the infamous Abner Louima police brutality case. On Christmas Day of that same year he died of colon cancer at the age of 41.
DeRose credits, in large part, the Brooklyn College M.F.A. in Acting program for her being selected as a member of the cast. "In 2008, I realized that, in addition to performing, I wanted to teach acting," she says. "So I auditioned for the Brooklyn College program and was accepted. Two years later I came away from that experience with a new confidence in myself and in my abilities."
Acting program director Judylee Vivier made quite a positive impression on DeRose. "She was really hands-on," she says. "There was a lot of individual attention in the program, which is sort of rare. You're usually just one of many in acting classes."
"Paula has a very special quality and talent," says Vivier. "I'm thrilled that it has been noticed and she has been given this opportunity." It also didn't hurt that Heidi Griffiths, casting director at the Public Theater, was casting Lucky Guy and recalled DeRose from an earlier visit to Brooklyn College.
Lucky Guy will officially open on April 1 for a limited run through June 16. Noted playwright Ephron, who died in 2012, is best known for her romantic comedies, which include When Harry Met Sally and Sleepless in Seattle.
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William I of Weimar
William I (died 16 April 963) is the first known member of the house of the Counts of Weimar.
Life
William was first mentioned in a 949 deed as a count (Graf) in Thuringia. Originating from the Saalfeld region, he held large estates around Weimar, Jena, and Apolda, possibly stemming from late Duke Burchard of Thringia, whose sons were expelled by King Henry the Fowler in 913.
He was probably married to a daughter of the Babenberg duke Poppo of Thuringia, margrave of the Sorbian March, who had been deposed by the East Frankish king Arnulf in 892. William too appeared in the rank of a Thuringian margrave. From 953 to 955, he and several Wettin counts joined the revolt of Duke Liudolf of Swabia against King Otto the Great, wherefore he was temporarily deposed and exiled to the court of Otto's brother Duke Henry of Bavaria. By 956, however, William was re-installed into his offices.
He had at least three children:
William II (d. 1003), called the Great, succeeded his father as Count of Weimar, Duke of Thuringia from 1002
Poppo
Sigbert
Category:963 deaths
Category:Year of birth missing
Category:House of Weimar
Category:10th-century German people
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Tuesday, September 27, 2016
Jay and Sam prepare for a multi-episode discussion of The Oz Kids
video series, starting by giving some general information about the
series, including its characters, premise and general availability.
First off, I got contacted by RAMstar Studios, who says they're producing a live action movie adaptation of Donald Abbott's How The Wizard Came To Oz, set to be released to theaters in 2018, directed by Cole S. McKay. Producers are BJ Plott, Dan Guardino, and Derrick Iloni. The budget is a modest $35 million, but it's not always about how much you have as much as how you use it.
The synopsis provided is as follows...
When a runaway balloon carries Oscar Zoroaster Diggs to the war torn
Land of Oz he inadvertently manages to bring peace to its people, and
finds himself hailed as a great wizard. Now he has to defeat a vengeful
witch to maintain the peace.
THE WICKED WIZARD OF OZ is set after the events of The Wonderful Wizard of Oz.
Dorothy finds herself transported back to the marvellous Land of Oz and
hunted by the Wicked Witch of the West's flying monkeys. But how can
the Witch be back? And why has Dorothy been brought back to Oz? There's
only one way to find out.
Joined by her friends - the Scarecrow,
the Tin Woodman, and the Lion - Dorothy sets off for the Emerald City.
Surrounded by enemies on all sides, will you uncover the secrets of THE WICKED WIZARD OF OZ?
I was contacted about this just today, so I don't really have any more information than what can be found on the Kickstarter website. But lovers of all things Oz might want to look into supporting this to help it happen and get their hands on some unique Oz collectibles.So, finally, what to do on the blog after blogging for so long? Aside from blogging about Oz books I've read (which I've even fallen behind on that as I read a new edition of Wonderful Wizard and Marvelous Land on my return from Oz Con I meant to write about), it feels like most of the ideas there would be to write about I have written about!Well, I had an idea. How about breaking down the history of Oz and our own culture into a timeline and begin going in for indepth looks at the world L. Frank Baum created his stories in, and how his stories later influenced that world? The scope is wide enough to basically include anything related to Oz. A blog about Baum's life might be flanked by examinations of his work at the time or about where he lived and what was going on in the US and the world. I'd certainly welcome guest posts.
I'd like to tie podcasts into this as well, I could certainly see me inviting David Maxine to discuss the 1902 Wizard of Oz musical. "Movies of Oz" would run separately, but blogs about the movies would certainly pop up, perhaps multiple posts.Basically, whenever we're done, what we'd have would hopefully be a
massive body of work about Oz.
Legal
All original content on this blog is copyright of the respective writers. No copying of posts is allowed except for private purposes, including offline viewing, printing, but this excludes use in commercial print materials and other media without the consent of the writer. (This means posting it elsewhere online is not allowed!) Quoting blog entries is allowed as long as a link is provided to the original blog. In addition, quotes are allowed in print materials, as long as the source is cited.
Illustrations, photographs, screencaptures, and videos are the copyrights of their respective owners and used under the fair use clause of the copyright law. If you feel such use violates your copyrights, please contact Mr. Davis. Following the DMCA, we will remove any infringing material promptly. Any completely original artwork or photography is copyright of its producer, and should not be copied without permission.
All opinions expressed are those of the person expressing them and may not be shared by other writers on this blog.
AUTHORS AND CREATORS OF MATERIAL THAT MAY BE REVIEWEDIf I review a book or other media created by you, the statements in my review reflect my own opinions from the first exposure to your work. All reviews will be unbiased, except in the case of series, where the logical comparison to previous entries will apply. Any quotes or use of images are used under the terms of Fair Use.
If I am asked to review your work, this does not promise a positive review. You, as the author or creator, must accept what review I write. I reserve the right to remove the review with or without notice to you. Please note that retaliation for negative reviews is highly unprofessional, and acts of such may be viewed as harassment.
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#+SETUPFILE: org-setup.inc
#+TITLE: Expanding snippets
This section describes how YASnippet chooses snippets for expansion at point.
Maybe, you'll want some snippets to be expanded in a particular
mode, or only under certain conditions, or be prompted using
* Triggering expansion
You can use YASnippet to expand snippets in different ways:
- When [[sym:yas-minor-mode][=yas-minor-mode=]] is active:
- Type the snippet's *trigger key* then calling [[sym:yas-expand][=yas-expand=]]
(bound to =TAB= by default).
- Use the snippet's *keybinding*.
- By expanding directly from the "YASnippet" menu in the menu-bar
- Using hippie-expand
- Call [[sym:yas-insert-snippet][=yas-insert-snippet=]] (use =M-x yas-insert-snippet= or its
keybinding =C-c & C-s=).
- Use m2m's excellent auto-complete
TODO: example for this
- Expanding from emacs-lisp code
** Trigger key
[[sym:yas-expand][=yas-expand=]] tries to expand a /snippet abbrev/ (also known as
/snippet key/) before point. YASnippet also provides a /conditional
binding/ for this command: the variable [[sym:yas-expand][=yas-maybe-expand=]] contains a
special value which, when bound in a keymap, tells Emacs to call
[[sym:yas-expand][=yas-expand=]] if and only if there is a snippet abbrev before point.
If there is no snippet to expand, Emacs will behave as if [[sym:yas-expand][=yas-expand=]]
is unbound and so will run whatever command is bound to that key
normally.
When [[sym:yas-minor-mode][=yas-minor-mode=]] is enabled, it binds [[sym:yas-maybe-expand][=yas-maybe-expand=]] to =TAB=
and =<tab>= by default, however, you can freely remove those bindings:
#+begin_src emacs-lisp :exports code
(define-key yas-minor-mode-map (kbd "<tab>") nil)
(define-key yas-minor-mode-map (kbd "TAB") nil)
#+end_src
And set your own:
#+begin_src emacs-lisp :exports code
;; Bind `SPC' to `yas-expand' when snippet expansion available (it
;; will still call `self-insert-command' otherwise).
(define-key yas-minor-mode-map (kbd "SPC") yas-maybe-expand)
;; Bind `C-c y' to `yas-expand' ONLY.
(define-key yas-minor-mode-map (kbd "C-c y") #'yas-expand)
#+end_src
To enable the YASnippet minor mode in all buffers globally use the
command [[sym:yas-global-mode][=yas-global-mode=]]. This will enable a modeline indicator,
=yas=:
[[./images/minor-mode-indicator.png]]
When you use [[sym:yas-global-mode][=yas-global-mode=]] you can also selectively disable
YASnippet in some buffers by calling [[sym:yas-minor-mode][=yas-minor-mode=]] with a negative
argument in the buffer's mode hook.
*** Fallback behaviour
YASnippet used to support a more complicated way of sharing
keybindings before [[sym:yas-expand][=yas-maybe-expand=]] was added. This is now
obsolete.
** Insert at point
The command [[sym:yas-insert-snippet][=yas-insert-snippet=]] lets you insert snippets at point
/for your current major mode/. It prompts you for the snippet key
first, and then for a snippet template if more than one template
exists for the same key.
The list presented contains the snippets that can be inserted at point,
according to the condition system. If you want to see all applicable
snippets for the major mode, prefix this command with =C-u=.
The prompting methods used are again controlled by
[[sym:yas-prompt-functions][=yas-prompt-functions=]].
*** Inserting region or register contents into snippet
It's often useful to inject already written text in the middle of a
snippet. The variable [[sym:yas-wrap-around-region][=yas-wrap-around-region=]] when to t substitute
the region contents into the =$0= placeholder of a snippet expanded by
[[sym:yas-insert-snippet][=yas-insert-snippet=]]. Setting it to a character value (e.g. =?0=)
will insert the contents of corresponding register.
Older (versions 0.9.1 and below) of Yasnippet, supported a setting of
=cua= that is equivalent to =?0= but only worked with =cua-mode=
turned on. This setting is still supported for backwards
compatibility, but is now entirely equivalent to =?0=.
** Snippet keybinding
See the section of the =# binding:= directive in
[[./snippet-development.org][Writing Snippets]].
** Expanding from the menu
See [[./snippet-menu.org][the YASnippet Menu]].
** Expanding with =hippie-expand=
To integrate with =hippie-expand=, just put
[[sym:yas-hippie-try-expand][=yas-hippie-try-expand=]] in
=hippie-expand-try-functions-list=. This probably makes more sense
when placed at the top of the list, but it can be put anywhere you
prefer.
** Expanding from emacs-lisp code
Sometimes you might want to expand a snippet directly from your own
elisp code. You should call [[sym:yas-expand-snippet][=yas-expand-snippet=]] instead of
[[sym:yas-expand][=yas-expand=]] in this case. [[sym:yas-expand-snippet][=yas-expand-snippet=]] takes a string in
snippet template syntax, if you want to expand an existing snippet you
can use [[sym:yas-lookup-snippet][=yas-lookup-snippet=]] to find its contents by name.
As with expanding from the menubar, the condition system and multiple
candidates doesn't affect expansion (the condition system does affect
[[sym:yas-lookup-snippet][=yas-lookup-snippet=]] though). In fact, expanding from the YASnippet
menu has the same effect of evaluating the follow code:
#+BEGIN_SRC emacs-lisp
(yas-expand-snippet template)
#+END_SRC
See the internal documentation on [[sym:yas-expand-snippet][=yas-expand-snippet=]] and
[[sym:yas-lookup-snippet][=yas-lookup-snippet=]] for more information.
* Controlling expansion
** Eligible snippets
YASnippet does quite a bit of filtering to find out which snippets are
eligible for expanding at the current cursor position.
In particular, the following things matter:
- Currently loaded snippets tables
These are loaded from a directory hierarchy in your file system. See
[[./snippet-organization.org][Organizing Snippets]]. They are named
after major modes like =html-mode=, =ruby-mode=, etc...
- Major mode of the current buffer
If the currrent major mode matches one of the loaded snippet tables,
then all that table's snippets are considered for expansion. Use
=M-x describe-variable RET major-mode RET= to find out which major
mode you are in currently.
- Parent tables
Snippet tables defined as the parent of some other eligible table
are also considered. This works recursively, i.e., parents of
parents of eligible tables are also considered. As a special case,
if a mode doesn't have a parent, then =fundamental-mode= is
considered to be its parent.
- Buffer-local list of extra modes
Use [[sym:yas-activate-extra-mode][=yas-activate-extra-mode=]] to
consider snippet tables whose name does not correspond to a major
mode. Typically, you call this from a minor mode hook, for example:
#+BEGIN_SRC emacs-lisp
;; When entering rinari-minor-mode, consider also the snippets in the
;; snippet table "rails-mode"
(add-hook 'rinari-minor-mode-hook
#'(lambda ()
(yas-activate-extra-mode 'rails-mode)))
#+END_SRC
- Buffer-local [[sym:yas-buffer-local-condition][=yas-buffer-local-condition=]] variable
This variable provides finer grained control over what snippets can
be expanded in the current buffer. For example, the constant
[[sym:yas-not-string-or-comment-condition][=yas-not-string-or-comment-condition=]] has a value that disables
snippet expansion inside comments or string literals. See [[condition-system][the
condition system]] for more info.
** The condition system <<condition-system>>
Consider this scenario: you are an old Emacs hacker. You like the
abbrev-way and bind [[sym:yas-expand][=yas-expand=]] to =SPC=. However, you don't want
=if= to be expanded as a snippet when you are typing in a comment
block or a string (e.g. in =python-mode=).
If you use the =# condition := directive (see [[./snippet-development.org][Writing Snippets]]) you
could just specify the condition for =if= to be =(not
(python-syntax-comment-or-string-p))=. But how about =while=, =for=,
etc? Writing the same condition for all the snippets is just boring.
So you can instead set [[sym:yas-buffer-local-condition][=yas-buffer-local-condition=]] to =(not
(python-syntax-comment-or-string-p))= in =python-mode-hook=.
Then, what if you really want some particular snippet to expand even
inside a comment? Set [[sym:yas-buffer-local-condition][=yas-buffer-local-condition=]] like this
#+BEGIN_SRC emacs-lisp
(add-hook 'python-mode-hook
(lambda ()
(setq yas-buffer-local-condition
'(if (python-syntax-comment-or-string-p)
'(require-snippet-condition . force-in-comment)
t))))
#+END_SRC
... and for a snippet that you want to expand in comments, specify a
condition which evaluates to the symbol =force-in-comment=. Then it
can be expanded as you expected, while other snippets like =if= still
can't expanded in comments.
For the full set of possible conditions, see the documentation for
[[sym:yas-buffer-local-condition][=yas-buffer-local-condition=]].
** Multiples snippet with the same key
The rules outlined [[Eligible%20snippets][above]] can return more than
one snippet to be expanded at point.
When there are multiple candidates, YASnippet will let you select one.
The UI for selecting multiple candidate can be customized through
[[sym:yas-prompt-functions][=yas-prompt-functions=]] , which defines your preferred methods of being
prompted for snippets.
You can customize it with
=M-x customize-variable RET yas-prompt-functions RET=. Alternatively you
can put in your emacs-file:
#+BEGIN_SRC emacs-lisp
(setq yas-prompt-functions '(yas-x-prompt yas-dropdown-prompt))
#+END_SRC
Currently there are some alternatives solution with YASnippet.
*** Use the X window system
[[./images/x-menu.png]]
The function [[sym:yas-x-prompt][=yas-x-prompt=]] can be used to show a popup menu for you to
select. This menu will be part of you native window system widget, which
means:
- It usually looks beautiful. E.g. when you compile Emacs with gtk
support, this menu will be rendered with your gtk theme.
- Your window system may or may not allow to you use =C-n=, =C-p= to
navigate this menu.
- This function can't be used when in a terminal.
*** Minibuffer prompting
[[./images/ido-menu.png]]
You can use functions [[sym:yas-completing-prompt][=yas-completing-prompt=]] for the classic emacs
completion method or [[sym:yas-ido-prompt][=yas-ido-prompt=]] for a much nicer looking method.
The best way is to try it. This works in a terminal.
*** Use =dropdown-menu.el=
[[./images/dropdown-menu.png]]
The function [[sym:yas-dropdown-prompt][=yas-dropdown-prompt=]] can also be placed in the
[[sym:yas-prompt-functions][=yas-prompt-functions=]] list.
This works in both window system and terminal and is customizable, you
can use =C-n=, =C-p= to navigate, =q= to quit and even press =6= as a
shortcut to select the 6th candidate.
*** Roll your own
See the documentation on variable [[sym:yas-prompt-functions][=yas-prompt-functions=]]
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UPA should withdraw its affidavit on Lord Rama: BJP
Published: Thursday, September 13, 2007, 21:35 [IST]
Subscribe to Oneindia News
Patna, Sep 13 (UNI) The BJP today urged the UPA to withdraw its affidavit filed before the Supreme Court in connection with the Setusamudram project raising doubts over the very existence of Lord Rama.
BJP National General Seceretary Kiran Ghai said here that instead of withdrawing some of the paragraphs of the affidavit which triggered heat in all walks of life, the UPA should withdraw the complete affidavit filed in connection with the project.
''The announcement of the UPA to withdraw the controversial paragraphs of the affidavit was an open testimony to the fact that it admits to have 'misled' the apex court. In such circumstances the entire affidavit automatically becomes 'irrelevant' and 'misleading,' and instead of filing a supplimentary affidavit the UPA should withdraw it as a whole,'' she said.
Ms Ghai said influenced by the left parties, the UPA had hurt the religious sentiments of 70 crore Hindus living in India.She also pointed out that it was Congress which had accepted Lord Rama as 'Rahstra Purush' and the Indian Constitution drafted during Congress regime carried the photographs of Lord Rama.
She alleged that with the sole motive to safeguard its power, Congress was trying to appease the left parties by questioning the very existence of Lord Rama in the affidavit. ''Rama is an ideologue relevant right from birth to death and for hurting the sentiments of Hindus UPA Chairperson Sonia Gandhi should apologise,'' she said.
Ms Ghai further said through the affidavit the UPA government raised doubts stating that there was no scientific evidence of Ram Setu, a creation of mankind, and had mentioned that it was actually a natural construction evolved during geological process over a long period.
She said all available informations revealed that the Ram Setu was consturcted during the Holy battle between Ram and Ravan fought to restore the supermacy of 'dharma' over 'adharma'(evil forces).
Meanhwile, BJP state president Radha Mohan Singh also came in open support of Ms Ghai's demands and asked the Centre to constitute an inquiry panel to fix ministerial responsibility for the 'blunder' made in the affidavit. While talking to newspersons here Mr Singh asked the Centre to ensure the safety and security of the Rama Setu at any cost by reviewing the project.
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Archive
Back to school is all about inciting those opportunities of education and self-knowledge, and as it has always been my pleasure to educate Argyle families with monthly dental advice, I am even more grateful to initiate the school year with
by Susan Neuhalfen Long before summer is over and school starts, the practices begin for the Argyle High School Marching Band. The multi award-winning band started its season on July 28 as the new members came together to meet and
by Susan Neuhalfen One of the most exciting and yet stressful things in a high school student’s life is choosing a college. However, according to Toni King, Director of Academic Advising and College Planning at Liberty Christian, it doesn’t have
by Susan Neuhalfen Now that the weather is going to cool down and the kids are back in school, it’s time to start thinking about the three-day weekends and taking the family camping. We polled readers and found a few
by Susan Neuhalfen If one has never experienced migraines, it is hard to understand the pain attached to them. Migraines are debilitating headaches that make performing daily tasks difficult for even the most determined of people. They affect roughly 12%
by Susan Neuhalfen Have you ever dreamed of being a model? There’s a new business in Argyle designed to help you experience that dream and you might just end up in front of industry professionals in the process. “We have
by Becka Materne Community Relations and Advertising Consultant Argyle Living [email protected] 972.800.8548 It is such an honor to be writing the editorial for Argyle Living this month. I started my job with Murray Media a few months ago and I
New Argyle girls volleyball coach Megan DeGroot was asked recently if she had seen the latest preseason polls, which apparently had the Lady Eagles ranked pretty high in Class 4A. DeGroot hadn’t seen them – nor did she want to.
Argyle has been a state power for so long now that it’s difficult to imagine a season where the Eagles are not competing for a state title. After all, Argyle didn’t just raise the bar – in many ways, it
Dr. Matt Artho Practicing dentist and owner of Country Lakes Family Dental www.CountryLakesDental.com The school year has arrived, and with it all the joys of backpacks, lunch bags, homework, afterschool activities, PTA meetings, class party preparations, early wakeups, and I
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Giving the blood of Ebola survivors to patients didn't seem to make a difference, doctors found in the biggest study so far on the approach, prompting some scientists to say it's time to abandon the strategy.
Oral contraceptives taken just before or during pregnancy do not increase the risk of birth defects, according to a new study by researchers from Harvard T.H. Chan School of Public Health and the Statens Serum Institut in ...
A landmark Phase II study led by Winship Cancer Institute of Emory University and instrumental in the recent approval of a new multiple myeloma treatment was published online today in The Lancet, one of the oldest and most ...
Factors in the blood from calorie-restricted rats can modify energy-producing mitochondria within the insulin-producing cells that regulate blood sugar levels, new research shows. This has a positive impact on glucose-stimulated ...
A newly NIH funded clinical trial (NCT02528942) by University of Colorado Cancer Center investigators and collaborators at Beaumont Health in Michigan and the University of Texas Medical Branch is evaluating a new method ...
A new study conducted at Columbia University Medical Center (CUMC) has revealed some of the underlying mechanisms that may increase the risk of heart disease in people with sleep apnea. The study also found that statins—the ...
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Beach VolleyBall
Thomas FitzMaurice and Cole Wehsener are players on the beach volleyball team while Robert Chakarian is the head coach of the team.
The sand here at Clairemont is not actual sand like at the beaches....
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Should Schools Put Tracking Devices In Student ID Cards?
Although it seems like a dumb idea to most, it does have some good sides to it. Even if it is a bad idea, schools in Texas have started doing it.
In 2012, a one-year...
They can be seen around campus. Students falling asleep in class, taking naps in the library, or grabbing a few minutes of rest in the front office chairs.
Sleeping habits, in general, are a growing problem in today's...
Sewage from the Tijuana River in Mexico has traveled to the beaches of San Diego, causing them to shut down from all the pollution and bacteria.E. Coli, Vibrio, Salmonella and several viruses and intestinal parasites have...
What people eat has a large impact on their mental and physical abilities, especially for kids. School lunches also impact how students perform and behave in school.
Having schools provide balanced lunches has been a priority over the past years. Campuses are required to serve fresh fruits and vegetables, low-fat or fat-free milk, whole grains, and protein.
About one in three kids in America...
Beach VolleyBall
Thomas FitzMaurice and Cole Wehsener are players on the beach volleyball team while Robert Chakarian is the head coach of the team.
The sand here at Clairemont is not actual sand like at the beaches.
“The sand at Clairemont is more like dirt, it's not like sand,” says Thomas.
Cole said, “It is easier to play at beaches because its actual sand, here it's like...
Megan Jo Payne is a 14-year-old freshman who goes to Clairemont High School. She is also an only child who lives with both of her parents and four pets; two dogs, one cat, and one hamster.
A recent ex...
The mission of The Arrow, Clairemont Senior High School’s student newspaper, is to serve its campus and community by providing news, information, insights, and discussions of news, activities, and topics relevant to the student body of CHS in a well-rounded, unbiased, and objective manner.
The staff strives to produce a newspaper that is timely, accurate, fair, interesting, visual and accessible.
As a student news publication, The Arrow staff adheres to the ethical and moral guidelines of professional journalism, district, state, and federal laws and regulations while following the right of a free press guaranteed under the 1st Amendment.
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Buyang Huanwu Decoction ameliorates ischemic stroke by modulating multiple targets with multiple components: In vitro evidences.
Buyang Huanwu Decoction (BYHWD) is a well-known traditional Chinese medicine prescription which is used to treat ischaemic stroke and stroke-induced disabilities. However, the exact mechanism underlying BYHWD's amelioration of ischaemic stroke and its effective constituents remain unclear. The present study aimed to identify the effective constituents of BYHWD and to further explore its action mechanisms in the amelioration of ischaemic stroke by testing the activities of 15 absorbable chemical constituents of BYHWD with the same methods under the same conditions. The following actions of these 15 compounds were revealed: 1) Ferulic acid, calycosin, formononetin, astrapterocarpan-3-O-β-D-glucoside, paeonol, calycosin-7-O-β-D-glucoside, astraisoflavan-7-O-β-D-glucoside, ligustrazine, and propyl gallate significantly suppressed concanavalin A (Con A)-induced T lymphocyte proliferation; 2) Propyl gallate, calycosin-7-O-β-D-glucoside, paeonol, and ferulic acid markedly inhibited LPS-induced apoptosis in RAW264.7 cells; 3) Propyl gallate and formononetin significantly inhibited LPS-induced NO release; 4) Hydroxysafflor yellow A and inosine protected PC12 cells against the injuries caused by glutamate; and 5) Formononetin, astragaloside IV, astraisoflavan-7-O-β-D-glucoside, inosine, paeoniflorin, ononin, paeonol, propyl gallate, ligustrazine, and ferulic acid significantly suppressed the constriction of the thoracic aorta induced by KCl in rats. In conclusion, the results from the present study suggest that BYHWD exerts its ischaemic stroke ameliorating activities by modulating multiple targets with multiple components.
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Canadian Public Accountability Board
The Canadian Public Accountability Board (CPAB) () is a national body, organized by the Canadian Securities Administrators (CSA), that oversees Canadian accounting firms that perform auditing work.
Formation
The CPAB was formed in 2003 as part of Canada's response to the occurrence of accounting scandals that were happening worldwide, such as at Enron and Worldcom. It was different in approach from the Sarbanes-Oxley Act adopted in the United States. In 2016, its CEO stated that the Board "encourages a more holistic approach to better understand the root causes of lapses in audit quality," in contrast to that taken by the US Public Company Accounting Oversight Board.
The CSA have specified that a "reporting issuer" (ie, a publicly traded company) must have its financial statements audited by a "participating audit firm," being one that has entered into a participation agreement with the CPAB which has not been terminated. Its authority is reinforced through legislation passed at the provincial level, of which Ontario has passed the most extensive example.
Scope
164 Canadian and 133 foreign firms have entered into participation agreements with the CPAB. These firms audit approximately 4,000 reporting issuers and 3,000 investment funds. Of these firms, fourteen are inspected annually, of which the Big Four account for 98% of total market capitalization on Canadian markets, and the other 10 large firms account for a further 1.5%. The other firms are subject to inspection on a triennial basis.
Governance
The CPAB has two governing bodies. The Council of Governors consists of six members: the Superintendent of Financial Institutions, the Chair of the Ontario Securities Commission, the Chair of the Autorité des marchés financiers, the Chair of the Canadian Securities Administrators, a Governor selected by the CSA, and public accountant that has audit oversight regulatory experience, selected by the other five. In turn, the Council appoints the Board of Directors, who are responsible for supervising the activities of the organization.
Deficiencies and controversies
A 2007-8 review by CPAB of financial statements audited by the Big Six firms revealed that of 130 audit files examined, 11 were found to have deficiencies.
In 2011, the Board raised concerns that auditors only reacted when issues were raised by its inspectors, and that they were not taking proactive measures to improve the quality of their work. The report also noted that the same findings were being noted year after year, and that the majority of deficiencies related to basic audit procedures. Little progress was seen to have occurred in 2012, and a low level of professional skepticism was still seen as a major issue in 2013.
In 2012, CPAB released a review it conducted of work done by Canadian audit firms with Chinese clients. It found flaws in 12 of the 24 companies examined, and barred one auditor from doing such work until it upgraded its procedures. This was significant, as, in 2011, 56 companies from China and other parts of Asia were listed on the TSX or TSX Venture Exchange, many getting their listings through reverse takeovers of dormant shell corporations, and Sino-Forest Corporation had collapsed in mid-year after irregularities were found in its financial results. In 2014, the Board reported that it was still experiencing difficulties in being able to review foreign operations of some Canadian-based companies.
Because of irregularities such as those occurring at Sino-Forest, the CSA issued proposals in 2013 to require mandatory notification of certain events to reporting issuers and regulatory authorities, which were subsequently adopted in 2014.
In November 2015, the Board reported that the incidence of significant findings in files examined was increasing, and that the most prominent audit issues concerned the execution of audit fundamentals and the understanding of a client's business processes that are relevant to financial reporting. A report earlier that year stated that the incidence of deficiencies observed appeared to be declining in files concerning the Big Four and other national/network firms, but was increasing in files concerning regional firms.
Further reading
Notes
References
External links
Category:Financial regulation in Canada
Category:Accounting in Canada
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Tietoja kirjasta
Arvioinnit
Fayoz Nematov
★★★★★
23 marraskuuta 2013
Smart and easy understandable book
Kuvaus
After reading the theory book about Microeconomics it is time to test your knowledge to make sure that you are well prepared for your exam.
This exercise book follows the same structure as the theory book about Microeconomics. Answer questions about for example consumer theory, demand, production and cost. All the exercises are followed by suggested solutions.
Sisältö
Consumer Theory
Preferences
The Budget Line
Utility Maximization
Demand
Price Changes
Income Changes
Elasticities
Production
Definitions
The Production Function
Costs
Costs in the Short Run
Costs in the Long Run
Perfect Competition
Definitions and Assumptions
The Firm’s Short-Run Profit Maximization
The Firm’s Long-Run Profit Maximization
Monopoly
Monopoly Profit Maximization and Efficiency Problems
Price Discrimination
Game Theory
Basic Concepts
Games on Normal Form
Games on Extensive Form
Oligopoly
The Cournot Model
The Bertrand Model
Monopolistic Competition
Labor
The Supply of Labor
The Demand for Labor
General Equilibrium
Definitions
Efficient Production
Choice under Uncertainty
Other Market Failures
Basic Concepts
Externalities
Public Goods
Suggested Solutions
Consumer Theory
Preferences
The Budget Line
Utility Maximization
Demand
Price Changes
Income Changes
Elasticities
Production
Definitions
The Production Function
Costs
Costs in the Short Run
Costs in the Long Run
Perfect Competition
Definitions and Assumptions
The Firm’s Short-Run Profit Maximization
The Firm’s Long-Run Profit Maximization
Monopoly
Monopolies
Monopoly Profit Maximization and Efficiency Problems
Price Discrimination
Game Theory
Basic Concepts
Games on Normal Form
Games on Extensive Form
Oligopoly
The Cournot Model
The Bertrand Model
Monopolistic Competition
Labor
The Supply of Labor
The Demand for Labor
General Equilibrium
Definitions
Efficient Production
Choice under Uncertainty
Other Market Failures
Basic Concepts
Externalities
Public Goods
This website uses cookies to improve user experience. By using our website you consent to all cookies in accordance with EU regulation.
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Animals are intelligent, sentient individuals. We should refer to them as “he/she” or “them/they”, or by species. The words “it” or “thing” should not be used to refer to an animal, and “who” is used rather than “that”. If you do not know the gender, choose one: “he” or “she”. Even if your gender choice is wrong, it is more respectful than “it.” This is an important way of demonstrating the respect we ask others to afford to all animals.
Wild animals should not be kept in captivity for the purpose of subjecting them to the stress of a public display for educational or other purposes, even when the display is happening in a classroom. Public releases are in our opinion not acceptable either, because they do not any good to the animal concerned and only serve the ego of the person releasing the animal.
Should A Sentient Animal Being Used For Educational Purposes?
There are a multitude of more efficient educational media available in our days, which can be specifically tailored to suit the audience targeted. The abuse of animals in this manner sends a message to the public that animals can or should be tamed, or kept as “pets” or that they are objects for human diversion, entertainment, recreation or educational tools.
It is often believed that species should be considered and preserved because they have some sort of value in themselves, a value unrelated to what’s in the best interests of the individuals who are members of the species. We don’t share this view. Sentient individuals have morally relevant interests in being alive and in not being harmed.
The interests in being alive and in not being harmed do not vary according to the fact whether a species is rare or common. It is very important to thoroughly establish whether an animal, who might not be releasable straight away, or at all is coping well with being kept in captivity. This is a difficult complex assessment depending on many factors requiring experience and intuition, a process which eventually is also very dependent on the individual animal and her or his adaptability.
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Storage solutions that are perfect for small spaces
It’s not unusual for families to out grow their homes and, as their family grows, many struggle to find suitable storage space for all of their belongings.
After all, over time, you accumulate an awful lot of stuff, and it’s often the case that you won’t have the space to store it, particularly if you’re working with small spaces.
The good news is that there are a whole host of smart, storage solutions that are perfect for optimising the available space in your home, without encroaching on the rest your available space.
From multi-functional furniture through to innovative storage solutions that have been carefully designed to accommodate the smallest spaces, there are lots of ways that you can minimise clutter and mess in your home. Check out our storage solutions that are perfect for small spaces.
Fitted wardrobes
Fitted wardrobes are a great way to maximise floor to ceiling storage space in your home. And one of their main advantages is that they cannot only be designed to meet your exact requirements; they can also be integrated into the smallest and most awkward of spaces.
Available in a wide range of designs and finishes, fitted wardrobes offer a whole host of storage opportunities, especially when it comes to providing a unique home for your hats, shoes, accessories, clothes, hand bags, and any other items that would over wise clutter the floor space in your home.
Here at Kenneth Installations in Glasgow, we’re experts when it comes to integrating stylish, practical, inviting and functional storage solutions into your home. Our friendly and helpful team are always on hand to answer any questions, so please do not hesitate to get in touch if you have any questions.
Alcove Storage
Rather than leaving the alcoves in your home deserted, why not make use of them by investing in built in storage? This is a great way to utilise a room’s natural space. Many people choose to invest in built in chest of drawers to occupy their alcoves or innovative shelving to populate the space.
Make use of the walls in your home!
Many people avoid populating their walls with shelving etc. due to the fact that they believe it can make a small space feel smaller than it actually is.
But if you get the proportions right, this can be a great way to optimise floor and storage space in your home, in a wide range of living environments.
So if you have a small kitchen, hang your everyday utensils on the wall! And don’t be afraid to think outside the box when it comes to hanging even the most unexpected items onto your wall! This season, people have even been hanging their bicycles on the wall to create a striking focal point.
Make use of all of the available space in your home
There are lots of storage opportunities in your home that you have probably not even thought about. For example, have you considered transforming the staircase in your home into an effective storage solution?
One of this season’s most popular storage trends involves integrating pull out drawers into the steps of your staircase. This is a great way to store everyday items such as toys, bed linen, shoes and any other everyday item that would clutter your home.
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liamdrgu147blog.thezenweb.com
Menu
Profit, Aim of this class : This course is composed of four matters that are listening, speaking, writing and reading through. While in the listening aspect, The scholars focus on the various different concern forms, dictation and unique English expressions.
Feed-back??over the side in the display if you are All set to finish the survey.|The Gonzaga spirit, blended with effort and devotion in athletic endeavors, yields achievements both on the field of play and in the classroom.|婆婆?�內衣褲 ?�位媽咪好評?�集�??��??�敦?�力?�緩?�摩滾珠，隨?�滾走身體緊�??�享體驗心得?��?�?! ?�應該怎麼辦…�??�遊美食|It looks like you may well be obtaining troubles enjoying this video clip. If that's the case, please check out restarting your browser.|In 2008, a Japanese e-learning System was released to deliver excess Discovering guidance outside of the classroom.|The SIL necessities for hardware security integrity are depending on a probabilistic Investigation of the unit. So as to obtain a presented SIL, the product should fulfill targets for the maximum likelihood of risky failure and a minimal Protected failure portion.|Even so, merely a 12 months soon after her arrival, the school stated that it will reduce tuition by 29 per cent. The autumn of 2016, In line with Hanycz, is the start of a "renaissance" in the College, citing big enhancements in college rankings and improvements on and off campus. The reasoning for the significant tuition Slice was to help make La Salle extra attractive and obtainable for college kids from more varied socioeconomic backgrounds.[eight] Governance[edit]|At UCR, learners and college from distinct backgrounds and cultures come alongside one another to produce our Local community more powerful, sharper, and smarter. Carry your brilliance to UCR. We'll allow you to share it with the whole world.|The 1st day of a scholar's time at La Salle occurred at a student orientation plan called Working day One particular, which stood for Orienting New Explorers. The day consisted of providing critical facts to new students as well as their households, but its Main goal is to create relationships: associations between The brand new students and various new learners, amongst The brand new college students as well as their higher division pupil hosts, involving new pupils and administration and school, and in between The scholars' households along with the university.|Push release QQ English recognized itself in Cebu in 2009 and it has since developed to become among the list of regions Leading on the internet language universities. QQ English is officially credited for utilizing the 'Callum Technique' of instruction, that has been shown being as much as 4 instances as helpful as other strategies.|Continue to be linked with campus and educated about all factors UCSB via Digital school fairs, on the net advising possibilities, and admissions webinars.|?�不?�浪費來往補習??��?�間，不?�擔心刮風下?�，�?��?�用?�的?�慧?�手機隨?�上課，讓�?習更?�效??There are several issues inherent in using basic safety integrity levels. These is usually summarized as follows:[citation necessary]}
A person requested me with regard to the teachers in this article, and I told them, deal with the instructors. Attempt to learn every thing the teachers say. Check with them any inquiries. They can be often willing to assistance.??ESL Program Facts|Speaking course is to the pronunciation, vocabulary and expressions. The scholars learn the way to elucidate graph and prepare creating in numerous essay types. Reading course can help pupils to receive the particular message and memorize tricky terms very easily. |Curriculum : This program conducts mandatory self-analyze and the students ought to pay a penalty when they're absent.}
The bottom counts of fewer than 32 sections for each thousand are found more info in the far north as a lot less evaporation of seawater normally takes area in these frigid areas.[fifty three] The motion of Pacific waters is normally clockwise from the Northern Hemisphere (the North Pacific gyre) and counter-clockwise inside the Southern Hemisphere. The North Equatorial Current, driven westward together latitude fifteen°N via the trade winds, turns north close to the Philippines to be The nice and cozy Japan or Kuroshio Current.[54], classes not just target the language but also uv語言學校 what's taking place in Spokane and in America along with popular society such as the ??MeToo??movement, gun Regulate and American politics.??This class relies on the number of textbooks designed through the Japan Basis for Older people Understanding Japanese to be a foreign language. The term Marugoto implies ??whole|entire|complete|total|full}??or ??everything|every thing|every little thing|almost more info everything|anything|all the things}?? and was chosen as the title from the textbooks simply because, from the words and phrases with the Japan Basis, ?�the program encompasses more info each language and culture, attributes conversation among folks in A variety of conditions??and makes it possible for learners to ??experience|encounter|expertise|knowledge|practical experience|working experience} a range of aspects of Japanese tradition??|CIA is volunteering the companies for the kids that are in will need each individual Tuesday. Through numerous extracurricular things to do, learners and academics could become more close each other and CIA delivers numerous opportunities to ensure that the students to expertise the lifestyle of your Philippines by having orphanage volunteer, home visits, bazaars, Valentine working day, Halloween bash, Xmas social gathering and outside class.}
??I found The college truly great, LSI teachers are amazing. All people is delighted and ready to assist you to if you'll find any inconveniences...??*Program fees contain accommodation charges. Outlined prices involve triple Bed room university student home Price. College students wishing to remain at A non-public, single or double home must shell out added charges.|I think I will never ignore the innumerable encounters that I have experienced in The varsity and with friends I created. Eurocentres is undoubtedly a great college due to its personalised schooling and center on each individual university student?�s desires. (Michelle Larios; Colombia)|Do you think you're planning to go overseas to review for a longer interval? This class is often discounted for students who would like to take an extended training course.|The east side with the ocean was uncovered by Spanish explorer Vasco Núñez de Balboa in 1513 right after his expedition crossed the Isthmus of Panama and attained a brand new ocean.|On top of that, WiFi is out there in Each individual place in the residence. There is an out of doors pool beside of the cafeteria.|This assists us give you the proper trial terms. Some nations require us to provide place-particular phrases based on where you reside.|A stay overseas could be complicated, so we?�re listed here that can help. We prepare top quality accommodation for you in new residences and welcoming homestays. We even have thoroughly qualified employees in order that you're feeling happy and safe all through your programme.|?�們相信由專�??�師，結?�高科�?影音多媒體，不但?�便?�簡??��?�可以幫?�您迅速提?�英?�能?�，�???��?貴的?�間?�金??UCR is an establishment around the go, located in among the list of speediest expanding metropolitan areas from the U.S., boasting globe-class academics and world wide study impacts.|請問?�可以買?��??�地機的店面?�？ ?�橋�?��?�城?�要打?�阿姨的人�?迎致?�詢??�?��?�童?�敏??��科掛主任級的心得 工商消息|?�本?�道源於室町?�代，由佛前供花演變?�今?�為一?�術?�設?�本課程?�中介紹?�本?�花?�術?�基?�形式及風格，示範及?�導?�花?�術?��?巧，讓�??�由欣賞?��?踐的?�程�?��?�受?�有?�日?�傳統花?�文?�氣??�? |?�本?�道源於室町?�代，由佛前供花演變?�今?�為一�?��術擺�?��本課程?�接?�本?�道I課程，進�?步介紹日?�草?�流?�花?�術?�形式及風格，並?�場示範?�指導插?�藝術的?�巧，讓�??�在欣賞?��?踐的?�程�?��?�受?�有?�日?�傳統花?�文?�氣??�?The Pacific Ocean was born 750 million a long time ago within the breakup of Rodinia, even though it is usually called the Panthalassic Ocean right until the breakup of Pangea, about 200 million yrs ago.}
Pioneers in Worldwide language teaching since 1965, we?�re obsessed with language Studying and we?�ve been establishing and championing the latest language acquisition methodology for over fifty decades.
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I'd personally explain to future college students to be ready to find out the language in this article If they're making ready for grad/undergrad courses. Amount 5 below has made me All set for my graduate program.??Dangers of the Management procedure have to be discovered then analysed by means of hazard Evaluation. Mitigation of such hazards proceeds till their Over-all contribution towards the hazard are viewed as satisfactory.|Carely, Venezuela "I am able to realize that consumers are various, and it?�s very good. It?�s truly fantastic to know that Other folks are distinctive and you may continue to Have a very relationship with them."|The ocean's recent name was coined by Portuguese explorer Ferdinand Magellan throughout the Spanish circumnavigation of the earth in 1521, as he encountered favorable winds on reaching the ocean. He referred to as it Mar Pacífico, which in both equally Portuguese and Spanish indicates "peaceful sea".[four]|In the Southern hemisphere, as a result of stormy and cloudy conditions connected to extratropical cyclones riding the jet stream, it is actually normal to check with the Westerlies since the Roaring Forties, Furious Fifties and Shrieking Sixties in accordance with the varying degrees of latitude.[sixty four] Geology[edit]|Why go to London and how one can find out beautiful parks next to second-hand bargains and with slightly luck also fulfill Brooklyn Beckham.|This software program will not be appropriate with all your operating technique, however , you can download it for installation on another machine. Pick your language:|Cebu Intercontinental Academy presents a comfortable residence. The home in CIA offers clear home environment by frequently cleaning air conditioner, exchanging mattress sheets and cleansing 2 times a week.| There is usually a variety of ages and nationalities at The varsity, and facilities consist of a spacious roof yard, a self-obtain study centre, interactive whiteboards, and an ELT library with wonderful assets.|Start off Study >> If This is certainly your very first check out click here to the location Click the link to shut this window and click on ??Feedback|Suggestions|Comments|Opinions|Responses|Feed-back}??on the side from the display screen while you are ready to finish the study.|Curriculum : This program conducts necessary self-examine and The scholars really should pay back a penalty when they're absent.}
Are you currently planning to go abroad to study for an extended interval? This study course is usually discounted for college kids who want to take an extended program.
?�對?�、說?��??��??�個考試?�目，分?�規?�課程，?�來?�美?�、加?�大?�英?�、澳洲�?��?�國專�??�師?�課，藉?�與不同?�音?�不?�語調和說話?�度?�老師?�行練習，密?�強?�您?�多?�考試?�聽?�與?�說；藉?�專�?��師帶領?��?作與?��?題庫?�析解題，讓?�輕鬆獲?�高??A 2nd island variety fashioned of coral is definitely the uplifted coral platform, which is usually somewhat larger compared to the reduced coral islands. Examples consist of Banaba (formerly Ocean Island) and Makatea in the Tuamotu team of French Polynesia.[forty nine][fifty]
It really is our most popular Examination, approved by hundreds of companies and educational institutions around the world. E book an Test
Curriculum : This class conducts necessary self-analyze and The scholars should fork out a penalty when they are absent.
During the Southern hemisphere, due to the stormy and cloudy ailments related to extratropical cyclones Driving the jet stream, it is common to refer to the Westerlies since the Roaring Forties, Furious Fifties and Shrieking Sixties in accordance with the varying levels of latitude.[64] Geology[edit]
entire??or ??everything|every thing|every little thing|almost everything|anything|all the things}?? and was chosen as being the title in the textbooks simply because, during the words and phrases from the Japan Basis, ?�the system encompasses each language and society, characteristics communication concerning men and women in a range of cases??and makes it possible for learners to ??experience|encounter|expertise|knowledge|practical experience|working experience} a number of components of Japanese tradition??}
Pricing is in , Pricing is in , Pricing is in , and it is existing as of , on the other hand prices are matter to alter and should be distinctive at time of booking.
As outlined by IEC 61508, the SIL principle has to be related to the perilous failure amount of a program, not only its failure charge or the failure rate of a element element, such as the software. Definition of your unsafe failure modes by security analysis is intrinsic to the appropriate perseverance in the failure rate.[two]
Talking course is within the pronunciation, vocabulary and expressions. The scholars learn how to clarify graph and prepare crafting in a variety of essay types. Reading through course aids learners to acquire the precise concept and memorize complicated terms conveniently.
*System expenses incorporate accommodation charges. Shown rates include triple Bed room scholar residence Price. Students wishing to remain at A personal, solitary or double room will have to fork out added fees.
Anything was terrific...I manufactured lots of mates and my classes were being quite helpful... I'd a good time in class....I'm likely property but hope I...??It really is our most popular Examination, accepted by countless numbers of businesses and academic institutions around the globe. Ebook an Examination|November is the only thirty day period during which many of the tropical cyclone basins are active.[sixty one] The Pacific hosts The 2 most Energetic tropical cyclone basins, which can be the northwestern Pacific and the japanese Pacific. Pacific hurricanes form south of Mexico, sometimes placing the western Mexican coast and occasionally the southwestern U . s . involving June and October, even though typhoons forming inside the northwestern Pacific relocating into southeast and east Asia from May to December. Tropical cyclones also kind during the South Pacific basin, in which they often effect island nations.|During the arctic, icing from October to May possibly can present a hazard for transport though persistent fog occurs from June to December.[sixty two] A climatological small inside the Gulf of Alaska retains the southern coast wet and delicate during the Winter season months. The Westerlies and involved jet stream within the Mid-Latitudes might be particularly robust, specifically in the Southern Hemisphere, as a result of temperature difference between the tropics and Antarctica,[sixty three] which documents the coldest temperature readings on the planet.|Subscribe to our Specific Gives e-newsletter and we will ship you an electronic mail whenever a new present come to be obtainable.|Are you presently a college student check here in need of advising or educational staff searching for information and facts? Study inquiries? You?�re in the best location.|The tolerable stage of such hazards is specified as a security prerequisite in the form of a goal 'chance of the unsafe failure' within a supplied period of time, stated like a discrete SIL.|This page takes advantage of cookies. In order to continually boost This page, we try to remember and shop details about how you employ it. Figure out additional. Settle for and shut Contact Get in touch with|A B2 Very first qualification proves you might have the language techniques to Stay and do the job independently within an English-Talking country or study on courses taught in English.|The very first day of a university student's time at La Salle happened in a university student orientation program called Day 1, which stood for Orienting New Explorers. The day consisted of providing important details to new pupils as well as their family members, but its Key aim is to develop interactions: interactions involving The brand new pupils together with other new learners, in between the new college students and their upper division pupil hosts, among new pupils and administration and college, and amongst The scholars' households along with the university.|Obtain FACTSHEET I will never neglect St Giles London Central. I'd an unforgettable time Together with the instructors. All are quite helpful, humorous and Skilled. The school felt like my household. I improved my English and satisfied new pals from The full earth!|?�牌?�英?�斯巴達，校?�小巧應?�盡?�，?�理位置?�勢?�每?�強迫自習、日記�?作�?
Universalis Cosmographia, the Waldseemüller map dated 1507, from a time when the character on the Americas was ambiguous, specifically North America, for a doable Portion of Asia, was the very first map to show the Americas separating two distinctive oceans.
Feed-back??on the side on the monitor when you are Prepared to finish the study.|Learners won't only boost their fluency and also their precision in Talking English. Curriculum is prepared systematically each and every 7 days and native lecturers and specialised teachers use confirmed program supplies.|From the methods offered higher than, LOPA is by far the most often employed by huge industrial amenities.|In addition, several shorter courses go over a wide range of topics such as Kansai dialect, Japanese calligraphy and ikebana.|Curriculum : This program conducts necessary self-examine and The scholars really should pay back a penalty when they are absent.|La Salle almost closed once more on account of an absence of students through Earth War II, as well as football team was disbanded because of a lack of players, but the college knowledgeable a period of progress while in the late nineteen forties. Quite a few new buildings had been built inside the forties and nineteen fifties, which includes a whole new library, scholar union, plus a science making. It absolutely was also in the course of this time that the primary college student home halls have been created at La Salle, mostly on land obtained from the former Belfield Nation Club.|See and find out firsthand from existing college students, faculty click here and workers about what can make UC Santa Barbara this type of lively Neighborhood of scholars.|?�I spent a pretty long period of time at LSI Toronto (seven months), And that i am self-assured to mention that it had been effective and satisfying! I...??As a result of Area constraints, in 1930 La Salle moved to its present campus in the intersection of 20th Avenue and Olney Avenue during the Logan community of the town. The new place had a suburban come to feel with sufficient land, but was linked to the town by trolleys plus the freshly constructed Broad Street Subway.}
The 1930s proved to become a tumultuous ten years for La Salle, which was virtually bankrupt following remaining not able to sell the 1240 North Wide Street residence. The key tutorial making on campus, School Corridor was not able to be concluded on account of a lack of cash, and the college just about closed from the late 1930s.
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WiFi is available in each dormitory home. CIA delivers nutritious foods that satisfy Korean college students' taste. The team during the home supplies refreshment stand(bacon, bread, salad and juice) as breakfast and Korean eating plans of one meal 5 aspect dishes as supper.
渡假?�環境、豪??��泳池，選�?��豐富多元，專精於訓練多益高分?�老牌學校?�不定時?�課?�修課程?�潛水執?�訓練等�?.?�制?�月份台?�人比例，以容納?�國籍英?�交流，?�常?�合?�年齡層就�?�?Speaking course is on the pronunciation, vocabulary and expressions. The students learn the way to clarify graph and get ready creating in several essay kinds. Looking at class will more infouv語言學校費用 help students to acquire the precise message and memorize tricky words simply. is my last working day. I've used the final three months below in Brighton and After i glance back again I am able to say, it absolutely was one of the best times in my...??}
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+ "u002fu2563u202fu0085u17d5u200bu0020U000e0043u2014u058au3d0aufe57u2035u2028u2029",??packed sequences, coupled with it some outrageous scenes which makes it a worthwhile comedy.|They may also include facts like your website?�s most current updates, frequency of modifications and the importance of URLs.|Information regarding acquiring evidence for undocumented very long-phrase people of the UK to show their standing listed here.|+??��ＳＮ'�???��９日 # to test for bug #4098467 # What follows is actually a string of Korean people (I discovered it inside the Telephone book|The whole quantity of people that shared the studydiy homepage on Google Moreover by a google +one button. The overall amount of people that shared the studydiy homepage on StumbleUpon. The overall amount of people that shared the studydiy|Analytics Medium influence Quick to resolve Google Analytics World-wide-web analytics Allow you to evaluate customer exercise on your site. You ought to have at least a person analytics Device mounted, nonetheless it will also be fantastic to put in a next to be able to cross-Verify the information.|The table earlier mentioned highlights the most often made use of keywords and phrases on the webpage and how persistently you might be making use of them.|- "u99abu0027u003bu2026ueaf0u0020u0020u0313u0020u3099uff09u208eu2011u2007u2060u000au0020u0020u300bu0bf9",|Reveals the amount of will it consider to load the web site. Colors on picture reveals suitability, eco-friendly for speedy and ideal, yellow for average and needs enhancement, red for pretty sluggish and needs urgent advancement.|?�上??��些小主題中，大家�?定會比較要找?��??��?代辦�?��，或?�心�?��經有屬意?��??�，?�去?�尋?�代�?��幾家�??�的代辦�?��，�?後確認�?些細節後，決定?�底要給?��?家辦，選?�哪一家�??�等等，?�著?�後就???些比較繁?�的細�?，填表匯款辦?�手續都完成，就算是?�前?�的工作?�完?�啦�?Don?�t consist of personal or fiscal information and facts like your Nationwide Coverage selection or charge card details.|住�?學校宿舍請遵守�??��??�的?�活規範，並?�惜宿舍?�物?�，保持?�人?�間?�公?�環境之?�齊?�清潔。如?�因?�人?�素?�?�成之物?�損毀�?學校得要求�??�賠?��?
{後來?�想了又?�、如?�約翰已經把?�上?�名條給?�掉?�我?�也?�是一?�寒?�的?�候應該他也不?�提?�住?�的事、當?�也?�可?�因?�他不想讓我?�擔心�?以覺得不必要?�起?�畢竟這算??��人問題可以不?�跟你的客戶討論?��?以見?�寒?�的?�場?�、真?�只??��衍性的?�候語?��??�只??��了當?�方對話?�開?�白???�覺得曼?�頓?�自?��??�某?�面很類似，風評?�不??��規模不大但很活潑，但比較??��?�是，有些周?�資訊比較沒?�麼多，但他?�網站做得也不錯，算??��活化?�簡????��?- "u2762u1680u002du2028u0027u01dcufe56u003au000auffe6u29fdu0020u30eeu007cU0001d178u0af1u0085",|?�請學校:?�助?�完?�全套申請流程，?�寄資料�?��絡�??�，?�到?�到?��?許可|- "u20a9u2014u00a2u31f1u002fu0020u05b8u200bu0cc2u003bu060du02c8ua4e8u002fu17d5",|Settlement expert services: aid ahead of departure at preferential exchange amount to get traveler's checks, Safe and sound and practical and lower your expenses|宿舍?�方?�呢～每?��??�的?�質不�?，但大�?要有心理準備，不要用高級�?��?�標準來審視一?�唷，假如你住過?�年?�社，那大概就會?�概念了?�剛好我學校?�附屬�??�在一?�類似國高中?�校?�中，建築和�?��?�然?�點?�但??��乾淨，到學校?�要搭車通勤但很近，大約?�小?�內??��?�。住宿舍??��?�有?�己?�空?�，也不?�像寄�?家庭一樣顧忌其他人?�生活作??��安?�方?�也Okay，重?�的密碼?�，要進去也不容易，�??�就??��?��???��|?��??�各家�??�都不太一樣，?�以也??��跟代辦中心要學校宿舍?�照?�來?�看?�況，寄�?家庭?��??�各?��?壞，?�把?�缺點整?�出來給大�?，可以自行判?�嘿～：|?�為見過很多次面了、也?�過天、我也就很大?�的?�他?�上綁著?�條?�名條“是什麼？?�時約翰尷尬?�看?�我?�、覺得要說�?話了?�才?�到?�兩天大?�抽?�非常嚴?�、嚴?�到?�生?�他住院觀察、因?�醫?�擔心他??��?�始對吃?��?壓藥?�不?�的?�應?�他也說?�以?�要?�我?�這筆?�意讓給他朋?�接了、因?�不確定何時??��?�院也不確定?�己?�能夠開?�途路程。�?以昨天醫?�讓他出?�他一?�開心也忘了?�手上的?�條�?��下�?Meta Description tag enables you to explain to search engines what your web site is about. This method has Advantages. You could find facts of how must be a meta description tag on reviews below.|When we analyse your tamahimeden.jp Site's codes, we decided that you choose to didn't use a sitemap. If you do not utilize a sitemap, It's going to be efficent to present link this sitemap web page from the homepage. Also sitemap web pages identify is generally determined as sitemap.xml. You'll be able to put together a sitemap website page named|?�想?��??�篇起因?�上?�三?�跟?�們長?�合作的貨車?�機?�公?�收貨、幫?�們把?�巴黎展覽用?�桌子及?�品?�貨車運?�過?�。隨便哈?�了一下、當?�見?�就??���?Language in meta language portion on tamahimeden.jp Net web page is. If you believe that your Web-site's written content was written Within this language, It implies that you employ proper meta language.|?�辦?��??�行?�集學校課程?�當?�生活、旅?�資訊， ?�擇?�就讀?��??�及課程，再依�??�規定填妥表?�申請�??�，將後續有?�住宿代訂、簽證申請、繳交�?費、訂機票等相?�事?�聯繫�??�填妥申請書�?��?�手續，就可以出?�囉!|?�於宿舍?�～裡面很多帥哥美女?�本小型?�聯?�國，在?�裡??��?�來?��?也可以當?�交?�花（咦？）??It is made up of some vulgarities as you could potentially imagine, some thing reminiscent of scenes from another well-known Television sequence become massive display ?�the|A superb description functions as a possible natural and organic ad and encourages the viewer to simply click through to your site.|We checked msms.tw/robots.txt failed to discover a robots.txt file. Use Google Research Console to post and check your robotic.txt file. You may also check specific web pages to be certain Google just isn't crawling any restricted files.|?�覺得既?�都?�錢?�了，過?�自己想要的?�活，參?��?下語言課程，參?��?點團體活?�，?�些?�候可以自己去走走?�很不錯，我很滿?�我?�遊學生活，每天?�很?��???js JavaScript framework SWFObject Miscellaneous more info Get to understand the technologies employed for your web site. Some codes could decelerate your web site. Talk to your webmaster to Consider this.|Publishing your written content on other web pages is useful, but publishing it yourself web page is way more practical. Probably the greatest means To achieve this is thru a web site.|.....也有??��被當?�愛?�怨的?�唆鬼、老是?�東?��??�滿負面?�量??也沒人喜歡老是?�拉?�筒?�怨�???住�??�的話會?�廚?�，??��??��己喜歡的?��??�，?�去?�了宿舍，很貼心?�有常溫?�存櫃和?��?，還?��?些基?�的調味?�可以使?�，但自己煮就要?�錢?�己買食?�囉，�??�是??��??��己愛?�食?��?
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每個老師?�風?�不一樣，?�其�???�老師??��?�作�?��，他覺得?�們都?�錢來�?習了，該?�有主動?�，作�?就是一?�想�?��?�生活中練習?�文，我?�都人在?�柏?�了，這就????�英?�的世界?�！第二?�師說�?語文要開心，?��?每天上課?�很歡樂??��跟在?��??�時?�的???氣氛?�的�?��多�?Not sure about 'the best comedy of your calendar year' tag presented by magazine, THE WEEK. Thus far this yr I haven't seen
{Ｑ：?��??�天?�班?�試??��??��??��？?�萬一?�完?�到?�班級還??��得不?�合?�己??��??��?�班?�？|+ // address root node as Exclusive situation: don't simply call unpackOneNode() or unpackHorizontalArray() immediately|However, endeavor to host your site over a server and that is geographically close to your guests. Search engines go ahead and take geolocation of a server under consideration plus the server speed.|?�次?�著?�待準備了�??�，?�打?�篇?�章?�我已經?�到工作崗位，覺得準?�了好久?�發?�過程就?�坐?�霄飛車?�只????�間，但?�穫?�有?�些深刻?�腦子裡?��?習與經驗?�的?�以言?��?That will help us boost GOV.British isles, we?�d like to learn more regarding your take a look at nowadays. We?�ll ship you a website link to the responses type. It is going to consider only two minutes to fill in. Don?�t be concerned we gained?�t send out you spam or share your email tackle with anyone.|Make use of your key phrases from the headings and make sure the 1st level () consists of your most vital search phrases. Never replicate your title tag content with your header tag.|With Meta Language tag you can determine your internet site language. This doesn't appear to convey any reward at all, but You need to use it as a standard.|Using the Nofollow attribute in the backlinks helps prevent some hyperlink juice, but these links remain taken under consideration when calculating the value that is definitely passed by means of each url, so applying plenty of NoFollow back links can still dilute PageRank.|Your server responded Together with the HTTP position code: 404 404 error internet pages are displayed once the site you are trying to open up cannot be discovered on the positioning's server for several different causes.|?��??�很不希?�自己的語�?學校?�師就像????�來說補習班?�師?�樣，你?�知?�的，台?�也?�很多補習班，很多是比較沒經驗、或?�只??��?�科系畢�?��來教，補習班�?��?�點費也不高，以?�於師資水平很不一，�??�拿?�課?�依樣畫?�蘆就這樣?�隆?�去??Your internet site now features a robot.txt file. You may use Google Search Console's Robots.txt Tester to submit and examination your robotic.txt file and to verify Googlebot is just not crawling any restricted data files.|UK Visas and Immigration is to blame for earning thousands and thousands of choices on a yearly basis about that has the appropriate to go to or stay in the nation, using a business emphasis on countrywide security along with a culture of buyer pleasure for those who occur right here lawfully. UKVI is part of the Home Office environment. Go through more details on what we do|When switching to HTTPS, be certain your site remains optimized and see to it that your site will even now operate quickly. Adhere to these greatest procedures for your sleek changeover:|- // ":;u309bu309cu3005u309du309eu30fdu30feu2019u201du00b0u2032u2033u2034"|"Thanks to the hospitality and kindness of my host family members as well as the Emerald Cultural Institute I constantly felt like I used to be at home"|+ "u20a9u2014u00a2u31f1u002fu0020u05b8u200bu0cc2u003bu060du02c8ua4e8u002fu17d5",|+??uc0c1ud56d ??ud55cuc778 ??uc5f0ud569 ??uc7a5ub85cuad50ud68c ??u1109u1161u11bcu1112u1161u11bc ??u1112u1161u11abu110bu1175u11ab ??u110bu1167u11abu1112u1161u11b8 ??u110cu1161u11bcu1105u1169u1100u116du1112u116c ???�著就是了解資訊?�細節??��?�就????�長?�的?�程，會?�覆?�來?�去，了解適?�自己的學校?�住宿方式，?�時要試算費?�等等，?�時大概??��?��??�苦?�時?�吧～哈?�哈?�～太太?�題很多，問?�來?�問?�去，剛好我?�顧?�winnie也在?�爾??��學過，我?�去?��??�他也�??�，?�以我就搬?�了?�萬?�為什麼的姿態?�著他狂?��?- "u1806u060du30f5u00b4u17e9u2544u2028u2024u2011u20a3u002du09ccu1782u000duff6fu0025",|?��?活動?�間，煩請�??�務必妥?�保管私人金?�及貴重?�品，國外�??�及?�公?�無法為學生?�?�失之財?�負責�?- "u1781u0b68u0f0cu3010u0085U00011f7au0020u0dd6u200bU000e007au000au2060u2026u002fu2026u24dcu101eu2014u2007u30a5",|?�是上半天課程唷！因?�我希望?�己?????��課�??�旅行，?�以我每天上午上課，下課後?�會?��??�泡麵或存糧，然後再?�發?�市?�，每天去一?�點，慢?�把?�柏?�的??��?�完，雖?�我?�是覺得?�己沒走完，但不管世?�上?�個城市，?�很?�有?�掘完的一天�??�如你也?��??�找?��?資料，想要到歐洲來�??�迷人的?�倫口?�，?�爾??��?�是不錯?�選?�，綜合了語言?�勢?�消費、�??�的?�擇?�，?�且?�這裡，你??��?�見?�多?�個國家的人，不會一?�語言學校，通通遇見的?�是?�灣人，?�後大家還??��講台語！？（?�萬不要?�子�?
utilizing engineering, investigate and style. Here?�s just a couple examples of how we?�re accomplishing it:|Login listed here to apply on the web for your Get the job done visa. Should you have not acquired an account, you are able to make 1 in this article.|Use our on the internet products and services assortment, box to the proper, to help make a web-based software for chosen visas. Or uncover more about our on the internet products and services.|To post an expression of interest, you?�ll initial will need to make an account. When you finally?�ve carried out this, you may then login and submit an EOI. You can even make use of your login to check the standing of your EOI.|Get the job done abroad to aid fund the trip of a life span. Gain new capabilities, learn new languages, expertise distinctive cultures and take a look at spots that you choose to in no way considered you can.|In case you signed in to your account to check your eligibility, click on ??Continue|Carry on|Proceed|Keep on|Continue on|Go on}.??You received?�t get a personal reference code. You don?�t want just one.|We?�re committed to producing a favourable contribution to the global Neighborhood ??from our guidance for good triggers and social adjust, to our endeavours to drive progress in how folks study.|I'm browsing the U.S. and need to go to Canada. Do I need an eTA? What do I do if my application is just not accredited without delay? Get far more solutions to your eTA queries Products and services and information|This Unique Emphasis Programme brings together twenty classes of Standard English with ten lessons focused on language examine encouraged by your destination. Pay a visit to interesting locations, from museums and galleries to productive regional companies and charming neighbourhoods.|It appears like pixnet.Internet does not have a 404 mistake webpage. This damages your internet site's usability. Generic 404 error webpages strand end users with a webpage with no backlinks or strategies of how to proceed subsequent.|Tiny courses, great academics Regular specific counselling and productive study course structure ensure that you make rapid development in vital communication expertise. Our lecturers are meticulously selected, pleasant, valuable, and able to hear.|??�� ?�治 社會 ?�方 ?�際 財經 ?�活 評論 體育 影視 消費 ??�� ?�道總覽|[citation desired] The nightlife and the availability of cultural venues in these places has slowly started to evolve Therefore.[citation needed]|Entrepreneurial At EF, we have an entrepreneurial culture exactly where new Tips are listened to, Imaginative pitfalls are taken and possession is inspired. Dare to generate anything transpire therefore you?�ll look for a supportive staff powering you.|Calgary is usually a city that is developed on the confluence of two rivers in a spot the Blackfoot referred to as Moh-Kins-Tsis, the elbow. We will not go the town. We won't make area to the river. This is where the rivers are. Because of this, it is actually incredibly vital that we do the engineering Focus on the upstream mitigation. |Residences normally have energetic atmospheres suited to anyone who enjoys socialising. Our accommodation options are easy for general public transportation, which makes it effortless so that you can get to school.|LSI teachers have good instructing techniques and all personnel are already meticulously chosen to make certain a friendly and practical company is often prolonged to all LSI pupils. They may be on hand to guide you through your scientific tests.}
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Tim is forced to look at his thoughts for Casey. Amy is effective having a former racehorse in need of a new owner. Jack steps outside of his consolation zone to guidance Lisa. Wyatt returns using a warning for Georgie.
The Eurocentres Mission is to arrange college students to check, perform, and Dwell properly in the overseas language and tradition.We match our college students with one particular of numerous great programs, wherever they might learn a brand new language and immerse by themselves in a fresh society at the same time.，假如你?�的要來?�裡就�?，可以下載來使用，每?�的活動?�各�?��??��??��?�唷�?Test to minimize the amount of alt textual content figures to 150 or fewer (together with spaces!) to enhance webpage load times.|When you are fearless, if you believe larger than Absolutely everyone all over you, if you're keen on to get your palms dirty and if you are substantial Vitality, there isn't any enterprise which can conquer EF for its probable to get an in-corporation entrepreneur.|And Countless other titles. Regular monthly designs now out there There was an error trying to load your ranking for this title.|??Some people|Some individuals|Many people|A number of people|A lot of people|Lots of people} sense anxious or overwhelmed about the thought of dwelling and dealing Abroad, nonetheless it's really much less scary than you think. So if you have an interest, just Choose it!??Though switching to HTTPS, ensure your website remains optimized and see to it that your internet site will even now run quickly. Stick to these very best tactics for your easy transition:|On the final English Study course, you go to a core of twenty lessons every week, which offers you a practical comprehension of the English language and get you the many technique to fluency.|Even though nobody was killed or injured,[36] town officials drafted a law demanding all massive downtown buildings to generally be created with Paskapoo sandstone, to stop this from going on yet again.[37]|Significantly of Calgary's street community is over a grid in which roads are numbered with avenues jogging east?�west and streets functioning north?�south. Right up until 1904 the streets were named; following that date, more info all streets got figures radiating outwards from the city centre.[171] Streets in predominantly residential parts along with freeways and expressways do not normally conform towards the grid and tend to be not numbered Due to this fact.}
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Outside of Seville are 9 PS20 solar energy towers which use town's sunny weather conditions to supply the vast majority of it with thoroughly clean and renewable Vitality.
even though it is far far too moderate in Winter season for being described as a 'correct' continental space. It's at a relative distance in the three more substantial metropolitan areas while in the place, in addition to Lisbon in Portugal, making it certainly the most important metropolis inside the south in the Iberian peninsula.|However, make an effort to host your site on the server that is geographically close to your readers. Search engines take the geolocation of the server under consideration together with the server pace.|A great deal of great factors happened through my journey in Vancouver. EC is a superb college and organizes fun actions way too. Every week we could find out the town and Canadian traditions. We can go mountaineering in Stanley Park, have some fun with contests or satisfy students within a pub!|Website Medium effect Tough to solve We found a Web site on this Web site. Setting up a web site is a terrific way to engage with the audience and enhance your on-line visibility by attracting qualified targeted traffic from new resources.|Update your XML sitemap to ensure the URLs include HTTPS and update the robots.txt file to reference this Variation|Common desserts from Seville consist of pestiños, a honey-coated sweet fritter; torrijas, fried slices of bread with honey; roscos fritos, deep-fried sugar-coated ring doughnuts; magdalenas or fairy cakes; yemas de San Leandro,[citation required] which offer the city's convents having a supply of income; and tortas de aceite, a skinny sugar-coated cake made with olive oil.|General performance and Investigation: These cookies collect information about how you use the Wikimedia Web sites, to ensure we could much better know how the Wikimedia Internet sites get the job done and strengthen them to suit your needs and also other users.|It was originally built as Element of a mosque once the Moors dominated in Spain and was later added on to by the Christians. Vacationers now can climb the tower by strolling up a series of ramps that were previously utilized by officials who rode their horses to the highest on the tower. La Giralda receives its name from your weathervane attached to your pretty major of it, as "gira" suggests "turning one particular" in the Spanish language.|Produce a Twitter account for your personal brand and backlink it with your site to stop brandjacking and assistance make your social media marketing advertising more practical. Here are a few guidelines to help produce a Twitter advertising strategy.|Login below to use on the net on your Student visa. For those who haven't bought an account, you may develop 1 below.|All people for the Philippines are necessary to carry a passport legitimate for at least six months immediately after their arrival day. Guests towards the Philippines from the United Kingdom, United states, Australia and New Zealand can remain in the Philippines for the greatest of 60 times without having a visa and this can certainly be prolonged.|When you are a present visa holder and supply your specifics to a third-party (such as a lender), they're able to use this information and facts to validate your visa using the Visa Verification Service. Please look at this info before you login.|There exists also an important variety of Muslims during the cities, consisting of Filipino Muslims of different ethnicities and Muslims of other nationalities.|The harmony from the program fee need to be compensated by income, PayPal or lender transfer directly to the education Middle on the primary day of the program.|Understand how you use the Wikimedia Internet sites throughout diverse equipment, so that we may make our diversified Wikimedia Websites additional effective and successful for yourself.|Tourism is among Baguio's primary industries as a result of its neat local climate and heritage. Town is one of the region's best vacationer Places. In the calendar year end vacations lots of people from the lowlands prefer paying their family vacation in Baguio, to expertise chilly temperatures they rarely have in their house provinces.|Bitter Seville oranges expand on trees lining the town streets. Previously, significant portions were being collected and exported to Britain for use in marmalade.[citation essential] These days the fruit is made use of predominantly as compost regionally, instead of as a foodstuff.|Each individual member of EC staff members is rather helpful and usually aid us. I've achieved lots of friends in EC. My English is enhancing since I test to speak to them in English. You can find men and women from the good deal of nations, from all over the world. We train and correct one another which really aids us to enhance.|Login right here to use on the internet for the Scholar visa. In the event you haven't received an account, you are able to build a person here.|We provide a number of foreign language programs: Spanish, English, Italian and French. The maximum number of students for each class is eight ??Commonly you can find only all around 5.|The Spanish presidencia, which was Found at Bagiw for the vicinity of Guisad Valley was later on moved to Cariño's home where by The present city hall stands. Bagiw, a local term for "moss" the moment plentiful in the area was transformed through the Spaniards into Baguio, which served because the name on the rancheria.[four][7]|Citizens from all other nations around the world should Get in touch with their area consulate to get present vacation polices.*|Seville grew to become the dean from the Spanish provincial press in 1758 Along with the publication of its 1st newspaper, the Hebdomario útil de Seville, the first being printed in Spain outside the house Madrid.|Do you might have any queries or are you presently All set to apply? Call us at the email address given on The task heading to begin the application method.}
centralnotice_fundraising one year Operation Enables us to stop showing banners to folks the moment they?�ve donated. those manufacturing People items but there had been no efforts from town to suitable travelers' perception?? she said. |Making the most of the heat with the Sunshine, try to eat delectable lunch buffet with Filipino dishes and splashing around Using the crystal crystal clear h2o.|DUTIES AND RESPONSIBILITIES: Provide well-ready EFL lessons to varied lecture rooms of Worldwide highschool pupils in an experienced and interesting method. Assessment the curriculum supplied by In addition to sufficiently put together for every lesson; instructors should really be prepared to nutritional supplement the curriculum with their very own resources, as correct. Evaluate whether or not pupils are already placed in the right level of instruction. Orally evaluate students??proficiency ranges, as directed from the Educational Supervisor.|Each and every member of EC staff members is incredibly friendly and always assist us. I have satisfied a lot of good friends in EC. My English is increasing since I consider to speak to them in English. You can find people today from a good deal of countries, from everywhere in the planet. We teach and correct one another which definitely aids us to enhance.|Simultaneously, locals including blended-media artist Santiago Bose and filmmaker Kidlat Tahimik ended up also setting up do the job in the town. Even currently, artists like painters and sculptors from all around the place are drawn into the Baguio Arts Festival which can be held on a yearly basis.[21]|cellular-betaoptin-token Neighborhood Storage, not a cookie Choices Will help us to grasp around the cell site if we've Earlier asked you to definitely enroll in beta, in order that we do not prompt you unnecessarily.|?�超?�薦?�英?��?代辦，全?�的顧問從不?�我?�英?�程�?��拒絕我，反?�鼓?�我認真?�書！菲律賓?��??�代�?��多，?�代�?��?�程?�的?�很！辛！苦！」。我??��?�人，�??�始?�尋代辦?�司?�範?�只?�在?�北，而光?�北就有很多?�律賓遊學代�?��?�親?�跑了五家以上！但多?�代�?��?�薦宿霧...|In case you are a latest visa holder and supply your specifics to a third-social gathering (like a financial institution), they will use this information to verify your visa using the Visa Verification Service. Be sure to look at this data before you decide to login.|Town council signed a agreement With all the multinational corporation JCDecaux, an outside advertising company. The general public bicycle rental system is financed by an area promoting operator in return for town signing about a 10-yr licence to exploit citywide billboards.|stopMobileRedirect 30 times Choices Tells us not to redirect on the mobile internet site if you do not like that.|Resource: Seek out a very good area title. If no good names are available, take into account a second hand area. To avoid brand name theft, you may look at trademarking your area name.|Town's growth ongoing after the Castilian conquest in 1248. Public buildings were being made together with church buildings, most of which were being built-in the Mudéjar style, as well as the Seville Cathedral, crafted throughout the 15th century with Gothic architecture.}
It appears like you may well be obtaining difficulties actively playing this movie. If that is so, be sure to test restarting your browser. flamenco celebration all over the world??and lasts for just about per month. [forty nine]|Favicon Terrific, your internet site provides a favicon. Favicons are definitely the tiny icons that show up next to your website?�s identify or URL inside a browser. They can be displayed within the deal with bar, a browser tab title or bookmarks. Ensure it really is per your brand name.|A small selection can suggest that bots are not able to find out your web pages, which is often attributable to poor website architecture & interior linking, or you are unknowingly blocking bots and serps from crawling & indexing your webpages. An unusually significant quantity may very well be an indication of copy information on account of URL parameters.|This has become included to the combo of other cultures and developed extravaganzas of music and dance including the Sinulog festival. The ways the overseas influences intertwine with local fore make for A really superb celebration.}
?�有任何?�題，�?迎隨?�到?�英?��??�辦?��?來聊?�，?�直?�來?�或線上�?��?�全?�的夥伴?�立?�安?�專屬的顧問?�您?�務！平常忙碌於工作?�小資們，也�?迎預約週末�?��?�！ Studio of Languages?? We had been the franchisee of your Berlitz in Istanbul for the earlier fourteen many years and have been delivering high quality education in all languages more than twenty years with more than one hundred twenty skilled native speaking academics and Turkish personnel.|This modern day architecture construction properties the central marketplace and an underground archaeological complicated. The terrace roof can be a metropolis viewpoint.[45]|If you'd like to become a Section of Qualified academics workforce, study and observe environment renowned communicative technique, world high-quality training and train the language with new materials, sign up for us!|Babylangues is undoubtedly an ever-developing firm and we're normally trying to find new talent! This is an excellent way to get started on your TEFL profession. With its technique based upon scientific exploration and punctiliously tailored for the ... Posted: two months ago|... When the road duration stretches to only a little bit more than a hundred kilometres (sixty two miles) from La Trinidad city in Benguet on the Mountain Province capital of Bontoc, All those raring for experience and new sights must be ready to invest six hours about the highway. |Install TeamViewer Host on a vast amount of personal computers and units. Being a certified user, you might have use of all of them!|com.tw. Twitter, simply put, is large: sixty seven million month-to-month American users and 310 million folks around the globe. Even better, there's a optimistic correlation in between social websites use and education and learning and residence money. By not possessing a Twitter account, you are possibly missing out on a big viewers.|Inspired students Discovering from an integrated ,skilled, staff of teachers that are inspired to coach with passion.|Google sees hyphens as phrase separators even though underscores are disregarded. So the internet search engine sees as all a person word. Use hyphens within your URLs as a substitute: .|To submit an expression of curiosity, you?�ll to start with need to generate an account. When you?�ve accomplished this, you can then login and submit an EOI. It's also possible to use your login to check the standing within your EOI.|This developed a tremendous mixture of cultures which existed amicably with the Malay affect. Throughout the 400-calendar year duration of Spanish rule and a further forty decades of American influence, a uniquely cosmopolitan society evolved.|Deal with items & downloads Account configurations Sign out U.s. Now we have redirected you to an equivalent site on your local web page where you can see regional pricing and promotions and buy on the internet. Keep on our U.S. web-site}
standard??pronunciation clinics for all learners and clinics qualified at particular accents. Totally free activity.|The federal government uncovered 471 ??disaster|catastrophe} spots??together the route, which the Mines and Geosciences Bureau attributed to your fragility with the rock foundation, the abandoned mining functions near the street as well as the organic ground fractures that were undetectable in the 1900s. |The A?�s On line Tutorial Institute aims to provide English instructing to pupils of various amounts (novice, intermediate and Innovative) of various ages to create a powerful foundation for them to achieve excellence in English.|It's an outstanding example of Regionalist Revival Architecture, a strange and loftily conceived combination of assorted historic kinds, for example Artwork Deco and lavishly ornamented with regular glazed tiles.[forty six][forty seven]|Understand how you use the Wikimedia Web-sites, to ensure we really know what functions and what is beneficial. One example is, we might use cookies to find out about the listing of articles or blog posts you will be next on the watchlist making sure that we can easily propose related content articles that you may perhaps have an interest in.|Vancouver and EC became the best choice of my existence. I had experiences in this article which i under no circumstances imagined just before. I hiked mountains and trails, I saw wonderful lakes, I expert snow for very first time in my lifestyle. Vancouver and EC features all that you just need and it'll change your daily life eternally!|A ?�session??cookie is one that normally expires when you shut your World wide web browser or mobile application. A ?�persistent??cookie is one That is still within your device, even after you near your browser or cell software.|A ?�cookie??is usually a little knowledge read me file that we transfer onto your Pc, mobile phone, or another product that you just use to entry the Wikimedia Web sites, frequently utilized for authentication and monitoring.|So self-confident are we in the standard and value of our courses, that if you are not absolutely pleased with the support or item that you get, then We're going to refund your payment without any questions questioned.|This extension was postponed Even though the Metropolis Council experienced created expanding the metro traces a priority.[citation essential]|The tapas scene is one of the major cultural sights of the town: folks go from a person bar to another, having fun with little dishes identified as tapas (practically "lids" or "covers" in Spanish, referring to their possible origin as snacks served on compact plates accustomed to address drinks).|Seville is considered the most populated town in southern Spain, and it has the largest GDP (gross domestic product) of any in Andalusia,[sixty three] accounting for a person quarter of its whole GDP.[63] All municipalities within the metropolitan space rely immediately or indirectly on Seville's financial state, though agriculture dominates the financial system from the more compact villages, with some industrial activity localised in industrial parks. The Diputacion de Sevilla (Deputation of Seville), with provincial headquarters while in the Antiguo Cuartel de Caballería (Old Cavalry Barracks) on Avenida Menendez Pelayo, supplies general public providers to distant villages which they cannot offer by themselves.|The value of Cebu was initially noticed because of the Chinese, who established it being a investing publish in 900 Advertisement. As soon as the Philippines were colonized by the Spanish, Cebu was an apparent alternative given that the Philippines initial metropolis, as a consequence of its superb spot. At the time established since the de facto funds from the Spanish colony, Cebu was a central location in the buying and selling and delivery industries.}
No matter if beginning, Innovative or Experienced, We've got the appropriate course to suit your needs. Inside our lessons you'll study don't just grammar and creating, and also fluent dialogue.
The climate of Cebu is mostly heat yr spherical, typically involving 23-330C. Rain falls evenly thought the 12 months aside from the dry summer time months, amongst March and could. The island is surrounded by wonderful beaches, coral atolls and also other islands. The seas all-around Cebu can also be abundant fishing grounds. the fold" information in less than one particular 2nd.|Earlier versions: These downloads are only encouraged for customers with more mature licenses That won't be utilized with the newest launch of TeamViewer.|XML Sitemap Medium impression Uncomplicated to unravel XML sitemaps consist of the record within your URLs that are available to index and allow the major search engines to go through your webpages extra intelligently.|A descriptive URL is better acknowledged by serps. A person ought to be able to look at the handle bar and make an accurate guess regarding the information from the site ahead of achieving it (e.g., ).|The instructing staff members is extremely-experienced and seasoned. Also, They can be quite sort and individual to college students so that each pupil would understand and strengthen their English competencies in an exceedingly fascinating, comfy and efficient way.|Be sure to only consist of the pages you'd like search engines to crawl, so leave out any that were blocked in a very robots.txt file. Keep away from making use of any URLs that bring about redirects or mistake codes and make sure you be constant in using your preferred URLs (with or without www.|You are not obliged to utilize the accommodation furnished by The college and you also are welcome to produce your personal accommodation arrangements. If you end up picking to implement our accommodation, it should be paid for possibly by hard cash, PayPal or lender transfer directly to the school at the start from the program.|Baguio was established to be a hill station from the People in america in 1900 at the site of the Ibaloi village often known as Kafagway. It was The usa' only hill station in Asia.[6] The title of the town is derived from bagiw, the Ibaloi phrase for "moss".|Login in this article to use on-line in your University student visa. For those who haven't obtained an account, it is possible to create one particular listed here.|Mobile Frameworks get more info No mobile frameworks happen to be detected. Mobile or responsive frameworks are an important part of website optimization since they assist developers in making programs that happen to be applicable to numerous devices.|Yet another crucial source of income for Baguio is its position as being the industrial hub for your province of Benguet. Lots of agricultural and mining products generated in Benguet go through Baguio for processing, sale or more distribution to the "lowlands".[citation required]|Implement Now! Our present day, air conditioned TESOL teaching facility offers a cushty setting during which to understand and study. Free tea, coffee and internet access is offered and each of the resources and components you will require during your course are going to be readily available.|In places throughout the Philippines, TEFL career options are available, but do demand a bit of work as a way to acquire them. The islands also function an incredible jumping off issue for finding TEFL posts in lots of nations around the world within the region.|com.tw. Getting active During this social network is significant for claiming your brand name, influencing your online search engine rankings and interacting along with your community. You might also contemplate running your profile with Google My Enterprise (previously Google Places).}
localdom. Utilizing an SSL certification produces an encrypted relationship amongst your customer's browser and your website's server including an extra layer of safety. In 2014, Google announced that HTTPS would come to be aspect in their rating algorithm and because your site will not be HTTPS, it will eventually probable rank under your HTTPS competitors. When going to HTTPS, observe these ideal practices for your easy changeover: Baguio beans throughout the Philippines?�are shipped to big urban marketplaces across the archipelago.)[citation essential]|To all our Macau customers, you should Observe the applicable content and get in touch with facts relevant to you ev語言學校 for virtually any enquiries.|Make use of the meta viewport tag inside the to set the viewport to your system?�s screen sizing. It need to look like this: .}
Excellent! Manufactured a great number of good friends and the whole team is great, caring and supportive! Once i experienced a problem with my place and family members they adjusted it in in the future! levels Celsius reduced when compared to the temperature while in the lowland area.|It is found south of town center. A result of the limited length with the runway and that is one,802 meters or 5,912 toes, it's restricted to commuter size aircraft. The airport is made use of mostly by helicopters, turbo-prop and piston engine aircraft, Despite the fact that on scarce event mild business jets (LBJ) have flown in the airport.|Also, we may possibly use cookies to study the topics searched in order that we could improve the search results we provide to you.|Program: The work time period is in the course of summer season 2018; dates may very well be adaptable dependant on teacher flexibility. Most learners are with the PLUS program for 2-7 days periods; In addition runs back-to-again classes about the program from the summer.|?�自費活?�：?�摩?�潛水、離島旅行、高?�夫?�等??���?(學校?�供?�關資訊)??Kings Summer season get more info is devoted to the safeguarding of our students. All summer workers will likely be expected to adhere to our Kid safeguarding plan. References (2 current professional references) might be adopted up and gaps in CVs needs to be defined satisfactorily.|Also, throughout summertime, In particular all through Holy Week, holidaymakers from all over the nation flock to the town. For the duration of this time, the whole range of persons in town doubles.[35] To accommodate all of these persons there are actually a lot more than eighty hotels and inns readily available.[36] Nearby festivities including the Panagbenga Festival also attracts the two more info community and international tourists.|Polvorones and mantecados are traditional Xmas products, While pestiños and torrijas are generally consumed throughout the Holy Week.|MetroCentro is often a floor tramway serving the centre of town. It started running in Oct 2007.| $wgCookiePrefix BlockID up to 24 several hours Functionality Helps us enforce autoblocks, a process used to forestall vandalism and disruption|An excellent meta description acts as an natural and organic ad, so use attractive messaging with a transparent phone to action to maximize simply click-via rate. 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Vancouver and EC provides all that you need to have and it will change your lifetime forever!|Like a Berlitz coach, the corporate encourages you to pursue further more growth of your personal and EFL vocation targets.|In 2004 the Metropol Parasol project, normally generally known as Las Setas (English: The Mushrooms - as a result of the looks in the composition), was introduced to revitalise the Plaza de la Encarnación, For some time made use of as a vehicle park and seen being a dead location among more well-liked vacationer Locations in the town.|Google introduced a different cell position algorithm that expanded the usage of cellular-friendliness in its mobile lookup rankings. With Virtually 50 percent of all Google search queries originating with a cell device, it is necessary to be sure your mobile site is optimized for these users.|?�校規：?�禁?�入?�性房?�、喝?�、外?�申請限??��宿霧市等??���??�違?�校規者將禁足?�開?�處????In case you are a present visa holder and provide your aspects to a 3rd-bash (like a bank), they could use this information to confirm your visa utilizing the Visa Verification Provider. Please read through this details prior to deciding to login.|The accommodation costs are not Component of the training course rate so you are absolutely free to decide on whichever accommodation solution you prefer.|If you must regulate licenses across various campuses or educational institutions, which include for a sizable college district, be sure to see this short article for possibilities. AutoCAD for Mac and|Choice text permits you to insert an outline to an image. 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To find out more on our privacy procedures, you should visit our Privacy Plan.|Enquiries and purposes, such as a cover letter and resume, must be sent to Heather White within the e-mail handle provided on the job heading. Applications near on four April 2018.|To apply for this visa, you?�ll very first will need to create an account. When you finally?�ve done this, you are able to then login and use. You can even make use of your login to check your application position.|The Alcázar Gardens, within the grounds in the Alcázar palace, include various sectors made in various historic kinds.}
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Baguio is the melting pot of various peoples and cultures in the Cordillera Administrative Area. Because of this, several investments and small business opportunities are lured to town.[11] Baguio has a large retail market, with consumers coming to the town to make the most of the variety of competitively priced industrial goods on sale.[27] The city can also be popular with cut price hunters??some of the preferred bargaining parts include things like Baguio Current market and Maharlika Livelihood Heart.|While in the late 16th century the monopoly was broken, With all the port of Cádiz also authorised being a port of trade. The good Plague of Seville in 1649 decreased the population by Pretty much 50 %, and it wouldn't Recuperate until finally the early 19th century.|To post an expression of desire, you?�ll initially need to have to make an account. Once you?�ve done this, you'll be able to then login and post an EOI. You can also use your login to check the status of your EOI.|AutoCAD Structure and condition the earth all-around you With all the effective, connected style and design equipment in AutoCAD software program. Create amazing 3D patterns, speed documentation, and hook up With all the cloud to collaborate on styles and obtain them from the mobile machine.|Use our on the net products and services choice, box to the correct, to produce an internet software for chosen visas. Or discover more details on our on-line products and services.|The neighbourhood of Triana, located on the west financial institution from the Guadalquivir River, performed a crucial role while in the history of town and constitutes by itself a folks, monumental and cultural Middle.|Babylangues strives to ensure that your remain in France be as stress-absolutely free as possible, encouraging you out in minor ways for making your stay genuinely unforgettable.|The largest mosque in the region is Masjid Al-Maarif, which can be a known centre of Islamic reports in the Philippines. Town also has more compact quantities of Buddhists and atheists, coupled with members of other faiths.|學生?�提高英語�??�的?�時?�能了解彼�??�文?�，也是?�高?�際?�光?��?機會??Login listed here to apply on-line for the Perform visa. In the event you haven't obtained an account, you'll be able to build just one in this article.|Backlinks are hyperlinks that point to your site from other Web sites. They are like letters of advice for your web site.|It can be a tremendous school, with astounding instructors and classmates I actually get pleasure from every day which i devote there. Thanks EC Vancouver with the exclusive and incomparable experience.|Given that this issue is very important to Search engine optimization, you need to have a technique to strengthen the quantity and good quality of backlinks.|Mastering English via a?�s Online Tutorial Institute is really a optimistic Finding out practical experience. You can know more about us by clicking the backlinks on this website page or by picking out a button within the menu over.|Using the Nofollow attribute with your one-way links helps prevent some hyperlink juice, but these backlinks are still taken into consideration when calculating the worth that may be handed via Each and every url, so working with many NoFollow links can nonetheless dilute PageRank.|For all input and tutorial sessions with the training site, there is just one unique costume necessity: Equally Adult men and girls ought to have a shirt masking their shoulders.|Village University Guatemala, a very well founded trilingual faculty located over the outskirts of Guatemala Metropolis, has a chance for an EFL Instructor who is accessible to remain for a minimum of one tutorial 12 months. Facilities consist of a fully equipped gymnasium, baseball fields, basketball courts, roller hockey courtroom, volleyball court docket and soccer discipline having a running observe.|Kings Summer is usually a thriving division of Kings Instruction offering a wonderful selection of four summer time household locations for junior college students in britain. We are now recruiting enthusiastic Qualified EFL teachers for our a variety of ... Posted: 5 days back|The St. Mary of the See Cathedral was developed from 1401??519 once the Reconquista on the previous web site of town's mosque. It is actually amongst the most important of all medieval and Gothic cathedrals, with regard to both spot and quantity. The inside would be the longest nave in Spain, and is lavishly decorated, with a large amount of gold evident. La Giralda is really a tower hooked up to your Cathedral that dates back into the twelfth century.|We have been presently recruiting enthusiastic TEFL Instructors on short-term contracts to join our fantastic staff. At Kingswood we've been totally dedicated to safer recruitment and safeguarding youngsters, all thriving applicants might be needed to bear a DBS Increased Disclosure Verify. Any gaps in your employment heritage will be completely explored for the duration of job interview and it's essential to be able to give two Expert references.|This made Seville the top defended port to bring the riches from your Americas. A 'golden age of enhancement' commenced in Seville, due to its getting the sole port awarded the royal monopoly for trade Along with the rising Spanish colonies in the Americas and the influx of riches from them. Because only sailing ships leaving from and returning towards the inland port of Seville could engage in trade Using the Spanish Americas, merchants from Europe along with other trade centres necessary to head to Seville to amass New Entire world trade products. The town's populace grew to a lot more than 100 thousand people.[eighteen]|We attach wonderful worth to the safety of our online and mobile banking providers. Shoppers are encouraged to access their e-Banking accounts from the Lender?�s Formal website �?or the|or even the|or perhaps the|or maybe the} Hang Seng mobile app.|?�拜 ?�及 希臘 伊朗 以色??約旦 黎巴�??�塔???�利�??�耳其|A persistent cookie expires in accordance with the period set by us (or if you delete it manually). Find out more on Wikipedia.|In 1519, Ferdinand Magellan departed from Seville for the 1st circumnavigation of your Earth. Coinciding While using the Baroque period of European heritage, the seventeenth century in Seville represented one of the most excellent flowering of the town's tradition; then began a gradual financial and demographic decline as silting in the Guadalquivir compelled the trade monopoly to relocate into the close by port of Cádiz.}}
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2017 Inter-Provincial Cup
The 2017 Inter-Provincial Cup was the fifth edition of the Inter-Provincial Cup, a List A cricket competition played in Ireland. It was held from 1 May to 10 September 2017. It was the first edition of the competition to be played with List A status, following the outcome of a meeting by the International Cricket Council (ICC) in October 2016. Three teams competed; Leinster Lightning, North West Warriors and Northern Knights, with Leinster Lightning being the defending champions. Leinster Lightning retained their title, after North West Warriors won their match against Northern Knights on 6 August, giving Leinster Lightning an unassailable lead in the competition.
Points table
The following teams competed:
Champions
Fixtures
1st match
2nd match
3rd match
4th match
5th match
6th match
References
External links
Series home at ESPN Cricinfo
Inter
Category:Irish domestic cricket competitions
Category:Inter-Provincial Championship seasons
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Sotalol versus propafenone for long-term maintenance of normal sinus rhythm in patients with recurrent symptomatic atrial fibrillation.
This prospective, randomized, single-blinded, placebo-controlled study compared the efficacy and safety of sotalol and propafenone when used for long-term prevention of atrial fibrillation. For the long-term maintenance of normal sinus rhythm, propafenone seems to be more effective than sotalol.
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Inhibition of ubiquitin specific protease 17 restrains prostate cancer proliferation by regulation of epithelial-to-mesenchymal transition (EMT) via ROS production.
Prostate cancer is one of the most frequently diagnosed neoplasms among men in the world. However, molecular mechanisms underlying the progression of prostate cancer are still unclear. In the study, we investigated the effects of ubiquitin specific protease 17 (USP17) on prostate cancer growth. The results indicated that USP17 expression was markedly increased in prostate cancer tissues and cell lines. Repressing USP17 expression significantly reduced the proliferation, migration and invasion of prostate cancer cells using cell counting kit-8 (CCK-8), colony formation and transwell assays. In addition, apoptosis was significantly induced by USP17 knockdown via increasing the expression of cleaved Caspase-9/-3 and poly (ADP)-ribose polymerase (PARP), as well as Cyto-c. Further, USP17 silence evidently promoted reactive oxygen species (ROS) production in prostate cancer cells. Nuclear nuclear factor-κB (NF-κB)/p65 expression and total NF-κB/p65 phosphorylation were markedly down-regulated by USP17 repression. Intriguingly, blocking ROS generation using its scavenger of N-acetyl-l-cysteine (NAC) significantly abrogated USP17 knockdown-induced apoptosis and -inhibited NF-κB/p65 signaling in vitro. Our data also showed that USP17 silence impaired tumor growth in the subcutaneous mouse model in vivo. Taken together, our results suggested that USP17 decrease might exert anti-tumor activities against prostate cancer growth by inducing apoptosis and suppressing NF-κB/p65 signaling via the promotion of ROS. Thus, USP17 could be served as a promising candidate to develop effective therapeutic strategy against prostate cancer progression.
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Ideals(12 Dec. 1984)
When the daughter of the hotel's guests gets sick, Christine tries to get her medical assistance but her parents refuse treatment cause it's against their beliefs. Christine tries to ... See full summary »
Storyline
When the daughter of the hotel's guests gets sick, Christine tries to get her medical assistance but her parents refuse treatment cause it's against their beliefs. Christine tries to convince them to reconsider. Mark has been seeing an older woman and asks her to marry him. But her son's disapproval and a career opportunity might keep her from accepting. And Mrs. Cabot tries to get a painting she did in art show but the man in charge doesn't think it's good. Written by
[email protected]
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Manic Panic Cream Formula Hair Color
The actual color is more like the gem stone turquoise, a unique and ethereal shade. ATOMIC TURQUOISE™ is available in two MANIC PANIC Hair Color formulas: Classic Cream, and Amplified™ Cream.
ATOMIC TURQUOISE™ must be applied to bleached or pre-lightened hair for best results.
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TD-SCDMA (Time Division-Synchronous Code Division Multiple Access), is a standard for 3G in China. It is available from China Mobile in several cities. A TD-SCDMA pre-paid card called "Beijing 2008 USIM", designed to be economical and easy to use, was first provided for foreigners by China Mobile during the Beijing Olympic Game period.
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Drug information quality assurance program used to appraise students' performance.
A quality assurance program developed for a drug information service was used to objectively measure the performance of doctor of pharmacy degree students on rotation in the service. Two five-point rating scales based on objective criteria were developed so that judgmental and nonjudgmental drug information responses could be evaluated separately. Preceptors used the scales to evaluate 30 randomly selected responses from each of 22 Pharm.D. students (15 responses from midrotation and 15 from the end of the rotation). Written responses were also evaluated on a five-point scale by the requesters. In all of the evaluations, a score of 5 was excellent and a score of 1 was unacceptable. The preceptors assigned a score of 5 to 52.3% of the 660 responses evaluated, 4 to 29.1%, 3 to 12.9%, 2 to 4.5%, and 1 to 1.2%. No significant difference was found based on the academic quarter during which the rotation took place. The difference in scores between judgmental and nonjudgmental responses was not significant. End-of-rotation scores tended to be higher than midrotation scores, although the difference was not significant. Testing for interrater reliability revealed moderate agreement between raters. Requesters gave mean scores higher than 4 for accuracy, completeness, objectivity, and usefulness of the written responses. Timeliness scores were significantly lower but still acceptable. A drug information quality assurance program provided a structured, objective means of evaluating student performance.
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“You know what I think about before I pull the trigger? I think about the infield fly rule. I love that fucking rule. It says sorry batter, you're a smuck for poppin' up with runners on, and you stupid ass infielder you don't get to cheat and drop the ball just because you caught a break.”Al Pacino - Rooster
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Introduction
============
The blood--retinal barrier (BRB), similar to the blood--brain barrier, tightly regulates the passage of water, ions, and other macromolecules from the vascular space into the interstitium of the surrounding tissue. In the BRB, vasculature has a continuous endothelium with tight intercellular junctions and few fenestrations. These barrier properties of the retinal endothelium in the BRB result in high transendothelial electrical resistance (TEER) and restricted paracellular permeability. Because the BRB plays a fundamental role in maintaining tissue fluid homeostasis and preserving vulnerable neural tissues from detrimental substances circulating in the blood, the BRB breakdown associated with increased retinal vascular permeability could cause visual impairment and complete vision loss in ocular diseases such as diabetic retinopathy, retinal vascular occlusion, and exudative macular degeneration \[[@r1]-[@r3]\]. In this regard, the identity of the mediators of the BRB breakdown and retinal vascular hyperpermeability has been a subject of intense research scrutiny, and elucidation of their mechanisms of action could facilitate their potential use as pharmacological intervention targets in ocular diseases.
Stem cell factor (SCF) is a multifunctional cytokine that binds to and activates the receptor tyrosine kinase, cKit. SCF/cKit signaling has been found to play a crucial role in normal hematopoiesis, pigmentation, fertility, and gut movement \[[@r4]-[@r7]\]. Recently, we reported for the first time that SCF acts as a potent endothelial permeability factor \[[@r8]\]. In human umbilical vein endothelial cells, SCF-induced activation of cKit disrupts endothelial adherens junctions and increases endothelial permeability as strongly as does the vascular endothelial growth factor (VEGF). The SCF-induced increase in endothelial permeability contributed to the development of hyperpermeable vasculature in the retina of mice with streptozotocin-induced diabetes. Inhibition of SCF/cKit signaling using anti-SCF neutralizing immunoglobulin G (IgG) or cKit inhibitors prevented diabetes-induced BRB breakdown \[[@r8],[@r9]\]. Increased expression of SCF in the ocular tissues of patients with diabetic retinopathy was recently reported \[[@r10],[@r11]\]. These findings suggested that SCF/cKit signaling might be a novel target for diabetic retinopathy therapeutics. However, the mechanism underlying SCF-induced endothelial hyperpermeability has not yet been fully elucidated, although our previous studies pointed to an important role of the endothelial nitric oxide synthase.
Multiple mechanisms that regulate vascular endothelial permeability have been identified \[[@r12],[@r13]\]. These mechanisms do not operate separately but are closely interconnected. Among intracellular signaling molecules involved in regulation of vascular permeability, Src, a member of the Src family kinases, has been implicated as one of the major signaling proteins that lead to a loss of endothelial barrier function \[[@r14]\]. Mice deficient in Src showed no vascular permeability response to stimulation with VEGF and displayed reduced edema and infarct size following stroke and myocardial infarction \[[@r15],[@r16]\]. In addition, it has been reported that phosphorylated tyrosines of cKit interact with Src \[[@r17]\]. Considering the critical actions of Src in the regulation of vascular permeability and its interaction with phosphorylated cKit, we hypothesized that Src might be involved in SCF/cKit-mediated endothelial hyperpermeability. The present study addressed the role of Src in the SCF-induced breakdown of the BRB and retinal vascular leakage.
Methods
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Measurement of endothelial paracellular permeability and TEER
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Human retinal microvascular endothelial cells (HRMECs; Cell Systems, Kirkland, WA) were cultured in endothelial growth medium (Lonza, Walkersville, MD). HRMECs were seeded on to 6.5-mm diameter transwell permeable supports (Corning, Cambridge, MA) and cultured to form confluent monolayers. Recombinant human SCF (rh SCF; R&D Systems, Minneapolis, MN) or PBS (137 mM NaCl, 2.7 mM KCl, 10 mM Na~2~HPO~4~ and 1.5 mM KH~2~PO~4~) was added to the culture medium in the upper chamber of the transwell. For the cKit and Src inhibition experiments, imatinib mesylate (10 μM; Selleckchem, Houston, TX) or SU6656 (1 μM; Sigma, St. Louis, MO) was added 30 min before the stimulation with SCF. In the TEER assay, electrical resistance across a monolayer of HRMECs established on a transwell membrane was measured using a Millicell™ ERS-2 Voltohmmeter (Millipore, Billerica, MA). Rh SCF, rh VEGF (R&D Systems), or PBS was added to the medium in the upper chamber at time zero, and serial changes in electrical resistance were measured thereafter. The TEER values were calculated by first subtracting the background TEER from the experimental TEER and then by multiplying the result by the surface area of the filter. In the paracellular permeability assay, fluorescein isothiocyanate (FITC)-conjugated dextran (MW = 40 kDa, Sigma) at a final concentration of 1 mg/ml was added to the transwell upper chamber. After 30 min, a 50-μl aliquot of the medium was taken from the lower chamber, and the amount of FITC-dextran in the medium was determined by measuring the absorbance at 485 nm and 530 nm using a fluorescence plate reader (Tecan, Durham, NC). Permeability was expressed as the fold increase ± standard error of the mean (SEM) with respect to the value obtained from the PBS-treated controls.
Animals
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Animal experiments were conducted with Kit*^W-sh/W-sh^* mice (Jackson Laboratory, Bar Harbor, MA) and wild-type (WT) littermates. All animal protocols were reviewed and approved by the Institutional Animal Care and Use Committee in accordance with the animal care guidelines published by the Institute for Laboratory Animal Research. For the surgical procedures, the mice were anesthetized with an intraperitoneal injection of 120 mg/kg ketamine and 16 mg/kg xylazine. The adequacy of the anesthesia was assessed by monitoring the pedal withdrawal reflex response. At the end of the experiments, the animals were euthanized using carbon dioxide inhalation, and tissues were collected for further analysis.
Retinal vascular permeability assay
-----------------------------------
Under light anesthesia, recombinant mouse SCF (rm SCF; R&D Systems) was injected into the vitreous cavity of one eye, and an equal volume of PBS was injected into the other eye. For the Src inhibition experiment, PP2 (2 mg/kg; Sigma) or vehicles were intraperitoneally administered 1 h before the rm SCF injection. Retinal vascular leakage was evaluated by measuring extravasation of the Evans blue (EB; Sigma) dye \[[@r18]\]. Briefly, 0.15 ml of the 20 mg/ml EB solution (sonicated and filtered) was injected intravenously. After the dye had circulated for 4 h, a small volume of blood was collected via an intracardiac puncture, and the retinas were dissected from eyeballs, dried, and weighed. The EB dye was extracted by incubating the retina in formamide (Sigma) overnight at 78 °C. The extract was then centrifuged and filtered through an ultrafree MC tube (Millipore) to remove any proteins. The EB dye in the filtered solution was spectrophotometrically detected by measuring absorbance at 620 nm and 740 nm. The amount of EB dye was calculated from a standard curve of the EB solution in formamide. The EB concentration in the blood sample was determined similarly by measuring the absorbance of the diluted blood sample in formamide. EB leakage was calculated using the following equation: \[retinal EB amount (μg) / retinal weight (g)\] / \[blood EB concentration (μg/μl) × circulation time (h)\].
Western blotting analysis
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Cell lysates were separated using sodium dodecyl sulfate--polyacrylamide gel electrophoresis. The blots were hybridized with the appropriate primary IgGs, phospho-Y416 Src (p-Y416 Src, Invitrogen, Carlsbad, CA) and Src (Santa Cruz Biotechnology, Santa Cruz, CA), and phospho-cKit (p-cKit; Cell Signaling Technology, Danvers, MA) and cKit (R&D Systems), followed by incubation with horseradish peroxidase-conjugated secondary IgGs (Vector Laboratories, Burlingame, CA). Then, the immunoreactive bands were visualized with a chemiluminescent reagent as recommended by Amersham Biosciences Inc. (Piscataway, NJ).
Immunocytochemistry
-------------------
For the analysis of p-Y416 Src localization, confluent HRMECs were fixed with 4% paraformaldehyde (Sigma), permeabilized with 0.5% Triton X-100, and blocked in 10% normal donkey serum. Cells were double stained using a goat anti-vascular endothelial (VE)-cadherin IgG (Santa Cruz Biotechnology) and a rabbit anti-p-Src IgG (Invitrogen), followed by incubation with the respective secondary IgGs that were labeled with either Alexa Fluor^®^ 594 or with Alexa Fluor^®^ 488 fluorescent secondary IgGs (Vector Laboratories). For the analysis of VE-cadherin internalization, HRMECs were incubated with an anti-VE-cadherin IgG (R&D Systems) at 4 °C for 1 h and then washed with cold basal medium to remove unbound IgG. Next, the cells were treated with rh SCF (50 ng/ml) or PBS in the presence or absence of imatinib mesylate (10 μM) or SU6656 (1 μM) at 37 °C for 30 min. The cells were washed with acidic PBS to remove membrane-bound IgG. Cells with or without the acid wash were fixed, blocked, and stained with Alexa Fluor^®^ 488-conjugated secondary IgG. For the double immunofluorescence labeling for an early endosomal marker, the cells were further stained with an antiearly endosome antigen 1 (EEA1) IgG (BD Pharmingen, Palo Alto, CA), followed by incubation with an Alexa Fluor^®^ 594-conjugated secondary IgG. Nuclei were stained with 4',6-diamidino-2-phenylindole (DAPI). Images were obtained using a fluorescence microscope (Nikon, Melville, NY). The number of samples examined ranged from five to seven per group.
Immunohistochemistry
--------------------
Retinal flat mounts were zinc-fixed, soaked in blocking solution (5% bovine serum albumin, 5% normal donkey serum, and 0.5% Triton X-100 in PBS), and stained with an anti-VE-cadherin IgG (BD Pharmingen) and an Alexa Fluor^®^ 488-conjugated secondary IgG. The flat mounts were then further stained with Alexa Fluor^®^ 594-conjugated isolectin GS-IB4 overnight \[[@r19]\]. The nuclei were counterstained with DAPI. Images were obtained using a fluorescence microscope (Nikon). The number of sections examined ranged from six to ten per group.
Statistical analysis
--------------------
All data are presented as the mean ± the standard error of the mean (SEM). Statistical significance was evaluated using the unpaired Student *t* test or one-way ANOVA followed by the Bonferroni post hoc multiple comparison test. Differences were considered statistically significant if the p value was less than 0.05. The number of samples is indicated as n.
Results
=======
SCF/cKit signaling induces retinal vascular hyperpermeability
-------------------------------------------------------------
We first performed in vitro TEER and in vivo retinal vascular leakage experiments to investigate whether SCF enhances retinal vascular permeability. We found that SCF significantly reduced electric resistance across the human retinal endothelial monolayer with potency comparable to that of VEGF ([Figure 1A](#f1){ref-type="fig"}). Pretreatment with the cKit inhibitor, imatinib mesylate, substantially inhibited the decrease in TEER induced by SCF ([Figure 1B](#f1){ref-type="fig"}). We also observed that intravitreal injection of SCF significantly increased retinal vascular leakage of EB in the WT mice, whereas SCF failed to induce retinal vascular hyperpermeability in the cKit mutant (Kit*^w-sh/w-sh^*) mice that exhibited a low amount of cKit-expressing endothelial cells due to a mutation in the 5′ regulatory element of the cKit encoding gene ([Figure 1C](#f1){ref-type="fig"}) \[[@r20],[@r21]\]. These data confirmed that SCF plays a key role in induction of retinal vascular hyperpermeability via activation of the cognate receptor, cKit.
{#f1}
SCF/cKit signaling induces strong activation of Src in human retinal vascular endothelial cells
-----------------------------------------------------------------------------------------------
To elucidate whether SCF-mediated retinal vascular hyperpermeability depends on Src activity, we performed western blotting analysis and determined whether Src was activated upon the treatment of HRMECs with SCF. [Figure 2A](#f2){ref-type="fig"} shows that cKit and Y416 Src were phosphorylated within 30 min after exposure to SCF. Pretreatment with imatinib mesylate completely abrogated SCF-induced phosphorylation of Y416 Src, which indicates that Src is one of the downstream molecules in the SCF/cKit signaling pathway in HRMECs. As previous studies have shown that translocation of activated Src from the cytoplasm to the plasma membrane is necessary for its biologic function, we next determined the localization of phosphorylated Src in HRMECs \[[@r22],[@r23]\]. First, it was confirmed that pretreatment with the Src inhibitor, SU6656, inhibited the SCF-induced Src activation ([Figure 2B](#f2){ref-type="fig"}). The immunocytochemical analysis showed a substantial increase in the p-Y416 Src signal at the VE-cadherin-positive adherens junctions in SCF-treated HRMECs compared to the staining intensity in the PBS-treated controls. The increase in the p-Y416 Src signal was abolished by pretreatment with either imatinib mesylate or SU6656 ([Figure 2C](#f2){ref-type="fig"}). These results indicate that SCF/cKit signaling promotes phosphorylation of Src and localization of the phosphorylated Src in the plasma membrane of HRMECs.
{#f2}
SCF-induced retinal vascular hyperpermeability requires the activation of Src
-----------------------------------------------------------------------------
To investigate whether SCF-induced activation of Src contributes to SCF-mediated retinal vascular hyperpermeability, we performed an in vitro endothelial permeability assay with HRMECs that were pretreated with the Src inhibitor, SU6656. As shown in [Figure 3A](#f3){ref-type="fig"}, blocking Src activation abolished SCF-induced endothelial hyperpermeability in HRMECs. An in vivo retinal vascular permeability assay also revealed that intraperitoneal injection of Src inhibitor, PP2, almost completely prevented the SCF-induced retinal vascular leakage of EB ([Figure 3B](#f3){ref-type="fig"}). This result suggests that Src activation plays a predominant role in SCF-mediated retinal vascular hyperpermeability.
{#f3}
SCF/cKit/Src signaling enhances internalization of VE-cadherin in retinal vascular endothelial cells
----------------------------------------------------------------------------------------------------
Because Src activation has been known to mediate the breakdown of endothelial junctions through internalizing VE-cadherin that is a major endothelial adherens junction protein, we investigated whether SCF-induced activation of Src might change the distribution of VE-cadherin at retinal endothelial junctions \[[@r24]\]. Immunofluorescence analysis revealed that VE-cadherin in PBS-treated HRMECs appeared as a continuous line at the endothelial cell--cell junction ([Figure 3C](#f3){ref-type="fig"}). However, the treatment with SCF induced a focal loss in the staining of VE-cadherin at endothelial borders and increased staining for the punctate form of intracellular VE-cadherin that was colocalized with the endosomal marker EEA1. Pretreatment of imatinib mesylate or SU6656 substantially blocked SCF-induced internalization of VE-cadherin. However, the treatment with imatinib mesylate or SU6656 alone did not change the distribution of VE-cadherin relative to that observed in the PBS-treated control. Having examined murine retinal vasculature, we observed that intravitreal injection of SCF induced the disappearance of the VE-cadherin signal from the retinal vasculature ([Figure 3D](#f3){ref-type="fig"}). However, intraperitoneal injections of imatinib mesylate or PP2 before SCF injection abolished the SCF-mediated focal loss of VE-cadherin in the retinal endothelium. These results support the notion that SCF-induced activation of cKit and Src leads to internalization of VE-cadherin in the retinal vasculature.
Discussion
==========
This study demonstrated that Src plays a critical role in the SCF-induced breakdown of the BRB. SCF-mediated activation of cKit strongly induced activation of Src and promoted its localization to the plasma membrane of human retinal endothelial cells. In vitro and in vivo experiments showed that Src inhibitors potently blocked SCF-induced internalization of VE-cadherin and retinal vascular hyperpermeability. These data showed that Src is one of the signal transduction molecules in the SCF/cKit signaling pathway in retinal endothelial cells and that Src activation is required for the SCF-induced breakdown of the BRB.
In the basal state, Src is inactive due to the intramolecular interaction between the Src homology 2 (SH2) domain and the C-terminal phosphotyrosine (Y573) and/or between the SH3 domain and the proline-rich sequence \[[@r14]\]. The inactive clamped conformation of Src is switched into an active conformation through changes in the phosphorylation state and intermolecular interaction. In response to the stimulation with SCF, cKit becomes autophosphorylated on Y568 and Y570 residues, which have been reported to strongly interact with the SH2 domain of the Src family of kinases \[[@r17]\]. This disrupts the inhibitory interaction of the SH2 domain with the phosphorylated Y573 and induces the open conformation of Src, which is necessary for its tyrosine kinase activity. In addition, the phosphorylated tyrosine residues of cKit have been shown to interact with the SH2 domain-containing phosphatase that opens the SH1 kinase domain of Src through dephosphorylating Y527 \[[@r25]\]. These findings suggest that SCF-induced activation of cKit might directly or indirectly induce the active conformation of Src and phosphorylate Y416 that is a crucial residue for Src tyrosine kinase activity. In accordance with these findings, we observed strong phosphorylation of Y416 in Src and a distinct localization of p-Y416 Src in the plasma membrane of SCF-treated retinal endothelial cells, which was abolished by the treatment with the cKit inhibitor, imatinib mesylate.
VE-cadherin is the primary component of endothelial adherens junction complexes. Many studies have shown that alteration in the cellular localization of VE-cadherin and its dissociation from actin cytoskeleton affect vascular permeability due to the disruption of endothelial cell--cell junctions \[[@r12]\]. Recent studies demonstrated an important role of Src in VEGF-induced internalization of VE-cadherin. Upon binding to VEGF, the phosphorylated VEGF receptor 2 (VEGFR2) interacts with Src through the cytoplasmic SH2 domain of VEGFR2 and activates it. Src activation, in turn, induces phosphorylation and subsequent internalization of VE-cadherin leading to the disruption of the endothelial cell barrier \[[@r24],[@r26],[@r27]\]. As reported in VEGF-mediated endothelial permeability, the present data revealed that Src activation was also important in the SCF-mediated breakdown of the BRB. In human retinal endothelial cells, SCF enhanced the phosphorylation (data not shown) and internalization of VE-cadherin. SCF-induced internalization of VE-cadherin was abolished by an Src inhibitor. In our in vivo experiments, the focal loss of VE-cadherin shown in the SCF-injected retinal vascular junction was not observed when the Src inhibitor was injected intravitreally. These data suggest that Src activation in response to SCF/cKit signaling mediates the BRB breakdown and the retinal vascular leakage, at least in part through promoting internalization of VE-cadherin. Src increases vascular permeability through many different mechanisms. In addition to enhancing the internalization of VE-cadherin, Src activation disrupts endothelial barriers by promoting the cytoskeletal contraction and remodeling of the cell--matrix connections \[[@r28]-[@r30]\]. Changes in the cellular shape and the cell-- matrix interactions lead to the gap formation between endothelial cells and enhance paracellular permeability. In this regard, further studies are necessary to understand other potential mechanisms by which Src regulates SCF-induced endothelial hyperpermeability.
Taken together, the present data firmly support the role of Src in mediating the SCF-induced breakdown of the BRB and retinal vascular leakage. Increased retinal vascular permeability is a common manifestation of ocular diseases, such as diabetic retinopathy and age-related macular degeneration. It is likely that in many of these disorders activation of the SCF/cKit/Src signaling pathway makes a substantial contribution to the development of the hyper-permeable retinal vasculature.
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) \[2012M3A9C6050368\] \[2015R1A2A1A15052509\] \[2015R1D1A1A02061724\]. The authors do not have any conflict of interest to declare.
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Kosovo taskforce to return to region
1999-07-09T00:00:00+01:00
The government’s Kosovo taskforce could be back in the war-torn region as early as next week.
Taskforce chairman Nigel Thompson said he wanted to get teams of suitably skilled people into Kosovo to work with the British Army as soon as possible and encouraged British contractors to “think Serbia”.
Thompson said: “There is no money in Serbia until the political situation is sorted out, but people should be thinking about longer term alignments. There’s more to come in the rest of the region, and if British firms are in Kosovo early, they stand a better chance of getting work in Serbia.”
He added: “At the moment, there’s a 30m ecu fund at the disposal of the European Union taskforce which is now based in Pristina, and we want to get British firms attached to that as soon as possible.”
Thompson said that a number of small companies had already shown an interest in establishing links with contractors and consultants in Macedonia.
However, he emphasised that he was currently looking for skilled individuals, rather than companies, to travel to Kosovo.
“I hope to get some people over there next week, or, failing that, the week after,” said Thompson.
“I’m trying to assemble teams of qualified individuals to go out and help, not under the banner of companies, but providing the skills needed in the region.”
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EEVblog #600 – Opamps Explained
The most often requested video! Dave explains what Operational Amplifiers (OpAmps) are and how they work. The concepts of negative feedback, open loop gain, virtual grounds and opamp action. The comparator, the buffer, the inverting and non-inverting amplifiers, the differential amplifier, and the integrator circuit configurations are also explained.
Then a practical breadboard circuit to demonstrate a virtual ground and the effect of voltage rail limitations.
All EEVblog Opamp related videos are HERE
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On June 17, 2015, Alex Rodriguez, a star slugger for the New York Yankees, hit a home run for his 3,000th hit. Zach Hample, a passionate baseball fan, was sitting in the bleachers, and snagged the ball with his glove. He was immediately approached by Yankees personnel, who offered to exchange the ball for other valuable Yankee merchandise. Hample, however, was hearing none of it, and told the Yankees that he was keeping the ball.
Subsequently, Hample started to have second thoughts, and said that he might give the ball to the Yankees in exchange for a large donation to his favorite charity. Finally, on July 3, 2015, the drama came to a close, as Hample gave the ball to Rodriguez, in exchange for a $150,000 donation to charity by the Yankees and some signed memorabilia. While Hample should be lauded for his generous gesture, he is probably unaware of the complex tax issues relating to catching a historic home run ball — issues that were exacerbated by his flip-flopping.
The issue of taxes and catching baseballs is nothing new, but some of the tax implications are still uncertain. In September 1998, when Mark McGwire was about to break the single-season home-run record, the Internal Revenue Service declared that the “catchers” of record-setting balls would be taxed, even if they returned the ball to the player. The IRS statement caused an uproar, angering Congress and baseball fans alike. The IRS, in the face of much criticism, quickly retracted its initial announcement, and issued a press release stating that there is no taxable event if the catcher “immediately returns” the baseball (IR-98-56).
There are two questions, however, that the IRS has left unclear. First, what are the tax implications of a fan who chooses to keep the baseball — much less sell it? The IRS chose not to clarify that issue when it stated in its release that “The tax results may be different if the fan decided to sell the ball.” Second, exactly how much time does the fan have to “immediately” return the ball to the player (or to the team)? Hample, with his lucky grab, brought both of these issues to light.
Keeping the Baseball
Section 61 of the Internal Revenue Code states broadly that "gross income means all income from whatever source derived." The Treasury Regulations (§1.61-14) add that gross income includes finding a "Treasure Trove." Probably the most famous “Treasure Trove” case is Cesarini v. United States, 296 F. Supp. 3 (N.D. OH 1969), aff’d, 428 F.2d 812 (6th Cir. 1970) (per curiam). In Cesarini, a couple found $4,467 in cash while cleaning their piano. The court held that the cash was considered income in the year in which it was found.
Finding a Treasure Trove is distinguishable from self-created property, which is not taxable until the taxpayer sells it. An example of self-created property is where the taxpayer is a professional fisherman who catches a fish. The fisherman in this case does not have to pay tax until the fish is actually sold.
The precise tax treatment of catching baseballs has evoked different opinions from noted tax experts. Although most tax experts agree that a fan who catches a record ball should be taxed, they disagree as to the exact point in time at which the tax liability is created. Is the catching of the ball the taxable event, or the subsequent sale? The root of the argument is whether catching a record baseball is akin to finding a treasure or more similar to self-created income. Some authorities are of the opinion that the fan should be taxed immediately on the fair market value of the baseball, as the fan catching the ball has essentially found a treasure.[1] Others, however, argue that catching a baseball is more similar to self-created property, as the fan made the effort to come to the ballpark and reach for the ball. Additionally, similar to a fisherman who obtains a fishing license, baseball fans pay for their ticket, which gives them the right to catch any balls that are hit their way.
In most cases, the analogy of self-created property to catching a record-setting baseball is rather weak. In a typical case of self-created property, such as the case of a fisherman, the fisherman has certain unique skills and expends a significant amount of money and effort to catch the fish. A baseball fan, on the other hand, comes to a game with no unique catching skills and does not expend any monetary or physical effort beyond paying for his ticket and reaching up his hand. At least that was the case until Hample caught Rodriguez’s record ball.
Hample is, for lack of a better title, a professional catcher of baseballs. He has written three books on baseball, one of them entitled, How to Snag Major League Baseballs. He has reportedly caught more than 8,000 balls at over 51 different major league stadiums. Hample also holds a world record for catching a baseball dropped from an altitude of 1,050 feet. In Hample’s case, it is definitely plausible to argue that the ball is self-created property, as it is a product of his effort and skill, and should not be taxable until it is sold.
Can Hample Still Change His Mind?
Once Hample caught the record ball, he had two choices with relatively clear tax consequences. Return the ball immediately and pay no tax, or keep the ball and pay tax (at some point in time). Instead, Hample — clearly not thinking of the tax ramifications — after initially claiming that he was keeping the ball, later decided to return the ball to Rodriguez. If Hample is assuming that he will not be taxed, he may be very wrong. The IRS in its 1998 press release only explicitly allowed for an exception if a fan “immediately returns it.” While the IRS may be somewhat flexible regarding what “immediately” means, it may also be very wary of extending the exception further and allowing fans to change their minds a significant amount of time after the catch. This is especially true because the exception to gross income that the IRS created for returning the ball was already — according to a number of tax experts — a clear deviation from undisputed tax principles.
When Hample files his tax return, he may take the position that he has no income under the “immediate” standard, and the Yankees will likely report a charitable contribution of $150,000. In the best-case scenario, the IRS will accept both of those tax positions. There is a chance, however, that the IRS will challenge Hample’s classification of his returning the ball as “immediate,” and claim that Hample has income equal to the value of the ball. Although Hample will presumably be entitled, in such case, to take a charitable deduction of $150,000 — for the donation the Yankees made on his behalf — charitable deductions are subject to certain significant limitations, which could give rise to a certain amount of tax leakage.
So, while Hample’s intentions are generous and impressive, he should probably engage a tax counsel to clarify what role taxes might play in the equation.[2]
[1] Even assuming that a fan catching a baseball is comparable to the finding of a treasure, a taxpayer may try to argue that, as the value of a record-setting baseball is unique and not readily determinable until sold, under an “open transaction doctrine” type analysis, the catching of such a baseball is not be taxable until such time that the baseball is sold and the value can be accurately determined.
[2] Some of the information in this article, and in particular the Treasure Trove/Self-created Property distinction, came from an article by Andrew D. Appleby, Ball Busters: How the IRS Should Tax Record-Setting Baseballs and Other Found Property under the Treasure Trove Regulation VERMONT LAW REVIEW, VOL. 33, P. 43, (2008)
Read the full article on Law360 (with subscription).
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Q:
обработка строки из str в int
в модуле pyautogui есть функция position(), которая возвращает координаты курсора мыши в данный момент
но возвращает она их в виде такой строки: Point(x=567, y=350)
Как обработать эту строку так, чтобы на выходе было два числовых значения(соответственно x и y), с которыми уже можно работать как с числами? Отсечь все лишнее.
A:
position() из PyAutoGui возвращает никакую не строку, а кортеж из двух чисел. Т.е. именно два числовых значения, как вам и требуется.
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DNA sequence analysis of an abl-related gene in the blow fly, Calliphora erythrocephala.
The Ceabl locus is a member of a small family of abl-related sequences in C. erythrocephala. The catalytic, SH2 and SH3 domains of the Ceabl-encoded protein show greater than 75% sequence identity to vertebrate abl protein tyrosine kinases and greater than 95% identity to the D. melanogaster abl polypeptide. Ceabl diverges from the vertebrate proteins, however, at the extreme amino terminus, near the beginning of the vertebrate abl exon involved in differential splicing. The carboxyl region shows no detectable similarity to the vertebrate abl proteins, while identity to Drosophila abl falls to 55%. Regions conserved between the two dipteran genes revealed no strong similarities to other proteins in the Genbank and EMBL databases.
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Bounty has successfully ended. Thank you everyone for your support!
Token distribution is ongoing.
A big thank you to our 8,533 bounty hunters, earning an average reward of 2,812.609867573 TTV.
Dear Bounty Hunters,We have received an updated opinion from our legal council that urges TV-TWO to perform KYC on all individuals and companies that receive our tokens. While this is nothing new concerning our investors, it does come as a surprise to us that this also covers any entity that participated in marketing and bounty activities. The change comes in light of new regulation that qualifies transferring tokens to sanctioned parties as aiding and abetting in criminal activity.What does this mean? We need to ask any bounty hunter to complete the following KYC form on the TV-TWO website: https://tv-two.com/bounty.html During the process, please enter the same Ethereum address that you have used in the bounty spreadsheets. Once your KYC is reviewed and approved, we will transfer the tokens that you have earned during the campaign to your wallet. Distribution starts on August 24.We are sorry that this requirement is only communicated now. We would have loved to do the bounty without KYC, but if regulations change, companies that want to flourish need to adapt. We are here for the long-run, so we ask you for your support.Questions: Please do not post any bounty related questions in the TV-TWO Telegram group. This chat is purely for investors. Bounty discussions will be deleted. We do answer all your questions via email: [email protected]
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Footage has been recorded by the BBC showing the extreme lengths a group of armed people-smugglers were prepared to go to to get migrants in Calais across the Channel to Kent.
The masked men blocked the main route to the French port with a felled tree.
BBC South East witnessed migrants being directed to break into lorries brought to a sudden halt.
Special correspondent Colin Campbell and his producer said the people-traffickers were "ruthless and territorial", controlling the situation armed with large sticks.
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Peter Reiley
Biography: Peter Reiley is the stud of all studs. But not only does he love the ladies, he can be a guys guy and just sit back and watch a football game. Peter often gets the comment , "wow, I don't usually like small dogs but Peter is pretty cool." Fetch is Peter's favorite game. Peter loves to bring you a toy to throw so he can then run after it and bring it back. Peter lives in a apartment with wooden floors so he gets quite excited when he steps on carpet....he'll take a few laps at lighting speed just to check the grip of the carpet! Peter is such a pleasure to have around that I have a sign up sheet for puppy sitters!! No matter where he is though, he has his quirks. He loves chewing his greenie at night on your chest or lap. He'll even bark at the jar to tell you if he's ready for his greenie a little early. He does all the tricks he knows for a liver treat and he just loves to go for walks outside. Peter is now working to be a therapy dog so he can add happy moments to those not as fortunate as others.
Hello Peter,
I hope you will be my friend. You look so very cute and sweet, and could be my boyfriend !!
With very best wishes,
Snowdrop the Maltese xox
ps. I am off on holiday to France in the morning, so if you do reply, forgive me for not being able to reply until we return in a couple of weeks.
x
Hi Peter,I don't think they come any cuter then you....you are such a handsome Lil guy.I wish you a very Happy birthday and many more to come.Big kisses n hugs sweetie..please come see my dogs n comment
A very happy birthday to a very special boy. Peter could life anyone's spirits, and brighten anyone's day. He'll make a fantastic therapy dog. Who couldn't love such a face? Big hugs for him and lots of greenies!
Puppy Up Your Blog
Here at The Daily Puppy, we love puppies of all shapes, sizes, breeds, and colors.
We encourage visitors to browse our puppy picture archives to look at all the adorable photos of past daily puppies
, and to bookmark this page and visit often to see what cutie-pie graces the front page.
Want us to run a feature of your special little puppy? We are always looking for submissions of the cutest puppies on the planet.
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Q:
Delete action in AngularJS app wired onto Ruby on Rails
I'm working on a "To-Do List" application, built on AngularJS sitting on Ruby on Rails.
Now I'm trying to setup a delete button, "X" to remove 'to-do' items that will persist to the db.
I haven't found many Angular on ROR examples online so I'm kindof lost on making it work.
Current error when clicking on a delete button in view is https://.../todos/6.json 404 (Not Found)
I've attached what i think is relevant code i've worked on so far. Any advice would be very appreciated!
_home.html
<div ng-repeat="todo in todos">
{{todo.desc}}
<button type="button" ng-click="removeTodo(todo.id)" class="close">×</button>
</div>
mainCtrl.js
angular.module('App')
.controller('MainCtrl', [
'$scope',
'todos',
function($scope, todos) {
$scope.todos = todos.todos;
$scope.removeTodo = function(id) {
todos.delete(id);
};
}]);
todos.js
angular.module('App')
.factory('todos', ['$http', function($http) {
var o = {
todos : []
};
o.delete = function(id) {
return $http.delete('/todos/' + id + '.json').success(function(data) {
o.todos.delete(data);
})
}
return o;
}])
schema.rb
create_table "todos", force: :cascade do |t|
t.string "desc"
t.datetime "created_at", null: false
t.datetime "updated_at", null: false
end
routes.rb
Rails.application.routes.draw do
root to: 'application#angular'
resources :todos, only: [:create, :index, :show, :delete]
end
todos_controller.rb
class TodosController < ApplicationController
def delete
respond_with Todo.find(params[:id])
end
private
def todo_params
params.require(:todo).permit(:desc)
end
end
A:
Thanks Oleg for giving advice regarding routes.rb and todos_controller.rb.
I decided to continue using ajax with $http. After fixing above, and the following two changes, it was able to persist to db, and update in browser.
.factory
o.delete = function(id) {
return $http.delete('/todos/' + id + '.json').success(function(data) {
for (var i = o.todos.length -1; i >=0; i--) {
if(o.todos[i].id === id) {
o.todos.splice(i, 1);
}
}
})
}
mainCtrl
$scope.removeTodo = function(todo) {
todos.delete(todo.id);
};
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Master of Business Systems
Master of Business Systems (MBS) is a Postgraduate/Master's degree in Business Systems.
Business Systems programs combine Information Technology (IT) and Business/Management courses and are common in Australia.
Australian universities, like most in the UK education systems, pay more attention on how IT would help the business and financial process online, rather than how IT would be the product itself in conceptualization to be sold as most institutions do in South Korea, Japan and the US. However, for international students interested to enter IT, it would be a good choice of kick-start.
Typical areas of study
Basic Technology:
Courses may include topics like applied computer science, computer networks and Internet technology, website engineering, web designing, programming, or information security.
Business Informatics Methods:
Courses may focus on information systems development, database management, information systems architectures, business intelligence, or business process modelling.
Management:
Management oriented topics may be studied in courses on management information systems, information management, management control, database management, risk management, neural networks, project management, knowledge management, management and organization of IT departments, or software engineering management etc.
Applications:
Important application domains of Business Systems may be investigated in courses like enterprise resource planning, E-Commerce, SAP and e-business networking, industrial information systems, or electronic finance/electronic banking, web security, simulation models etc.
References
Master of Technology （Business System）of Swinburne university.（now incorporated as Master of Business Information System ）
Business Administration, Master
Category:Business qualifications
Category:Information systems
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795 P.2d 285 (1990)
STATE of Hawaii, Plaintiff-Appellee,
v.
Jeffrey A. YOUNG, Defendant-Appellant.
No. 13891.
Intermediate Court of Appeals of Hawaii.
July 26, 1990.
*288 Earle A. Partington (Partington & Foley, of counsel), on the brief, Honolulu, for defendant-appellant.
James M. Anderson, Deputy Pros. Atty., on the brief, Honolulu, for plaintiff-appellee.
Before BURNS, C.J., and HEEN and TANAKA, JJ.
TANAKA, Judge.
Defendant-Appellant Jeffrey A. Young (Defendant) was convicted by a jury of driving under the influence of intoxicating liquor (DUI) in violation of Hawaii Revised Statutes (HRS) § 291-4(a)(2) (1985)[1] (driving with a blood alcohol level of .10 percent or more).[2] On appeal, Defendant contends that the trial court reversibly erred in (I) admitting the breath test result from an intoxilyzer model 4011AS (Intoxilyzer) into evidence; (II) its rulings regarding the testimony of the State of Hawaii's (State) witness, Honolulu Police Department (HPD) criminalist Claire Chun (Chun); (III) refusing to give certain jury instructions and giving certain instructions over Defendant's objection; and (IV) denying Defendant's motion to dismiss with prejudice Count I (violation of HRS § 291-4(a)(1)) of the complaint on the ground of double jeopardy. We affirm.
FACTS
On June 4, 1988, Defendant was arrested for DUI. He consented to take a breath test. HPD Officer William Wardle (Wardle), a certified Intoxilyzer operator, administered the breath test to Defendant. At trial, Wardle testified that (1) he observed Defendant for fifteen minutes prior to administering the breath test to ensure that Defendant did not eat, drink, smoke, or regurgitate anything; (2) he carefully and sequentially followed the seventeen-step Intoxilyzer Operational Checklist in administering the breath test; (3) the calibration verification test of Intoxilyzer No. 103292 was done with a beam attenuator bearing an identical serial number; and (4) Intoxilyzer No. 103292 was working properly because the alphanumerics of the test results were printed out in proper order on the printout card and no error light appeared.
The trial court qualified Chun as "a qualified and certified operator supervisor of the intoxilyzer machines and as an expert criminalist regarding the intoxilyzer instrument who is competent to testify about the accuracy and reliability of the Honolulu Police Department's intoxilyzer instruments." May 23, 1989 Transcript at 107. Chun testified that on June 2 and 14, 1988, she tested Intoxilyzer No. 103292 for accuracy with two simulator solutions of .05 and .30 percent alcohol concentration, respectively. The temperature of the solutions was 34° centigrade. On both dates, Chun also used the Intoxilyzer's beam attenuator to check it for accuracy. Chun concluded that based on these tests, Intoxilyzer No. 103292 was working properly and accurately on June 4, 1988. She further testified that the Intoxilyzer has a margin of error of ± .01 percent.
*289 On cross-examination, Defendant questioned Chun in depth about the Intoxilyzer's use of a 2,100 to 1 breath to blood partition coefficient or ratio to calculate a person's blood alcohol concentration (BAC). Questions regarding the beam attenuator were also directed at Chun.
Over Defendant's objection, the court admitted into evidence the breath test result showing a BAC of .204 percent.
The jury found Defendant guilty of Count II (driving with a BAC of .10 or more), but was unable to reach a verdict on Count I (driving under the influence). Over Defendant's objection, the court declared a mistrial as to Count I.
DISCUSSION
I.
Defendant first contends that the trial court erred in admitting the Intoxilyzer test result into evidence. He argues as follows: (1) in laying a proper foundation for the admission of the Intoxilyzer test result into evidence, the State must show strict compliance with the provisions of the State Department of Health's Rules for the Testing of Blood, Breath and Other Bodily Substances for Alcohol Concentration (Rules) which have a direct impact on the validity and accuracy of the test result, State v. Souza, 6 Haw. App. 554, 559, 732 P.2d 253, 257 (1987); (2) the Rules mandate that breath testing instruments and their accessories be evaluated and approved; (3) there was no showing that the State Department of Health (DOH) evaluated the Intoxilyzer before its approval or approved the beam attenuator; and (4) therefore strict compliance with the Rules as required by Souza was lacking and the breath test result was improperly admitted. The argument is without merit.
In State v. Tengan, 67 Haw. 451, 691 P.2d 365 (1984), the supreme court stated that "the Director of Health approved the use of the Intoxilyzer in accord with the requirements of Chapter 47 [of the Public Health Regulations which were superseded by the Rules] and informed the Director of Transportation of the approval on December 16, 1980." Id. at 461, 691 P.2d at 372 (footnote omitted). Section 11-111-2.1(a) of the Rules provides that breath-testing instruments approved by the DOH "as of December 31, 1985, shall continue to be approved[.]"
In State v. Christie, 70 Haw. 158, 766 P.2d 1198 (1988), cert. denied, ___ U.S. ___, 109 S.Ct. 2068, 104 L.Ed.2d 633 (1989), the supreme court reiterated:
The department [DOH] found the Intoxilyzer and its related accessories met the prescribed standards in December 1980, and the instrument and the accessories have since been used by the county police departments to measure blood alcohol concentration.
Id. at 168, 766 P.2d at 1204. The supreme court also held:
That the instrument [Intoxilyzer] and related accessories have been found accurate when used as intended by their designer and manufacturer is ... implicit in the department's approval.
Id. at 172, 766 P.2d at 1206. The beam attenuator is a related accessory to the Intoxilyzer.
In our view, Tengan and Christie lay to rest Defendant's contention that the DOH did not evaluate and approve the Intoxilyzer and the beam attenuator.
Accordingly, the trial court did not err in admitting the Intoxilyzer test result into evidence.
II.
Defendant next contends that the trial court erred in precluding him from cross-examining Chun as to why she described the beam attenuator as a lens. He also claims that the court erred in allowing Chun, over his objection, to testify regarding articles and studies she had read concerning the 2,100 to 1 partition ratio or coefficient. We find no error.
A.
In State v. Faulkner, 1 Haw. App. 651, 624 P.2d 940 (1981), we stated:
*290 The law is well-settled that the admissibility of evidence, generally, and the scope of cross-examination at trial are matters exercised within the discretion of the trial court.
* * * * * *
The trial court's exercise of its discretion to limit the scope of cross-examination will not be ruled as reversible error when it limits irrelevant and repetitious questions by counsel which do not result in manifest prejudice to the defendant.
Id. at 654-55, 624 P.2d at 943-44 (citations omitted).
In State v. Christie, supra, the supreme court concluded that a beam attenuator, "a circular piece of quartz that absorbs a known quantity of infrared radiation emitted by a particular source[,]" came within The Random House Dictionary of the English Language definition of "lens." 70 Haw. at 169, 766 P.2d at 1204-05. Since the issue of whether the beam attenuator is a lens was decided in Christie, Defendant's questions relating to a beam attenuator vis-a-vis a lens were irrelevant. Moreover, the barring of those questions did not result in manifest prejudice to Defendant.
Accordingly, the court did not abuse its discretion on this point.
B.
Defendant claims that Chun "had no expertise in the field of science involved in the partition coefficient." Therefore, Defendant argues that the court should not have allowed her to testify about articles and studies regarding the partition ratio or coefficient. We disagree.
At trial, Chun was qualified as a "certified operator supervisor of the [Intoxilyzer] ... competent to testify about the accuracy and reliability of the [Intoxilyzer]." May 23, 1989 Transcript at 107. Defendant sought to challenge the accuracy and reliability of the Intoxilyzer by cross-examining Chun about the use of the 2,100 to 1 breath to blood partition ratio in the Intoxilyzer.
Clearly, an expert may consider or rely upon "any scientific, technical, or professional text, treatise, journal or similar publication" in forming an opinion and may be cross-examined about those publications. Hawaii Rules of Evidence (HRE) Rule 702.1(b). Here, Chun's opinion regarding the use of the 2,100 to 1 partition ratio in Intoxilyzers and the reliability of the ratio was based upon her research and reading of relevant articles and studies. As a qualified expert regarding the accuracy and reliability of the Intoxilyzer, Chun was qualified to render an opinion regarding the 2,100 to 1 partition ratio, which had a bearing on the Intoxilyzer's accuracy and reliability. When cross-examined, she testified about the articles and studies of the partition ratio she considered and relied upon to form her opinion. Moreover, Chun's opinion testimony "assist[ed] the trier of fact to understand the evidence or to determine a fact in issue [the accuracy and reliability of the Intoxilyzer]." HRE Rule 702.
We conclude that the trial court did not err in permitting Chun to testify about the articles and studies she considered and relied upon in forming her opinion testimony.
III.
Regarding the giving or failure to give jury instructions, the standard of review is "whether, when read and considered as a whole, the instructions given are prejudicially insufficient, erroneous, inconsistent or misleading." State v. Halemanu, 3 Haw. App. 300, 306, 650 P.2d 587, 592 (1982).
A.
Defendant contends that regarding the elements of the HRS § 291-4(a)(2) offense, the trial court incorrectly refused to instruct the jury that a "finding of a mens rea as to the element of operating a vehicle [was required]." We disagree.
HRS § 702-204 (1985) provides that when a statute is silent as to the state of mind required to establish an element of an offense, the element is established by proving that "a person acts intentionally, knowingly, or recklessly." However, HRS *291 § 702-212(2) (1985) states that the state of mind requirements do not apply to:
A crime defined by statute other than this [Hawaii Penal] Code, insofar as a legislative purpose to impose absolute liability for such offense or with respect to any element thereof plainly appears.
By enacting HRS § 291-4(a)(2), "the legislature permitted proof of DUI by merely showing that a defendant drove a vehicle with a BAC of 0.10 percent or more." State v. Wetzel, 7 Haw. App. ___, ___, 782 P.2d 891, 895 (1989) (footnote omitted). Thus, the legislative purpose of HRS § 291-4(a)(2) was "to impose absolute liability for such offense or with respect to any element thereof," as provided in HRS § 702-212(2). Accordingly, we stated in State v. Christie, 7 Haw. App. ___, ___, 764 P.2d 1245, 1246, aff'd, 70 Haw. 158, 766 P.2d 1198 (1988), cert. denied, ___ U.S. ___, 109 S.Ct. 2068, 104 L.Ed.2d 633 (1989), that DUI has been "a per se offense" under HRS § 291-4(a)(2) since 1983.
The trial court did not err in refusing to instruct the jury that a finding of mens rea was required under HRS § 291-4(a)(2).
B.
Defendant also contends that the trial court erred "in refusing to instruct the jury as to timeliness, venue, and jurisdiction" as to the HRS § 291-4(a)(2) offense. This contention is meritless.
HRS § 701-114(1) (1985) requires proof beyond a reasonable doubt of facts establishing jurisdiction, venue, and timeliness. However, we held in State v. Correa, 5 Haw. App. 644, 706 P.2d 1321 (1985), that where there is uncontradicted and undisputed evidence of timely prosecution and proper venue in the record, the trial court's failure to instruct the jury regarding those items is "error that is harmless beyond a reasonable doubt." Id. at 650, 706 P.2d at 1325. See also Hawaii Rules of Penal Procedure (HRPP) Rule 52(a) (an error which does not affect substantial rights shall be disregarded).
In this case, the record clearly indicates that the prosecution was timely and the trial court had proper venue and jurisdiction. Moreover, Defendant did not dispute any of these items at trial.
Consequently, the trial court did not commit reversible error in this regard.
C.
Based on Chun's testimony, the trial court instructed the jury that the Intoxilyzer has "a recognized margin of error of one one-hundredth, that is .01 percent[.]" May 24, 1989 Transcript at 52. Defendant sought to have the court instruct the jury that "there are one or more margins of error in an intoxilyzer test[,]" and that all margins of error must be deducted from the Intoxilyzer test result. The court refused to give Defendant's instruction. We find no error in the refusal.
Chun testified that the Intoxilyzer has a margin of error of ±.01 percent. This margin of error is inherent in the Intoxilyzer and is applicable to every breath test. In addition to the ±.01 percent, there was no evidence of any margin of error inherent in the Intoxilyzer due to the 2,100 to 1 partition ratio. Chun testified that based on studies, the National Safety Council and the National Highway Transportation Safety Administration determined 2,100 to 1 "as a fair partition ratio for the general population" and that "this value was to be used in the manufacture of breath testing instruments in the United States." May 23, 1989 Transcript at 136. Chun also testified that a person's partition ratio may vary from the 2,100 to 1 value and that, if a person's partition ratio was lower than 2,100 to 1, his test would register a false high.
Based on the foregoing evidence in the record, the court did not err in refusing to instruct the jury about an additional margin of error arising from the use of the 2,100 to 1 partition ratio in the Intoxilyzer.
We stated in State v. Gates, 7 Haw. App. ___, 777 P.2d 717 (1989), that the testimony regarding the 2,100 to 1 partition ratio "goes to the weight the jury should accord the Intoxilyzer test result with respect to its accuracy[.]" Id. at ___, 777 P.2d at 721. Defense counsel fully argued to the jury the possibility of error in the Intoxilyzer *292 test result because the decision to use the 2,100 to 1 partition ratio was based on "a good statistic," but "not science." The trial court instructed the jury "to determine the weight to be given any evidence properly admitted," and "to determine whether the Intoxilyzer machine used in this case was reliable." May 24, 1989 Transcript at 53.
We conclude that the court did not err in refusing to instruct the jury as to "one or more margins of error."
D.
Over Defendant's objection, the trial court gave its Special Instruction Nos. 10 and 11 (No. 10 and No. 11). Those instructions read as follows:
[No. 10]
The State Department of Health has issued rules governing the use of chemical tests of blood alcohol levels. These rules are known as Title 11, Chapter 111, and must be complied with before any breath or blood test may be admitted into evidence against the defendant.
The Court has admitted the test performed on the defendant in this case.
It is up to the jury to determine the weight to be given any evidence properly admitted, including tests for blood alcohol levels.
[No. 11]
The Intoxilyzer machine 4011AS, has been approved by the Director of Health, State of Hawaii, and has met the Federal Standards for devices to measure breath alcohol and approved by the Director of [T]ransportation, State of Hawaii, as a generally reliable breath testing instrument.
Judicial notice of this fact of the general reliability of the Intoxilyzer does not establish this as an unquestioned fact, and may be challenged. It is for the jury to determine whether the Intoxilyzer machine used in this case was reliable.
May 24, 1989 Transcript at 53.
Defendant contends that these instructions are erroneous and prejudicial because they "created a mandatory presumption as to the accuracy of the Intoxilyzer test result." Conversely, the State argues that the instructions "were legally correct and Defendant suffered no prejudice therefrom."
We do not agree with either Defendant or the State. In our view, the instructions dealing with the admissibility of the Intoxilyzer test result and judicial notice of the approval and general reliability of the Intoxilyzer were unnecessary and inappropriate.
HRE Rule 104(a) states that "[p]reliminary questions concerning... the admissibility of evidence shall be determined by the court[.]" HRE Rule 1102 provides that "[t]he court shall instruct the jury regarding the law applicable to the facts of the case, but shall not comment upon the evidence." The giving of Nos. 10 and 11 violated both HRE Rules 104(a) and 1102.
The admissibility of the Intoxilyzer test result was wholly within the province of the court to determine. Consequently, the portions of No. 10 relating that the Rules must be complied with before a test result may be admitted into evidence and that the court did admit the test result into evidence were unnecessary and inappropriate in a jury instruction.
In State v. Lowther, 7 Haw. App. 20, 740 P.2d 1017 (1987), we stated:
One of the foundational prerequisites for the admission of the Intoxilyzer test result into evidence is a "showing that the testing method is reliable[.]" People v. Bowers, 716 P.2d 471, 473 (Colo. 1986). The effect of Tengan is to satisfy the "reliability" prong of the foundational requirements for admissibility. See State v. Souza, 6 Haw. App. [554], 732 P.2d 253 (1987). It relieves the State of the burden of presenting expert testimony regarding the general reliability of the Intoxilyzer as a breath testing device in each DUI prosecution for purposes of *293 admissibility of the test result. Nothing in Tengan suggests that the general reliability of the Intoxilyzer is an unquestioned fact.
Id. at 24, 740 P.2d at 1020 (footnote omitted). In the case at bar, the trial court took judicial notice of Tengan solely for the purpose of admitting the Intoxilyzer test result into evidence because "we doubt that the Intoxilyzer's general reliability may be judicially noticed as an adjudicative fact[.]" Lowther, 7 Haw. App. at 25, 740 P.2d at 1020. Thus, the portion of No. 11 concerning judicial notice that the Intoxilyzer was approved by the DOH dealt with the admissibility of the test result and, consequently, was also unnecessary and inappropriate in a jury instruction.
The portions of both instructions deemed unnecessary also constituted unwarranted comments on the evidence in violation of HRE Rule 1102. See Ray v. State, 749 S.W.2d 939 (Tex. App.Ct. 1988) (where an instruction singles out a piece of evidence for heightened scrutiny by the jury, it is an improper comment on the weight of evidence).
Notwithstanding the unnecessary and inappropriate portions of the instructions, No. 10 closed with an admonition that it was for the jury to determine the weight to be given to the evidence, including the test result. Likewise, No. 11 concluded with an admonition that the jury was to determine whether the Intoxilyzer used in the case was reliable. These statements effectively preserved the issue of the reliability of the Intoxilyzer and accuracy of the breath test result for the jury to determine. Thus, contrary to Defendant's contention, Nos. 10 and 11 did not create a mandatory presumption as to the accuracy of the test result. In our view, the admonitions and general instructions relating to the presumption of innocence and the necessity of proof beyond a reasonable doubt rendered the unnecessary and inappropriate portions of Nos. 10 and 11 harmless, thereby "not affect[ing] substantial rights" of Defendant. HRPP Rule 52(a).
IV.
Finally, Defendant contends that the trial court erred in denying his motion to dismiss Count I with prejudice on the ground of double jeopardy. We hold that State v. Grindles, 70 Haw. 528, 777 P.2d 1187 (1989), has rendered the issue moot.
On May 24, 1989, the jury returned a verdict finding Defendant guilty of Count II, but was unable to reach a verdict as to Count I. On the same day, the court sentenced Defendant and declared a mistrial as to Count I. On June 2, 1989, the court denied Defendant's oral motion to dismiss Count I with prejudice.
Thereafter, on July 27, 1989, Grindles was decided. In Grindles, the supreme court held that "HRS § 291-4(a) provides two alternative means of proving the single offense of driving under the influence of intoxicating liquor." Id. at 531, 777 P.2d at 1190 (footnote omitted).
In the case at bar, although the complaint consisted of two counts, consistent with Grindles, only one offense was charged. The jury found Defendant guilty of Count II, one of the alternative means of proving DUI, which we are affirming. Therefore, Count I, the other alternative means of proving DUI, which ended in a mistrial, is irrelevant and a nonissue.
Accordingly, Defendant's appeal on this point is moot.
CONCLUSION
Finding no reversible errors, we affirm.
NOTES
[1] Hawaii Revised Statutes (HRS) § 291-4(a) (1985) provides as follows:
Driving under influence of intoxicating liquor.
(a) A person commits the offense of driving under the influence of intoxicating liquor if:
(1) The person operates or assumes actual physical control of the operation of any vehicle while under the influence of intoxicating liquor; or
(2) The person operates or assumes actual physical control of the operation of any vehicle with 0.10 per cent or more, by weight of alcohol in the person's blood.
[2] The complaint charged defendant Jeffrey A. Young with violation of HRS § 291-4(a)(1) (Count I) and HRS § 291-4(a)(2) (Count II). The trial court declared a mistrial as to Count I because the jury could not reach a verdict on that count.
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Damning the Koch Bros.
Despite that loophole, Koch Industries in 2007 went beyond what was required by U.S. law and voluntarily stopped doing business with Iran in any form. By contrast, many companies, including corporate donors to Democrats, stayed in Iran after Koch Industries had left. General Electric, whose CEO Jeffrey Immelt is chairman of President Obama’s Council on Jobs and Competitiveness, continued to do business in Iran until 2008. Another Democratic funder, the industrial conglomerate Honeywell International Inc., is still selling security technology to Iran. In that time, those companies gave generously to Democrats. The Weekly Standard’s Mark Hemmingway points out that between 2003 and 2010, the Democratic Senatorial Campaign Committee took at least $343,000 in donations from corporations doing business with Iran, including from Koch’s political action committee. (That history did deter the DSCC from trying to make political hay of the Bloomberg Markets story by demanding that Republicans call on Koch Industries to cut ties with Iran, something the company had already done.) If Koch’s prior involvement in Iran tainted its political contributions, why was the same not true for the funds that flowed to left-wing coffers and causes from the likes of GE and Honeywell? Neither the Bloomberg Markets article nor the left-wing bloggers who trumpeted its findings paused to consider the question.
Instead, the magazine explored the absurd and offensive theory that Koch Industries’ willingness to do business with Iran stemmed from the libertarian politics of the Koch brothers. Although the connection was never concretely spelled out, the implication was that the brothers’ dislike for government regulations was behind their company’s willingness to break the law to do business in Iran. The charge was baseless on several counts. First and foremost, the company’s business in Iran, conducted through a subsidiary, was entirely legal. More to the point, there was not a shred of evidence connecting libertarian politics to Koch Industries’ involvement in Iran. One could just as plausibly suggest that liberal politics drove Democratic donors to set up shop in Iran. Indeed, those companies arguably have more to answer for, since they continued to business in Iran after Koch Industries had left.
All those flaws help explain why, aside from ecstatic coverage by left-wing partisans, the Bloomberg Markets has gotten little traction since its publication last week. If one aim of the story was to discredit the Koch brothers and their company in the eyes of the Tea Party and conservatives generally, it has clearly failed. If anything, it has confirmed that while left-wing billionaires like George Soros – who has been convicted for insider trading in Europe – get a free pass in the media, conservatives will be demonized regardless of the facts. But then, they already knew that.
It's the classic leftard tactic, as laid out by Alinsky, that basically comes down to "pick a target and throw lots and lots of sh*t, eventually enough will stick, even if there is no basis in truth of any of it".
That and of course that there are two sets of rules, one for leftards and one for everybody else.
Sort of like the article in yesterday's FPM edition that claims Obama wanted to apologize for the atomic bomb. No evidence, just a rumor reported as fact. And of course all the sheep commenters simply agree – "baaah, baaaah, baa-aaa-aaahhhhh!"
akbass
Ha ha ha……you Lefttards are all the same. You want to see a flock of sheep? Check out the videos from the Atlanta OWS demonstrations (or from any other city for that matter).
Questions
Rep. Ron Paul has publicly endorsed the demonstrators, especially its anti-Fed signs. Does that make Paul a "Lefttard," too?
It's amazing to see the left and right both attack each other as Evil. Are both right? Are both wrong? Or are both partially right and partially wrong?
But one thing is clear as it stands now: with the country split down the middle, with each side convinced the other is the Evil one…how long before real blood starts to flow? How long before Civil War Two becomes a reality? Who or what is behind these amazingly different paradigms of the world? God help us. Good luck to everyone.
Beth
"God help us" yes
And thank God, there are 2 sides. That means there is still a side that refuses to get into bed with those who bow to a murderer.
Traveler
now it it time for Bloomberg to our George Soros, the master pupperteer and owner of one of the other political parties, oops…right that will never happen…does he have a share of Bloomberg too?
Traveler
that was suppose to be out George Soros
SoCalMike
The Left lies.
They can't open their mouths without lying so for Bloomberg to smear the Koch Brothers with lies makes perfect sense.
Bloomberg and NY Times writers just don't feel like their feet are on the ground if they aren't busy selling their own leftist gospel or aiding and abetting mass murder.
The Party of Pinocchio is at it again.
scum
Sure Mike, while 1 in 6 kids goes to school hungry.
Neils60
There are free and/or reduced breakfasts and lunch programs available in just about every school in the USA, based upon a parent/guardians income. (I can tell you, too, from experience, there's little to sometimes no scrutiny of parent/guardians income statements.)
NY Times defended (made excuses) for the murderers of the Beslan children. (I will never forget them for that)
leopards can not change their spots
davarino
I have seen posts here lately by lefties that mention the EVIL KOCH BROTHERS and their ties to the EVIL TEA PARTY (the capped words should be said with an echo and errie). That was all you had, and now you know the truth? Big deal, now go back home and get some more talking points you miserable twitts
scum
It goes far deeper than that Davarino. Forget the 'Tea Party' connection. Like Cheney being indicted by Nigeria, the Koch Bros doled out millions in under the counter deals in dozens of countries. And that's only the beginning….
nightspore
What on earth does "Cheney being indicted by Nigeria" mean?
"And that's only the beginning …." I'm sure it is.
Why do leftwing trolls always sound like South Park extras? Why do their posts always resemble a mirror that isn't completely smooth, so that the reflection is oddly disconnected …
http://jewishdefense.org AJ Weberman
It is still wrong even if it is legal. It is like doing business with Hitler. But as long as the Right benefits anything goes including global warming.
Neils60
Tell that to President Obama's most prestigious member of his Job's Council, Jeffrey Immelt of GE.
howdydoody
Well, it's a well known fact (not rumour nor hearsay) that the Koch fortune was made in Stalinist Russia, so how is it surprising that they would find a way to make a profit in Iran?. They'll make money wherever they can, no matter how oppressive and bloodthirsty the regime is, they're capitalists, that's what they do. It's about money, not ethics or morals.
derekcrane
And the Kennedys are all bootleggers because Joe Kennedy earned his fortune mainly by "importing" liquor during Prohibition? And Al Gore is a traitor because his father conspired with Armand Hammer to make Occidental Petroleum an important contributor to the Soviet oil industry? The sins of the father cannot be conferred to the sons.
Josh
I am frankly shocked that Front Page would apologize for anyone who does business with the Iranian regime, which seeks to wipe Israel off the face of the earth. I have been skeptical of the attacks on the Koch brothers for some time, but even they aren't denying their business dealings with the Hitlerian regime in Tehran. For shame, Koch brothers, an for shame to anyone who excuses their business dealings with the greatest enemies of Israel.
Beth
I'm with you Josh on this: Shame on anyone who has ANY dealings with Iran
But the article here is coverage of the deep bias of the left – and not an apology for dealing with murderers. That's another topic.
Dennis X
The so-called " grass roots tea baggers" are in fact the koch brothers.
Amused
Frontpage is sympathetic to ANYONE who opposes Democrats or Obama . Which by the way is Horowitz's right , but at the expense of his own credibility .
Just like the PHONY OBAMA APOLOGY story , which if any honesty existed on "Daves blog " there would have been a retraction , or atleast a correction [dont hold your breath ]
Now here we have the Koch Bros. Truly a slimey crew , fought tooth and nail aginst having some of the chermicals their plants spew into the enviromnment listed as carcinogenic , having poisoned people in Arkansas , but hey they support with their millions the Conservatives therefore are off limits for criticism , EVEN WHEN IT IS JUSTIFIED .
Oh yea , poor v,poor Koch Bros . attacked by those dirty lefties ,being called EXACTLY what they are .LOL….and they had to "investigate themselves " to find out if they were ilegally dealing with Iran ?
Frontpage , you've sold your souls for your ideology ….and that aint a good thing . True Breitbart-ians . Makes one wonder if any of the " Koch Bros. Juice " has reahed out an touched you .
** BTW , that's NOT fact , just my OPINION , but shaped by your behavior .
Beth
I find it amusing that FP articles are able to keep you awake at night (obviously)
Amused
No , they dont keep me awake at night Beth . They are entertainment , though I am a bit surprised about just how many ignorant people there are in this country . And of course it provides evidence for a theory I've held for the past 30 or so years . Have you heard about it ?
I call it " The Theory of ARSEHOLES in the Unverse " [ and their exponential propogation ] . All my hypothesis' thusfar have been confirmed . It's a great thing in science to have observation match exactly a hypothesis .
Glad you're amused , so am I .
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Universities Avoid Kindle Over Accessibility Barriers
Three US universities have agreed not to use Amazon's e-book reader the Kindle until it is easily usable by blind people. A fourth settled a complaint from blind people's advocacy groups by saying that it will strive to use accessible devices in future.
Though the Kindle DX reader can read out text, making it potentially useful to blind people or those with low vision, it offers no way to navigate its controls and menus that is accessible to blind users.
Along with a student, US groups the National Federation of the Blind and the American Council of the Blind sued Arizona State University last year over its trial of Kindle readers. The suit said that the University was in violation of the Americans With Disabilities Act (ADA).
That Act prohibits discrimination against people on the basis of their disability and applies to public bodies and all post-secondary educational institutions whether public or private.
Though maintaining that it had not broken the law, the University settled that case and the trial of the machines will be allowed to conclude this spring.
The American Council of the Blind said that it reached the agreement because of "the university's agreement that should ASU deploy e-book readers in future classes over the next two years, it will strive to use devices that are accessible to the blind", according to a Council statement.
The Department of Justice said that three other universities had agreed not to use or promote Kindle devices or other e-book readers that were not fully accessible to blind users.
"Under the agreements reached today, the universities generally will not purchase, recommend or promote use of the Kindle DX, or any other dedicated electronic book reader, unless the devices are fully accessible to students who are blind and have low vision. The universities agree that if they use dedicated electronic book readers, they will ensure that students with vision disabilities are able to access and acquire the same materials and information, engage in the same interactions, and enjoy the same services as sighted students with substantially equivalent ease of use.
The universities which have agreed to refrain from using the Kindle or any non-compliant machine are Case Western Reserve University in Cleveland; Pace University in New York; and Reed College in Oregon.
"Advancing technology is systematically changing the way universities approach education, but we must be sure that emerging technologies offer individuals with disabilities the same opportunities as other students," said assistant US attorney general Thomas E. Perez. "These agreements underscore the importance of full and equal educational opportunities for everyone."
The universities will be allowed to complete their pilot programmes before the agreements take effect.
Amazon said in December that it would release Kindle machines with an audio menu by summer of this year.
"[The Kindle] has enabled many vision-impaired readers to enjoy books more easily than before, and has also helped dyslexic readers and those with learning disabilities improve their reading skills," said its statement. "To make Kindle more useful for the blind, the Kindle team is currently working on an audible menuing system so blind and vision-impaired readers can easily navigate to books unassisted."
"In addition, a new super size font will be added to Kindle, increasing the number of font sizes from six to seven. This seventh font size will be twice the height and width of the current largest font. These new features are scheduled for release by the summer of 2010," said the statement.
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Accelerated partial breast irradiation with IMRT: new technical approach and interim analysis of acute toxicity in a phase III randomized clinical trial.
To evaluate with a randomized clinical trial the possibility of treating the index quadrant with external intensity-modulated radiotherapy (IMRT) in a selected group of patients with early-stage breast cancer and to analyze the acute toxicity. From September 2005, a randomized Phase III clinical trial has been conducted to compare conventional (tangential field) fractionated whole breast treatment (Arm A) with accelerated partial breast irradiation plus intensity-modulated radiotherapy (Arm B). For intensity-modulated radiotherapy, the clinical target volume was drawn with a uniform 1-cm margin around the surgical clips in three dimensions. The ipsilateral and contralateral breast, ipsilateral and contralateral lung, heart, and spinal cord were contoured as organs at risk. All the regions of interest were contoured according to the International Commission on Radiation Units and Measurements reports 50 and 62 recommendations. In September 2008, 259 patients were randomized and treated. The mean clinical target volume in Arm B was 44 cm(3) and the mean planning target volume was 123 cm(3). The mean value of the ratio between the planning target volume and the ipsilateral breast volume was 21%. The rate of Grade 1 and Grade 2 acute skin toxicity was 22% and 19% in Arm A (Radiation Therapy Oncology Group scale), respectively. The tolerance in Arm B was excellent with only 5% Grade 1 and 0.8% Grade 2 acute skin toxicity. The planning constraints were fully satisfied in most patients. In a very few cases, this was not possible because of very unfavorable anatomy. Quality assurance procedures were performed according to our internal quality assurance protocol, with excellent results. In the present preliminary analysis, we have demonstrated that accelerated partial breast irradiation is feasible, with very low acute toxicity.
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Q:
eliminating quotation marks from an expression
I have the following variables between " and "
A<-"Dxi2 , Dxu2 , Dxa2 , Dxb2 , Dxc2 , Dxd2"
How could I take out the " as to obtain
A<-data.frame(Dxi2 , Dxu2 , Dxa2 , Dxb2 , Dxc2 , Dxd2)
or
A <-c(Dxi2 , Dxu2 , Dxa2 , Dxb2 , Dxc2 , Dxd2)
Thank you
A:
I think what you actually want is:
as.data.frame(mget(unlist(strsplit(A, "\\s*,\\s*"))))
which will produce the data frame from the variables referenced by A. However, if you want to get the expression, you can:
parse(text=paste0("A <- data.frame(", A, ")"))[[1]]
which produces:
A <- data.frame(Dxi2, Dxu2, Dxa2, Dxb2, Dxc2, Dxd2)
You can also evaluate it to get the data frame, but if you're going to do this, I would recommend the mget solution:
eval(parse(text=paste0("A <- data.frame(", A, ")")))
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Thursday, 29 September 2016
Secundipara continued....
Okay, now the little lady is having her lunch, let's try again (with one hand).
What's it like having a three year old and a three month old? Well for this white British, middle class, academic mother......its good! Of course new parents usually say that. And while I'm so chronically tired that a few days ago I accidentally drank some bleach (I'm fine, don't worry, though there were a few minutes of frantic googling and water-drinking); so time -poor that my teeth are unbrushed at 1pm today; and in such bad physical shape that I'm considering getting one of those neck cones they put on dogs so that I stop accidentally catching a glimpse of my midriff....despite all this I am gloriously, ecstatically happy. Why?
- My daughter is objectively amazing, perfect and the finest specimen of humanity the world ever saw, obvs.
- Any second-time apathy that might have occurred has been totally offset by the relief I feel after not knowing if she would make it for so long.
- Her brother has adjusted surprisingly well and hasn't tried to commit fratricide at all (yet) or at least not while I was looking.
- We are in all truth ridiculously fortunate and really well placed to just enjoy things right now. I've had three months leave on full pay, Papa's hours are really flexible, we are comfortable, financially and physically. And we have two healthy and cheerful children. What's not to love?
We've got several advantages compared to our first-time parenting experience. We now have a dishwasher, a car and a cleaner.....these help so much. This time around we didn't have any night-time social life we needed to adjust to living without. And we have tons of lovely friends nearby who are in the same stage of life whereas last time we felt like the only parents in the world.
And of course we have a bit more experience than last time: it does help! I remember being in a blind panic one time when Orson was asleep in his Moses basket and he threw up a little. I was thinking 'if you vomit while unconscious you can choke and die, I've got to get him into the recovery position!' Turns out there are different rules for babies and drunk people, babies are pros at not choking.
So my worries about if I'd have enough love to go round everyone were unfounded - love really *is* like a magic penny.
I'll have to write when I'm having a bad day next time to balance this nauseating cheeriness a little.......
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Hinge assemblies are commonly used to allow electronic device components to move relative to one another. For example, a laptop computing device can include a base component that is rotationally coupled to an upper display component by way of a hinge assembly. It is often desirable to provide some biasing or resistive force when moving the upper component of a laptop between closed and open positions, or between two different open positions. Many types of conventional friction-based clutches can provide such a resistive force for a hinge assembly. Such friction-based clutches can also provide a braking force that holds the upper component in a fixed position with respect to the base component once a user sets the upper component at a desired fixed position.
Unfortunately, many conventional friction-based clutches provide a fixed level of resistance at all times over a full range of motion of the hinge assembly. Consequently, the level of resistance cannot be lowered for specific portions of the range of motion, particular directions, or different times or circumstances. For example, a user may need to hold the base component at the same time that he or she adjusts the position of the upper component in order to prevent any simultaneous lift or following motion of the base component. This can be inconvenient when the user merely wishes to adjust slightly the upper component position and may only want or have one hand to do this. Further, a fixed level of resistance can often be too much and a nuisance when a user wishes to open a laptop from a closed position.
While current hinge and clutch designs for electronic devices have worked well in the past, there is often room for improvement. Accordingly, there is a need for improved clutch designs for electronic devices that allow for varying levels of resistance.
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Q:
Salesforce SOQL query return all values including NULL
I have a simple SOQL query:
select Count(ID), CampaignId, Campaign.Name
from CampaignMember
where CampaignId in ('701U0000000MVoQ', '701U0000000MLFR', '701U0000000MVoL')
group by CampaignId, Campaign.Name
The result of the query brings back 2 records as there are contacts in two of the campaign member lists.
I would also like to bring back the 3rd record in which the count will be 0. Is there a way to do this in SOQL, I don't believe there is an ISNULL() function that can be used on the select.
A:
Any special reason why you need an aggregate query? One way to do it would be to use relationships, like that:
SELECT Id, Name, (SELECT Id FROM CampaignMembers)
FROM Campaign
WHERE Id IN ('701U0000000MVoQ', '701U0000000MLFR', '701U0000000MVoL')
Later in code it can be accessed like that
List<Campaign> campaigns = [Id, Name, (SELECT Id FROM CampaignMembers)
FROM Campaign
WHERE Id IN ('701U0000000MVoQ', '701U0000000MLFR', '701U0000000MVoL')];
for(Campaign c : campaigns){
System.debug(c.Name + ': ' + c.CampaignMembers.size());
}
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A new method for absolute quantitation of MRS metabolites.
A new method for absolute quantitation of MRS spectra is presented. This method is not based on a reference peak, derived from a real NMR signal, but rather on a synthesized NMR reference produced by an electronic device, transmitted by a broad-band antenna to avoid quality factor variations. This signal is therefore received at the same time as the sample signal. The reference line produced is stable in time (maximum variation lower than 2%) and allows precise and accurate measurement of absolute concentrations (mean error lower than 3%) in vitro and in vivo.
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Home
"[...] the striving for freedom never died out in Russia, and over the centuries in each generation there have been people who devoted their lives to the struggle for freedom, and sacrificed their lives for freedom's sake."
Liudmila Alekseeva
Welcome to Rights in Russia, a website providing news, views and reviews about human rights in the Russian Federation. You can also find links to our publications on Facebook, Twitter, Blogger and Wordpress.
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Team 29: What's worth remembering2 November 2018Hi,
this is Kolya Ovchinnikov. Recently I have been experiencing some problems with
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HRO.org in English
Memorial after Arseny Roginsky1 February 2018Source: HRO.orgThe death of Arseny Roginsky is a huge loss for Memorial. He was not only the chair of the board of the International Memorial ...
Posted 8 Feb 2018, 06:39 by Rights in Russia
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1. Field of the Invention
The present invention relates to a method for dividing a first binary number N1 by a second binary number which can be written in the form 2n/k, n and k being whole numbers, to obtain a result N2.
2. Description of the Related Art
Binary division is an arithmetic operation which can be implemented in various ways in an integrated circuit. When possible, the binary division can be done with a hard-wired logic circuit having a very simple structure. For example, the division of a number N1 by a number forming a power of 2, i.e., the calculation of N1/2n, is done by performing n right shifts of the bits of the number N1. For example, the division of 15, i.e., 00001111 in binary, by 16, is obtained by performing four right shifts of the bits of the number N1, because 16=24. The number 00000000.1111 is obtained, i.e., 0.9375 in decimal.
Within the scope of the production of a radio frequency identification (RFID) contactless integrated circuit conforming to the industrial specification EPC™-GEN2 (“Radio-Frequency Identity Protocols Class-1 Generation-2—UHF RFID Protocol for Communications at 860 MHz-960 MHz”), the authors of the present invention were faced with the need to provide a circuit capable of dividing a binary number by 64/3.
Such a division by 64/3 is provided for by the above-mentioned specification to divide a counting value supplied by a counter that is activated for the duration of an event. The counting is paced by an internal clock signal. After acquisition of the counting value, the integrated circuit divides this value by 64/3. The result of the division is then used as a set-point value for supplying an output signal the period of which is synchronized with the duration of the event.
Although such a division can be done with sophisticated calculation algorithms, using a microprocessor or an arithmetic coprocessor, the UHF contactless integrated circuits produced according to the specification EPC™-GEN2 are intended for the manufacture of low cost price contactless tags. They should consequently have a very simple structure. Thus, the use of a costly calculation circuit which occupies a large surface area of silicon is not possible. In particular, the use of a microprocessor or of a coprocessor is ruled out. The division should be done by a hard-wired logic circuit and preferably asynchronously, i.e., without the need to pace calculation steps by means of a clock signal.
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Frank Darrbo is a hapless fry cook. When his wife Sarah falls off the wagon and dumps him for Jacques, a drug dealer, Frank tries to get her back by reporting her kidnapped, grabbing her from Jacques' car, and wailing for her to return. After watching Christian TV and having a vision, he becomes a superhero to fight evil. He sews a costume, finds a weapon (a pipe wrench) and looks for crimes to stop. He has problems: his wrench inflicts real injury, so the cops want him for being a vigilante, his sense of boundaries is flawed, and Jacques' gang has guns. Libby, a clerk at a comic book store, becomes his sidekick, and it's time to go save Sarah. What chance do they have? Written by <[email protected]>
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Q:
Can we use gmail api to access outlook, yahoo mail etc?
Does gmail api allow us to access other email provider api or it is just limited on gmail ?
A:
It's limited to Gmail and Google Apps accounts. To standardize across email providers, you should probably use a protocol like IMAP.
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The concept of immunosuppressive T cells was proposed for the first time by Gershon R.K at the beginning of the 1970s.[@R1] Gershon described a CD8^+^ T cell population that inhibits T cell activation and B cell-induced antibody production.[@R1] At the same time, Nishikuya and colleagues described a new suppressive CD4^+^T cell population.[@R2] They showed that generalized autoimmunity appeared when three day-old (but not seven day-old) mice were thymectomized.[@R2] However, the lack of specific markers prohibited an in-depth study of this T cell population and led to the disinterest of the scientific community, which largely ignored the concept of a "suppressive T cell population."
Phenotype of Regulatory T Cells
===============================
In 1982, Sakaguchi and colleagues and, in the 1990s, Powrie and Mason identified two surface markers, CD5 (Lyt-1) and CD45RB, which are both expressed at low levels on suppressive T cells.[@R3] In 1995, the α chain of IL-2R (CD25) was reported to be constitutively and highly expressed by suppressive CD4^+^ T cells.[@R4] Suppressive CD4 T cells were renamed "regulatory T cells" (Treg) because of the skepticism in relation to the first "suppressive" T cell population described by Gershon.
The real revolution in the phenotype determination of Treg came in 2003 with the identification of a new gene called *foxp3*.[@R5] This gene codes for a transcription factor expressed in the nucleus of Tregs, Foxp3 (forkhead box P3). In humans, absence of this gene is associated with a generalized autoimmune disorder called IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked), which comprises diabetes, eczema and food allergies. In a "scurfy" mouse model, a spontaneous mutation in *foxp3* gene is linked to a very similar disorder.
Foxp3 is a specific marker of Treg in mice but, in humans, it can be transiently expressed by activated T cells[@R6]. In humans, Foxp3^+^ regulatory and activated T cells can be distinguished by the differential expression of CD127 (which is present at high levels in activated T cells and at low levels in Treg)[@R7] and by the methylation status of the transcription factor Foxp3 detected by a Foxp3 methylation-specific PCR assay (with demethylation in the DNA encoding Foxp3 in Treg but not in activated T cells).[@R8]
Tregs also express effector surface molecules such as CTLA4, LAG3, CD39 or CD73 and co-stimulation molecules, CD28, CD80/86, CD40, OX40 or 4--1BB, which appear to be important for their peripheral maintenance and functions.[@R9] Integrins and chemokine receptors such as CD62L, CCR4, CCR7 and CCR8 are responsible for Treg homing and migration to lymph nodes, skin and inflammatory sites and tumor tissues in response to various molecules or chemokines[@R10].
Other regulatory CD4^+^T cell (Tr1, TH3) and regulatory CD8^+^T cell populations have also been described, but this review will only focus on the Foxp3^+^CD4^+^ Treg.
Origin of Foxp 3^+^Treg
=======================
Two main populations of Foxp3^+^Treg have been described: a "natural" (n) population, which differentiates within the thymus during T cell ontogenesis, and another "induced" (i) population, which arises in the periphery from conventional CD4^+^T cells. Conversion of CD4^+^T cells into iTreg occurs in response to various mechanisms, for example, suboptimal antigenic stimulation in the presence of TGFβ[@R11]. Dendritic cells (DC) blocked at an immature stage in the cancer microenvironment, secondary to the presence of inhibitors (IL-6, IL-10, VEGF, PGE2...) express membrane TGFβ and promote Treg differentiation.[@R3]^,^[@R11]
iTreg differentiation from peripheral naïve CD4^+^T cells in periphery was initially described to be strictly opposed to Th1, Th2 or Th17 differentiation. Nevertheless, recent studies report that differentiation to a particular phenotype is not definitive and that iTreg present a real plasticity. For example, it has been shown that, regulatory T cells can be converted to Th17 cells in presence of IL-6 or IL-21 and TGFβ[@R12].
Mechanisms of Action of Treg
============================
iTreg and nTreg share various ways to inhibit immune response ([Fig. 1](#F1){ref-type="fig"}). Both populations use cytokine- dependent mechanisms and are able to secrete immunosuppressive cytokines (IL-10, TGFβ) or IL-35 (at least in mice), but also immunosuppressive metabolites such as adenosine.[@R9]^,^[@R13]
{#F1}
Treg may also lyse effector cells by means of granzyme A and B[@R14] or disrupt the metabolism of effector cells by causing their IL-2 deprivation.[@R15]
nTreg also use contact-dependent mechanisms. They are able to inhibit DC maturation by means of the interaction of CTLA-4 with CD80/CD86 on DC, which delivers a negative signal to DC preventing priming of anti-tumor responses. Induction of an immunosuppressive enzyme, IDO (indoleamine 2,3 dioxygenase), by CTLA-4 may also participate in inhibition of effector T cells[@R16]. Other surface molecules (Lag3, CD39, Nrp, galectin1...) expressed by Treg may also contribute to their suppressive activity.[@R3]
Given these immunosuppressive properties, Treg are therefore important for peripheral tolerance and confer protection against autoimmunity and inflammation.
Treg and Cancer
===============
Most tumor-associated antigens are self-proteins, which elicit weak natural or induced T cell responses after immunotherapy.[@R17] It has been demonstrated that Treg are able to recognize tumor-associated self-antigens and control T cell responses against various cancer antigens, which may explain the failure of many cancer vaccines.[@R18]^,^[@R19] For example, tyrosinase and NY-ESO1-specific CD4^+^T cells can expand and become detectable by in vitro antigenic stimulation of peripheral CD4^+^T cells only after depletion of Treg.[@R20] In addition, therapeutic cancer vaccines could induce tumor-specific Treg that blunt the expansion and function of anti-tumor T cells[@R18]. In line with these results, Treg depletion or blockade has been shown to enhance tumor immunity elicited by vaccination.[@R21]
Treg are recruited to the tumor bed mainly but not exclusively via chemokine gradients, mainly the CCL22/CCR4 axis, as many tumor cells or myeloid intratumor cells produce CCL22 ([Fig. 2](#F2){ref-type="fig"}).[@R22]^,^[@R23] Hypoxia also attracts Treg into the tumor, mostly through induction of the CCL28 chemokine.[@R24]
{#F2}
Treg infiltration of tumor and draining lymph node has been widely described in mouse models and cancer patients. Treg expansion has been correlated in most cancers (gastric, breast or ovarian) with a poor prognosis associated with a decrease in the CD8^+^ T cell/Treg ratio.[@R25]^,^[@R26] This supports the idea that the suppressive activity of Treg can inhibit priming of CD8^+^ T cells by mature DC in tumor-draining lymph nodes and promote tumor growth. More recently, it has been shown that intratumor Treg produce VEGF and promote angiogenesis.[@R24]
However, Treg are not always "tumor bodyguards." Treg infiltration has also been correlated with good prognosis in hematological malignancies and in some solid tumors such as head and neck or colon cancer[@R27]^,^[@R28] that are often associated with chronic inflammation.[@R29]^,^[@R30] This may be explained by the fact that Treg negatively control inflammation and that inflammation plays an important role in disease progression in these cancers.
Why and When Do We Need to Inhibit Treg in Cancer?
==================================================
Tumor-associated antigens are often self-antigens, which elicit weak immune responses partly due to the presence of antigen-specific Treg. This may explain why elimination of Treg improves induction of CD8^+^T cells response for priming of anti-tumor T cells.
In addition, it has been observed that some immunostimulatory molecules such as IL-2 and IFNα used in immunotherapy may be linked to immunosuppressive activities partly due to the concomitant induction of Treg via Stat5 activation.[@R31]^,^[@R32] Helper peptides derived from tumor antigens may also increase Treg, which partially inhibit anti-tumor CD8^+^T cell induction.[@R33] Anticancer immunotherapies could therefore be improved by concomitant Treg blockade. Importantly, transient depletion of Treg during priming of anti-tumor immunity rather than chronic depletion of Treg should be considered to avoid the development of autoimmune side effects.
Many strategies are currently used to manipulate Treg, including Treg depletion, inhibition of Treg function or blockade of Treg trafficking into lymph nodes or tumors. We will briefly describe these approaches by emphasizing their potential limitations.
Strategies Currently Used to Block or Inhibit Treg
==================================================
Treg depletion
--------------
### Chemotherapy
Some chemotherapies may lead to immunogenic cell death resulting in activation of DC and priming of anti-tumor immune responses.[@R34] This promotion of DC maturation might also explain the capacity of some chemotherapies to reduce Treg. In addition, as a higher frequency of proliferating cells is observed in Treg compared with the non-Treg compartment, chemotherapy, which mostly destroys proliferating cells, may tilt the balance from Treg toward effector T cells. Cyclophosphamide (CTX) is the leading product of this therapeutic class. Reversal of immunological tolerance by CTX via inhibition of suppressor cells was reported more than 35 years ago.[@R35] Selective depletion of Treg induced by CTX or other chemotherapeutic drugs such as paclitaxel requires the use of these agents at low, so-called metronomic doses.[@R36]^,^[@R37] Some studies in humans have shown improvement of T cell effector function associated with a reduction in Treg numbers after low dose CTX administration.[@R38] However, "clinical benefit/toxicity (deletion of effector T cells)" therapeutic index for this kind of drug is low and no consensus has been reached concerning a robust CTX-based protocol able to induce significant ablation of Treg inhibitory functions in patients.
### CD25 antibody and Denileukin diftitox (ONTAK)
The implication of Treg in tumor immunity was initially studied by systemic depletion of CD25^+^ T cells. Studies in mice demonstrated that in vivo administration of CD25-specific antibody (PC61) suppressed growth of progressively growing tumors.[@R39] However CD25 is also expressed by activated effector T cells, complicating the CD25-based Treg targeting strategy. In this regard, it was shown that while administration of anti-CD25 mAb before tumor inoculation triggered effective antitumor responses, anti-CD25 mAb treatment after tumor inoculation was much less effective to eradicate tumors.[@R39]
In humans, an anti-CD25 mAb, daclizumab, has been used to deplete Treg with contradictory results.[@R8]^,^[@R40] More recently, the recombinant IL-2 diphtheria toxin conjugate called denileukin diftitox (ONTAK) was developed to target T cells with high CD25 expression. Upon internalization, diphtheria toxin irreversibly inhibits protein synthesis, ultimately triggering cell death. Diftitox administration combined with vaccine has demonstrated some efficacy in renal cell carcinoma (RCC) and melanoma patients.[@R41] However, recent studies performed in melanoma patients reported neither a reduction in peripheral Treg numbers nor any favorable clinical improvement after diftitox treatment.[@R8] This therapeutic failure might be explained by the presence of CD25^low^Foxp3^+^T cells, which cannot be depleted by diftitox.
Targeting Treg function
-----------------------
One possible strategy to avoid Treg depletion is to use antibodies that target molecules constitutively expressed by Treg leading to their functional inhibition.
### Anti-CTLA-4
CTLA-4 is expressed on both regulatory and activated T cells. Early studies have reported that CTLA4 blockade resulted in improved tumor immunity and tumor regression. However, a recent study elegantly demonstrated that blockade of CTLA-4 specifically on Treg failed to enhance anti tumor responses.[@R42] In contrast, concomitant blockade on both effector T cells and Treg led to a synergistic effect with maximal anti-tumor activity.[@R42] Surprisingly, anti-CTLA-4 recently approved for metastatic melanoma patients, induced activated effector T cells, Foxp3^+^ Treg as well as IL-10-producing Treg.[@R43] Despite this Treg expansion, anti-CTLA-4 mAb administration resulted in severe autoimmunity. This might be explained by the fact that conventional T cells become resistant to the inhibitory effects of Treg during therapy with anti-CTLA4 mAb.[@R44]
### Anti-GITR
Like CTLA-4, GITR is constitutively expressed by Treg, but it is also detected, albeit at lower levels, on CD4^+^ and CD8^+^ effector T cells. Stimulation by agonistic antibodies to either GITR or GITR ligand has a dual effect leading to suppression of Treg activity (at least in mice) and enhanced proliferation of effector T cells and possible resistance to Treg-mediated suppression. Administration of GITR mAb protected mice from B16 tumor challenge,[@R45] and induced tumor regression in mice bearing methylcholanthrene-induced fibrosarcoma.[@R46] The tumors were infiltrated by large numbers of effector T cells, and an increase in INFγ was observed. Importantly, anti-GITR mAb therapy was more effective in mice with established tumors than in prophylactic settings.[@R46] A study performed on GITR-knockout mice revealed that reversal of suppression by GITR signaling may be attributed to the costimulatory activity of GITR on responder CD4^+^CD25^-^ T cells, which made them resistant to Treg suppression.[@R47] This indicates that anti-GITR stimulation enhances the activity and expansion of antigen-primed effector T cells rather than their generation. Altogether, a direct role of GITR mAb on Treg cell functions remains elusive.
### Anti-OX40
OX40, a costimulatory molecule of the TNF receptor family, is constitutively expressed on Treg and transiently expressed on activated T cells. An early study showed that activation of OX40 signaling by an agonistic anti-OX40 mAb was able to inhibit the suppressive activity of Treg.[@R48]A recent murine study demonstrated that intratumoral injection of anti-OX40 mAb induced strong inhibition of tumor growth.[@R49] The authors demonstrated that activation of OX40 signaling has a dual role, inhibiting Treg suppression while enhancing effector T cells functions. Further studies are required before translating agonistic anti-OX40 mAb strategies to patients especially in combination with conventional therapies.[@R50]
Taken together, targeting CTLA-4, GITR or OX40 may have a huge therapeutic potential, as recently demonstrated for the anti-CTLA4 mAb (ipilimumab). However, discrepancies exist in the literature as to whether Treg functions are indeed affected by such regimens. Moreover, non-specific co-stimulatory effects of these mAbs on effectors CD4 and CD8 T cells may lead to severe systemic inflammation (induction of a cytokine storm) and multi organ-specific autoimmunity.[@R51]
### TLR ligands, adenosine inhibitors and peptide inhibitors of Foxp3
Treg express various TLRs and notably high levels of TLR4, TLR5, TLR7 and TLR8;[@R52] TLR 8 activation by its natural or synthetic ligands has been shown to inhibit Treg function and enhances in vivo tumor immunity.[@R53] Appropriate TLR stimulation might therefore be an important tool for vaccination strategies, since it could inhibit Treg-mediated tolerance.[@R54] However, this area of research requires further investigation as many counteracting effects might emerge due to the expression of TLRs on almost all murine and human normal and tumor cells.[@R55] In addition, TLR ligands could also induce IL-10- producing Treg. This unfavorable bystander effect could be reversed by blocking p38 MAPK signaling.[@R56]
Treg produce adenosine via catabolism of adenine nucleotides (ATP, ADP and AMP) by extracellular ectonucleotidases, CD39 and CD73. Adenosine is a major immunosuppressive factor that may participate in the immunosuppressive activity of Foxp3^+^ T cells.[@R16] Low molecular weight inhibitors and adenosine receptor antagonists, some of which are already used in clinic settings for other indications, are available to block adenosine-mediated immune suppression.[@R57] Inhibition of CD39 with enzymatic inhibitors blocks Treg function and improve the effects of chemotherapy.[@R58]
A peptide inhibitor of Foxp3 (P60) impairs Treg activity and improves vaccine efficacy in mice.[@R59] P60 administration to newborn mice but not in adult mice induced a lymphoproliferative autoimmune syndrome resembling the reported pathology in scurfy mice lacking functional Foxp3.[@R59]
### Disrupting lymph node and tumor homing of Treg
Another strategy to control Treg function is to target chemokine/chemokine receptor molecules (i.e. CCL17/CCL22-CCR4 axis) that are involved in Treg trafficking. It has been shown that Treg preferentially express CCR4 compared with conventional T cells, both in mice and humans.[@R10]^,^[@R60] CCR4-expressing Treg mainly represent activated Treg with potent suppressive activity. The binding of CCL17 and CCL22 produced by DC in the lymph node to their CCR4 receptor guides CCR4-expressing Treg toward DC. This interaction can suppress DC-mediated immune responses by inhibiting DC maturation and expression of costimulatory molecules required for effector T cell activation, as well as by inhibiting stable contact between DC and effector cells.[@R61] The role of CCR4 in the migration of Treg toward lymph nodes is also reinforced by studies showing that CCR4-deficient Tregs fail to traffic to lymph nodes to inhibit pathogenic T cells.[@R62]
Tumor cells and their microenvironment also attract Treg by the secretion of CCL22,[@R22] and a correlation has been reported between the presence of tumor-infiltrating Treg and CCL22 in breast cancer.[@R23] In a murine model, it has been shown that monoclonal antibodies specific for CCL22 significantly reduce the migration of Treg into ovarian tumors.[@R22]
Recently, small molecule antagonists to CCR4, designed in silico, have been shown to prevent the interaction of CCL22/CCL17 with their receptor. In vitro experiments in human showed that these CCR4 antagonists inhibit the recruitment of Treg mediated by CCL22 and CCL17. Preclinical studies showed that, when administered in combination with vaccines, CCR4 antagonists increased CD4^+^ T cell and humoral responses directed against foreign antigens.[@R63]^,^[@R64] We found that immunization of mice against relevant tumor-associated self antigens (Her2/neu, gp100...) failed to reverse the tolerance controlled by Treg. In contrast, the same vaccines combined with a CCR4 antagonist led to the induction of effector CD8^+^ T cells and partial tumor protection.[@R21] The CCR4 antagonist was more efficient than CTX to elicit anti-self CD8^+^ T cells. One of the main advantages of this CCR4 antagonist is its short lifespan (\~24 h)[@R63] allowing transient inhibition of Treg only during the priming phase and avoiding the potential autoimmune complications caused by long-term blockade or depletion of Treg by mAbs (e.g., anti-CD25, anti-OX40, anti-GITR...) with longer half-lives (2--3 weeks).[@R65] We found that administration of the CCR4 antagonist did not lead to induction of biological markers of autoimmunity.[@R21] In addition, it appears that Treg expressing CCR4 mainly represent activated Treg with potent suppressive activity.
Other chemokine receptors such as CCR7 and CCR5 may also play a role in Treg migration. For example, the CCL5/CCR5 interaction has been shown to be crucial for Treg attraction in pancreatic adenocarcinoma.[@R66] Disrupting this interaction by systemic administration of a CCR5 inhibitor reduced Treg migration into the tumor and led to significant tumor reduction.[@R66] In some models, CCL5 blockade improved the efficacy of immunochemotherapy.[@R67] However, it should be noted that, chemokine/chemokine receptor molecules especially CCL5/CCR5 and CCL20-CCL21/CCR7 may also be involved in trafficking of effector T cells, and disruption of these pathways might therefore be deleterious to killing of tumor cells.
### Anti-angiogenic molecules and tyrosine kinase inhibitors
Accumulating evidence strongly suggests that angiogenesis inhibition overcomes various immunosuppressive networks including Treg.[@R68] In mice and human, it has been demonstrated that sunitinib, an inhibitor of tyrosine kinases involved in angiogenesis (VEGF-R, PDGF-R, FGF-R...), reduced the percentage and absolute number of Treg,[@R69]^-^[@R71] which have been shown to be increased in many tumors.[@R25]^,^[@R27] We more thoroughly analyzed this decrease in Foxp3^+^ Tregs in humans and observed a progressive reduction in circulating Foxp3^+^ Tregs after each cycle of sunitinib therapy. This reduction became statistically significant after the second cycle of therapy. A significant (at least 20%) reduction in the absolute number of Foxp3^+^ Treg occurred in 32% and 40% of patients after the first and second cycle respectively, and in 70% of patients after the third cycle. We found a correlation between the number of Foxp3^+^ Treg at baseline and the changes in this population during sunitinib-based therapy. Patients with baseline Treg levels above the median value were more likely to experience a decrease in this population after the second or third cycles of sunitinib-based therapy than patients with low baseline Treg levels.[@R70] Sunitinib appears to have an indirect effect on Treg, as sunitinib did not inhibit in vitro Treg expansion even over a 14 d coincubation period.[@R69] The impact of anti-angiogenic molecules on Treg has been mainly demonstrated with sunitinib. The ability of other molecules (sorafenib, bevacizumab...) to mimic this effect is currently debated.[@R71]^-^[@R73]
Two mechanisms have been proposed to explain the impact of anti-angiogenic molecules on Treg: (1) at an immature stage, DC in the presence of TGFβ are able to induce Foxp3^+^CD4^+^CD25^hi^ Treg.[@R74] Pioneering studies showed that VEGF inhibits DC maturation via a nuclear factor κB (NFκB)-dependent pathway mediated by VEGFR-1 signaling[@R75] (2) Since Treg express VEGFR2, a modulation of Treg activity by VEGF could also be hypothesized.[@R76]
Other immunosuppressive cell populations, especially MDSC (myeloid -derived suppressor cells), could also be blocked by anti-angiogenic therapy.[@R68]
This role of anti-angiogenic molecules on reversal of immunosuppression in cancer may explain the synergy observed in preclinical models between anti-angiogenic molecules and immunotherapy. Studies are ongoing to address the ability of these molecules to potentiate immunotherapy in human clinical trials.[@R77]
Other tyrosine kinase inhibitors (imatinib mesylate, dasatinib, temozolomide) have demonstrated an impact on the decrease of Treg number or functions.[@R78]^,^[@R79] An elegant study in a mouse model of gastrointestinal sarcoma (GIST) and in human GISTs showed that imatinib mesylate induced Treg Suppress (T(reg) cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase.[@R78] Reduction of Treg numbers unleashes NK cell functions and contribute to NKp30-dependent antitumor effects in GIST.[@R80]
Conclusions and Perspectives
============================
Treg and activated T cells share several common features and surface markers, which explain the weak selectivity of several drug candidates to specifically inhibit Treg. New strategies are designed to inhibit Treg function rather than eliminate Treg, in order to improve their specificity. This field has recently benefited from the finding that many drugs (chemotherapies, anti-angiogenic molecules, tyrosine kinase inhibitors...) exhibit off-target effects and inhibit Treg, thereby accelerating their evaluation in clinical trials either as monotherapies or in combination with immunotherapy. In terms of the clinical indications of these molecules, elimination or inhibition of Treg might be particularly useful in the context of therapeutic vaccination against tumor-associated antigens. For this kind of indication, transient inhibition of Treg during the short window of immune priming (few days) rather than long-term blockade might be particularly appropriate to minimize organ-specific or generalized autoimmune side effects.
This work was supported by Canceropole Ile de France, ANR (Agence Nationale de la Recherche), Ligue contre le Cancer, Association pour la Recherche sur le Cancer, Institut National du Cancer, Centre d'investigation Clinique en Biothe´rapie (CIC-BT505), and the Labex Immuno-Oncology.
Previously published online: [www.landesbioscience.com/journals/oncoimmunology/article/18852](http://www.landesbioscience.com/journals/oncoimmunology/article/18852/)
DC
: dendritic cell
Treg
: regulatory T cell
TLR
: toll-like receptor
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Chick-Fil-A, Technology and Politics: Student Press Analysis
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Chick-Fil-A, Technology and Politics: Student Press Analysis
Aug 03, 2012 |
1. The controversy over the fast food chain Chick-Fil-A’s evangelical Christian owners and their views on marriage received some ink over the past week, as an increasing number of undergraduate newspapers continue to publish over the summer months. A columnist writing in the Oklahoma Daily explains why, even though the food is pretty good, he won’t be eating there anymore. Similarly, the editor of the UT/Knoxville Daily Beacon notes that, although he was recently very hungry one morning, he decided not to stop at the handy local Chick-Fil-A, and kept on driving. Another activist interviewed in the Pitt News thinks it’s important that the chain’s customers know that their patronage helps to support ant-gay causes. On a contrasting note, a writer for the USC Daily Gamecock suggests that you shouldn’t eat at Chick-Fil-A because the food is just plain bad for you, but commenters take issue. From a somewhat different angle, a guest columnist and Christian evangelical suggests to readers of the U of Georgia’s Red and Black that open support for Chick-Fil-A by his coreligionists may be ill-advised, since it could impede their efforts at evangelizing. Meanwhile, the Daily Texan offers a pictorial comment on the controversy, while on a related issue, two former Eagle Scouts deplored the Boy Scouts’ recent decision to exclude openly gay members, here and here.
2. The Penn State scandal’s aftermath continued to generate commentary, and two writers for the Daily Illini presented opposing views of the sanctions imposed by the NCAA. For one, the NCAA’s decision represented the best outcome the circumstances warranted. His colleague, however, argues that the measures missed the mark by a mile, and won’t change what really needs changing. The NCAA’s punishment of PSU was entirely appropriate as the editors of the Daily Pennsylvanian saw it, and the Michigan Daily noted that the U of M was not interested in accepting any transfers from its chastened gridiron rival in Pennsylvania. And at the Daily Texan, the editors noted that, as another big football school, UT/Austin should carefully consider the consequences when an athletic program morphs into a cult.
3. An increasing number of schools are implementing campus-wide smoking bans, as the Ohio University Post reports will be considered there on recommendation by the school’s board of directors. A similar ban is already on the table at neighboring Ohio State, and a news item in The Lantern indicates that the policy faces stiff resistance from students. At the University of Maryland, where a smoking ban has been approved and will become effective soon, the editors of the Diamondback conclude that it is misconceived and unenforceable. And in the Oklahoma Daily, a self-professed nicotine addict says there’s no way he won’t be defying the ban, as his fellow puffers will likewise do. In The Dartmouth, meanwhile a summer columnist argues that his school’s new drinking regulations are also bound to flop. In any case, the editors of the DePaulia in Chicago suggest that the fixation with smoking is misplaced: obesity is a much more serious health issue, among college students and the nation overall.
4. Sustainability and the environment: A writer for the Iowa State Daily thinks it’s really great that concern for sustainable energy has seemingly gone global, and he recommends pursuing “green energy” alternatives to fossil fuels as the optimal starting point toward realization of that goal. For a colleague at the MSU State News, the best place to start is locally, as in his own school’s plan to end dependency on coal. A staffer for The Dartmouth, on the other hand, makes the case for simultaneously going green and drilling for more oil. They’re not at all incompatible, he thinks. A far more ominous opinion comes from an op ed writer at the UNLV Rebel Yell: he thinks that it’s probably already too late to avert an environmental catastrophe, and that remarkably few people seem to know or care.
5. The omnipresence of “social media” seems to be on the minds of those who use them. One columnist for the Central Michigan University Life seems troubled by her attachment to the new communications technology, and also acknowledges how hard it would be to put them down. Another at the U of Missouri, Columbia Maneater, wonders if people realize how much of their privacy they’re surrendering when they blithely place so much personal information on Facebook or Twitter. It’s even more dire in the view of a columnist at the Oklahoma Daily, who thinks that smartphone text messaging is turning us into asocial, inarticulate robots. But not everyone is so negative, and another writer at the Minnesota Daily argues that technology itself is neutral, and its effects will depend on what you decide to make of it. Likewise a colleague at the OSU Lantern, who thinks that the ubiquitous gadgets can be very useful if you’re looking for a job.
6. Miscellaneous Politics: Election years bring all sorts of people into the limelight, some of whom don’t realize that they’ve stayed there far too long. A political analyst for the Auburn Plainsman can’t believe that the presidential “birthers” are still at it, and wishes they’d take a hike. But at the KSU Collegian, a summer staffer sees Massachusetts GOP Senator Scott Brown as a genuine political moderate, and wishes there were more like him, while a colleague at the Daily Texan endorses the type of Democrat he’d like to see elected to the Senate. Meanwhile, a one-time editor of the Columbia Spectator returns to correct the misuse of one of his columns, which he contends was used by a present-day blogger to smear President Obama. And if you want to fix the economy, a staff writer for The Dartmouth suggests that present-day politicians all around could learn a few things form President Calvin Coolidge.
7. Tragic as the recent mass shootings in a Colorado theater were, an op ed writer for the Iowa State Daily is dismayed by the opportunistic lawsuits already being filed against the management by patrons who suffered no injuries. At the Daily Nebraskan, the editors believe that the frenzied media coverage surrounding the incident focused excessively on the accused shooter. Finally, a columnist for the Oklahoma Daily argues that the enactment of stricter gun laws, now so widely demanded, would have no effect on anyone determined to obtain weapons and commit crimes.
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Puget Sound Defeats Bearcats in Three Close Sets, 26-24, 25-23, 25-23
TACOMA, WASH. -- Willamette University, which upset the University of Puget Sound, 3-2, in Salem, Ore., on Sept. 28, battled the Loggers once again on Friday, Oct. 26. The Bearcats almost defeated the nationally ranked Loggers in each set, but 10 serving errors by Willamette and six service aces for Puget Sound led to a 26-24, 25-23, 25-23 win for UPS.
Puget Sound improved to 16-5 overall, 10-3 in the Northwest Conference. The Loggers are ranked #14 in this week's NCAA Division III Poll released by the American Volleyball Coaches Association. Willamette fell to 7-13 overall, 5-8 in the NWC.
Willamette's Elisa Ahern (So., OPP, Lake Forest Park, WA/Shorecrest HS) produced 12 kills and 10 digs, as she recorded her first double-double of the year in her fourth start. Carly Hargrave (Jr., MH, Happy Valley, OR/Clackamas HS) tacked on nine kills and made just one attacking error, while earning a .421 hitting percentage. Hargrave registered two block assists.
Willamette recorded 44 kills compared to 39 kills for the Loggers. The Bearcats earned a team hitting percentage of .154, while Puget Sound ended the match hitting .141. WU also achieved a 75-71 advantage in digs.
Serving and blocking made the difference for Puget Sound. In addition to earning six service aces, the Loggers made only four serving errors. On defense, UPS was credited with 7.0 team total blocks. Willamette relinquished eight points on its serve, as the Bearcats earned just two service aces to offset 10 serving errors. The WU defense supplied 4.0 team total blocks.
UPS scored the first point of the opening set, but Willamette answered with a 7-1 run for an early lead. The run ended with three consecutive kill -- one each by Waltz, Danica Reed (Sr., Arvada, CO/Ralston Valley HS) and Ahern.
The Bearcats enjoyed an 13-8 lead later in the set following an attacking error by the Loggers. Puget Sound went on a 12-3 run to surge into a 4-point advantage at 20-16.
Puget Sound also led 22-18, but Willamette rallied, eventually tying the score at 22-22 on a kill by Madisyn Leenstra (Sr., OH/MH, Bellingham, WA/Sehome HS), two hitting errors by UPS and a combo block from Leenstra and Hargrave. The teams were tied again at 23-23, but WU moved in front on an attacking error by Marissa Florant of the Loggers.
UPS tallied the final three points of the set on a kill by Best, a kill by Florant and a service ace by Chun for a 26-24 win.
In the second set, Puget Sound developed a 10-6 lead, only to have WU tie the game at 11-11 and eventually move in front 14-13. The set was close the rest of the way, with neither team leading by more than two points. UPS held a 19-18 advantage, but the Bearcats won the next two points on attacks from Nicole Mertens (Sr., OH, Olympia, WA/Olympia HS) and Ahern.
The Loggers tied the score at 20-20 and then WU tacked on two more points. An attacking miscue by UPS provided the first point and a kill by Hargrave resulted in the second point for a 22-20 lead. Service errors by both teams led WU with a 23-21 edge.
Puget Sound closed out the set with four consecutive points to rally for a 25-23 win. A service ace by Jalene Toy completed the run.
The teams were close together on the scoreboard for most of the third set. Willamette managed to build a 19-15 lead with a 5-0 run that included kills by Compton and Leenstra, plus a service ace by Waltz. UPS countered with a 7-3 surge of its own that tied the set at 22-22.
A service ace by Karly Edwards and a combo block by Reynaud and Brehove gave Puget Sound a 24-22 lead. Waltz registered a kill for Willamette before Florant ended the match with a kill for the Loggers.
Willamette will take on #15 ranked Pacific Lutheran University on Saturday, Oct. 27 in Tacoma, Wash. Match time is set for 7 p.m. (PDT).
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Q:
how to filter input value in AngularJS
I'm trying to implement filtering on my input element.
I want to make filtering for input with type="text" field.
For instance, if the model contain more than available characters than I want to change my input value.
I've created jsfiddle
I have directive that generate html template dynamically and it contains input field.
var app = angular.module('app', [])
.controller('ctrlr', function($scope){
$scope.myModel = "test";
$scope.availableCharacters = 5;
$scope.$watch('myModel', function(newValue, oldValue){
if(!newValue){
return;
}
if(newValue.length > 5){
$scope.cutString();
}
});
$scope.cutString = function(){
var length = $scope.myModel.length;
var string = $scope.myModel.slice(0, $scope.availableCharacters);
var countStars = length - string.length;
$scope.myModel = $scope.createStars(string, countStars);
}
$scope.createStars = function(string, countStars){
for(var i = 1; i <= countStars; i++){
string = string+'*';
}
return string;
}
})
.directive('awesome' , function(){
return {
restrict:'E',
template:'<input type="text" ng-model="myModel" ng-value="myModel | filter:my" />'
}
})
Could it possibly to move my code into the filter function? I have a lot of business logic and I don't want to keep my code in the controller, because it will be reusable directive.
A:
I think that implementing this part of functionality as a filter is not the best idea.
It would be much more dynamic if you will implement it as directive on your input element like:
<input type="text" ng-model="myModel" ng-value="myModel" max-length="20" />
In this case it would be more flexible. You will be able to pass an argument into directive (for example length of acceptable value).
Also it is not really readable for another developers to make your input as a template of your directive because of you are using model as attribute of input field and not binding it from directive.
Is there any reason why you use directive to render simple input?
If not, then just live it as input in your view and add directive instead of filter to work with data checks limitations.
Another approach is to implement custom form controls. That will allows you to control incoming and out-coming data.
Here is a example from documentation - Implementing custom form controls (using ngModel)
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Parahippocampal activation evoked by masked traumatic images in posttraumatic stress disorder: a functional MRI study.
Posttraumatic stress disorder (PTSD) has been widely studied, but its neural mechanism is still unclear. The purpose of this study is to identify dysfunctional areas in PTSD throughout the whole brain to help to elucidate the neural mechanisms of PTSD. Sixteen patients with PTSD and sixteen healthy controls participated in this study. Traumatic images under perceptual threshold including scenes of earthquakes, traffic accidents, ambulances, emergency rooms, and crimes were presented to the participants, and brain activation was measured using functional MRI. Functional brain images of both groups were evaluated with random effect analysis for the whole brain. In the control group, activation in the ventral frontoparietal areas correlated significantly with presentation of the masked traumatic stimuli. In the PTSD group, activation was not observed in these areas, but significant activation correlated with the masked traumatic stimuli in the parahippocampal region including the left parahippocampal gyrus and tail of the left hippocampus. These results suggest that in PTSD patients activation in the ventral frontoparietal network associated with visual attention processing is attenuated, while the left hippocampal area associated with episodic and autobiographical memory is abnormally easily activated. This pattern of activation corresponds well to the clinical characteristics of PTSD, in which even slight traumatic stimuli tend to induce intrusive recollection or flashbacks, despite a general decrease in attention and ability to concentrate.
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Furious Facebook users have launched a campaign to stop changes to the website's privacy policy.
Site bosses have proposed ending the practice of letting users vote on privacy changes and replacing it with a "more meaningful" system of monitored comments and reviews.
In an email to users, Facebook said the voting system had "incentivised the quantity of comments over their quality."
But the proposal has angered users, who have started a campaign to keep the vote.
The Our-Policy.org website is urging people to post a comment on the page where the plans were announced.
According to Facebook's current privacy policy they put changes up for a vote if 7,000 people comment on the same issue - so far 10,535 people have commented since the announcement was posted on Wednesday.
"Please don't take away our rights on this. I oppose this proposition," wrote one user.
Another added: "This is unacceptable. OPPOSE."
In the email, Vice President Elliot Schrage wrote: "We deeply value the feedback we receive from you during our comment period.
"In the past, your substantive feedback has led to changes to the proposals we made.
"However, we found that the voting mechanism, which is triggered by a specific number of comments, actually resulted in a system that incentivised the quantity of comments over their quality.
"Therefore, we're proposing to end the voting component of the process in favour of a system that leads to more meaningful feedback and engagement."
He added that "significant changes" to the website's Data Use Policy will continue to be posted and there will be a seven-day period for review and comment.
"As always, we will carefully consider your feedback before adopting any changes," he said.
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