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Speak up for Road Safety - Qld Road Safety Week
The Department of Transport and Main Roads (TMR) and the Queensland Police Service (QPS) Road Policing Command have joined together for the third year to run Queensland Road Safety Week (QRSW) which runs from 21-25 August 2017.
The Week is a chance for all Queenslanders to be involved in making our roads safer.
‘Speaking up for road safety’ continues to be the QRSW theme and TMR/QPS seek your company's support in 2017.
During Queensland Road Safety Week, each day will focus on a different road user behaviour: | {
"pile_set_name": "Pile-CC"
} |
Asset Inventory Management Software
ServiceDesk Plus has an integrated Asset Management solution along with the basic help desk functions. With the integrated Asset Management, ServiceDesk provides you with an accurate inventory of all the hardware, software assets in your organization. It automatically scans and updates every asset/nodes with an IP address within your network. | {
"pile_set_name": "Pile-CC"
} |
[Biomechanical analysis through numerical simulation of rupture of the tibial posterior tendon in valgus flat foot: a cadeveric study].
The insufficiency of the posterior tibial tendon is the most common acquired cause of pain related to valgus flatfoot deformity in adults. The acquired flatfoot adult is a very painful symptomatic deformity resulting from a gradual stretching (attenuation) of the posterior tibial tendon and ligaments that support the arch of the foot. The progressive pain acquired flatfoot adult affects four times more women than men. Some factors that contribute to increased risk of acquired flatfoot in adults, are diabetes, hypertension and obesity. It is thought that the combination of the following events is the cause of acquired flatfoot adult. Johnson Strom classification modified by Mayerson evaluates in 4 stages. This study was divided into 3 stages: Stage 1: Dissection and three-dimensional analysis of the tendon, Step 2: Application of tools bioengineering to determine the causes of rupture of the tibial tendon: Stage 3: Evaluation of 24 patients with flatfoot disease valgus for describe the deformity. | {
"pile_set_name": "PubMed Abstracts"
} |
Epstein-Barr virus related central nervous system lymphoma in a child after renal transplantation.
In this report, we describe the development of a rapidly progressive Epstein-Barr virus (EBV) related cerebral lymphoma in an 11 year old girl, eight months after renal transplantation. No serological evidence for a persistent EBV infection was found, but Epstein-Barr nuclear antigen (EBNA) could be demonstrated in the tumor. The clinical course of our patient was different from EBV-related syndromes in renal transplanted patients described in previous reports. Furthermore, pathological investigations of the biopsy specimen and tumor cells obtained at necropsy revealed a discrepancy in light chain expression. The possibility that lymphoproliferative disorders represent multiclonal B cell lymphomas is discussed. | {
"pile_set_name": "PubMed Abstracts"
} |
// Copyright 1998-2017 Epic Games, Inc. All Rights Reserved.
#include "CoreMinimal.h"
#include "Interfaces/NetworkPredictionInterface.h"
UNetworkPredictionInterface::UNetworkPredictionInterface(const FObjectInitializer& ObjectInitializer)
: Super(ObjectInitializer)
{
}
| {
"pile_set_name": "Github"
} |
Twitter Rolling Out Curation Tool and Interactive Features For Publishers
Twitter is growing up; in an effort to tidy up the Twitter experience, add more features and functionality, and generally bring more maturity to the microblogging platform, the company will be rolling out some changes soon.
More to the point, Twitter is declaring itself as a neutral platform for users to create and share content as opposed to a media company. That may seem like semantics, but it’s a hugely important distinction. Even though Twitter is boxing out third-party apps and restricting access just to Twitter, the the company is trying to portray the move as more like a streamlining of the platform instead of increasingly restrictive controls--a sore spot for many users indeed.
"It's not about being a destination," said Twitter CEO Dick Costolo. "I'm a huge believer in syndication. Platform companies always outflank and outlast point solutions and individual products."
Twitter CEO Dick Costolo
According to a Reuters report, Twitter will be unveiling a tool for users (especially journalists) to curate their tweets during breaking events to provide a more cohesive story. Other new features will include “tweet boxes” that will include content from or about a given event that will augment the stream of posts--Costolo gave the example of interactive live polls for an NBA All-Star game--as well as the long-awaited ability to for users to download and keep archives of their own tweets.
Said Costolo: "We want to migrate to a world in which the 140 characters can serve as a caption for additional functionality. We'd like that to include things like real-time data, even an application functionality."
It sounds like the Twitter of old will become a thing of the past, and it’s all purportedly coming by the end of the year. | {
"pile_set_name": "Pile-CC"
} |
In the manufacture of printed circuit boards in the electronics industry there is a need for an ink for marking printed circuit boards and electronic components which will not be removed by the solvent baths and vapor degreasers used to clean the completed printed circuit boards in the final stages of manufacture. At the present time the only inks which do this are (1) Thermosetting inks or (2) Epoxy inks.
The thermosetting inks are satisfactory for individual components which are designed to stand the baking temperatures but not for marking on assembled printed circuit boards where there are also components which will not stand the baking temperatures. The epoxy inks must be mixed at the time of use and have a pot life usually of less than one hour. They also require periods of more than an hour to harden to the point the printed circuit boards may be handled without smearing the ink. Epoxy inks also do not stand extended solvent vapor degreaser action with good predictability. They may come off some surfaces and stick on others. It is desirable also that there be a method of removing the ink without destroying other markings on the component or printed circuit boards.
In hospitals and chemical laboratories there is a need for an ink for bottles and specimens which will not be attacked or dissolved by organic solvents in the bottles or used in processing. | {
"pile_set_name": "USPTO Backgrounds"
} |
Rapid changes in metabolic cold defense and GDP binding to brown adipose tissue mitochondria of rat pups.
To determine developmental changes of brown adipose tissue (BAT) thermogenic activity at defined circadian and thermal states, we evaluated the time course of cold-induced increases of in vitro guanosine 5'-diphosphate (GDP) binding in parallel with whole body metabolism (oxygen consumption, VO2) and core temperature (Tc) in 1- to 11-day-old rat pups. During the maximum phase of the juvenile diurnal cycle, Tc of littermates was recorded continuously and VO2 alternately until 2 min before animals were killed for removal of interscapular BAT. GDP binding after 1.5 h at thermoneutrality and its increase during physiologically comparable cold loads were significantly lower in 1-day-old pups than in 5- and 11-day-old pups. Cold defense was activated more rapidly in the older pups, but GDP binding in even the 1-day-old pups was significantly increased during the second 10-min period of cold exposure. We conclude that rapid changes in thermogenic activity, in connection with the known developmental changes in the dependence of the suckling rat's metabolic cold defense on maternal and sibling contact and circadian phase, will distort longitudinal studies of any fast-changing BAT parameter when the conditions immediately before tissue removal are not thoroughly controlled. | {
"pile_set_name": "PubMed Abstracts"
} |
Q:
g++ optimization makes the program unable to run
I implemented a path planning algorithm based on D*-Lite. When I do not turn on optimization (-O0), the program can run normally. But when I turn on the optimization level (-O1/2/3), the program cannot be terminated. In Visual Studio, both debug mode and release mode can run normally. In the above cases, the codes are the same.I don’t know how to find the problem, can anyone help me?
class DstarLite {
public:
DstarLite() = delete;
DstarLite(GridStatus* a, GridStatus* b, FILE* fp)
: k_m_(0), start_(a), last_(start_), goal_(b), open_close_(fp) {}
void calculateKey(GridStatus* s);
void updateVertex(GridStatus* u);
void initialize();
void computeShortestPath();
void rePlanning(vector<pair<GridStatus*, int>>& node_change);
GridStatus* getStart();
void setStart(GridStatus* val);
GridStatus* getGoal();
private:
Fib frontier_;
double k_m_;
unordered_map<GridStatus*, handle_t>
heap_map_;
GridStatus* start_;
GridStatus* last_;
GridStatus* goal_;
FILE* open_close_;
};
void DstarLite::calculateKey(GridStatus* s) {
s->f = min(s->g, s->rhs) + heuristic(start_, s) + k_m_;
s->k2 = min(s->g, s->rhs);
}
void DstarLite::initialize() {
fprintf(open_close_, "%d %d\n", start_->x, start_->y);
fprintf(open_close_, "%d %d\n", goal_->x, goal_->y);
goal_->rhs = 0;
calculateKey(goal_);
handle_t hand = frontier_.push(goal_);
heap_map_[goal_] = hand;
}
void DstarLite::updateVertex(GridStatus* u) {
bool heap_in = heap_map_.find(u) != heap_map_.end();
if (u->g != u->rhs && heap_in) {
calculateKey(u);
frontier_.update(heap_map_[u]);
} else if (u->g != u->rhs && !heap_in) {
calculateKey(u);
handle_t hand = frontier_.push(u);
heap_map_[u] = hand;
} else if (u->g == u->rhs && heap_in) {
calculateKey(u);
frontier_.erase(heap_map_[u]);
heap_map_.erase(u);
}
}
void DstarLite::computeShortestPath() {
int count = 0;
while (smaller(frontier_.top(), start_) || !myEqual(start_->rhs, start_->g)) {
count++;
auto u = frontier_.top();
pair<double, double> k_old = {u->f, u->k2};
pair<double, double> k_new;
k_new.first = min(u->g, u->rhs) + heuristic(start_, u) + k_m_;
k_new.second = min(u->g, u->rhs);
if (k_old < k_new) {
calculateKey(u);
frontier_.update(heap_map_[u]);
} else if (myGreater(u->g, u->rhs)) {
u->g = u->rhs;
frontier_.pop();
heap_map_.erase(u);
for (auto s : neighbors(u)) {
if (s->rhs > u->g + cost(u, s)) {
s->next = u;
s->rhs = u->g + cost(u, s);
updateVertex(s);
}
}
} else {
double g_old = u->g;
u->g = kDoubleInfinity;
auto neighbor = neighbors(u);
neighbor.push_back(u);
for (auto s : neighbor) {
if (myEqual(s->rhs, cost(s, u) + g_old)) {
if (!equal(s, goal_)) {
double pp_s = kDoubleInfinity;
for (auto succ : neighbors(s)) {
double dis = succ->g + cost(succ, s);
if (dis < pp_s) {
pp_s = dis;
s->next = succ;
}
}
s->rhs = pp_s;
}
}
updateVertex(s);
}
}
}
cout << "Dstar visited nodes : " << count << endl;
}
void DstarLite::rePlanning(vector<pair<GridStatus*, int>>& node_change) {
k_m_ += heuristic(last_, start_);
last_ = start_;
for (auto change : node_change) {
GridStatus* u = change.first;
int old_threat = u->threat;
int new_threat = change.second;
double c_old;
double c_new;
u->threat = new_threat;
u->rhs += (new_threat - old_threat) * threat_factor;
updateVertex(u);
for (auto v : neighbors(u)) {
u->threat = old_threat;
c_old = cost(v, u);
u->threat = new_threat;
c_new = cost(v, u);
if (c_old > c_new) {
if (v != goal_) {
if (v->rhs > u->g + c_new) {
v->next = u;
v->rhs = u->g + c_new;
}
}
} else if (myEqual(v->rhs, c_old + u->g)) {
if (v != goal_) {
double pp_s = kDoubleInfinity;
for (auto pre : neighbors(v)) {
double dis = pre->g + cost(pre, v);
if (dis < pp_s) {
pp_s = dis;
v->next = pre;
}
}
v->rhs = pp_s;
}
}
updateVertex(v);
}
}
}
GridStatus* DstarLite::getStart() { return start_; }
void DstarLite::setStart(GridStatus* val) { start_ = val; }
GridStatus* DstarLite::getGoal() { return goal_; }
DstarLite dstar(start, goal, open_close);
dstar.initialize();
dstar.computeShortestPath();
Sorry, I think it is difficult to locate the problem in the code, so the code was not shown before. Now I have re-edited the question, but there are a lot of codes, and the main calling part is computeShortest().
A:
As you did not provide any code, we can give you only some general hints to fix such problems.
As a first assumption your code has definitely one or more bugs which causes what we call undefined behaviour UB. As the result is undefined, it can be anything and is often changing behaviour with different optimization levels, compiler versions or platforms.
What you can do:
enable really ALL warnings and fix them all! Look especially for something like "comparison is always...", "use of xxx (sometimes) without initialization", " invalid pointer cast", ...
try to compile on different compilers. You should also try to use gcc and/or clang, even on windows. It is maybe hard in the first time to get the environment for these compilers run on windows plattforms, but it is really worth to do it. Different compilers will give different warnings. Fixing all warnings from all compilers is a really good help!
you should use memory tracers like valgrind. I have not much experience on windows, but I believe there are also such tools, maybe already integrated in your development suite. These tools are really good in finding "of by x" access, access freed memory and such problems.
if you still run into such trouble, static code analyser tools may help. Typically not as much as managers believe, because today's compilers are much better by detecting flaws as expected by dinosaur programmers. The additional findings are often false positives, especially if you use modern C++. Typically you can save the money and take a class for your own education!
Review, Review, Review with other people!
snip the problem small! You should spend most of your development time by setting up good automated unit tests. Check every path, every function in every file. It is good to see at minimum 95% of all branches covered by tests. Typically these tests will also fail if you have UB in your code if you change optimizer levels and or compiler and platforms.
using a debugger can be frustrating. In high optimized code you jump through all and nothing and you may not really see where you are and what is the relation to your code. And if in lower optimizer level the bug is not present, you have not really much chance to see find the underlying problem.
last but not least: "printf debugging". But this may change the behaviour also. In worst case the code will run always if you add a debug output. But it is a chance!
use thread and memory sanitizers from your compiler.
| {
"pile_set_name": "StackExchange"
} |
SRAM
X7 3x10 Front
Derailleur
Product Description
The Sram X.7 3x10 10 Speed Front Derailleur is part of Sram's 10 speed mountain group. The first of it's kind, this front derailleur offers a full range of usable gears, less weight, and easier and smoother shifting in all terrains.
There have been no reviews posted yet for this product. Be the first by clicking Submit a Review | {
"pile_set_name": "Pile-CC"
} |
Special Presentations
There will be a number of special presentations to fill in the time
between training and competing. Presentations open to the public
include a Scientific Panel of three researchers
into diving medicine, a talk by Kim McCoy of Ocean Sensors,
and a special screening of The Freediver.
Three distinguished researchers in diving medicine will be presenting talks
at the 4th AIDA World Freediving Championships. These will be held
on Friday, August 6th from 7:15 to 10:00pm at the Isabel MacInnes
room at Gage Towers, UBC.
Admission is $10.00 Cnd for the general public and free for athletes,
coaches and volunteers. A panel discussion will be held after
talk the talks. Tickets available at the door.
This talk will discuss the dynamic responses of the cardiovascular system
during a breath-hold. These will include a discussion of blood volume
shifts and circulatory adjustments associated with increasing hypoxia
and hypocapnia. A live demonstration of some of these interactions will
be presented through non-invasive measurements of arterial oxygen
saturation, heart rate, blood pressure and cerebral blood flow. There
will be time for hands on activities.
The physiological changes that occur during breath-hold diving are
largely consequences of apnea, immersion, and compression. Responses are
complex, and include circulatory adjustments, blood shifts, lung
compression, cardiac arrhythmias, spleen contraction, altered gas exchange,
hypoxia, and nitrogen effects. Since many of these phenomena are linked
together, yet difficult to study invasively, we have developed a new
computer model to simulate deep breath-hold diving. The model will be
demonstrated, and responses and predictions will be discussed in light of
recent scientific controversies.
Michael Lepawsky, BA, MD, CCFP(C), FPFC, DMO
University of British Columbia Medical School
Vancouver, British Columbia
Paumotan pearl divers are internationally known to
under water scientists, merchants or any who may have been impressed by
the empirically derived breath hold diving techniques proven by trial and
error since time pre dating recorded history. A nutritional necessity in
archeo pelagic times, breath hold diving became gainful employment in
economically challenged, emerging shoaled nations. In pursuing the oyster
that is their prey, breath hold Tuamotu Archipelago pearl divers cannot
break free of their evolutionary physiology and have been found to develop
signs and symptoms of the most serious types of decompression illness (DCI).
A universal Polynesian Island name for the most dreaded of the forms of
the breath hold diving diseases is called by all the peoples of that realm
"taravana". This talk will describe classical breath hold diving habits,
equipment, techniques and outcomes of those who pursue the precious gem
that can be as exquisite an object of beauty as well as a brutal and
vicious assassin.
Kim McCoy is a physical oceanographer with extensive experience in scientific research,
data acquisition, autonomous instrument system design, development.
He is experienced in coastal, deepwater and Polar field operations.
This talk will be in the Isabel MacInnes room at Gage Towers, UBC,
Saturday, August 7, 9:30 to 10:30pm. Admission to this event is
$10.00, payable at the door or
online via PayPal. | {
"pile_set_name": "Pile-CC"
} |
NOT PRECEDENTIAL
UNITED STATES COURT OF APPEALS
FOR THE THIRD CIRCUIT
_____________
No. 08-2563
_____________
UNITED STATES OF AMERICA
v.
ROMANUS OKORIE,
Appellant
_____________
On Appeal from the United States District Court
for the District of New Jersey
(D.C. No. 2:07-cr-00477)
District Judge: Hon. William H. Walls
Submitted Under Third Circuit LAR 34.1(a)
March 18, 2011
Before: BARRY, CHAGARES, and ROTH, Circuit Judges.
(Filed April 26, 2011)
_____________
OPINION
_____________
CHAGARES, Circuit Judge.
Romanus Okorie appeals his conviction, asserting that the District Court erred in
admitting various pieces of evidence during his trial. For the reasons set forth below, we
will affirm the District Court‟s evidentiary decisions and Okorie‟s conviction.
I.
Because we write solely for the benefit of the parties, we will only briefly recite
the facts. Okorie ran a business preparing taxes. The allegations of the underlying
conviction were that he falsely claimed that his clients were sole proprietors of businesses
and then created excessive business expenses to decrease his clients‟ taxable incomes.
He would then file tax returns without first presenting them to his clients for review and
signature, and also failed to identify himself as the preparer of the returns. His scheme
was discovered when one client, Maria Brown, received her refund check, realized that it
was for far too much, returned it to the IRS, and began cooperating in an investigation of
Okorie. As part of this investigation, the Government received a warrant to search
Okorie‟s home and to seize any documents relating to the preparation of taxes for the
years 2003 and 2004. In executing this warrant, the Government agents were required to
sort through stacks of papers that had not been separated by year, and noticed that forms
from 2002 also contained suspicious information. The Government then received a
second search warrant and seized all documents relating to 2002 as well.
Okorie was indicted on June 11, 2007, and charged with ten counts of preparing
and filing false tax returns only for the years 2003 and 2004, in violation of 26 U.S.C. §
7206(2). He was convicted by a jury on all counts on January 22, 2008, and was
sentenced to 72 months of imprisonment on May 14, 2008. The instant appeal was filed
on May 15, 2008.
2
II.
The District Court had jurisdiction over this case pursuant to 18 U.S.C. § 3231 and
this Court has jurisdiction under 28 U.S.C. § 1291. We review the underlying factual
findings of a District Court‟s refusal to suppress evidence for clear error, but exercise
plenary review over the application of the law to these factual findings. United States v.
Brown, 595 F.3d 498, 514 (3d Cir. 2010). On issues regarding the District Court‟s
decision to admit evidence, we review for abuse of discretion, United States v. Kemp,
500 F.3d 257, 295-96 (3d Cir. 2007), and this includes consideration of whether the
admission of evidence violated the Sixth Amendment‟s Confrontation Clause. United
States v. Jimenez, 513 F.3d 62, 76-77 (3d Cir. 2008).
III.
Okorie first argues that the District Court erred in denying his application to
suppress all evidence seized from his residence because the Government conducted a
broader search than authorized by the first warrant when it looked at documents from
2002 as well as 2003 and 2004. He argues that all evidence seized, including the
evidence that was plainly within the scope of the first search warrant, must be suppressed
“due to the blatant Fourth Amendment violation” that occurred when the executing
officials viewed his 2002 documents, which were not within the scope of the first
warrant.
As a general matter, the exclusionary rule is used only in circumstances where it
will have a deterrent effect. United States v. Leon, 468 U.S. 897, 906 (1984). “Whether
the exclusionary sanction is appropriately imposed in a particular case . . . is „an issue
3
separate from the question whether the Fourth Amendment rights of the party seeking to
invoke the rule were violated by police conduct.‟” Id. (quoting Illinois v. Gates, 462 U.S.
213, 223 (1983)).
We see no reason that would justify the suppression of the 2003 and 2004
documents that were collected under the first warrant. Okorie does not allege that the
first warrant was defectively obtained or executed. Instead, he argues that the
overbreadth of the first search justifies the suppression of all evidence obtained during
that search, regardless of whether it was plainly within the scope of the warrant. The
conduct at issue in this case, however, is insufficient to impose the “substantial social
costs exacted by the exclusionary rule.” Id. at 907. Okorie‟s files were not neatly
organized or easily separable, and the agents were required to look through all of
Okorie‟s papers in order to separate out those that were from the years 2003 and 2004.
The evidence introduced at trial was obtained as a result of a valid warrant that was
properly executed, and we will affirm the District Court‟s refusal to suppress this
evidence.1
1
We also note, per Okorie‟s contention that the search exceeded the scope of the initial
warrant, that the Supreme Court has made clear that “elaborate specificity” in a warrant is
not required. United States v. Ventresca, 380 U.S. 102, 108 (1965). Whether evidence is
within a search warrant‟s scope requires not a “hypertechnical” analysis, but a “common-
sense, and realistic” one. United States v. Srivastava, 540 F.3d 277, 291 (4th Cir. 2008).
In line with such reasoning, we have observed that “[w]hen an entire, discrete body of
evidence is described, the naming of every component of that body is mere surplusage.”
United States v. Kepner, 483 F.2d 755, 763 (3d Cir. 1988) (quotation marks omitted). In
addition, “the government is to be given more flexibility regarding the items to be
searched when criminal activity deals with complex financial transactions.” United
States v. Yusuf, 461 F.3d 374, 395 (3d Cir. 2006). On the facts here, both the warrant
and the search executed pursuant to it easily pass muster.
4
Okorie next argues that the District Court erred in allowing Maria and Raymond
Brown to testify as to their dealings with Okorie, despite the fact that their experience did
not form one of the underlying counts of Okorie‟s indictment. He argues that the
evidence was cumulative and that the Browns‟ testimony could not have served any non-
cumulative purpose other than to encourage the jury to convict based upon prior bad acts
or a propensity to commit crime, neither of which is permitted under Federal Rule of
Evidence 404(b).
Federal Rule of Evidence 404(b) provides as follows:
[e]vidence of other crimes, wrongs, or acts is not admissible to prove the
character of a person in order to show action in conformity therewith. It
may, however, be admissible for other purposes, such as proof of motive,
opportunity, intent, preparation, plan, knowledge, identity, or absence of
mistake or accident, provided that upon request by the accused, the
prosecution in a criminal case shall provide reasonable notice in advance of
trial, or during trial if the court excuses pretrial notice on good cause
shown, of the general nature of any such evidence it intends to introduce at
trial.
This Court has noted that the threshold established by this rule is not overly high, and that
almost all evidence can be admitted under 404(b) so long as it is for a purpose other than
to demonstrate the defendant‟s bad character in order to encourage the jury to convict on
the basis of a propensity to commit crime. United States v. Green, 617 F.3d 233, 248-29
(3d Cir. 2010).
In this case, the testimony of the Browns went to the non-propensity purpose of
demonstrating motive, voluntariness, and lack of mistake, as well as providing
background information regarding how the IRS began its investigation. The testimony
helped demonstrate that the criminal conduct was initiated by Okorie and not his clients,
5
and, because Maria Brown returned her refund check, provided testimony from
individuals without any motivation to lie. In addition, the District Court provided a
limiting instruction immediately after each of the Browns testified, and then again when
charging the jury. The District Court did not abuse its discretion in allowing this
testimony, and we will affirm its decision on this issue.
Finally, Okorie asserts that the District Court‟s decision to allow Deborahann
Westwood, the custodian of records for the New Jersey Department of the Treasury, and
Margaret Coe, a Human Resources specialist with the IRS, to testify regarding the results
of employment-records searches in their respective departments. Although the
Government initially planned to introduce only a certification of the non-existence of an
official record, the District Court directed that individuals be produced to testify to this
fact in order to avoid Confrontation Clause issues. This testimony was introduced to
demonstrate that Okorie never worked for either of these agencies, despite his
representations to the contrary to his clients. Okorie argues that he has a Sixth
Amendment right to cross-examine those who actually performed the searches of the
records, and that the production of a supervisor is insufficient to meet the Constitution‟s
demands.
The Sixth Amendment prevents, with limited exceptions, the introduction of any
testimonial statement at trial without the opportunity for the defendant to cross-examine
the individual who made the statement. Crawford v. Washington, 541 U.S. 36, 50-51
(2004). The Supreme Court‟s more recent decision in Melendez-Diaz v. Massachusetts,
129 S. Ct. 2527 (2009), makes clear that the type of report produced in this case would
6
certainly constitute a testimonial statement. Unlike Melendez-Diaz, however, where only
a single analyst‟s report was at issue, this case deals with a report that was produced
through the work of multiple individuals. In the present case, although Westwood and
Coe did not conduct the entire search personally, the testimonial import of the report that
was produced was simply that Okorie had not worked in either of their organizations.
Westwood and Coe certainly had sufficient knowledge about this report to justify the
admission of their testimony; both had knowledge of their institutions‟ records, the
searches conducted, and their results, and both were subject to cross-examination on
these issues. That they were not the individuals who physically sorted through every
piece of paper or who personally typed the search into the computer program does not
cause a constitutional problem. They both had knowledge of the ultimate testimonial fact
supplied by the report (that Okorie had not worked in either agency), and had knowledge
of the process that produced this testimonial fact. We certainly are not prepared to state
the District Court abused its discretion in its decision to admit the evidence, and we
therefore will also affirm its decision to allow the testimony of Westwood and Coe.
IV.
For the foregoing reasons, we will affirm the judgment of the District Court.
7
| {
"pile_set_name": "FreeLaw"
} |
With three tumblers on the table, a measuring cup filled with water, paper towels, and food dye, I told my sons we were going to fill a cup with water without pouring a single drop in it. "HOW?!?" they said. "Let me show you!"
This experiment is simple. It did require patience, though. We prepared our cups in the afternoon and then watched throughout the evening and overnight. How We Did It Fill two identical drinking cups 2/3rds full of water. Put an empty cup of the same size between them. Squirt 8-10 drops of food coloring in the water-filled cups. We used yellow in one and blue in the other. Now take a paper towel - we used a half sheet since we have the select-a-size rolls - and fold it the long way so the paper towel is about an inch wide. Do the same to another paper towel so you have two long flattened 1-inch wide rolls of paper towel. Fold them in the middle and put one end in the food dye, and the other in the empty cup. Now observe what happens.
What Happens The paper towel absorbs the water and in doing so, the colored water is transferred from one cup to another. When the two primary colors, yellow and blue combine, they make green. Even more fascinating is how the water level ends up perfectly even among all three cups. The water has been evenly distributed! It took about 36 hours for our water to "walk" from each of the end cups to the middle and even distribute between the three cups. Have patience! This great experiment came from Coffee Cups and Crayons. Stop there to see other color combinations! | {
"pile_set_name": "Pile-CC"
} |
Pierre Bouchet
Pierre Bouchet (6 January 1752 – 6 January 1794) was a French physician born in Lyon.
Biography
He was trained in medicine in Paris as Pierre-Joseph Desault pupil then came home in Lyon Hôtel-Dieu where he became Head Surgeon.
He was the first in France to modify then use a knotted-string snare device to ligate and remove uterus and vagina polyps.
He also practiced internal necrosis surgery and tibia drilling.
His son, Claude-Antoine Bouchet, was the first, in France, to ligate external iliac artery to cure groin aneurysm.
Pierre Bouchet was always kind and good-hearted, so that his fellow citizens held him in the highest regard and esteem. He suffered a stroke and died under arrest on 1794 physically and psychologically exhausted by the Revolutionary armies siege of Lyon after the Revolt of the city against the National Convention.
References
Category:1752 births
Category:1794 deaths
Category:18th-century French physicians
Category:People from Lyon
Category:French surgeons | {
"pile_set_name": "Wikipedia (en)"
} |
Obliteration of a coronary artery aneurysm with a PTFE-covered stent: endoluminal graft for coronary disease revisited.
This is the first reported use of the JOSTENT stent graft for aneurysm disease in native coronaries. Consideration can be given to using this polytetrafluoroethylene (PTFE)-covered stent in situations such as dissections and restenosis in saphenous vein grafts or in long native coronary arteries without side branches, though further investigation is warranted. | {
"pile_set_name": "PubMed Abstracts"
} |
Q:
POST collection type data from silverlight to aspx page.
I have a problem posting the data from silverlight to the aspx page which is in same domain.
I need to open aspx page in a new tab that needs data of type combination (id, amount) like
3-XX-YY-ZZ, 12
4-XX-YY-ZZ, 20
5-XX-YY-ZZ, 15
etc...[many]
and process it and display.
I tried to do it using querystrings and HtmlPage.PopupWindow(). It works but that would come with size limits.
Please help.
A:
I can access javascript from silverlight application. And this problem was solved by using javascript function from silverlight to post the hidden field data to aspx page.
| {
"pile_set_name": "StackExchange"
} |
Q:
What constitutes proof of relationship/intention to marry for a UK immigration visa?
Being disabled, I don't really have to worry so much about funds or some of the more complicated issues with getting my partner over to the UK (from the USA). But there is one thing that concerns and confuses us: Proof of relationship/intention to marry.
Would it help if we booked the marriage before applying for the visa? We have an arrival date (7th of May), we've considered every other angle we need to, I think (going crazy with that)... But I don't want us to be refused the Visa and this is one question hanging over our heads.
We're going to include letters from ourselves and whatever third parties we can that will serve to explain our relationship, but since we communicate over Skype (we've had calls going 24/7 for over four years, now), we don't have phone records.
Any... Any information (especially from experience) would be helpful. We really want to make this work. Thank you!
A:
You asked if you should get a provisional booking at the Registry Office (from this I assume that your gf is seeking a fiance visa). The answer is yes, it's always a good idea, but its evidential value is close to nil since it costs £35 and anybody can get one.
You asked about how to establish that your relationship is genuine. Since part of the rules for a fiance visa is proof that you met (and that means you met person-to-person in the physical, real-world) I assume that you have met. You will have some hard evidence of this including, passport stamps, hotel and meal receipts, and a few photos together. If you have visited together on multiple occasions, get that hard evidence also. The more the better.
Also, you will have (presumably) evidence of how you met on the net. If not, you will be able to explain it in a way that makes sense to them.
They don't want to see reams and reams of emails, and it can backfire if they read something and take it the wrong way. It can also slow the whole process down if somebody has to read through piles and piles of crap. Having a huge Skype log or similar can lead to the impression that you are addicted to cybersex and the relationship is not physically subsisting or viable. Be careful.
When I was doing casework for clients seeking a fiance visa, I would send the hard evidence I listed above along with a MAX of 3 photos, and 3 emails spaced out over the length of the relationship. I would include a cover letter that explained in detail how the couple met (doing this is critically important). If the couple had progressed to intimacy, I would explain when and where that took place. It's not a requirement, but it's an abrupt end to any questions about genuine relationship. Sham marriages and forced marriages do not have intimacy beforehand.
You asked about getting evidence from third parties, possibly an attestation that the relationship is genuine. It's not appropriate. They will look at it and wonder why you thought it was necessary. It's a poor idea. If the relationship is genuine, there will be a sufficient amount of hard evidence readily available without having to rely upon third parties.
Adding...
If it's a US/UK relationship, they will not worry a lot about if the relationship is genuine or not. The approval rate for family path applicants from the USA is about 98%.
| {
"pile_set_name": "StackExchange"
} |
Much has been written about the incorporation of digital broadcasting receivers into mobile handheld terminals, such as mobile telephones, personal digital assistants (PDAs), laptop computers and the like.
A system has been proposed in which data services are transmitted on a time-sliced, or time-multiplexed, basis allowing plural services to be transmitted at a given channel frequency. This has advantages for mobile terminals since their receivers only need to be powered and they only need to buffer, decode and process received data when data relating to the service of interest is being broadcast, and can be switched off at other times. This would normally result in a receiver being switched on for a relatively short period at regular intervals.
The present invention aims to provide a mechanism whereby the power consumption of data broadcast receivers can be further reduced. | {
"pile_set_name": "USPTO Backgrounds"
} |
Gold/Silver and Mining Stock Review
Gold and the mining stocks have taken a severe beating of late as supply-related pressures weigh heavily against the precious metals markets. In the weeks ahead gold and silver and mining stocks will have to work their way through the heavy overhead supply that has built up in recent weeks as too many "weak-handed" gold bulls have jumped into the market to allow for a sustainable upward trend. Once these weaker players have been sufficiently shaken out of the market, the market will be cleared for an upward trend resumption, probably not until later in the summer (around the time when the broad market will be falling under the weight of the crashing cycles). Investors must smell fear before they really commit to the gold and silver markets and there really isn't much fear out there yet. The fear, however, will come as the summer wears on.
In our May 24 issue of Bear Market Report we advised exiting the gold/gold stock market in advance of the correction. We wrote, "Those traders who haven't already done so should take profits (or partial profits in the case of long-pull traders) on all mining share profits as the odds favor an across-the-board pullback." The "pullback" turned out to be a bit steeper than we anticipated, nonetheless, it is very much in keeping with the natural forces of supply and demand which regulate the market and is a necessary "cleaning out" process before gold can resume its upward trend.
The story across the board in mining shares is the story of the Fibonacci 50% and 62% retracement levels. An astounding number of these stocks have either hit or are approaching 50-62% retracements of their 6-month upward trends this week. The XAU gold and silver mining index tested the 75-76 area referenced in Friday's newsletter, failing the test. If 75 does not hold on Tuesday, a drop down to 68-70 appears likely since this area represents the absolute low point of the 6-month upward trend from around 50 to this month's highs near 90. The 70 area also approximates to the 50% retracement level of the XAU's 6-month up-swing. Therefore, we must watch it closely.
August Gold futures are hovering near the $320 area and will almost certain test the 38% retracement area near $310-$312. This area also represents a chart support from a previous breakout and is intersected by a rising trend line off the March lows. Should $310 fail to hold, the next likely test would be at $310 in coming weeks and possibly even $305. The $305 level approximates to the 50% retracement level and also coincides with a rising trend channel bottom extending back into December 2001. At its absolute worst this gold market correction should not exceed $300, which represents the super floor of gold's 2002 bull market. It is an area where heavy insider buying took place and as such represents a powerful chart support should gold drop this low. When all technical factors are considered, gold has a good chance of staying above $310 and an excellent chance of being supported above $300-$305.
July Silver should hold above $4.80 in order to remain technically strong heading into the summer season. Should $4.80 fail a powerful chart support exists above $4.60. Interestingly, silver's predicted angle of ascent based on the December/January highs, shows a greater upside potential in percentage terms compared to gold later this summer when the cycles bottom and precious metals take off again.
Pan American Silver (PAAS) should decline no lower than $7 on a closing basis this week in order for its uptrend to remain intact. This level represents not only the 50% retracement area but also the extreme lower boundary of a 6-month rising trend channel.
Silver Standard Resources (SSRI) should ideally remain above $5 to remain on a solid foundation in coming months. The potentially bullish aspect of Silver Standard's chart is that the late January/early February highs in the daily bars project an extreme upside target of $11-$12 by the end of the year based on the technical discipline known as Predicted Trend Line Theory.
In typical Wall Street fashion, the financial press is doing its job of "warning" investors of coming danger by giving out the warning signal too late. First, the financial press advises investors to get long gold and gold stocks at an interim peak, then switches gears and tells them to avoid being long stocks when the broad market has already fallen significantly. A story appearing over the weekend on the Reuters news wire with the headline "Beware of Falling Stocks" cautioned investors that "widespread mistrust of corporate management, fears of more violence in the Middle East and sluggish corporate profit growth could conspire to drive stocks down in the week ahead." Notice how the press, including Reuters, were promoting stocks and leading the bullish camp's cheerleading squad all through the decline from the March highs near 10,700 down to the present lows near 9500. Only now after the market has fallen some 1,200 points do they tell people to "be careful." Undoubtedly, the press will be vocally bearish once the 40-week cycle bottoms and it's time to buy stocks again ahead of the summer rally.
The temerity (some would say criminality) of the Wall Street-controlled financial press has reached epidemic proportions. One recent banner advertisement on a prominent investment web site offers readers the chance to buy a book about "How America Made a Fortune and Lost its Shirt." For $21.95 you can discover how millions of gullible Americans were led to invest in the stock market during the boom years of the '90s, only to lose a fortune in the tech crash of 2000-2002. This "valuable" info comes to us, of course, well after the fact and is of no practical value at this point. The same people who told America to "buy, buy, buy" and who never told them when to sell (let alone sell short) now have the gall to sell them a book telling them exactly where they went wrong! As one of our colleagues recently said, the Wall Street press has turned into one giant "media bucket shop."
What this latest precious metals correction represents is the necessary "shaking out" of the newcomers, general public, and weak-handed traders by the insiders. The financial press and investment advisories were laying it on too heavy with the bullish talk on gold; consequently, the investing public loaded themselves up with gold and gold stocks too quickly and were not sufficiently strong to carry their holdings through a market downturn. This is all part of the sorting process of the market and it is very typical of the early stages of a long-term bull market. The insiders will be busy snapping up the supply dumped onto the market by the public in coming weeks, thus we can probably expect a trading range along the June lows into the August timeframe when the cycles are due to perk up again and gold/silver should see one a blast-off into the fall. We predict the next phase of the gold bull market later this summer will be the most dynamic one to date in terms of percentage gain and rate of ascent.
A colleague recently shared these thoughts with us, "It is so funny to talk to people about gold and gold miners. They don't have a clue and this latest TANK (vicious if not a trader) will keep them away for another 3 years. One of my clients called me and said "he couldn't take it". He dumped his gold mining stocks this A.M. [Tuesday] on the gap down. Have to remember, he was talking 'long term' and he bought last week!!! Try GIVING someone a one oz. Maple leaf or American Eagle. They won't take it. Now that is really funny. They'd have $300.00 in their hot littlehands and nooopppe, 'gold is useless!'" All too true, yet all too typical. And yet very much in keeping with the market forces which influence this behavior.
Clif Droke is the editor of the three times weekly Momentum Strategies Report newsletter, published since 1997, which covers U.S. equity markets and various stock sectors, natural resources, money supply and bank credit trends, the dollar and the U.S. economy. The forecasts are made using a unique proprietary blend of analytical methods involving cycles, internal momentum and moving average systems, as well as investor sentiment. He is also the author of numerous books, including most recently “Kress Cycles.” For more information visit www.clifdroke.com | {
"pile_set_name": "Pile-CC"
} |
INTRODUCTION {#sec1-1}
============
Topical timolol maleate is a nonselective beta-adrenergic receptor blocker that is commonly used for treatment of open-angle glaucoma. It has been frequently used as first-line therapy for reduction of associated ocular hypertension. While systemic concentration after administration of topical beta-blockers is low in comparison to that achieved with oral beta-blockers, it is well known that topical therapy can induce cardiovascular, respiratory, central nervous system, and metabolic side effects.\[[@ref1]\] We report an interesting case of a sinus bradycardia with intermittent atrioventricular block induced by topical timolol maleate.
CASE REPORT {#sec1-2}
===========
A 70-year-old black woman with a history of dyslipidemia, diabetes, hypertension, obesity, depression, and primary open-angle glaucoma presented to her cardiology appointment complaining of intermittent palpitations and dyspnea. At the time of examination at 9:00 AM, she was found to be bradycardic, with a normal sinus rhythm of 44 beats per minute; her cardiopulmonary examination was otherwise unremarkable. She had no history of structural or acquired cardiac disease. Her medications included hydrochlorothiazide, lisinopril, simvastatin, bupoprion, topical timolol, and topical brimonidine.
She was admitted to the telemetry unit for further monitoring and evaluation of bradycardia. A serum electrolyte panel, complete blood count, and cardiac marker panel were drawn and all were within normal limits. Initial management consisted of inpatient telemetry monitoring with collection of serial cardiac enzymes and potential cardiac catheterization the following day. While on telemetry, she returned to normal sinus rate and rhythm until 9:45 PM, when her heart rate dropped to 41 beats per minute. An EKG at that time revealed atrioventricular block \[[Figure 1](#F1){ref-type="fig"}\]. She was asymptomatic and after approximately 14 minutes spontaneously converted back to a regular rate and rhythm. The next morning at 8:50 AM, the same phenomenon occurred, where she transiently went into an episode of asymptomatic atrioventricular heart block with a rate of 44 beats per minute \[[Figure 2](#F2){ref-type="fig"}\]. Upon questioning we discovered that she had instilled her topical timolol maleate approximately 30 minutes prior to each of these episodes. Topical timolol was discontinued and the conduction abnormality resolved. She was diagnosed as having intermittent sinus bradycardia with intermittent atrioventricular block, likely induced by topical beta-blocker therapy. Subsequently, topical timolol was substituted with topical dorzolamide and a permanent pacemaker was placed.
{#F1}
{#F2}
DISCUSSION {#sec1-3}
==========
Topical timolol maleate has long been known to be effective in the treatment of ocular hypertension.\[[@ref2]\] It typically lacks direct myocardial depressant activity.\[[@ref3]\] Timolol maleate like most topical ophthalmic agents is absorbed into the conjunctival, nasal, oropharyngeal, and gastrointestinal mucosal capillaries.\[[@ref1]\] After administration, onset of action is in 20 minutes, with peak effect in 4 hours; the total effect usually lasts 24 hours.\[[@ref3]\] Peak plasma levels following topical administration have been shown to vary from undetectable to 9.6 ng/ml, but on average is accepted to be approximately 1 ng/ml. Although this is significantly lower than plasma concentrations following oral administration, it is sufficient to induce some degree of systemic beta-adrenergic blockade.\[[@ref1]\]
With regard to cardiac side effects, topical timolol has been shown to induce a decrease in heart rate and diastolic blood pressure.\[[@ref4]\] This effect has been shown to be synergistic with oral beta-blockers. A recent randomized controlled trial showed that in the subset of glaucoma patients not using either topical or oral beta-blockers, the mean resting pulse was 76 beats per minute (bpm); in comparison, patients using topical beta-blockers had a resting pulse of 70.3 bpm, patients on oral beta-blockers had a resting pulse of 64.7 bpm, and patients using both topical and oral beta-blockers had a resting pulse rate of 58 bpm.\[[@ref5]\] Our patient was not using oral beta-blockers. However, this information is important in the management of patients with both ocular and systemic hypertension.
Numerous reports exist of various cardiac and respiratory disturbances occurring as a result of topical timolol. Third-degree atrioventricular block has been reported as a consequence of topical administration.\[[@ref6]\] However, our case report is the first to describe sinus bradycardia with intermittent atrioventricular block.
CONCLUSIONS {#sec1-4}
===========
Topical timolol maleate is an effective treatment for ocular hypertension, acting by reducing aqueous fluid production. However, it can induce systemic side effects and should be used with caution in patients with, or predisposed to, cardiac or respiratory depression. More recently, topical prostaglandin E2 has emerged as a first-line therapy in glaucoma owing to its effect of increasing aqueous outflow while avoiding the systemic effects of topical beta-blockade.\[[@ref2]\] Additionally, a variety of medications and therapeutic options exist for both systemic hypertension and ocular hypertension associated with open-angle glaucoma. The clinician treating patients with coexisting ocular and systemic hypertension should be aware of these options, especially since topical beta-blockers can induce severe systemic effects in patients without known cardiac or pulmonary dysfunction.
**Source of Support:** Nil
**Conflict of Interest:** None declared.
| {
"pile_set_name": "PubMed Central"
} |
Martin Stellman
Martin Stellman (London, July 28, 1948) is a British screenwriter and director best known for creating and writing The Interpreter, starring Nicole Kidman and Sean Penn, and co-writing with Franc Roddam the 1979 British cult classic Quadrophenia.
He wrote and directed the action thriller For Queen and Country starring Denzel Washington playing a Malvinas/Falklands War veteran. He attended Bristol University, before joining the psychedelic band Principal Edwards Magic Theatre and is a graduate of the National Film and Television School. He often collaborates with British screenwriter and director Brian Ward.
He recently teamed up with Idris Elba co-writing Yardie, Elba's feature debut. Elba took inspiration from Stellman's earlier film Babylon, a drama about sound-system culture in London during the 1970s.
Filmography
Writer
Yardie (2018)
The Interpreter (2005)
Shoebox Zoo (TV series, 3 episodes) (2004)
Tabloid (2001)
For Queen and Country (1988)
Defence of the Realm (1986)
Babylon (1980)
Quadrophenia (1979)
Director
Harry (TV series, 3 episodes) (1993)
For Queen and Country (1988)
References
External links
Category:1948 births
Category:Living people
Category:British male screenwriters
Category:British television writers
Category:Alumni of the National Film and Television School
Category:Male television writers | {
"pile_set_name": "Wikipedia (en)"
} |
Q:
Set WordPress permalinks directly in httpd.conf?
Is is possible to configure WordPress permalinks directly in Apache httpd.conf?
I have a server situation (Apache 2.2.3 CentOS PHP5.1.6) where I can't use .htaccess for performance reasons, but can use httpd.conf.
The admin says that mod_rewrite is enabled, but AllowOverride is not, and I can't change those settings.
And I need to restrict the permalinks to just the "blog" directory.
This is what would go in .htaccess but needs to go into httpd.conf:
<IfModule mod_rewrite.c>
RewriteEngine On
RewriteBase /blog/
RewriteCond %{REQUEST_FILENAME} !-f
RewriteCond %{REQUEST_FILENAME} !-d
RewriteRule . /blog/index.php [L]
</IfModule>
Thanks...
A:
Put this within the container for your site.
<Directory /path/to/blog/>
<IfModule mod_rewrite.c>
RewriteEngine On
RewriteBase /blog/
RewriteCond %{REQUEST_FILENAME} !-f
RewriteCond %{REQUEST_FILENAME} !-d
RewriteRule . /blog/index.php [L]
</IfModule>
</Directory>
| {
"pile_set_name": "StackExchange"
} |
May 25 - Bloomberg: "China's central bank weakened its currency fixing to
the lowest since March 2011 as the dollar strengthened. The reference rate
was set 0.3% weaker at 6.5693 per dollar. A gauge of the greenback's strength
rose to a two-month high Tuesday... A resurgent greenback is shaking up a strategy
that the People's Bank of China pursued over the past three months -- a steady
rate against the dollar, combined with depreciation against other major currencies."
The U.S. dollar index increased 0.4% this week to 95.7 (down 3.0% y-t-d).
For the week on the upside, the British pound increased 0.8% and the Canadian
dollar gained 0.7%. For the week on the downside, the Brazilian real declined
2.6%, the euro 1.0%, the New Zealand dollar 0.9%, the Mexican dollar 0.7%,
the Australian dollar 0.6%, the South African rand 0.6%, Swiss franc 0.4%,
the Swedish krona 0.4%, the Norwegian krone 0.1% and the Japanese yen 0.1%.
The Chinese yuan declined 0.3% versus the dollar.
May 23 - Bloomberg (Tracy Alloway): "Bond investors appear to have placed
their faith in commodities exceptionalism, with many positing that the recent
pick-up in U.S. default rates will defy historical trends and remain confined
to that industry. New research from Deutsche Bank AG pours cold water on that
idea, arguing that there are already signs of contagion in junk-rated debt
outside of the commodities space. A look at previous peaks in default rates
shows the potential for more pervasive corporate stress. While default rates
were higher amongst particular sectors--such as telecoms in the early 2000s
or financials during the 2008 crisis--the rate for junk bonds excluding these
specialized industries also increased significantly."
May 24 - Financial Times (Eric Platt): "The triple A rated company is nearly
extinct. Just a handful of companies in the world retain the coveted rating
from Standard & Poor's after ExxonMobil was downgraded last month. In the
US, the number has fallen to two -- Johnson & Johnson and Microsoft. In
1992, there were 98 US companies that held the highest credit rating from S&P.
The demise of triple A-rated companies reflects a dramatic rise in the use
of debt to help bolster shareholder returns and fund takeover activity."
May 26 - Reuters (Suzanne Barlyn): "New York state's financial regulator,
which recently launched a probe into LendingClub Corp, is preparing to look
into the activities at other online lenders and whether they should be licensed
in New York... Last week, NYDFS subpoenaed San-Francisco based LendingClub,
a so-called peer-to-peer lender..."
May 25 - Bloomberg (Matt Scully): "Some of Wall Street's biggest banks are
making contingency plans to cut their exposure to online consumer loans if
the market deteriorates further after the recent crisis at LendingClub Corp.,
people with knowledge of the reviews said. While firms including Credit Suisse
Group AG and Deutsche Bank AG haven't scaled back exposure, they're concerned
about financing they provide to institutional investors that buy loans from
companies like LendingClub and Prosper Marketplace Inc., the people said."
May 25 - Associated Press (Stan Choe): "CEOs at the biggest companies got
a 4.5% pay raise last year. That's almost double the typical American worker's,
and a lot more than investors earned from owning their stocks -- a big fat
zero. The typical chief executive in the Standard & Poor's 500 index made
$10.8 million... That's up from the median of $10.3 million the same group
of CEOs made a year earlier. The raise alone for median CEO pay last year,
$468,449, is more than 10 times what the typical U.S. worker makes in a year.
The median full-time worker earned $809 weekly in 2015, up from $791 in 2014."
May 22 - Wall Street Journal (Sam Goldfarb): "The esoteric securities market
underpinning demand for the riskiest corporate loans is perking up, raising
hopes that it could become easier for banks to sell a range of loans, including
those that they failed to syndicate last year. More corporate loans are being
bundled this spring into collateralized loan obligations, which buy loans from
junk-rated companies and repackage them into securities that pay varying levels
of interest based on which get paid off first if the underlying loans go bad."
May 25 - Bloomberg (Elizabeth Campbell): "Illinois lawmakers have been busy
in the last week of the regular legislative session. They moved to establish
a youth-only turkey hunting season, set standards on where podiatrists can
perform amputations and allowed for the adoption of retired police dogs. Yet,
the Land of Lincoln remains the only state in the nation without a budget,
mired in the longest such standoff in its history... If no deal is struck,
the consequences will become more dire: Prisons may run out of food, schools
may not open on time, and the state's credit rating -- already the lowest in
the U.S. -- is at risk of falling even further as the government's deficit
continues to grow."
Global Bubble Watch:
May 26 - Financial Times (Robin Harding): "The global economic outlook is
as grim as it was after the Lehman Brothers crisis in 2008, Shinzo Abe claimed
on Thursday, as the Group of 7 revealed its stark divisions on economic policy.
Seeking to rally support for a global fiscal stimulus at the G7 summit, the
Japanese prime minister showed his fellow world leaders a series of alarming
graphs comparing today's economic conditions with those of 2008. But, according
to people close to the discussions, Mr Abe struggled to win over opponents
such as Germany's chancellor Angela Merkel or UK Prime Minister David Cameron."
May 26 - Reuters (Chris Gallagher and William Mallard): "Japanese Prime Minister
Shinzo Abe warned his Group of Seven counterparts of a crisis on the scale
of Lehman Brothers, Nikkei reported, offering a potential justification to
again delay an increase in the national sales tax. Abe presented data at a
Thursday session of the G7 summit he is hosting, showing that commodities prices
have fallen 55% since 2014, the same margin they fell during the global financial
crisis, the newspaper said, interpreting this as 'warning of the re-emergence
of a Lehman-scale crisis'."
May 26 - Bloomberg (Claire Boston and Sally Bakewell): "A borrowing binge
by companies globally is poised to make May one of the the busiest months ever,
thanks to investors who continue to devour the relatively juicy yields on corporate
debt in a negative-rate world. Global issuance of non-financial company debt
will be in excess of $236 billion by month-end... In Europe, companies sold
48.5 billion euros ($54.2 billion) making it the busiest May on record."
May 23 - Reuters (Anjuli Davies): "Revenue at the world's 12 largest investment
banks fell 25% in the first quarter from a year ago as economic uncertainty
and investor caution led to the slowest start since the financial crisis, a
survey showed... Investment banks have been hit by a steep decline in oil prices,
near-zero interest rates and worries about China's economy, which triggered
a wave of volatility in financial markets at the start of the year, normally
the most lucrative period when investors put their money to work. Trading in
fixed income, currencies and commodities (FICC) divisions... declined 28% year-on-year
to $17.8 billion, data from... Coalition shows."
May 26 - Financial Times (Joe Rennison): "Global equity markets experienced
further strong outflows this week, despite soothing economic data and rising
stock prices. Equity funds suffered their seventh consecutive week of outflows,
shedding another $9.2bn for the week ending May 25, taking their total outflows
for the year above $100bn, according to data from EPFR."
U.S. Bubble Watch:
May 23 - CNBC (Jeff Cox): "That American companies have been wadding up huge
amounts of cash is no secret. What may be less well-known is that they're also
accumulating debt at a much faster pace. Total debt among more than 2,000 nonfinancial
companies swelled to $6.6 trillion in 2015, dwarfing the $1.84 trillion in
cash on their balance sheets, according to a study... by S&P Global Ratings.
The ratio of cash to debt is the lowest it's been in about 10 years, or just
before the global financial crisis. As financial markets came to grips with
the prospect of higher rates ahead, corporate America went on a debt bonanza.
Debt grew 50 times that of cash, with companies rolling up $850 billion of
new IOUs compared to just $17 billion, or 1%, cash growth."
May 26 - MarketWatch (Ciara Linnane): "First-quarter earnings season is close
to over, and the numbers it's produced are as gloomy as they have been since
the Great Recession. Overall profit for S&P 500 companies was the weakest
in 6 1/2 years. The financial sector showed a double-digit percentage decline,
while even stodgy utilities saw earnings fall into the red as unusual weather
weighed. After selling assets, cutting capital expenditures and buying back
their own shares at a record pace in recent years, companies are now clearly
struggling to produce any kind of growth... A full 98.4% of S&P 500 companies
have now reported through early Thursday, and profit measured by earnings per
share is down 7% from a year ago, according to FactSet. On the heels of a 3.2%
decline in the fourth quarter, that marks the fourth straight quarter of year-over-year
earnings declines, and it was the biggest drop since the third quarter of 2009."
May 25 - Bloomberg (Jeanna Smialek): "A substantial share of Americans lacked
retirement savings and fewer households were confident in the outlook for their
income at the end of last year. That's according to a Federal Reserve report
on the economic well-being of U.S. households in 2015... The findings show
that while respondents increasingly reported that they are 'doing OK' or 'living
comfortably,' a smaller share said they expected income growth than in the
prior year's survey. Thirty-one percent of non-retired Americans said they
had no retirement savings at all, unchanged from 2014."
May 26 - Wall Street Journal (Jesse Newman): "Banks are tightening credit
for U.S. farmers amid a rise in delinquencies, forcing some growers to turn
to alternative sources of loans. When U.S. agriculture was booming this decade,
banks doled out ample credit to strong performers and weaker growers alike,
said Michael Swanson, an agricultural economist at Wells Fargo & Co. But
with the farm slump moving into its third year, banks have become pickier,
requiring some growers to cough up more collateral and denying financing outright
to some customers who need it to pay for seeds, crop chemicals and rent."
May 27 - Bloomberg (Romy Varghese): "California's three-year boom run is showing
signs of fatigue. Shaking off recession-era comparisons to Greece, the most-populous
U.S. state rebounded with surpluses and an economy fueled by the fast-growing
technology industry, which garnered it eight bond-rating upgrades. Governor
Jerry Brown is now forecasting that revenue growth is slowing along with the
economy after April's income-tax collections lagged expectations, in part because
of the sputtering stock market. Even if voters in November decide to keep a
temporary income-tax increase from ending -- a measure that Brown hasn't endorsed
-- the budget would 'barely be balanced, his administration said..."
May 27 - Bloomberg (Prashant Gopal): "Miami's crop of new condo towers, built
with big deposits from Latin American buyers and lots of marketing glitz, are
opening with many owners heading for the exits. A third of the units in some
newly built high-rises are back on the market, though most are listed for more
than their owners paid in the pre-construction phase. At the current sales
pace, it would take 29 months to sell the 3,397 condominiums available in the
downtown area, according to South Florida development tracker CraneSpotters.com.
With the U.S. dollar strong, South American investors who piled into the downtown
Miami market after the real estate crash are now trying to unload their recently
built condos, adding inventory to an area where 8,000 units are under construction
and nine towers were completed since the end of 2013."
May 24 - Bloomberg (Michelle Jamrisko): "Purchases of new homes in the U.S.
surged in April to the highest level since the start of 2008, pointing to a
robust spring selling season for builders... (Sales) Rose 16.6% to 619,000
annualized rate (forecast was 523,000). Monthly increase was biggest since
1992, while pace was strongest since January 2008. Median selling price jumped
9.7% to a record $321,100."
May 25 - Bloomberg (Prashant Gopal): "U.S. home prices rose 5.7% in the first
quarter from a year earlier as buyers competed for a limited supply of listings.
Prices climbed 1.3% on a seasonally adjusted basis from the previous three
months, the 19th consecutive quarterly gain... There were 1.98 million houses
for sale at the end of March, down 1.5% from the same month last year... While
the U.S. has a whole had robust gains, prices fell from the previous quarter
in 12 states and the District of Columbia, the FHFA said."
May 25 - Wall Street Journal (Louise Radnofsky): "Big health plans stung by
losses in the first few years of the U.S. health law's implementation are seeking
hefty premium increases for individual plans sold through insurance exchanges
in more than a dozen states. The insurers' proposed rates for individual coverage
in states that have made their 2017 requests public largely bear out health
plans' grim predictions about their challenges under the health-care overhaul.
According to the insurers' filings with regulators, large plans in states including
New York, Pennsylvania and Georgia are seeking to raise rates by 20% or more."
China Bubble Watch:
May 24 - Bloomberg (Paul Panckhurst): "Charlene Chu, a banking analyst who
made her name warning of the risks from China's credit binge, said a bailout
in the trillions of dollars is needed to tackle the bad-debt burden dragging
down the nation's economy. Speaking eight days after a Communist Party newspaper
highlighted dangers from the build-up of debt, Chu... said she was yet to be
convinced the government is serious about deleveraging and eliminating industry
overcapacity. She also argued that lenders' off-balance-sheet portfolios of
wealth-management products are the biggest immediate threat to the nation's
financial system, with similarities to Western bank exposures in 2008 that
helped to trigger a global meltdown."
May 26 - Bloomberg: "China's government still has room to borrow more to finance
the investment and construction needed to shore up economic growth, the Ministry
of Finance said. Overall risks associated with government debt, which amounted
to 26.66 trillion yuan ($4.1 trillion) at the end of last year, are under control,
the ministry said in a statement late on Thursday. The government can add leverage
gradually because its debt ratio is still below international warning levels,
it said."
May 25 - Bloomberg (Lisa Pham): "In the creative world of Chinese lending,
there's a new trade in town: the cow leaseback. China Huishan Dairy Holdings
Co., which operates the largest number of dairy farms in the country, is selling
about a quarter of its herd -- some 50,000 animals -- to Guangdong Yuexin Finance
Lease Co. for 1 billion yuan ($152 million) and then renting them back. With
an estimated $1.3 trillion of risky loans in the country, Chinese banks are
becoming more cautious about lending, forcing some companies to look for new
ways to borrow. Finance leasing has been growing in popularity, especially
for purchases of equipment. But cows?"
May 24 - Bloomberg (Zhe Huang and Justina Lee): "The People's Bank of China
scrapped its market-based mechanism for managing the yuan on Jan. 4 and returned
to setting the exchange rate based on what suits authorities the best, the
Wall Street Journal reported, citing unidentified people close to the central
bank. An unidentified official from the PBOC in March told economists and bankers
that 'the primary task is to maintain stability' when they asked the central
bank to stop fighting markets and let the yuan's value fall at a closed door
meeting, citing previously undisclosed minutes of the gathering.
May 26 - Reuters (Elias Glenn): "Profit growth at China's industrial firms
slowed in April, in line with other data for the month which suggested the
economy may be losing steam again after picking up earlier in the year. China's
industrial firms made 502 billion yuan ($76.59 billion) in profits last month,
up 4.2% from the same period last year and compared with growth of 11.1% in
March..."
EM Bubble Watch:
May 26 - Bloomberg (Matthew Martin, Archana Narayanan and Deema Almashabi): "Banks
in Saudi Arabia are coming under fresh pressure over products that allow speculators
to bet against the kingdom's currency peg, according to people with knowledge
of the matter. The Saudi Arabia Monetary Agency has asked lenders to explain
why they are offering dollar-riyal forward structured products to customers
less than four months after the regulator banned options contracts that let
speculators place wagers on a currency devaluation, the people said. The authority,
known as SAMA, didn't reply to requests for comment. Hedge funds... have made
bets that the country's peg to the dollar will be broken as oil revenue plunges..."
May 24 - Bloomberg (Onur Ant): "Turkey's central bank cut its overnight lending
rate for a third month on Tuesday, calling the reduction a 'measured' step
toward simplifying its monetary policy. The bank lowered the rate by 50 basis
points to 9.5%..."
May 22 - Bloomberg (Kartik Goyal): "Massive, game-changing and overwhelming
were among the descriptions investors used for Indian Prime Minister Narendra
Modi's election victory in May 2014. Two years on, the slow pace of implementing
policy threatens to sap interest. The rupee is the worst performer among currencies
of the four biggest emerging markets this year. Indian sovereign bonds have
lagged peers in Brazil and Russia this quarter, after delivering the best returns
among the BRIC nations since the election win."
Japan Watch:
May 22 - Reuters (Stanley White): "Japanese manufacturing activity contracted
at the fastest pace in more than three years in May as new orders slumped...
putting fresh pressure on the government and central bank to offer additional
economic stimulus. The Markit/Nikkei Flash Japan Manufacturing Purchasing Managers
Index (PMI) fell to 47.6 in May..."
May 22 - Reuters (Tetsushi Kajimoto and Leika Kihara): "Japan's exports fell
sharply in April and manufacturing activity suffered the fastest contraction
since Prime Minister Shinzo Abe swept to power in late 2012, providing further
evidence that the premier's Abenomics stimulus policy is struggling for traction.
The bleak readings on the health of the world's third-largest economy follow
Japan's failure last week to win support from its global counterparts to weaken
the strong yen, which Tokyo fears could do further damage to the sputtering
economy... Data on Monday showed Japan's exports fell 10.1% in April from a
year earlier..."
ECB Watch:
May 24 - Bloomberg (Alessandro Speciale): "The European Central Bank warned
that risks of financial-market turmoil have increased amid slower growth in
emerging economies, weak bank profitability and the rise of populist movements
across the 19-nation euro region. 'A sharper-than-expected fall in Chinese
growth could well lead to a synchronized downturn across other emerging-market
economies, particularly commodity-exporting economies,' the ECB wrote in its
twice-yearly Financial Stability Review... 'Under such a scenario, the financial
systems of advanced economies may be challenged by a reduction in consumer
and business confidence, and renewed financial-market volatility potentially
intensified by sudden stops in or reversals of cross-border capital flows.'"
Europe Watch:
May 24 - Bloomberg (Laura J Keller, Stephen Morris and Macarena Munoz Montijano): "Deutsche
Bank AG Chief Executive Officer John Cryan said his bank has never had more
capital and could easily repay its debt many times over, responding to a credit-rating
cut by Moody's... The ratings company on Monday said the German lender faces
mounting challenges in carrying out its turnaround, and cut the bank's senior
unsecured debt metric one level to Baa2, two grades above junk. The firm's
long-term deposit rating fell to A3 from A2."
May 25 - Bloomberg (Thomas Penny, Patrick Donahue and Ian Wishart): "When
Germany hosted last year's Group of Seven summit, European leaders assured
President Barack Obama they were up to dealing with the crises on their doorstep.
Twelve months on, Europe's challenges have multiplied to an extent that questions
the wisdom of making the 6,000-mile trip to Japan for the G-7. From Brexit
to migration, home-grown terrorism to the destabilizing impact of surging populism,
Europe has seldom looked in more need of political leadership at home. Global
summits usually provide an opportunity for heads of government to play the
role of international dealmakers. But right now Prime Ministers David Cameron
and Matteo Renzi, Chancellor Angela Merkel and President Francois Hollande
are faced with coalescing crises -- and restive electorates -- that demand
attention in their own countries"
Brazil Watch:
May 23 - Bloomberg (Carla Simoes, Arnaldo Galvao and Mario Sergio Lima): "Brazil's
newly-appointed Budget Minister Romero Juca said he will take a leave of absence
after allegations surfaced that he wanted to obstruct the sweeping corruption
probe known as Carwash. Juca, the leader of Acting President Michel Temer's
political party, will return to his former job as senator and make room for
Dyogo Oliveira to take the helm of the Budget Ministry... The surprise announcement
on Monday afternoon capped a day of speculation about Juca's future in the
cabinet after he initially refused to step down. The dramatic departure highlights
the challenges facing Temer..."
Leveraged Speculation Watch:
May 25 - Bloomberg (Scott Deveau and Devin Banerjee): "The $2.9 trillion hedge-fund
industry may lose about a quarter of its assets in the next year as performance
slumps, said Tony James, Blackstone Group LP's billionaire president. 'It's
kind of a day of reckoning that we face here,' James said... 'There will be
a shrinkage in the industry and it will be painful. That's going to be pretty
painful for an awful lot of places.' The hedge-fund industry is having its
worst start to a year in performance and investor withdrawals since global
markets reeled after the financial crisis."
May 24 - Financial Times (John Authers and Mary Childs): "It was the shot
heard around the hedge fund world. After the New York City Employees' Retirement
System decided to cash all its investments inhedge funds, Letitia James, the
city's public advocate, delivered a message to the industry straight out of
Occupy Wall Street: 'Let them sell their summer homes and jets and return those
fees to their investors.' Hedge funds, she said last month, 'believe they can
do no wrong, even as they are losing money'... 'Let's face it: if you go back
to the 1990s, hedge funds delivered something very special: high returns or
very differentiated returns that you could not get elsewhere, and that is what
hedge fund investors have been looking for,' said Neil Chriss, founder of Hutchin
Hill Capital... 'The problem is, since the crisis, a lot of hedge funds have
not been delivering. Returns have been mediocre," he told the Milken Global
Conference..."
Geopolitical Watch:
May 27 - Reuters (David Lawder): "Corrosion-resistant steel from China will
face final U.S. anti-dumping and anti-subsidy duties of up to 450 percent under
the U.S. Commerce Department's latest clampdown on a glut of steel imports,
the agency said... The department also issued anti-dumping duties of 3% to
92% on producers of corrosion-resistant steel in Italy, India, South Korea
and Taiwan... China's Commerce Ministry said it was extremely dissatisfied
at what it called the 'irrational' move by the United States, which it said
would harm cooperation between the two countries."
May 26 - Reuters (Thomas Wilson and Kiyoshi Takenaka): "Group of Seven (G7)
leaders agree... on the need to send a strong message on maritime claims in
the western Pacific, where an increasingly assertive China is locked in territorial
disputes with Japan and several Southeast Asian nations. The agreement prompted
a sharp rejoinder from China, which is not in the G7 club but whose rise as
a power has put it at the heart of some discussions at the advanced nations'
summit in Ise-Shima, central Japan."
May 22 - Associated Press (Suzan Fraser and Geir Moulson): "German Chancellor
Angela Merkel told Turkey's president on Monday that Ankara must fulfill all
the European Union's conditions to secure visa-free travel for its citizens,
but Turkey responded that it would suspend agreements with the EU if the bloc
does not keep its promises. The EU says Turkey must narrow its definition of
'terrorist' and 'terrorist act.' The bloc is concerned that journalists and
political dissenters could be targeted. But Turkish president Recep Tayyip
Erdogan has said that is out of the question."
May 26 - MarketWatch (Nicole Perlroth and Michael Corkery): "Security researchers
have tied the recent spate of digital breaches on Asian banks to North Korea,
in what they say appears to be the first known case of a nation using digital
attacks for financial gain. In three recent attacks on banks, researchers working
for the digital security firm Symantec said, the thieves deployed a rare piece
of code that had been seen in only two previous cases: the hacking attack at
Sony Pictures in December 2014 and attacks on banks and media companies in
South Korea in 2013. Government officials in the United States and South Korea
have blamed those attacks on North Korea..."
I just wrapped up 25 years (persevering) as a "professional bear." My lucky
break came in late-1989, when I was hired by Gordon Ringoen to be the trader
for his short-biased hedge fund in San Francisco. Working as a short-side
trader, analyst and portfolio manager during the great nineties bull market
- for one of the most brilliant individuals I've met - was an exciting, demanding
and, in the end, a grueling and absolutely invaluable learning experience.
Later in the nineties, I had stints at Fleckenstein Capital and East Shore
Partners. In January 1999, I began my 16 year run with PrudentBear, working
as strategist and portfolio manager with David Tice in Dallas until the bear
funds were sold in December 2008.
In the early-nineties, I became an impassioned reader of The Richebacher Letter.
The great Dr. Richebacher opened my eyes to Austrian economics and solidified
my lifetime passion for economics and macro analysis. I had the good fortune
to assist Dr. Richebacher with his publication from 1996 through 2001.
Prior to my work in investments, I worked as a treasury analyst at Toyota's
U.S. headquarters. It was working at Toyota during the Japanese Bubble period
and the 1987 stock market crash where I first recognized my love for macro
analysis. Fresh out of college I worked as a Price Waterhouse CPA. I graduated
summa cum laude from the University of Oregon (Accounting and Finance majors,
1984) and later received an MBA from Indiana University (1989).
By late in the nineties, I was convinced that momentous developments were
unfolding in finance, the markets and policymaking that were going unrecognized
by conventional analysis and the media. I was inspired to start my blog,
which became the Credit Bubble Bulletin, by the desire to shed light on these
developments. I believe there is great value in contemporaneous analysis,
and I'll point to Benjamin Anderson's brilliant writings in the "Chase Economic
Bulletin" during the Roaring Twenties and Great Depression era. Ben Bernanke
has referred to understanding the forces leading up to the Great Depression
as the "Holy Grail of Economics." I believe "The Grail" will instead be
discovered through knowledge and understanding of the current extraordinary
global Bubble period.
Disclaimer: Doug Noland is not a financial advisor nor is he providing investment
services. This blog does not provide investment advice and Doug Noland's comments
are an expression of opinion only and should not be construed in any manner
whatsoever as recommendations to buy or sell a stock, option, future, bond,
commodity or any other financial instrument at any time. The Credit Bubble
Bulletins are copyrighted. Doug's writings can be reproduced and retransmitted
so long as a link to his blog is provided. | {
"pile_set_name": "Pile-CC"
} |
Saturday Night Live (season 22)
The twenty-second season of Saturday Night Live, an American sketch comedy series, originally aired in the United States on NBC between September 28, 1996, and May 17, 1997.
This season is notable for the host selection. Seven of the 20 hosts were former cast members. They included Dana Carvey, Robert Downey, Jr., Phil Hartman, Chris Rock, Martin Short, Chevy Chase and Mike Myers. This would mark Chase's final time hosting before getting banned (returning much later for numerous guest appearances).
Cast
Many changes happened before the start of the season. David Koechner and Nancy Walls were both let go after one season with the show. David Spade left the show on his own terms.
Ana Gasteyer and Tracy Morgan were hired to replace David Koechner and Nancy Walls.
Chris Kattan was promoted to repertory status, while Colin Quinn and Fred Wolf remained as featured players.
This would be the final season for Mark McKinney and Fred Wolf. Wolf would leave his position as featured player and co-head writer after the season's first three episodes. Also, this is the final season to show the Dolby Surround and NBC captioning during the opening montage.
Cast roster
Repertory players
Jim Breuer
Will Ferrell
Ana Gasteyer
Darrell Hammond
Chris Kattan
Norm Macdonald
Mark McKinney
Tim Meadows
Tracy Morgan
Cheri Oteri
Molly Shannon
Featured players
Colin Quinn
Fred Wolf (final episode: October 19, 1996)
bold denotes Weekend Update anchor
Writers
Robert Carlock and Stephen Colbert join the writing staff in this season.
Episodes
References
22
Category:Saturday Night Live in the 1990s
Category:1996 American television seasons
Category:1997 American television seasons
Category:Television programs directed by Beth McCarthy-Miller | {
"pile_set_name": "Wikipedia (en)"
} |
Q:
Attempt to invoke virtual method 'android.content.Context android.support.v4.app.FragmentActivity.getApplicationContext()' on a null object reference
Following is my code for my fragment, i get the above error of null exception
/**
* Created by USer on 09-04-2016.
*/
public class FeaturedFragment extends android.support.v4.app.Fragment {
private List url;
private SliderLayout sliderLayout;
private GridView gridView;
private int firstVisiblepos;
AppnextAPI api;
@Nullable
@Override
public View onCreateView(LayoutInflater inflater, ViewGroup container, Bundle savedInstanceState) {
View rootView = inflater.inflate(
R.layout.featured, container, false);
url = new ArrayList<String>();
url.add("http://192.168.5.51/Wallpapers/Autumn.jpg");
url.add("http://192.168.5.51/Wallpapers/Tree.jpg");
url.add("http://192.168.5.51/Wallpapers/Flower.jpg");
url.add("http://192.168.5.51/Wallpapers/Lion.jpg");
api = new AppnextAPI(getActivity(), "my id");
sliderLayout = (SliderLayout) rootView.findViewById(R.id.slider);
gridView = (GridView) rootView.findViewById(R.id.gridView);
ThemeShowcase theme = new ThemeShowcase();
theme.execute("getThemes");
for (int i = 0; i < url.size(); i++) {
TextSliderView textSliderView = new TextSliderView(getActivity().getApplicationContext());
textSliderView.image((String) url.get(i));
sliderLayout.addSlider(textSliderView);
}
sliderLayout.setDuration(4000);
sliderLayout.setPresetTransformer(SliderLayout.Transformer.Stack);
return rootView;
}
private class ThemeShowcase extends AsyncTask<String, Integer, ArrayList<ThemeModel>> {
private final String NAMESPACE = "http://tempuri.org/";
private final String URL = "http://192.168.5.51/WebApplication/WebService.asmx";
private final String SOAP_ACTION = "http://tempuri.org/";
private String responseString;
private ArrayList model = null;
private ThemeModel dummy;
@Override
protected void onPreExecute() {
super.onPreExecute();
model = new ArrayList<ThemeModel>();
}
@Override
protected ArrayList<ThemeModel> doInBackground(String... params) {
try {
SoapObject request = new SoapObject(NAMESPACE, params[0]);
PropertyInfo sayHelloPI = new PropertyInfo();
sayHelloPI.setName("page");
sayHelloPI.setValue("1");
sayHelloPI.setType(Integer.class);
request.addProperty(sayHelloPI);
SoapSerializationEnvelope envelope = new SoapSerializationEnvelope(
SoapEnvelope.VER11);
envelope.dotNet = true;
envelope.setOutputSoapObject(request);
HttpTransportSE androidHttpTransport = new HttpTransportSE(URL);
androidHttpTransport.call(SOAP_ACTION + params[0], envelope);
SoapPrimitive response = (SoapPrimitive) envelope.getResponse();
responseString = response.toString();
if (!responseString.equalsIgnoreCase("Error occured")) {
JSONArray array = new JSONArray(responseString);
for (int i = 0; i < array.length(); i++) {
JSONObject objct = array.getJSONObject(i);
dummy = new ThemeModel();
dummy.preview = objct.getString("Preview");
dummy.name = objct.getString("Name");
model.add(dummy);
}
}
} catch (Exception e) {
model = null;
return model;
}
return model;
}
@Override
protected void onPostExecute(ArrayList<ThemeModel> model) {
if(model!=null) {
gridView.setAdapter(new ImageAdapter(getActivity().getApplicationContext(), model));
firstVisiblepos = gridView.getFirstVisiblePosition();
}else{
try {
Toast.makeText(getActivity().getApplicationContext(), "Site Unreachable", Toast.LENGTH_LONG).show();
}catch (Exception e){
Log.d("MyApp","exception");
}
}
}
}
}
here's my image adapter
public class ImageAdapter extends BaseAdapter implements View.OnClickListener{
private Context context;
private LayoutInflater inflater;
private ArrayList<ThemeModel> model;
public ImageAdapter(Context context,ArrayList<ThemeModel> model) {
this.inflater = LayoutInflater.from(context);
this.context = context;
this.model = model;
}
@Override
public int getCount() {
return model.size();
}
@Override
public Object getItem(int position) {
return null;
}
@Override
public long getItemId(int position) {
return 0;
}
@Override
public View getView(int position, View convertView, ViewGroup parent) {
convertView = inflater.inflate(R.layout.custom_item,null);
CardView cardView = (CardView)convertView.findViewById(R.id.cardView);
cardView.setOnClickListener(this);
ImageView imageView = (ImageView)convertView.findViewById(R.id.imageView);
final ProgressBar progressBar = (ProgressBar)convertView.findViewById(R.id.progressbar);
TextView textView = (TextView)convertView.findViewById(R.id.contentName);
ImageButton imageButton = (ImageButton)convertView.findViewById(R.id.downloadButton);
textView.setText(model.get(position).getName());
Picasso.with(context).load(model.get(position).getPreview()).into(imageView, new Callback() {
@Override
public void onSuccess() {
progressBar.setVisibility(View.GONE);
}
@Override
public void onError() {
}
});
return convertView;
}
@Override
public void onClick(View v) {
}
}
i keep getting force close on below line
gridView.setAdapter(new ImageAdapter(getActivity().getApplicationContext(), model));
the error is
java.lang.NullPointerException: Attempt to invoke virtual method 'android.content.Context android.support.v4.app.FragmentActivity.getApplicationContext()' on a null object reference
i have tried using getActivity(),getContext() etc but none of them work
A:
The reason is because when you call getActivity() in the onPostExecute(), the Fragment is already detached from the Activity (for example, when the AsyncTask is executing, user click back button to exit the activity), so getActivity() would be null.
The solution is before getActivity(), check isAdded() is true or not, if not true, that means the fragment is already detached, call to getActivity() will return null.
Remember in the AsyncTask, everywhere before you call getActivity(), you'd better to check isAdded() again, because user may exit the activity at anytime during the AsyncTask is executing.
| {
"pile_set_name": "StackExchange"
} |
Effects of selection for postweaning gain on testicular function in mice.
Changes in testicular and epididymal function and selected endocrine organ size were examined in a line of mice selected for rapid postweaning gain (M16) and in reciprocal crosses with an unselected pedigree control line (ICR). The larger body weight of the M16 line was accompanied by larger testes, epididymides, seminal vesicle, pituitary, thyroid and adrenal weights (P smaller than .01) although the testes, epididymides, seminal vesicle and adrenal weights of M16 mice, expressed per gram body weight, actually decreased (P smaller than .01) relative to the ICR line. Testicular and epididymal sperm reserves were higher in M16 mice but the difference was not significant. However, when adjusted for gland size, testicular and epididymal sperm reserves were lower in the M16 line (P smaller than .01). Absolute and relative weights of testes, epididymides and pituitary were larger (P smaller than .01) in M16 male times ICR female crosses than in ICR male times M16 female crosses. Although testicular and epididymal sperm reserves were higher in M16 male times ICR female males the reciprocal difference was significant only for testicular sperm (P smaller than .05). Heterotic effects were significant for both absolute and relative weights of testes, epididymides (P smaller than.01), pituitary (P smaller than .05) and relative weight of siminal vesicles (P smaller than .05). Although percent heterosis was 8.5 for testicular and epididymal sperm reserves, significant heterotic effects were found only for epididymal sperm (P smaller than .05). | {
"pile_set_name": "PubMed Abstracts"
} |
Small organic and metal-containing molecules (MW \< 1000) can catalyse synthetically useful reactions with the high levels of stereo-selectivity typically associated with macromolecular enzymatic catalysts. Whereas enzymes are generally understood to accelerate reactions and impart selectivity by *stabilising* specific transition structures through networks of cooperative interactions, enantioselectivity with chiral, small molecule catalysts is typically rationalised by the steric *destabilisation* of all but one dominant pathway. However, it is increasingly apparent that stabilising effects play an important role in small-molecule catalysis as well, although the mechanistic characterisation of such systems is rare. Here it is shown that arylpyrrolidino amido thiourea catalysts catalyse the enantioselective nucleophilic ring opening of episulfonium ions by indoles. Evidence is provided for selective transition state stabilisation of the major pathway by the thiourea catalyst in the rate- and selectivity-determining step. Enantioselectivity is achieved through a network of attractive anion binding, cation-π, and hydrogen bonding interactions between the catalyst and the reacting components in the transition structure assembly.
Multi-functional urea and thiourea derivatives have been shown to promote enantioselective reactions of cationic species in non-polar media by binding the corresponding counteranion through hydrogen bonding,^[@R1],[@R2],[@R3],[@R4]^ with selectivity imparted through a combination of electrostatic association and additional noncovalent interactions that differentiate the diastereomeric transition structures leading to the product enantiomers.^[@R5],[@R6],[@R7]^ We sought to extend the anion-binding catalysis concept to episulfonium ions, highly reactive electrophilic species that readily undergo diastereospecific bond-forming reactions with nucleophiles.^[@R8],[@R9],[@R10],[@R11]^ Recently, Toste and coworkers demonstrated enantioselective catalysis of the addition of alcohols to episulfonium ions using a chiral phosphoric acid catalyst.^[@R12]^ On the basis of our previous work in anion-binding catalysis, we envisioned that a (thio)urea could serve as a suitable host for an in situ formed episulfonium ion through interactions with the counteranion ([Figure 1](#F1){ref-type="fig"}). High enantioselectivity might be achieved if additional interactions between the catalyst and episulfonium intermediate could be incorporated to differentially stabilise the diastereomeric pathways. This hypothesis was investigated in the context of a Friedel--Crafts-type indole alkylation reaction.^[@R13]^
Results and Discussion {#S1}
======================
A. Reaction Methodology Development {#S2}
-----------------------------------
Preliminary efforts to identify a suitable episulfonium ion precursor revealed that a relatively non-nucleophilic leaving group was required in order to achieve the desired reactivity. Ultimately, we found that stable trichloroacetimidates (TCA) of type **1a**^[@R12]^ were particularly useful substrates (eq. 1), undergoing protonolysis and substitution with a variety of strong Brønsted acids to form a *meso*--episulfonium ion with a counteranion that is readily varied based on the identity of the acid employed.
A wide variety of chiral urea and thiourea derivatives was evaluated in the model reaction ([Table 1](#T1){ref-type="table"}). Only arylpyrrolidine-derived thioureas of type **3** were found to induce reactivity above the background rate of **1a** and acid alone. A broad screen of Brønsted acids revealed a pronounced counterion effect. In conjunction with thiourea **3b**, mineral acids with a nucleophilic counter-anion, such as HCl, produced only trace amount of the desired indole addition product **2a** (entry 1), with the corresponding chloride addition product predominating. In contrast, sulfonic acid co-catalysts afforded **2a** in useful yields and varying levels of enantioselectivity, with 4-nitrobenzenesulfonic acid (4-NBSA) providing the most promising result (entry 5). The identity of the aromatic substituent on the pyrrolidino amide portion of the catalyst was also found to exert a profound effect on reaction enantioselectivity (entries 5, 7-12). Catalyst **3a**, lacking an aryl group, induced little rate acceleration above the background reaction (entry 6) and afforded nearly racemic product. In contrast, catalyst **3c-3g** bearing more extended aromatic substituents proved more enantioselective than catalyst **3b**. Correlation between ee and either the electronic properties of the aryl substituents or the polarisability of the aromatic ring has been noted in other reactions using this family of catalysts.^[@R2],[@R6],[@R14]^ However, in the present case no such straightforward relationship was observed. Instead, ee was observed to improve upon expanding the aryl group from phenyl to phenanthryl (entries 7-10), and then to descrease slightly with more expansive aryl substituents (entries 11-12). Urea catalyst **4e** induced only marginally lower ee than its thiourea counterpart (entries 10 vs 13), indicating that any mechanism wherein the thiourea sulfur is engaged productively as a Lewis base catalyst is not operative.^[@R15],[@R16],[@R17],[@R18]^
A variety of substrate combinations was evaluated in order to define the scope as well as gain insight into the mechanism of the reaction ([Table 2](#T2){ref-type="table"}). Substrates bearing electronically and sterically diverse sulfur substituents (R^2^) underwent enantioselective reactions (entries 1-9), with *S*-benzyl-substituted derivatives affording highest ee's (entries 1 & 7). Electron potential maps calculated using DFT showed that the benzylic protons in the *S*-benzyl episulfonium ions bear a substantial amount of partial positive charge, and this may serve to enhance attractive interactions between the cationic intermediate and an electronegative functionality on the catalyst (*vide infra*). Various indole derivatives bearing electron-donating and -withdrawing substituents at the 2-, 4-, 5- or 6-positions all underwent the addition reaction with high levels of enantioselectivity (entries 10-16). In sharp contrast, *N*-methyl indole provided the desired product **2p** with moderate yield and in almost racemic form (entry 17). This suggested that the indole N-H motif may be involved in a key interaction during the ee-determining transition state (*vide infra*). Benzotriazole also underwent the addition reaction, forming a C-N bond with synthetically useful ee (entry 18). Less nucleophilic heterocycles (i.e., π-nucleophiles with Mayr nucleophilicity parameters *N* \< 4)^[@R19]^ proved unreactive. Variation of the substituents on the carbon backbone of the electrophile revealed that aryl groups with *meta*- and *ortho*- functionalities were compatible (entries 19-22); substrates bearing a *para*-substituent, regardless of its steric and electronic properties, resulted in substantially lower enantioselectivity (entries 23-26). Ongoing computational studies suggested that in the transition state leading to the major enantiomeric product, one of the *para*-C--H bonds is engaged in an attractive, electrostatic interaction with the thiourea-bound sulfonate. We reasoned that the lack of this interaction in the cases with *para*-substituted substrates might result in a less well-organized transition structure and reduced selectivity. Finally, three different acetimidate leaving groups displayed essentially the same reactivity and enantioselectivity, suggesting that the leaving group is not directly involved in the ee-determining step (entries 28-30).
B. Determination of the Rate- and Enantio- Determining Step {#S3}
-----------------------------------------------------------
Thiourea derivatives of type **3** bearing specific arylpyrrolidino residues have been identified as highly enantioselective catalysts for nucleophilic additions to a remarkable variety of cationic electrophilic intermediates, including oxocarbenium ions,^[@R2]^ acyliminium ions,^[@R6]^ acylpyridinium ions,^[@R20]^ and now episulfonium ions. Elucidation of the mechanisms that underlie catalytic activity and stereoinduction by these thioureas may potentially serve as a foundation for new reaction discovery and provide broader insights into cooperative non-covalent pathways. We therefore undertook a detailed experimental and computational investigation of the indole addition to episulfonium ions promoted by **3e** and related catalysts. On the basis of the qualitative observations described above and previous studies involving thiourea anion-binding pathways, a simple catalytic cycle for the reaction of indoles with **1** mediated by **3e** can be advanced ([Figure 2](#F2){ref-type="fig"}). The absence of dependence of enantioselectivity on the identity of the acetimidate group suggests that the reaction begins with protonation of the trichloroacetimidate substrate, followed by episulfonium ion formation in a step that may or may not be under the influence of the thiourea catalyst. A series of ^1^H NMR studies of pre-formed episulfonium ion derivatives^[@R17]^ revealed that the episulfonium sulfonate most likely exists as a covalent adduct both in the presence or absence of the thiourea catalyst, so an endothermic ionization to the episulfonium ion complex is presumably taking place before addition of the indole nucleophile. Finally re-aromatisation to form the product and regenerate the acid closes the catalytic cycle. In the thiourea-promoted pathway, the chiral catalyst must therefore induce enantioselectivity through association with the charged intermediates and transition structures, indicated in [Figure 2](#F2){ref-type="fig"} as taking place via direct binding to the sulfonate counterion.
In order to identify the rate- and enantioselectivity-determining step in the catalytic mechanism, reaction progress kinetic analysis^[@R21]^ of the reaction employing substrate **1a**, indole, thiourea **3e**, and 4-NBSA in toluene at 0 °C was conducted with in situ IR spectroscopy.^[@R22],[@R23]^ Using reaction rates measured over 10% to 60% conversion with "different excess" experiments,^[@R22]^ the empirical rate equations were determined for both the racemic reaction catalysed by only 4-NBSA ([equation 3](#FD1){ref-type="disp-formula"}) and the asymmetric reaction co-catalysed by 4-NBSA and thiourea ([equation 4](#FD2){ref-type="disp-formula"}). $$r_{rac} = d\lbrack 1\mathbf{a}\rbrack/dt = k_{rac}{\lbrack 4{NBSA}\rbrack}_{T}\lbrack{indole}\rbrack$$ $$r_{asym} = d\lbrack 1\mathbf{a}\rbrack/dt = k_{asym}{\lbrack 4{NBSA}\rbrack}_{T}{\lbrack 3\mathbf{e}\rbrack}_{T}\lbrack{indole}\rbrack$$
Here, *k*~rac~ is the second-order rate constant for the racemic reaction, and *k*~asym~ is the third-order rate constant for the asymmetric reaction, and \[4-NBSA\]~T~ and \[**3e**\]~T~ are the total initial concentrations of acid and thiourea, respectively.
The rate of the asymmetric reaction was accelerated by the chiral thiourea catalyst relative to the reaction catalysed by 4-NBSA alone. For instance, at 273 K, \[**3e**\]~T~ = 50 mmol/L, *r*~asym~/*r*~rac~ at 10% conversion of **1a** is 43.4 ± 5.0. This rate acceleration corresponds to a lowering of the free energy of activation of the reaction by **3e** by 2.0 ± 0.1 kcal/mol.
The 0^th^-order rate dependence on **1a** and first-order rate dependence on 4-NBSA indicate that quantitative protonation of the substrate occurs under the reaction conditions prior to the rate-determining step (p*K*~a\ (4-NBSA)~ \~ −7, p*K*~a\ (**1a**)~ \~ 2).^[@R24]^ In support of this conclusion, treatment of substrate **1a** with 1 equiv of 4-NBSA resulted in instantaneous, complete consumption of **1a** and concomitant, quantitative formation of trichloroacetamide (the by-product generated during episulfonium ion formation) as determined by in-situ IR spectroscopy. The first-order dependence on indole in both the reaction catalysed by 4-NBSA alone or by 4-NBSA/**3e** reveals that indole is present in the rate-determining transition structure and that episulfonium•4-nitrobenzenesulfonate (existing predominantly as the covalent adduct) is the resting state of the substrate in the reaction. The kinetic data are consistent with the reaction with indole involving either addition or reversible addition followed by slow re-aromatisation as the rate-determining step ([Figure 2](#F2){ref-type="fig"}).
To distinguish between these two possibilities, linear free energy relationship and kinetic isotope effect studies were carried out. In the racemic reaction catalysed by 4-NBSA alone, a linear correlation was observed between reaction rate and Mayr's nucleophilicity parameter *N* for five different 5-substituted indoles (log(*k*~rac~) vs. *s*~N~*N*, R^2^ = 0.997), consistent with the indole addition step resulting in nucleophilic ring opening of episulfonium ion being the rate-limiting step.^[@R25]^ A correlation between indole nucleophilicity and rate was also obtained in the thiourea-catalysed reaction (log(*k*~asym~) vs. *s*~N~*N*, R^2^ = 0.757). As discussed below, a strict linear correlation is not observed in this case because the Brønsted acidity of the indole N-H group also influences reaction rate in the thiourea-catalysed reaction (see Section C2). Evaluation of 3-deuterioindole in the thiourea-catalysed addition reaction revealed a very small effect of isotopic substitution (*k*~H~/*k*~D~ = 0.93 ± 0.12). This rules out re-aromatisation as the rate-determining step, which would be expected to display a significant primary isotope effect (*k*~H~/*k*~D~ \> 2.5),^[@R26]^ and is fully consistent with rate-determining indole addition. It can be concluded that indole addition is enantio-determining as well, since the product's stereogenic centers are generated in this rate-determining step.^[@R27]^
C. Elucidation of the Catalyst--Substrate Interactions in the Enantio-Determining Step {#S4}
--------------------------------------------------------------------------------------
While the kinetic studies served to define the stoichiometry of the transition structure in the rate- and ee-determining addition of indoles to **1**, they do not provide any direct insight into the specific manner by which the thiourea catalyst induces rate acceleration and enantioselectivity. This proved attainable, however, through the series of structure-reactivity and structure-enantioselectivity studies detailed below.
### C.1 Thiourea Dual Hydrogen Bond Donation to the Sulfonate Anion {#S5}
Anion-binding catalysis has been recognised as the primary mode of substrate activation in a variety of asymmetric reactions involving H-bond donors.^[@R1]^ In studies relevant to the system described here, sulfonate ion association to urea or thiourea derivatives via dual hydrogen bond donation interactions has been identified in both binding and reactivity studies.^[@R28],[@R29]^ To test whether such sulfonate binding is operative in the current reaction, model binding studies and catalyst structure--activity studies were conducted. Titration of solutions of thiourea **3e** in *d*~8~-toluene with dibenzylmethylsulfonium triflate \[(Bn~2~MeS)^+^(OTF)^−^\] (**5**) revealed formation of a 1:1 complex as determined by ^1^H NMR. Resonances assigned to each of the thiourea N-H protons sharpened and shifted downfield upon complexation, consistent with a dual hydrogen bonding interaction.^[@R29],[@R30]^ Perturbations to the chiral catalyst that diminished its ability to act as an H-bond donor, either by reduction of its acidity through substituent effects or by excision of one of the donor groups, led to strong or complete decreases in reactivity and enantioselectivity in the indole addition reaction (see [Supplementary Information](#SD2){ref-type="supplementary-material"}, Section 4). These data, taken together with the strong ee-dependence on the sulfonate counterion of the Brønsted acid ([Table 1](#T1){ref-type="table"}) suggests strongly that the thiourea--sulfonate interaction is a key element in the mechanism for catalysis and stereoinduction.
### C.2 Hydrogen Bonding Interaction with the Indole N-H {#S6}
As noted above, a striking difference in enantioselectivity was observed between *N*-H indole and *N*-methyl indole analogs in the addition reaction (93% vs 3% ee using catalyst **3e** in additions to **1a**). This suggests an important organisation role of the indole N-H in the stereoinduction mechanism, likely through hydrogen bonding to a Lewis basic functionality on the catalyst. To define the catalyst-indole interactions, a structure-reactivity and structure-enantioselectivity relationship study was undertaken with a series of π-nucleophiles ([Figure 3a](#F3){ref-type="fig"}). In general, the absence of an N-H motif in a (1,3) relationship with the reactive nucleophilic site leads to very low levels of rate acceleration and enantioselectivity (entries 1-2 vs. entries 3-5).
To further probe the role of H-bonding interactions between indole nucleophile and catalyst, various 5-substituted indoles were evaluated in competition experiments under both racemic and thiourea-catalysed reaction conditions. The degree of rate acceleration induced by thiourea **3e** was found to be linked directly to the acidity of the indoles, and a linear correlation between log(*k*~asym~/*k*~rac~) and the p*K*~a~ of indoles was observed ([Figure 3b](#F3){ref-type="fig"}). Therefore, in the presence of thiourea, the rate of the reaction is correlated not only to the intrinsic nucleophilicity of the indole, but also to its H-bond donor properties. No correlation was observed between reaction enantioselectivity and the acidity of the indoles, however, indicating that this interaction is likely to exist to a similar degree in both the major and the minor pathways. The kinetic data are thus consistent with general base activation of indole through an indole N-H--catalyst hydrogen bonding interaction in the rate-determining addition to episulfonium ions.^[@R31],[@R32],[@R33],[@R34]^ Catalyst **3e** possesses few Lewis basic functionalities -- namely the thiourea, the amide, and perhaps the extended arene substituent -- and therefore the possible catalyst H-bond acceptor sites are limited in number. The similar reactivity and enantioselectivity displayed with urea **4e** and thiourea **3e** would appear to rule out a direct role of the thiourea sulfur atom. As discussed below, the extended aromatic plays a key role that can be tied to interactions with the episulfonium ion. By this simple process of elimination, we therefore propose that the amide oxygen is the most likely H-bond acceptor site for activation of the indole.^[@R35],[@R36]^ Consistent with this hypothesis, catalyst **3a** was found to be more reactive than the corresponding thioamide analog in the model reaction (eq 2). In addition, the reaction catalyzed by **3a** is ca. 4 times as fast as the reaction with Schreiner's thiourea \[1,3-bis(3,5-bis(trifluoromethyl)phenyl)thiourea\], which is a stronger H-bond donor but lacks an amide appendage.
### C.3 Stabilisation of the Cationic Transition State Through Cation-π Interactions {#S7}
The strong correlation between reaction enantioselectivity and the identity of the arene on the catalyst suggests a direct role of the extended π-system in the mechanism of stereoinduction. In principle, this arene effect may be due primarily either to acceleration of the major pathway through transition state stabilisation, or to inhibition of pathways leading to the minor enantiomer through destabilising interactions. This question was addressed through kinetic analysis of the reaction, taking advantage of the fact that the indole addition step is both rate- and ee- determining. The rate constant corresponding to the major pathway (*k*~asym,major~) could be deduced for catalysts **3a-3g** from in situ IR-based kinetic measurements combined with er (enantiomeric ratio) determinations. A strong correlation between this rate and reaction enantioselectivity was observed, with plots of ln(*k*~asym,major~) vs ln(er) providing a good linear fit ([Figure 4a](#F4){ref-type="fig"}). This provides unambiguous evidence that enantioselectivity increases due to variation of the aryl component of the catalyst **3** are indeed tied to stabilisation of the major transition structure.^[@R14]^ The rate of the pathway leading to the minor enantiomer also displays a linear, positive correlation with reaction er, indicating that the minor transition structure is also stabilised selectively by the more enantioselective catalysts, albeit to a substantially lesser extent.
Insight into the nature of the transition state stabilising interactions that may be at play was provided through spectroscopic analysis of thiourea derivatives **3a** and **3e** complexed to a sulfonium ion model system. The dibenzylmethylsulfonium ion triflate **5** was selected for these studies because episulfonium sulfonate could not be examined directly (see section B), and the cation in **5** was found by computational methods to have a very similar charge distribution to the episulfonium ion ([Figure 4 c](#F4){ref-type="fig"}). With thiourea **3e**, the resonances of the benzylic and the methyl protons of **5** underwent a significant upfield shift (0.6-0.8 ppm) upon formation of the 1:1 complex ([Figure 4b](#F4){ref-type="fig"}).^[@R37]^ In contrast, the chemical shift of those protons was bearly perturbed to any measurable extent (Δδ \< 0.05 ppm) upon complexation of **5** with the thiourea derivative **3a**, which lacks an aryl substituent. This points to an attractive cation-π interaction between the π-face of the arene in catalyst **3e** and the sulfonium ion in the model system.^[@R38],[@R39],[@R40],[@R41],[@R42]^ Such interaction in the transition structure of the indole addition to episulfonium ions could underlie the observed enantioselectivity effects, as the cation-π interaction would be expected to increase in magnitude with more extended aromatic substituents.^[@R43],[@R44]^ Based on the kinetic and enantioselectivity data, we therefore propose that the difference in the strength of the cation-π interaction between the major and minor pathways lies at the origin of the observed high reaction enantioselectivity.^[@R6],[@R14],[@R45]^ It should be noted that on the basis of polarisability effects alone, which are known to correlate directly with cation-π binding ability,^[@R46]^ the most expansive aryl-substituted catalysts **3f** and **3g** might be expected to be most enantioselective. However, as noted above ([Table 1](#T1){ref-type="table"}) these two thiourea derivatives afford slightly lower ee's in the model reaction than the smaller, phenanthryl catalyst **3e**. The reason for the lack of an exact correlation between the polarisability of the aromatic substituent and reaction enantioselectivity has not yet been established; however, it seems reasonable to expect that any number of minor steric or conformational factors could attenuate the ability of the largest substituents to engage fully in the stabilising cation-π interaction.
Taken together, the data presented above allow construction of a detailed mechanistic model for the enantioselective reaction, wherein rate-acceleration and enantioselectivity are induced by the thiourea catalyst through a network of attractive non-covalent interactions. In particular, we propose that the transition structure for the rate-determining addition of indole to the episulfonium ion is stabilised by a combination of anion binding of the thiourea to the sulfonate, general base activation of the indole via a catalyst amide--indole N-H interaction, and a cation-π interaction between the arene of the catalyst and the benzylic protons of the episulfonium ion ([Figure 5](#F5){ref-type="fig"}). We anticipate that characterisation of these enzyme-like non-covalent stabilising elements with small molecule catalysts such as **3e** may enable the future design and application of such biomimetic strategies in organic asymmetric synthesis.
Methods {#S8}
=======
General procedure for thiourea 3e-catalysed nucleophilic ring opening of episulfonium ions with indole derivatives {#S9}
------------------------------------------------------------------------------------------------------------------
An oven-dried 1.5 dram vial was charged with substrate **1** (0.05 mmol, 1.0 equiv), **3e** (3.2 mg, 0.0050 mmol, 0.10 equiv), indole (11.7 mg, 0.10 mmol, 2.0 equiv) and 4Å molecular sieves (25 mg, powder, activated) under an atmosphere of N~2~. The vial was cooled to −30 °C, and toluene (1 mL) was added with stirring. Once the reactants and catalyst were fully dissolved, the mixture was cooled to −78 °C, and solid 4-NBSA (0.7 mg, 0.0035 mmol, 0.07 equiv) was added at once against a counterflow of N~2~. The resulting solution was stirred at −30 °C and the progress of the reaction was monitored by thin layer chromatography (TLC) (see [Supplementary Information](#SD2){ref-type="supplementary-material"}, Section 3). When the progress of the reaction was determined to be complete, triethylamine (\~10 μL) was added at −30 °C. The resulting mixture was applied directly to a pipette column containing 4-5 cm of silica gel, and product was isolated by eluting hexanes/ethyl acetate (20:1 to 10:1) and solvent removal.
**The Supplementary Information contains:** detailed experimental procedures, synthesis of substrates and catalysts, characterisation data for all new compounds, procedures and data for mechanistic investigations (including reaction progress kinetic analysis, linear free energy relationship studies with Mayr's reactivity parameters, kinetic isotope effect studies, model binding studies by ^1^H NMR, and other experimental kinetic studies). Crystallographic information for compounds **2b, 2g** and **2q** have been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition numbers (CCDC 862750, 862751 and 862752, respectively).
Supplementary Material {#S10}
======================
This work was supported by the NIGMS (P50 GM-69721 and RO1 GM-43214) and by a predoctoral fellowship to S.L. from Eli Lilly. We thank Dr. Robert Knowles, Dr. Katrien Brak and Prof. Dr. Herbert Mayr for helpful discussions, Adam Brown, Dr. Dan Lehnherr and Dr. Alan Hyde for the use of catalysts, and Dr. Shao-Liang Zheng for crystal structure determinations.
Author Contributions
S.L. conducted the experiments; S.L. and E.N.J. wrote the manuscript; E.N.J. guided the research.
Supplementary information and chemical compound information accompany this paper at [www.nature.com/naturechemistry](www.nature.com/naturechemistry).
The authors declare no competing financial interests.
{#F1}
{#F2}
{ref-type="supplementary-material"}, Section 14 for detailed experimental procedure and data analysis). Error bars reflect the range of experimental data from 2-3 individual measurements, and the line represents the least-squares fit.](nihms399652f3){#F3}
{ref-type="disp-formula"} & [4](#FD2){ref-type="disp-formula"}) and the following equations: (a) *r*~asym~ = *r*~asym,major~ + *r*~asym,minor~, (b) er = *r*~asym,major~/*r*~asym,minor~. Lines represent least-squares fits. **b**. ^1^H NMR binding study of thiourea and **5** in *d*~8~-toluene, showing attractive interactions between the aromatic group in **3e** and the a-protons in **5**. The resonances of the benzylic protons and the methyl protons in **5** are labled with blue and green dots, respectively. In the two bottom spectra, the methyl resonance overlaps with the solvent peak, but can be identified when zoomed-in **c**. Electrostatic potential maps for fully optimized structures (B3LYP/6-31G(d)) of the episulfonium ion derived from **1a** and the sulfonium ion in **5**, revealing a similar distribution of positive charge over the benzylic protons. Negative potentials are shown in red and positive potentials in blue.](nihms399652f4){#F4}
{#F5}
######
Reaction optimisation.[a](#TFN1){ref-type="table-fn"}
---- -------- ------------ ---- -----
1 **3b** HCl 10 5
2 **3b** HOTf 73 32
3 **3b** FSO~3~H 78 19
4 **3b** 2,4-diNBSA 79 63
5 **3b** 4-NBSA 72 73
6 -- 4-NBSA 7 n/a
7 **3a** 4-NBSA 16 12
8 **3c** 4-NBSA 84 84
9 **3d** 4-NBSA 80 85
10 **3e** 4-NBSA 93 93
11 **3f** 4-NBSA 91 91
12 **3g** 4-NBSA 97 88
13 **4e** 4-NBSA 98 92
---- -------- ------------ ---- -----
Optimisation reactions were performed on 0.05 mmol scale.
Isolated yields of material purified chromatographically.
Enantiomeric excesses (ee's) determined by HPLC analysis.
MS = molecular sieves; 2,4-diNBSA = 2,4-dinitrobenzenesulfonic acid; 4-NBSA = 4-nitrobenzenesulfonic acid.
######
Substrate scope of nucleophilic ring opening of episulfonium ions with indole derivatives.[a](#TFN5){ref-type="table-fn"}
----------------------------------- ------------------ --------------- ----- ----------------------------------------------- -------- ------ ----
1 Bn **2a** 99 93
2 Ph **2b** 83 85
3[b](#TFN6){ref-type="table-fn"} Ph **2b** 84 80
4 4-F-C~6~H~4~ **2c** 73 81
5 Ph 4-Me-C~6~H~4~ H **2d** 76 87
6 2-naphthyl **2e** 90 88
7 PMB **2f** \>99 94
8 Me **2g** 72 84
9 *t*-Bu **2h** 89 87
10 5-Me **2i** 97 91
11 5-MeO **2j** 93 93
12 5-Br **2k** 83 92
13 5-F **2l** 88 95
14 Ph Bn TCA 6-F **2m** 92 85
15 4-MeO **2n** 83 91
16 2-Me **2o** 95 79
17 *N*-Me **2p** 54 3
18 benzotriazole[f](#TFN10){ref-type="table-fn"} **2q** 92 80
19[c](#TFN7){ref-type="table-fn"} 3-MeO-C~6~H~4~ **2r** 85 93
20 3-F-C~6~H~4~ **2s** 97 95
21 3-Me-C~6~H~4~ **2t** 95 93
22 2-Me-C~6~H~4~ **2u** \>99 79
23 4-F-C~6~H~4~ Bn TCA H **2v** 91 45
24 4-Me-C~6~H~4~ **2w** 89 60
25[c](#TFN7){ref-type="table-fn"} 4-MeO-C~6~H~4~ **2x** 67 6
26 4-CF3-C~6~H~4~ **2y** 18 5
27[d](#TFN8){ref-type="table-fn"} ---(CH~2~)~4~--- **2z** 16 9
28[e](#TFN9){ref-type="table-fn"} TCA **2b** 87 87
29[e](#TFN9){ref-type="table-fn"} Ph Ph H **2b** 91 85
30[e](#TFN9){ref-type="table-fn"} **2b** 85 85
----------------------------------- ------------------ --------------- ----- ----------------------------------------------- -------- ------ ----
Isolated yields of material purified chromatographically are reported.
With urea **4e**.
Yields determined by ^1^H NMR are reported. Product isolated via flash column chromatography usually contains a small amount of **3e**.
R^2^ = Ph, with HOTf.
With 20 mol% **3e** and 10 mol% 4-NBSA.
Benzotriazole as nucleophile instead of indole.
| {
"pile_set_name": "PubMed Central"
} |
945 So.2d 1113 (2006)
Arthur Dennis RUTHERFORD, Petitioner(s)
v.
Charles J. CRIST, Jr., etc., et al., Respondent(s).
No. SC06-2023.
Supreme Court of Florida
October 17, 2006.
Arthur Rutherford, who is under a pending death warrant, has filed a Petition Seeking to Invoke this Court's All Writs Jurisdiction and a Motion for Stay of Execution, which is scheduled for October 18, 2006. Rutherford's petition concerns the Department of Corrections' denial of a public records request for current lethal injection procedures, followed by the circuit court's denial of a motion to compel production. The State has filed a response to which it has attached the Department's procedures governing execution by lethal injection, effective August 16, 2006. We permitted Rutherford to file a reply.
We deny relief. Our review of the current lethal injection procedures, attached to the State's response, reveals nothing that would cause this Court to revisit our previous conclusions "that procedures for administering the lethal injection as attested do not violate the Eighth Amendment's prohibition on cruel and unusual punishment." Rutherford v. State, 926 So.2d 1100, 1113 (Fla.2006) (quoting Hill v. State, 921 So.2d 579, 583 (Fla.2006), and Sims v. State, 754 So.2d 657, 668 (Fla. 2000)).
Accordingly, Rutherford's petition and motion for a stay of execution are hereby denied. No motion for rehearing will be allowed.
It is so ordered.
LEWIS, C.J., and WELLS, PARIENTE, QUINCE and CANTERO, JJ., concur.
ANSTEAD, J., concurs specially with an opinion.
BELL, J., recused.
ANSTEAD, J., concurring specially.
I concur in the majority's denial of relief because I, too, am bound by the rulings of this Court rejecting similar challenges to the State's procedures for execution by lethal injection in Hill and Rutherford as cited by the majority. I am troubled, however, by the fact that the State has not at all times made its execution procedures and protocols a matter of public record, and by the fact that since our initial decision in Sims approving the use of lethal injection based substantially on theory, there has been no public evidentiary hearing focused on the purpose and effectiveness of the State's procedures, and on what actually takes place during the course of an execution by lethal injection. Now that this method of execution has been in place for a number of years we would all benefit by such a hearing.
| {
"pile_set_name": "FreeLaw"
} |
Subarachnoid hemorrhage without detectable aneurysm. A review of the causes.
In 15% to 20% of patients with a spontaneous subarachnoid hemorrhage, no aneurysm is found on the first angiogram. This review emphasizes that this group of patients is in fact heterogeneous and describes the clinical features, pattern of hemorrhage on early computed tomographic (CT) scan, prognosis, and proposed management in the several and distinct subsets of these patients. Patients in whom no aneurysm is revealed on the initial angiogram can be subdivided mainly according to the pattern of hemorrhage on an early CT scan. In two thirds of these patients the CT scan shows a perimesencephalic pattern of hemorrhage (ie, blood confined to the cisterns around the midbrain); these patients invariably have a good prognosis, which obviates the need for a second angiogram. Patients with diffuse or anteriorly located blood on CT scan are at risk of rebleeding. In most of these patients the source of hemorrhage is an occult aneurysm, but intracranial artery dissections, dural arteriovenous malformations, mycotic aneurysms, trauma, bleeding disorders, substance abuse, or a cervical origin of the hemorrhage should also be considered. Patients with no blood revealed on an early CT scan but with xanthochromic cerebrospinal fluid are extremely rare. These patients deserve a second reading of the scan for blood in the prepontine cistern, which can be the only site of hemorrhage in perimesencephalic hemorrhage. The prognosis and management of patients in whom no aneurysm is found on the initial angiogram depends on the pattern of hemorrhage on the initial CT scan. Patients should no longer be designated with the umbrella term "angiogram-negative subarachnoid hemorrhage." | {
"pile_set_name": "PubMed Abstracts"
} |
Blood rheology and oxygen uptake.
Continuously measured oxygen uptake during constant work exercise (15' 50W) reveals increasing oxygen consumption in individuals with elevated blood viscosity parameters, indicating persistent contribution of anaerobic glycolysis during steady state exercise far below expected "anaerobic threshold". Improvement of viscosity parameters by prostaglandin E1--infusion (Prostavasin) 40 micrograms i.v., naftidrofurylhydrogenoxalat (Dusodril pi) 400 mg i.v. or hemodilution with 500 ml 6% hydroxyethylamylum MW 40000 (Onkohaes) in 5 patients results in significant reduction of this oxygen gradient in subsequent exercise test. Integrated VO2 during exercise above the mean value at rest or the quotient of VO2 during 15 min by VO2 during 30 min (including recovery time) are not differing significantly due to high variations inter- and intraindividually. Oxygen gradient during submaximal constant exercise permits direct clinical determination of microcirculatory performance in involved muscle tissue as a function of blood viscosity. | {
"pile_set_name": "PubMed Abstracts"
} |
Q:
How seriously do we take the finger-inspection in Havdala?
After saying the blessing over fire during Havdala, we do something (customs vary) involving looking at our fingers by the light of the Havdala candle. I'm wondering how seriously we take this part of the ritual. In particular:
If the person making Havdala doesn't do this, is the fire blessing or the Havdala invalidated?
If the people discharging their obligation by observing the Havdala don't do this, do they lose credit for this blessing of for the Havdala?
How certain must the finger-looker be that the light involved is from the Havdala candle? If most of the light cast on the fingers is from electric lights, does that invalidate the finger-looking?
A:
Shulchan Aruch Orach Chaim 298:3-4 says:
The person needs to be close enough to the fire to potentially benefit from it, should he so choose (It is described there as being able to sort money by the light of the torch). The Mishna Berurah there (S"K 13) says that if one who is listening wants to fulfill his obligation, he too must be that close.
Our custom is to look at our fingers and nails to make sure we are close enough to differentiate between them (Mishna Berurah S"K 9, quoting the Tur - see there for other reasons as well).
I understand this to mean that even if we don't look at our nails, as long as we are that close we have fulfilled our obligation.
A:
Based on the answer given in this other question (which matches with what I remembered to be the halacha) - the concept is merely to benefit from the light of the havdala candle.
If one turns off all of the lights in the room before reciting the havdala blessings, and the reciter reads them out of a siddur / bircon (a.k.a "bentscher"), that is also benefiting from the candlelight.
Since I can't find an explicit source which states that those who listen to havdala must benefit from the light, it stands to reason that there is no such requirement.
In normative practice, the listeners are not required to drink the havdala wine. Generally, the reciter pauses from the end of "borei minei b'samim" until all of the listeners have smelled the spices - but it would seem that even this is not essential (lo m'akev) for the listeners.
In summary, my answers to the bullet points are:
No.
No.
The reciter should try to benefit from the candlelight in some way. The listeners need not be concerned about it.
| {
"pile_set_name": "StackExchange"
} |
988 F.2d 322
Bankr. L. Rep. P 75,161In re CHATEAUGAY CORPORATION, Reomar, Inc., and LTVCorporation, Inc., et al., Debtors.OFFICIAL COMMITTEE OF UNSECURED CREDITORS OF LTV AEROSPACEAND DEFENSE CO. INC., Appellant,v.OFFICIAL COMMITTEE OF UNSECURED CREDITORS OF LTV STEEL CO.,INC., Chateaugay Corporation, Reomar, Inc., et al., PensionBenefit Guaranty Corporation, LTV Corporation, et al.,Official Parent Creditors' Committee of the LTV Corporation,Appellees.
No. 759, Docket 92-5056.
United States Court of Appeals,Second Circuit.
Argued Jan. 6, 1993.Decided March 9, 1993.
Max O. Truitt, Jr., Washington, DC (William J. Perlstein, Stephen M. Cutler, Anne D. Bolling, Gregory S. Lane, Wilmer, Cutler & Pickering, Washington, DC, Carla E. Craig, Steven M. Schwartz, Hertzog, Calamari & Gleason, New York City, on the brief), for appellant.
Brian M. Cogan, New York City (Mark S. Wintner, Mark A. Speiser, Leslie Payson, David Simonetti, James McGovern, Stroock & Stroock & Lavan, Harold S. Novikoff, Wachtell, Lipton, Rosen & Katz, New York City on the brief), for appellee Official Committee of Unsecured Creditors of LTV Steel Co., Inc.
Lewis B. Kaden, New York City (Karen E. Wagner, Lawrence J. Portnoy, Davis Polk & Wardwell, Michael J. Crames, Kaye, Scholer, Fierman, Hays & Handler, New York City on the brief), for appellees LTV Corp. and LTV Steel Co., Inc.
James J. Armbruster, Asst. Gen. Counsel, Pension Benefit Guar. Corp., Washington, DC (Carol Connor Flowe, Gen. Counsel, William G. Beyer, Deputy Gen. Counsel, Pension Benefit Guar. Corp., Charles G. Cole, Nancy K. Hayes, Sara E. Hauptfuehrer, Carina J. Campobasso, Steptoe & Johnson, Washington, DC, on the brief), for appellee Pension Benefit Guar. Corp.
Thomas E. Biron, Philadelphia, PA (Raymond L. Shapiro, Blank, Rome, Comisky & McCauley, Philadelphia, PA, on the brief), for appellee Official Parent Creditors' Committee of the LTV Corp.
Before: KEARSE, WINTER, and WALKER, Circuit Judges.
KEARSE, Circuit Judge:
1
The Official Committee of Unsecured Creditors of LTV Aerospace and Defense Co. ("Aerospace Committee" or "Committee") appeals from an order of the United States District Court for the Southern District of New York, David N. Edelstein, Judge, dismissing its appeal from a November 5, 1991 order of the United States Bankruptcy Court for the Southern District of New York, Burton R. Lifland, Chief Judge, which, inter alia, authorized the payment of funds from the estate of LTV Steel Co. ("LTV Steel") to a pension plan through the end of September 1992. The district court dismissed Aerospace Committee's appeal on the ground that the Committee lacked standing to attack the bankruptcy court's order. See In re Chateaugay Corp., 141 B.R. 794 (S.D.N.Y.1992). On appeal, the Committee challenges the district court's standing ruling. For the reasons below, we conclude that the present appeal is moot, and we accordingly vacate the district court's order and remand with instructions to dismiss the Committee's appeal to the district court on the ground of mootness.
I. BACKGROUND
2
In July 1986, LTV Corporation ("LTV") and 66 of its subsidiary and affiliated companies (collectively "debtors"), including LTV Steel and LTV Aerospace and Defense Co. ("Aerospace"), filed voluntary petitions for relief under Chapter 11 of the United States Bankruptcy Code, 11 U.S.C. § 1101, et seq. (1988) ("Code"). The individual cases were consolidated for procedural, though not substantive, purposes and are being jointly administered.
3
A. Proposed Settlement of LTV Steel's Pension Fund Liabilities
4
At the time of the Chapter 11 filings, LTV Steel was the sponsor of four pension plans administered by LTV, including the Jones & Laughlin Hourly Pension Plan ("J & L Hourly Plan" or "Plan"). The Pension Benefit Guaranty Corporation ("PBGC") at first terminated these plans and took over their assets and liabilities. It subsequently reinstated the J & L Hourly Plan and two others, see generally Pension Benefit Guaranty Corp. v. LTV Corp., 496 U.S. 633, 640-44, 110 S.Ct. 2668, 2672-75, 110 L.Ed.2d 579 (1990), returning responsibility for their administration and funding to LTV, see generally In re Chateaugay Corp., 973 F.2d 141, 142 (2d Cir.1992).
5
Since both Aerospace and LTV Steel are subsidiaries of LTV, Aerospace is a member of LTV Steel's "controlled group" for purposes of the Employee Retirement Income Security Act ("ERISA") and is jointly and severally liable with LTV and other LTV subsidiaries for claims made against the LTV Steel pension plans upon termination. See 29 U.S.C. § 1362(a) (1988 & Supp. I 1989); In re Chateaugay Corp., 973 F.2d at 142. Accordingly, PBGC filed proofs of claim against Aerospace, as well as against LTV Steel and the remaining controlled group members, for the amount by which the terminated plan and the three restored plans were underfunded--a total of more than $3 billion. With respect to the restored pension plans, the PBGC claims are, in effect, contingent claims to be pressed if one or more of those plans terminates prior to the confirmation of a reorganization plan.
6
Any reorganization of the debtors' estates will have to resolve these claims in a manner acceptable to PBGC. To this end, the debtors filed a proposed joint plan of reorganization in May 1991, the catalyst for which was a tentative settlement between the debtors and PBGC with respect to the pension obligations. The debtors' Disclosure Statement Pursuant to § 1125 of the Bankruptcy Code, dated May 1, 1991, described the proposed plan as "dependent to a great extent upon [the debtors'] reaching final agreement with the PBGC substantially in accordance with the terms of the tentative Pension Settlement," and stated that one of the chief goals of the tentative settlement was to have the debtors provide sufficient funds to the plans to "ensure that beneficiaries of the restored pension plans will be paid in full."
7
B. The Orders for Interim Funding of the J & L Hourly Plan
8
During the reorganization proceedings, the J & L Hourly Plan was continuing to pay benefits to its participants, though it was not receiving postpetition contributions from the debtors. In May 1991, the debtors estimated that the Plan's liquid assets would be exhausted by the end of July 1991. Seeking to avoid a mandatory termination of the plan under § 4042(a) of ERISA, 29 U.S.C. § 1342(a) (1988 & Supp. I 1989), and to preserve the tentative settlement with PBGC, the debtors sought authorization from the bankruptcy court for the "immediate payment by LTV to the J & L Hourly Plan of an amount equal to the benefit payments expected to be due under such plan for July, August and September, 1991, but not exceeding $40 million." (Application in Support of Order Authorizing Payments to J & L Hourly Pension Plan, dated May 13, 1991, at 9.) Over the objections of certain creditor committees, the bankruptcy court entered an order in June 1991 authorizing the immediate payment by LTV Steel to the J & L Hourly Plan of $27 million, representing two months of benefit payments. The Official Committee of Unsecured Creditors of LTV Steel Company, Inc. ("Steel Committee"), and Cold Spring Management, Inc., a creditor of Aerospace and then-chair of an unofficial Aerospace creditors' committee, appealed that order. Their appeals were subsequently withdrawn pursuant to an accord in which the two appellants agreed not to oppose any application by the debtors to fund the J & L Hourly Plan through November 30, 1991, and the debtors agreed not to seek authorization for any additional funding beyond that date without the consent of the two appellants.
9
On October 30, 1991, the Steel Committee, having also reached a tentative settlement with PBGC, sought an order authorizing the immediate payment by LTV to the J & L Hourly Plan of an amount equal to three months' benefits and, subject to the occurrence of certain events, any additional monthly payments necessary thereafter to provide sufficient funding through June 1992. Following a hearing, the bankruptcy court issued an order on November 5, 1991 ("November 1991 Order") granting the request, finding that additional payments to the J & L Hourly Plan were "necessary to the process of developing a plan of reorganization for The LTV Corporation and its affiliates." Accordingly, the November 1991 Order authorized and directed LTV Steel (a) to make an immediate payment to the J & L Hourly Plan sufficient to fund three months' benefits, providing a "Three-Month Cushion," and (b) thereafter to make monthly contributions to the Plan from December 1991 through September 1992 of amounts "sufficient to fund benefits in each month and thereby replenish the Three-Month Cushion." November 1991 Order at 2. The order also provided, inter alia, that these payments would constitute a dollar-for-dollar offset against any ultimate distributions to the J & L Hourly Plan or the other restored plans, or to PBGC with respect to any of the plans pursuant to a plan of reorganization.
10
The Aerospace Committee timely appealed from the November 1991 Order. It did not, however, request a stay pending appeal. Its appeal remained pending until July 7, 1992.
11
In the meantime, LTV Steel made the required payments to the J & L Hourly Plan; by September 30, 1992, its payments totaled approximately $163 million. All of these funds have been paid out as pension benefits to the Plan's participants.
12
In addition, after lengthy negotiations, LTV Steel and the United Steelworkers of America reached an agreement governing their continued relationship ("Collective Bargaining Agreement"). A key provision of this agreement is LTV Steel's commitment "to continue the funding of the J & L Hourly Pension Plan through the earlier of the effective date of the Plan of Reorganization or September 5, 1993." In an order dated August 12, 1992 ("August 1992 Order"), the bankruptcy court approved the Collective Bargaining Agreement, including LTV Steel's commitment to continue funding the J & L Hourly Plan. After the September 1992 expiration of the funding requirement contained in the November 1991 Order, LTV Steel continued to fund the Plan pursuant to the August 1992 Order. The Aerospace Committee neither objected to nor appealed from the August 1992 Order.
C. The District Court's Decision
13
The district court dismissed the Aerospace Committee's appeal from the bankruptcy court's November 1991 Order. In an Opinion and Order dated July 7, 1992, the district court ruled that the Committee did not have standing to appeal because the creditors of Aerospace are not creditors of LTV Steel and therefore lack a direct pecuniary interest in the November 1991 Order. The present appeal followed.
II. DISCUSSION
14
On appeal, the Aerospace Committee contends that it had standing to appeal the November 1991 Order because (1) the sole purpose of that order was to preserve the tentative settlement with PBGC, which purports to bind Aerospace, (2) under the proposed reorganization plan, the claims of Aerospace's creditors will be satisfied with LTV common stock, and (3) Aerospace has a claim for contribution and indemnification against LTV Steel. The appellees, which include LTV, LTV Steel, creditors' committees of both, and PBGC, are divided on the question of whether or not the Aerospace Committee had standing to challenge the November 1991 Order; but all of the appellees contend that intervening events have made the appeal moot. We do not reach the merits of the Committee's present appeal because we agree with appellees that, since the Committee did not obtain a stay of the November 1991 Order, and as a result LTV Steel made the required payment to the J & L Hourly Plan, which in turn distributed the funds to the pensioners, its appeal to the district court became moot, and this appeal is likewise moot.
15
The duty of an Article III court is to decide live controversies, "not to give opinions upon moot questions or abstract propositions, or to declare principles or rules of law which cannot affect the matter in issue in the case before it." Mills v. Green, 159 U.S. 651, 653, 16 S.Ct. 132, 133, 40 L.Ed. 293 (1895); see Murphy v. Hunt, 455 U.S. 478, 481, 102 S.Ct. 1181, 1183, 71 L.Ed.2d 353 (1982) (per curiam); Blackwelder v. Safnauer, 866 F.2d 548, 550-51 (2d Cir.1989). Accordingly, when, during the pendency of an appeal, events occur that would prevent the appellate court from fashioning effective relief, the appeal should be dismissed as moot. Lewis v. Continental Bank Corp., 494 U.S. 472, 477-78, 110 S.Ct. 1249, 1253-54, 108 L.Ed.2d 400 (1990); Mills v. Green, 159 U.S. at 653, 16 S.Ct. at 133.
16
An appeal should also be dismissed as moot when, even though effective relief could conceivably be fashioned, implementation of that relief would be inequitable. In re AOV Industries, Inc., 792 F.2d 1140, 1147 (D.C.Cir.1986); In re Roberts Farms, Inc., 652 F.2d 793, 798 (9th Cir.1981). Such a dismissal is appropriate when the "appellant has made no effort to obtain a stay and has permitted 'such a comprehensive change of circumstances to occur as to render it inequitable' for the appellate court to reach the merits of the appeal." In re Crystal Oil Co., 854 F.2d 79, 82 (5th Cir.1988) (quoting In re Roberts Farms, Inc., 652 F.2d 793, 798 (9th Cir.1981)).
17
These principles are especially pertinent in bankruptcy proceedings, where the ability to achieve finality is essential to the fashioning of effective remedies. See, e.g., In re Stadium Management Corp., 895 F.2d 845, 848 (1st Cir.1990); In re Public Service Co. of New Hampshire, 963 F.2d 469, 471-72 (1st Cir.) (equitable considerations reflecting "the important public policy favoring orderly reorganization and settlement of debtor estates" may render an appeal moot), cert. denied, --- U.S. ----, 113 S.Ct. 304, 121 L.Ed.2d 226 (1992). As a practical matter, completed acts in accordance with an unstayed order of the bankruptcy court must not thereafter be routinely vulnerable to nullification if a plan of reorganization is to succeed. See, e.g., In re Stadium Management Corp., 895 F.2d at 848-49; In re Highway Truck Drivers Local 107, 888 F.2d 293, 297-98 (3d Cir.1989); In re Onouli-Kona Land Co., 846 F.2d 1170, 1174-75 (9th Cir.1988); In re Tiana Queen Motel, Inc., 749 F.2d 146, 152 (2d Cir.1984), cert. denied, 471 U.S. 1138, 105 S.Ct. 2681, 86 L.Ed.2d 699 (1985); In re Combined Metals Reduction Co., 557 F.2d 179, 188-89 (9th Cir.1977). Thus, though the Code itself does not require a party to seek a stay pending appeal except in limited circumstances, see 11 U.S.C. § 363(m) (1988) (sale or lease of estate property to good faith purchaser or lessor not affected by reversal or modification on appeal absent stay); id. § 364(e) (1988) (same with respect to debt or lien granted good faith creditor), Bankruptcy Rule 8005 sets forth a procedure by which a party may seek a general stay of a bankruptcy court's order pending appeal so that the estate and the status quo may be preserved pending resolution of the appeal. See In re Onouli-Kona Land Co., 846 F.2d at 1172. The party who appeals without seeking to avail himself of that protection does so at his own risk.
18
These principles guide our consideration of the present case. In failing to request a stay of the November 1991 Order, the Aerospace Committee allowed that order to be fully implemented. As a consequence, LTV Steel has paid into the J & L Hourly Plan all of the funds that order required it to pay. Those funds have been disbursed to the Plan's participants in payment of their benefits; and the order has expired of its own terms. The Plan's numerous participants have presumably used the benefits they have received to meet their living expenses. The recoupment of these funds from them, in addition to being impracticable, would impose an unfair hardship on faultless beneficiaries who are not parties to this appeal. Moreover, the continued funding of the J & L Hourly Plan was apparently a key component of the Collective Bargaining Agreement reached by LTV Steel in the aftermath of the November 1991 Order, an agreement that appears to have cleared the way for a reorganization of all the debtors' estates. Undoing these events at this juncture would be contrary to the Code's strong policies favoring finality and settlement.
19
The Aerospace Committee advances a number of suggestions as to why its appeal may not be moot, all of which are meritless. It contends first that it was not required to seek a stay because it was "highly unlikely" that the bankruptcy court would have granted one. A party cannot escape the obligation to protect its litigation position by so facile an argument. If the Committee wished to prevent LTV Steel from making payments to the J & L Hourly Plan pursuant to the November 1991 Order, it should have requested a stay from the bankruptcy court; if that request had been denied, the Committee could have appealed from the denial of the stay and moved in the district court for a stay pending that appeal. We suspect, however, that the real reason for the Committee's failure to seek a stay may be found in its statement that "[i]f the funding authorized by the November 5 Funding Order were stayed, the J & L Hourly Plan would have run out of money and been forced to terminate." (Aerospace Committee's reply brief at 8.) As indicated in Part I.A. above, termination of the Plan prior to reorganization would have removed any contingency from PBGC's claims with respect to the J & L Hourly Plan against Aerospace as an ERISA "controlled group" member.
20
The Aerospace Committee argues also that its appeal is not moot because either the J & L Hourly Plan, which currently has funds, or PBGC could be ordered to repay the $163 million paid by LTV Steel pursuant to the November 1991 Order. Both suggestions are specious. An order requiring PBGC to reimburse LTV Steel, if lawful, would likely trigger termination of the Plan, resulting in liability for funding the Plan promptly being shifted back to the debtors. Further, an attempt to shift the burden of funding the Plan to PBGC would be inconsistent with the tenor of the tentative settlement agreements and would likely impede the settlement and result, similarly, in termination of the Plan. The Committee's suggestion that this Court order the Plan itself to repay the moneys to LTV Steel has a parallel flaw, for it ignores the obligation imposed on LTV Steel by the August 1992 Order, from which the Committee did not bother even to appeal. Under the latter order, funds paid out by the Plan must be replenished by LTV Steel, an entity with which Aerospace is jointly and severally liable. In sum, the relief that the Committee contends is still available is illusory.
21
Indeed, the practical thrust of the Aerospace Committee's arguments here is to ask this Court to provide it with an advisory opinion as to the validity of, and its standing to assert, claims it may seek to press against LTV Steel or against PBGC. We decline the invitation.
CONCLUSION
22
We have considered all of the Aerospace Committee's arguments in support of the viability of this appeal and have found them to be without merit. The present appeal is moot, and we express no view as to the merits of the Committee's challenge to the district court's July 7, 1992 order. The order of the district court is vacated, see Great Western Sugar Co. v. Nelson, 442 U.S. 92, 99 S.Ct. 2149, 60 L.Ed.2d 735 (1979) (per curiam), and the matter is remanded for entry of an order dismissing the Aerospace Committee's appeal from the November 1991 Order as moot.
23
Costs to appellees.
| {
"pile_set_name": "FreeLaw"
} |
Q:
How to create a page with just one post?
I am creating a small blog using Flask. But I didn't find any tutorials or information that would solve the following problem: Create a dynamic page with just one post. I want this page to appear only a complete post, that is, coming out of a database. Without showing all at once (using the for repeater)
I already have an automatic redirector that takes you to a dynamic page for each post title, I just need to know how to show just one post on that page instead of several.
@app.route('/<url_post>', methods=['GET'])
def daily_post(url_post):
with sqlite3.connect("sample.db") as connection:
c = connection.cursor()
c.execute("SELECT * FROM posts")
data = c.fetchall()
Page Post.html
{% extends "layout.html" %}
{% block content %}
{% for item in data %}
<article class="media content-section">
<div class="media-body">
<div class="article-metadata">
<a class="mr-2" href="/home">{{ item[0] }}</a>
<small class="text-muted">{{ item[1] }}</small>
</div>
<p class="article-content">{{ item[2] }}</p>
</div>
</article>
{% endfor %}
{% endblock content %}
I want a dynamic page with only one post (use sqlite3)
A:
The issue is you're grabbing every post from within your posts table and are then passing that result query set into your view to be rendered. This is the problematic code:
c.execute("SELECT * FROM posts")
data = c.fetchall()
Instead you should be filtering your results with a WHERE clause to only extract those records that fulfill a specified condition, i.e. your specific post.
Something along the lines of:
c.execute("SELECT * FROM posts WHERE <table_column_identifier>=?", (url_post))
data = c.fetchall()
Where <table_column_identifier> is the column within your posts table schema uniquely identifying your desired post. I would have to see your table schema definition to give you the exact field, but it's probably something along the lines of id
Note: You can reuse your page post view providing your new route endpoint provides the filtering as described above.
Hopefully that helps!
| {
"pile_set_name": "StackExchange"
} |
Great Indian invasion of Australia?
India's wealthy, from old money to nouveaux riches IT entrepreneurs, are quietly snapping up hotels and mines Down Under just as Australia embarks on an immigration campaign to attract long-term investment.
The Jindal family, ranked among the world's top 80 richest by Forbes, in May bought two minor stakes, worth a total of A$26 million (US$26.99 million), in Australian iron ore and coal mines through Jindal Steel & Power.
That followed a US$2 billion purchase by Indian self-made billionaire and college-dropout Gautam Adani of a coal mine in the state of Queensland last year.
Image: Naveen Jindal, Chairman and Managing Director of Jindal Steel and Power Ltd. | {
"pile_set_name": "Pile-CC"
} |
#!/usr/bin/env python
# -*- coding: utf-8 -*-
import json
from alipay.aop.api.constant.ParamConstants import *
class ZolozIdentificationCustomerEnrollcertifyQueryModel(object):
def __init__(self):
self._biz_id = None
self._face_type = None
self._need_img = None
self._zim_id = None
@property
def biz_id(self):
return self._biz_id
@biz_id.setter
def biz_id(self, value):
self._biz_id = value
@property
def face_type(self):
return self._face_type
@face_type.setter
def face_type(self, value):
self._face_type = value
@property
def need_img(self):
return self._need_img
@need_img.setter
def need_img(self, value):
self._need_img = value
@property
def zim_id(self):
return self._zim_id
@zim_id.setter
def zim_id(self, value):
self._zim_id = value
def to_alipay_dict(self):
params = dict()
if self.biz_id:
if hasattr(self.biz_id, 'to_alipay_dict'):
params['biz_id'] = self.biz_id.to_alipay_dict()
else:
params['biz_id'] = self.biz_id
if self.face_type:
if hasattr(self.face_type, 'to_alipay_dict'):
params['face_type'] = self.face_type.to_alipay_dict()
else:
params['face_type'] = self.face_type
if self.need_img:
if hasattr(self.need_img, 'to_alipay_dict'):
params['need_img'] = self.need_img.to_alipay_dict()
else:
params['need_img'] = self.need_img
if self.zim_id:
if hasattr(self.zim_id, 'to_alipay_dict'):
params['zim_id'] = self.zim_id.to_alipay_dict()
else:
params['zim_id'] = self.zim_id
return params
@staticmethod
def from_alipay_dict(d):
if not d:
return None
o = ZolozIdentificationCustomerEnrollcertifyQueryModel()
if 'biz_id' in d:
o.biz_id = d['biz_id']
if 'face_type' in d:
o.face_type = d['face_type']
if 'need_img' in d:
o.need_img = d['need_img']
if 'zim_id' in d:
o.zim_id = d['zim_id']
return o
| {
"pile_set_name": "Github"
} |
/* impure.c. Handling of re-entrancy data structure for OpenRISC 1000.
Copyright (C) 2014, Authors
Contributor Stefan Wallentowitz <[email protected]>
* The authors hereby grant permission to use, copy, modify, distribute,
* and license this software and its documentation for any purpose, provided
* that existing copyright notices are retained in all copies and that this
* notice is included verbatim in any distributions. No written agreement,
* license, or royalty fee is required for any of the authorized uses.
* Modifications to this software may be copyrighted by their authors
* and need not follow the licensing terms described here, provided that
* the new terms are clearly indicated on the first page of each file where
* they apply.
*/
#include <reent.h>
#include "or1k-internals.h"
#include <string.h>
/* As an exception handler may also use the library, it is better to use
* a different re-entrancy data structure for the exceptions.
* This data structure is configured here and as part of the exception
* handler (or1k_exception_handler) temporarily replaces the software's
* impure data pointer.
*
* During initialization, the libraries standard _impure_data and the exception
* impure data (_exception_impure_data) are initialized. Afterwards,
* the current value _current_impure_ptr is set to _impure_ptr.
*
* At runtime __getreent is called to return the current reentrancy pointer,
* which is stored in _current_impure_ptr.
*
* In the or1k_exception_handler the _current_impure_ptr is set to point to
* _exception_impure_ptr. After the exception handler returned, it is set back
* to _impure_ptr.
*/
/* Link in the external impure_data structure */
extern struct _reent *__ATTRIBUTE_IMPURE_PTR__ _impure_ptr;
#ifdef __OR1K_MULTICORE__
struct _reent **_or1k_impure_ptr;
struct _reent **_or1k_exception_impure_ptr;
struct _reent **_or1k_current_impure_ptr;
#else
struct _reent *__ATTRIBUTE_IMPURE_PTR__ _or1k_impure_ptr;
/* Create exception impure data structure */
static struct _reent _or1k_exception_impure_data = _REENT_INIT (_or1k_exception_impure_data);
/* Link to the exception impure data structure */
struct _reent *__ATTRIBUTE_IMPURE_PTR__ _or1k_exception_impure_ptr = &_or1k_exception_impure_data;
/* Link to the currently used data structure. */
struct _reent *__ATTRIBUTE_IMPURE_PTR__ _or1k_current_impure_ptr;
#endif
#ifdef __OR1K_MULTICORE__
#define OR1K_LIBC_GETREENT _or1k_current_impure_ptr[or1k_coreid()]
#else
#define OR1K_LIBC_GETREENT _or1k_current_impure_ptr
#endif
void
_or1k_libc_impure_init (void)
{
#ifdef __OR1K_MULTICORE__
uint32_t c;
_or1k_impure_ptr = _sbrk_r(0, sizeof(struct _reent*) * or1k_numcores());
_or1k_exception_impure_ptr = _sbrk_r(0, sizeof(struct _reent*) * or1k_numcores());
_or1k_current_impure_ptr = _sbrk_r(0, sizeof(struct _reent*) * or1k_numcores());
_or1k_impure_ptr[0] = _impure_ptr;
_REENT_INIT_PTR(_impure_ptr);
for (c = 1; c < or1k_numcores(); c++) {
_or1k_impure_ptr[c] = _sbrk_r(0, sizeof(struct _reent));
_REENT_INIT_PTR(_or1k_impure_ptr[c]);
}
for (c = 0; c < or1k_numcores(); c++) {
_or1k_exception_impure_ptr[c] = _sbrk_r(0, sizeof(struct _reent));
_REENT_INIT_PTR(_or1k_exception_impure_ptr[c]);
}
for (c = 0; c < or1k_numcores(); c++) {
_or1k_current_impure_ptr[c] = _or1k_impure_ptr[c];
}
#else
// Initialize both impure data structures
_REENT_INIT_PTR (_impure_ptr);
_REENT_INIT_PTR (_or1k_exception_impure_ptr);
// Use the standard impure ptr during normal software run
_or1k_impure_ptr = _impure_ptr;
// Set current to standard impure pointer
_or1k_current_impure_ptr = _impure_ptr;
#endif
}
struct _reent*
_or1k_libc_getreent(void) {
return OR1K_LIBC_GETREENT;
}
#ifdef __OR1K_MULTICORE__
struct _or1k_reent (*_or1k_reent)[];
#else
struct _or1k_reent _or1k_reent;
#endif
void
_or1k_reent_init(void)
{
#ifdef __OR1K_MULTICORE__
size_t memsize = sizeof(struct _or1k_reent) * or1k_numcores();
_or1k_reent = (struct _or1k_reent*) _sbrk_r(0, memsize);
#endif
}
| {
"pile_set_name": "Github"
} |
Q:
send html + JS in ajax
im using jQuery load() method to send another html to my webpage.
The html being loaded contains Javascript generated HTML.
Im using this function to load the html:
$(document).ready(function(){
$("img#links").click(function(){
$("div#content").load("links.html");
});
});
The links.html contains:
<h1 id="content">Links</h1>
<br>
<script>add_link("http://google.com");</script>
The add_link function generates me a table:
var add_link = function(link) {
document.write("<table border=\"0\" width=\"100%\" height=\"50\" id=\"link\">");
document.write("<tr>");
document.write("<td width=\"50\"><img src=\"img/star.png\" /></td>");
document.write("<td><a href=\"" + link + "\"><div class=\"link\">" + link + "</div></a></td></tr></table>");
}
However, when called instead of writing that js generated code into the webpage, it gets written to a blank page, containing only the table generated by JS.
A:
When you call document.write() after the page loading has completed — definitely the case here — the browser will wipe out the original page. In other words, the browser interprets a call after the page is done to be an implicit request to "start over" with a blank page.
Instead of using document.write(), then, you can use DOM APIs to append new content to the page.
| {
"pile_set_name": "StackExchange"
} |
Garage Door Spring Repair in La Marque, TX
If you are having any type of problem with your garage door, regardless of whether you have a residential or commercial door, call us today for fast professional repair service. A garage door spring is a mechanical piece that is subject to wearing out over time. If you wait until it breaks altogether you may not be able to open your garage door.
Service Fee: $29
Phone: (281) 402-6222
Service areas: La Marque, TX and surrounding cities
Location: 1631 FM 519, La Marque, TX 77568
We have been doing business in the Houston area for over 20 years and all of our technicians are professionally trained and certified. We not only do emergency calls, but we also do and recommend preventative maintenance calls. Our bonded, licensed and insured technicians will come to your location and inspect your entire garage door mechanism. Some of the things that we will inspect for and repair are the spring, the cables, the rollers, the weather seal, the tracks, etc. If any of these components are found to be defective or are in need of any type of repair or adjustment, we will economically fix it right on the spot.
When we arrive, our professionally certified technician will be in a fully stocked truck with parts and supplies for all brands of garage door springs. We are available 24 hours per day for emergency service and all of our work is backed up by our 100% satisfaction guarantee. If you need garage door spring repair or any other repair or service on your commercial or residential garage door; call us right now. | {
"pile_set_name": "Pile-CC"
} |
Manifesto (Roxy Music album)
Manifesto is the sixth studio album by the English rock band Roxy Music. It was released in March 1979 by E.G. in the UK, Polydor in Europe and by Atco Records in the US.
Following an almost four-year recording hiatus, Manifesto was Roxy Music's first studio album since 1975's Siren. The first single from Manifesto was "Trash", which barely made the UK top 40. However, the second single, the disco-tinged "Dance Away", peaked at no.2, beaten to no.1 for three weeks from 26 May 1979 by Blondie's "Sunday Girl". Regardless, it became one of the band's biggest hits and was also the 9th best-selling single in the UK in 1979. The song was also released as a 12" extended version (running at six and half minutes), a format that had started to become popular in the late 1970s. The third single from the album was a re-recorded version of "Angel Eyes", which was far more electronic and "disco" in nature than the power-pop album version. An extended 12" mix was also released. The single also made the UK Top 5 in August.
The album itself peaked at no. 7 in the UK. The cover design which featured a variety of mannequins (a concept also used for the covers of the singles from the album), was created by Bryan Ferry with fashion designer Antony Price and American TV actress Hilary Thompson amongst others. The picture disc version of the album featured a version of the design in which the mannequins are unclothed. The cover's typography, as well as the album's title, were inspired by the first edition of Wyndham Lewis's literary magazine Blast.
Release history
On the original vinyl release, side one was labelled "East Side" and side two was labelled "West Side".
After the song became a hit, the second pressings of the album substituted the original version of "Dance Away" with its single remix. Later on, the LP version of "Angel Eyes" was also replaced by the more popular re-recorded version released as a single. The original CD versions of the album used the revised track list, until the LP version of "Angel Eyes" was restored in the 1999 remaster. Manifesto was finally released on CD in its original version on The Complete Studio Recordings box in 2012. The LP versions of both songs first appeared on CD in 1995 on The Thrill of It All box set.
Critical reception
Manifesto was positively received by critics but not as well regarded as previous Roxy Music albums. Melody Maker review of the album stated
Max Bell of NME gave it a lukewarm review:
Similarly, Village Voice critic Robert Christgau wrote: "This isn't Roxy at its most innovative, just its most listenable – the entire "West Side" sustains the relaxed, pleasantly funky groove it intends, and the difficulties of the "East Side" are hardly prohibitive. At last Ferry's vision seems firsthand even in its distancing – he's paid enough dues to deserve to keep his distance. And the title track is well-named, apparent contradictions and all."
Greil Marcus wrote in Rolling Stone:
It was ranked 30th in the Village Voice Pazz & Jop critics poll of the best albums of 1979. The 1992 Rolling Stone Album Guide gave the album four stars and says "the regrouped Roxy seems better for the rest: deftly blending fresh rhythms into its signature sound, shortening the musical passages and concentrating more on song craft.
Track listing
All songs written by Bryan Ferry except as noted.
Personnel
Roxy Music
Bryan Ferry – vocals, keyboards, harmonica
Andy Mackay – oboe, saxophone
Phil Manzanera – electric guitar
Paul Thompson – drums
Additional personnel
Alan Spenner – bass
Paul Carrack – keyboards
Gary Tibbs – bass
Steve Ferrone – drums
Rick Marotta – drums
Richard Tee – piano
Melissa Manchester - backing vocals
Technical personnel
Rhett Davies – recording engineer
Jimmy Douglass – engineer
Phill Brown – engineer
Randy Mason – engineer
Charts
Album
Single
Certifications and sales
Notes
Category:1979 albums
Category:Roxy Music albums
Category:E.G. Records albums
Category:Polydor Records albums
Category:Atco Records albums
Category:Reprise Records albums
Category:Virgin Records albums | {
"pile_set_name": "Wikipedia (en)"
} |
Q:
Python - how to check if weak reference is still available
I am passing some weakrefs from Python into C++ class, but C++ destructors are actively trying to access the ref when the real object is already dead, obviously it crashes...
Is there any Python C/API approach to find out if Python reference is still alive or any other known workaround for this ?
Thanks
A:
From Python C API documentation:
PyObject* PyWeakref_GetObject(PyObject *ref)
Return value: Borrowed reference.
Return the referenced object from a weak reference, ref. If the referent
is no longer live, returns None. New in version 2.2.
A:
If you call PyWeakref_GetObject on the weak reference it should return either Py_None or NULL, I forget which. But you should check if it's returning one of those and that will tell you that the referenced object is no longer alive.
| {
"pile_set_name": "StackExchange"
} |
Q:
How can I block linked ads on Google Chrome
Some days back I suddenly got ads in Google Chrome whenever I try to open any page. After searching online how to block ads, I found one adblock extension. I have installed adblock and it was working fine and ads were blocked. But today I am getting linked ads.
What do I mean by linked ads In the first screenshot you can see web applications ,user experience are in blue colors and underlined. If I Mouse over the linked ads (in the screenshot I mouse over on "user experience") then a pop-up comes up showing the ads. You can see I have enabled adblock in the screenshot. Can anybody please tell me why these ads are appearing?
And yes, I have reinstalled Google Chrome and still the same
A:
I am certain that you've got a Chrome Extension that has had a brain transplant.
It probably started out as a good, useful extension. It may still have the functionality you got it for. However, a recent trend is for nefarious advertisers to buy extensions from their developers and take over. Since the extension is already installed no extra permissions are needed to add extra "functionality" to it in the form of injected ads. It's not "malware" in the strictest sense, so anti-virus checkers won't pick up on them.
It was in the tech news quite a bit recently. Ars Technica has a very good writeup about it: Adware vendors buy Chrome Extensions to send ad- and malware-filled updates
Worse actors have gone beyond ads to actual malware.
I had a few Extensions where this happened, including one Extension much beloved (and missed).
You should disable each of your Extensions one-by-one until you find the culprit, then uninstall it with extreme prejudice.
If you're willing to trust another extension there are a couple that purport to find these bad extensions for you.
ExtShield (Lifehacker review)
Extension Defender (Lifehacker review)
| {
"pile_set_name": "StackExchange"
} |
Fear during labor.
The aims of the present study were to compare primiparous and multiparous women's experiences of fear of delivery during an early stage of active labor (cervix dilatation 3-5 centimeters) and to study whether fear of delivery, measured during the early stage of active labor, was a predictor of the amount of pain relief received during the remaining part of labor (cervix dilatation 5 cm - partus), of the duration of the remaining part of labor, and of the occurrence of instrumental vaginal delivery and emergency cesarean section. Thirty-five primiparous and 39 multiparous women answered the Delivery Fear Scale (DFS) once during the early stage of labor and before they had received any pain relief. Primiparous women reported higher levels of fear than multiparous women did. Fear during the first phase of labor predicted only the total amount of pain relief received during labor. The clinical implications of the study are that the delivery staff should consider women's fear during labor and pay attention especially to primiparous women's increased risk of higher levels of fear during an early stage of active labor, as compared with multiparous women's. The challenge for staff of a delivery ward is to support the woman in labor in a way that decreases fear, which in turn might reduce the woman's need of pain relief. | {
"pile_set_name": "PubMed Abstracts"
} |
Toxic anterior segment syndrome following penetrating keratoplasty.
To describe an outbreak of toxic anterior segment syndrome (TASS) following penetrating keratoplasty (PK) and to examine its possible causes. Owing to a series of TASS following PK between June 6, 2007, and October 2, 2007, we reviewed the records of all patients who had undergone PK during that time. In addition to routine microbial tests on organ culture media, we looked for specific pathogens and endotoxins in all of the materials used for organ culture or PK. Furthermore, we analyzed all of the perioperative products and instrument processing. Of the 94 patients who underwent PK, we observed 24 cases of postoperative sterile keratitis. Causal research revealed that the accumulation of cleaning substances or heat-stable endotoxins on the surface of the routinely used guided trephine system was most likely responsible for the TASS. To our knowledge, this is the first report on TASS following PK. Suboptimal reprocessing of surgical instruments may be an important cause of TASS as in this series the TASS-like symptoms resolved after modified instrument-cleaning procedures. The standardization of protocols for processing reusable trephine systems might prevent outbreaks of TASS following PK. | {
"pile_set_name": "PubMed Abstracts"
} |
Parama Group began its journey and legacy in architecture and construction industry back in 1982 under PT. Parama Dharma. With a strong vision, aspiration and strong wotk ethic, we managed to be one of the most prestigious leading construction development company in Indonesia.
With more than 30 years of experience and success, we grow ourselves into a multi-division business which supported our main framework in architecture and construction industry. Now we are striving to be the best at we do, as we take part in building Indonesia. | {
"pile_set_name": "Pile-CC"
} |
; This file is for use with available_externally_a.ll
; RUN: true
@foo = hidden unnamed_addr constant i32 0
| {
"pile_set_name": "Github"
} |
Q:
How to tell whether elaboration has completed at a breakpoint?
When I hit a breakpoint in a VLAB script, how can I find out if I have caused elaboration to finish or not, yet?
My script reaches a statement that raises an error:
Error: (E529) insert module failed: elaboration done
(The command that causes this is vlab.instantiate("stim", "stim"))
So obviously elaboration was unexpectedly (for me) already completed. I need to somehow go back in the process and find out where that happened - so I need some way of asking "is elaboration complete?" at the point where I set breakpoints earlier in the script.
A:
SystemC provides the following function to query the current phase of elaboration or simulation.
sc_status sc_get_status();
It returns either SC_ELABORATION, SC_BEFORE_END_OF_ELABORATION, SC_END_OF_ELABORATION, SC_START_OF_SIMULATION, SC_RUNNING, SC_PAUSED, SC_STOPPED, or SC_END_OF_SIMULATION.
See section 4.5.8 in the SystemC Language Reference Manual for more details. Note that this function was only added in the most recent version of the standard, IEEE Standard 1666-2011.
In VLAB, the SystemC API is available from the sysc Python package, so the following script can be used to test if the current phase is at elaboration:
import sysc
print "Is elaboration phase:", sysc.sc_get_status() == sysc.SC_ELABORATION
| {
"pile_set_name": "StackExchange"
} |
Poké Ball
From Bulbapedia, the community-driven Pokémon encyclopedia.
Revision as of 14:00, 14 February 2013 by Playerking95(talk | contribs)(Yes, it's Dragonite, but theres no picture on the page of Psyduck so there doesn't need to be any specific Pokemon name as the image name to me and I think my image was fine. It is the Poké Ball's inside.)
A Poké Ball (Japanese: モンスターボールMonster Ball) is a type of item that is critical to a Trainer's quest, used for catching and storing Pokémon. Both a general term used to describe the various kinds as well as a specific term to refer to the most basic among these variations, Poké Balls are ubiquitous in the modern Pokémon world. Up to six Pokémon can be carried with a Trainer in Poké Balls, while any number of other Poké Balls can be held in the Bag for later use. These six Pokémon in the Poké Balls can be attached to the user's belt for carrying them around. Some Pokémon do not like to be carried around in Poké Balls, such as Ash's Pikachu.
The strength of a Poké Ball is determined by how much it raises a wild Pokémon's catch rate, and may in fact vary depending on the conditions of the battle. Poké Balls limit the power of Pokémon contained inside, taming them, though they do not cause the Pokémon inside to always obey the Trainer.
The invention of Poké Balls apparently occurred in the Johto region, where Apricorns grow; these fruit were cut apart and carved out, then fitted with a special device, and used to catch wild Pokémon prior to the mass production of the Balls that occurs in modern times under Silph Co. and the Devon Corporation. Some Trainers still use Poké Balls made from Apricorns, while Kurt, a resident of Azalea Town, still constructs them. Drayden claims that Poké Balls did not exist during his childhood.
Prior to the invention of Poké Balls, Pokémon were referred to as "magical creatures" (Japanese: 魔獣majū), indicating that the name Pokémon, short for Pocket Monster, did not come into common parlance as a term until these devices allowed the various Pokémon to be stored easily. This also shows that in these times they were believed to be supernatural creatures, not natural ones.
Stylized Poké Balls are used in many places to symbolize Pokémon in general: the logos of both Battle Frontiers feature a Poké Ball in their design, while several Poké Balls can be seen in every Pokémon Center. The headgear of the protagonists of Kanto, Hoenn, Sinnoh, and Unova-based games feature Poké Ball designs, as do the Bags of the protagonists of Johto-based games. Ethan's headgear is also similar to the top half of an Ultra Ball, and Lucas's Bag prominently features a Poké Ball.
Mechanics and design
A schematic displaying Poké Ball size, storage and mechanics
Though the technology behind a Poké Ball remains unknown and has evolved through the centuries to accommodate the diverse requirements of their creators, the basic mechanics are simple enough to understand and tend to remain constant: in a Pokémon battle, once an opposing wild Pokémon has been weakened, the Pokémon Trainer can throw a Poké Ball at it. When a Poké Ball hits the Pokémon, as long as it is not deflected, the Poké Ball will open, convert the Pokémon to a form of energy, pull it into its center, and close. A Pokémon in this state is given a chance to struggle to attempt to break free from the ball and escape, being instantly re-converted from energy into matter. Should a Pokémon escape a Poké Ball, the device will either be destroyed (in the games and some manga) or will return to the Trainer (anime), who can attempt once again to capture the Pokémon. A Pokémon who does not escape the ball will be caught.
Interior of a Poké Ball from the anime
Poké Balls are specifically constructed for Pokémon capture, transport and training. As well as being physically difficult to escape from (as they seal tightly shut as soon as a Pokémon is taken into them) the environment of a Poké Ball is designed to be attractive to Pokémon also; according to Lucian of the SinnohElite Four, weakened Pokémon instinctively curl up tight in an attempt to heal themselves, an action that the environment of the Poké Ball encourages. Furthermore, while it is not known how a captured Pokémon perceives their time inside their Ball, the device is said to replicate a "Pokémon-friendly" environment that is "designed for comfort". All of these factors strongly discourage Pokémon from escaping their Balls. In the manga, Bugsy refers to his "capture net" as being the net that is supposedly inside a Poké Ball, but visible and already deployed. According to Kurt, this invisible net captures and physically stores a Pokémon.
Poké Balls are not always at full size. Pressing the button on the front will convert it between its full size, about the size of a baseball, to a smaller size, about that of a ping-pong ball, and back again. The larger size makes throwing the ball easier, while the smaller one makes for easier storage on a belt clip, in pockets, and in Bags.
As mentioned, the generic Poké Ball design is not constant and has been remodelled and altered innumerable times in order to create new Poké Balls that are adapted for specific conditions. For example, it is seen in several anime episodes such as Gulpin it Down! and Claydol Big and Tall that normal Poké Balls have difficulty catching Pokémon which are extremely large or extremely heavy. In the latter episode, it is revealed that ancient civilizations overcame this issue by constructing immense Poké Balls many times the size of the standard model known today, and made from stone instead. Other civilizations such as Pokémopolis also discovered new technologies that more closely resembled modern Poké Ball technology, such as the Dark Device and the Unearthly Urn, which were also adapted for the capture and storage of massive Pokémon but in small containers. However, devices like these became lost to the ages and their roles were subsequently supplanted by Heavy Balls in the modern world.
When a Pokémon is released from a Poké Ball, it will be accompanied by a bright light as it returns from its energy form, and materialize nearby, often on the ground. This bright light has been shown to vary depending on the type of Ball that the Pokémon is contained in in the games, while it has always been shown to be white in the anime. Pokémon are recalled to their Poké Ball by holding up the Poké Ball with its button pointed at the Pokémon. A beam of red light will shoot from the button, converting the Pokémon back into energy and returning it to the Ball. The beam, however, has a limited range, and can be dodged by the Pokémon. If the beam hits a person, they will be stunned for a moment, but aside from that no ill effects will make themselves apparent. Releasing Pokémon from a Trainer's ownership, unlike normally sending the Pokémon out, will bathe the Pokémon in a blue glow, and the Poké Ball will no longer mark it, making it able to be caught by another Trainer's Poké Ball.
A Poké Ball can also be broken, which will release it from ownership, and if a Trainer has done so accidentally, it must somehow be fixed before the Pokémon can be recalled. In the manga, if a Poké Ball is broken before a Pokémon is sent out, then that particular Pokémon can't be used until their Poké Ball has been repaired. This happened several times in the Pokémon Adventures manga, such as during Red's battle against Giovanni, where the opening mechanism for the Poké Balls of Red's Venusaur and Gyarados were damaged, preventing either of them from being used in the match.
Pokémon appear to be conscious while inside Poké Balls. Several Pokémon have shown the ability to leave and return to their Poké Balls at will, most notably among them Jessie's Wobbuffet, Misty's Psyduck, Ash's Oshawott, and Brock's Croagunk, which tend to do so in every episode they appear in. In Dig Those Diglett!, many Pokémon belonging to Gary Oak, as well as other Trainers, including Ash Ketchum, demonstrated the ability to prevent themselves from being sent from their Poké Balls, as they refused to fight against the Diglett, though this has not been demonstrated since. Pokémon have also shown to be able to hear orders given by their Trainer right before they are sent out.
Poké Balls are able to communicate with a Trainer's Pokédex, as the system updates itself with information on newly-caught Pokémon, and keeps track of how many Pokémon the Trainer has with them. If a Trainer catches a new Pokémon with the full six already with them, the Pokédex will automatically send the newly-caught Pokémon in its Poké Ball to the Pokémon Storage System that the Trainer is using. As shown in Two Degrees of Separation, a Pokémon caught by a Poké Ball is "marked" by it, and thus most Poké Balls thrown at it will have no effect aside from temporarily stunning it. In the games, as well as in Bad to the Bone, however, the Trainer of the Pokémon will block a Poké Ball thrown by another, though it is possible that this is more out of courtesy to their Pokémon than to prevent capture outright.
Other wireless capabilities of Poké Balls are shown in Destiny Deoxys, as when the electricity of the city is down, Audrey could not release her Masquerain from the Poké Ball, claiming that the "Poké Ball Management System" was no longer working without power. There has been no mention of any such system since.
Poké Balls are able to be decorated to no ill effect, with several Poké Balls that have been painted with special colors being seen in the anime. In the games, a Ball Capsule and seals can release special effects when the Pokémon is sent out.
Poké Ball accuracy
Except for the Master Ball, all Poké Balls have a chance of breaking and not capturing the Pokémon in question, however, in several cases, it is possible for the Poké Ball to miss the wild Pokémon completely.
In Generation I games, it was possible for a ball to miss the Pokémon when the likelihood of catching the Pokémon in question was particularly low—rather than the ball throwing animation playing and the ball wiggling zero times, a message would come up stating "You missed the Pokémon!".
A Poké Ball cannot be thrown during a wild Double Battle, unless one of the two wild Pokémon is defeated, with the game claiming "It's no good! It's impossible to aim when there are two Pokémon!". A player can however snag Pokémon in Pokémon Colosseum and Pokémon XD: Gale of Darkness even if there are two on the opposing side of the field; presumably the Snag Machine assists in aiming.
Pokémon Black and White introduces wild Double Battles that are encountered alone instead of with a partner like in Diamond, Pearl and Platinum. In addition to the prior requirements, a command cannot be issued to a Pokémon during the same turn a Poké Ball is thrown; however, if the second Pokémon is using a two part move like Dig or Dive, a Poké Ball can still be thrown and Dig or Dive will continue if the ball fails.
Capture chances
Types of Poké Ball
In the Pokémon games so far, there have been 26 different varieties of Poké Ball, all differing from each other in some effect, whether it be an increased ability to catch a Pokémon from the wild or an effect which occurs only after the Pokémon has been caught. From Generation III onward, each variety of Poké Ball has a unique animation when they open to draw in a Pokémon and when a Pokémon is sent out, and the type of Poké Ball used to catch the Pokémon is preserved on its status screen.
Introduced in Generation I
The following Poké Balls were introduced in Pokémon Red and Green, and have appeared and been available in all games since then, with the exception of the Safari Ball, which is not present in Generation II. They were developed by Silph Co., with the development of the Master Ball factoring into the plot of the Generation I games and their remakes heavily.
When a Pokémon in one of these Balls is used in a link battle in Generation IV, it will appear as an ordinary Poké Ball, regardless of if the link is made with a Johto or Sinnoh-based game. Using a Pokémon in one of these Balls in one of the Battle Frontier facilities will show it as it should appear during the battle, but as an ordinary Poké Ball if the battle is saved to the Vs. Recorder and played back. Trading a Pokémon in one of these Poké Ball variations into Diamond, Pearl, and Platinum or registering it in Pokémon Battle Revolution will cause it to display as a normal Poké Ball, though if the Pokémon is traded back into a Johto-based game or transferred forward into Generation V, it will regain its variant Ball.
In Pokémon data, information for these Poké Balls on the status screen and in battle is stored in a separate location from the variants introduced in other generations, so that the Pokémon can be traded back to Diamond, Pearl, and Platinum from HeartGold and SoulSilver and display an ordinary Poké Ball there (the data space for these balls being ignored in the earlier games).
Level BallレベルボールLevel Ball
POKÉ BALLSpocket
INTRODUCED IN
GEN II
Cannot be bought
Sell for:150
Effect:
Allows the player to catch wild Pokémon; works better on Pokémon of levels lower than the Pokémon currently in battle.
Catch rate:
1× if the player's Pokémon is the same level as or a lower level than the wild Pokémon2× if the player's Pokémon is at a higher level than the wild Pokémon but less than double it4× if the player's Pokémon is more than double but less than four times the level of the wild Pokémon8× if the player's Pokémon is of a level four times or more than that of the wild Pokémon
-20 if used on Pokémon weighing less than 220.6lbsGSC/451.5 lbsHGSSNo modifier if used on Pokémon weight between 220.6lbs and 441.0 lbsGSC+20 if used on Pokémon weighing between 451.5 lbs and 677.3 lbs+30 if used on Pokémon weighing more than 661.5 lbsGSC+30 if used on Pokémon weighing between 677.3 lbs and 903.0 lbsHGSS+40 if used on Pokémon weighing more than 903.0 lbsHGSS
Introduced in Generation III
The following Poké Balls were introduced in Pokémon Ruby and Sapphire. While the main four Poké Balls and the Safari Ball returned to central usage, these specialty Balls were only available at certain Poké Marts in the Hoenn region, and the Luxury Ball only available via completion of certain quests in the games. Generally, they can be seen to be counterparts to Generation II's Apricorn Balls, which were not available in the Generation III games, with the Nest Ball and Level Ball, Net Ball and Lure Ball, and Luxury Ball and Friend Ball being very similar in effect to each other.
The Premier Ball is functionally identical to the standard Poké Ball; it is simply a premium (hence the name) given with the purchase of ten Poké Balls. Only one is given with each purchase of ten or more, so buying 20 or more Poké Balls still only yields one gift Premier Ball. To obtain multiple Premier Balls, the Poké Balls must be purchased in separate transactions of 10 at a time.
These Ball variants continued to be available in Pokémon FireRed and LeafGreen, though most must be traded in from a Hoenn-based game, with only the Timer Ball and Repeat Ball available to be bought, and even then, only in Two Island. The Dive Ball's effect was altered, with it now having greater chance to catch Pokémon encountered on water rather than under it, as Hoenn-based games are the only ones where wild Pokémon can be encountered while using Dive. In Generation IV, all but the Dive Ball are readily available to be bought, though the Dive Ball can still be obtained through use of Pal Park and other special events. The Johto-based HeartGold and SoulSilver make the Timer, Repeat, and Luxury Balls hard to find once more, though the returning Apricorn Balls help to take their place. All of these Poké Balls can be purchased in Generation V. Additionally, the Timer Ball's effectiveness now increases much more quickly as the battle goes on.
Unlike the Poké Balls introduced in Generation I, these Poké Balls were developed by the Devon Corporation.
Introduced in Generation IV
The following Poké Balls were introduced in Pokémon Diamond and Pearl. The set of seven introduced in Generation III, as well as the original set of five, are preserved in this generation, and are available either for purchase or by trade in all Generation IV games. The Generation II Poké Balls also make a return in this generation, but only in Pokémon HeartGold and SoulSilver.
Note: Pokémon recaught with this ball in Pal Park will retain the ball in which they were originally caught in Generation III. Not to be confused with Sport Balls, which were known as Park Balls in Generation II.
Introduced in Generation V
Only one new Poké Ball was introduced in Pokémon Black and White, though all Poké Balls of previous generations are programmed into the game, both as items and on the status screen. If they are hacked into the game, however, the Apricorn Balls, Sport Ball, and Park Ball cannot be used to catch wild Pokémon, though the Safari Ball and Cherish Ball can. If a Pokémon is transferred to Generation V from an earlier generation with the Poké Transfer, it will appear to have the same ball it was originally caught with.
The Dream Ball can only be used in the Entree Forest, where it never fails. Pokémon transferred from Pokémon Dream Radar are obtained in Dream Balls.
In the anime
In the anime, the basic Poké Ball is the most commonly used of all varieties, with other varieties appearing either very few times or not at all. A vast majority of Pokémon are shown to be stored in regular Poké Balls, to the point that large collections of Poké Balls can be seen with no variation among them. Even Ash's Pikachu, the most prominent Pokémon in the anime which spends all its time outside with Ash, has a plain Poké Ball that differs from others only by the small yellow lightning bolt symbol on it, as seen in Pokémon - I Choose You!.
Despite this, the various other types of Poké Ball have been seen in the anime, usually to illustrate a special property about that particular ball. The lack of the different types is unsurprising, however, due to the fact that, when the anime was first created, the games themselves did not even keep track of the Poké Ball that a Pokémon was caught in, and thus, it made no difference in sending a Pokémon out.
The first time that a Poké Ball aside from the normal variation was seen was in EP035, where Ash was given 30 Safari Balls in order to compete in the Safari Game. With these 30 Safari Balls, Ash attempted to catch various rare Pokémon; however, he only managed to capture an entire herd of Tauros. They appeared in Safari Balls in Showdown at the Po-Ké Corral; afterward; however, whenever Ash uses one of his Tauros in a battle, it is sent out from a standard Poké Ball.
The GS Ball was the second of the variant Poké Balls to appear in the anime, this time with a special purpose. This mysterious ball was unable to be opened by Professor Ivy, and served as the reason for Ash's journeys to the Orange Archipelago (to pick it up) and Johto (to deliver it to Kurt), so that what was contained within it could be discovered. Celebi was long rumored to be related to the ball, something which the Pokémon Adventures and game canons verify, while a director of the anime confirmed that, had it not been insisted that Celebi appear in a central role in the fourth movie, the GS Ball arc would have concluded with Celebi being released from the ball and traveling with Ash and his friends.
A Poké Ball after catching a Pokémon in the anime
Also related to Kurt, as in the games, the first non-standard Poké Ball variants, the Apricorn balls, made an appearance in the anime, and several were given to the members of the main cast. All three members of the main cast received Fast Balls in Going Apricorn!, with Brock using his to catch a Pineco shortly after receiving it. In the next episode, Brock received a Heavy Ball, while Ash and Misty received Lure Balls. While Brock's Heavy Ball and Ash and Misty's Fast Balls would remain unused (and have not been mentioned since), both Ash and Misty would use their Lure Balls to capture a Totodile and Corsola, respectively. Another Heavy Ball appeared in Gulpin It Down, where it was used to capture a giant Gulpin, though this was not the one belonging to Brock.
The Master Ball itself has only appeared once as an actual Poké Ball, in Whiscash and Ash, where it was used by Sullivan in a last resort attempt to catch a wild Whiscash called "Nero". Despite the fact that a Master Ball cannot be escaped from, the Whiscash swallowed the Master Ball, thus preventing capture, and disappeared back into the water. While not a Poké Ball itself, Misty owns a beach ball that is designed like the Master Ball, which can be seen in Beauty and the Beach and A Hot Water Battle.
Ash calling out a Pokémon
The Generation III specialty balls have only been seen in cameos, with only the Repeat Ball and Luxury Ball appearing, in the opening of Jirachi: Wish Maker. These balls contained Brendan's Shiftry and Aggron, respectively.
The debut of most of the specialty balls, both from Generation III and IV, came in the ending Which One ~ Is It?, which contained the first appearance of the Great Ball and Ultra Ball, as well as the first anime appearance of the Premier, Heal, Net, Dusk, Nest, Quick, Timer, and Dive Balls.
Many other Poké Balls have been shown in the anime; however, most of these are cosmetic alterations alone, such as Poké Balls with gold plating, diamond studded Poké Balls, and Poké Balls with special designs on them, usually to denote an organization.
Most notably, a broken Poké Ball, snapped in half at its rusted hinges, is kept by both Ash and Gary, symbolizing their rivalry.
In Mystery at the Lighthouse, it was shown that if a Trainer catches a Pokémon while they already have six on hand, it is automatically sent to the regional professor. This was again demonstrated in Sparks Fly for Magnemite. Sewaddle and Burgh in Pinwheel Forest shows a major difference in what happens after a Pokémon is captured. Instead of being automatically sent to the regional Professor, the Poké Ball is sealed and the button becomes red. The Pokémon is kept inactive until it is switched out by another actively in the Trainer's party.
In the manga
In the various Pokémon manga, Poké Balls have been shown to appear differently, as an attempt to explain how a Trainer knows which Pokémon is in which ball, as most Pokémon manga series were, like the anime, developed at a time when the games could not keep track of the ball a Pokémon was contained in.
In the Electric Tale of Pikachu manga
In the manga The Electric Tale of Pikachu, the rules are more similar to the anime; however, Poké Balls are numbered on the outside, on the button, so that a Trainer knows which member of their team they are sending into battle.
It is also possible for a Pokémon to be placed inside a Poké Ball without it being owned by a Trainer. In Days of Gloom and Glory, Meowzie steals a Poké Ball from a shop and puts her kitten in it so that it will not be hurt by a flood affecting the city.
In the Pokémon Adventures manga
In the Pokémon Adventures manga, the tops of Poké Balls are semitransparent, allowing the Pokémon inside, which is miniaturized, to be seen through the ball, while the Pokémon can likewise see out of the ball it is contained in. In this manga, unlike in the anime, Pokémon already captured can be recaught in another Poké Ball, as is seen when Red recatches Misty's Gyarados (though Blue states that catching a Pokémon that belongs to another is not possible in Lapras Lazily). Like in the anime and games, specialty balls do exist, and Gold and Silver received a Friend Ball and Heavy Ball, respectively. It has also been shown that unlike the games, Pokémon placed in their balls recover from status conditions; however, like in the games, they do not recover health points. Additionally, the three original types of Poké Ball are used to identify the Trainer's rank; most Trainers keep their Pokémon in Poké Balls, Gym Leaders use Great Balls, and Elite Four members and Frontier Brains use Ultra Balls.
In the TCG
Ultra Ball
Several variants of Poké Ball have been released in card form in the Pokémon Trading Card Game, ranging from the standard variants found in the games and other media to variants specific to the TCG.
The standard Poké Ball card, which was the first released, debuted in the Jungle expansion and has since been featured in many others. It features a TCG-centric mechanic, requiring a coin flip to search the deck for a Pokémon to be put in the hand. Most of the Poké Ball variants, both adapted from the games and exclusive to the TCG, are similar to this, with several requiring coin flips to use their effect.
The Ultra Ball can be seen in the artwork of Rocket's Sneak Attack, from the Team Rocket expansion. The Ultra Ball would make its actual first appearance, with its effect requiring the player to discard 2 cards from the player's hand to search the player's deck for a Pokémon. The 'H' on this Ultra Ball is derived from its Japanese name, Hyper Ball.
The Great Ball, which first appeared in the TCG expansion coinciding with the remakes of the Generation I games, is somewhat of an upgrade to the Poké Ball, and does not require the coin flip that the Poké Ball does, instead restricting the search of Pokémon to Basic Pokémon. Later, in Emerging Powers, Great Ball's effect was changed to have you instead search the top 7 cards of your deck for any 1 Pokémon card & put it in your hand.
The Master Ball, first appearing in the Gym Challenge expansion, and in the games the most powerful of the Poké Balls, provides a vastly different effect than the standard. Rather than searching the entire deck, only the top seven cards may be searched. One Pokémon found in these seven can be put into the hand, while the rest must be shuffled back into the deck.
Debuting in the Skyridge expansion, the Lure Ball is different from the basic Poké Balls in that it draws from the discard pile rather than the deck. For each heads flipped, with a maximum of three, an Evolution card can be returned from the discard pile and put into the hand. It has not appeared since.
Also debuting in Skyridge, the Friend Ball, another Apricorn Ball, has a unique effect entirely, allowing the user to search their deck for a Pokémon of the same type as one of the opponent's Pokémon, making it effective in decks that typically match up well against their own type. It also has not appeared since.
The Fast Ball allows the player to go through their deck, turning over cards one at a time until they find the first evolution card, and then taking that into their hand, shuffling afterward. Like the other two Apricorn Balls, it debuted in Skyridge and has not appeared since.
The Premier Ball, debuting in the Great Encounters expansion, is special, much as in the games, and allows the player to search either the deck or the discard pile for a Pokémon LV.X to put into their hand.
The Luxury Ball, first found in the Stormfront expansion, is among the rarest of the Poké Ball varieties in the games, though its catch rate is the same as that of a normal Poké Ball. Likewise it is so with the TCG, allowing a non-LV.X Pokémon to be searched from the deck, but only if another Luxury Ball card is not in the discard pile.
The Quick Ball released in the Mysterious Treasures expansion has a similar effect to the Fast Ball released in Skyridge, allowing the player to uncover cards from their deck until they find a Pokémon. An expansion of the Fast Ball's use, any Pokémon can be found, though this may prove an issue if the player is looking for an Evolution card specifically and finds a Basic Pokémon first.
The Dusk Ball, also first found in Mysterious Treasures, features an effect somewhat opposite from the Master Ball's: Instead of the top seven cards being searched, only the bottom seven cards may be, and a Pokémon found there may be put into the player's hand.
The Heavy Ball, first found in Next Destinies, allows the player to search through their deck for a Pokémon who has a retreat cost of 3 or more and put it in their hand, whereas the Level Ball, also found in Next Destinies, allows them to do the same with a Pokémon that has 90 HP or less.
In the Super Smash Bros. series
The Pokémon series is represented in the Super Smash Bros. series by a Poké Ball icon. The first two games show the Poké Ball with both halves and the center filled in, while the third goes with Generation IV's redesigned icon with only the top half filled in.
These balls are used to catch and contain wild Pokémon. Most Pokémon must be weakened in some way before they can be caught, but once they're inside a Poké Ball, they enjoy their new home, since Poké Balls contain an environment specially designed for Pokémon comfort. Master Balls are the strongest type.
"An item used for capturing Pokémon and calling them out into battle. Pokémon live in these items which despite appearances, actually contain a wide, comfortable Pokémon-friendly world inside them. In Super Smash Bros., Pokémon give temporary support to who calls them out. You never know which you will get, but some are devastatingly powerful."
Other variants
The following Poké Ball variants are found outside of the standard games. They are often very unusual compared to the 26 types found in the games, and it is sometimes questionable whether or not they even qualify as Poké Balls. Many have separate articles, where their unique properties are described in greater detail.
In the games
Pester Balls: These objects, which appear similar to Poké Balls at a glance, are not used to catch Pokémon, and instead will release a Pokémon repellent on contact. They are only found in Pokémon Snap.
A Snag Ball is a Poké Ball variant that has been "unlocked" by the Snag Machine, allowing it to snag an already caught Pokémon during a battle. While it is able to be used on any Pokémon, Rui will only allow Wes to use it on Shadow Pokémon, while Michael's Aura Reader will render the Snag Machine inoperable when a Pokémon other than a Shadow Pokémon is targeted.
When transferring Pokémon via Poké Transfer, a blue-colored Poké Ball is used to catch the Pokémon in the mingame. They are shot using a bow.
Typing Balls are used in Learn with Pokémon: Typing Adventure. They are thrown after one successfully types a Pokémon's name. It has the overall design like that of a normal Poké Ball, only having an additional vertical line at the bottom, resembling the letter "T".
Several objects were used to contain and control Pokémon before Poké Balls themselves were developed. Large monumental objects have been shown several times in episodes to be containers for large ancient Pokémon, as seen most notably in The Ancient Puzzle of Pokémopolis. Smaller objects have also been used, such as the staff belonging to Sir Aaron, which contained his partner, Lucario, until Ash released it in the current era. Special armor developed by Marcus was used to control Pokémon in ancient Michina Town, though it did not directly contain the Pokémon; unlike other methods of using Pokémon, these Pokémon were enslaved, instead of befriended, and they turned against him the moment the armor was broken.
Mewtwo had a collection of strange Poké Balls in Mewtwo Strikes Back, which incorporated an eye into their design, and were used primarily as a means of capture of Pokémon to be cloned. These balls had no trouble catching Pokémon which were already captured—even if they were already inside of Poké Balls. They have been called by several names by fans, such as "Mewtwo Balls" and "Clone Balls".
Molly Hale, whose imagination caused the power of the Unown to change the world around them, was able to use strange, crystalline Poké Balls when she challenged Brock and Misty in Spell of the Unown. The Pokémon sent from these appeared normally, but dissolved into crystal, rather than being recalled. These crystal Poké Balls only appeared when used by her imagined older selves, and do not appear to actually exist.
A special variant of Poké Ball, the Lake Ball, was used during the Seaking Catching Competition in Hook, Line, and Stinker; this is viewed by many to be similar to the Sport Ball used in the Bug-Catching Contest. They appear as blue and white Poké Balls, with a fish pattern around the edge, and a yellow arrow on the top and bottom of the ball. They don't shake after capture, implying an automatic catch.
Older Poké Balls have also appeared in the anime, specifically the one carried by Sammy in Celebi: Voice of the Forest, which was colored differently, and it had a knob that needed to be twisted before the Pokémon inside could be sent out. While it is unknown how these types were manufactured, it is likely that they were made by hand using Apricorns, prior to the standardization and mass production of modern-day Poké Balls.
The Iron-Masked Marauder, an agent of Team Rocket, used special Dark Balls that corrupted Pokémon caught inside them and made them into mindless servants of the Trainer, as well as raising their power significantly. Multiple Pokémon were caught in these Poké Balls, including the legendary Celebi and a powerful Tyranitar. They seem capable of catching any Pokémon without fail.
As in the games, the GS Ball appeared in the anime, and was the primary motivation for Ash's trip to the Orange Archipelago, where he would compete in his second Pokémon League. It also served as the catalyst for his journey to Johto, as he needed to deliver the ball to Kurt. Former director Masamitsu Hidaka revealed that a shelved storyline, that would have concluded the GS Ball's arc, involved a Celebi that would have traveled with Ash and his friends through at least part of Johto. The storyline was viewed as redundant after the decision was made to introduce Celebi in the fourth movie instead.
In Claydol, Big and Tall, the "Stone Ball", a huge Poké Ball made of stone used to keep an evil, giant Claydol that levied destruction everywhere. This Poké Ball is about the size of a 2-story house.
In A Fishing Connoisseur in a Fishy Competition!, a specially marked Poké Ball, called the "Fishing Poké Ball", was used in the fake fishing contest set up by Team Rocket. This Poké Ball highly resembled the regular red and white Poké Ball, except that it had a dark fish mark on its red part.
In the manga
Pokémon Adventures
In addition to various Poké Balls introduced in the games, Pokémon Adventures also has several Trainers modifying their Poké Balls to suit their fighting styles
Bruno has modified his Poké Balls so that they are fitted onto the ends of his nunchucks. By swinging them quickly and throwing the nunchuck forward, Bruno can have his Pokémon quickly attack his opponent, giving him the advantage.
Koga and his daughter Janine modified their Poké Balls into shuriken to fit their ninja theme. In addition to being used as weapons, they can also be used to have their Pokémon pop up from different locations to surprise the opponent or to hold items to help an ally.
Bugsy had Kurt modify his Butterfly net into something he calls a Capture Net. His net has a Poké Ball nested into the middle of it. The bag of the net is made of the same material of the inside of a Poké Ball. Once a Pokémon is covered in the bag, they will automatically be sucked into the Poké Ball.
Falkner has modified his Poké Balls into boomerangs using the feathers of his Skarmory. Because of Skarmory's feathers being transparent, they have the tendency to turn invisible, confusing enemies when Falkner throws them in random directions only for them to turn around and go straight for them.
Bruno's nunchuck with Poké Balls on them
Koga's Shuriken Poké Ball
Bugsy's Capture net
Falkner's boomerang Poké Balls
In the TCG
The Dual Ball is merely two Poké Balls together, and has a similar effect to using two plain Poké Ball cards, requiring two coin flips to search for up to two Pokémon, depending on how many heads appear.
The Team Magma Ball is Team Magma's Poké Ball variant, found only in the EX Team Magma vs Team Aqua expansion. It works similarly to a Poké Ball, however, it only can be used to find Team Magma's Pokémon, and will still allow a player to find a Pokémon, though only a Basic one, if the coin flip results in tails.
Item balls
In both the anime and games, it has been shown that items can be contained in Poké Balls, apparently able to be captured in much the same way as a Pokémon. The anime has used this as a gag on several occasions, most notably in Primeape Goes Bananas, where Ash accidentally catches a rice ball when he throws a Poké Ball in an attempt to catch a wild Mankey.
Items contained in Poké Balls have been present from the very first games, with many items that are found on the field being found in Poké Balls in conspicuous locations. These items are sometimes important, and usually will be among the required items for pickup along the way. Sometimes, even Poké Ball variants can be found in item balls, though it may be that the item ball itself is supposed to represent the ball that is found. Many other items, however, are hidden, and are not in item balls, instead being directly on the field, and can be found more easily using an Itemfinder or Dowsing Machine.
In battle
Generation I and II
Generation III
Sprites are the same for both summary and battle.
Poké Ball
Great Ball
Ultra Ball
Master Ball
Safari Ball
Premier Ball
Repeat Ball
Timer Ball
Nest Ball
Net Ball
Dive Ball
Luxury Ball
Generation IV
This section is incomplete.Please feel free to edit this section to add missing information and complete it. Reason: In-battle for Park Ball, if there's any (as there is no for summary since Pokémon retain the original Poké Ball).
Poké Ball
Great Ball
Ultra Ball
Master Ball
Safari Ball
Level Ball
Lure Ball
Moon Ball
Friend Ball
Love Ball
Heavy Ball
Fast Ball
Sport Ball
Premier Ball
Repeat Ball
Timer Ball
Nest Ball
Net Ball
Dive Ball
Luxury Ball
Heal Ball
Quick Ball
Dusk Ball
Cherish Ball
Generation V
This section is incomplete.Please feel free to edit this section to add missing information and complete it. Reason: All images.
Generation II Poké Balls, while programmed into the game, cannot be used to catch Pokémon and can be seen only when sending out a Pokémon. Sprites seen below are at full size as they are seen as they are when player's Pokémon is sent out after a switch.
Pokémon Stadium
Outside of the battles, Generation I Poké Balls (except the Safari Ball) are all seen in the minigame Furret's Frolic in Pokémon Stadium 2. Poké Ball is worth 1 point, Great Ball 2, Ultra Ball 3 and Master Ball 5.
Furret's Frolic
Poké Ball
Great Ball
Ultra Ball
Master Ball
Poké Ball on instructions screen
Great Ball on instructions screen
Ultra Ball on instructions screen
Master Ball on instructions screen
Trivia
While any Pokémon species can be caught by any Poké Ball, due to Pokémon distribution, no Pokémon species can legitimately be in all of the 26 in-game Poké Ball variants. The Pokémon that come the closest are the Paras and Venonat families, as they are found in the wild in all five generations, and can be obtained in the Pokémon Dream World; the only Ball they cannot be legitimately contained in is the Cherish Ball, as they have not not been given out as an event Pokémon during Generation IV or V.
In Pokémon Pinball, the Poké Balls serve as the balls in the machine; they can be used to capture Pokémon and are upgraded depending on the multiplier bonus at the time.
Many of the types of Poké Balls introduced in Generation III function similarly to those introduced in Generation II: the Nest Ball, like the Level Ball, is better if used on Pokémon of lower levels, the Net and Dive Balls are both useful against Pokémon found while in the water, much like the Lure Ball, and the Luxury Ball raises a Pokémon's friendship quickly, similarly to a Friend Ball. Excluding the Sport Ball, which many see as a parallel to the Safari Ball which made its return in Generation III, the specialty Balls made by the Devon Corporation in Hoenn number seven, the same amount as the Apricorn Balls made by Kurt.
In Generation II, the Park Ball's name is written as one word on the menu, rather than as two, as the rest of the Poké Balls are. This is due to the size limitation placed on the text by the Game Boy Color's small screen. The Generation IV Park Ball does not have this issue, as Nintendo DS screens are wider and the font used is thinner.
In some early artwork for Pokémon Red and Green, Poké Balls are shown on the ground in two pieces while the Pokémon are in battle, rather than in the more familiar hinged form they take now. This may be a carryover from when Pokémon was known as Capsule Monsters, as the Poké Ball sprites in Generation I also do not show the button on the ball. In Generation II, Poké Balls split in half when capturing a Pokémon as part of their animation, while the anime had been using the hinge style since the very first episode.
Poké Balls are inspired by the capsules for gashapon machines, which contain small, handheld toys.
In HeartGold and SoulSilver and the TCG, Lure Balls are shown to have a green outer coloring; however, in official artwork and the anime, they are shown to have a blue outer coloring.
However, in Generation V, the Lure Ball has both its Bag sprite, status screen sprite, and battle animation altered to the official blue color.
Similarly, the Fast Ball is shown to be red in official art; however, it is orange in its Bag and status screen sprites, and only appears red in battle in Generation V.
While most Poké Balls cannot capture Pokémon that have already been caught, there are some types that can easily catch a Pokémon that already is owned. These are usually rare or use-restricted balls.
The Park Ball, which is used to capture Pokémon migrated from a Generation III game to a Generation IV game, is one of these. It reverts to the original ball used to catch the migrated Pokémon in the Summary screen.
In the anime, Mewtwo's "Mewtwo Balls", seen only in Mewtwo Strikes Back, can catch any Pokémon despite being owned. These Balls have been shown to even catch owned Pokémon even when inside of their Poké Balls. After the Pokémon's DNA is extracted through Mewtwo's cloning device, "Mewtwo Balls" automatically release the caught Pokémon.
While the Apricorn Balls and the Sport Ball exist in the coding of the Generation V games, they are completely unobtainable. If they are hacked into the Bag, they cannot be held by a Pokémon, much as in HeartGold and SoulSilver, and will not be recognized by the game as Poké Balls for in-battle use. Despite this, a Pokémon caught in one of these Poké Balls in HeartGold and SoulSilver will retain the Ball in Generation V.
The sprite color of the Lure Ball was altered in Pokémon Black and White, changing its base color to a light blue color as opposed to the green it had in Pokémon HeartGold and SoulSilver.
The Moon Ball, while it returns in HeartGold and SoulSilver and appears in the coding of Generation V, cannot legitimately contain Pokémon in the Skitty and Munna families, even though both evolve with the Moon Stone. This is due to their unavailability in the wild in HeartGold and SoulSilver.
The Premier Ball is the only variety of Poké Ball so far whose name approaches the character limit for item names.
In Generation II, after catching a Pokémon, the Poké Ball's color palette changes to that of the Pokémon that was just caught. It then changes back to normal thereafter.
Generation V introduced fewer types of Poké Balls than any other generation, only introducing one.
The Safari Ball has a catching animation programmed into Black and White despite not being legitimately able to be used, as there is no Safari Zone.
Both the Safari Ball and Sport Ball appeared in the anime prior to sprites being introduced for items in the games, in EP035 and EP161, respectively. In these appearances, their designs were vastly different from their later-introduced in-game sprites. | {
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[Therapeutic bath and Alzheimer's disease].
To safeguard the quality of life of people suffering from Alzheimer's by the creation of an individual care plan, by identifying pleasurable activities or fond memories of the individual, thereby restoring a sense of present well being. The therapeutic bath, an action which might be considered somewhat straightforward, in fact enables the measurement of the capability of an elderly person to respond to stimulation by medical staff. | {
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This invention relates to a brake lathe for drum and disc rotor brakes for grinding the inside cylindrical surface of a brake drum and for machining the opposite parallel surfaces of a disc rotor and, more particularly, to a brake lathe for use in automotive repair shops.
Brakes lathes for resurfacing brake drums and disc rotors are well known and have been used in the art. These lathes commonly utilize a rotating spindle provided along an axis of the brake lathe housing and which accepts at one end thereof the brake device to be machined. The other end of the spindle is driven by a source of power such as a motor. A cutting tool is provided on a moveable platform attached to the lathe so as to advance the cutting tool into the brake drum or disc rotor. The depth of cut can be adjusted by moving the tool platform or by a depth-of-cut adjustment on the tool itself. These known brake lathes have the disadvantage that the cutting tool or boring bar which is normally used to resurface or grind the inside cylindrical surface of the brake drum is located on a mounting surface or platform which is disposed between the operator and the axis of the lathe housing. Accordingly, when the operator needs to adjust the depth of cut for work on a brake drum or to otherwise observe the cutter operation, the operator must lean over the lathe to view the cutting operation which takes place along the horizontal radius of the brake drum located on the operator's side of the lathe. This procedure is awkward and, therefore, the adjustment or observation is difficult to perform. Further, in combination brake-drum and disc-rotor lathes, the location of the guide surface or platform for the boring bar interferes with the placement of inboard and outboard cutters which are utilized to machine the opposite parallel surfaces of a disc rotor and which are also located between the operator and the brake lathe housing.
These and other disadvantages are overcome by the present invention wherein there is provided a brake lathe for use with both brake drums and disc rotors which permits the operator to view the cutting operation of a brake drum machining without leaning over the machine. Further, the brake drum and disc rotor cutting tools are advantageously provided on opposite sides of the brake lathe housing. Still further, the present invention also provides separate platforms for brake drum and disc rotor operations which are independent of one another. | {
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Plasma aldosterone and cortisol levels in experimental acute renal failure.
Deranged adrenal cortical function was previously described in different stress situations. The aim of this work was to study the plasma cortisol and aldosterone levels in acute renal failure induced by the uranyl nitrate injection or bilateral ureteral ligation. In both groups of uremic dogs on the first day of uremia there was a significant elevation of the plasma cortisol level, being more pronounced and lasting longer after bilateral ureteral ligation. In sham operated controls a modest elevation was recorded. The plasma aldosterone level rose significantly from the first day in both groups of uremic animals. A further progressive elevation continued the following days and a highly elevated aldosterone levels remained until the end of the experiments. A minor but significant elevation of plasma aldosterone was also found in sham operated controls. This study has established increased plasma cortisol and aldosterone levels attributable to the operative stress and failing kidney function in acute uremia. | {
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Theater Review: "The Taming Of The Shrew"
An updated classic comes to Diversionary Black Box Theatre
Let’s face it, the forced submission of Kate “the Cursed” to bounty-hunter husband Petruchio in Shakespeare’s “The Taming Of The Shrew” is enough to bring on hives in the modern woman, and even more so when she does that last bit about placing your foot beneath your husband’s hand as a sign of obedience.
But if you can get past that sticky plot point, “Shrew” offers giggles on the order of those to be had in “A Midsummer Night’s Dream,” fun enough for a summer’s eve.
Remember the old dictum “follow the money?” Our protagonist Petruchio (Steve Froehlich) lives by it, and has come to “wive it wealthily in Padua.”
So when he finds out that the very rich Baptista (Joel Castellaw) has decreed that his charming younger daughter Bianca (Jamie Channell Guzman) – who has no dearth of suitors – cannot marry until shrewish elder daughter Katherina (Kym Pappas) gets hitched (and whoever marries Kate will be well off), Petruchio volunteers for the shrew-taming job sight unseen.
He gets a bit more than he bargained for – Kate has an extremely sharp tongue and is not about to be buffaloed by this gold-digging turkey – but of course starvation and sleep deprivation can work wonders in the behavior department and it will all work out the way Petruchio wants it to.
Director Carla Nell updates the story with an opening-scene video portraying a bit of women’s history (credit Margo Flitcraft) including suffrage, Rosie the riveter and female athletes along with the traditional family scenes, played while Kate gets dressed.
Costume designer Alanna Serrano contributes some spiffy clothes of the 20th century variety. They look great, but setting this utterly unlikely plot in modern times gave me a bit of cognitive dissonance.
Highlights of the show: Froehlich and Pappas, who make fine adversaries as Petruchio and Kate, and even pretty fine allies.
Jamie Channell Guzman’s Bianca is absolute charmer, and her array of suitors (Kevin Six (Hortensio), Alex Guzman (Lucentio) and a gender-bending Kira Vine as Gremio) are an amusing lot.
Bravo to Nell for managing to put this rather oversized work in the tiny Diversionary Black Box at all, and for succeeding rather nicely despite little help from either Shakespeare or the space. This “Shrew” isn’t perfect, but neither is the source material, and it does offer enough giggles to keep you in your seat (but take a pillow). | {
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General Sharif’s visit also offered me the opportunity to express once again our condolences following the appalling recent terrorist attack on the Army school in Peshawar.
The re-opening of the school this week underlines the admirable resolve of the Pakistani people.
We will continue to stand shoulder-to-shoulder with Pakistan in the fight against terrorism and extremism.
As an indication of our support, I am pleased to announce that I have agreed to provide Pakistan’s armed forces with a range of specialist bomb disposal equipment to help it counter the threat from terrorist groups and save Pakistani lives.
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} |
Measurement of the rate of uptake and subcellular localization of porphyrins in cells using fluorescence digital imaging microscopy.
A fluorescence imaging system incorporating a cooled slow-scan charge-coupled device camera was used to study the rate of uptake and subcellular localization of prophyrins in living cells. Measurements were carried out on human dermal fibroblasts (D532) using two different prophyrins meso-tetra(4-N-methylpyridyl)porphine (TMPP) and meso-tetra(4-N-hexylpyridyl)porphine (THPP). It was observed that TMPP was rapidly taken up by cells and principally located in the nucleus. The THPP, on the other hand, internalized more slowly and exhibited a particulate distribution in the cytoplasm. | {
"pile_set_name": "PubMed Abstracts"
} |
Equal treatment and unequal benefits: the Medicare program.
This paper analyzes the distribution of Medicare benefits among elderly persons on the basis of income, race, and geographical location. It first presents available statistical evidence from Medicare on the distribution of benefits and the magnitude of differentials among these elderly. It then sorts out the contribution to differentials arising from differences in the availability of medical resources. prices of medical services, and other demographic factors. The importance of various Medicare program features on remaining differentials--such as the cost-sharing provisions of Medicare, reimbursement policies, and nondiscrimination enforcement procedures--are then investigated. The effect of health status on utilization of medical services by the elderly is also analyzed, and the distribution of Medicare benefits by income for elderly persons of similar health status is presented. The paper concludes with recommendations for reducing differentials in Medicare benefits and indicates those policy changes which would result in a distribution of benefits more closely related to health care needs of the elderly. | {
"pile_set_name": "PubMed Abstracts"
} |
San Ching Tian Temple
San Ching Tian Temple () (also called as Lian Hua San Chieng Tien) is a Chinese temple located in a 1.5-acre site bordered by housing area in Krokop 9 Road of Miri, Sarawak, Malaysia, where it is also considered as the largest Taoist temple in Southeast Asia.
History
The temple was built in 2000 and completed after three years with its entire decorations and motif including the dragon and its Three Pure Ones statues were imported from China.
References
External links
Category:Chinese-Malaysian culture
Category:Taoist temples in Malaysia
Category:Religious buildings and structures completed in 2003
Category:Buildings and structures in Kuching
Category:Tourist attractions in Sarawak | {
"pile_set_name": "Wikipedia (en)"
} |
Q:
What is the best comparison algorithm for comparing the similarity of arrays?
I am building a program that takes 2 arrays and returns some value showing to what degree they are similar. For example, images with few differences will have a good score, whereas images that are vastly different will have a worse score.
So far the only two algorithms I have come across for this problem are the sum of the squared differences and the normalized correlation.
Both of these will be fairly simple to implement, however I was wondering if there was another algorithm I haven't been able to find that I could use?
Furthermore, which previously mentioned method will be the best? Would be great to know both in terms of their accuracy and efficiency.
Thanks,
A:
Comparing images usually depends on application you are dealing with. Normally distance functions used depends on image descriptor.
Take look at Distance functions
Euclidean Distance
Squared Euclidean Distance
Cosine Distance or Similarity [THIS SHOULD WORK FINE]
Sum of Absolute Differences
Sum of Squared Differences
Correlation Distance
Hellinger Distance
Grid Distance
Manhattan Distance
Chebyshev Distance
statistics distance function
Wasserstein Metric
Mahalanobis Distance
Bray Curtis Distance
Canberra Distance
Binary Distance functions
L0 Norm
Jacard similarity
Hamming Distance
As you are directly comparing images, taking cosine similarity should work for you.
| {
"pile_set_name": "StackExchange"
} |
Q:
Assembler. Распознавание эмуляции среды
Некоторые программы(например, антивирусные) эмулируют изолированную среду для PE файлов. Как можно при помощи Assembler распознать такую среду? Идеально было бы кусок кода, но буду вполне доволен и описанием алгоритма. Заранее спасибо.
A:
Если я правильно понял вопрос, то по идее тут подход должен быть комплексным. Универсальным способо определить эмулятор (хотя точнее говорить, это все-таки некая виртуалка), думаю, нельзя. Но при этом вряд ли какие-то программы (антивирусы) будут использовать полностью самостоятельно написанну VM, а это значит, что они используют что-то готовое. Поэтому можно попробовать взять некие типовые способы определения каждой виртуалки поотдельности и последовательно выполнять все проверки
Если говорить про то, какими способами это можно делать, то тут разные варианты: ключи регистра, какие-то особые драйвера, команды, железо и т.д.
Примеры (возможно немного устаревшие) можете посмотреть в статье (даже английский знать не обязательно, чтобы скопипастить): https://www.symantec.com/avcenter/reference/Virtual_Machine_Threats.pdf
| {
"pile_set_name": "StackExchange"
} |
Trekking in the province of Parma
For the trek and excursions lovers the territory of Parma is rich with itineraries either for short easy walks and tracks for more expert hikers, to reach the summits of the Appennino Tosco Emiliano's crests.
In the Ceno valley around Bardi, where ther's also the beautiful castle, there are many possibilities to enjoy the nearby woods and mountains, among which the Carameto and Barigazzo.
In the Taro valley, the area around the villages of Borgo Val di Taro, Bedonia and Albareto offers many different paths, as the ones at the valley floor and the ones among the chestnut woods and rivers up on mountains like the amazing Penna.
All these walks can also be made accompanied by the guides of the Associazione Guide Ambientali Escursionistiche Valtaro e Valceno: www.trekkingtaroceno.it
In the national park of the Appennino Tosco-Emiliano as well, there are countless paths on the mountains, in the woods and to the lakes of the Parco dei Cento laghi, among these we point out the ones to the Santo or Ballano lakes, the Monte Marmagna, Monte Orsaro, Monte Sillara or Monte Caio.
In the winter it is possible to ski on the resorts around Parma as Schia and Prato Spilla according to the snow situation.
In the Baganza valley, in the Municipality of Calestano, there's the chance to make a very peculiar experience, under stone towers and grey walls that come out of the woods, near the Scaletta and Cassio mountains: they are the famous Salti del diavolo, formed by polygenic conglomerations on the ocean bottom.
Otherwise in the low land, in the area of Fidenza, there are walks in nature along the Siccomonte valley, crossing the hills line located South of Fidenza in direction Tabiano, on tarmac roads, occasionally cross country and stoney paths. For details and maps, check the website www.valsiccomonte.it
If you wish to know our territory in a natural and slow way but never forgetting our gastronomy, you may contact one of the guides Parma City of Gastronomy. | {
"pile_set_name": "Pile-CC"
} |
Lemon Bar
Lemon Bar
3.50
Based on my Grandmother's traditional lemon bar this sweet and sour treat has an amazing lemon flavor that is rich and tart. A sweet lemon filling sits on a Gluten-Free shortbread style crust. Also available on a dairy-free crust! | {
"pile_set_name": "Pile-CC"
} |
Gold Dust Lounge closing, but hoping to move
San Francisco's Gold Dust Lounge, the Union Square drinking establishment that is being evicted from its current Powell Street home, is closing Wednesday night.
But not forever, according to Lee Houskeeper, a publicist for the bar.
The bar's owners, James and Tasios Bovis, plan to recreate the Gold Dust Lounge piece by piece in a larger space in Fisherman's Wharf, he said.
Houskeeper said he cannot yet disclose the exact location, for which a lease is still in the works.
He said "we don't expect a problem," but said he could not say exactly where it will be until the ink on the lease dries, which he hopes will happen before an afternoon news conference scheduled for Wednesday, he said.
"There's a lot of moving parts," Houskeeper said.
Work to be done includes stripping the existing space of its furnishings and decorations and reinstalling the items in the new space.
The process, which will get under way Thursday, is expected to take about four months, according to Houskeeper.
"I think people are grateful that the place is going to exist ... and that the Bovises are going to spend all this time to recreate the thing that they love," Houskeeper said of the bar's loyal patrons.
Fans of the establishment created a grassroots movement in support of the bar that ultimately failed to keep it in its current location.
In the meantime, Houskeeper said, the Bovis family will set up a temporary Gold Dust Lounge in a back room at Lefty O'Doul's, which it also owns. | {
"pile_set_name": "Pile-CC"
} |
Report: Carson Wentz (back) not expected to play vs. Rams
Anticipation was high for the second meeting between Jared Goff and Carson Wentz on Sunday when the Eagles visit the Rams, but it looks like Los Angeles will be facing a Super Bowl MVP instead. According to Ian Rapoport, Wentz is not expected to play this weekend against the Rams due to a back injury.
It’ll be Nick Foles at quarterback.
#Eagles QB Carson Wentz, dealing with a back issue, is not expected to play this week, sources say. Depending on the result, given the time of year, Wentz may not play again in 2018. The team is still gathering info on his health.
Wentz has been limited in practice with a back injury before, dating all the way back to October. This has seemingly been a lingering issue, and with the Eagles nearly falling out of the playoff hunt, the team is playing it safe with its franchise quarterback.
In last year’s meeting with the Rams, Wentz suffered a torn ACL, which ended his season and gave the keys to Foles, who led Philadelphia to a Super Bowl title.
This is a huge break for the Rams, who were 9.5-point favorites over the Eagles prior to this announcement.
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"pile_set_name": "Pile-CC"
} |
1. Field of the Invention
The present invention relates to novel guanidinobenzene derivatives, a process for the production thereof, and an antiviral agent comprising a guanidinobenzene derivative. These derivatives are useful for the treatment for various viral-related diseases.
2. Description of the Related Art
Japanese Unexamined Patent Application (KOKAI) No. 49-24917 discloses thiol esters of guanidino organic acid having an antiviral activity represented by the general formula: ##STR2## wherein A represents a linear or branched alkylene group having 1 to 10 carbon atoms; B represents p-phenylene group or a cycloalkylene group; a represents 0 or 1; b represents 0 or 1; a+b totals 1 or 2; R represents a linear or branched alkyl group having 1 to 10 carbon atoms, a carboethoxyalkyl group having 1 to 10 carbon atoms, a cycloalkyl group, an aromatic group or a phenylalkyl group, wherein the cycloalkyl group and the aromatic group can be substituted with a lower alkyl group, a carboethoxy group, a carboethoxy-lower alkyl group, a carboxyalkyl group, a halogen atom, an alkoxy group, an arylamide group, an alkylsulfonyl group, a carboxy group, a thiocarboxy group, a mercaptocarboxy group, a nitro group or a carbamoyl group. These types of compounds, however, exhibit an antiviral activity that is too weak for practical use.
In addition, as different types of antiviral agents, various kinds of nucleic acid derivatives are known; for example, amantadine, etc., are known as anti-influenza virus agents. The nucleic acid derivative type antiviral agents, however, cause side-effects such as liver function disorder, mutagenity and subacute toxicity, and the amantadine causes side effects such as teratogenicity, and further, the higher the frequency of use, the lower becomes efficacy (Virology, Raven Press, pp 323-348, 1985).
Therefore, new antiviral agents not having the above-mentioned drawback are urgently required. | {
"pile_set_name": "USPTO Backgrounds"
} |
Introduction
============
Neurotrophic keratitis (NK) is a rare degenerative corneal disease caused by damage of trigeminal innervation. Corneal nerves play an essential role in tear production and preservation of the normal metabolism and function of the ocular surface. Loss of sensitivity impairs corneal wound healing, leading to epithelial changes including punctate epithelial keratopathy, persistent epithelial defects, and corneal ulcer.[@b1-eb-10-037]
Various ocular and systemic diseases can cause damage to the fifth cranial nerve at different levels, from the trigeminal nucleus to the corneal nerve endings. Common causes are herpetic keratitis, diabetes, chemical or surgical damage, and neurosurgical procedures.[@b2-eb-10-037],[@b3-eb-10-037] Medical treatment consists mainly of supportive measures that do not address the underlying cause of the disease. Recently, novel promising treatments have been proposed and are currently under evaluation. These include mainly topical treatment with nerve growth factor (NGF) and surgical corneal neurotization. Such approaches target the pathogenic elements of NK, carrying the potential of restoring normal corneal innervation and sensitivity.
Pathogenesis
------------
The cornea is innervated by the ophthalmic branch of the trigeminal nerve as well as by autonomic nerves. Nerve bundles enter the cornea at the limbus, move toward the center below the anterior third of the stroma, penetrate Bowman's layer, and create a dense network of nerve fibers between Bowman's layer and basal epithelial cells (i.e., sub-basal nerve plexus).[@b4-eb-10-037] The great number of sensory nerve endings makes the cornea the most densely innervated tissue in the human body.[@b5-eb-10-037] Nerves have a key role in maintaining a healthy ocular surface, both by triggering protective reflexes after injury, and by providing trophic factors to the corneal cells. Corneal denervation causes decreased vitality, metabolism, and mitosis of epithelial cells, with subsequent epithelial changes including intracellular edema, loss of microvilli, and abnormal development of the basal lamina.[@b6-eb-10-037],[@b7-eb-10-037]
Corneal sensory innervation reacts to mechanical, chemical, and thermal stimuli with two reflex arcs: a motor arc eliciting blinking, and an autonomous arc stimulating tear secretion. Therefore, the reduction of corneal sensation impairs these two reflexes with an alteration of production and stability of the tear film.[@b8-eb-10-037]
Corneal nerves and epithelial cells support each other mutually through the release of trophic factors promoting epithelial cell proliferation, migration, and differentiation as well as nerve development and survival. Corneal nerves express many epitheliotrophic neuromediators, such as substance P, calcitonin gene-related peptide, acetylcholine, noradrenaline, serotonin, neuropeptide Y, and vasointestinal peptide. On the other side, corneal epithelial cells release various neurotrophic growth factors, including NGF, ciliary neurotrophic factor, and glial-cell-derived neurotrophic factor. These factors are fundamental in ocular surface homeostasis and wound healing.[@b4-eb-10-037]
In particular, NGF is a neurotrophin discovered in the early 1950s by R. Levi-Montalcini that promotes neuronal sprouting by intact and injured neurons. It provides trophic support to neurons after injury and reverses pathologic changes induced by peripheral nerve damage.[@b9-eb-10-037] NGF exerts its biologic functions by binding to low-affinity p75NTR (neurotrophin receptor, a member of the tumor necrosis factor receptor superfamily) and high-affinity TrkA receptor (a tyrosine kinase receptor family). The human cornea produces NGF and expresses high-affinity NGF receptors.[@b10-eb-10-037] NGF demonstrated an important role in the integrity and function of the ocular surface, stimulating both epithelial and nerve fiber proliferation and survival.[@b11-eb-10-037] In vivo studies proved that NGF concentration increases after injury, and that administration of NGF accelerates corneal healing.[@b10-eb-10-037]
These complex reciprocal relations between epithelial cells and nerves are crucial for the corneal physiologic renewal and wound healing. An impairment of corneal sensitivity interrupts these trophic relations and may produce the pathologic changes typical of NK.
Causes
------
All conditions that impair trigeminal innervation at any level can cause NK, such as ocular surface diseases, systemic diseases, and central or peripheral nervous damages ([Figure 1](#f1-eb-10-037){ref-type="fig"}).[@b12-eb-10-037],[@b13-eb-10-037]
Herpes simplex and herpes zoster eye infections are among the most common conditions leading to corneal anesthesia. In a large case series from Bonini et al, herpetic keratitis was the most common cause of NK (27% of the patients).[@b2-eb-10-037] A severe reduction of sub-basal nerve plexus density was demonstrated in herpetic keratitis.[@b14-eb-10-037]
Corneal surgeries like laser-assisted in situ keratomileusis, keratoplasty, and corneal incisions for cataract may disrupt corneal innervation and cause NK.[@b15-eb-10-037],[@b16-eb-10-037] After nerve transection at the peripheral cornea, the distal nerves undergo Wallerian degeneration with immediate loss of sensation to the corresponding region. Nerve regeneration occurs gradually over months with variable return of corneal sensitivity.[@b15-eb-10-037] Other ocular surface conditions associated with NK are corneal chemical and traumatic injuries, corneal dystrophies, contact lens wearing, and chronic use of topical medications (such as anesthetics, beta-blockers, antivirals, glaucoma medications, antibiotics, and nonsteroidal anti-inflammatory drugs).[@b12-eb-10-037],[@b13-eb-10-037]
Surgical procedures for the treatment of trigeminal neuralgia may induce permanent damage to the trigeminal nerve with subsequent corneal anesthesia. The main surgical options include microvascular decompression, balloon compression, radiofrequency thermocoagulation, and gamma knife radiosurgery. The intraoperative damage occurs at the preganglionic or ganglionic region of the nerve and is not associated with a reduction of sub-basal nerve plexus density.[@b17-eb-10-037] Other less common causes of trigeminal palsy are intracranial and orbital tumors, facial trauma, aneurysm, and stroke.[@b1-eb-10-037],[@b12-eb-10-037]
Systemic conditions like diabetes, multiple sclerosis, and leprosy may impair corneal sensitivity and cause NK. In particular, neuropathy is one of the most common complications of diabetes mellitus and results from microvascular damage of myelinated nerve fibers. The extent of nerve damage has been demonstrated to be associated with the duration of hyperglycemia.[@b18-eb-10-037] Corneal nerve evaluation in patients with diabetes has shown that the decreased corneal sensitivity was related to a reduction of sub-basal nerve density, with abnormally tortuous nerve fiber bundles. Additionally, a correlation between the decrease of corneal sensitivity and the degree of somatic polyneuropathy was found.[@b18-eb-10-037] Recent studies using in vivo confocal microscopy (IVCM) have reported an association between levels of glycated hemoglobin and the density of corneal innervation.[@b19-eb-10-037]
Long-term systemic therapy with antipsychotics and antihistamines may also cause NK. Very rare congenital causes of NK include Riley--Day syndrome, Moebius syndrome, Goldenhar--Gorlin syndrome, and congenital corneal anesthesia.[@b12-eb-10-037]
Clinical presentation
---------------------
The clinical presentation of NK is characterized by well-defined and progressive ocular surface changes, which are caused by the loss of sensitivity, regardless the cause of trigeminal damage. A three-stage classification of NK based on severity of corneal damage was introduced by Mackie.[@b1-eb-10-037]
Stage 1 is characterized by corneal abnormalities such as punctate keratopathy, corneal edema, corneal epithelial hyperplasia, and irregularity ([Figure 2A](#f2-eb-10-037){ref-type="fig"}). Rose Bengal staining of the conjunctiva, increased tear viscosity, and decreased breakup time are often associated. In long-standing cases, stromal scarring and superficial corneal neovascularization may develop.
Stage 2 is characterized by a recurrent or persistent epithelial defect, commonly located paracentrally in the superior half of the cornea. The epithelial defect is often delimited by smooth, rolled, and loose edges of an opaque and edematous epithelium ([Figure 2B](#f2-eb-10-037){ref-type="fig"}). Stromal edema with Descemet's membrane folds may be observed and sometimes anterior chamber inflammation is associated.
Stage 3 is characterized by corneal ulcer ([Figure 2C](#f2-eb-10-037){ref-type="fig"}). The stromal melting may progress to corneal thinning and eventually perforation. This may occur without significant ocular symptoms because of impaired corneal sensitivity; however, patients may complain of blurred vision in case of corneal ulcer, edema, or scarring.[@b1-eb-10-037],[@b12-eb-10-037]
Diagnosis
---------
Patient's clinical history should be accurately collected and reviewed to identify any ocular or systemic disease potentially associated with the disorder, such as ocular surface conditions (e.g., previous herpetic infection, ocular surgery, chemical burns, topical drug use, contact lens wearing), systemic diseases (e.g., diabetes, multiple sclerosis), and neurologic conditions (e.g., brain tumors, neurosurgery, stroke, trauma).
A careful ocular surface examination should be performed. In particular, eyelids should be examined to rule out the presence of lagophthalmos or blepharitis. Slit-lamp examination is fundamental to detect sings of NK and to classify NK severity, ranging from punctate corneal keratopathy to stromal melting and corneal perforation. Corneal anesthesia causes lack of ocular discomfort symptoms; thus, NK should be always suspected in case of significant discrepancy between ocular signs and symptoms. Ocular examination helps to identify also possible causes of decreased corneal sensitivity: corneal scarring may indicate previous injuries or infections; patchy iris atrophy may be a sign of previous herpetic infection. Fundus examination may show signs of diabetic retinopathy or optic nerve abnormalities due to intracranial pathology.[@b12-eb-10-037],[@b13-eb-10-037]
Vital staining with fluorescein or lissamine green is useful to assess corneal and conjunctival epithelial integrity. Tear film production and stability should be evaluated with lacrimal function tests. It is known that neurotropic keratitis is associated with an increase of tear osmolarity and a decrease of both Schirmer test and tear breakup time values.[@b8-eb-10-037],[@b20-eb-10-037]
The decrease or absence of corneal sensitivity is the diagnostic hallmark of NK. Corneal sensitivity can be quantitatively measured by Cochet--Bonnet esthesiometer, which employs a nylon monofilament of adjustable length touching the cornea and recording the patient's response. Each quadrant of the cornea may be tested. As the length of the filament is decreased, the pressure transmitted is increased.[@b21-eb-10-037] The noncontact Belmonte esthesiometer is another device allowing to investigate also chemical and thermal corneal sensitivity.[@b22-eb-10-037] However, it is typically reserved for research purposes, and not routinely used in clinical practice to date.
IVCM is a noninvasive imaging technique that allows the in vivo study of the different layers of the ocular surface at a cellular level. IVCM has been used to evaluate corneal nerve morphology in healthy and diseased corneas. A significant reduction of corneal nerve density strongly correlated with the decrease of corneal sensation was shown in patients with NK.[@b14-eb-10-037]--[@b18-eb-10-037] In addition, IVCM showed also a higher number of hyper-reflective keratocytes and a lower epithelial and endothelial cell density in patients with NK.[@b16-eb-10-037] These findings suggest that corneal sensory nerves play a role also in the function and survival of the corneal endothelium.
Treatment
---------
Treatment approach of NK should be prompt and based on the stage and severity of the disease. Despite various medical and surgical therapies having been proposed, NK remains yet difficult and challenging to treat, and the lack of positive response is commonly observed in the clinical practice.
In stage 1, the therapy aims at preventing an epithelial breakdown and improving epithelial quality. All topical and systemic medications associated with ocular surface toxicity should be discontinued. Preservative-free tear substitutes and lubricant ointments are useful to improve lubrication and ocular surface health. Other associated ocular surface diseases, such as dry eye, exposure keratitis, and limbal stem cell deficiency, should be properly treated.[@b12-eb-10-037]
In stage 2, therapy is addressed to promote healing of the epithelial defect, and to prevent the progression to corneal ulcer. Patient should be monitored frequently, because the progression to stromal melting and perforation may occur without any symptom. Topical antibiotics are recommended in this stage to prevent infections. On the contrary, topical steroids should be used with caution, because they may inhibit the healing process and increase the risk of corneal melting. Therapeutic contact lenses are useful to promote corneal healing, maintaining a fluid layer in stable contact with the cornea, and protecting it from the rubbing of the eyelids. However, attention should be paid because of the increased risk of infections.[@b23-eb-10-037]
Autologous serum eye drops have become increasingly popular for treating ocular surface disorders, including NK.[@b24-eb-10-037] Autologous serum contains several natural components of the normal tears, such as growths factors, neuromediators, cytokines, and vitamins.[@b25-eb-10-037] These substances are known to promote proliferation, migration, and differentiation of the ocular surface epithelium, and are essential in corneal homeostasis and wound healing.[@b26-eb-10-037] Matsumoto et al reported the complete healing of all the 14 eyes with NK treated with autologous serum drops and an increase in corneal sensitivity in 64.2% of cases.[@b26-eb-10-037] The study demonstrated that serum harbors neurotrophins and growth factors to the ocular surface. Other more recent studies confirmed that autologous serum eye drops allowed high rates of corneal healing, and also the improvement of corneal nerve morphology with increased number, length, width, and density detected by IVCM.[@b27-eb-10-037]--[@b29-eb-10-037]
The use of autologous serum may be inconvenient or contraindicated in patients with coexisting general conditions, such as anemia and blood discrasia. Therefore, the use of allogeneic sera obtained from healthy donors has been proposed as a viable alternative. Among these, umbilical cord blood serum is rich of epitheliotrophic growth factors, with higher levels of epidermal growth factor, insulin-like growth factor, transforming growth factor-beta, and vascular endothelial growth factors compared to peripheral blood serum.[@b30-eb-10-037],[@b31-eb-10-037] It has been shown that umbilical cord blood serum eye drops is effective in treating NK, achieving a complete corneal healing in all the patients under study.[@b32-eb-10-037] A recent IVCM study showed an improvement in corneal nerve morphology in patients treated with umbilical cord serum eye drops, with an increase of total nerve number and a decrease of nerve tortuosity.[@b33-eb-10-037] Two randomized clinical trials are currently ongoing to evaluate safety and efficacy of topical umbilical cord blood serum and plasma rich in growth factors in patients with NK (NCT02707120, NCT03084861).
Surgical treatment is usually limited to corneal ulcers (stage 3) not responding to medical treatment, and/or to the related complications. Several approaches are available, including tarsorraphy, conjunctival flap, and amniotic membrane transplantation. Tarsorraphy is the most commonly used procedure to promote corneal healing in NK. It reduces the width of the palpebral fissure, protecting the cornea from the traumatic rubbing of eyelids and decreasing tear evaporation rate.[@b34-eb-10-037] However, the poor cosmetic outcome is often a major concern for patients. The injection of Botulin A toxin into the superior elevator palpebrae superioris muscle is an effective alternative, allowing also an easier and better examination of the ocular surface compared to tarsorraphy.[@b35-eb-10-037]
The use of conjunctival flaps was first proposed by Gundersen in 1958 and became a standard surgical procedure to treat corneal ulcers with or without perforation.[@b36-eb-10-037] After a 360° peritomy, a pedunculated conjunctival flap is mobilized from the upper bulbar conjunctiva and sutured to the conjunctiva in the lower limbus to cover the affected cornea. The conjunctival flap provides metabolic and mechanical support for corneal healing, thanks to the conjunctival blood vessels, which transport nutrients and growth factors to the corneal surface.[@b37-eb-10-037] The procedure restores the anatomical integrity of the ocular surface but sacrifices visual function.
Amniotic membrane transplantation has been successfully used to treat corneal ulcers and persistent epithelial defects from different causes, including NK.[@b38-eb-10-037],[@b39-eb-10-037] The amniotic membrane provides mechanical protection, releases growth factors, and supports epithelial cell adhesion and proliferation.[@b38-eb-10-037] Evidence from a randomized controlled trial showed that both amniotic membrane transplantation and conventional management (tarsorraphy or therapeutic contact lenses) are effective in treating refractive NK.[@b40-eb-10-037]
Small perforations can be effectively treated with cyanoacrylate gluing followed by application of a bandage contact lens, whereas lamellar or penetrating keratoplasty is required for larger defects.[@b41-eb-10-037] However, persistent anesthesia causes impaired wound healing and a high risk of recurrence of corneal ulceration in the graft. This explains the low success rate of corneal transplantation in patients with NK.
Three cases from our cohort patients, which may be representative of different history and course of the disease, are shown in [Figure 3](#f3-eb-10-037){ref-type="fig"}. Explanation of each case is given in the legend.
Future prospects
----------------
NK was traditionally considered an orphan disease with no effective treatment. In recent years, novel promising medical and surgical treatments have been developed and are currently under investigation. Recent articles of novel medical treatments are summarized in [Table 1](#t1-eb-10-037){ref-type="table"}.
Regenerating agent (RGTA, Cacicol20^®^; OTR3, Paris, France) is a new matrix agent containing large polymers mimicking heparan sulfates. RGTA creates a microenvironment that induces cell migration and adhesion and promotes epithelial healing. A Phase III clinical trial is currently ongoing (NCT01794312). In a recent study, topical drops containing RGTA achieved complete healing of corneal ulcer in 73% of 11 patients with NK.[@b42-eb-10-037] Another work showed less favorable results, with a failure of corneal healing in 67% of treated patients.[@b43-eb-10-037] The combined therapy of RGTA and umbilical cord blood serum eye drops has been recently proposed, thanks to their synergistic effect.[@b44-eb-10-037] RGTA could replace destroyed heparan sulfates, protecting the bioavailability of growth factors and providing a matrix in which cells can migrate and multiply.[@b45-eb-10-037]
Thymosin beta-4 is an intracellular protein with various functions in different cellular processes, including wound healing, suppression of inflammation and apoptosis, synaptogenesis, and axon growth.[@b46-eb-10-037] The efficacy of topical treatment with thymosin beta-4 in nine patients with NK was described in an open study that reported a complete corneal healing in six patients with corneal ulcers, while the remaining three patients with punctuate epithelial defects did not show significant clinical changes.[@b46-eb-10-037] A randomized-controlled trial is currently ongoing to evaluate safety and efficacy of topical treatment with thymosin beta-4 in patients with NK (NCT02600429).
Topical substance P (SP) and insulin-like growth factor 1 (IGF-1) stimulate synergistically the proliferation and migration of corneal epithelial cells both in vitro and in vivo.[@b47-eb-10-037],[@b48-eb-10-037] In two recent studies, patients with epithelial defects associated to NK were treated with eye drops containing a combination of an SP-derived peptide and IGF-1-derived peptide.[@b49-eb-10-037],[@b50-eb-10-037] The treatment induced the healing of the epithelial defects in 89%[@b49-eb-10-037] and 73% of cases[@b50-eb-10-037] without any adverse side effect.
Topical treatment with NGF represents one of the most promising therapies for NK. NGF is a neurotrophin that promotes growth and survival of sensory and sympathetic neurons and can restore the function of injured neurons.[@b9-eb-10-037] NGF demonstrated a key role in the immune modulation, trophism, and healing of the ocular surface.[@b11-eb-10-037] Two open-label studies tested murine-derived NGF in patients with moderate (stage 2) and severe (stage 3) NK. The treatment induced rapid corneal healing in all the patients, with improved corneal sensitivity, tear production, and visual acuity without any adverse event.[@b2-eb-10-037],[@b51-eb-10-037] A recombinant human NGF eye drop formulation has been subsequently developed, and Phase I studies showed a good safety profile.[@b52-eb-10-037] Phase II trials are currently ongoing to evaluate the efficacy of two different formulations of this treatment in patients with NK stage 2 and 3 (NCT02227147, NCT01756456).
Nicergoline is an ergoline derivative used to treat degenerative and vascular dementia. In animal rat models, it was shown to promote corneal healing and to increase NGF levels in the cornea.[@b53-eb-10-037] A recent study evaluated treatment with oral nicergoline in patients with NK, demonstrating a healing of the epithelial defect in 23 out of 27 eyes, with an improvement of NGF levels and corneal sensitivity.[@b54-eb-10-037]
Corneal neurotization is a novel and promising surgical procedure for NK, which can be performed through two different techniques, based on the transposition of the supraorbital and/or supratrochlear nerves (direct neurotization),[@b55-eb-10-037],[@b56-eb-10-037] or on the sural nerve graft (indirect neurotization).[@b57-eb-10-037] In the first technique, contralateral healthy supraorbital and supratrochlear nerves are harvested through a large coronal incision, tunneled across the bridge of the nose and inserted around the limbus of the anesthetic eye. Six patients with NK were treated with this technique, and all the patients showed the improvement of corneal health and sensitivity.[@b55-eb-10-037] Allevi et al performed corneal neurotization according to the same technique, combined with upper eyelid neurotized platysma graft, and followed by penetrating keratoplasty in a patient with associated seventh and fifth cranial nerve palsy. The overall procedure was successful allowing patient to regain corneal sensitivity, eyelid movement, and visual acuity.[@b56-eb-10-037] As the ipsilateral frontal nerve is still intact in case of isolated corneal anesthesia from local damage to the long ciliary nerves, ipsilateral supraorbital nerve can be used to directly neurotize the cornea, allowing the decrease of the size of the scalp incision and the extent of the dissection needed.[@b58-eb-10-037]
In the indirect technique, corneal neurotization was performed using a sural nerve autograft anastomosed to the supratrochlear nerve and tunneled through the upper eyelid incision. Unlike the direct technique, this approach enables the management of bilateral NK and avoids the large bicoronal incision. Four eyes with NK were included in the study: three of them had noticeably improved corneal sensitivity 6 months after surgery.[@b57-eb-10-037] A recent cadaver feasibility study described a new minimally invasive technique for corneal neurotization using an endoscopic approach for direct nerve supraorbital nerve transfer.[@b59-eb-10-037] The potential advantages of the endoscopic corneal neurotization include smaller incisions, decreased operative and healing time, decreased forehead edema, less risk for facial nerve injury, and minimal blood loss. A pilot study is currently ongoing for NK stages 2 and 3 (NCT03037450).
The patients gave their consent for the photographs to be used in medical publication.
**Disclosure**
The authors report no conflicts of interest in this work.
{#f1-eb-10-037}
{#f2-eb-10-037}
{#f3-eb-10-037}
######
Novel medical treatments for neurotrophic keratitis
Study Eyes (no.) Treatment Posology Onset-treatment interval (days) Complete healing Healing time (days)
-------------------------------- ------------ -------------------- ----------------------------------- --------------------------------- ------------------ ----------------------------------------------------
Aifa et al[@b42-eb-10-037] 11 RGTA 1x/on alternate days \>15 72.7% 60.9
Arvola et al[@b43-eb-10-037] 6 RGTA 1x/on alternate days 45 33% 56
Dunn et al[@b46-eb-10-037] 9 Thymosin beta-4 4x/day \>42 67% 45
Nishida et al[@b49-eb-10-037] 9 SP and IGF1 4x/day 141 89% 13.3
Yamada et al[@b50-eb-10-037] 26 SP and IGF1 4x/day 96 73% 10.5
Lambiase et al[@b51-eb-10-037] 14 NGF Every 2 h for 2 days, then 6x/day 45 100% 21
Bonini et al[@b2-eb-10-037] 45 NGF Every 2 h for 2 days, then 6x/day 38 100% 22.8/26.6[a](#tfn1-eb-10-037){ref-type="table-fn"}
Lee et al[@b54-eb-10-037] 27 Nicergoline (oral) 10 mg 2x/day \>60 85% 15.6
**Note:**
Range (minimum/maximum).
**Abbreviations:** RGTA, regenerating agent; SP, substance P; IGF, insulin-like growth factor; NGF nerve growth factor; h, hours.
| {
"pile_set_name": "PubMed Central"
} |
Introduction {#s0005}
============
Cholangiocarcinoma (CCA) is a malignant cancer with an unknown etiology and an unfavorable prognosis. The morbidity and mortality of CCA have increased year by year worldwide [@bb0005]. Because of limited diagnostic methodologies, the majority of patients are diagnosed at advanced stages and are not eligible for surgery, and many of these patients are further chemo-resistant to conventional chemotherapy [@bb0010]. Therefore, for the past three decades, the 5-year survival rates of CCA has remained only 10% [@bb0010]. Consequently, it is essential to find novel curative targets and therapeutic strategies for CCA.
To meet the high demand for rapid proliferation under different stressed conditions, cancer cells reprogram their metabolisms [@bb0015]. Known as the Warburg effect, this metabolic reprograming is marked by a conversion from oxidative phosphorylation to aerobic glycolysis [@bb0020], [@bb0025]. This metabolic reprogramming produces anti-oxidant substances, reduces tumor oxidative stress, thereby finally promoting the proliferation of tumors. These metabolic changes facilitate the accumulation of lactate and glycolytic intermediates to promote the growth and invasion of tumor. Hence, reversing the Warburg effect can be a potential mechanism for cancer therapy [@bb0030]. Changes in the expression of key enzymes that catalyze these biosynthesis pathways have been found in multiple tumor metabolic reprogramming [@bb0035]. Pyruvate dehydrogenase (PDH) complex is a multi-enzyme complex that regulates carbohydrate and fat metabolism, of which PDHA1 is the major component [@bb0040]. PDH can catalyze the irreversible decarboxylation of pyruvate into acetyl-CoA, which plays a crucial role in many biological reactions [@bb0045]. Abnormal expression of PDH has been found in a variety of tumors. Several studies have found that PDH activates the metabolism of cancer cells from glycolysis to glucose oxidation, which reduces the lactate production and increases reactive oxygen species (ROS), thus inducing the apoptosis and proliferation of tumor cells [@bb0050].
In the process of metabolic reprogramming, another important factor for cancer cell proliferation is the activation of the serine synthesis pathway (SSP) [@bb0055]. Serine is a non-essential amino acid in mammals, but plays an essential role in cancer progression [@bb0060]. Glycolytic metabolisms of glucose can be catalyzed by 3-phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT1), and phosphoserine phosphatase (PSPH) to produce serine. Therefore, PHGDH, PSAT1, and PSPH are considered important components of SSP. As a scavenger of ROS, serine contributes to the redox balance to promote the proliferation of cancer cells [@bb0065]. However, the specific role of SSP in cancer remains largely unexplored.
Post-translational modifications in metabolism regulation have attracted attention because of their ability to respond to changes in cellular metabolic status and regulate through upstream signal transduction pathways. Acetylation is a crucial post-translational modification found in the metabolic enzymes of cell regulation [@bb0070]. Deacetylases are classified into four groups (I-IV), wherein sirtuin (SIRTs) are NAD^+^-dependent class III histone deacetylases (HDACs). Among the seven SIRT homologues in mammals [@bb0075], SIRT2 catalyzes a variety of biological processes such as metabolism and gene expressions [@bb0080]. There is growing evidence that SIRT2 promotes proliferation in malignant tumors [@bb0080], [@bb0085]. Studies have demonstrated that SIRT2 inhibitors have anti-tumor, anti-diabetic, and anti-inflammatory effects [@bb0090]. Recent studies have shown that SIRT2 can inhibit the ubiquitin degradation of cMYC, thus contributing to the stability of cMYC and the proliferation of cancer. However, a SIRT2 inhibitor, thiomyristoyl (Tm), can inhibit the growth of cancer cells by degrading cMYC [@bb0095]. cMYC is an important transcription factor, which is up-regulated in numerous human tumors [@bb0100]. A recent research has further found that cMYC can stimulate SSP activation by transcriptionally up-regulating the expressions of SSP-related enzymes [@bb0105]. Together, these findings suggest that targeting the inhibition of SIRT2/cMYC may play a crucial role in cancer prevention and treatment. However, it remains unclear regarding whether the SIRT2/cMYC pathway has a synergistic effect on the metabolic reprogramming of CCA.
In the present study, we found that SIRT2/cMYC promoted metabolic reprogramming in CCA through two signaling pathways: 1) promoting PDHA1 phosphorylation (p-PDHA1) to inhibit oxidative phosphorylation; and 2) promoting serine synthesis by activating the SSP pathway to reduce apoptosis. The SIRT2/cMYC pathway plays a crucial role in transforming glucose oxidative metabolism to serine anabolic metabolism and thus provides antioxidants for stress resistance. SIRT2/cMYC-induced metabolic reprogramming may thus represent a new therapeutic target for treating CCA.
Materials and Methods {#s0010}
=====================
Ethics Approval and Consent to Participate {#s0015}
------------------------------------------
All experiments utilizing human samples and involving animals were reviewed and approved by the Ethical Committee and Animal Welfare Committee of Drum Tower Hospital, Nanjing University.
Cell Culture {#s0020}
------------
The cells were maintained at 37°C with 5% CO~2~. Three human CCA cell lines were used: HIBEpic (ScienCell, Carlsbad, CA, USA), HuCCT1 (JCRB, Osaka, Japan) and RBE (The Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China). The cells were maintained in RPMI-1640 medium (Invitrogen, Waltham, MA, USA) containing 10% fetal bovine serum (Biological Industries, Cromwell, CT, USA), penicillin (Invitrogen) (100 U/ml), and streptomycin (Invitrogen) (100 U/ml). N-acetyl-L-cysteine (NAC, A7250) and CPI-613 (S2776) were purchased from Sigma-Aldrich (St. Louis, MO, USA) and Selleck (Houston, TX, USA), respectively. Tm (MCE, Monmouth Junction, NJ, USA) was commercially purchased.
Cell Transfection {#s0025}
-----------------
SiRNAs targeting cMYC (5′-GUCAAGAGGCGAACACACA-3′), PDHA1 (5′-CCGAATGGAGTTGAAAGCAGAT-3′), and negative control siRNA were purchased from RiboBio (Guangzhou, China). The full-length cMYC and PDHA1 plasmids were gifts from the Zhao lab of Fudan University (Shanghai, China). HuCCT1 and RBE cells were transfected using Lipofectamine RNAiMax reagent (Invitrogen) according to the manufacturer's instructions.
Cell Viability Assay {#s0030}
--------------------
Cell viability was investigated by CCK-8 assay in 96-well plates (5×10^3^ cells/well). Different concentrations of Tm or 0.1% dimethyl sulfoxide (DMSO) were added at indicated times. A total of 10 μl CCK-8 solutions (Dojindo, Minato-ku, Tokyo, Japan) was added to each well and they were incubated at 37 °C for 1 h. Absorbance was recorded at 450 nm. For each experimental trial, wells were conducted in triplicate and each well was assayed in triplicate.
Migration and Invasion Assays {#s0035}
-----------------------------
Cellular motility and invasive abilities were determined using Transwell (Corning Life Sciences, Bedford, MA, USA) and Matrigel invasion (BD Biosciences, San Jose, CA, USA), respectively. For the transwell migration and invasion assay, 5 × 10^4^ cells and 2 × 10^5^ cells were seeded, respectively. The cells that migrated to the underside of the membrane were fixed and stained with 0.1% crystal violet, and 10 microscopic fields were counted. The average values of the migrating or invading cells were expressed as percentages. Each experiment was performed in replicate inserts, and the average value was calculated from three independent experiments.
Colony Formation Assay {#s0040}
----------------------
CCA cells were counted and seeded in 6-well plates with 500 cells/well. After treatment with 25 μM Tm for 24 hours, the Tm was removed and normal medium was added for 14 days. The cells were fixed in methanol and colonies were counted after staining with 0.1% crystal violet in 25% methanol for 20 mins. The results were presented as the average number of counted colonies per well under each condition. All the experiments were performed in triplicate and repeated three times independently.
Apoptosis Assay {#s0045}
---------------
Apoptosis was detected by flow cytometry using the Annexin V-fluorescein isothiocyanate (FITC) Apoptosis Detection Kit (556, 547, BD Biosciences), following the manufacturer's instructions.
Western Blotting {#s0050}
----------------
The cells were lysed using RIPA buffer (150 mM NaCl, 50 mM Tris-HCl at pH 7.4, 1 mM EDTA, 0.1% SDS, 1% Triton X-100, 1% sodium deoxycholate and 1% NP-40) mixed with a protease and phosphatase inhibitor cocktail (Roche Diagnostics GmbH, Mannheim, Germany) and phenylmethylsulfonyl fluoride (PMSF) (Biosharp, Hefei, China) for 15 min on ice. The proteins were subjected to western blotting according to standard protocols. Antibodies were as follows: SIRT2 (HPA011165,Sigma), SIRT2 (s8447, Sigma), cMYC (ab32072, Abcam, Cambridge, UK), p293-PDHA1 (ab92696, Abcam), GAPDH (ab128915, Abcam), cleaved-caspase3 (9664s, CST, Danvers, MA, USA), cleaved-PARP (5625s, CST), PDHA1 (ab110334, Abcam), PHGDH (14719-1-AP, Proteintech, Chicago, IL, USA), PSAT1 (10501-1-AP, Proteintech), PSPH (14513-1-AP, Proteintech), HRP-conjugated anti-rabbit (7074, CST), and anti-mouse antibodies (7076, CST).
Metabolite Analysis {#s0055}
-------------------
Metabolism experiments were carried out as described previously [@bb0110]. Metabolite extracts were collected. A total of 2 μl of metabolite extracts were injected for gas chromatography-mass spectrometer (GC-MS) analysis using an Agilent 6980 GC coupled to an Agilent 5973 MS system. Relative metabolite abundances were investigated by comparing the abundance of each metabolite with internal standards and cell protein standards.
Mitochondrial Oxidative Phosphorylation Analysis {#s0060}
------------------------------------------------
The real-time oxygen consumption rate (OCR) was detected using an XF96 Extracellular Flux Analyzer (Seahorse Bioscience, North Billerica, MA, USA). According to the manufacturer's instructions, the cells were seeded at 1x10^4^ cells/well in 96-well XF cell culture microplates and incubated at 37 °C for 24 h. A total of 25 μM Tm was added to each well of each plate. Before measurement, the medium was replaced with 175 μl/well XF-96 running medium (supplemented with RPMI-1640 without serum) and pre-incubated at 37°C without CO~2~ for 20 min. For each analysis, different compounds that modulate mitochondrial respiration were injected into each well, according to standard protocols: for the OCR -- oligomycin, carbonylcyanide p-trifluoromethoxy-phenylhydrazone, rotenone and antimycin A; for the extracellular acidification rate (ECAR) -- glucose, oligomycin and 2-deoxy-D-glucose. Cell number was used for data normalization. The OCR was expressed as picomoles/minute (pmol/min). The ECAR was expressed as milli-pH units per minute (mpH/min).
ROS and Glutathione Measurement. {#s0065}
--------------------------------
For cellular ROS the analyses, 3 × 10^5^ cells/well were seeded into a six-well plate and different concentrations of Tm were added at the indicated times. After treatment, the redox-sensitive probe DCF (5 μM) was incubated for 30 min. Fluorescence intensity was measured immediately by flow cytometry analysis in the six-well plate-treated cells. The levels of GSH and GSSG were measured in the cells or tumor lysates according to the GSH and GSSG Assay Kit instructions (S0053, Beyotime Biotechnology, Jiangsu, China). The experiments were conducted in triplicate and repeated three times independently.
Differentially expressed genes (DEGs) of Paired-CCA from the Cancer Genome Atlas (TCGA) Data {#s0070}
--------------------------------------------------------------------------------------------
The CCA RNA-Seq data was downloaded from the TCGA database using the GDC Data Portal at <https://gdc-portal.nci.nih.gov>. The mRNA expression data included 18 samples consisting of 9 normal samples and 9 matched CCA samples. The sequencing data were public, and ethical issues were not relevant. The edgeR package in Bioconductor was used to screen the DEGs in the CCA and normal tissue samples. The edgeR package is based on a negative binomial (NB) distribution, which corrects the problem of overdispersion in RNA-Seq data using the Poisson model and the Bayes procedure. Data with a value of zero were deleted. If \|FoldChange\| \>2, the genes were considered to be DEGs with a *P* value \<.01 and a false discovery rate (FDR) \<0.05.
Functional Annotation {#s0075}
---------------------
The Database for Annotation Visualization and Integrated Discovery (DAVID) online tool (<https://david.ncifcrf.gov/>) was used to perform functional and pathway enrichment analyses in our study. GO and KEGG pathway enrichment assays were performed to detect the potential biological functions and pathways of the high- and low-expression genes in CCA.
Immunohistochemistry {#s0080}
--------------------
Two to five human CCA specimens from one patient were used in the immunohistochemistry (IHC) study. Tumor specimens from humans and mice were fixed in 4% paraformaldehyde and embedded in paraffin. Except for target detection, the IHC followed standard procedures. The intensity of staining in each tissue was evaluated by multiplying the staining's range and intensity [@bb0115].
CCA Cancer Xenograft Model {#s0085}
--------------------------
Female nude mice were subcutaneously injected in the flanks with 100 μL PBS or 2 × 10^6^ HuCCT1 cells suspended in 100 μL Matrigel. The mice were allowed to recover after the injections and monitored for three weeks. Tumors were measured using a caliper and once the majority of tumors reached a threshold size of 200 mm^3^, intraperitoneal (IP) injections of DMSO or Tm were initiated. IP injections of 1.5 mg Tm in 50 μL DMSO were administered once a day. After one month of treatment, or if the mice met the humane endpoint criteria, they were euthanized via CO~2~ asphyxiation. Tissues were collected, fixed with 10% neutral formaldehyde, embedded in paraffin, sectioned, and stained with hematoxylin and eosin (HE). Serum, organs, and tumor tissues were frozen in liquid nitrogen and then stored at -80°C for subsequent analyses.
Statistics {#s0090}
----------
All the data were presented as means ± SEM. The data were analyzed using one-way ANOVA followed by post hoc Duncan tests (GraphPad Prism version 5.0, GraphPad Software, La Jolla, CA, USA). *P* \< .05 was considered significant.
Results {#s0095}
=======
SIRT2, cMYC, and p-PDHA1 contributed to CCA metabolic reprogramming and were associated with poor prognosis {#s0100}
-----------------------------------------------------------------------------------------------------------
Metabolic reprogramming can be regulated through the expression of multiple genes to accelerate the malignant behavior of tumor cells [@bb0120]. Therefore, differentially expressed genes (DEGs) in CCA were analyzed using data from the Cancer Genome Atlas (TCGA) and the most relevant DEGs associated with metabolism and apoptosis were confirmed ([sFigure 1](#f0040){ref-type="graphic"}*A*). As a transcription factor and downstream protein of SIRT2, cMYC has attracted extensive interest for its potential role in tumorigenesis in many different human cancers -- especially for its role in regulating the expression of metabolic genes such as lactate dehydrogenase (LDH) and muscle-specific pyruvate kinase 2 (PKM2) [@bb0125], [@bb0130]. Furthermore, PDH is a gatekeeper of tricarboxylic acid cycle (TCA) and is always highly phosphorylated, thereby leading to an inactive state and contributing to the Warburg effect [@bb0135]. In order to identify the relevant protein targets of metabolic reprogramming, we first screened the cMYC-related targets in a normal bile duct epithelial cell line (Hibepicc) and two human CCA cell lines (HuCCT1 and RBE). We confirmed high levels of p-PDHA1, SIRT2, and its upstream target cMYC in CCA cells ([Figure 1](#f0005){ref-type="fig"}*A*). Because the Warburg effect is the key feature of tumor metabolism, the metabolic reprogramming changes were then evaluated by over-expressing SIRT2 in CCA cells. We found that while SIRT2 decreased the levels of TCA-related metabolites, it increased the level of lactate, thereby promoting the Warburg effect ([Figure 1](#f0005){ref-type="fig"}*A* and [sFigure 1](#f0040){ref-type="graphic"}*B*). Overall, 48 CCA samples were used and the clinical characteristics were summarized in [Table 1](#t0005){ref-type="table"}. We found that the expressions levels of SIRT2, cMYC, and p-PDHA1 were elevated in CCA tissues compared to those in adjacent tissues ([Figure 1](#f0005){ref-type="fig"}, *C* and *D*). In addition, these elevated expressions were associated with lower survival rates ([Figure 1](#f0005){ref-type="fig"}*E*). Collectively, these results revealed that high levels of SIRT2, cMYC, and p-PDHA1 contributed to CCA metabolic reprogramming and were associated with a poor prognosis.
PDHA1 is the Downstream Target of SIRT2/cMYC, But Is Unnecessary for CCA Apoptosis {#s0105}
----------------------------------------------------------------------------------
PDHA1 is the downstream target of SIRT2/cMYC, but is unnecessary for CCA apoptosis. As a well-known metabolic regulator, cMYC can be stabilized by the deacetylation activity of SIRT2 [@bb0095]. We confirmed that SIRT2 stabilized cMYC protein through post-translational modification in CCA ([sFigure 1](#f0040){ref-type="graphic"}*B* and 1C). To further investigate how SIRT2 regulates metabolic reprogramming, Tm (a SIRT2 inhibitor) was added to CCA cells. After the inhibition of SIRT2, cMYC and p-PDHA1 decreased while apoptosis-related proteins (c-Caspase 3 and c-PARP) increased ([Figure 2](#f0010){ref-type="fig"}*A*). Furthermore, after knocking-down cMYC in CCA cells, we found that p-PDHA1 and apoptosis-related proteins decreased ([Figure 2](#f0010){ref-type="fig"}*B*). Also, rescue experiments showed over-expressing cMYC help CCA cells resist apoptosis in the presence of TM ([Figure 2](#f0010){ref-type="fig"}*C*). This suggests that PDHA1 is the downstream of the SIRT2/cMYC pathway. Conversely, neither CPI613 (a PDHA1 inhibitor) nor PDHA1 knockdown could significantly change the levels of apoptotic proteins in CCA cells ([Figure 2](#f0010){ref-type="fig"}, *D* and *E*). Additionally, the inhibition of PDHA1 led to a reduction of the OCR, which suggests a decrease in TCA ([Figure 2](#f0010){ref-type="fig"}*F*). The aforementioned results together suggest that PDHA1 is the downstream target of SIRT2/cMYC by regulating glucose metabolism in CCA. The inhibition of PDHA1 alone was insufficient to promote apoptosis in CCA.
SIRT2 Inhibition Reduces CCA Biological Activity {#s0110}
------------------------------------------------
To observe the effects of SIRT2 inhibitor on the biological activity of CCA, HuCCT1 and RBE cells were treated with indicated Tm. After the inhibition of SIRT2, CCA cells showed marginal differences in phenotypes ([Figure 3](#f0015){ref-type="fig"}*A*). The cell growth was consistently affected after Tm treatment ([Figure 3](#f0015){ref-type="fig"}*B*). In accordance with these results, colony formation in CCA cells decreased when treated with Tm ([Figure 3](#f0015){ref-type="fig"}*C*). Additional transwell assays were then performed, and when SIRT2 was inhibited, a reduction in cell migration and invasion was observed ([Figure 3](#f0015){ref-type="fig"}*D*). Next, flow cytometry was used to study the mechanism by which Tm inhibited CCA cell proliferation. It was found that Tm enhanced apoptosis in CCA cells ([Figure 3](#f0015){ref-type="fig"}, *E* and *F*). This indicates that Tm, the SIRT2 inhibitor, can reduce the biological activity of CCA cells.Figure 1**High expression levels of SIRT2, cMYC, and p-PDHA1 were found in CCA and are associated with poor prognosis.**(A) The expression levels of SIRT2, cMYC, and p-PDHA1 in a normal bile duct epithelial cell line (HIBEpic) and two human CCA cell lines (HuCCT1 and RBE) were determined by western blotting. (B) CCA cells were overexpressed with either SIRT2 plasmids or control vectors; the cells were then collected and lysed and the concentrations of metabolites were measured by MS. (C & D) The SIRT2, cMYC, and p-PDHA1 protein levels in the tumors and adjacent tissues from 60 CCA patients were detected by IHC and quantified. The magnification is ×200. Scale bars, 100 μm. (E) The 3-year survival was evaluated in CCA patients with SIRT2, cMYC, and p-PDHA1 protein expressions, respectively. Data represent mean ± SEM, n ≥ 3. \*\**P* \< .01.Figure 1Figure 2**PDHA1 is the downstream target of SIRT2/cMYC.**(A) HuCCT1 and RBE cells were treated with 0, 25, or 50 μm Tm and subjected to western blotting. (B & C & D & E) HuCCT1 and RBE cells were transfected with siRNA of cMYC, plasmids of cMYC, CPI-613, Tm, or siRNA of PDHA1, respectively, and subjected to western blotting. (F) The OCRs were detected at different time points. The OCR was under oligomycin, carbonyl cyanide-m-chlorophenylhydrazone (FCCP), and antimycin A/rotenone treatments, respectively. Data represent mean ± SEM, n ≥ 3.Figure 2Table 1Clinical characteristics of patients with cholangiocarcinomaTable 1nLow (%)High (%)X^2^*P* valuecMYC expression, n (%)Gender0.333.564Male2411 (45.8)13 (54.2)Female2413 (54.2)11 (45.8)Age1.371.242≤60208 (40.0)12 (60.0)\>602816(57.1)12 (42.9)Location0.785.675Intrahepatic198 (42.1)11 (57.9)Hepatic portal95 (55.6)4 (44.4)Extrahepatic2011 (55.0)9 (45.0)Size (mm)0.403.525≥40146 (42.9)8 (57.1)\<403418 (52.9)16 (47.1)Differentiation6.155.046Well164 (25.0)12 (75.0)Medium2818 (64.3)10 (35.7)Poor42 (50.0)2 (50.0)T Stage0.949.330T1\~T23519 (54.3)16 (45.7)T3\~T4135 (38.5)8 (61.5)Lymph node metastasis0.403.525Negative3418 (52.9)16 (47.1)Positive146 (42.9)8 (57.1)Distant metastasis1.091.296Negative4423 (50.0)21 (50.0)Positive41 (50.0)3 (50.0)Venous invasion0.085.771Negative2714 (51.9)13 (48.1)Positive2110 (47.6)11 (52.4)Nerve invasion1.613.204Negative145 (35.7)9 (64.3)Positive3419 (55.9)15 (44.1)*SIRT2 expression, n (%)*Gender0.784.376Male2413 (54.2)11 (45.8)Female2416 (66.7)8 (33.3)Age0.002.960≤602012 (60.0)8 (40.0)\>602817 (60.7)11 (39.3)Location0.843.656Intrahepatic1913 (68.4)6 (31.6)Hepatic portal95 (55.6)4 (44.4)Extrahepatic2011 (63.6)9 (36.4)Size (mm)0.089.766≥40148 (57.1)6 (42.9)\<403421 (61.8)13 (38.2)Differentiation0.463.793Well169 (56.3)7 (43.8)Medium2818 (64.3)10 (35.7)Poor42 (50.0)2 (50.0)T Stage6.553.010T1\~T23525(71.4)10 (28.6)T3\~T4134 (30.8)9 (69.2)Lymph node metastasis0.089.766Negative3421 (61.8)13 (38.2)Positive148 (57.1)6 (42.9)Distant metastasis6.660.010Negative4429 (65.9)15 (34.1)Positive40 (0.0)4 (100.0)Venous invasion0.167.683Negative2717 (63.0)10 (37.0)Positive2112 (57.1)9 (42.9)Nerve invasion1.002.317Negative1410 (71.4)4 (28.6)Positive3419 (55.9)15 (44.1)Gender4.269.039*SIRT2 expression, n (%)*Male2411 (45.8)13 (54.2)Female2418 (75.0)6 (25)Age3.407.065≤60209 (45.0)11 (55.0)\>602820 (71.4)8 (28.6)Location3.220.200Intrahepatic1910 (52.6)9 (47.4)Hepatic portal94 (44.4)5 (55.6)Extrahepatic2015 (75.0)5 (25.0)Size (mm)0.897.344≥40147 (50.0)7 (50.0)\<403422 (64.7)12 (35.3)Differentiation3.388.184Well167 (43.8)9 (56.3)Medium2820 (71.4)8 (28.6)Poor411(50.0)10 (50.0)T Stage4.365.037T1\~T23518 (48.6)17 (51.4)T3\~T41311 (84.6)2 (15.4)Lymph node metastasis2.859.091Negative4425 (56.8)19 (43.2)Positive44 (100.0)0 (0.0)Distant metastasis01Negative5628 (50.0)28 (50.0)Positive42 (50.0)2 (50.0)Venous invasion0.167.683Negative2717 (63.0)10 (37.0)Positive2112 (57.1)9 (42.9)Nerve invasion5.043.025Negative145 (35.7)9 (64.3)Positive3424 (70.6)10 (29.4)Figure 3**SIRT2 inhibitor reduces CCA biological activity.**(A) HuCCT1 and RBE cells were treated with or without 25 μM Tm for 24 h or 72 h and the morphological changes were observed. Scale bars, 100 μm. (B) CCA cells were treated with 0-100 μM Tm for 0-72 h, and the cell proliferation was then quantified via CCK-8 assays. (C) CCA cells were treated with or without 25 μM Tm; colonies were stained with crystal violet (left) and quantified (right). Scale bars, 1 cm. (D) CCA cells were treated with or without 25 μM Tm; cell invasion was quantified. (E & F) CCA cells were treated with 0, 25, or 50 μM Tm; apoptotic cells were measured and quantified using flow cytometry. Data represent mean ± SEM, n ≥ 3. \**P* \< .05, \*\**P* \< .01, and \*\*\**P* \< .001.Figure 3
The SIRT2/cMYC Pathway has Antioxidant Effects on CCA by Promoting the Downstream SSP Pathway {#s0115}
---------------------------------------------------------------------------------------------
The imbalance between the antioxidants and pro-oxidants caused by superfluous reactive oxygen species (ROS) can promote apoptosis [@bb0140]. On the other hand, SSP plays a key role in antioxidant (T-GSH/GSSG/GSH) production and anti-apoptotic processes [@bb0145]. Consequently, we investigated whether Tm-induced apoptosis is related to ROS production. We found that Tm increased ROS level in a concentration-dependent manner ([Figure 4](#f0020){ref-type="fig"}*A*). More importantly, Tm decreased antioxidant (T-GSH/GSSG/GSH) levels, which can be reversed by NAC (acetylcysteine, a known antioxidant) ([Figure 4](#f0020){ref-type="fig"}*B*). We also found that Tm treatment decreased serine synthesis and the SSP pathway ([Figure 4](#f0020){ref-type="fig"}, *C* and *D*). Our results further revealed that Tm treatment inhibited the SSP pathway in both mRNA and protein levels ([Figure 4](#f0020){ref-type="fig"}, D--*F*, *H* and *I*). Similar to Tm treatment, cMYC knockdown also significantly decreased the levels of SSP pathway proteins in CCA cells ([Figure 4](#f0020){ref-type="fig"}, *G* and *J*). These results suggest that the SIRT2/cMYC pathway inhibited oxidative stress by promoting the SSP pathway and antioxidant production.Figure 4**SIRT2/cMYC has antioxidant effects on CCA by promoting the downstream SSP pathway.**(A) HuCCT1 and RBE cells were treated with 0, 25, or 50 μM Tm and the levels of ROS were detected. (B) CCA cells were treated with NAC, Tm, or a combination of both. The levels of T-GSH, GSSG, and GSH were detected. (C & D) CCA cells were treated with or without indicated Tm. The levels of pyruvate and serine were detected by MS. The relative mRNA levels of PHGDH, PSAT1, and PSPH were detected by qPCR. (E) The expressions of PHGDH, PSAT1, and PSPH in the HIBEpic and CCA cells were determined by western blotting. (F) CCA cells were treated with 0, 25, or 50 μM Tm and the levels of PHGDH, PSAT1, and PSPH were detected by Western blotting. (G) CCA cells were transfected with siRNA of cMYC and subjected to western blotting. Data represent mean ± SEM, n ≥ 3. \**P* \< .05 and \*\**P* \< .01Figure 4
SIRT2/cMYC Pathway Inhibits Oxidative Stress-Related Apoptosis by Promoting Antioxidants Production {#s0120}
---------------------------------------------------------------------------------------------------
Studies have found that both lowering glycolytic metabolism and promoting antioxidant production can lead to tumor apoptosis [@bb0140], [@bb0150]. As previously demonstrated, the SIRT2/cMYC pathway promotes metabolic reprogramming in CCA through two signaling pathways: 1) promoting p-PDHA1 to inhibit oxidative phosphorylation and 2) promoting serine synthesis by activating the SSP pathway to increase antioxidant production. To evaluate whether the SSP pathway plays a key role in CCA cell apoptosis, NAC (an antioxidant) was used in combination with Tm. Our results revealed that NAC treatment alone did not affect apoptosis in CCA cells, though Tm treatment alone was able to promote apoptosis. The combination of Tm and NAC, however, led to a significant decrease in apoptosis as compared with Tm used alone ([Figure 5](#f0025){ref-type="fig"}, *A* and *B*). Accordingly, ROS levels did not change in the NAC-treated cells and increased in the Tm-treated cells, and the combination of Tm and NAC led to a decrease in ROS compared to Tm used alone ([Figure 5](#f0025){ref-type="fig"}*C*). Detection of apoptosis proteins showed similar results ([Figure 5](#f0025){ref-type="fig"}*D*), suggesting that the SIRT2/cMYC pathway reduced oxidative stress-induced apoptosis by promoting the downstream SSP pathway.Figure 5**The SIRT2/cMYC pathway inhibits oxidative stress-related apoptosis by promoting antioxidant production.**(A & B) After treatment with Tm, NAC, or a combination of both, CCA cells were analyzed using Annexin V/PI staining and apoptosis was measured by flow cytometry. Percentages of early and late apoptotic cells were quantified. (C & D) After treatment with Tm, NAC, or a combination of both, the levels of ROS and proteins were detected. Data represent mean ± SEM, n ≥ 3. \**P* \< .05 and \*\**P* \< .01.Figure 5
SIRT2 Inhibitor has an Antitumor Effect on CCA *In Vivo* {#s0125}
--------------------------------------------------------
Finally, the expression levels of SIRT2, cMYC, and p-PDHA1 were assessed in fresh human CCA tissues. We found that these proteins significantly increased in tumor tissues as compared to that in adjacent tissues ([Figure 6](#f0030){ref-type="fig"}*A*). To further validate our findings, the anti-tumor effects of Tm were evaluated *in vivo* using a CCA cell tumor xenograft model. We observed that the Tm treatment group significantly inhibited tumor growth ([Figure 6](#f0030){ref-type="fig"}, *B* and *C*) without affecting mouse body weight ([Figure 6](#f0030){ref-type="fig"}*D*), suggesting that Tm treatment was safe *in vivo*. Lastly, the expression levels of these proteins were assessed in fresh xenograft tissues by both staining and western blotting, and we found that cMYC, p-PDHA1, PHGDH, PSAT1, and PSPH were markedly down-regulated following Tm treatment ([Figure 6](#f0030){ref-type="fig"}, *E* and *F*). These findings indicated that by inhibiting SIRT2 activity, Tm can degrade cMYC to decrease p-PDHA1 and SSP, thus exerting an anti-tumor effect *in vivo*.Figure 6**SIRT2 inhibitor has an anti-tumor effect on CCA *in vivo*.**(A) The levels of cMYC, p-PDHA1, and SIRT2 proteins in tumors and adjacent normal tissues from 6 donors were detected by western blotting. (B) HuCCT1 cells were injected subcutaneously into the flanks of nude mice. When tumors were palpable, DMSO (control) or Tm were administered. Tumors were collected and photographed. Scale bars, 1 cm. (C) Tumor volumes of mice were measured. (D) The body weights of mice were compared among the groups. (E & F) cMYC, p-PDHA1, PHGDH, PSAT1 and PSPH protein levels in xenograft tissues from control and Tm group were detected by staining and Western blotting. Data represent mean ± SEM, n ≥ 3. \**P* \< .05 and \*\**P* \< .01.Figure 6
Discussion {#s0130}
==========
Metabolic reprogramming of tumor cells includes abnormal metabolism in glucose and other substances such as amino acids and fats. Among these, the metabolic reprogramming of glucose is called the Warburg effect. Nonetheless, the question of how metabolites in metabolic reprogramming help induce tumorigenesis and which proteins are key targets for this metabolism remains unanswered. In this study, we identified the promoting role of the SIRT2/cMYC pathway in CCA, identified its downstream targets, and evaluated its therapeutic effect ([Figure 7](#f0035){ref-type="fig"}).Figure 7**Schematic model of the effects of SIRT2/cMYC pathway in CCA cells.**SIRT2 and cMYC reprogrammed the metabolism of CCA cells by up-regulating downstream p-PHDA1 and PHGDH/PSAT1/PSPH. The metabolic reprogramming increased SSP and decreased mitochondrial oxidative phosphorylation, thus contributing to redox homeostasis, consequently protecting CCA cells from oxidative stress-induced apoptosis.Figure 7
SIRT2 is a highly conserved enzyme that widely exists across species, from bacteria to humans. The removal of the acetyl group from lysine residues is coupled with the hydrolysis of NAD to generate nicotinamide, lysine, and O-acetyl-ADP-ribose. SIRT2 is responsible for catalyzing many biological processes, including genetic control, development and metabolism. Many previous studies have shown that SIRT2 increases the migration and invasion of cancer cells, demonstrating that it may play a role in promoting cancer proliferation and metastasis [@bb0155], [@bb0160]. However, some studies have shown that SIRT2 may be a tumor-suppressor gene in various other cancers [@bb0165]. Therefore, SIRT2 might promote tumor progression in certain cases, such as human gastric cancer and pancreatic cancer, while under other conditions it may inhibit tumor progression. It is worth noting that LDH-A [@bb0170], tubulin [@bb0175], and phosphoenolpyruvate carboxykinase (PEPCK) [@bb0180] are substrates of this deacetylase, suggesting that SIRT2 affects different metabolism in different tumors to promote the biological behaviors of various tumors. In fact, after inhibiting SIRT2 in CCA cells, two significant changes in different metabolic pathways are observed: one is glycolysis reversal by promoting PDHA1 phosphorylation (p-PDHA1) to inhibit oxidative phosphorylation and the other is promotion of the SSP pathway via aiding serine synthesis activity. Interestingly, we found that the reversal of PDHA1 phosphorylation alone was insufficient to induce significant apoptosis. This indicates that although glucose metabolism changes induced by SIRT2 are observed in CCA apoptosis, a high degree of serine anabolic metabolism provides an antioxidant effect against stress, which plays a more important role.
There are many kinds of SIRT2 inhibitors, mainly including nicotinamide, which inhibits NAD^+^-dependent reactions [@bb0185], and competitive inhibitors such as sirtinol, spitomicin, and cambinol [@bb0190]. Researchers have found that SIRT2 inhibitors have anti-tumor [@bb0125], anti-inflammatory [@bb0195], and anti-diabetic properties. SIRT2 shares a common structure with other members of the SIRT family, such as SIRT1, which is one of the most widely studied SIRTs and regulates cell migration, apoptosis, and proliferation [@bb0200]. Therefore, the off-target effects of inhibitors should not be ignored. Consequently, a specific inhibitor (Tm) was used. It inhibited SIRT2 with an IC50 value of 0.028 mM and SIRT1 with an IC50 value of 98 mM, but did not inhibit SIRT3, even at 200 mM [@bb0125]. Hence, the inhibition of SIRT2, rather than other SIRTs, may play a leading and more efficient role in reversing metabolic reprogramming. In addition, in the CCA tumorigenesis mouse model in which SIRT2 was inhibited by Tm, tumor growth was delayed without significant side effects.
As an oncogene, *cMYC* has received much attention as a result of its potential role in promoting tumorigenesis. There are many mechanisms by which cMYC induces tumorigenesis, and the enhancement of the Warburg effect is one method. This study found that cMYC is a crucial downstream target of SIRT2. Many studies have also elucidated that cMYC can elevate metabolic proteins such as LDHA and PKM2 [@bb0130], and is therefore considered a promising anti-cancer target. The present study demonstrates that cMYC has an elevated expression in CCA and predicts an unfavorable prognosis. In addition, cMYC is positively associated with p-PDHA1 and SSP-related enzymes and contributes to a high serine level. Our work has determined that the inhibition of cMYC can be used to reduce serine, thereby effectively promoting apoptosis in CCA cells.
Glucose is the main source for serine biosynthesis [@bb0205]. However, little is known about how glycolysis intertwines with SSP activation to coordinate cell survival and proliferation. Previous studies have reported that increased SSP activation was observed in breast cancer during serine starvation to maintain cell survival [@bb0210]. Herein we confirmed the importance of SSP activation in CCA proliferation. We also observed that by inhibiting the SIRT2/cMYC pathway, the reduced glycolytic metabolism changed to an elevated serine synthesis metabolism. These results suggest that high serine anabolic metabolism, which provides antioxidants for stress resistance, is essential for preventing apoptosis in CCA cells. We further observed that SIRT2/cMYC and its downstream targets may represent the intersecting points of metabolic reprogramming between glycolysis and SSP, highlighting the importance of SIRT2 for cell survival under redox imbalance conditions.
Our data show that the SIRT2/cMYC pathway plays a crucial role in the conversion of glucose oxidative metabolism to serine anabolic metabolism, thus providing antioxidants for stress resistance. SIRT2/cMYC-induced metabolic reprogramming may thus represent a new target for the treatment of CCA.
The following are the supplementary data related to this article.Supplementary Figure 1(A) Differentially expressed genes (DEGs) in CCA were analyzed using data from The Cancer Genome Atlas (TCGA). (B & C) CCA cells were treated with or without indicated Tm, MG132 or CHX for 24 hours. Cells were harvested and lysed, and endogenous cMYC was visualized by Western blotting. Data represent mean ± SEM, n ≥ 3.Supplementary Figure 1
Author contributions {#s0135}
====================
Mingming Zhang, Lei Wang, and Xiaoping Zou designed the study. Lei Xu, Dehua Tang, and Yida Pan conducted the cell experiments. Yuming Wang and Lei Xu collected the tissue samples. Lei Xu and Mingming Zhang performed the protein analysis. Lixing Zhou, Yuming Wang, Mingming Zhang, and Dehua Tang drafted the manuscript and conducted the immunohistochemistry experiments. Lei Xu performed the metabolite analysis. Robert G. Dorfman and Mingming Zhang wrote the manuscript. Mingming Zhang and Xiaoping Zou supported the study. All of the authors read and approved the final manuscript.
Acknowledgments {#s0140}
===============
We thank the Zhao lab for their assistance.
Grant support {#s0145}
=============
This work was supported by grants from the National Natural Science Foundation of China (Nos. 81602076, 81672935, and 81472756), the Outstanding Youth Project of Nanjing City (No. JQX17002), the Jiangsu Clinical Medical Center of Digestive Disease (BL2012001), the Natural Science Foundation from the Department of Science & Technology of Jiangsu Province (BK20160113), the Fund of Jiangsu Provincial Commission of Health and Family Planning (No. Q201611) and the Fundamental Research Funds for the Central Universities (No. 021414380244).
Conflicts of interest {#s0150}
=====================
The authors declare no conflicts of interest.
[^1]: These authors contribute equally to this work.
| {
"pile_set_name": "PubMed Central"
} |
Superficial and deep defects in dyschondroplastic and degenerated pig articular cartilage.
Normal and pathological (osteochondrotic and osteoarthrotic) pig articular cartilages from medial humeral and femoral condyles were studied by scanning electron microscopy. The pathological cartilages showed primitive osteochondrotic lesions with progressive aspects according to the severity of the pathology (flaking, fibrillation and cracks) and other superficial changes (micro-undulation, micro-fissurations, clefts) that appeared to be a consequence of the action of intense mechanical stresses such as shearing forces, compressive deformation, friction of the articular surfaces. The observation of deep lesions such as cracks and fractures at or near the interface between cartilage and calcified zone, frequently observed both at medial condyle and at intercondylar crista of the humerus, often evolving in cartilagineous flaps, were related to excessive tangential and shear forces induced by an abnormal articular topography resulting in joint instability. This pathological joint dynamic could be also worsened by an anomalous leg conformation (cross-legs) and/or by an increased occurrence of environmental micro- and macrotrauma (impact loading). Also in this case, the frequency and severity of the lesions can be increased if the deep layer is affected by osteo-chondrotic lesions. The results stress the pathogenetic importance of mechanical load in initiating and worsening the articular lesions in pigs; they also suggest that the resulting alterations can be influenced by a pre-existing different maturity or pathological condition of the cartilage. | {
"pile_set_name": "PubMed Abstracts"
} |
Bruno Teles
Bruno Martins Teles (born 1 May 1986), known as Bruno Teles, is a Brazilian footballer who plays as a left back in Portugal for Paços de Ferreira.
Career
Grêmio
Promoted from Under-20's in 2006, and made professional debut in the Gre–Nal derby in a 0–0 away draw on July 30, 2006.
Scored 1st senior goal in a 3–1 home victory over Santa Cruz on November 18, 2006. Has already been signed to the club until December 31, 2008.
Portuguesa
In July, 2008, Portuguesa signed Bruno, on loan from Grêmio.
Vitória de Guimarães
On 24 January 2010 Vitória de Guimarães signed the Brazilian left-back from Grêmio.
Honours
Grêmio
Campeonato Gaúcho: 2007
References
External links
Category:1986 births
Category:Living people
Category:People from Tocantins
Category:Brazilian footballers
Category:Campeonato Brasileiro Série A players
Category:Grêmio Foot-Ball Porto Alegrense players
Category:Associação Portuguesa de Desportos players
Category:Sport Club do Recife players
Category:Esporte Clube Juventude players
Category:CR Vasco da Gama players
Category:Mogi Mirim Esporte Clube players
Category:América Futebol Clube (MG) players
Category:Primeira Liga players
Category:Vitória S.C. players
Category:Rio Ave F.C. players
Category:F.C. Paços de Ferreira players
Category:Russian Premier League players
Category:LigaPro players
Category:FC Krylia Sovetov Samara players
Category:Brazilian expatriate footballers
Category:Brazilian expatriate sportspeople in Portugal
Category:Brazilian expatriate sportspeople in Russia
Category:Expatriate footballers in Portugal
Category:Expatriate footballers in Russia
Category:Association football defenders | {
"pile_set_name": "Wikipedia (en)"
} |
Q:
Converting from double to single
Given 64 bits which represent a number in IEEE 754 double precision format, what is the algorithm for converting them to 32 bits which represent the same number, but in IEEE 754 single precision format (perhaps with loss of precision)?
Also, is there an easy way to perform this conversion in Ada, without having to manipulate the bits?
A:
There is indeed an easy way to do this in Ada (quite similar to the way you would do the same thing in C!):
with Ada.Numerics;
with Ada.Text_IO; use Ada.Text_IO;
procedure Floating_Conversion is
D : constant Long_Float := Ada.Numerics.Pi;
F : Float;
begin
F := Float (D); -- The conversion!
Put_Line ("double:" & Long_Float'Image (D));
Put_Line ("single:" & Float'Image (F));
end Floating_Conversion;
| {
"pile_set_name": "StackExchange"
} |
Q:
How to prove to friend I have solution to puzzle (without revealing it)?
My friend Paul set me this arithmetic puzzle:
To make 21 from the numbers 1, 5, 6, 7. You can use the operations add, subtract, multiply, divide as well as brackets. You must use each number once.
After I solved it myself, I set the puzzle to another friend Ollie. He thinks it's impossible. How can I prove otherwise to Ollie—without revealing the solution? Can it be done without a trusted third party?
Also, how should I show my solution to Paul? I suspect he might not have one himself. If that's the case, I'd rather not tell mine—or at least expose him in the process.
A:
You can use a zero-knowledge proof to demonstrate that you have a solution to a general class of problem. (For example: "I can efficiently find the prime factorization of any number. I won't tell you how I do it, but I'll prove my ability by quickly factorizing any number you throw at me.") However, here, the solution is how you solved the problem; it's tautological to say you can't show how you solved the problem without giving away how you solved the problem.
You could secretly but provably declare your solution via cryptographic commitment. For example, you publish a hash of your solution and then later publish your solution. That allows you to prove that you had the solution for at least as long as the hash has been public. However, it only becomes clear that the secret you committed is a valid solution after you make the secret public. (This approach will allow Paul to compare his (non-)answer with yours -- simply compare hashes, using a standard format -- but it will not prove anything to Ollie.)
For Ollie, you need some way of demonstrating a solution to a different problem that maps onto the actual problem in some provable way. I briefly considered some kind of fully homomorphic encryption, but I don't see how you could homomorphically demonstrate the problem in a way that 1) doesn't allow your friend to decrypt it and 2) still allows your friend to verify the result. For example, consider an attempt at an iterative zero-knowledge proof with a homomorphic scheme that can encrypt (Enc) with a public key and decrypt (Dec) with a private key:
Show your friend Enc(1), Enc(5), Enc(6), and Enc(7) in a random order, and separately show Enc(21). At this point, your friend may stop these steps, demand the private key and verify that you are not lying about the values of the numbers. (This prevents you from using the wrong values, since you'd probably get caught if you played enough times.)
Perform the necessary mathematical operations on the first four encrypted values to produce 21. (This step gives away the necessary operations, which is suboptimal, but it does not reveal which values go with which operations.) At this point we can no longer give your friend the decryption key, or else he will be able to view the entire solution.
Perform a homomorphic equality test of the result from step 2 against the Enc(21) from step 1. This produces an encrypted boolean.
There is no way to allow your friend to decrypt the boolean without also allowing him to decrypt every other value, which would reveal your solution entirely. Therefore, there is no way to verify to your friend the correctness of your solution.
A:
There are only 7680 possible expressions using exactly once each of the four values, and binary operators in a list of four possible binary operators. A number of these expressions are in fact duplicates of each other, since two of the operators (addition and multiplication) are commutative. You can tell Ollie and Paul that they are lazy bastards.
This short number of candidates invalidates most cryptographic endeavours, since a zero-knowledge proof is always relative to a core hard problem: a ZK proof is a proof where you demonstrate that you know a solution without giving to the verifier any information that he could not obtain by himself. Here, trying out all possible solutions is simply too easy, so Ollie and Paul can already gain by themselves all the information that is to be obtained.
(Besides, according to my own computations, there is no solution. Hence, the solution to the puzzle must be some sort of pun or loophole, which by nature evades mathematical analysis.)
Edit: there was a bug in my program (damned silent conversion double to int; no warning from GCC even with -W -Wall). Indeed there is one solution, the one found by @Gudradain (and it is unique). For those interested in such things, here is my horrible program.
| {
"pile_set_name": "StackExchange"
} |
This invention is generally directed to a carrier device which is used to secure containers together to form a package having novel zip strips for allowing the quick and easy removal of the containers from the carrier device one at a time or in rapid succession.
Currently, several types of carrier devices can be found in the art for securing containers together into a package. Some of these carrier device provide quick release structure for allowing a consumer to quickly and easily release the containers from the carrier device.
One such carrier device can be found in U.S. Pat. No. 3,038,602 which discloses a container carrier device that holds six cans in a package array. The carrier device is positioned near the top of each can. A zipper strip is provided on the carrier device and is positioned between the rows of cans. A consumer releases the cans from the carrier device by tearing the zipper strip. When the zipper strip is torn, the carrier device creates two sets of packages, each consisting of three cans.
One problem which arises with this type of quick release carrier device is that when the zipper strip is torn, two separate packages are formed which may be undesirable for handling the cans.
Another such carrier device can be found in U.S. Pat. No. 5,174,441 which discloses a tear-open container carrier device that holds a plurality of cans in a package. Each can is held within a container encircling band. Zip strips are provided on the carrier device exterior to the container encircling bands. A consumer releases the cans from the carrier device by tearing the zip strips. The removal of the strip ruptures each individual band.
The present invention presents a novel quick release structure or zip strip for a carrier device which allows the containers to be released from the carrier device one at a time or in succession. | {
"pile_set_name": "USPTO Backgrounds"
} |
Psychopathology and hemispheric dysfunction: a review.
In the past 15 years, investigators have attempted to relate psychiatric disorders to our developing knowledge about the asymmetrical organization of the cerebral hemispheres. This paper summarizes the varied, limited, and often conflicting results. The authors suggest that progress in this fascinating and potentially fruitful area will be improved by: a) more critical evaluation of the current literature with regard to its contradictions and to the techniques and theories utilized; b) systematic study of carefully diagnosed, large groups of patients; c) concurrent attempts to identify and carefully assess unusual patients; d) control of laterality measures for drug effects, institutionalization, and such cognitive and affective states as anxiety, depression, paranoia, and psychosis; and e) validation of the localizing value of neuropsychological tests in psychiatric patients by the study of previously diagnosed psychiatric patients with acquired focal brain disease. | {
"pile_set_name": "PubMed Abstracts"
} |
MRI-derived radiomics: methodology and clinical applications in the field of pelvic oncology.
Personalized medicine aims at offering optimized treatment options and improved survival for cancer patients based on individual variability. The success of precision medicine depends on robust biomarkers. Recently, the requirement for improved non-biologic biomarkers that reflect tumor biology has emerged and there has been a growing interest in the automatic extraction of quantitative features from medical images, denoted as radiomics. Radiomics as a methodological approach can be applied to any image and most studies have focused on PET, CT, ultrasound, and MRI. Here, we aim to present an overview of the radiomics workflow as well as the major challenges with special emphasis on the use of multiparametric MRI datasets. We then reviewed recent studies on radiomics in the field of pelvic oncology including prostate, cervical, and colorectal cancer. | {
"pile_set_name": "PubMed Abstracts"
} |
Were not complaining. After all, this is something you'd expect in Kennebunk, the coastal Maine playground for the really rich and not-necessarily-famous. (Power is not measured in Twitter followers, dahling.) New Englanders heading up for a summer retreat at The White Barn Inn will now be able to book the bespoke experience of a customized Crustacean Crawl with the Relais & Chateau propertys esteemed chef Jonathan Cartwright. (Hes also the toque behind the fine dining Muse restaurants at two other tony Grace Hotels properties, Newports Vanderbilt Grace and Connecticut's Mayflower Grace.) ]]>
Scott Kearnan2014-06-13T13:41:50-05:00Find a Tax Deduction at a Maine Innhttp://www.hotelchatter.com/story/2008/2/10/225456/156
<![CDATA[<p><img src="http://www.hotelchatter.com/files/admin/Inn_entrance.jpg" class="imgborder"><p>"Nature hates calculators," Ralph Waldo Emerson once said, likely around tax time. If slaving away at 2007's taxes have shown you that you need to create more opportunities for deductions this year, might we suggest planning a weekend getaway to the <a href="http://www.hotelchatter.com/hotel-reviews/Waldo+Emerson+Inn/local/1106"><b>Waldo Emerson Inn</b></a>, a bed and breakfast believed to be one of the oldest houses in Kennebunk, Maine?<p> Book a stay in May, when the inn--and other members of the Maine Innkeepers Association--cut room rates in half to support "Hospitality for Habitat," a program that raises funds for Habitat for Humanity projects in Maine. In exchange for the discount, guests who stay between May 1-23 will be asked to write a $35 check to Habitat forjennm2008-02-12T12:05:01-05:0043.381850 -70.519585Search HotelChatterSearch HotelChatterstringhttp://www.hotelchatter.com/search/ | {
"pile_set_name": "Pile-CC"
} |
Drug addiction remains a scourge of all societies, whether supplier or consumer. The predominant drugs used today are cocaine, heroin and methamphetamine in the order of their usage. There is no present antagonist for cocaine, as there is for heroin. Cocaine acts in an entirely different way from heroin in blocking the channels of the presynaptic neuron for retrieval of dopamine. Therefore, any antagonist must bind to the channel in a way which inhibits cocaine binding, while permitting the channel to retrieve the dopamine from the synaptic space. In the absence of an antagonist, other ways of responding to various hazards associated with cocaine are necessary.
There have been recent reports that a vaccine against cocaine is being developed, which is the subject matter of WO96/30049. Also, there has been a report that a compound has been found which binds to the dopamine channel without closing the channel and inhibits the action of cocaine. However, these efforts are in the early stages of development and may never demonstrate efficacy in patients and drug addicts.
Cocaine is known to be rapidly metabolized to benzoylecgonine, which is believed to be physiologically inactive. Furthermore, cocaine becomes rapidly distributed in the various compartments of the body and can provide a rush in less than a minute, depending upon the method of administration. It is known that if one imbibes alcohol when taking cocaine, there is a rapid transesterification to the ethyl ester called "cocaethylene." Cocaethylene is known to retain efficacy longer.
In the absence of a specific antagonist, the treatment for cocaine overdose is to sedate the patient and provide drugs to ameliorate the bradycardia. Therefore, during the time that it is important for the doctor to communicate with the patient, the patient is comatose. Since cocaine appears to be able to distribute itself rapidly into different compartments, the ability to remove the cocaine from the blood, should also result in reducing the amount of cocaine in the brain and heart. However, there are uncertainties with the use of antibodies to sequester cocaine in the blood as part of the treatment of cocaine overdose, in that antibodies have a much larger molecular weight than cocaine and the amount of antibody required for efficacy could be prohibitive, both physiologically and economically, the therapeutic response is uncertain, the average dose of cocaine in the case of overdose is not known and the antibodies should be able to bind to whatever active compound is present in the blood, while not binding to physiologically inactive compounds. | {
"pile_set_name": "USPTO Backgrounds"
} |
Q:
Convert EPS to SVG
I'm looking for a free tool to convert EPS (encapsulated postscript) to SVG (scalable vector graphics).
I am aware that I can convert EPS to PDF with Ghostscript, then import the PDF with Inkscape and save the result as SVG. However, I want a simpler workflow with less tools, basically I want a single button "convert it".
I need that for Windows and offline use. I cannot upload my EPS to an online service.
A:
I think Scribus - an Open Source Desktop Publishing software - should be able to do it. Open an EPS, let it save the converted file into its native format, and export as SVG.
| {
"pile_set_name": "StackExchange"
} |
Introduction: tracking energy expenditure in athletes {#s1}
=====================================================
One of the unique characteristics of athletes is that energy requirements of training and competition increase their total daily energy expenditure (TDEE) beyond those of the general population (Westerterp, [@B52]). Energy requirements can vary considerably depending on exercise type, intensity, and duration, but sustained levels of energy expenditure (EE) can be in the range of 5,000--8,000 kcal/day (Westerterp et al., [@B53]; Westerterp, [@B51]). This high energy turnover has implications not only for weight gain and weight loss practices, which are prominent in sports with weight classes, anti-gravitational sports, or aesthetic sports; it also necessitates a sufficient dietary energy intake, as sustained energy deficiency can result in long-term detriments including impaired bone health and infertility (Loucks et al., [@B30]). In addition, recent data suggest that athletic performance may also be impaired in energy-deprived athletes (Vanheest et al., [@B44]).
Because of the high energy demands and the consequences of energy deficiency, tracking EE is paramount for many athletes and their support staff. Considering that athletes expend up to 75% of their TDEE during exercise (Westerterp, [@B52]), quantifying energy needs during training and competition requires particular attention. The current gold-standard method for the assessment of TDEE in free-living situations is the doubly labeled water (DLW) method, which has been used in numerous athletic settings (Westerterp et al., [@B53]; Sjödin et al., [@B40]; Trappe et al., [@B43]; Hill and Davies, [@B20], [@B21]; Ebine et al., [@B15]; Ekelund et al., [@B16]; Koehler et al., [@B26]). However, the time resolution is limited and the method does not differentiate between various components contributing to TDEE, such as exercise energy expenditure (ExEE) (Westerterp et al., [@B53]). Improved resolution is provided by indirect calorimetry (IC), the reference method for EE quantification in controlled laboratory settings (Haugen et al., [@B19]). However, despite recent methodological advances, the method remains mostly limited to research and exercise testing. Further, the requirement of a face mask hinders natural training behaviors such as fluid or food intake. Therefore, other approaches that do not interfere with training and competition practices are needed to reliably quantify EE, and particularly ExEE, in athletes.
Available methods include accelerometry, pedometry, heart-rate monitors, and self-report methods (Ndahimana and Kim, [@B35]). With the exception of self-report methods, which only provide subjective information and show low accuracy and reliability (Ndahimana and Kim, [@B35]), all of these approaches have been incorporated in activity monitors. These devices are less cost-prohibitive than DLW or IC, can be used during a wide range of activities and numerous settings, and allow for data collection over prolonged time intervals in large cohorts (Düking et al., [@B12]). Several such wearable devices, including the ActiGraph, Actical, RT3, ActivePAL, or GeneActiv, have been developed for research purposes, and various companies have introduced commercial physical activity trackers (e.g., Fitbit, Garmin, Jawbone, Nike). However, as these devices typically rely only on accelerometry, they provide mixed accuracy with regard to its ability to predict EE or time spent in different activities (Welk et al., [@B49]) and the ability to detect when devices are worn may be limited (Jaeschke et al., [@B22]).
Technology of the SenseWear armband: features, functions, and modifications {#s2}
===========================================================================
The SenseWear armband (SWA) developed by BodyMedia Inc. (Pittsburgh, PA, USA) combines accelerometry with additional biological variables, such as heat flux, skin temperature, near-body ambient temperature, and galvanic skin response. The device only collects data when it is in direct contact with the skin and its pattern-recognition algorithm has been shown to provide more accurate results for estimating EE and time spent in various activities when compared to the ActiGraph (Welk et al., [@B49]). Given these benefits, the SWA became a promising tool to objectively monitor EE in various exercise and non-exercise settings (Fruin and Rankin, [@B17]). Most basic principles and functions have remained the same since the initial introduction of the first prototypes in the late 1990s, but there have been several upgrades, the most notable modification being the addition of a third dimension accelerometer axis (Riou et al., [@B39]) along with increased data transfer and storage capacity. Per manufacturer instructions, the SWA is worn on the upper left arm, and can be used to record data continuously for up to 3--4 weeks (Koehler et al., [@B28]). Data can be downloaded, viewed, and exported for subsequent data processing using manufacturer software (InnerView, BodyMedia, Pittsburgh, PA). A proprietary algorithm converts raw data into estimates of EE, which are expressed both in kcal/min and metabolic equivalents (METs). In efforts to improve the validity of the SWA, this algorithm has been modified several times (Jakicic et al., [@B23]; Van Hoye et al., [@B45]). Although the technology was purchased by a competitor in 2013 and has since been discontinued (Welk et al., [@B50]), the SWA continues to be used extensively in research and clinical settings (Figure [1](#F1){ref-type="fig"}). Considering the continued popularity and the current lack of alternatives on the market, it was our goal to provide a critical review of the applicability of the SWA to measure EE specifically in athletes. As such, we provide a general overview of the strength and limitations of the SWA in the general population (section Validity of the SenseWear Armband in the General Population: Energy Expenditure, Physical Activity, and Exercise), followed by a review of the validity of the SWA in athletes and during various types of high-intensity exercise (section Validity of the SenseWear Armband during High-Intensity Exercise). We further discuss possible reasons for limitations (section Limitations of the SenseWear Armband: Algorithm vs. Methodology) and non-traditional applications of the SWA in athletic settings (section Application of the SenseWear Armband in Athletic Populations). To identify appropriate literature, a quasi-systematic PUBMED search (<https://www.ncbi.nlm.nih.gov/pubmed/>) was conducted in June 2017 independently by both authors, using "SenseWear" in combination with "exercise," "activity," or "athletes" as search terms. In addition, we included literature cited. Final inclusion was decided on by a joint decision from both authors based on each paper\'s relevance to the review\'s target group.
{#F1}
Validity of the SenseWear armband in the general population: energy expenditure, physical activity, and exercise {#s3}
================================================================================================================
In the general population, the SWA has been validated extensively and has been shown to provide accurate estimates of TDEE as well as EE at rest and during activities of light to moderate intensities when compared to DLW or IC (Cole et al., [@B7]; Fruin and Rankin, [@B17]; Jakicic et al., [@B23]; King et al., [@B25]; Mignault et al., [@B34]; Papazoglou et al., [@B36]; Malavolti et al., [@B32]; Patel et al., [@B37]; St-Onge et al., [@B41]; Johannsen et al., [@B24]; Casiraghi et al., [@B6]; Brazeau et al., [@B5]). When specific time periods of varying activity intensities were examined, however, the SWA generally overestimated EE at lower intensities, while EE was underestimated at higher intensities (Cole et al., [@B7]; Fruin and Rankin, [@B17]; Jakicic et al., [@B23]; Patel et al., [@B37]; Dwyer et al., [@B13]; Berntsen et al., [@B4]; Benito et al., [@B3]; Gastin et al., [@B18]). Accordingly, TDEE was overestimated in participants with low levels of TDEE and underestimated in participants with high TDEE (St-Onge et al., [@B41]; Johannsen et al., [@B24]).
It should further be considered that the accuracy of the SWA is impacted by external factors such as treadmill incline, exercise mode (e.g., running vs. bicycling), or the use of the upper vs. lower body exercise (Fruin and Rankin, [@B17]; Jakicic et al., [@B23]; Berntsen et al., [@B4]; Vernillo et al., [@B47]; Brazeau et al., [@B5]; Gastin et al., [@B18]). Specifically, underestimation of EE during uphill walking has been reported in several studies, with increasing measurement errors at steeper inclines (Fruin and Rankin, [@B17]; Jakicic et al., [@B23]; Vernillo et al., [@B47]). Downhill walking, on the other hand, was associated with an overestimation of EE, and---although less pronounced---measurement errors increased as declines became steeper (Vernillo et al., [@B47]). During stationary cycling, total EE did not differ between the SWA and IC, but individual time point data were poorly correlated: At the beginning of the cycling trial, EE was underestimated, but EE estimates by the SWA increased gradually over time even though IC values remained stable (Fruin and Rankin, [@B17]; Brazeau et al., [@B5]). Further, Gastin et al. ([@B18]) reported an underestimation of EE during resistance type circuit exercise, most likely due to inaccuracies at higher intensities. In addition to problems related to activity type and intensity, body weight has been shown to affect measurement accuracy. Even though no particular bias toward over- or underestimation of EE was observed, measurement error increased with increasing BMI (Dwyer et al., [@B13]; Malavolti et al., [@B31]). Considering that athletes typically are on the extreme ends of the body composition spectrum (Meyer et al., [@B33]), it is unclear to which degree body weight or composition contribute to measurement errors in athletes.
Differences in body weight or composition may also contribute to the considerable variability of measurement accuracy at the individual level (Fruin and Rankin, [@B17]; Brazeau et al., [@B5]). Nevertheless, a recent study reported accurate measurements of TDEE with a mean difference of 2.8 kcal/day and narrow 95% confidence intervals (−34.8 to 40.3 kcal/day) and a correlation coefficient of *r* = 0.88 when comparing SWA values to DLW in 191 generally healthy adults with diverse body weight and physical activity levels (Drenowatz et al., [@B11]). Overall, the SWA provides valid estimates of TDEE and ExEE with a measurement error of typically \<10% in a recreationally active population.
Validity of the SenseWear armband during high-intensity exercise {#s4}
================================================================
To our knowledge, only one study has assessed the validity of SWA-measured TDEE specifically in athletes. Koehler et al. ([@B27]) reported an average difference of 65 kcal/day (\<2% of TDEE) between TDEE measured by SWA and DLW in 14 endurance trained athletes and a moderate to strong correlation (*r* = 0.73) However, higher levels of TDEE tended to be underestimated by the SWA, and the level of underestimation was related to the participant\'s exercise capacity, whereby EE was underestimated to a greater degree in better trained athletes (Koehler et al., [@B27]).
Validity during high-intensity aerobic exercise
-----------------------------------------------
Several studies have tested the validity of the SWA during high-intensity, continuous aerobic exercise. In two independent studies in trained male athletes, the SWA underestimated ExEE during treadmill running at speeds of \~10.1 km/h (6.3 miles/h) and greater (Koehler et al., [@B27], [@B28]). These findings were replicated by Drenowatz and Eisenmann ([@B9]), who demonstrated that ExEE was consistently underestimated in endurance-trained athletes running at 65, 75, and 85% of their aerobic capacity, corresponding to a similar speed range (9.9--14.6 km/h; 6.2--9.1 miles/h). In another study, the SWA underestimated ExEE even at speeds from 6.0 to 7.2 km/h (3.7--4.5 miles/h) (van Hoye et al., [@B46]). Similar findings were also reported during stationary bicycling, whereby the SWA underestimated ExEE at workloads between 140 and 380 W (Koehler et al., [@B27]). In all cases, the level of underestimation increased with increasing exercise intensity (Drenowatz and Eisenmann, [@B9]; Koehler et al., [@B27], [@B28]; van Hoye et al., [@B46]). However, visual inspection of the combined data from all five studies (Figure [2](#F2){ref-type="fig"}) suggests that differences between SWA and IC are rather modest at low-to-moderate exercise intensities. At exercise intensities above 35 mL/kg/min (10 METs) SWA-measured ExEE, however, tends to plateau whereas IC-measured ExEE increases continuously, resulting in a stark increase in the level of underestimation. It is noteworthy that all studies employed an incremental exercise test to assess the validity of the SWA at multiple exercise intensities. To our knowledge, only one study separately used a 30 min exercise bout at a self-selected intensity, resulting in a similar level of underestimation of 27% (Drenowatz and Eisenmann, [@B9]).
![Previously published data reporting the discrepancy between energy expenditure measured with the SenseWear armband (black symbols) in comparison to the reference method (indirect calorimetry; open symbols) and the difference between SenseWear and indirect calorimetry (gray symbols). The dotted line depicts an exercise intensity of 35 mL/kg/min (10 METs). Data published by Drenowatz and Eisenmann ([@B9]) stem from 20 male and female runners (VO~2peak~: 57 mL/kg/min); Data published by Koehler et al. ([@B27]) stem from 14 triathletes (VO~2peak~: 58 mL/kg/min) who were assessed while running and biking; Data published by Koehler et al. ([@B28]) stem from 19 endurance and strength trained men (VO~2peak~: 55 mL/kg/min) who were assessed while running; Data from van Hoye et al. ([@B46]) stem from 23 male kinesiology students (VO~2peak~: 69 mL/kg/min) and 20 female kinesiology students (VO~2peak~: 53 mL/kg/min) who were assessed while walking and running; Data published by Van Hoye et al. ([@B45]) stem from 39 male and female kinesiology students (VO~2peak~: 58 mL/kg/min) who were assessed while walking and running.](fphys-08-00983-g0002){#F2}
Validity during resistance exercise
-----------------------------------
Only few studies have examined the accuracy of the SWA during resistance-type exercise. Benito et al. ([@B3]) reported an underestimation of ExEE during circuit-type resistance training at 30, 50, and 70% of the 15RMmax in a mixed sample of 29 recreationally active participants. Compared to IC, SWA-estimated ExEE was 32% lower in men, corresponding to a difference of 2.3 METs, and 21% lower in women (1.1 METs). Furthermore, the degree of underestimation increased with increasing exercise intensity, although this effect was only significant in men (Benito et al., [@B3]). On the other hand, the SWA slightly overestimated exercise EE by an average 35 kcal per session during self-selected resistance exercise in a mixed sample of 52 participants of varying age and fitness level (Bai et al., [@B2]). The measurement error at the individual level was reported at 15%. However, the average exercise intensity was rather low during these sessions (3.2 METs) and may not resemble a typical resistance exercise session in athletic populations. Using a more traditional resistance training protocol of 9 exercises covering all major muscle groups with 3 sets of 10 repetitions at 70% of the 1-reptition maximum, the SWA provided accurate estimates of ExEE with an error of less than 5% and a strong correlation for ExEE (*r* = 0.77) and TDEE (*r* = 0.97) (Reeve et al., [@B38]). Measurement errors also remained constant across the ExEE spectrum with an almost perfect reliability of the SWA (test-retest *r* = 0.96). It should, however, be considered that ExEE was integrated over the course of the exercise bout; no information was provided on the measurement accuracy for specific exercise types (Reeve et al., [@B38]).
Validity during mixed exercise forms
------------------------------------
Similar to studies addressing resistance-type exercise, there has been only limited research examining the accuracy of the SWA during mixed exercise forms, particularly in athletic populations. Zanetti et al. ([@B55]) assessed the accuracy of the SWA during a 42-min sport-specific intermittent exercise trial in 14 male rugby players. While there was no clear trend toward over- or underestimation of ExEE with a mean bias of −0.2 kcal/min (−1.9%), results revealed only a moderate correlation between the SWA and IC (*r* = 0.55). During a 30-min basketball-specific skill session, the SWA, however, was shown to underestimate ExEE by 1.1 kcal/min (15%) (Taylor, [@B42]). EE during recovery period following intermittent exercise training, on the other hand, was overestimated by 17% by the SWA when compared to IC (Zanetti et al., [@B55]).
Limitations of the SenseWear armband: algorithm vs. methodology {#s5}
===============================================================
Despite the tendency to underestimate ExEE during high-intensity exercise, available data suggest that the SWA can reliably detect activity patterns, rest periods, and varying levels of exercise intensity within individuals. For example, significant intra-individual correlations between IC and SWA was reported in 90% of endurance athletes who ran at exercise intensities between 65 and 85% VO~2max~ (Drenowatz and Eisenmann, [@B9]). In another study involving incremental treadmill running at speeds between 10.8 and 17.3 km/h, raw data including acceleration counts, and particularly counts in the longitudinal plane, increased continuously as workload increased (Koehler et al., [@B28]), demonstrating that the technology is suited to detect movement patterns even at higher exercise intensities. Consequently, limitations to the proprietary algorithm are a candidate source for the underestimation of ExEE during high-intensity exercise. Several studies have tested whether algorithm adjustments could improve the validity of the SWA during exercise. In one of the first published validation studies, Jakicic et al. ([@B23]) reported that the accuracy of the SWA improved after algorithm revisions. After the initial algorithm underestimated ExEE during walking, stepping, and cycling by 7--29% and overestimated ExEE during arm ergometry by 29%, the researchers provided a subset of their data to develop exercise-specific proprietary equations, which reduced errors in ExEE measured by the SWA to a non-significant level. However, ExEE values, which peaked during stair stepping at 5.3--9.2 kcal/min, did not exceed the 10 MET-threshold. More recently, Van Hoye et al. ([@B45]) compared two different algorithms during low- and moderate-intensity treadmill running in well-trained students, reasoning that a newer algorithm would provide more accurate estimates of EE as the manufacturer updates proprietary algorithms on a regular basis. When compared to the initially used algorithm (version 2.2.), data processed using a newer algorithm (version 5.2) reduced the measurement error from 18--24 to 5--17%, although ExEE remained underestimated.
Application of the SenseWear armband in athletic populations {#s6}
============================================================
Despite the previously mentioned limitations, several groups have used the SWA to track EE in athletes. In adolescent sprinters undergoing high-intensity exercise training, Aerenhouts et al. ([@B1]) measured TDEE, ExEE, and activity patterns using the SWA. When compared to self-report, the SWA registered less time spent in high-intensity activity, although this difference did not result in differences in TDEE, which was within 6% of the TDEE derived from activity diaries. The authors also highlighted the need for additional information when athletes fail to wear the SWA for 24 h. The SWA was also used to record ExEE during the competitive season in volleyball players (Woodruff and Meloche, [@B54]). SWA-recorded ExEE was found to be higher during games when compared to practice and warm-up sessions. Combining SWA data with diet logs and body composition assessment, the authors further concluded that the majority of the athletes were in an energy-balanced state. Using the SWA to quantify non-exercise activity thermogenesis (NEAT) among endurance athletes undergoing periods of high and low training volume, Drenowatz et al. ([@B10]) demonstrated that the high training volume did not result in a compensatory reduction in NEAT; instead, athletes reduced their sedentary activities to allow for more training time. In professional Australian Football players, the SWA was used to document the contribution of NEAT to TDEE, which was greater on training days (85%) when compared to match days (69%) (Walker et al., [@B48]).
Because the SWA can be worn continuously for several days, it has also been used for the assessment of sleep quantity and quality. In male elite rugby union players, SWA-derived sleep duration was shown to be lower during game nights when compared to non-game nights, although sleep efficiency was not different (Eagles and Lovell, [@B14]). In another trial comparing high-intensity interval training to strength training, SWA-derived sleep efficiency was lower in the high-intensity interval condition (Kölling et al., [@B29]). These applications demonstrate that the SWA is well-suited to capture other biological factors, such as characteristics of sleep and NEAT, that may have important implications for athletic performance.
Conclusion and summary {#s7}
======================
Considering that the SWA has been designed for a broad market, it is not surprising that the device tends to underestimate ExEE for periods of high-intensity exercise. Although most data has been established for aerobic exercise, the SWA seems to equally underestimate ExEE during other exercise forms. When energy expenditure is integrated over longer time periods, including rest and recovery, the measurement error becomes less pronounced and estimations of TDEE tend to be more accurate, even in athletic populations. Adjustments to the proprietary algorithm that is used to derive EE may further help to improve the validity of the SWA. Unfortunately the sale of the SWA has been terminated. Recently, a new disposable device with similar functionality has been introduced but is not available for commercial application at this time (Welk et al., [@B50]). Another viable option is the combination of GPS data with accelerometry and heart rate to assess EE in outdoor sports (Costa et al., [@B8]), although the accuracy of such devices remains to be explored. Given the current lack of alternatives, the SWA continues to be used in research and practice, emphasizing the need for the continued development of wearable devices that reliably measure EE and related variables in athletic settings.
Author contributions {#s8}
====================
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
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.
[^1]: Edited by: Billy Sperlich, Universität Würzburg, Germany
[^2]: Reviewed by: Salvatore Tedesco, University College Cork, Ireland; Beat Knechtle, University of Zurich, Switzerland
[^3]: This article was submitted to Exercise Physiology, a section of the journal Frontiers in Physiology
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Parag Tyagi to be the next ‘bad man’ in Zee TV’s Maharakshak Aryan
Zee TV’s Maharakshak Aryan (Esselvision Productions) will get its next main villain in actor Parag Tyagi.
Parag, who got hooked to the ‘Kaanta Laga’ girl Shefali Zariwala, got his name and fame playing the character of Vinod Karanjkar, brother to Ankita Lokhande in Pavitra Rishta. The guy has also played the role of Sharifuddin Hussain in Jodha Akbar. With Shefali, Parag had participated in the dance reality show Nach Baliye 5.
After Mishal Raheja and Reshmi Ghosh, the maker has now roped in their next villain to plot and plan against Aryan (Aarakshan Singh).
As per a source, “Parag will essay the mighty character of ‘lohpurush’. And as suggested by his name, this iron man will pose to be a tough challenge for Aryan.”
When contacted, Parag confirmed the news stating, “Yes, I will be starting shoot for Maharakshak Aryan in a day or two. I will play a villain in the show, and Aryan will have to fight and win over me.”
Get ready for this new battle between good and evil in the Zee TV show. | {
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Pelican Bottles
Pelican’s latest line of drinkware is a go anywhere, do anything, must have addition to your way of life. Ruggedly engineered with 18/8 pro grade stainless steel, featuring a sweat-proof, powder coated finish that ensures your hands won’t slip from condensation, plus a non-Slip rubber base for increased durability.
We’ve also made sure that our new Pelican™ Bottles are effortless to transport, as each spill-proof lid is also an easy-carry handle. Just loop this through your fingers or attach it to your favorite backpack – the contents will be stowed safely inside until you’re ready for your next sip or pour. Able to hold hot or cold beverages, Pelican Bottles come in your choice of black or white, with size capacities of 18 oz., 32 oz., and 64 oz. | {
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{#sp1 .21}
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{
"name": "angular",
"version": "1.4.8",
"description": "HTML enhanced for web apps",
"main": "index.js",
"scripts": {
"test": "echo \"Error: no test specified\" && exit 1"
},
"repository": {
"type": "git",
"url": "https://github.com/angular/angular.js.git"
},
"keywords": [
"angular",
"framework",
"browser",
"client-side"
],
"author": "Angular Core Team <[email protected]>",
"license": "MIT",
"bugs": {
"url": "https://github.com/angular/angular.js/issues"
},
"homepage": "http://angularjs.org"
}
| {
"pile_set_name": "Github"
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A fluorescent receptor assay for benzodiazepines using coumarin-labeled desethylflumazenil as ligand.
This article describes a novel nonisotopic receptor assay for benzodiazepines with fluorescence detection. As labeled ligand (coumarin-labeled desethylflumazenil, CLDEF), a metabolite of the benzodiazepine antagonist flumazenil (desetheylflumazenil, Ro15-3890) has been coupled to a coumarin fluorophore, via a spacer. CLDEF had a Ki of 6.5 nM. To avoid the interference of the background fluorescence of the receptors in the measurement step, the bound CLDEF was dissociated from the receptors after the filtration step. This dissociation was achieved by incubating the CLDEF-bound to the receptors on the filters-with a weakly acetate buffer. The second filtrates then contained the previously bound CLDEF, which was then quantitated with a RP-HPLC system with a fluorescence detector. The results with a fluorescent receptor assay were very similar to those with a radioreceptor assay, in that the IC50 values of lorazepam were 7.2 +/- 0.5 and 6.6 +/- 0.7 nM, respectively. | {
"pile_set_name": "PubMed Abstracts"
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One Of Many Planned Hotel and Resort Floating Bed Placements In Coming Months
Floating Bed Featured in recent issue of ‘Plenty Magazine’
LOS ANGELES, April 6 /PRNewswire-FirstCall/ — Orbit Brands Corporation (“Orbit”) announced today that its wholly-owned subsidiary, Floating Bed International (fka BBKO Corporation) has received another new media placement after its unique bed was installed in Pollywogg Holler, a Mountain Resort/Retreat located in Upstate New York.
William Castle had good feelings when he installed the Floating Bed in his Resort. “The Floating Bed room is our guests’ favorite room,” says William. “When calling for reservations, the #1 question they ask is whether the Floating Bed is available.” After his guests experience it, “They say it is the closest thing they have ever experienced to sleeping on a cloud.” It has received more media attention too. Mr. Castle’s resort, complete with a photo of the Floating Bed, was featured in a recent issue of Plenty Magazine (http://www.plentymag.com/). Floating Bed CEO, John Huff, added, “This is one of many planned Floating Bed hotel and resort placements you will see in the coming months. The Floating Bed is a very desirable product for hotels. If your business is about sleep, it makes sense to have the best bed in the world. Users often comment that they have never slept better than in the Floating Bed. Hotels are a great way to introduce individuals to it; then it sells itself. With 6 billion potential customers worldwide using this product 8 hours a day, our company is poised for dramatic growth. Who wouldn’t want the best bed available?”
About Orbit Brands Corp.
Orbit is a publicly traded Delaware corporation listed on the OTC Pink Sheets. The primary focus of the company is growth via the acquisition and development of early-stage, high-growth companies in the technology, health and fitness, and consumer goods industries. Orbit is positioned to identify, acquire, fund and develop these companies for the purpose of creating business and shareholder value.
About Floating Bed International
Floating Bed International is a specialty bed manufacturer. It designs and manufactures beds that are uniquely advantageous for the human mind and body by focusing on improving blood circulation. With its true pendulum motion, the “Floating Bed” actually balances the hemispheres of the brain, thereby inducing a relaxed, meditative state to facilitate faster and deeper sleep. For further information, please visit the company’s website at http://www.floatingbed.com/.
Hilton Completes its Portfolio in Beijing with Two New Hotel BrandsChina’s First Conrad, the Luxury Name of Hilton, and Scandic by Hilton, The Group’s Mid Market Offering, to Open in 2008 SINGAPORE, June 7 /Xinhua-PRNewswire/ — Hilton International (HI) has signed two new management contracts for Beijing, including the first Conrad hotel in China and...
Cruise Ships to Serve as Floating Hotels for Super Bowl XXXIXCLIA Members Providing 3,819 Rooms to Meet Hotel Demand JACKSONVILLE, Fla., Jan. 31 /PRNewswire/ — Superlative service, outstanding cuisine, limitless activities and great value are but a few of the reasons why cruise vacations have soared in popularity. In fact, it is because cruise ships...
Hotel Resort Fees Are Back and Bigger Than EverHotel resort fees are perhaps one of the most annoying (and expensive) things in travel these days. Many large hotels, resorts and corporations insist on upsetting their own guests for profit. Kingman, AZ (PRWEB) August 15, 2006 — Hotel resort fees are perhaps one of... | {
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Percutaneous umbilical cord blood sampling in the evaluation of fetal platelet counts in pregnant patients with autoimmune thrombocytopenia purpura.
Autoimmune thrombocytopenia purpura in pregnancy is associated with fetal thrombocytopenia. Twenty-one patients with autoimmune thrombocytopenia purpura (22 fetuses) underwent 26 umbilical cord punctures to assess the fetal platelet count. Blood could not be obtained from one fetus. Thrombocytopenia (less than 150,000/microL) was found in five cases, but in none was it of sufficient degree to preclude vaginal delivery. Persistent fetal bradycardia necessitating emergency cesarean delivery occurred in two cases. Umbilical cord puncture was found to be technically more difficult in the term fetus than in the second-trimester fetus studied in previous investigations. | {
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Synthesis and characterization of branched polymers from lipase-catalyzed trimethylolpropane copolymerizations.
Lipase-catalyzed terpolymerizations were performed with the monomers trimethylolpropane (B3), 1,8-octanediol (B2), and adipic acid (A2). Polymerizations were performed in bulk, at 70 degrees C, for 42 h, using immobilized lipase B from Candida antartica (Novozyme-435) as a catalyst. To determine the substitution pattern of trimethylolpropane (TMP) in copolymers, model compounds with variable degrees of acetylation were synthesized. Inverse-gated 13C NMR spectra were recorded to first determine the chemical shift positions for mono-, di-, and trisubstituted TMP units and, subsequently, to determine substitution of TMP units along chains. Variation of TMP in the monomer feed gave copolymers with degrees of branching (DB) from 20% to 67%. In one example, a hyperbranched copolyester with 53 mol % TMP adipate units was formed in 80% yield, with Mw 14 100 (relative to polystyrene standards), Mw/Mn 5.3, and DB 36%. Thermal and crystalline properties of the copolyesters were studied by thermogravimetric analysis and differential scanning calorimetry. | {
"pile_set_name": "PubMed Abstracts"
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Q:
Error running Libreoffice 6.0.5. Did ubuntu 18.04 fix itself after I looked up the version number?
I followed these instructions:
How do I install LibreOffice 6 in Ubuntu?
In Terminal, I typed libreoffice. This error appeared:
/usr/lib/libreoffice/program/oosplash: error while loading shared
libraries: libuno_sal.so.3: cannot open shared object file: No such
file or directory
Then the Software Updater opened and I ran an update that fixed the error.
In Terminal, I typed libreoffice and the application ran.
Simultaneously, this error appeared:
func=xmlSecCheckVersionExt:file=xmlsec.c:line=188:obj=unknown:subj=unknown:error=19:invalid
version:mode=abi compatible;expected minor version=2;real minor
version=2;expected subminor version=25;real subminor version=26
At first, I thought there was something wrong, but since it mentioned something about a version, I went back to terminal and typed:
libreoffice --version
LibreOffice 6.0.5.2 00m0(Build:2)
Next, commands
soffice
The application opened without the error. I closed the application
Next, command
libreoffice
The application opened without the error.
Did Ubuntu fix itself after looking up the version number?
A:
Hi i stumbled upon this one:
https://bugs.documentfoundation.org/show_bug.cgi?id=118373
The first part of your question about why the error message changed:
Yes after you did a software update, some previously missing dependencies may have been declared, and thus the library libuno_sal.so.3 was installed.
The second part is a bit more mystery:
My assumption is, that Libreoffice starting from some point in time to at least version 6.0.7-0ubuntu0.18.04.2 was compiled with libxmlsec1 1.2.26 but in Ubuntu 18.04 the current version of libxmlsec1 is still 1.2.25-1build1.
Libreoffice does not load that library on every call, and if your terminal command does not load an ODS for example, you dont see this message.
If you try to open a Calc sheet for example, i assume you will still see this message, until the devs of libreoffice push a solution, to silence the warning, or solve the dependency issue.
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"pile_set_name": "StackExchange"
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Indoleamine 2,3--dioxygenase 1 (IDO1, also known as tryptophan pyrrolase) is a heme-containing enzyme that catalyzes the oxidative cleavage of L-tryptophan to N-formyl-L-kynurenine in the first and rate-limiting step of tryptophan metabolism[@b1]. The great majority of tryptophan is known to be metabolized by the kynurenine pathway in which tryptophan is degraded through a series of metabolic reactions[@b2][@b3]. It has been reported that IDO1 is ubiquitously expressed in the colon[@b4], small intestine[@b5], brain[@b6], spleen[@b7], lung[@b8] and epididymis[@b9] as well as in myeloid cells including macrophages and dendritic cells[@b10]. Although the highest levels of expression were found in the colonic intestinal tissues[@b4], the specific function of IDO1 in this location has not been fully studied.
IDO1 has attracted considerable attention in recent years because of its major roles in non-metabolic functions. The first discovery of the biologic relevance of IDO1 occurred in the placenta, where maternal T cells regulate immunity during gestation. These studies used 1-methyl-tryptophan (1-MT), an inhibitor of IDO1 activity[@b11], and showed that IDO1 regulated T cell activity by suppressing proliferation. In addition, several other studies have shown an immunosuppressive role of IDO1 in conditions involving T cell activation such as graft-versus-host disease (GVHD)[@b12][@b13], HIV infection[@b14] and immunodeficiency diseases[@b15]. It has been shown that enhanced expression of IDO1 increased the production of tryptophan metabolites, which promotes cell-cycle arrest of and apoptosis of T cells and induce the differentiation of T regulatory cells (T~regs~)[@b16].
Despite knowledge of the immune-modulatory role of IDO1, the mechanism by which IDO1 mediates inflammatory reactions is a field of active investigation and remains controversial. A contradictory effect of IDO1 on inflammatory responses during the development of colitis was recently described. Mechanistic studies using trinitrobenzene sulfonic acid (TNBS)-induced colitis suggested that inhibition of IDO1 leads to increased severity of colitis due to down-regulation of T~reg~ cell responses within the intestinal tract[@b17][@b18]. Conversely, another study reported that local increases in IDO1 production during active inflammatory responses resulted in more severe colitis promoted by key mediators of pro-inflammatory signaling[@b19]. Most previous results were drawn from studies of T cell-associated functions of IDO1. For example, TNBS is a chemical that induces colitis in a T cell-dependent manner[@b17] as a result of delayed-type hypersensitivity reaction to haptenized proteins; however, because other studies raised the points that IDO1 may play inflammatory roles in a T cell-independent manner, different approaches are needed to elucidate the role of the enzyme in the development of colitis. One of the potential approaches is to study the roles of IDO1 using dextran sulfate sodium (DSS) which induces colitis by disrupting epithelial barrier function of colon tissues.
In this study, we performed for the first time an array-based transcriptome analysis to identify differentially-expressed genes targeted by IDO1 using *Ido1* knock-out (*Ido1*^−/−^) mice. We identified new molecular targets of IDO1 and described functionally distinct molecular mechanisms regulated by IDO1. In addition, we further examined the pathophysiological roles played by IDO1 in colitis development in studies using DSS-induced colitis model. We determined the effects of *Ido1* expression on colitis-related clinical parameters and histopathological damage. We also assessed changes in inflammatory cell recruitment using flow cytometry, and performed gene expression profiling analyses. To our knowledge, this is the first report of a comprehensive gene expression profile analysis of *Ido1*^−/−^ mice in either non- stimulated or DSS-stimulated conditions. This large-scale profiling may enhance our understandings of the contributions of IDO1 to colitis development, and provide novel target genes regulated by IDO1.
Results
=======
Identification of differentially expressed genes in *Ido1* knock-out mice
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As a first attempt to identify the targets of IDO1, which catalyzes the first and rate-limiting step of tryptophan degradation, transcriptome analysis was performed using *Ido1*^−/−^ and *Ido1*^+/+^ mice. Total RNAs from the colon tissue of each mouse was respectively applied to Illumina Mouse WG-6 v.2 BeadChip arrays containing a total of 45,281 transcripts. Principal component analyses (PCA) confirmed that the gene expression profiles of *Ido1*^−/−^ mice were readily distinguishable from those of *Ido1*^+/+^ mice as shown in [Fig. 1a](#f1){ref-type="fig"}. Differentially expressed genes in *Ido1*^−/−^ and *Ido1*^+/+^ mice were identified by unpaired t-test with thresholds of 1% false discovery rate \[FDR\] and 2-fold change restriction. A total of 102 significant genes were identified with 37 up- and 65 down-regulated genes. We confirmed that transcripts of *Ido1* (IDO1, marked by an asterisk in [Fig. 1b](#f1){ref-type="fig"}) were completely absent in *Ido1*^−/−^ mice. To gain a broader understanding of the biological processes regulated by IDO1, we performed a series of bioinformatic analyses. Hierarchical clustering analysis showed three distinct gene clusters ([Fig. 1b](#f1){ref-type="fig"}). Cluster 1, composed of up-regulated genes in *Ido1*^−/−^ mice was classified further to explore biological implications. Functional classification and Fisher's exact test identified Gene Expression, Embryonic Development, Nervous System Development and Function, Organ Development, and Organismal Development as the top 5 significant biological processes. Accordingly, the expression of many genes in the gene expression-related transcriptional network was significantly increased including *Hoxd10*, *Barx2*, *Msx1*, and *Pbx1* ([Fig. 1c](#f1){ref-type="fig"}). Likewise, the top five molecular and cellular functions of genes in cluster 2 were Inflammatory Response, Dermatological Disease and Conditions, Immunological Disease, Infectious Disease, and Cancer. The most significant category modulated by the absence of IDO1 was Inflammatory Response (P = 5.39E-05). These included *Cd6*, *Scrib*, *Il1rap*, *Cd80*, and *Trem3* in *Ido1*^−/−^ mice, suggesting that IDO1 might be an important mediator in inflammatory response ([Fig. 1d](#f1){ref-type="fig"}). In addition, gene set enrichment analysis (GSEA) confirmed that genes associated with the inflammatory response were significantly enriched in the set of differentially expressed genes between *Ido1*^−/−^ and *Ido1*^+/+^ mice (FDR q \< 0.01, [Fig. 1e](#f1){ref-type="fig"}). These findings prompted us to explore the roles of IDO1 in colonic inflammatory responses.
Contribution of IDO1 to development of DSS-induced colitis
----------------------------------------------------------
Based on the array analyses showing that the inflammatory response was the most significant biological process affected by the absence of IDO1 in untreated mice, we next sought to study the effects of IDO1 deficiency on colitis development. We used an established murine model of colitis induced by oral administration of DSS, a reagent that disrupts the barrier function of mucosal epithelial cells[@b20]. *Ido1*^−/−^ and *Ido1*^+/+^ mice were given either 1% or 2% DSS in their drinking water for 7 days and daily water intakes were measured. There was no difference in DSS-containing water consumption among all groups (see [Supplementary Fig. S1](#S1){ref-type="supplementary-material"}). While treatment with 2% DSS resulted in a marked inflammatory reaction, 1% DSS treatment did not produce significant inflammatory reaction compared to the 0% control in *Ido1*^+/+^ mice. In treatment with 2% DSS, progressive weight loss, increased disease activity index (DAI) including severe diarrhea and intestinal bleeding, and greater shortening of colon length were detected in *Ido1*^+/+^ compared to *Ido1*^−/−^ mice ([Fig. 2a--c](#f2){ref-type="fig"}). These results suggest that IDO1 may play roles in promoting the inflammatory response in DSS-challenged mice. In addition, although treatment with 1% DSS did not induce significant differences in body weight and DAIs between *Ido1*^−/−^ and *Ido1*^+/+^ mice, it caused histological changes showing that the extent of tissue damage in *Ido1*^+/+^ mice was much greater than those for *Ido1*^−/−^ mice ([Fig. 2d](#f2){ref-type="fig"}). Inflammatory cell infiltration and crypt damage was more apparent in these mice as evidenced on H&E staining.
Furthermore, to explore whether pharmacological inhibition of IDO1 reproduces the results observed following *Ido1* gene deletion, we administered *Ido1*^+/+^ mice with L-1MT, a specific IDO1 inhibitor, then followed by colitis induction with 2% DSS treatment. IDO1 blockade by L-1MT ameliorated severe diarrhea and intestinal bleeding, resulting in significant reduction in the DAI. Shortening of colon length was notably attenuated in mice administered with L-1MT compared to the placebo ([Fig. 2e,f](#f2){ref-type="fig"}). Taken together, our data indicate that the severity of DSS-induced colitis development was significantly reduced in *Ido1*^−/−^ mice and L-1MT administered mice, suggesting that IDO1 deficiency might protect against pro-inflammatory signals. We next carried out transcriptome analysis to elucidate the underlying molecular mechanisms of this effect.
Gene expression profiling analysis of inflamed colon tissues in *Ido1* ^−/−^ mice
---------------------------------------------------------------------------------
We analyzed the gene expression profiles of three to five *Ido1*^−/−^ or *Ido1*^+/+^ mice from the controls and from cohorts treated with 1% or 2% DSS ([Fig. 3a](#f3){ref-type="fig"}). As expected, the transcription levels of *Ido1* were significantly increased in the inflamed colon tissues of *Ido1*^+/+^ mice, suggesting that the inflammatory response induced *Ido1* transcription (data not shown). PCA analysis showed that *Ido1*^−/−^ mice had a distinct pattern compared with *Ido1*^+/+^ mice only in the 2% DSS treatment group ([Fig. 3a](#f3){ref-type="fig"}). We performed a one-way ANOVA analysis to identify differentially-expressed genes with statistical thresholds of 5% FDR and 2-fold change restriction among the six groups. A total of 6,421 genes were identified as significant and were classified further based on their biological functions. As expected, the Inflammatory Response category was the most significant key function (p = 1.23E-35 to 3.89E-08) ([Fig. 3b](#f3){ref-type="fig"}). In comparisons of *Ido1*^−/−^ and *Ido1*^+/+^ mice, much higher numbers of genes were differentially expressed under DSS-stimulated conditions than in the basal non-stimulated state. Cytokines including interleukins and interferons are known to induce a broad inflammatory reaction in response to infection or injury[@b21][@b22][@b23]. This prompted us to further investigate cytokine and chemokine gene expression signatures. Strikingly, the expression levels of pro-inflammatory cytokines and chemokines, such as *Il-1β*, *TNF, Cxcl1,* and *Ccl7*, which are central mediators of inflammation were significantly elevated in a dose-dependent manner by DSS treatment in *Ido1*^+/+^ mice, however, the elevation was substantially attenuated in *Ido1*^−/−^ mice ([Fig. 3c](#f3){ref-type="fig"}). In contrast, IL-7 and IL-18 are anti-inflammatory cytokines and their expression was much lower in DSS-treated *Ido1*^+/+^ compared with DSS-treated *Ido1*^−/−^ mice. These gene expression signatures suggested that *Ido1*^−/−^ mice would be less likely to develop severe colitis than *Ido1*^+/+^ mice. The pro-inflammatory cytokines and chemokines noted above were previously reported to be induced in inflammatory cells, including monocytes, as part of the inflammatory reaction[@b24][@b25]. These findings led us to assess CD11b^+^Gr-1^+^ cells in peripheral blood (PBL) and colon using FACS. The frequencies of CD11b^+^Gr-1^+^ (Ly6G) cells were higher in the PBL and colon of *Ido1*^+/+^ mice than in *Ido1*^−/−^ mice following treatment with 2% DSS, although the difference in PBL was not significant ([Fig. 4a](#f4){ref-type="fig"}). Interestingly, in the CD11b^+^Gr-1^+^ cells, the difference in the proportion of the Ly6G^hi^Ly6C^low^ subpopulation was significant between the two genotypes of mice with 2% DSS-treatment: the proportion of Ly6G^hi^Ly6C^low^ was higher in the *Ido1*^+/+^ mice than in the *Ido1*^−/−^ mice ([Fig. 4b](#f4){ref-type="fig"}). To verify the role of IDO1 in the expansion of CD11^+^Gr-1^+^ cells in the DSS-induced colitis model, we examined whether treatment with the IDO1 inhibitor, L-1MT, would reproduce the results from *Ido1*^−/−^ mice. Consistently, the frequency of CD11^+^Gr-1^+^ cells and the proportion of the Ly6G^hi^Ly6C^low^ subpopulation in CD11^+^Gr-1^+^ cells were lower in the L-1MT-treated mice with DSS-induced colitis, compared with their vehicle-treated control counterparts ([Fig. 4c,d](#f4){ref-type="fig"}). Moreover, the proportion of colonic granulocytes (CD11b^+^Ly6G^+^Ly6C^low^F4/80^-^CD11c^−^)[@b26] was significantly lower in both *Ido1*^−/−^ and L-1MT-treated *Ido1*^+/+^ mice compared to the *Ido1*^+/+^ control mice after DSS treatment (see [Supplementary Fig. S2a](#S1){ref-type="supplementary-material"}). However, no significant difference was observed in monocyte populations (CD11b^+^Ly6C^+^Ly6G^-^CD11c^−^)[@b26] among the three groups ([Supplementary Fig. S2b](#S1){ref-type="supplementary-material"}). This indicates that loss of the functional activity of IDO1 may contribute to reduced expansion of CD11b^+^Gr-1^+^ cells including granulocytes in the DSS-induced colitis model. These results suggest that IDO1 induced a systemic inflammatory response including a gut inflammatory response associated with increased expression of pro-inflammatory cytokines and chemokines.
IDO1 deficiency results in down regulation of TLR and NF-kB signaling pathways
------------------------------------------------------------------------------
We next conducted an upstream regulator analysis to identify major upstream molecules of the differentially expressed genes identified in our data set[@b27]. It would be critical to identify the upstream regulatory molecules and their associated mechanisms of action to provide biological insights into the observed expression changes. In addition to transcription factors, upstream regulators can include any gene or small molecule that has been observed experimentally to affect gene expression directly or indirectly. The top 9 predicted upstream regulators ranked by z-score are lipopolysaccharide (p = 2.66E-170), TNF (p = 2.79E-166), IFNG (p = 3.00E-140), IL1B (p = 2.66E-114), NF-kB complex (p = 1.25E-83), STAT3 (p = 3.65E-69), MYD88 (p = 2.39E-54), p38 MAPK (p = 5.47E-47), and TLR (p = 1.51E-45) ([Fig. 5a](#f5){ref-type="fig"}). Surprisingly, all regulators are well known contributors to the development of inflammatory responses. As a point of interest, the greatest overlap with the regulators was in the pathways related to the Toll-like receptor and NF-kB signaling. Given these findings, we focused on genes belonging to those pathways in more detail. The most striking result was that expression of the majority of genes involved in TLR signaling was down-regulated in DSS-treated *Ido1*^−/−^ mice, suggesting that TLR signaling is essential for the contributions of IDO1 to the development of DSS-induced colitis ([Fig. 5b](#f5){ref-type="fig"}). In the basal state (non-stimulated), expressions of *Tlr2*, *Tlr6*, and *Myd88* remained low and the levels were similar in *Ido1*^−/−^ and *Ido1*^+/+^ mice. However, treatment with DSS resulted in dramatic increases in the expressions of those genes in *Ido1*^+/+^ mice in a dose-dependent manner. The expressions of these genes were not significantly induced by DSS treatment in IDO1-deficient mice ([Fig. 5d](#f5){ref-type="fig"}). Importantly, MyD88 is a key adaptor protein in the signal transduction cascades shared by most TLRs and MyD88-dependent TLR signaling pathways were found to be down-regulated in our study ([Fig. 5b](#f5){ref-type="fig"}). This suggests that the differences in colitis development between *Ido1*^−/−^ and *Ido1*^+/+^ mice result from dysregulation of the TLR-MyD88 signaling pathway. We also ascertained that TLR-triggered cascades downstream of NF-kB signaling molecules like NF-kB (nuclear factor kB, p = 1.54E-4), JNKs (JUN N-terminal kinases, p = 6.62E-3), and IRF5 (interferon regulatory factor 5, p = 1.20E-3), which were all down-regulated in DSS-treated *Ido1*^−/−^ mice ([Fig. 5c](#f5){ref-type="fig"}). These results implied that in mice with DSS-induced colitis, TLR signaling was inhibited by IDO1-deficiency, which suppressed pro-inflammatory cytokine and chemokine production through the regulation of a multitude of transcription factors such as NF-kB.
Discussion
==========
IDO1-mediated tryptophan metabolism in various tissues is linked to numerous biological and physiological functions. Heightened expression of IDO1 in colonic intestinal tissues led to the hypothesis that IDO1 plays critical roles in gut homeostasis. Various microorganisms and food antigens exist in the lumen and challenge the intestinal immune system. As the luminal surface of the gastrointestinal tract continually interacts with foreign antigens such as pathogenic bacteria, the mucosal immune system maintains immune tolerance to limit inflammatory responses elicited by these antigens. In the present study, we showed that in the basal state in which there was no chemical induction of inflammation, IDO1 deficiency did not lead to pathophysiologic changes in the gut. However, gene expression profiling analysis revealed that a transcriptional network of inflammatory responses was significantly down-regulate in the absence of IDO1.
When the mucosal immune system fails to maintain tolerance, pathogenic microbes are able to infect the host. Impaired immune tolerance in the intestine can lead to inflammatory bowel diseases such as Crohn's disease and ulcerative colitis[@b28][@b29][@b30]. Treatment with DSS treatment mimics the condition of impaired immune tolerance because it disrupts the mucosal barrier of epithelial cells on the luminal surface. Studies of the DSS-induced colitis model system enabled us to characterize the role of IDO1 in driving inflammatory response, which is not apparent in the non-stimulated state. We showed that DSS-treated IDO1-deficient mice did not develop colitis of the same severity as normal control mice by assessing the loss in body weight, intestinal bleeding, diarrhea, shortening of colon length and histological lesions. It should be noted that there are conflicting results regarding the role of IDO1 in different mouse models of colitis. In studies that utilized TNBS to induce colitis, inhibition of IDO1 was found to exacerbate colitis[@b17][@b31]. This discrepancy can probably be explained, at least in part, by the fact that TNBS induces a T cell-dependent disease while the DSS induction is in a different manner. Although both DSS and TNBS colitis are used for inflammatory bowel disease animal model, DSS colitis has been distinguished from TNBS models by many others in the several points[@b20][@b32]. For instance, while TNBS-induced colitis develops as a result of delayed-type hypersensitivity reaction to haptenized proteins, DSS-induced colitis is the result of a change in epithelial barrier function[@b32]. Additionally, it is known that while TNBS induces Crohn's disease-like colitis, DSS induces ulcerative colitis[@b20]. Therefore, disease exacerbation in IDO1-deficient TNBS-treated mice was attributed to the inhibition of T~reg~ activity[@b17][@b31], which is a distinct mechanism from what we found in IDO1-deficient DSS-treated mice.
It is well established that TLRs and NF-kB signaling pathways make important contributions to inflammatory responses. Strikingly, our transcriptome analyses showed that the expression of members of the TLR-MyD88-NF-kB signaling pathways was significantly decreased in the absence of IDO1. Consequently, down-regulation of those signaling pathways resulted in dramatic changes in the expression of cytokines and chemokines. We showed that in IDO1 deficient mice, the frequencies of circulating inflammatory cells in peripheral blood and in the gut were decreased as well. These findings suggest that IDO1 may require TLR-MyD88-NF-kB signaling to promote the development of colitis. It is notable that compared to normal mice, IDO1-deficient mice had higher expression of *Muc1,* which encodes mucin protein, the first line of host defense against invading bacteria ([Fig. 5d](#f5){ref-type="fig"}, p = 3.20E-3). Reduction in the expression of *Muc1* severely affects epithelial barrier function[@b33][@b34]. Several studies reported that mucin may be a negative regulator of TLR signaling[@b35][@b36]. This suggests that the absence of IDO1 may lead to increased mucin expression and subsequently down-regulate TLR-MyD88-NF-kB signaling.
IDO1 has become an emerging target for the treatment of cancer, infection, autoimmunity, and other diseases associated with inflammatory responses and immunosuppression[@b37][@b38][@b39][@b40]. The present report utilizing the *Ido1*^−/−^ mouse model provides the first comprehensive analysis of IDO1 targets at the transcriptome level and broadens our understanding of the diverse functions of IDO1 during inflammatory responses. This study also suggest that IDO1 is likely to be a promising target of therapeutic intervention in colitic diseases.
Methods
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Mice
----
*Ido1*^−/−^ mice of the C57BL/6 (B6) genetic background were obtained from The Jackson Laboratory (Bar Harbor, ME, USA). *Ido1*^−/−^ mice were crossed with C57BL/6 wild-type (The Jackson Laboratory) to generate the *Ido1*^−/−^ and *Ido1*^+/+^ offspring used in this study. Genotypes of knockout mice were verified via PCR typing. The mice used were 10--12 weeks old and weighed 18--23 g. Age- and weight-matched female littermates were used as controls. C57BL/6 mice and *Ido1*^−/−^ mice were maintained under specific pathogen free (SPF) condition at the Center of Animal Resource Development, Seoul National University College of Medicine. The mice were maintained based on the guidelines of Seoul National University Animal Experiment Ethics Committee. All animal experimental protocols were approved by the Committee on the Ethics of animal experiments of Seoul National University (Institutional Animal Care and Use Committee permit number: SNU-150119-5). All experiments were carried out in accordance with the guidelines and regulations.
Induction of colitis and evaluation of colitis severity
-------------------------------------------------------
To generate an acute colitis experimental model, dextran sulfate sodium (DSS) (molecular mass 36--50 kDa; MP Biomedicals, Illkirch, France) was added to the drinking water at concentrations of 1% or 2% (w/v) given *ad libitum* for 7 days. Control mice received drinking water without DSS. The subsequent course of colitis development was evaluated by monitoring daily weight changes. Colitis severity also was scored by evaluating clinical disease activity through daily observation of the following parameters: weight loss (0 points = No weight loss or weight gain, 1 points = 5--10% weight loss, 2 points = 11--15% weight loss, 3 points = 16--20% weight loss, 4 points = \>21% weight loss); stool consistency (0 points = normal and well formed, 2 points = very soft and unformed, 4 points = watery stool); and bleeding stool score (0 points = normal color stool, 2 points = reddish color stool, 4 points = bloody stool). The disease activity index (DAI) was calculated based on the combined scores of weight loss, stool consistency, and bleeding ranging from 0 to 12. All parameters were scored from day 0 to day 7. At the 7^th^ day after DSS-colitis induction, mice were sacrificed and the entire colon was quickly removed. After colon length was determined as a marker of inflammation, the entire colon was cut open lengthwise and gently flushed with sterile phosphate-buffered saline (PBS) to remove any traces of feces. Colon segments were immediately frozen in liquid nitrogen and stored at −80 °C for subsequent extraction of total RNA. For histological analysis, colon segments were fixed in 10% neutral buffered formalin phosphate and stored at room temperature until study for evidence of inflammation.
Administration of L-1MT
-----------------------
9--11 weeks old *Ido1*^+/+^ mice were administered L-1MT. To prepare L-1MT for oral gavage, 1g of L-1MT (purchased from Sigma-Aldrich) was added to a 15 ml conical tube with 10 ml Methocel/Tween \[0.5% Tween 80/0.5% Methylcellulose (v/v in water; both from Sigma-Aldrich)\]. The mixture was bead milled overnight by adding 2--3 mm glass beads and mixing inversion. The next day, the L-1MT concentration was adjusted to 80 mg/ml by adding an additional 2.5 ml Methocel/Tween and mixing again. The L-1MT slurry was administered by oral gavage at 400 mg/kg/dose (100 μl of total volume) using a curved feeding needle (20-gquge 1^1/2^ in; Fisher) as previously described[@b41]. For twice a day dosing, L-1MT was administered once in the morning and once in the evening. On day 5 of the experiment, all mice received 2% DSS treatment and mice were sacrificed on day 13.
Histological analysis of colitis
--------------------------------
Routinely processed, 4--6 μm paraffin-embedded sections of colon samples were prepared and stained with hematoxylin and eosin (H&E) for histological grading. Histological scores, including severity of colitis, were evaluated in a blinded manner as previously described by Laroui *et al.*[@b42]. Grades were evaluated from 0--4 for the following three criteria: severity of inflammation (0, rare inflammatory cell in the lamina propria; 1, increased inflammatory cells in the lamina propria; 2, confluent inflammatory cells extending into the submucosa; and 3, transmural extension of the inflammatory cell infiltrate); damage (0, none; 1, loss of the basal 1/3 of the crypt; 2, loss of the basal 2/3 of the crypt; 3, loss of the entire crypt but intact epithelial cells; and 4, loss of the entire crypt and of the surface epithelial cells); extension (0, none; 1, focal; 2, lesion involving 1/3 of the intestine; 3, lesion involving 2/3 of the intestine; and 4, lesion involving the entire intestine). Scores for each criterion were added to give an overall inflammation score for each sample with a range of 0--11. The histological grades were determined for each section, and the sum of the grades was reported as the histological score for each mouse. The level of colitis was blindly assessed by two histopathologists.
Flow cytometry (FACS) analyses
------------------------------
Fresh peripheral blood lymphocytes (PBLs) were prepared by incubating blood with ACK (ammonium-chloride-potassium) buffer to lyse red blood cells at room temperature for 3--5 minutes, and stained using FACS buffer (1X phosphate-buffered saline \[PBS\] with 0.1% bovine calf serum and 0.05% sodium azide). Colonic cells in the lamina propria of mice were isolated according to the previously described protocol[@b43]. Briefly, colon pieces (1 cm pieces) were treated with 5 ml of predigestion solution (1× HBSS containing 2 mM EDTA and 1 mM DTT) for 20 min at 37 °C. After incubation, cells epithelial cells were decanted and again incubated the pieces for 20 min at 37 °C. Intestinal pieces were washed with 1× PBS to remove remaining EDTA. And collected tissues were incubated with digestion solution (1.5 mg/ml of collagenase D \[Roche\], 0.1 mg/ml of DNase I \[Sigma-Aldrich\] and 5% of fetal bovine serum in 100 ml of 1× PBS) for 20 min at 37 °C and repeated. Cells were harvested and centrifuge for 10 min at 1,500 rpm, and resuspended with 5 ml of 40% percoll solution and overlayed to 80% percoll solution. Cells were centrifuged for 20 min at 1,000g and resuspended with FACS buffer. And cells were stained FITC- and eFluor® 450-conjugated anti-Ly6G (Gr-1; RB6-8C5, eBioscience, San Diego, CA, USA), PE- and PE-Cy7-conjugated anti-CD11b (M1/70, eBioscience), APC-conjugated anti-Ly6C (HK1.4, eBioscience), PE-Cy5-conjugated anti-F4/80 (BM8, eBioscince), APC-Cy7-conjugated anti-CD11c (N418, Biolegend, San Diego, CA, USA) antibodies at 4 °C for 30 min. After washing with FACS buffer, the cells were analyzed by a FACS Calibur (BD Bioscience, Franklin Lakes, NJ, USA) and FACS LSRII (BD Bioscience) and Flowjo software (Tree star, Ashland, OR, USA).
Microarray hybridization
------------------------
The gene expression profile was determined using the MouseWG-6 v.2 Expression BeadChips (Illumina®). For microarray hybridization, total RNA was isolated by homogenizing colon tissue samples and was purified using a DNA-free RNA isolation kit (RNAqueous-4PCR kit; Ambion, Austin, TX, USA) in accordance with the manufacturer's instructions. Total RNA integrity and quantity were assessed with a Nanodrop-2000 Spectrophotometer (Thermo Fisher Scientific, Wilmington, DE). Only total RNA with an OD 260/280 ratio \>2.0 was used for microarray hybridization. RNA samples were first amplified for array analyses using the Illumina Total Prep RNA Amplification Kit (Ambion, Austin, TX, USA) according to the manufacturer's instructions. Briefly, 500ng of total RNA, isolated from colon tissue, was used to prepare labelled cRNA with overnight incubation according to the manufacturer's protocol. The quality and quantity of the labelled cRNA were monitored using a Nanodrop-2000 Spectrophotometer. Amplified cRNA (1.5 μg) was hybridized on MouseWG-6 Expression BeadChip arrays, containing more than 45,281 well-annotated Ref transcripts, according to the manufacturer's standard protocol. The arrays were then scanned on a BeadArray Reader (BeadStation 500G Instrument, Illumina Inc.), and Spot images identification and quantification were obtained by the Genome Studio software v1.0.2. (Illumina Inc.).
Identification of significant genes
-----------------------------------
The raw data were pre-processed through three steps: background correction was performed, the data were then log-transformed to log 2 scale, and normalized by quantile normalization method implemented in the Genome Studio software (Illumina Inc.). Significant difference between two genotypes in each dose (0% DSS \[baseline\], 1% DSS treatment, 2% DSS treatment), differences between dose response effect in each genotype, and difference between genotype x dose interaction were identified using ANOVA test (*p* \< 0.05) on log 2-transformed normalized intensities using by Partek® Genomics Suite software v6.3 (Partek, St Louis, MI) (<http://www.partek.com/partekgs>). Transcripts with more than 2-fold differential expression and a false discovery rate (FDR) \< 0.01 were selected for each specific comparison analyzed.
Functional enrichment and clustering analysis
---------------------------------------------
Functional categorization analysis was performed based upon gene ontology consortium (GO). Broad Gene Set Enrichment Analysis (GSEA) was done to examine the significance of each functional category classified by GO[@b44] (<http://www.broadinstitute.org/gsea/index.jsp>). Hierarchical clustering analysis was carried out with Genesis software v1.7.5[@b45] using the Pearson correlation distance matrix with average linkage algorithm.
Statistical Analysis
--------------------
Data were expressed as the mean ±S.E.M. Statistical significance (*p* value \< 0.05) was evaluated either by unpaired student's *t* test between two groups or one-way analysis of variance (ANOVA) to compare multiple groups using dose and genotype as factors. Statistical analyses were performed using Graph Pad Prism 5 software (GraphPad Software Inc., La Jolla, CA, USA) and SAS Enterprise Guide 6.1 (SAS Institute Inc., Cary, NC, USA). For gene analyses, significances for functional enrichment of specific genes were determined by a right-tailed Fisher's exact test as the negative log of the probability that the number of focus genes is not due to random chance.
Additional Information
======================
**How to cite this article**: Shon, W.-J. *et al.* Severity of DSS-induced colitis is reduced in Ido1-deficient mice with down-regulation of TLR-MyD88-NF-kB transcriptional networks. *Sci. Rep.* **5**, 17305; doi: 10.1038/srep17305 (2015).
Supplementary Material {#S1}
======================
###### Supplementary Information
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) Grant funded by the Ministry of Science, ICT & Future Planning (NRF-2013R1A1A1007858) and grants Korea Healthcare Technology R&D project, Ministry of Health, Welfare, and Family affairs of Korea (HI12C0213).
**Author Contributions** D.S. and E.C designed the study. W.S., Y.L. and J.S. conducted the experiments. W.S., Y.L., E.C. and D.S. analyzed data and interpreted the results. W.S. and D.S. wrote the manuscript. All authors reviewed the manuscript.
![Differential gene-expression profiles of *Ido1*^−/−^ mice compared with *Ido1*^+/+^ mice detected by microarray analysis.\
(**a**) 3-D view of PCA scores plot of *Ido1*^−/−^ group (n = 3) *versus Ido1*^+/+^ group (n = 3). Groups are shown by different colors and dots represent individual strains. Blue spots represent *Ido1*^+/+^ group and the red spots represent *Ido1*^−/−^ group. On a 3D-PCA plot of *Ido1*^−/−^ group can be clearly distinguished from *Ido1*^+/+^ group. (**b**) Hierarchical clustering and heat map of up- or down-regulated genes that are differentially expressed (\>2-fold, 1% \[FDR\]) in the absence of IDO1. Red indicates high relative expression and green indicates low expression of genes as shown in the scale bar. Cluster analysis functionally categorized by IPA; Canonical pathway significantly detected in *Ido1*^−/−^ mice compared to *Ido1*^+/+^ mice. Statistical significance of pathway modulation was calculated via a right-tailed Fisher's exact test in Ingenutity Pathway. (**c**,**d**) Gene-pathway networks using IPA. (**c**) Gene Expression and (**d**) Inflammatory Response pathway are displayed as networks. Green and red symbols denote down-regulated and up-regulated genes in *Ido1*^−/−^ compared with *Ido1*^+/+^ mice, respectively. Arrows with unbroken lines indicate a direct interaction between two molecules, with the mode of action in the direction of the arrow; arrows with broken lines denote an indirect interaction. (**e**) We performed gene-set-enrichment analysis (GSEA) to determine whether the filtered gene list from *Ido1*^−/−^ mice *versus Ido1*^+/+^ mice showed specific enrichment in the inflammatory response in the rank-based analysis. Rank of 102 genes in our data sets ordered by expression level with enrichment plots for the up-regulated and down-regulated genes. ES (Enrichment Score) is a value that represents how well the gene set is enriched within the selected gene list. The FDR q value \<0.01 for specific enrichment of the gene set is as indicated. The leading edge analysis of our microarray data identified that the gene is highly correlated with Inflammatory Response.](srep17305-f1){#f1}
{#f2}
![Transcriptional Profiling of inflamed colon tissues in *Ido1*^+/+^ and *Ido1*^−/−^ mice after DSS treatment.\
(**a**) 3-D view of PCA scores plot of data obtained on *Ido1*^−/−^ mice *versus Ido1*^+/+^ mice treated with DSS. On a 3D-PCA plot of 2% DSS treated *Ido1*^−/−^ group can be significantly seperated from 2% DSS treated *Ido1*^+/+^ group. Each spots represents individual mouse in the group. Blue spots, *Ido1*^+/+^ group; Red spots, *Ido1*^−/−^ group; Purple spots, *Ido1*^+/+^ + 1% DSS treatment group, Green spots, *Ido1*^−/−^ + 1% DSS treatment group; Sky blue spots, *Ido1*^+/+^ + 2% DSS treatment group; Orange spots. *Ido1*^−/−^ + 2% DSS treatment group. (**b**) Functional categories by IPA; Canonical pathway significantly detected in *Ido1*^−/−^ mice compared to *Ido1*^+/+^ mice after DSS-induced colitis. Statistical significance of pathway modulation was calculated via a right-tailed Fisher's exact test in Ingenutity Pathway and represented as --log (p-value). A larger value on the x axis indicates a higher degree of significance, i.e., a smaller p value. The leading edge analysis of our microarray data identified gene highly correlated with Inflammatory Response. (**c**) Heat map of cytokine and chemokine genes that are differentially expressed \[5% FDR and 2-fold change restriction\] in DSS-challenged *Ido1*^−/−^ *versus Ido1*^+/+^. The given values are the average of normalized intensities (3--5 mice per group) with red representing higher levels of expression and green indicating lower levels. Color code: blue, pro-inflammatory cytokines; yellow, anti-inflammatory cytokines.](srep17305-f3){#f3}
{#f4}
{#f5}
[^1]: These authors contributed equally to this work.
| {
"pile_set_name": "PubMed Central"
} |
/*
Copyright 2017 The Kubernetes Authors.
Licensed under the Apache License, Version 2.0 (the "License");
you may not use this file except in compliance with the License.
You may obtain a copy of the License at
http://www.apache.org/licenses/LICENSE-2.0
Unless required by applicable law or agreed to in writing, software
distributed under the License is distributed on an "AS IS" BASIS,
WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
See the License for the specific language governing permissions and
limitations under the License.
*/
package storage
import (
"fmt"
"mime"
"k8s.io/apimachinery/pkg/runtime"
"k8s.io/apimachinery/pkg/runtime/schema"
"k8s.io/apimachinery/pkg/runtime/serializer/recognizer"
"k8s.io/apiserver/pkg/storage/storagebackend"
)
// StorageCodecConfig are the arguments passed to newStorageCodecFn
type StorageCodecConfig struct {
StorageMediaType string
StorageSerializer runtime.StorageSerializer
StorageVersion schema.GroupVersion
MemoryVersion schema.GroupVersion
Config storagebackend.Config
EncoderDecoratorFn func(runtime.Encoder) runtime.Encoder
DecoderDecoratorFn func([]runtime.Decoder) []runtime.Decoder
}
// NewStorageCodec assembles a storage codec for the provided storage media type, the provided serializer, and the requested
// storage and memory versions.
func NewStorageCodec(opts StorageCodecConfig) (runtime.Codec, runtime.GroupVersioner, error) {
mediaType, _, err := mime.ParseMediaType(opts.StorageMediaType)
if err != nil {
return nil, nil, fmt.Errorf("%q is not a valid mime-type", opts.StorageMediaType)
}
serializer, ok := runtime.SerializerInfoForMediaType(opts.StorageSerializer.SupportedMediaTypes(), mediaType)
if !ok {
return nil, nil, fmt.Errorf("unable to find serializer for %q", mediaType)
}
s := serializer.Serializer
// Give callers the opportunity to wrap encoders and decoders. For decoders, each returned decoder will
// be passed to the recognizer so that multiple decoders are available.
var encoder runtime.Encoder = s
if opts.EncoderDecoratorFn != nil {
encoder = opts.EncoderDecoratorFn(encoder)
}
decoders := []runtime.Decoder{
// selected decoder as the primary
s,
// universal deserializer as a fallback
opts.StorageSerializer.UniversalDeserializer(),
// base64-wrapped universal deserializer as a last resort.
// this allows reading base64-encoded protobuf, which should only exist if etcd2+protobuf was used at some point.
// data written that way could exist in etcd2, or could have been migrated to etcd3.
// TODO: flag this type of data if we encounter it, require migration (read to decode, write to persist using a supported encoder), and remove in 1.8
runtime.NewBase64Serializer(nil, opts.StorageSerializer.UniversalDeserializer()),
}
if opts.DecoderDecoratorFn != nil {
decoders = opts.DecoderDecoratorFn(decoders)
}
encodeVersioner := runtime.NewMultiGroupVersioner(
opts.StorageVersion,
schema.GroupKind{Group: opts.StorageVersion.Group},
schema.GroupKind{Group: opts.MemoryVersion.Group},
)
// Ensure the storage receives the correct version.
encoder = opts.StorageSerializer.EncoderForVersion(
encoder,
encodeVersioner,
)
decoder := opts.StorageSerializer.DecoderToVersion(
recognizer.NewDecoder(decoders...),
runtime.NewCoercingMultiGroupVersioner(
opts.MemoryVersion,
schema.GroupKind{Group: opts.MemoryVersion.Group},
schema.GroupKind{Group: opts.StorageVersion.Group},
),
)
return runtime.NewCodec(encoder, decoder), encodeVersioner, nil
}
| {
"pile_set_name": "Github"
} |
Minamikanra District, Gunma
was formerly a rural district located in Gunma Prefecture, Japan. Parts of the modern cities of Takasaki and Fujioka were formerly within the district.
Kanra District was the name of one of the ancient districts of Kōzuke Province, mentioned in the Shoku Nihongi of 711 AD. Modern Minamikanra District was created on December 7, 1878 with the reorganization of Gunma Prefecture into districts. It included 25 villages, which were formerly part of the tenryō holdings in Kōzuke Province administered directly by the Tokugawa shogunate. With the establishment of the municipalities system on April 1, 1889 the area was organized as four villages: Mihara, Nakasato, Kamikawa, and Ueno
On April 1, 1896, the district was merged with Tago, Midono to form Tano District
Category:Former districts of Gunma Prefecture | {
"pile_set_name": "Wikipedia (en)"
} |
Democracy books disappear from Hong Kong libraries - throwaway1997
https://hongkongfp.com/2020/07/04/democracy-books-disappear-from-hong-kong-libraries-including-title-by-activist-joshua-wong/
======
baylearn
You created the throwaway account > 1 year ago.
Must have seen everything coming.
| {
"pile_set_name": "HackerNews"
} |
JPR Foundation hires executive director for Jefferson Live!
Randy Bobst-McKay is vice president for marketing and finance at Symphony Silicon Valley in San Jose
The JPR Foundation announced late Thursday that it has hired Randy Bobst-McKay, of San Jose, Calif., as the new executive director of Jefferson Live!
Comment
DailyTidings.com
Writer
Posted Feb. 1, 2013 at 2:00 AM
Posted Feb. 1, 2013 at 2:00 AM
» Social News
The JPR Foundation announced late Thursday that it has hired Randy Bobst-McKay, of San Jose, Calif., as the new executive director of Jefferson Live!
Bobst-McKay will lead the effort to restore Medford's historic Holly Theatre and manage the Cascade Theatre in Redding, Calif. He begins his new job on March 18.
"Randy has a combination of experience and expertise that meshes perfectly with managing the Cascade Theatre's ongoing successful operation with spearheading the work necessary to restore the Holly Theatre in Medford," JPR Foundation President Steve Nelson said in a press release.
"We are excited to get the Holly Theatre project back on track."
Bobst-McKay was hired after a three-month national search overseen by a committee comprising representatives of the JPR Foundation, the Holly Theatre Restoration Committee and the Cascade Theatre Advisory Committee.
Bobst-McKay is currently vice president for marketing and finance at Symphony Silicon Valley in San Jose. Formerly he was general manager and executive director of the Empress Theatre in Vallejo, Calif., where he oversaw a fundraising campaign to restore the 1911 building. He managed all restoration/construction activities and established operating systems and programming following the theater's restoration.
Bobst-McKay holds a Bachelor of Arts in Drama degree with an emphasis in technical theater and management from San Francisco State University. He has lived in several Pacific Northwest cities and has numerous family members who live in the Klamath Basin.
Bobst-McKay was selected from a national/local field of 26 candidates, many of whom had extensive experience managing historic theatre restoration projects.
Paul Westhelle, who has been acting as interim executive director of both the JPR Foundation and Jefferson Public Radio after his predecessor, Ron Kramer, was fired from the university in June, will continue as director of the radio stations. | {
"pile_set_name": "Pile-CC"
} |
Q:
Calling sys_read two times [Nasm, Linux]
Twice i try to read character from input, the first time "call getUserAction" works fine, but the main problem is, that the system didn't call the second read func, it just exits. Here is a little part of my code
SECTION .bss
buffer resb 1
SECTION .text
global _start
_start:
...some unuseful and commented code
call getUserAction ;reading 1 byte from console, works fine
...
jmp count
call exit
count:
...
call getUserAction; don't work, just exits from program without err
...commented code to debug
call exit
getUserAction: ;proc to read from console 1 byte
mov eax, 3
mov ebx, 0
mov ecx, buffer
mov edx, 1
int 80h
ret
Also i tried to put code from getUserAction in "count" proc, but it changes nothing.
UPD: Answer on first comment:
After the second "getUserAction":
mov eax, [buffer]
cmp eax, 'u'
je setUsersValues
cmp eax, 'e'
je callFunc
call exit
UPD2: I'm so sorry, here is all code
%define newline 10,0
%define A1 -7
%define A2 3
%define A3 2
%define A4 4
%define A5 2
SECTION .data
labInfo db "============Lab_3============",newline
labInfoLen equ $ - labInfo
mainMenu db "Choose the ex:",newline,\
" r - call count",newline,\
" t - call beep", newline,\
" y - call exit func",newline
mainMenuLen equ $ - mainMenu
funcStr db "Here func func func", newline
funcStrLen equ $ - funcStr
countPromt db "Please,choose the variant of variables value",newline,\
" u - user defined values", newline,\
" e - execerciese defined values", newline,\
"Your choise:"
promtLen equ $ - countPromt
SECTION .bss
buffer resb 1
resultValue resb 1
%macro calculateFunc 5
push eax
push edx
push ecx
mov eax, %1
mov ecx, %2
add eax, ecx
mov ecx, %3
imul ecx
mov ecx, %4
xor edx, edx
idiv ecx
mov ecx, %5
add eax, ecx
mov [resultValue], eax
pop ecx
pop edx
pop eax
%endmacro
SECTION .text
global _start
_start:
;call showPromt
push labInfo
push labInfoLen
call printStr
add esp, 8
;call showVarsList
push mainMenu
push mainMenuLen
call printStr
add esp, 8
call getUserAction
;get get get action
mov eax, [buffer]
cmp eax, 'r'
je count
cmp eax, 't'
je beep
cmp eax, 'y'
je exit
jmp _start
count:
;showFuncInfo
push funcStr
push funcStrLen
call printStr
add esp, 8
;showProposal
push countPromt
push promtLen
call printStr
add esp, 8
call getUserAction
mov eax, [buffer]
cmp eax, 'u'
je setUsersValues
cmp eax, 'e'
je callFunc
call exit
ret
setUsersValues:
nop; add some code later
ret
callFunc:
calculateFunc A1,A2,A3,A4,A5
add byte [resultValue], '0'
push resultValue
push 1
call printStr ; print Result
add esp, 8
ret
printStr:
push ebp
mov ebp, esp
mov eax, 4
mov ebx, 1
mov ecx, [ebp+12]
mov edx, [ebp+8]
int 80h
pop ebp
ret
getUserAction:
mov eax, 3
mov ebx, 0
mov ecx, buffer
mov edx, 1
int 80h
ret
beep:
nop;add some code later
ret
exit:
mov eax, 1
xor ebx, ebx
int 80h
A:
without seeing all the code, your buffer should be at least 2 bytes. the size for both sys_read and sys_write should be 2 not 1.
| {
"pile_set_name": "StackExchange"
} |
News Item: Homepage
Harper JH Open Monday- No Threat to Campus Found
Dear DJUSD Parent/Guardian,
Harper Junior High School will be open on Monday, March 5, 2018.
Today Davis Police officers, working with the Davis Joint Unified School District, were able to identify the source of the threat made against Harper Jr. High on Friday, a male student in his early teens. Further investigation revealed the threat was a prank. Any legal or school disciplinary measures related to this matter are being handled by the appropriate entity.
Harper Junior High School will be in session for a regular school day on Monday, March 5. We are thankful for the assistance of the Davis Police Department for their thorough investigation and dedication the safety of Davis students. In light of the recent school shooting in Parkland, Florida and other recent tragedies effective partnerships with the Davis Police Department are more important than ever.
At this point in time, all DJUSD schools are open on Monday, March 5, 2018. There are no known threats to any campuses.
We understand that events like this can cause fear and stress. If you have questions or need support for your student, please contact your child’s principal or counselor. | {
"pile_set_name": "Pile-CC"
} |
Eat grapes to protect your teeth from decay
Eating grapes can protect your teeth from decaying as a recent study suggests a natural compound found in grapes can strengthen teeth and boost the strength of fillings.Scientists from the University of Illinois at Chicago College of Dentistry say this discovery could stop people from losing teeth as the grape seed extract - a byproduct of the wine making industry which can be purchased from health food shops - has long been linked to health benefits such as improved heart function and better circulation.
Now the substance could reduce tooth extractions by increasing the longevity of composite-resin fillings - or tooth-coloured fillings - which typically last only five to seven years.
The results suggested that the extract has been found to toughen dentin, the tissue that makes up the bulk of the tooth, which lies beneath the hard external enamel, reports the Mail Online.
This means that when teeth are damaged, the remaining structure can be made stronger to bond with materials used in fillings.
It could spell good news for patients who opt for resin fillings because they are more aesthetically pleasing, even though they are not as tough amalgam fillings, which last 10 to 15 years or more.
A researcher Dr Ana Bedran-Russo said that when fillings fail, decay forms around it and the seal is lost. The team wants to reinforce the interface, which will make the resin bond better to the dentin.
Tooth decay can occur when acid is produced from plaque, which builds up on your teeth.
If the plaque is allowed to build up, the acid can begin to break down the surface of your tooth, causing holes known as cavities.
The cavity begins to eat away at the second level of tooth material that lies beneath the enamel: the dentin.
Interlocking the resin and collagen-rich dentin provides better adhesion and does not rely on moisture, the researchers stated. | {
"pile_set_name": "Pile-CC"
} |
Q:
Should I dispose EventRecords from a EventLogReader?
Should dispose be called on the events that come back from the ReadEvent method of EventLogQuery?
var eventLogQuery = new EventLogQuery("application", PathType.LogName) ;
using (var logReader = new EventLogReader(eventLogQuery))
{
var eventInstance = logReader.ReadEvent();
while (eventInstance != null)
{
eventInstance.Dispose(); //Should this be done? Or is this not ours to dispose?
eventInstance = logReader.ReadEvent();
}
}
Should my code call a dispose on eventInstance? Or is that something else's job?
A:
If it implements IDispose, dispose of it before it leaves the scope where it was created -- unless you plan to keep it around for a while for some particular reason. And calling EventLogReader.ReadEvent() is the kind of thing you should presume qualify as creation unless MSDN says otherwise (I checked -- it doesn't).
"Unless you plan to keep it around for a while" is why logReader should be deeply reluctant to dispose of the objects it created for you: It just can't know what you plan to do with them, so it should leave the decision up to you. It's not a bad idea to check MSDN if in doubt, but it would be strange if EventLogReader.Dispose() disposed of the query results as well. If you look at EventLogRecord in MSDN, it doesn't say anything about the subject, so just take IDispose as a suggestion to call Dispose() on the thing when you are done with it.
| {
"pile_set_name": "StackExchange"
} |
Pages
Mama Mia! World's Best Spaghetti and Meatballs
Buon giorno! I have a real taste treat that you're going to flip for. You'll throw away all your other spaghetti sauce and meatball recipes once you try this. I did. My daughter turned me onto a similar recipe a few years ago. I've made a couple changes and added the best yummy meatballs to make it even more special. Both are wonderfully spiced as written in the recipe so don't hold back. A dear true Italian friend, Lu taught me years ago to always "fry" your tomato paste a few minutes before adding the other wet ingredients. She said true Italians never use "raw" tomato paste in their cooking. It adds a depth to your sauce. Lu, if you're reading this from heaven, ciao!
For browning the meats, have you seen this Mix 'n Choptool from Pampered Chef? It makes light work of breaking up meat for cooking. Even the men in the family freak out if they can't find their "meat tool". I ordered mine on a recommendation and love it! Great gift idea for 10 bucks. Speaking of breaking up the meat, in general I'm kinda' of a "if less if good, then more would be better" girl. Don't do it. I've done it and it makes things mushy. You gotta' know when to stop.
Also, you know to never cook with a wine that you wouldn't drink, right? My parents weren't wine drinkers so I didn't grow up cooking with wine. But lo and behold, there isn't hardly anything that a good wine doesn't make better. And now I cook with it too. :) Any decent red wine will do. I've used cabernet and merlot and like both those. Use your favorite robust red.
For the herbs for both recipes, fresh is great when you have it in the summer but I don't go to the extra expense in the winter. I always like the Muir Glen brand tomatoes. You can find them on sale (4/$5) to make them comparable to other brands.
This recipe is special enough to serve to company, just make sure you make copies of the recipe. I always double both recipes and put several containers in the freezer. It is my husband's favorite go-to dinner. I wish I had smell-a-vision for you - the house smells delicious! Without further ado, here is Mama's Famous Spaghetti and Meatballs.
Brown the meats, breaking up into small bite size bits. Add onions and cook until soft. Add garlic and cook for a minute. Stir in tomato paste and "fry" for 2-3 minutes until just beginning to brown.
Add diced tomatoes, tomato sauce and water. Add mushrooms, basil, parsley, brown sugar, salt, crushed red pepper flakes, black pepper and wine. Stir well and bring to a simmer. When the meatballs are done baking, add them to the sauce. Stir carefully from now on to not break up the meatballs. Simmer low and slow 2-3 hours.
I serve with garlic bread and an Italian salad (greens, garbanzo beans, sliced olives, pepperoni, croutons) and don't forget the rest of that bottle of wine you opened. Mangia!
yes, cook the meatballs but I leave them a little undercooked because they will finish cooking in the sauce. I have seen some recipes that put uncooked meatballs in sauce to cook but personally, can't bring myself to put raw meat into sauce. Thanks for your question!
Follow the Nest!
Hello!
Please come in and make yourself comfortable. Take your shoes off, I'll put the coffee on and I've got that creamer you like. Let's talk house & home!
I love to see what other people are up to in their houses, don't you? Who doesn't love a good walk at dusk when people have their inside lights on and drapes open? Please tell me you do that too. :) I love to see how you're decorating, where you found this or that and even what you made for dinner.
I hope that you'll come back here often. No need to call ahead. And I'll leave the lights on and drapes open just in case!
Terry
Ps. I appreciate the time you took visiting today. I'd be grateful if you'd become a follower, comment along the way and let me know what you think. | {
"pile_set_name": "Pile-CC"
} |
Introduction {#Sec6}
============
Selective logging is the dominant commercial activity in forested areas of the tropics with strong conservation potential (Frumhoff, [@CR11]; Struhsaker, [@CR38]). This potential is arguably strongest in central Africa, where a combination of weak communications and infrastructure, lack of logistics systems, and high transportation costs result in highly selective timber extraction, focusing on a few economically valuable species occurring at low densities (Boardman et al., [@CR6]; Clark et al., [@CR8]).
During the last decade, the timber industry has thrived in central Africa and many of the remaining forests have been allocated to timber concessions. With extraction rates of 1--4 trees harvested per hectare, damage to remaining forest is relatively limited and disrupts only 7--20% of the canopy (Hall et al., [@CR18]; Van Gemerden, [@CR42]). This is compared to extraction rates of 5--10 trees per hectare and associated disruption of 25--50% of the canopy typical of other forested regions of the tropics (Skorupa, [@CR36]; Chapman et al., [@CR7]). Whereas some species of wildlife thrive in such low-intensity operations, even low-level extraction appears to have a negative effect on some primate species, including chimpanzees (White, [@CR43]; Barnes and Lahm, [@CR4]; White and Tutin, [@CR44]; Matthews, [@CR24]).
Although logging is known to reduce the abundance of some primate species due to associated hunting and the loss of food sources for frugivores (Wilkie and Carpenter, [@CR45]; Chapman et al., [@CR7]), the potential role of parasite infections in such primate population declines remains largely unexplored. Logging results in a suite of alterations in host ecology forest structure and human-wildlife overlap that may alter infection prevalence and infection risk in resident populations. Patterns of parasitism in wildlife populations are influenced by host ranging patterns, density, intraspecific and interspecific contact rates, diet, and immune function (Hudson et al., [@CR21]; Nunn et al., [@CR28]; Gillespie et al., [@CR13], [@CR14]; Beldomenico et al., [@CR5]). Studies on a variety of species have demonstrated that these characteristics can be affected by changes in forest structure (Olupot et al., [@CR29]; Heydon and Bulloh, [@CR19]; Patriquin and Barclay, [@CR30]).
*Giardia* and *Cryptosporidium* are protozoal pathogens that infect humans, domestic animals, and wildlife worldwide (Appelbee et al., [@CR1]). In humans and livestock, these parasites cause diarrhea and other enteric disorders that can contribute to nutritional deficiencies and impaired weight gain (Savioli et al., [@CR34]; Thompson, [@CR40]). Little information exists about the clinical affects of these parasites on their wildlife hosts; however, environmental pollution with human fecal material is recognized as a potential pathogen pathway for wildlife infections with zoonotic protozoal parasites, such as *Giardia* and *Cryptosporidium* (Appelbee et al., [@CR1]). Considering the capacity of such infections to put wildlife populations at risk, it is important to monitor the health status of wildlife in general and endangered species in particular. It is equally important to identify potential pathogen transmission pathways from humans and domestic animals to wildlife.
To better understand the affect of selective logging on the transmission and persistence of these protozoal pathogens, we examined noninvasively collected fecal samples from 134 sympatric western lowland gorillas (*Gorilla gorilla gorilla*) and chimpanzees (*Pan troglodytes troglodytes*) in the northern Republic of Congo. We compared patterns of infection between ape samples from the Kabo Logging Concession with those sampled from the adjoining undisturbed forest of the Nouabalé-Ndoki National Park.
Methods {#Sec1}
=======
Study Site {#Sec2}
----------
The Sangha River Tri-National Conservation Area (36,236 km^2^) is notable for its extensive tracks of forest and transboundary protected area network: Nouabalé-Ndoki National Park in Republic of Congo, Lobéké National Park in Cameroon, and Dzanga-Ndoki National Park and Dzanga-Sangha Special Reserve in Central African Republic (Fig. [1](#Fig1){ref-type="fig"}). This region is largely unpopulated with human densities estimated at 0.7 to 0.8 people per km^2^ (Auzel and Wilkie, [@CR2]). Semi-nomadic Ba'Aka pygmies and Bantu agriculturalist-fishermen live in complex, interdependent economic and social relationships (Eves and Ruggiero, [@CR10]). Most villages are along major waterways leaving the remote interior forest with little human development and associated pressures. However, commercial logging is rapidly expanding along the periphery of the Tri-National Conservation Area. Timber exploitation in these remote areas is relatively labor-intensive and can result in the transient relocation of skilled workers and their families, introducing the risk of novel opportunities for pathogen transmission from people to resident wildlife.Figure 1Land use in the Sangha Tri-National Conservation Area at the boundary of Republic of Congo, Cameroon, and the Central African Republic. The Goualougo Triangle is located in the southern portion of the Nouabalé-Ndoki National Park. The Kabo Logging Concession is contiguous to the national park's southern boundary.
The Kabo Logging Concession (2800 km^2^), operated by the *Congolaise Industrielle des Bois,* has been logged to varying degrees for the past 40 years. The pristine forests of the adjoining Goualougo Triangle (310 km^2^) were initially part of the Kabo Concession until biological surveys by the Wildlife Conservation Society revealed the conservation significance of this region's great ape populations and their habitat. In June 2003, the Congolese government announced that it would annex the majority of the Goualougo Triangle to the Nouabalé-Ndoki National Park (4400 km^2^, 2.05′--3.03′N, 16.51′--16.56′E). However, the adjacent forest remains in an active logging concession. As part of the Goualougo Triangle Ape Project's mandate to evaluate the impacts of logging on wild apes, this area was stratified into study zones (A, B~1~, B~2~, C, and D) with relation to the national park boundaries and logging activities (Fig. [2](#Fig2){ref-type="fig"}). Zones A, B~1~, and B~2~ are undisturbed forest within the national park. Zone D was logged in the early 1970s, and zone C is slated for logging in the near future. All study zones are characterized by similar terra firma forest dominated by mixed species interspersed with monodominant *Gilbertiodendron dewevrei*, seasonally flooded forest, and open swamp forests (Morgan et al., [@CR25]).Figure 2Location of study zones within the Goualougo Triangle (A, B~1~, and B~2~) and adjacent logging concession (C and D) in Republic of Congo.
Sample Collection and Analysis {#Sec3}
------------------------------
Between 2004 and 2009, we conducted repeated reconnaissance and line transect surveys for ape signs in zone D of the Kabo Logging Concession and zones A and B~1~ within the Goualougo Triangle (Morgan et al., [@CR25], [@CR26]). Our first surveys of zone D were conducted after forestry activities had been dormant for more than 30 years. Ape fecal samples were collected opportunistically in the field and preserved in 10% neutral buffered formalin (Gillespie, [@CR12]). Fecal samples were characterized as chimpanzee or gorilla based on morphological features. At similar sites using similar methods, samples characterized in this fashion were verified to the correct species more than 94% of the time by genetic methods, with field researchers able to correctly identify gorilla dung (318/324 = 98%) more often than chimpanzee fecal remains (200/211 = 94%) (Arandjelovic, 2009, personal communication). When collected, fecal material was characterized as soft or firm depending on the consistency, assuming that sick apes will evacuate soft stools (Gillespie et al., [@CR14]). A Merifluor *Cryptosporidium*/*Giardia* Direct Immunofluorescent Detection Kit (Meridian Bioscience, Inc., Cincinnati, OH) was used to detect both parasites (Johnston et al., [@CR23]). Fecal samples were scored both for presence or absence of the pathogens as well as quantification of *Cryptosporidium* sp. oocysts and *Giardia* sp. cysts in feces. Fecal samples were concentrated and then resuspended in 1 g/1 ml suspensions. Counts were calculated by analyzing 10 μl of the 1 g/ml solution of concentrated feces from each sample. Oocysts or cysts were then quantified by counting total numbers in 150 microscope fields (400× magnification) and extrapolating results to the entire sample. This method was validated by spiking negative fecal samples with known numbers of *Cryptosporidium* sp oocysts and *Giardia* sp. cysts. Results were analyzed using EpiInfo, Version 3.3.2 (Centers for Disease Control, Atlanta, GA). A power analysis was conducted using the Finite Population Correction for Proportions (Israel 1992). The corrected sample sizes are calculated using the original sample size results calculated using the equation for a large population. These numbers are based on a confidence level of 95% and level of precision of 0.05.
Results {#Sec4}
=======
All 134 samples were negative for *Cryptosporidium* sp. (Table [1](#Tab1){ref-type="table"}). Three of 34 chimpanzee samples (8.82%) from the logged site, 1 of 33 chimpanzee samples from the undisturbed site (3.03%), 0 of 31 gorilla samples from the logged site (0%), and 1 of 36 gorilla samples from the undisturbed sites (2.78%) were infected with *Giardia* sp. (Table [1](#Tab1){ref-type="table"}). Prevalence of infection with *Giardia* sp. was not significantly different between logged and undisturbed forest for chimpanzees (χ^2^ = 1.00, *P* = 0.32, degrees of freedom (*df*) = 1) or gorillas (χ^2^ = 0.87, *P* = 0.35, *df* = 1).Table 1Prevalence and intensity of *Cryptosporidium* and *Giardia* spp. in chimpanzees and gorillas in the Goualougo Triangle of Nouabalé-Ndoki National Park and Kabo Logging Concession, Republic of CongoSpeciesPopulationSamples*CryptosporidiumGiardia*Prevalence (%)Mean intensityPrevalence (%)Mean intensityChimpanzeeGoualougo33003.031000Kabo34008.821833 ± 573.49GorillaGoualougo36009.78900Kabo310000Mean intensities are expressed as oocysts (*Cryptosporidium*) or cysts (*Giardia*) per gram, standard error of the mean; negative samples are not included in this calculation.
Of all 67 chimpanzee samples, one was characterized as soft (1.5%) and the remainder as firm (98.5%). Of all 67 gorilla samples, 3 were characterized as soft (4.5%) and the remainder as firm (95.5%). There was no relationship between fecal consistency and *Giardia* infection status for chimpanzees (χ^2^ = 0.00, *P* = 0.78, *df* = 1) or gorillas (χ^2^ = 0.07, *P* = 0.78, *df* = 1).
Our power analysis demonstrated that additional zone D chimpanzee sampling would be required to ensure that the lack of significance observed in intersite comparisons of chimpanzees *Giardia* sp. prevalence is indeed valid (47 zone D compared with the 34 collected thus far). Samples were collected during repeated line transect surveys during a period of 5 years. Collection of fresh ape feces in this system requires a tremendous amount of effort. Three to five samples can be collected in a day by a team of five trackers. Samples are collected by backtracking sighted apes to find feces voided within the past hour. Aged feces, such as those from night nests are not collected. Due to these limitations, we regard the lack of significant differences in *Giardia* sp. prevalence between sites for chimpanzees to be preliminary. Additional sampling will be required to definitively examine this comparison.
We also compared the intensity of infection for each ape species between logged and undisturbed sites. The mean intensity of infection was highest in chimpanzees from the disturbed site (1833 ± 573.49 cysts/g), followed by chimpanzees in the undisturbed site (1000 cysts/g). Mean intensity of infection was slightly lower for gorillas from the undisturbed site (900 cysts/g), and no infections were found in gorillas from the disturbed site, resulting in an intensity of zero (Table [1](#Tab1){ref-type="table"}); mean intensities of infection could not be compared statistically across sites due to rarity of infection.
Discussion {#Sec5}
==========
Our results demonstrate that *Giardia* sp. is present at low prevalence in chimpanzees and lowland gorillas in undisturbed forests and forests with a history of selective logging. In these same populations, there is no evidence of infection with *Cryptosporidium* sp. A lack of *Cryptosporidium* sp. in all samples examined suggests that *Cryptosporidium* sp. is not a natural component of ape parasite communities at this site and that historical land-use patterns are not exposing apes to zoonotic sources of this pathogen. Low prevalence of *Giardia* sp. in the study area regardless of historical land-use patterns suggest that a low level of circulating *Giardia* is a natural component of Congolese ape parasite communities and that historical land-use patterns are not exposing apes to zoonotic sources of this pathogen. Our study area is located only 32 km from the nearest village and the large river that serves as a major transportation source for the region. However, the forest is continuous and the encounter rate of human signs in the study zones was low, which confirms that these forests have remained relatively undisturbed despite past timber exploitation. This post-logging scenario is much different than the high human densities and forest fragmentation typical in east and west Africa.
*Giardia* and *Cryptosporidium* are notable for cross-species transmission (Thompson, [@CR40]). The propensity of these protozoans to cross species barriers results from the host nonspecificity of trophozoites of either genus, and the high infectivity and environmental stability of *Giardia* cyst and *Cryptosporidium* oocysts (Smith and Nichols, [@CR37]). Previous field-based studies confirm this pattern, demonstrating that high levels of primate--human overlap enhance transmission of potentially pathogenic protozoa, including *Giardia* sp. and *Cryptosporidium* sp. (Nizeyi et al., [@CR27]; Graczyk et al., [@CR15], [@CR16]; Graczyk et al., [@CR17]; Salzer et al., [@CR33]). The results of the current study are the first to examine the long-term effects of historical primate--human overlap on contemporary patterns of infection with these pathogens.
Considered among the most common human intestinal protozoa, *Giardia* ranges in clinical presentation from asymptomatic to highly pathogenic, causing chronic malabsorptive diarrhea in some patients (Thompson, [@CR40]). Both host factors (e.g., nutrition, immunity, coinfection with other agents) and pathogen factors (e.g., strain, infectious dose) are thought to contribute to the severity of clinical disease (Thompson, [@CR39]). Giardiasis is now considered by the World Health Organization to be a "neglected disease," due to its ubiquity in equatorial latitudes, its chronic detrimental health effects (especially in children), its propensity to infect economically disadvantaged populations, and the paradoxical availability of relatively inexpensive and effective pharmaceuticals for its treatment (Savioli et al., [@CR34]).
In our study, we found no relationship between infection status and fecal consistency (soft vs. firm). The lack of a strong measurable association between infection and acute gastrointestinal symptoms in our study population was surprising, but it is concordant with recent studies of humans. Although *Giardia* is associated with clinical diseases in developed economies, evidence is nevertheless mounting that it may be commensal in rural settings where people may normally be exposed to diverse parasite communities from an early age. For example, Peréz Cordón et al. ([@CR31]) found *Giardia* at 28.1% prevalence in diarrheic Peruvian children, as well as in 19.5% of nondiarrheic children, emphasizing the importance of asymptomatic patients in *Giardia* transmission where hygiene and sanitation are poor (Peréz Cordón et al., [@CR31]). Other studies in India (Traub et al., [@CR41]), Ethiopia (Ayalew et al., [@CR3]), Bangladesh (Dib et al., [@CR9]), and Peru (Hollm-Delgado et al., [@CR20]) have found similarly weak or nonexistent associations between *G. duodenalis* infection status and gastrointestinal symptoms, suggesting that *G. duodenalis* may coexist benignly with human hosts under conditions where acquired immunity to the pathogen can develop. Lack of early exposure and acquired immunity to *G. duodenalis* may, in fact, account for the role of the pathogen as a cause of sporadic diarrheal outbreaks in developed countries (Istre et al., [@CR22]), as well as a major cause of traveler's diarrhea for people from developed countries who visit endemic areas (Reinthaler et al., [@CR32]; Shlim et al., [@CR35]). The interplay between clinical symptoms and *Giardia* infections in wildlife are far less known. We hope to explore in detail the association between symptom and infection in apes in more detail in future work.
Our results from the Goualougo Triangle provide a rare opportunity to observe baseline patterns of infection in undisturbed ape populations. Baseline patterns of parasitism are necessary to understand both individual animal health status and to assess what would constitute an "outbreak": a level of disease or parasitism in excess of what is normally observed. Thus, these results provide a first step toward an index of population health and disease risk assessment for conservation and management plans of these endangered African ape populations.
Our results from the Kabo Concession suggest that a legacy of low-intensity selective logging did not result in the persistence of elevated prevalence of *Cryptosporidium sp*. and *Giardia* sp. in these ape populations. It is encouraging that the resident ape populations are not suffering from infections of these protozoa, because this suggests such potential health threats may be mitigated. However, if these protozoa are exceptionally pathogenic in wild ape populations, infected individuals may have been removed from the population long ago due to high associated mortality.
We have yet to examine how patterns and risk of parasitism may differ during the various stages of the active logging process (i.e., exploration, road construction, and timber harvesting) from those that are the product of a legacy of selective logging. The expansion of timber activities in the neighboring undisturbed forests of the Kabo concession will enable us to address these questions through an ongoing progressive monitoring program that involves documenting ape populations, human disturbance, and the health implications during their interactions.
Permission and logistical support for this research was provided by the Government of the Republic of Congo and the Congo Program of the Wildlife Conservation Society. C. Eyana assisted with data collection and a dedicated team of assistants from the villages of Bomassa and Makao provided invaluable assistance in the field. The authors thank N. Hauser and E. Canfield for laboratory assistance and two anonymous reviewers for helpful comments on an earlier draft of this manuscript. Funding for this research was provided the National Institutes of Health (NIH Grant T35 2006), the U.S. Fish and Wildlife Service (Great Ape Conservation Fund), and the National Geographic Society.
| {
"pile_set_name": "PubMed Central"
} |
Speculation that Google would be introducing alternative operating systems for its Pixelbook has been around for quite some time, with references to Windows Hardware Certification Kit (WHCK) seemingly confirming the shift back in June. It looks like this might be getting closer to becoming a reality, as a new code …
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"pile_set_name": "Pile-CC"
} |
Like most websites we uses cookies. In order to deliver a personalised, responsive service and to improve the site, we remember and store information about how you use it. This is done using simple text files called cookies which sit on your computer. These cookies are completely safe and secure and will never contain any sensitive information. They are used only by us. The information you provide will be used solely for dealing with you for your activities at Queen Mary Sailing Club. The club has a data privacy policy which can be found at https://queenmary.bookinglive.com/the-club/club-documents your data will be stored and used in accordance with this policy'.
London Youth Games
Welcome to the London Youth Games
The 2019 London Youth Games for sailing is taking place at Queen Mary Sailing Club over the weekend of 15/16 June 2019.
The London Youth Games have been inspiring young Londoners since 1977, when they were launched to mark the Silver Jubilee of Queen Elizabeth II. Since then, borough teams have competed on an annual basis for the prestigious Jubilee Trophy.
Primary and seconday schools right across London come together every year at the School Games. They face off in four kinds of competition: intra-school, local inter-school, county finals and the School Games National Finals. Sailing is just one of the many sports that make up the games.
This web page is to provide information on the Queen Mary, including Boat Hire (scroll to the bottom of this page to book now), club opening times etc.
If you're interested in entering the Sailing Regatta, then you will need to follow these simple steps:
1. Click on this linkhere and scroll down to the 'Contact Your Borough' Section.
2. Type in the Borough you would like to represent. You must live and / or go to school in a Borough to represent them.
3. Once you have typed in your Borough, contact details will appear. Please contact your Borough Team Co-ordinator expressing your interest in competing at the Sailing Competition. You will need to provide your name, DoB, School, Home Postcode and the Sailing event you would like to take part in, in order to be entered into the competition.
Should follow the instructions of marshals at all times (most will be wearing high-visibility jackets).
Due to limited space, cars on upper level may not be left unattended at any time, nor may cars be parked there, except for those using our Disabled Parking Bays.
Unload your boat and move it to the boat park as directed.
After unloading your boat please immediately take your car to the car park on the lower level.
It is a competitor's responsibility to clean the underside of their boat before leaving the site, using the wash stations in either the boat park or the lower car park.
All visitors and competitors
To enter and exit the main gates, press the intercom button on the lower keypad, await instructions and enter / exit on the green traffic light - on NO account 'tailgate'.
Please follow the marshals' instructions for parking.
No dogs are allowed on site except working Assistance Dogs.
Registration in the Marquee will begin at 8.00 am on each day of racing.
Briefing for competitors will be held at 09.30 on each day of racing, on the ground floor.
Morning racing is scheduled to start at 10.30 and afternoon racing scheduled to start at 14.00 on each day of racing.
Changing rooms and toilets are located on the ground floor of the Clubhouse; including Disabled access facilities.
All competitors and support staff must wear correctly fastened buoyancy aids while on the water.
All spectators and competitors not launching or landing their boats shall not go onto the sloping banks or pontoons of the reservoir.
Bar and catering is available on the upper deck throughout the day- cash only, no facility for cards.
Boat Drop Off & Pick Up
If you are bringing your own dinghy, access to the club is during opening hours only (see below for the specific opening hours around the event). Please call the office prior to arriving to get confirmation of where your kit can be left. There will be limited boat storage options on the upper level in the boat park, with most boats being stored on the lower level before and/or after the event.
Outside of club opening times, access is not available to the club and grounds secured.
Opening Times
Monday, Tuesday, Thursday and Friday : 0900-1700
Wednesday: 0900-2100
Saturday and Sunday : 0700-1900
Boat Hire
We have 12 Picos, 4 Fevas and 6 Toppers available for hire, at a cost of £30 per day. Boat hire is per day and is bookable through our website - see the links below. If you require the use of a boat for the full weekend you must book it out for each day. Payment is needed at time of booking and we are unable to invoice for boat hire.
Should you be interested in hiring a Hansa 303, please call the Office on 01784 248881 to discuss your requirements, as these boats are not bookable online.
Boat insurance is provided by QM (damage waiver up to £400 for damage sustained through negligence)
The Terms & Conditions for LYG boat hire are available below
The Hire Agreement Form will be emailed out at time of booking so can be downloaded and completed prior to arriving on the day
Any enquiries regarding the hiring of boats for this event please call the office on 01784 248881.
TERMS & CONDITIONS FOR LYG BOAT HIRE
Ability
Hirers are responsible for communicating to Queen Mary Sailing Club their ability relative to the weather conditions and choice of craft. The Duty Officer on the day will decide on eligibility for hire in the conditions.
MASTHEAD FLOATS MUST BE USED ON ALL DOUBLEHANDED DINGHIES and are provided
Hirers must keep within the designated sailing areas and must not sail within the exclusion zones around dredgers, as indicated by the surrounding buoys.
Directions of the Duty Officer and Safety Boat Drivers must be followed at all times.
Clothing
All equipment hire includes use of wetsuits. Wetsuits or drysuits must be worn from November 1 to March 31 by all water users.
All equipment hire includes buoyancy aids which should be correctly worn at all times whilst on the water, pontoon or banks.
Payments
Hire rate is as agreed by QM
Should damage be sustained to the dinghy or a claim be made against the hirer, the damage waiver is a maximum of £400
Credit/debit card details will be kept securely by the QM office should a successful claim be brought against the hirer post event. QM will make every effort to contact via the details above before a charge is made, however should no communication be possible, QM reserve the right to charge a fair price to the card details provided.
Other
All equipment damage must be reported at reception as soon as practicable and must be paid for unless the damage is deemed to be due to reasonable wear and tear.
A responsible adult must remain on site to supervise under-18’s hiring
Queen Mary Sailing Club reserve the right to refuse or curtail hire at any time for reasons of safety or if the weather conditions become unsuitable or for any other reason. | {
"pile_set_name": "Pile-CC"
} |
from __future__ import absolute_import
from __future__ import division
from __future__ import print_function
import _init_paths
import os
import cv2
import time
# from opts import opts
from opts_pose import opts
from detectors.detector_factory import detector_factory
image_ext = ['jpg', 'jpeg', 'png', 'webp']
video_ext = ['mp4', 'mov', 'avi', 'mkv']
time_stats = ['tot', 'load', 'pre', 'net', 'dec', 'post', 'merge']
def demo(opt):
os.environ['CUDA_VISIBLE_DEVICES'] = opt.gpus_str
Detector = detector_factory[opt.task]
detector = Detector(opt)
if opt.demo == 'webcam' or \
opt.demo[opt.demo.rfind('.') + 1:].lower() in video_ext:
cam = cv2.VideoCapture(0 if opt.demo == 'webcam' else opt.demo)
detector.pause = False
i = 0
start_time = time.time()
if opt.output_video:
fourcc = cv2.VideoWriter_fourcc(*'mp4v') # 如果是mp4视频，编码需要为mp4v
im_width = int(cam.get(cv2.CAP_PROP_FRAME_WIDTH))
im_height = int(cam.get(cv2.CAP_PROP_FRAME_HEIGHT))
write_cap = cv2.VideoWriter(opt.output_video, fourcc, 25, (im_width, im_height))
while cam.grab():
i += 1
_, img = cam.retrieve()
cv2.imshow('input', img)
ret = detector.run(img)
time_str = ''
for stat in time_stats:
time_str = time_str + '{} {:.3f}s |'.format(stat, ret[stat])
if opt.output_video:
write_cap.write(ret['plot_img'])
print('fps:{:.3f}'.format(i/(time.time()-start_time)), time_str)
if cv2.waitKey(1) == 27:
return # esc to quit
else:
if os.path.isdir(opt.demo):
image_names = []
ls = os.listdir(opt.demo)
for file_name in sorted(ls):
ext = file_name[file_name.rfind('.') + 1:].lower()
if ext in image_ext:
image_names.append(os.path.join(opt.demo, file_name))
else:
image_names = [opt.demo]
for (image_name) in image_names:
ret = detector.run(image_name)
time_str = ''
for stat in time_stats:
time_str = time_str + '{} {:.3f}s |'.format(stat, ret[stat])
print(time_str)
if __name__ == '__main__':
opt = opts().init()
demo(opt)
| {
"pile_set_name": "Github"
} |
Q:
Can I override "hide and disable all items on the desktop"?
Is it possible to add shortcuts and/or windows components to the desktop if "hide and disable all items on the desktop" is enabled via GPO? For example, if I have a few specific program icons I want to show up and nothing else, what is the best way to accomplish this?
I tried the steps at here and here.
But neither worked. Either the shortcut never showed up or the registry key didnt exist (on either Win7 or S2K8 machine).
A:
Redirecting the desktop to a read-only folder worked nicely.
Also, needed to add the reg entries to [HKEY_CURRENT_USER\Software\Microsoft\Windows\CurrentVersion\Explorer\HideDesktopIcons\NewStartPanel]... I only did the ClassicStartMenu/
I also had to add Computer Configuration -> Policies -> Windows Settings -> Security Settings -> File System -> %SYSTEMDRIVE%\Users\Public\Desktop (Users: Deny - List Folder Contents) otherwise icons previously installed by programs available to all users would still show up.
| {
"pile_set_name": "StackExchange"
} |
Advertising
'FlatOut 2' - v1.1 Euro Beta Patch Available NOW
Featuring an enhanced version of the originals lauded physics engine with even faster driving track designs, FlatOut 2 also boasts numerous improvements, enhancements and additions to make the title the definitive FlatOut experience. Twice as many vehicles, a more sophisticated career mode, additional race environments, double the number of tracks, twice as many mini-games along with brand new and much requested online multiplayer modes are just some of the exhaustive features that are included in FlatOut 2.
WARNING: This patch is BETA code, it is NOT officially supported by Bugbear Entertainment or Empire Interactive. The patch ONLY works with the European version and German version of FlatOut 2. It DOES NOT WORK with the North American version.
You may experience issues and bugs with this patch. Please report any issues you experience with this patch at http://forum.empireinteractive.com under FlatOut 2 Forum / FlatOut 2 PC PC gamers. Specify that you are running the BETA patch.
An official patch will be released soon when we have received feedback on the beta patch.
[1] INSTALLATION
Unzip all the files into the root of the installed folder (by default this is C:Program FilesEmpire InteractiveFlatOut2) and run the game as normal.
WARNING: If you experience any issues with the BETA patch, uninstall the full game then browse your installed folder (by default this is C:Program FilesEmpire InteractiveFlatOut2) and manually delete the following two files: patch & patch1.bfs
[2] NEW FEATURES
Voice chat added
Text chat added for the European version
Bandwidth detection, and adjustments to the network send bandwidth
Players are not disconnected if a race starts when they are not ready, instead they can wait in the lobby until the next race
Improved prediction of remote cars in multiplayer games
Simple cheat detection added for modified data and known hacks
The list of multiplayer games extended to show 100 games instead of 25
Only one kick vote can be initiated per race for the same player
Return to the list of multiplayer games when you exit the lobby and have previously been searching for a game
The draw distance for dynamic objects increased
Aspect ratio option added, widescreen support
Manual gearbox option added
Userdata added to network objects that can be used when making game modifications
New command line options added (see below, in COMMAND LINE OPTIONS)
[3] BUG FIXES
Fix for joining behind NAT devices
Fix for crash when refreshing the list of games
Fix for joining games that are just about to start
Fix for derby hang, when all other players disconnect before the derby starts
Fix for a hang when exiting the session at the same time as someone else is joining
Fix for the sorting of the list of multiplayer games. Now it sorts games in the lobby, with the games with least amount of players first
Fix for packet relaying between machines that cannot connect directly, now it uses bandwidth and latency for that
Fix for disconnects or crashes in stunt modes with low bandwidth
Fix for crash at the game start, just after the race has loaded
Fix for crash in races or derbies when more than one player gets disconnected at almost the same time
Fix for crash when searching for multiplayer games, and there's too many games in the list
Fix for a cheat where you are able to wreck the same player multiple times in derbies
Fix for time synchronization bug, when the PC clocks are running at different speed, caused the "No other players in the game" message to appear at the start of races
Longer timeout for joining, it was failing before due to timeouts in certain cases
Fix for the last character not appearing in the text chat for the North American version
Fix for text chat when the player names contains number for the North American version
Fixed a crash in the loading screen
Force feedback improved a bit
Fix for disappearing car in the desert town track
Fix for tournaments skipping races
Player details cannot be selected for players that are not fully connected
Fix for kicked players being able to join the same game again
Hardcoded 10% deadzone removed for steering wheels
[4] OUTSTANDING PROBLEMS
Black/White screen at the start of races. It's unsure if this is fixed or not, as an effect of some of the other fixes.
Sound issues with Creative sound cards. Use the WaveOut option in the game configuration to work around this problem.
Joins a game, either matching the matchname or the ip:port combination. If the game is a Gamespy game then the ip:port should be the public ports as registered on the Gamespy master server. If the game is a LAN game, then the ip:port combination could be any combination that would reach the host, preferably the private address on the same subnet. Matchname only works for Gamespy games.
-host
Creates a game on either the Gamespy master or on LAN, depending on whether the -lan parameter is specified. If a matchname is specified, the game will be joinable by a matching -join=matchname. Otherwise an ip:port combination has to be specified when joining. Matchname only works for Gamespy games.
-num_players
An optional parameter for -host=matchname. Normally when a game is created with that option it will not be publicly visible and joinable until one minute has expired. The only way to join it before that timeout is to specify -join=matchname. -num_players can make the timeout expire faster. If you specify this option, then the game will be publicly visible as soon as number_of_initial_players has joined
the game.
-lan
Specifies that you will join or create a LAN game instead of a Gamespy one.
-password
If this is specified, then only games that are created by a matching password will be visible and joinable. Games created when this option is set will be created with the password. The password option can be specified both when joining and creating from command line or when creating and joining the game normally.
-profilenr
Automatically selects a profile at game start. If the profile doesn't exist or is invalid, then the user has to choose the profile manually.
-public_addr
Can be used if you know your public address and port. Normally it shouldn't be necessary to specify this explicitly, but it can be used when joining LAN games, and port forward is enabled on the router, so that you know your public address. This option should be specified on LAN games, if the host is on the same subnet as a joiner and someone outside wants to join. Without this parameter the joiner inside the LAN and the joiner outside the LAN might not be able to communicate directly. Another case where this might be needed is if you have more than three IP addresses on the machine. This option is most useful for LAN games, as Gamespy games most likely will be able to connect anyway, however it might speed up the joining.
-private_addr
Forces the game to report this private address to other players. The game will automatically detect up to four IP addresses, but if you have more than that, then you might not be able to communicate with players on a subnet of an IP that isn't detected. Specifying -private_addr will force the game to put that IP first in the list. This option is most useful for LAN games, as Gamespy games most likely
will be able to connect anyway, however it might speed up the joining.
-join_timeout
Specifies the amount of time to try to join a game from command line. After this time expires, the user is given the option to retry or quit. The default is 30 seconds.
-join_retry
Specifies how often a new search will be done when joining a Gamespy game from the command line. The default is to do a search every 5 seconds. Dont set this option too small or it might overload the Gamespy servers.
-exportstats
Writes the game results of every multiplayer game into an xml file in the savegame folder. | {
"pile_set_name": "Pile-CC"
} |
Subsets and Splits