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The United States is the most accepting diverse society on earth and has been for decades.
How many Black people have risen to President of France? To Prime Minister of France? Of England? Of Germany? Of Spain? Of Russia? How many have been named Ambassador to the United Nations, Foreign Minister (akin to Secretary of State), Defense Minister (akin to Secretary of Defense), Justice Minister (Attorney General), to other cabinet posts, national security advisor, and such? How many non-ethnic-Chinese have attained such positions in China? Non-ethnic Japanese in Japan?
Ours is a remarkably kind, accepting, and fair country. Yes, this country once was blighted by slavery, but more than 300,000 White American men gave their lives to end that tragic institution more than 150 years ago. Slavery ended. Like the Holocaust of only 75 years ago, it is part of a history book now. It is history. It is something to remember, something from which to learn so that it never be repeated — and it is over. A proud and healthy culture cannot be built predominantly on a tragedy, even a historic tragedy of incalculable proportions. As a rabbi, the Judaism I teach is the Torah and the Talmud, the commentaries and writings of Rabbi Rambam Maimonides and of Rabbi Rashi and of so many others. I teach the history of 3,300 years since Sinai, the achievements even in the face of the challenges. Yes, we are informed by the Shoah, as we are by the destruction of the Holy Temple that someday will be rebuilt in Messianic times on its promontory on Mount Moriah, as we are by the expulsions, Inquisitions, blood libels, pogroms, Communist terrors, and other persecutions that have visited us. That makes us vigilant. But we do not build a culture on that. I wish so much for others in other cultures to understand that no culture can be built in 2019 America on a slavery that ended in 1865 by virtue of 300,000 White men giving up their lives to end it.
Today’s reality is that the United States is the most accepting diverse society on earth and has been for decades.
I associate with people of all political, theological, ethnic, and gender-oriented stripes. In actual life experience, racism like anti-Semitism has all but ended in open American society. Racist Democrat governors like Lester Maddox and George Wallace, racist Democrat Senators like KKK Exalted Cyclops Robert F. Byrd and J. William Fulbright are gone from the scene. Yes, one reads despicable hateful social-media comments in certain online vehicles. Call it “Godwin’s Law.” In a society of more than 300 million people from so many diverse backgrounds, it is what it is. But wanton hatred has departed from our open society. I have not met a conservative in more than twenty years who cares a whit about someone’s color. That simply is not part of the conservative mindset. We measure people by their trustworthiness, resourcefulness, good cheer, skills and intelligence, and readiness to contribute to team success. Nothing else matters.
To gin up racism hysteria and get more TV viewers and online Twitter clicks, those merchandising in amplifying racial tensions must search through yearbooks of forty years ago to find morons posing in Blackface and 60-thread-count white polyester hoods. Impressionistic experiences are confirmed by data. Yes, there were more ticks on the “anti-Semitic-incidents” chart last year, but that was primarily because of one single mentally ill Israeli teen with some high-tech equipment who phoned threats to 245 American Jewish locations. Likewise, a modest uptick in recorded racial incidents reflects primarily that more agencies reported data than ever before. In all, under 8,000 reported hate crimes in a population of more than 300 million. Reports get overblown by certain agencies who raise vast amounts of money when they scare their constituencies into believing that Hitler and Eichmann are down the block. For example, the ADL, which has been taken over by Obama White House alumni, raises money by reporting spiking anti-Semitism, even when the honest data contradict them. They merchandise in alternative facts. For Al Sharpton — one of America’s worst racists of the past fifty years (honorable mentions: Louis Farrakhan, Tamika Mallory, Linda Sarsour) — bogus allegations of racism feed his kitty and career, got him an MSNBC show, and got him invited to the Obama White House for more than seventy visits recorded in the visitor logs. But the truth we all know from our everyday real-life encounters is that the American People are a warm and welcoming nation. We don’t ask much — just that people respect our laws and keep their hands off us.
The most deeply conservative pro-Trump Republicans may be frustrated by Don Lemon or by Rachel Maddow or by Obama or by Ana Navarro, but I never have heard anyone hate Obama or Lemon because of color, or Maddow because of whatever she is, or Navarro because of ethnicity. I never hear the “N-word” spoken by anyone outside the African-American community, and I also never hear any other anti-Black epithet, nor anti-Hispanic epithet, nor any other of that sort regarding people of Irish, Polish, German, and Italian descent. Not even the low-octane “Archie Bunker” insults. I heard some of those words half a century ago when I was a little kid, but America evolved. As a Jew who wears a yarmulke, once every two or three years I hear someone yell an anti-Semitic epithet at me, invariably from a passing car that then speeds up to 100 mph to race away before I presumably find a phone booth to change outfits and wreak vengeance on the terrified fleeing gutless coward.
The United States is the most accepting diverse society on earth and has been for decades.
If the 9/11 attacks had occurred in any other country, there would have been a corresponding wave of anti-Arab and anti-Muslim violence unprecedented in that country. But not in George W. Bush’s and Dick Cheney’s America. The same America that once interned more than 110,000 patriotic Japanese-Americans who had been born here and loved this country, as America’s West Coast became consumed by a post-Pearl Harbor frenzy, had evolved to the point by 2001 of distinguishing between law-abiding loyal Arab-Americans and Muslim Americans and even Muslim and Arab visitors — all on the one hand — and the Al Qaeda, Hamas, Hezbollah, Fatah, Jihad sorts on the other hand, for all of whom we built beautiful soccer courts at Gitmo.
None of this changed after subsequent terrorist actions by individual Muslims and Arabs in this country — for example, the Chechen Muslim terrorists who bombed the Boston Marathon; Syed Rizwan Farook and Tashfin Malik, who perpetrated the San Bernardino Christmas attack; Omar Mateen, who murdered 49 at an Orlando gay bar. Americans continue to welcome and accept all people of all societies who enter legally and participate constructively in our republic. Despite the Minnesota-based Somali Muslim immigrant community having had people leave America to join ISIS, Congressional Democrats still have welcomed their first Jew-hating Somali-immigrant Muslim House representative, Rep. Ilhan Omar. Among American conservatives there are no religion tests, although the Democrat Left is beginning to impose religion tests, in violation of Article VI of the U.S. Constitution, on nominees to the federal judiciary. There are no ethnicity tests, although it seems obvious that Harvard and other major liberal universities have secret admissions policies aimed at keeping many qualified Asian-American applicants out.
The United States is the most accepting diverse society on earth. Period.
It is a blatant lie that racism and anti-Semitism are on a dramatic rise. The Big Lie is stirred by a cynical Democrat Left that has found pay-dirt, solid gold, in dividing voters into neat pockets of identity-politics constituencies. Obama showed that he could beat a Republican opponent if he somehow could run a close race among all but one constituency, and then carry more than 90 percent of the African American vote and a big part of the Hispanic vote. Hillary tried to replicate the divide-and-conquer strategy, so — like Obama — she tried setting Blacks against Whites, Gays against Straights, Women against Men, Muslims against Christians and Jews, Latinos and other Hispanics against Caucasians. That was her “Basketful of Deplorables” trope. It worked for Obama because he actually has one Black parent, though was reared by his White mother, White grandmother, and spent all his formative life outside any classically “Black American environment,” as he grew up in Hawaii, then Indonesia, later attended Occidental College, then Columbia, then Harvard. By contrast, it did not work for Hillary because a majority of Americans simply do not like her, never particularly liked her, never will, do not trust her, and did not want more drama emerging from the #MeToo lug she would be bringing back to D.C. with her.
So Obama found that, if manipulated correctly, divisive identity politics could win elections, especially when plied against uninspiring GOP opponents who could win caucuses in Iowa and cross-over primaries in New Hampshire but who did not reflect the values, concerns, or passions of the realigned Republican electorate. In the Wasted Obama Decade, identity politics took on a new centrality. Trayvon Martin. Ferguson and Michael Brown. Baltimore and Freddy Gray. Obama gave impetus to Black Lives Matter, a radical movement that attacks police but does not give a whit about the tragedies of inner-city mass murders that pock Chicago, Detroit, Memphis, St. Louis and that have stolen forever innocent Black lives in the thousands. When Obama was elected — and was there ever an objectively less qualified candidate for President besides, perhaps, Lyndon LaRouche and maybe Chester Arthur? — our country was at racial harmony.
The rise of cable television and of social media were the latest advances that were supposed to make our lives even better. In one era, it was the light bulb. In another, the car. Then came radio, TV, and air conditioning. And now we could watch a zillion shows and news all day and night, and we could find friends from years ago and drop them notes, and forward them emailed jokes, and FB or tweet that we were bored at work and eating spaghetti, so wassup? But those two newest advances set us back gravely. Social media meant that anyone with a keyboard and a chair in Mom’s basement secretly could ignite lies that can spread like a California wildfire. And 24/7 cable news meant that media now could make enormous amounts of money by identifying carved-out niche audiences and appealing to those targeted segments with sensationalism. The masses crave sensationalism: it is the sensationalist newspapers that are sold at the supermarket and drugstore checkout counter, not Applied Mechanics and Philosophy Today. So MSNBC identified their niche, and as Fox News took the conservative viewership, CNN abandoned any pretense of being centrist and instead moved all-out to the left. To keep viewers watching, they aimed for ever more sensationalist and overheated presentations: Malaysian Airlines Flight 370, Bourdain until he killed himself, and ever-more-extreme panels of bitter and divisive race-mongers like Van Jones and Don Lemon encouraged to say hateful things that make for great re-tweeting though they bear no relation to reality while inciting civil distrust and animus.
It is against that backdrop that the Left media’s fixation on Hate Hoaxes now is both their obsession and our societal blight. We are a good people. We do not lynch Blacks or others. Rather, we had Loretta Lynch. Outside of New York, we smile at people we do not know as we walk down the street. When we cross a street, we wave to the driver who waits to make a right turn. We make friendly small talk at the grocery cash register, even a guy with a yarmulke when paying a woman with a hijab. We are a good people. And we deserve better than the despicable Big Lie that this country is riven on racial, gender, religious, or ethnic lines. It is a lie that Left Democrats propel for electoral gain, as Hitler lied about the Jews, the Romanis, and the Freemasons to secure power. As the Tsar lied about the Jews to maintain power. And the Democrats lie about the American People, the Basketful of Deplorables, whom they can pigeon-hole outside their favored Intersectionalists in order to return to power — no matter the cost to the society’s well-being. This Lie is what defines Enemies of the People.
They lie. One racism or genderism hoax after another. The Oberlin College racism hoax perpetrated by campus Democrats. The racism hoax at the University of Buffalo where a Black student hung a “Whites Only” sign. The Grand Valley University racism hoax. The Montclair State University racism hoax. The University of Chicago racism hoax. The Albany racism hoax. The Princeton University racism hoax. The Vassar College racism hoax. There was no rape at the Duke University lacrosse team’s party. There was no rape at the University of Virginia. Al Sharpton’s Tawana Brawley was not thrown into a garbage dumpster, nor smeared with feces, nor even attacked. Lena Dunham lied about being raped. Blasey Ford lied to the Senate Judiciary Committee. Julie Swetnick lied about Justice Brett M. Kavanaugh. Avenatti facilitated Swetnick. It may be that a woman later lied about Avenatti. The Mattress Girl at Barnard College gained her fifteen minutes and Kirsten Gillibrand’s admiration by promoting a myth that police investigators exposed and for which Columbia University had to pay big time when it settled the falsely accused’s lawsuit. The Mediacracy lied about Nick Sandmann and the boys of CovCath, who behaved beautifully in the face of provocation by a proven liar who marched right up to them and menacingly beat a drum in their faces. Hoaxes one and all — and so many, many more — including racist lies and gender-driven lies aimed at driving up ratings, clicks, revenues, and Democrat votes.
And as for Jussie Smollett: I had heard of Empire, but I never had seen a minute of it. Most Trump MAGA conservatives, by and large, have no particular interest in a television program centering on the hip-hop music industry, even though appreciating Kanye West’s support for the President. Note that Trump rallies begin with Lee Greenwood’s “I’m Proud to Be an American,” and they end with the Rolling Stones’ “You Can’t Always Get What You Want.” The premise from Day One that a Trump MAGA crew would go after a Jussie Smollett — someone whose name means nothing to Trump supporters, whose show means almost nothing, and frankly whose very life is irrelevant — was preposterous. In a world where conservatives express our views about Nancy Pelosi, Alec Baldwin, Robert De Niro, the Hyphen and her Green New Deal, and Jim Comey and Andrew McCabe, the notion that Trump supporters would bring a rope to lynch this irrelevant character on a show outside our horizon was beyond absurd. But it provided one more racist hoax to divide the American people, to give Democrats vying for the Presidency something to tweet about frantically, something to re-Tweet and to draw some viewers to search curiously for the channel where CNN can be found if it still is on air.
The racist hoax was unfair and a crime against the most accepting diverse society on earth.
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Q:
Using JGit fetch() and check for updated files
Using JGit, I've checked out a branch (branch1). After some time, I want to fetch() and see which files have been updated (in the origin) since my last fetch.
FetchResult fetchResult = m_git.fetch().setRefSpecs(new RefSpec("refs/heads/branch1")).call();
// For example:
fetchResult.getUpdatedFiles()
How do I do this?
A:
I found something that worked for me.
Got most of this from a jgit cookbook: https://github.com/centic9/jgit-cookbook/blob/master/src/main/java/org/dstadler/jgit/porcelain/ShowFileDiff.java#start-of-content
The DiffEntry collection below shows me the modified files. (fyi, this can be done before a merge)
fetch();
// todo: isn't there a critical section here? Only within the same repo maybe. We could prevent simultaneous use of the same racfid.
Ref fetchHead;
try {
fetchHead = m_git.getRepository().findRef("FETCH_HEAD");
//todo: show the diff bewteen fetch-head and the current head.
// - get object id of fetch
// - get oid of head
ObjectId head = m_git.getRepository().resolve(Constants.HEAD);
AbstractTreeIterator oldTreeParser = prepareTreeParser(m_git.getRepository(), fetchHead.getObjectId());
AbstractTreeIterator newTreeParser = prepareTreeParser(m_git.getRepository(), head);
List<DiffEntry> diff = m_git.diff().
setOldTree(oldTreeParser).
setNewTree(newTreeParser).
// setPathFilter(PathFilter.create("README.md")).
// to filter on Suffix use the following instead
//setPathFilter(PathSuffixFilter.create(".java")).
call();
for (DiffEntry entry : diff) {
System.out.println("Entry: " + entry + ", from: " + entry.getOldId() + ", to: " + entry.getNewId());
}
}
private static AbstractTreeIterator prepareTreeParser(Repository repository, ObjectId objectId) throws IOException {
// from the commit we can build the tree which allows us to construct the TreeParser
//noinspection Duplicates
try (RevWalk walk = new RevWalk(repository)) {
RevCommit commit = walk.parseCommit(objectId);
RevTree tree = walk.parseTree(commit.getTree().getId());
CanonicalTreeParser treeParser = new CanonicalTreeParser();
try (ObjectReader reader = repository.newObjectReader()) {
treeParser.reset(reader, tree.getId());
}
walk.dispose();
return treeParser;
}
}
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// @ts-check
import styler from "../styler";
import flex from "./flex-classes";
import commonStyle from "./common-classes";
/**
* @typedef {{[selector:string] : object}} Style
*
/**
* @type {Array<Style>} layoutStyles
*/
export const layoutStyles = [flex, commonStyle];
/**
* @returns {void}
*/
export const addLayoutStyles = () =>
styler.add("pe-layout", flex, commonStyle);
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Researchers found that, even now, increasing amounts of intermittent renewables are forcing grid operators to order cycling of fossil fuel thermal plants in order to keep the grid balanced. While natural gas combustion turbines can start and stop fairly quickly, coal and nuclear plants were designed to run flat out, with start up and shut down taking comparably longer.
Integrating more renewables into the US grid will be costly and have unintended consequences, including potential for increased carbon emissions, that policymakers need to plan for, warns a new Massachusetts Institute of Technology Energy Initiative study.
The study, unveiled Monday, looked at what needs to be done to accommodate increasing percentages of renewables on electricity grids, said MITEI head Ernest Moniz.
The study’s message for policymakers and regulators is that intermittent sources will cost more for total operations, and they have to decide who is going to pay for it – a message that is “not popular,” conceded MIT Professor John Deutch.
Problematic for Generators
The US in 2011 received about 42% of its electricity from coal, 25% from natural gas, 19% from nuclear, 8% from hydro and less than 5% from renewables, but more than half the states are pursuing policies requiring more renewables use.
Researchers found that, even now, increasing amounts of intermittent renewables are forcing grid operators to order cycling of fossil fuel thermal plants in order to keep the grid balanced. While natural gas combustion turbines can start and stop fairly quickly, coal and nuclear plants were designed to run flat out, with start up and shut down taking comparably longer.
For nuclear, load-following – raising and lowering power to compensate for renewables whose output varies over time, like wind and solar – stresses equipment and raises safety issues, said MIT Professor Howard Herzog. Moniz added that nuclear operating costs are so relatively low that decreasing nuclear output makes no economic sense.
Natural Gas the Clear Choice – For Now
For coal, Herzog said, load-following increases thermal and chemical stresses on plant components, decreases efficiency of fuel use with a concomitant increase in carbon emissions per megawatt-hour, decreases efficiency of pollution controls, and increases costs overall.
“In the absence of affordable storage,” said Moniz, “natural gas remains the key backup for intermittent resources.”
Right now, natural gas is also inexpensive. But, Moniz noted, with tens of gigawatts of older coal plants that can’t meet new environmental rules expected to shut in the next few years, it’s not at all clear natural gas prices will remain at their current lows over the long term.
Ignacio Perez-Arriaga, an MIT visiting professor and an electricity regulator in Ireland, said systems with large hydro installations, such as Brazil and Norway, can use those turbines to compensate for renewables’ variability. But countries dependent on thermal systems like the US have much less flexibility, he said.
Every Unit Has to Make a Living
An additional complication, speakers noted, is the US system that regulates electricity state by state, so US policies are fragmented. Perez-Arriaga noted the 27 European Union countries all regulate at the national level, and they’ve agreed to form a single power market in 2014 to optimize resources.
Perez-Arriaga said the integration of intermittent sources affects the entire electricity chain, and the power industry needs far more advanced models to predict the effects of expensive decisions such as whether to upgrade long-distance transmission lines to high-voltage direct current. MIT professors and students are trying to develop such models.
Key to all decisions will be attracting investors, Perez-Arriaga said. On some systems in the US and Europe, he noted, prices have gone negative when supply exceeds demand. Prices also spike very high when demand peaks, but generating units must be maintained all the time.
Regulators need to move bidding periods as close to real-time as possible because renewables are difficult to predict, he said. However, regulators also need to price services like frequency and voltage regulation – which renewables cannot provide – at levels that ensure generators are available to provide those services.
This article is the work of the source indicated. Any opinions expressed in it are not necessarily those of National Wind Watch.
The copyright of this article is owned by the author or publisher indicated. Its availability here constitutes a "fair use" as provided for in section 107 of the U.S. Copyright Law as well as in similar "fair dealing" exceptions of the copyright laws of other nations, as part of National Wind Watch's noncommercial effort to present the environmental, social, scientific, and economic issues of large-scale wind power development to a global audience seeking such information. For more information, click here. Send takedown inquiry or request to excerpt to query/wind-watch.org. Send general inquiries and comments to query/wind-watch.org.
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Makes jokes about Amy Winehouse and Ryan Dunn's deaths "Don't joke about that. Gaddafi and Osama were humans, too"
640 shares
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Introduction {#s1}
============
Besides neurofibrillary tangles, Alzheimer\'s disease (AD) is characterized by cerebral deposition of β-amyloid (Aβ) in so-called senile or diffuse plaques [@pone.0038284-Duyckaerts1]. Similar vascular deposits of Aβ associated with cerebral amyloid angiopathy (CAA) lead to loss of vessel wall integrity increasing the risk of brain haemorrhages [@pone.0038284-Smith1]. Present in 30% of the non-demented population over 60 years of age, CAA co-exists in 90% of the AD patients and forms an important complication in the development of immunotherapeutic strategies [@pone.0038284-Weller1]--[@pone.0038284-Greenberg1]. Although, the exact role of Aβ regarding the underlying pathogeneses remains unsolved, accumulation is believed to start 20--30 years prior to clinical onset [@pone.0038284-JackCR1], [@pone.0038284-Frisoni1]. Distinctive *in vivo* detection of the different Aβ deposits therefore renders important knowledge regarding early diagnosis and preventive therapy development.
Currently, a gross differentiation can only be made based on the occipital predilection of CAA, while existing PET ligands, like ^11^C-PiB, target Aβ in its fibrillar amyloid form rather than specific vascular or parenchymal types of Aβ deposits [@pone.0038284-Johnson1].
Previously, we have selected heavy chain antibody fragments with high affinity specific for either CAA or all types of human Aβ deposits [@pone.0038284-Rutgers1]. Derived from the Camelid heavy chain antibody repertoire, which completely lack light chains, their single N-terminal domain (V~H~H) is fully capable of antigen binding with affinities comparable with those of conventional antibodies [@pone.0038284-HamersCasterman1], [@pone.0038284-Harmsen1].
Blood-brain barrier (BBB) passage was shown to be favorable in an *in vitro* assay [@pone.0038284-Rutgers2]; therefore, this study assessed the *in vivo* characteristics of two distinct Aβ targeting V~H~H, ni3A and pa2H, for their potential use to differentially detect AD and CAA. First, pharmacologic behaviour and biodistribution were examined after administration of radiolabeled V~H~H into a transgenic AD/CAA mouse model. Secondly, fluorescently labeled V~H~H were administered after the BBB was circumvented to evaluate their ability to specifically bind Aβ deposits *in vivo*.
{#pone-0038284-g001}
Materials and Methods {#s2}
=====================
Production of ni3A and pa2H {#s2a}
---------------------------
V~H~H ni3A and pa2H were selected from respectively a non-immune or an immune library created after immunisation with post-mortem brain parenchyma of a patient with Down\'s syndrome. V~H~H were subcloned and produced as previously reported including a myc- or VSV-tag for detection and a *his*-tag for purification [@pone.0038284-Rutgers1]. Similarly, pa2H free of any additional peptide tags was commercially produced by overexpression in yeast (BAC, Leiden, the Netherlands).
Animal studies {#s2b}
--------------
All studies were performed using 12--16 month old transgenic mice or wildtype littermates from a colony set up using the APPswe/PS1dE9 strain (APP/PS1) (JAX), known to accumulate vascular and parenchymal Aβ deposits [@pone.0038284-Jankowsky1], and have been approved by the institutional Animal Ethics Committee (DEC) at the Leiden University Medical Center, permit number 09132. Besides standard genotyping, after each experiment amyloid pathology was confirmed by standard Thioflavin T staining.
10.1371/journal.pone.0038284.t001
###### Biodistribution of ^99m^Tc-ni3A in mice.
{#pone-0038284-t001-1}
t = 3 hr t = 6 hr t = 24 hr
----------------------- ---------------- ---------------- ---------------- ---------------- --------------- -------------------------------------------------
blood 1.202*±0.379* 1.146*±0.131* 0.778*±0.048* 0.808*±0.115* 0.451*±0.073* 0.363*±0.051*
heart 0.525*±0.129* 0.508*±0.109* 0.347*±0.049* 0.337*±0.127* 0.252*±0.041* 0.216*±0.014*
lungs 0.850*±0.184* 0.819*±0.208* 0.659*±0.184* 0.743*±0.301* 0.375*±0.113* 0.291*±0.055*
liver 1.078*±0.235* 1.000*±0.293* 1.078*±0.188* 1.223*±0.424* 0.568*±0.149* 0.488*±0.164*
kidneys 15.531*±2.986* 15.192*±3.075* 10.266*±1.657* 14.294*±4.337* 9.089*±6.152* 9.901*±1.158*
spleen 0.590*±0.257* 0.531*±0.084* 0.792*±0.144* 0.753*±0.291* 0.397*±0.056* 0.465*±0.234*
muscle 0.171*±0.075* 0.120*±0.069* 0.111*±0.088* 0.086*±0.022* 0.043*±0.007* 0.048*±0.008*
cerebrum 0.035*±0.009* 0.035*±0.007* 0.031*±0.007* 0.035*±0.008* 0.018*±0.003* 0.019*±0.001*
cerebellum 0.073*±0.031* 0.063*±0.009* 0.098*±0.009* 0.096*±0.014* 0.029*±0.005* 0.026*±0.002*
cerebrum/blood ratio 0.030*±0.003* 0.030*±0.004* 0.040*±0.010* 0.043*±0.004* 0.040*±0.001* 0.053*±0.008* [\*](#nt101){ref-type="table-fn"}
cerebrum/muscle ratio 0.242*±0.142* 0.335*±0.116* 0.407*±0.270* 0.428*±0.171* 0.422*±0.029* 0.403*±0.100*
* = P\<0.05 wildtype mice compared to APP/PS1 mice.*
A bolus injection of 2 µg ^99m^Tc-ni3A was administered intravenously into 12--14 month old APP/PS1 mice or their wild type littermates. At three time points after injection the animals were sacrificed and various tissues and entire organs were removed, weighed and counted for radioactivity. Values are expressed as a percentage of the injected dose per gram tissue (mean ± SD).
Human material {#s2c}
--------------
Human brain tissue was obtained of AD/CAA patients or controls as confirmed by neuropathological examination in agreement with the guidelines of the ethics committee of the LUMC. Patient anonymity was strictly maintained. All tissue samples were handled in a coded fashion, according to Dutch national ethical guidelines (Code for Proper Secondary Use of Human Tissue, Dutch Federation of Medical Scientific Societies).
10.1371/journal.pone.0038284.t002
###### Biodistribution of radiolabeled pa2H in mice.
{#pone-0038284-t002-2}
^99m^Tc-pa2H DTPA(^111^In)-pa2H
----------------------- --------------- --------------- ---------------- ---------------- -------------------- ------------------------------------------------- --------------- ----------------
blood 0.566*±0.003* 0.654*±0.015* 1.009*±0.054* 1.244*±0.123* 0.575*±0.084* 0.696*±0.049* 0.006*±0.001* 0.004*±0.002*
heart 0.273*±0.121* 0.240*±0.017* 0.623*±0.101* 0.763*±0.031* 0.367*±0.059* 0.393*±0.007* 0.017*±0.084* 0.014*±0.003*
lungs 0.843*±0.256* 0.537*±0.010* 0.930*±0.242* 1.088*±0.035* 0.620*±0.160* 0.622*±0.031* 0.016*±0.011* 0.014*±0.003*
liver 2.615*±0.796* 1.866*±0.016* 3.014*±1.021* 3.392*±1.932* 1.430*±0.402* 1.161*±0.470* 0.066*±0.029* 0.075*±0.0.23*
kidneys 9.243*±1.787* 6.241*±0.530* 14.306*±4.105* 15.612*±1.042* 9.824*±2.810* 8.608*±0.738* 8.859*±3.623* 7.689*±2.930*
spleen 1.515*±0.503* 1.319*±0.060* 6.498*±1.623* 6.258*±0.208* 3.584*±1.381* 1.747*±0.100* 0.044*±0.022* 0.048*±0.006*
muscle 0.356*±0.379* 0.054*±0.006* 0.174*±0.022* 0.347*±0.026* 0.102*±0.023* 0.113*±0.018* 0.059*±0.020* 0.059*±0.044*
cerebrum 0.014*±0.003* 0.017*±0.001* 0.033*±0.005* 0.044*±0.004* 0.027*±0.004* 0.038*±0.002* [\*](#nt103){ref-type="table-fn"} 0.001*±0.000* 0.001*±0.001*
cerebellum 0.023*±0.001* 0.026*±0.001* 0.054*±0.016* 0.067*±0.001* 0.030*±0.007* 0.045*±0.000* [\*](#nt103){ref-type="table-fn"} 0.003*±0.001* 0.002*±0.001*
cerebrum/blood ratio 0.025*±0.005* 0.026*±0.003* 0.033*±0.004* 0.035*±0.004* 0.047*±0.003* 0.055*±0.008* 0.013*±0.011* 0.041*±0.055*
cerebrum/muscle ratio 0.083*±0.081* 0.309*±0.067* 0.190*±0.007* 0.177*±0.135* 0.270*±0.032* 0.346*±0.377* 0.113*±0.066* 0.203*±0.146*
* = P\<0.05 wildtype mice compared to APP/PS1 mice.*
A bolus injection of 2 µg radiolabeled pa2H was administered intravenously into 12--14 month old APP/PS1 mice or their wildtype littermates. At three or one time points after injection of radiolabeled pa2H respectively with or without additional peptide tags, the animals were sacrificed and various tissues and entire organs were removed, weighed and counted for radioactivity. Values are expressed as a percentage of the injected dose per gram tissue (mean ± SD).
Murine specificity of the selected V~H~H {#s2d}
----------------------------------------
To evaluate appropriate use of the APP/PS1 mouse model, murine cryosections (10 µm) were stained according previous protocols [@pone.0038284-Rutgers1], [@pone.0038284-Rutgers2] with in addition a standard anti-mouse-to-mouse kit (ARK, Dako Cytomation). Final preparations were analyzed with an automated Pannoramic MIDI microscope (3DHistech).
Biodistribution and clearance {#s2e}
-----------------------------
### Radiolabeling {#s2e1}
V~H~H were labeled according to two different protocols. First, *his*-tagged V~H~H were labeled directly with technetium-99m (^99m^Tc) using a previously published protocol [@pone.0038284-Welling1]. Briefly, 20 µl of V~H~H in PBS solution (450--500 ng/µl) was added to 8 µl of an aseptic mixture of 950 mg/l Sn(Cl)~2~.2H~2~O and 2 g/l Na~4~P~2~O~7~.10H~2~O (Technescan PYP, Covidien, Petten, the Netherlands) in saline. After addition of 4 µl of 10 mg/ml of KBH~4~ (crystalline, Sigma Chemical Co, St. Louis, MO) in 0.1 M NaOH, and 100 µl of Na\[^99m^TcO~4~\] solution (approximately 200--700 MBq/ml, Technekow, Covidien, Petten, the Netherlands) the mixture was gently stirred at room temperature for at least 30 min before use. Analysis of the labeling solution, referred to as ^99m^Tc-V~H~H, yielded a radiochemical purity of \>95% without detectable unreduced or free ^99m^TcO~4~ [@pone.0038284-Welling2].
Secondly, untagged V~H~H were chelated for indium-111 (^111^In) using diethylene triamine penta-acetic acid (DTPA). Untagged pa2H was chelated in a total volume of 1.0 ml with 20-fold molecular excess of *p*-SCN-Bn-DTPA (Macrocyclics, Dallas, TX) at pH 8.5 in phosphate buffer for 5 hr at 37.5°C and purified by dialysis using phosphate buffered saline (PBS). ^111^In chloride (25 µl, 111 MBq/ml, Covidien, the Netherlands) was added to DTPA-pa2H conjugate (0.1 ml) in 0.25 M ammonium acetate buffer (0.8 ml) at pH 5.5 and incubated for 1 hr at room temperature. The reaction was quenched with 50 mM ethylene diamine tetra-acetic acid (EDTA) (50 µl) to chelate residual non-bound ^111^In and the radiolabeled antibody was then purified using a Sephadex™ G-25 column (PD 10; GE Healthcare) eluted with PBS. Radiochemical purity assessed by instant thin layer chromatography (ITLC) yielded a purity of \>95%.
### Biodistribution and brain uptake {#s2e2}
To study the biodistribution, animals were injected intravenously with 0.2 ml radiolabeled V~H~H diluted with saline (5--10 MBq/ml, 10 µg/ml). At different intervals (t = 3--6--24 hrs) post-injection APP/PS1 (n = 4) and wildtype animals (n = 4) were sacrificed (Euthanasol, AST Pharma). Similar biodistribution experiments using untagged DTPA(^111^In)-pa2H were only performed at 24 hours post-injection for APP/PS1 (n = 6) and wildtype mice (n = 6). Blood was collected via cardiac puncture, and various organs were removed, including the brain, which was divided into the cerebrum and cerebellum. All were weighed and counted for radioactivity (Wizard^2^, Perkin Elmer). After decay correction, radioactivity was expressed as the percentage of the total injected dose of radioactivity per gram tissue (%ID/g). Blood/cerebrum ratios were calculated to correct for possible confounding effects accountable by residual blood. Similarly, muscle/cerebrum determined target-to-non-target ratios. Differences were regarded significant when *p*≤0.05 using an unpaired one or two tailed *t*-test. Experiments at t = 24 hrs were repeated twice using ^99m^Tc-pa2H.
{#pone-0038284-g002}
10.1371/journal.pone.0038284.t003
###### Blood half lives of radiolabeled V~H~H.
{#pone-0038284-t003-3}
Fast *t~½~* Slow *t~½~*
-------------------- ---------- ------------- ------------------ ------ ------ ------ --------------
^99m^Tc-ni3A APP/PS1 14.71 *(8.65--49.13)* 89.7 580 10.3 *(101.8--∞)*
Wildtype *ND* *ND* *ND* *ND*
^99m^Tc-pa2H APP/PS1 21.89 *(14.24--39.38)* 79.8 2562 20.2 *(975.0--∞)*
Wildtype 10.78 *(7.27--20.76)* 87.1 5861 12.9 *(969.3--∞)*
DTPA(^111^In)-pa2H APP/PS1 19.69 *12.63--44.60* 100 \- \-
Wildtype 15.83 *9.30--53.37* 100 \- \-
Half lives were determined by fitting a one or a two phase exponential decay model based on blood obtained from both tail vein and cardiac puncture at several time points after intravenous bolus injection of 2 µg radiolabeled V~H~H in 12--14 month old APP/PS1 mice and wildtype littermates, as depicted in [Figure 2](#pone-0038284-g002){ref-type="fig"}. Please note that DTPA(^111^In)-pa2H was produced without any additional peptide tags.
10.1371/journal.pone.0038284.t004
###### Blood distribution of ^99m^Tc-pa2H.
{#pone-0038284-t004-4}
Sample Time p.i. Fraction APP/PS1 Wildtype
-------------- ----------- ------------- --------- ---------- ------ -----
^99m^Tc-pa2H 10 Plasma 88,9 6,2 80,3 5,2
Cell Pellet 11,1 19,7
90 Plasma 83,6 8,7 72,0 8,2
Cell Pellet 16,4 28,0
At different time point after bolus injection of ^99m^Tc-pa2H blood collected from the tail vein of 12--14 month old APP/PS1 mice or wildtype littermates. Separated into the cell pellet and plasma, samples were counted for radioactivity. Fractions are expressed in percentage of total activity at that time point. No significant differences were calculated using a student *t*-test (*p*\<0.05).
### Blood clearance and analysis {#s2e3}
Simultaneously, blood half-life was examined by collecting 5 µl tail samples at several time points between 3--90 minutes post-injection of radiolabeled V~H~H into transgenic or wildtype mice (n = 4--6). Combined with the cardiac blood samples corresponding half-lives were calculated using GraphPad Prism.
Similarly, 10 µl samples obtained at 10 and 90 minutes post-injection were mixed with 90 µl heparin (34 U/ml saline) and 900 µl PBS. Centrifugation for 10 minutes at 7,000 rpm separated plasma from the cell pellet. Radioactivity was measured separately to determine the blood distribution of radiolabeled V~H~H over time.
### Specificity of radiolabeled pa2H {#s2e4}
Aβ specificity of pa2H-*his* after ^99m^Tc-radiolabeling was tested by quantitative competition autoradiography. Human and murine brain cryosections (20 µm) were blocked with 1% bovine serum albumin (BSA)/PBS at 37°C for 1 hour followed by similar application of the labeling solution, which was diluted to 1 µg/ml by 1%BSA/PBS with or without additional 1 hour pre-incubation with excess monomeric or fibrillar Aβ~1--40~ (rPeptide) at 37°C. Fibrils were produced using existing protocols [@pone.0038284-Klunk1].
After rinsing 3 times with PBS, radioactivity was counted for 15 minutes by a gamma camera (Toshiba GCA7100/UI). A similar region of interest was fitted for each scintigram to assess binding of ^99m^Tc-pa2H-*his* with 0.1 ml of diluted labeling solution as a reference. Binding was expressed as the % of radioactivity compared to the section without any competitor. Experiments were performed in triplicate.
10.1371/journal.pone.0038284.t005
###### Quantitative autoradiography.
{#pone-0038284-t005-5}
Brain tissue Binding of ^99m^Tc-V~H~H Competion binding
--------------- ------------------------------------------------ ------------------- --------------
APP/PS1 98.8 (±20,7)[\*](#nt108){ref-type="table-fn"} 60.1 (±22.2) 31.4 (±14.3)
Wildtype 86.4 (±14.8) 56.4 (±19.5) 27.1 (±12.5)
AD human 190.1 (±73.5)[\*](#nt108){ref-type="table-fn"} 81.4 (± N.D.) 42.3 (±29.2)
Control human 102.3 (±30.2) 27.2 (± N.D.) 49.9 (±17.4)
Differences in radioactivity were measured after application of 1 µg ^99m^Tc-pa2H to human and murine APP/PS1 brain sections.
Statistical difference (*p*\<0.05) between either murine or human control versus Aβ bearing sections.
*In vivo* Aβ targeting by V~H~H {#s2f}
-------------------------------
### Fluorescent labeling {#s2f1}
Tagged V~H~H were fluorescently labeled with Alexa Fluor 594 protein labeling kit (Molecular Probes, Invitrogen) according to the manufacturer\'s guidelines, except using only half of the recommended amount of dye. Briefly spun to remove possible aggregates, extensive dialysis removed excess free label. The labeling degree and protein concentration (200--600 ng/µl) were determined using the Nanodrop ND1000 (Isogen Life Sciences). Protein integrity was confirmed by mass spectrometry.
### Immunofluorescence using VHH-Alexa594 {#s2f2}
To examine whether the fluorescent labeling affected antigen recognition, human and murine cryosections (10 µm) were rinsed with PBS, fixed in ice-cold acetone for 10 minutes before overnight incubation with V~H~H- Alexa594 in 1% BSA/PBS in a wet chamber. Washed 3×5 minutes with PBS, sections were mounted and analyzed using a fluorescence microscope (Leica DMR5500B).
### In vivo Aβ imaging by topical application {#s2f3}
Four APP/PS1 animals received permanent cranial windows to allow serial *in vivo* imaging of the brain by multiphoton microscopy. Animals were anaesthetized using 2% isoflurane gas inhalation, and the exposed skull was partly replaced by a round glass coverslip glued into place using Krazyglue® according to previous surgical protocols [@pone.0038284-Skoch1], [@pone.0038284-Robbins1]. Prior to fixation of the cranial window, a drop of 40--60 µl of V~H~H-Alexa594 (275--400 ng/µl) was applied directly onto the exposed brain for 30 minutes and briefly rinsed with PBS. Colocalization with the Aβ deposits was based either upon their typical green autofluorescence or by intraperitoneal injections of Methoxy-X04 one day prior surgery [@pone.0038284-Klunk1]. Animals were imaged immediately following surgery, which was typically less than 90 minutes after beginning of the procedure, and re-imaged under isoflurane anaethesia (2%) for several days to study the washout. Images were acquired with a Bio-Rad 1024 multiphoton microscope equipped with a Ti:Sapphire laser (Mai Tai, Spectra Physics) and external photodetectors (Hamamatsu Photonics). Areas were imaged to approximately 200 µm deep in 5 µm steps with a 20× objective (UMPlanFl, NA = 0.95; Olympus). Maximum intensity projections were reconstructed using ImageJ.
### Specific in vivo Aβ binding after BBB disruption {#s2f4}
A systemic approach to study the in vivo behaviour of the VHH throughout a larger area within the brain involved intracarotid infusion (60 µl/min) of 100 µl pa2H-his-Alexa594 along with 600 µl 15% mannitol selectively into the right carotic artery to disrupt the BBB [@pone.0038284-Wadghiri1]. At t = 2 and 24 hours post-injection., transgenic (n = 9) and wildtype animals (n = 3) were euthanized (Euthanasol, AST Pharma), and perfused with 4% paraformaldehyde (PFA). Resected brains were stored in 4% PFA with 10% sucrose for 4 hours followed by overnight fixation in 4% PFA with 30% sucrose. Next, the brains were snap frozen and sectioned completely to obtain consecutive 30-µm-thick cryosections. Besides standard Thioflavin T staining for amyloid, adjacent sections were immunostained for Aβ (6F/3D, DakoCytomation) [@pone.0038284-Natte1] with 1∶100 goat-antimouse-Alexa488 (Invitrogen) to assess colocalization. Images obtained by a Leica DM5500B microscope were merged using Adobe Photoshop CS3.
Results {#s3}
=======
Murine specificity of the selected V~H~H {#s3a}
----------------------------------------
Immunostained brain sections of aged APP/PS1 and wildtype littermates using tagged V~H~H ni3A and pa2H were made to assess their capacity to selectively recognize different types of deposits. ([Figure 1](#pone-0038284-g001){ref-type="fig"}) Pa2H stained positive for all forms of Aβ depositions. In this transgenic mouse model, ni3A did not show selective affinity for vascular Aβ; both vascular and parenchymal Aβ depositions were clearly labeled. Compared to ni3A, equivalent staining protocols with pa2H resulted in higher specificity for Aβ combined with a low unspecific background binding. For neither V~H~H specific affinity was detected within the brain sections of wildtype animals.
{#pone-0038284-g003}
Biodistribution and clearance {#s3b}
-----------------------------
### Biodistribution and brain uptake {#s3b1}
The distribution of a bolus injection of radiolabeled tagged ni3A and pa2H over time is shown in [Table 1](#pone-0038284-t001){ref-type="table"} and [2](#pone-0038284-t002){ref-type="table"}. No significant differences in organ uptake between wildtype and transgenic animals were found, except for the brain uptake of ^99m^Tc-pa2H after 24 hours. Although the amount was low (0.038%I.D./g), cerebral uptake was 40% higher in the transgenic animals. The cerebrum/blood ratio did not differ, indicating that this difference was not caused by different V~H~H concentrations within the blood pool. For the cerebellum similar results were found. Repeated experiments for this particular endpoint resulted in similar findings.
{#pone-0038284-g004}
{#pone-0038284-g005}
To investigate whether these findings were not confounded by either the non-specific radiolabeling procedure or the presence of additional peptide tags, the biodistribution experiment was repeated with untagged DTPA(^111^In)-pa2H. ([Table 2](#pone-0038284-t002){ref-type="table"}) With this labeling protocol, we no longer observed a significantly higher cerebral uptake in amyloid-bearing mice. Regardless of the tag, the majority of radiolabeled V~H~H was excreted via the kidneys. Cellular involvement as shown by distinctive hepatic clearance or splenal activity was low. In comparison to ^99m^Tc-ni3A, ^99m^Tc-pa2H showed about 3 times higher clearance via liver and spleen. Also, the clearance rate for ^99m^Tc-pa2H was lower, independent of genotype. However, within the first 3 hours ^99m^Tc-ni3A resulted in a higher general organ uptake, with exception of the aforementioned liver and spleen.
### Blood clearance and analysis {#s3b2}
Blood clearance of the tagged ^99m^Tc-V~H~H consisted of a fast and a slow component. ([Figure 2A](#pone-0038284-g002){ref-type="fig"}) In general, the majority of the radiolabeled V~H~H was cleared from the blood with a half-life of 10--20 minutes ([Table 3](#pone-0038284-t003){ref-type="table"}). The actual half-life of the slow component of ^99m^Tc- V~H~H could only be calculated with limited accuracy, since the half-life was longer than the blood sampling period. In line with the above biodistribution, six hours post-injection, the blood levels of ^99m^Tc-pa2H were remarkably higher compared to earlier time points, which is characteristic for a second passage. Within the first 90 minutes about 80% of the ^99m^Tc-V~H~H remained within the blood plasma, indicating that no significant cellular uptake occurred. ([Table 4](#pone-0038284-t004){ref-type="table"})
In contrast to tagged ^99m^Tc- V~H~H, the blood clearance of untagged DTPA(^111^In)-pa2H was mono-exponential, with a similar rapid clearance within 20 minutes, but without a slow component. ([Figure 2B](#pone-0038284-g002){ref-type="fig"})
### Specificity of 99mTc-pa2H {#s3b3}
After radiolabeling of the tagged pa2H it\'s specificity for Aβ was unaffected, as shown by scintigraphic analysis; binding of ^99m^Tc-pa2H was higher in those sections including Aβ. ([Table 5](#pone-0038284-t005){ref-type="table"}) Furthermore, binding was significantly (p\<0.001) reduced when the tracer was pre-incubated with either monomeric or fibrillar Aβ.
In vivo Aβ targeting by V~H~H {#s3c}
-----------------------------
### In vivo Aβ imaging by topical application {#s3c1}
After direct application onto the exposed mouse brain, fluorescent V~H~H were followed up for at least 48 hours by *in vivo* multiphoton microscopy. ([Figure 3](#pone-0038284-g003){ref-type="fig"}) Specific *in vivo* labeling of Aβ plaques by ni3A-Alexa594 was initially confirmed by colocalization with Methoxy-X04, a known *in vivo* amyloid targeting fluorophore. Beside possible binding competition with the V~H~H, Methoxy-X04 hampered good validation due to signal cross-over into the red channel. However, colocalization based on the typical autofluorescence patterns of the different Aβ deposits resulted in similar findings. Selectivity was confirmed by lack of nonspecific background signal. Although both V~H~H were capable of targeting Aβ *in vivo*, only pa2H-Alexa594 was detectable after two days, mainly bound to vascular amyloid.
### Specific in vivo Aβ binding after BBB disruption {#s3c2}
Based on the above findings, co-injections of pa2H-Alexa594 with mannitol were done in the right carotid artery to selectively open the BBB in the ipsilateral hemisphere to study the in vivo characteristics throughout the brain. Two hours post-injection, fluorescence was detected in the right hemisphere, co-localizing with Aβ. ([Figure 4](#pone-0038284-g004){ref-type="fig"}) Even within the deeper brain structures, no nonspecific binding was observed. Aβ related fluorescent signal remained detectable for at least 24 hours post-injection. Without BBB disruption or within wildtype littermates, no apparent Aβ labeling could be detected.
### Immunofluorescence using VHH-Alexa594 {#s3c3}
Selectivity for specific Aβ deposits was not altered after fluorescent labeling of the VHH, since on human sections, ni3A-Alexa594 selectively stained vascular Aβ ([Figure 5](#pone-0038284-g005){ref-type="fig"} A--C), and pa2H-Alexa594 stained both parenchymal and vascular Aβ.([Figure 5](#pone-0038284-g005){ref-type="fig"} G--I) On murine material all Aβ deposits were stained by both fluorescent VHH.([Figure 5](#pone-0038284-g005){ref-type="fig"} D--F & J--L)
Discussion {#s4}
==========
In this study, we assessed two previously described V~H~H for their potential to cross the blood-brain barrier and distinctively detect vascular and parenchymal Aβ deposits *in vivo*.
Specific detection of parenchymal and vascular amyloid in APP/PS1 mice {#s4a}
----------------------------------------------------------------------
Both V~H~H stained positive for Aβ upon APP/PS1 brain sections confirming appropriate use of this transgenic model. *In vivo* binding to parenchymal and vascular Aβ was confirmed when the BBB was circumvented. Signal remained detectable for at least 24 hours while *in vivo* pa2H showed a high affinity combined with a low off-rate. However, previously shown selectivity for solely vascular Aβ in human post-mortem brain sections by ni3A was not observed within this mouse model ([Figures 1](#pone-0038284-g001){ref-type="fig"},[3](#pone-0038284-g003){ref-type="fig"},[5](#pone-0038284-g005){ref-type="fig"}). Fluorescent or radiolabeling prior *in vivo* application did not affect their specificity. The unique specific reactivity of ni3A for vascular amyloid deposition on human brain material is not yet completely understood [@pone.0038284-Rutgers1]. Known differences in morphology and composition of human and murine Aβ deposits might help to understand ni3A\'s specific reactivity [@pone.0038284-Duyckaerts2], [@pone.0038284-Guntert1]. Human plaques consist of discontinuous patches with decreased density and random fibrillar orientation within the amyloid core; murine plaques are generally built up by long organized fibrils, resulting in densely packed amyloid plaques with a relatively large core [@pone.0038284-vanGroen1]. Besides morphological differences, posttranslational modifications of Aβ differ from mouse to man leading to alterations of the Aβ molecule itself [@pone.0038284-Duyckaerts2], [@pone.0038284-Bussiere1], [@pone.0038284-Richardson1]. Differences in metal ion content are known to influence the tertiary structure [@pone.0038284-Adlard1], [@pone.0038284-Leskovjan1]. Previous epitope mapping revealed that ni3A has no other cross reaction but to Aβ~1--42~ [@pone.0038284-Rutgers1], which is highly abundant in parenchymal and vascular deposits in both humans and APP/PS1 mice. All together, this leads to the conclusion that the selective reactivity of ni3A must depend on the structural presentation of Aβ~1--42~, in which case murine parenchymal plaques probably show structural similarities to human CAA.
*In vivo* blood-brain barrier passage {#s4b}
-------------------------------------
Previous *in vitro* data suggested that our V~H~H actively migrated across the BBB in a more efficient way than FC5, a V~H~H specifically selected to pass the BBB [@pone.0038284-Rutgers2]. However, the *in vivo* experiments resulted only in a small cerebral uptake of the tagged ^99m^Tc-pa2H at 24 hours after intravenous administration, and the current brain uptake levels were insufficient to assess the uptake kinetics *in vivo* with for example SPECT imaging. (data not shown) Additional experiments with untagged DTPA(^111^In)-pa2H further confirmed the current limitations as hardly any cerebral uptake was observed with this labeling protocol. The increased brain uptake for 99mTc-pa2H compared to DTPA(^111^In)-pa2H may be due to the slower blood clearance for ^99m^Tc-pa2H. The observed fast blood clearance and relatively high renal retention for the VHH in this study is in line with previous reports [@pone.0038284-Gainkam1], [@pone.0038284-Huang1], and typical for peptides and proteins smaller than the filtering threshold of the glomerular membrane (\<60 kDa) [@pone.0038284-Behr1]. However, in general, a short blood residential time effectively reduces the blood-to-brain transfer.
*In vivo* studies with the BBB crossing V~H~H FC5 demonstrated 4%ID/g brain uptake, which is much higher than our findings [@pone.0038284-Muruganandam1]. This discrepancy may be due to the lower dose that we used, but several other factors may also play a part. For FC5 it is known it uses receptor-mediated endocytosis via the α(2,3)-sialoglycoprotein [@pone.0038284-Abulrob1]. For our V~H~H, *in vitro* active transport mechanisms are involved, but the specific receptors are as yet unknown [@pone.0038284-Rutgers2]. Possibly, the *in vivo* BBB passage may be limited by the availability of these receptors in our mouse model.
To improve BBB penetration for the amyloid-targeting V~H~H, one could increase the blood circulation time by multimerization or by conjugating the V~H~H to an albumin-targeting moiety or V~H~H [@pone.0038284-Coppieters1], [@pone.0038284-Tijink1]. An alternative approach would be to incorporate the V~H~H into a BBB-targeting nanoparticle. Recently, several nanoparticle carrier systems have been developed for brain delivery of therapeutics that would also be suitable for loading with V~H~H [@pone.0038284-Koffie1].
Diagnostic and therapeutic value of V~H~H {#s4c}
-----------------------------------------
In general, V~H~H constitute many unique characteristics that make them interesting tools for either diagnostics or therapeutics. Compared to conventional monoclonal antibodies or Fab\', V~H~H express a similar unique level of specificity and affinity, but because of their single domain, production and modification is relatively easy and cost-efficient [@pone.0038284-Huang1].
Currently used amyloid-targeting ligands, like ^11^C-PiB recognize amyloid plaques rather than Aβ. In contrast, we already showed that V~H~H may be more specific to a certain sub-types of Aβ accumulation [@pone.0038284-Rutgers1]. Further selection may allow the *in vivo* detection of the full range of Aβ aggregates from oligomers to dense core plaques to CAA.
Besides diagnostics, several V~H~H have shown their potential therapeutic value in vitro, preventing aggregation of amyloid fibrils, oligomeric forms of Aβ and polyA-binding protein nuclear 1 [@pone.0038284-Chartier1]--[@pone.0038284-Verheesen1]. In the latter case, even complete clearance of existing aggregates was reported. Whether V~H~H evaluated in this study possess similar abilities is currently under investigation. However, within the data presented here, we observed that several Aβ plaques, as detected by their autofluorescence, could no longer be seen two days after V~H~H application. ([Figure 3](#pone-0038284-g003){ref-type="fig"}) Whereas current passive immunotherapies targeting Aβ are hampered by unwanted immunogenic side effects, repetitive administration of V~H~H has shown to be non-immunogenic [@pone.0038284-Jicha1], [@pone.0038284-Stijlemans1]. Furthermore, their selective binding to different Aβ species, like ni3A\'s specific binding for CAA, could shift Aβ brain efflux in the favored direction, which could be used to tailor anti-Aβ therapy to further reduce therapy-induced complications, e.g. CAA related microbleeds [@pone.0038284-Jicha1], [@pone.0038284-Greenberg1], [@pone.0038284-Klunk2].
These initial *in vivo* studies to investigate whether Aβ specific V~H~H can be exploited as diagnostic tools show promising results for further development. Although capable of strong specific binding *in vivo* with low unspecific background binding and favorable wash-out, issues regarding higher brain uptake and clearance need to be addressed in the future.
**Competing Interests:**The authors have declared that no competing interests exist.
**Funding:**Research was supported by: (1) the Center for Translational Molecular Medicine, LeARN, <http://www.ctmm.nl>; (2) Innovatiegericht OnderzoeksProgramma (IOP)Genomics, IGE05005, <http://www.agentschapnl.nl/nl/programmas-regelingen/iop-genomics>; (3) the Center for Medical Systems Biology, CMSB2, <http://www.cmsb.nl>; and (4) The Netherlands Organisation for Scientific Research (NWO) Athena, 700.58.801, <http://www.nwo.nl/nwohome.nsf/pages/NWOA_6ZXCX3>. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
[^1]: Conceived and designed the experiments: RN KR MW BB MvB SM LW. Performed the experiments: RN KR MW AM MdB MR. Analyzed the data: RN KR MW AM MdB MR BB MvB SM LW. Contributed reagents/materials/analysis tools: RN KR MW AM MdB BB. Wrote the paper: RN KR MW BB MvB SM LW.
|
Rayman Legends headlines
The French government has released a number of figures to demonstrate the country’s importance in the games industry. It claims that the success of French companies such as Ubisoft and Arkane Studio helped global revenues increase to 60 billion Euros between 2011 and 2012.
Today’s updates to the Xbox One and PS4 digital storefronts bring with them Rayman Legends, which had been scheduled for next week but was moved forward to now. The Xbox One store had a pricing error this morning, listing the game at $60 instead of the proper $40, but that’s been corrected. The PlayStation Store […]
Rayman Legends players on Vita can now acquire the 28 Invasion Mode stages as a free update. Leaderboards have also been added. Ubisoft announced earlier this month the game would be arriving on next-gen systems in February.
Rayman Legends players on Vita will finally receive the 28 Invasion Mode stages as a free update on November 26. Leaderboards will also be added. Ubisoft announced earlier this week the game would be arriving on next-gen systems in February.
Ubisoft has published first half 2013-14 earnings, noting a 5% year-over-year increase to €293 million, and a Q2 sales increase of 46.6% to €217 million compared to €148 million year-over -year. Rayman Legends will also be released on next-gen systems in February, Ubisoft has announced.
This week, North American PlayStation Plus subscribers receive a copy of Rayman Origins on Vita for their Instant Collection. That’s it for solid content, but there are discounts on Limbo, Lone Survivor: The Director’s Cut, and more. For more detail, visit the PlayStation Blog.
Beyond Good & Evil 2 may be a 3D game, but that doesn’t mean it can’t run in Ubisoft Montpellier’s UbiArt Framework engine, which has so far only been used in 2D games like Rayman Legends. Michel Ancel has said it could be done.
Ubisoft has withdrawn Rayman Legends Challenges, a free Wii U eShop exclusive demo which was released to compensate Wii U owners for the wait after the well-received Ubisoft Montpellier title went multi-platform. An in-game message advises that Challenges are now closed, and points users towards the full game, which launched this week. Thanks, Polygon.
Rayman Legends on Vita will receive free DLC update containing the missing 28 levels included in the other versions, according to Ubisoft communications manager Gary Steinman. The exclusion was chocked up to “a longer development time than expected,” as the teams “couldn’t initially include the Invasion Mode – essentially, a second take on existing Rayman […]
The French government has released a number of figures to demonstrate the country’s importance in the games industry. It claims that the success of French companies such as Ubisoft and Arkane Studio helped global revenues increase to 60 billion Euros between 2011 and 2012.
Today’s updates to the Xbox One and PS4 digital storefronts bring with them Rayman Legends, which had been scheduled for next week but was moved forward to now. The Xbox One store had a pricing error this morning, listing the game at $60 instead of the proper $40, but that’s been corrected. The PlayStation Store […]
Rayman Legends players on Vita can now acquire the 28 Invasion Mode stages as a free update. Leaderboards have also been added. Ubisoft announced earlier this month the game would be arriving on next-gen systems in February.
Rayman Legends players on Vita will finally receive the 28 Invasion Mode stages as a free update on November 26. Leaderboards will also be added. Ubisoft announced earlier this week the game would be arriving on next-gen systems in February.
Ubisoft has published first half 2013-14 earnings, noting a 5% year-over-year increase to €293 million, and a Q2 sales increase of 46.6% to €217 million compared to €148 million year-over -year. Rayman Legends will also be released on next-gen systems in February, Ubisoft has announced.
This week, North American PlayStation Plus subscribers receive a copy of Rayman Origins on Vita for their Instant Collection. That’s it for solid content, but there are discounts on Limbo, Lone Survivor: The Director’s Cut, and more. For more detail, visit the PlayStation Blog.
Beyond Good & Evil 2 may be a 3D game, but that doesn’t mean it can’t run in Ubisoft Montpellier’s UbiArt Framework engine, which has so far only been used in 2D games like Rayman Legends. Michel Ancel has said it could be done.
Ubisoft has withdrawn Rayman Legends Challenges, a free Wii U eShop exclusive demo which was released to compensate Wii U owners for the wait after the well-received Ubisoft Montpellier title went multi-platform. An in-game message advises that Challenges are now closed, and points users towards the full game, which launched this week. Thanks, Polygon.
Rayman Legends on Vita will receive free DLC update containing the missing 28 levels included in the other versions, according to Ubisoft communications manager Gary Steinman. The exclusion was chocked up to “a longer development time than expected,” as the teams “couldn’t initially include the Invasion Mode – essentially, a second take on existing Rayman […]
|
Q:
SELECT COUNT com baixa performance no mySQL
Faço uso de uma query dentro do PHP para exibir a lista de categorias e subcategorias relacionadas, tenho de retorno mais de 10 mil resultados (está certo) em 3 segundos em média, mas depois que implementei uma subquery para verificar a quantidade de subcategorias relacionadas, a consulta oscilou entre 15-17 segundos.
Sem SUBQUERY (3s em média):
$sql_query = "SELECT t.* FROM `table` t
WHERE
t.`tbl_id` = '".mysqli_fetch_array($dbconn,$id)."'
ORDER BY
(CASE WHEN t.`tbl_nome` = 'Outros' THEN 1 ELSE 0 END) ASC,
t.`tbl_nome` ASC;
Com SUBQUERY (15> em média):
$sql_query = "SELECT t.*,
(SELECT COUNT(n.`tbl_id`) FROM `categoria` n WHERE n.`tbl_pai` = t.`tbl_id` LIMIT 1)
AS `numSubs`
FROM
`table` t
WHERE
t.`tbl_id` = '".mysqli_fetch_array($dbconn,$id)."'
ORDER BY
(CASE WHEN t.`tbl_nome` = 'Outros' THEN 1 ELSE 0 END) ASC,
t.`tbl_nome` ASC;
Adicionei o COUNT para verificar se outros registros no campo tbl_pai tem o ID diferente de NULL e se é o ID da categoria a ser consultada.
DÚVIDA:
Existe outro meio para verificar se outros campos possuem ID da categoria atual no campo tbl_pai que seja 1 apenas, que tem o campo pai com o ID da categoria atual. ? Assim otimizar a query e parar com a lentidão?
A:
Sua query possui inconsistências (como o LIMIT no COUNT), porém sem dados para uma resposta mais elaborada só posso sugerir o seguinte:
Crie um índice para a sua tabela:
ALTER TABLE categoria ADD INDEX categoria_index (tbl_pai);
Mais informações na resposta da pergunta Índices em consultas no MySQL e Para que serve o índice INDEX no MySQL?.
|
Storing Data on a seperate server??
Is it possible to store just the website/email on a seperate server that does not have cpanel running on it? We have access to a shared server but not root access that has a ton of space available to us and would like to use some of that space if possible. If it can't be done, we'll just add space to the existing server.
Is it possible to store just the website/email on a seperate server that does not have cpanel running on it? We have access to a shared server but not root access that has a ton of space available to us and would like to use some of that space if possible. If it can't be done, we'll just add space to the existing server.
Click to expand...
You'll need to mount the second server's drives to your cPanel server to take advantage of this. Your data center should be able to help out with this. There are many options for network mounts that you will wish to investigate:http://en.wikipedia.org/wiki/Network_file_system
|
Hallelujah Junction (ballet)
Hallelujah Junction is the eighth ballet made by New York City Ballet ballet master in chief Peter Martins to John Adams' eponymous music. The duo pianists appear in silhouette above the dancers throughout in Mark Stanley's lighting. The dance was made on the Royal Danish Ballet. The premiere took place on 24 March 2001 at the Royal Danish Theatre, Copenhagen. The NYCB premiere was on 22 January 2002 at the New York State Theater, Lincoln Center.
Casts
Original
Gitte Lindstrom
and four women in black
Andrew Bowman
Andrey Batalov
and four men in white
NYCB premiere
Gitte Lindstrom
Andrew Bowman
Benjamin Millepied
NYCB revivals
2008 Summer tour to Copenhagen and Paris
Janie Taylor
Daniel Ulbricht
Gonzalo Garcia
2009 Winter
first cast
Janie Taylor
Sébastien Marcovici
Andrew Veyette
second cast
Sterling Hyltin
Daniel Ulbricht
Gonzalo Garcia
2009 Spring
Sterling Hyltin
Daniel Ulbricht
Gonzalo Garcia
2009 Saratoga Springs
first cast
Sterling Hyltin
Daniel Ulbricht
Gonzalo Garcia
second cast
Janie Taylor
Andrew Veyette
Sébastien Marcovici
Notes
Reviews
NY Times by Anna Kisselgoff, January 24, 2002
NY Times by Anna Kisselgoff, May 17, 2003
External links
NYCB website
Category:Ballets by Peter Martins
Category:Ballets to the music of John Adams
Category:2001 ballet premieres
Category:New York City Ballet repertory
|
Academic Life
Academic and Personal Excellence
PrepNet’s commitment to academic and personal excellence is spelled out in our mission and vision. Our teachers and our staff believe strongly in the work we are doing and are committed to providing the individual attention needed to ensure students are well prepared for a lifetime of success.
Learn Through Interaction and Innovation
PrepNet schools offer a rich and challenging curriculum for academically motivated students. Because we want students to hit the ground running when they enter college, we require them to take at least two AP courses while in high school. We also ask that they give back to their communities by completing at least 60 hours of community service.
Discover Your Path to College and a Career
Each of our schools has a College Advisory program is designed to guide students and parents through the post-secondary planning process and to create plans for college or other post-secondary experiences. We want students to have the knowledge and resources necessary to make informed and successful post-secondary decisions. We work with each student during an advisory class, as well as group meetings, and also meet one-on-one with juniors and seniors for individualized planning.
|
As part of tuition and fee billing, the Bursar's Office is responsible for managing
system tuition bill codes and tuition adjustments for withdrawals, appeals, discounts
and waivers. Manual charges and adjustments are also posted for textbooks, traveler
charges, and miscellaneous fees and various fines.
The Bursar's Office processes student loan refunds and issues refunds for overpayments.
Refunds are also processed for the VA and other third party billing sponsors. Student
refunds are processed through a third party partner, HigherOne.
Charge and payment account activity is reported to students in an electronic billing
statement on a monthly basis. Students may access the monthly online e-bill statement
through their Connections account. Students are also able to make online payments and view their 1098-T form
through our online interface.
|
source 'https://rubygems.org'
gemspec
gem 'rake'
gem 'rdoc'
gem 'railties', '~> 6.0.0'
gem 'activemodel', '~> 6.0.0'
gem 'actionpack', '~> 6.0.0'
|
Q:
Ext JS 4: Setting a different root node for a TreeStore
I'm trying to set a different root node in my TreeStore in Ext JS 4.0.7, but I can't seem to do it correctly... I don't know if it's another bug in the framework or if I'm just using the functions incorrectly, so I'm asking for help. Here is the code that I'm working with.
Creating a blank node to use later on
var node = {
id: 'root',
text: 'root',
expanded: true,
children: [{
id: 'child1',
text: 'child1',
leaf: true
},{
id: 'child2',
text: 'child2',
leaf: true
}]
};
The store
var store = Ext.create('Ext.data.TreeStore', {
storeId: 'treestore',
proxy: {
type: 'memory',
reader: {
type: 'json'
}
},
snapshot: node,
root: {
id: 'root',
text: 'root',
expanded: true,
children: [{
id: 'dummy1',
text: 'dummy1',
leaf: true
},{
id: 'dummy2',
text: 'dummy2',
leaf: true
}]
}
});
Tree Panel
Ext.create('Ext.tree.Panel', {
store: store,
renderTo: Ext.getBody(),
height: 600,
width: 600,
id: 'mytree',
tbar: [{
xtype: 'button',
text: 'set child1 as root',
handler: function() {
var store = Ext.getCmp('mytree').store;
store.setRootNode(store.snapshot);
alert(store.getNodeById('child1').data.id); // alerts child1
}
},{
xtype: 'button',
text: 'set dummy1 as root',
handler: function() {
var store = Ext.getCmp('mytree').store;
store.setRootNode(store.snapshot2.copy(null, true));
alert(store.getNodeById('dummy1')); // alerts undefined
}
},{
xtype: 'button',
text: 'set dummy1 with diff copy',
handler: function() {
var store = Ext.getCmp('mytree').store;
store.getRootNode().removeAll();
store.snapshot2.eachChild(function(rec) {
store.getRootNode().appendChild(rec.copy(null, true));
});
alert(store.getNodeById('dummy1').data.id); // alerts dummy1
}
}]
});
Setting snapshot2 to the store's current root node
Ext.getCmp('mytree').store.snapshot2 = Ext.getCmp('mytree').store.getRootNode().copy(null, true);
So when you click the first button, you get the proper value ('child1') in the alert. However, when you click the second button ('set dummy1 as root'), you get undefined in the alert. The third button gives you the proper output ('dummy1'), and manually deep copies each child to the root.
To me, it seems like the copy function or the setRootNode function isn't doing something properly (leaning more toward the former). If I'm specifying a deep copy with copy(null, true), then the deep copy should be taking place, and everything should be fine... but I realize there's a problem with the copy function from the get go (see this thread). That's why I'm thinking it could be with the setRootNode, but that wouldn't make sense if setRootNode works for my created node but not for the deep copied original root node.
Can anyone offer any insight as to what I'm doing wrong? I'd appreciate any help. Thanks!
A:
I think copy has a bug that still hasn't been resolved:
http://www.sencha.com/forum/showthread.php?134844-tree-node-copy%28deep%29-not-working-%284.0.1%29&highlight=tree%20copy
|
import tensorflow as tf
debug=True
def simpleconv3net(x):
x_shape = tf.shape(x)
with tf.name_scope("simpleconv3"):
with tf.variable_scope("conv3_net"):
conv1 = tf.layers.conv2d(x, name="conv1", filters=12,kernel_size=[3,3], strides=(2,2), activation=tf.nn.relu,kernel_initializer=tf.contrib.layers.xavier_initializer(),bias_initializer=tf.contrib.layers.xavier_initializer())
bn1 = tf.layers.batch_normalization(conv1, training=True, name='bn1')
conv2 = tf.layers.conv2d(bn1, name="conv2", filters=24,kernel_size=[3,3], strides=(2,2), activation=tf.nn.relu,kernel_initializer=tf.contrib.layers.xavier_initializer(),bias_initializer=tf.contrib.layers.xavier_initializer())
bn2 = tf.layers.batch_normalization(conv2, training=True, name='bn2')
conv3 = tf.layers.conv2d(bn2, name="conv3", filters=48,kernel_size=[3,3], strides=(2,2), activation=tf.nn.relu,kernel_initializer=tf.contrib.layers.xavier_initializer(),bias_initializer=tf.contrib.layers.xavier_initializer())
bn3 = tf.layers.batch_normalization(conv3, training=True, name='bn3')
conv3_flat = tf.reshape(bn3, [-1, 5 * 5 * 48])
dense = tf.layers.dense(inputs=conv3_flat, units=128, activation=tf.nn.relu,name="dense",kernel_initializer=tf.contrib.layers.xavier_initializer())
logits= tf.layers.dense(inputs=dense, units=2, activation=tf.nn.relu,name="logits",kernel_initializer=tf.contrib.layers.xavier_initializer())
if debug:
print "x size=",x.shape
print "relu_conv1 size=",conv1.shape
print "relu_conv2 size=",conv2.shape
print "relu_conv3 size=",conv3.shape
print "dense size=",dense.shape
print "logits size=",logits.shape
return logits
|
We’ve finally made it to the ACC, the last remaining division one baseball conference to get the draft “preview” treatment. Below you’ll find my “preseason” all-prospect teams for the conference as well as links (with brief commentary where applicable) to team previews for eleven of the fourteen teams in the ACC. I’d like to do quick write-ups for the three remaining teams (Louisville, North Carolina, Wake Forest) in the coming days (perhaps all at once in a post for tomorrow) because I’m a completist by nature.
Keep in mind that the preseason teams you see below were more or less decided on coming into the season. I made a few minor tweaks, especially on the pitching side (mostly the second team). The one glaring oddity on this list is John LaPrise hanging on to a first team spot despite missing almost the entire season so far, but there weren’t any alternatives that jumped off the page (senior sign Logan Ratledge makes the strongest case) so I let it stand. The outfield was an unexpected mess to figure out outside of the top four names. Talk about a top heavy position. I didn’t rank the pitchers yet within each team, so don’t take the Matuella, Kirby, and Funkhouser 1-2-3 as where I currently see them falling. I need to think on that a bit more.
Does not include me comparing Matthew Crownover to Adam Morgan, so let me do that right here, right now. As somebody still holding out hope that Morgan can be a league average-ish big league starter, that’s a compliment.
Includes some thoughts on their top bat (with apologies to SR C Garrett Kennedy, a guy I considered a sleeper last year who disappointed but has come back with a vengeance as an unstoppable force in the Hurricanes lineup and is now one of this class’s finest potential senior signs) and their top arm, both of which I’ve excerpted below to save you the trouble of clicking through…
Through all the ups and downs physically, his [David Thompson] upside on the diamond remains fully intact from his HS days — I had him ranked as the 56th best overall prospect back then — and a big draft season is very much in play if he can stay healthy throughout the year. The bat will play at the next level (above-average raw power, plenty of bat speed, physically strong, plus athleticism, knows how to use the whole field), so the biggest unknown going into this season is where he’ll eventually call home on the defensive side. I’ve liked his chances to stick at third since his prep days; failing that, I’d prioritize a home in the outfield (he’s not known for his speed, but the athleticism and arm strength should make him at least average in a corner) over going to first, where, overall loss of defensive value aside, at least he’s shown significant upside. His strong showing at the end of the summer on the Cape is an encouraging way to get back into the grind of college ball, though he did appear to sacrifice some patience at the plate for power down the stretch. If he can find a way to marry his two existences — college (approach: 35 BB/45 K in his career) and Cape (power) — in this upcoming season (like in his healthy freshman season), Thompson should find himself off the board early this June.
…
JR LHP Andrew Suarez has the raw stuff to find himself selected once again in the top two rounds this June, but the peripherals leave something to be desired after two seasons (6.33 K/9 in 2013, 7.16 K/9 in 2014). Still, he’s a rapidly improving arm (especially his changeup) who throws a pair of quality breaking balls and can hit 94/95 from the left side. His control has also been really good and he’s been a workhorse for the Hurricanes after labrum surgery (believed to be as minor as a shoulder surgery can get, for what it’s worth) two years ago. He’s a reasonable ceiling (mid-rotation starting pitcher) prospect with a high floor (if healthy, he’s at least a quick-moving reliever). It’s a profile that’s really easy to like, but fairly difficult to love.
Includes an homage to Rick Pitino, which I stand by but admit could be a little harsh looking back on things. SR 2B/3B Logan Ratledge and rSO RHP Johnny Piedmonte aren’t Trea Turner and Carlos Rodon, but they aren’t half-bad, either.
I’m a little bit back and forth with LHP Nathan Kirby yet, though I think the recent overreaction to his below-average (for him) velocity and all-around stuff that can (maybe) be explained away (to a point) due to his recently diagnosed strained lat was a bit much. I still view him as a high-floor, TBD ceiling prospect worthy of the top half of the first round conversation.
|
I find that the hardest part of working with child themes. Things aren’t where they would normally be in a normal theme. Lots of times you have to look in the functions.php file to find it. I’m pretty sure that’s the case for you. Find this line in the functions.php file and comment it out (add a // at the beginning of the line). So change this:
|
This ebook is available for the following devices:
iPhone
iPad
Android
Kindle Fire
Windows
Mac
Sony Reader
Cool-er Reader
Nook
Kobo Reader
iRiver Story
more
At 170 billion barrels, Canada's Oil Sands are the third largest reserves of developable oil in the world. The Oil Sands now produce about 1.6 million barrels per day, with production expected to double by 2025 to about 3.7 million barrels per day. The Athabasca Oil Sands Region (AOSR) in northeastern Alberta is the largest of the three oil sands deposits. Bitumen in the oil sands is recovered through one of two primary methods – mining and drilling. About 20 per cent of the reserves are close to the surface and can be mined using large shovels and trucks. Of concern are the effects of the industrial development on the environment. Both human-made and natural sources emit oxides of sulphur and nitrogen, trace elements and persistent organic compounds. Of additional concern are ground level ozone and greenhouse gases.
Because of the requirement on operators to comply with the air quality regulatory policies, and to address public concerns, the not-for-profit, multi-stakeholder Wood Buffalo Environmental Association (WBEA) has since 1997 been closely monitoring air quality in AOSR. In 2008, WBEA assembled a distinguished group of international scientists who have been conducting measurements and practical research on various aspects of air emissions and their potential effects on terrestrial receptors. This book is a synthesis of the concepts and results of those on-going studies. It contains 19 chapters ranging from a global perspective of energy production, measurement methodologies and behavior of various air pollutants during fossil fuel production in a boreal forest ecosystem, towards designing and deploying a multi-disciplinary, proactive, and long-term environmental monitoring system that will also meet regulatory expectations.
Covers measurement of emissions from very large industrial sources in a region with huge international media profile
Validation of measurement technologies can be applied globally
The new approaches to ecological monitoring described can be applied in other forested regions
|
Sponsors: The National Institute of Mental Health (NIMH) and The HIV Prevention Trials Network (HPTN 043)
Study Objectives
The primary objective of this study is to test the hypothesis that communities receiving three years of the community-based HIV voluntary counseling and testing (CBVCT) intervention, relative to communities receiving three years of standard clinic-based VCT (SVCT), will have significantly lower incidence of recent HIV infection.
Aim 1 will be evaluated by comparing the post-intervention incidence of recent HIV infection in 24 intervention and 24 comparison communities, using an algorithmic approach comprised of CD4+ T-cell counts, the HIV-1 BED Incidence EIA (Calypte), Avidity Index (BioRad), and HPLC for ART residues (HPTN Core Lab/JHU). A combination of all these markers contains more information on infection duration than any single component.
The secondary objective of this study is to test the hypotheses that intervention communities, relative to comparison communities, will at the end of the intervention period report significantly less HIV risk behavior, higher rates of HIV testing, more favorable social norms regarding HIV testing, more frequent discussions about HIV, more frequent disclosure of HIV status, less HIV-related stigma, fewer HIV-related negative life events.
The Intervention
The NIMH Project Accept intervention consists of four main components: community mobilization, Community-Based (mobile) VCT, post-test support services and feedback of utilization rates and quality of the intervention. The intervention in each of the countries and sites is derived from the same theoretical model and contain the same strategies. The implementation of the elements of the intervention is tailored to each local culture and context. The intervention is based on the premise that HIV sexual risk behavior and HIV incidence will decrease in communities with increased knowledge of HIV status and more supportive community norms.
Communities randomized to Standard VCT (the "standard-of-care") will only receive the installment of clinic-based VCT services at existing facilities. The training for VCT counselors will be the same in the intervention and comparison communities; however, no active outreach/community mobilization, mobile/enhanced-access VCT services, or special post-test clubs will be provided in the comparison communities.
Communities randomized to intervention will receive, in addition to the standard VCT services, four components of the Project Accept intervention.
For a detailed description of the Project Accept intervention, please refer to the following publication:
This component of the intervention is based on diffusion of innovation theory, which contends that there are a small number of people in communities who are innovators. Then, early adopters influence others in a social network. Eventually, a threshold of behavioral adoption at the network level is reached that sustains the widespread uptake of a behavior. This is similar to what would be explained by the "law of the few" in tipping theory, but puts greater emphasis on the importance of timing. In particular, diffusion of innovation theory would predict that by enticing opinion leaders early on to adopt an innovative behavior deemed to be adaptive, the speed of uptake of the new behavior is facilitated. Thus, a community mobilization approach that promotes HIV testing among early adopters, particularly if these individuals are influential and central to the larger social network, can begin a process of changing community norms to both increase discussions about HIV in communities and decrease HIV-related stigma.
Community mobilization uses community outreach to enhance the uptake of VCT, thus increasing the rate of HIV testing and frequency of discussions about HIV. This component is also designed to reduce stigma through community education and mobilization. The community mobilization phase of the intervention consists of educating communities about HIV, providing HIV testing, and encouraging discussion in the community with the intent to increase awareness and decrease stigma. Ultimately, these efforts are intended to increase acceptance and utilization of the mobile VCT component of the study.
Easy Access to VCT
This component of the intervention is based on tipping point theory and is designed to remove practical barriers (fees, inconvenience, and the need to return for results) and increase safety of VCT (anonymity, high-quality counseling and post-test support). This ease of access is designed to increase rates of HIV testing, change social norms about testing, and increase the frequency of discussions about HIV in communities. This approach should also decrease behavioral risk for HIV. Mobile vans or temporary units set up at local community sites provide free, anonymous VCT in specific, chosen sites where people gather, such as market areas, shopping centers, and community centers.
Post-Test Support Services
The third component of the intervention is based on a social action model and is designed to build psychosocial support to improve the quality of life for individuals diagnosed with HIV. The expected outcomes include a reduction in social harm, an increase in social support through disclosure to those most likely to provide support, and a reduction in internalized stigma. Social support should also decrease the behavioral risk of further transmission. Our objective in providing post-test support services (PTSS) is to create a culturally appropriate support system for community members following their decision to test for HIV.
Feedback--Utilization Rates and Quality Assurance
Throughout the intervention feedback on utilization of the various components has been monitored and feedback provided to intervention field staff. This has allowed those implementing the project to make adjustments in the day-to-day operations to increase participation. In addition, quality assurance procedures were instituted at all sites and this feedback was important for maintaining fidelity to the intervention.
Comparison Communities
In comparison communities, standard VCT services are provided at existing district hospitals, community-based health care centers, or other local health delivery facilities. The procedures for counseling and HIV rapid testing are the same as those in the intervention communities, except that referrals will be limited to existing community agencies rather than study-related post-test support services.
In the first year of the study, a four-fold increase in testing was observed in the intervention versus comparison communities. We also found an overall 95% adherence to intervention components. Study outcomes, including prevalence of recent HIV infection and community-level HIV stigma, are currently being assessed.
Project Sites
The NIMH Project Accept is a multisite, community randomized intervention trial being conducted at 5 sites in 4 different countries.
The Tanzania site is in Kisarawe district, a rural coastal region approximately 100 km from Dar es Salaam adjacent to a major transit route. The area is largely agricultural and the project is locally referred to as Project Afiki.
The Thailand site is in the Chiang Mai Northern province, with communities located in rural areas near the border with Myanmar, largely populated by ethnic minorities. The project is locally referred to as PA-Thai Project.
The Zimbabwe site is in Mutoko, a rural district located in the Mashonaland East province, approximately 150 km from the capital, Harare, a largely agricultural area. The project is locally referred to as CBVCT Project.
The Vulindlela site is in South Africa, KwaZulu-Natal province, a rural area located approximately 25 km from Pietermaritzburg. Employment opportunities are provided mostly through the forestry industry and in nearby towns. The project is locally referred to as Ukwamukela Project.
The second South African site is in Soweto, in the Gauteng province, the largest urban township in South Africa, historically created to accommodate the work force for the city of Johannesburg. The project is locally referred to as PHRU Project Accept.
|
Q:
Make a UITableView that is not 100% width
I would like to make a grouped UITableView where the cells are not 100% width, this is because I want to show the background, and each cell will have rounded corners.
Sort of like this;
However, I'm not sure how to do this using Storyboard; or is it only something you can do in code?
Ideally, I'd like the whole area scrollable; but make the cells appear less than 100% width
A:
Not sure if this is the best solution; the one I have so far is...
In storyboard
Create UITableView as normal as child of a UIView, set up
delegates, data source as required
Add a UITableViewCell to this
Create my own custom subclass of UITableViewCell;
- (void)setFrame:(CGRect)frame {
frame.origin.x += kInset;
frame.size.width -= 2 * kInset;
[super setFrame:frame];
}
-(void) drawRect:(CGRect)rect {
[self.layer setCornerRadius:kCornerRadius];
[self.layer setMasksToBounds:YES];
}
The constants are just any number for now, say 10
Next I ensure my UITableViewCell is pointing to this subclass.
Now my cells appear with a margin and the uitableview itself is 100% width.
I will have to keep playing around with it; maybe there is a better solution
|
Q:
How can I open irc:// links in Pidgin from Chromium?
I want to open irc:// links in pidgin from chromium.
When i am logged-in to a irc server(irc.freenode.net) running purple-url-handler irc://irc.freenode.net/#ubuntu in terminal works fine.
But when i click the same link in chromium (which uses xdg-open to open irc:// links) it does nothing. Any idea how to make this happen?
I am using Ubuntu 12.04.
A:
OK I found it!So I will answer here.
FOR UBUNTU(>=11.04)
Gconf settings(/desktop/gnome/url-handlers) didn't do anything since as of Natty the file-open functionality is handled by gvfs-open, which doesn't use gconf settings. Rather, gvfs-open looks at the ".desktop" files bundled with each application to determine what file types can be handled.if it is not installed, run :
sudo apt-get install gvfs-bin
In all x-scheme handler urls( like irc://, xmpp://, sip://, aim://) are handled by purple-url-handler.We are going to create a desktop file for it.
gksudo gedit /usr/share/applications/purple-url-handler.desktop
& put following content in it:
[Desktop Entry]
Name=Purple URL Handler
GenericName=Internet Messenger
Comment=URL handler forGoogle Talk, Jabber/XMPP, MSN, Yahoo and more
Exec=purple-url-handler %U
Icon=pidgin
StartupNotify=true
Terminal=false
Type=Application
MimeType=x-scheme-handler/irc;
Categories=Network;InstantMessaging;
X-Ubuntu-Gettext-Domain=pidgin
Now to make irc:// links open with purple-url-handler run :
xdg-mime default purple-url-handler.desktop x-scheme-handler/irc
This informator is stored in ~/.local/share/applications/mimeapps.list.
Now when you click any irc:// link in chromium for the first time, the following prompt will appear:
Select remember my choice & launch application. If you are already logged in it will open the room in pidgin.
DONE!
|
SCP – Containment Breach Download Free PC Game Full Version + Crack
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You play as D-9341, one of many Class-D test subjects used by the SCP Foundation, an organization dedicated to containing and safe-guarding anomalous creatures and artifacts from the rest of the world.
Not long after receiving your first assignment, the facility undergoes a massive containment breach, leaving you alone in the darkness with the escaped entities roaming around the facility.
Your goal throughout the whole game is to escape the facility alive, while trying to avoid any hazards along the way. The most prominent hazards being SCPs which have escaped containment.
|
Q:
NSDate month addition and subtraction
I have a class that holds an start date and an end date, normally initialised to the firt and last second of the month.
The following function works correctly going from Nov 2010 forwards into December and back again however going backwards from November ends up with startDate set to
2010-09-30 23:00:00 GMT
Ie. a month and an hour ago.
Strangely the endDate is still correctly set to
2010-11-01 00:00:00 GMT
And going forward a month from this incorrect date also results in the correct time and date.
Is this a bug or am I doing something I shouldn't be ?
-(void) moveMonth:(NSInteger)byAmount { // Positive or negative number of months
NSCalendar *cal = [NSCalendar currentCalendar];
NSDateComponents *components = [[[NSDateComponents alloc] init] autorelease];
// Update the start date
[components setMonth:byAmount];
NSDate *newStartDate = [cal dateByAddingComponents:components toDate:[self startDate] options:0];
[self setStartDate:newStartDate];
// And the end date
[components setMonth:1];
NSDate *newEndDate = [cal dateByAddingComponents:components toDate:[self startDate] options:0 ];
[self setEndDate:newEndDate];
}
SOLUTION: Answer correctly pointed out this is a DST issue
If you want to deal in absolute times and date then using the following avoids any DST being involved.
NSCalendar *cal = [[NSCalendar alloc ] initWithCalendarIdentifier:NSGregorianCalendar] autorelease];
NSTimeZone *zone = [NSTimeZone timeZoneWithName:@"GMT"];
[cal setTimeZone:zone];
A:
It is probably not a bug but something related to DST changes in October-November period.
|
Q:
Can I install another linux os without bootloader?
I have a debian Gnu/linux installed in my system and I want to dual boot ubuntu.Can I install ubuntu without replacing debian bootloader?
A:
You can let Ubuntu replace grub with Ubuntu's or keep the old one. This is the default, and works well. You will be able to boot the other linux system(s) too.
In BIOS mode, if you want to keep the old one, you should select 'Something else' at the partitioning page, where you can select to install grub to the partition instead of the head of the drive. This does not work in UEFI mode: even if you select correctly, it will use the default settings.
If you keep the old bootloader, you will not see the new system (Ubuntu) until you run
sudo update-grub
in the old system (and reboot).
|
Q:
How can I format java.sql.Timestamp in a XML way using XStream?
I have some Java objects that I want to transform to XML. Some of the objects has a field java.sql.Timestamp datetime and I want them formatted in XML as datetimes is usually formatted in XML.
From what I know datetimes in XML should contain a T or a Z for UTC time. But if I use XStream the java.sql.Timestamp is formatted as <datetime>2011-04-20 14:24:29.334</datetime> in the XML.
Is there any way I can format Timestamps in a XML-way using XStream?
A:
You can do it using Custom Converter
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.33 rounded to the nearest one hundred?
366600
What is 24196.2627 rounded to the nearest ten?
24200
Round 34.9580783 to three decimal places.
34.958
What is -67090.46385 rounded to the nearest 10?
-67090
Round -67788.0623 to the nearest ten.
-67790
Round 15688593.734 to the nearest ten thousand.
15690000
What is -99.503714 rounded to two dps?
-99.5
What is 8628684208 rounded to the nearest 1000000?
8629000000
What is 3.155582169 rounded to 3 dps?
3.156
Round -110168.481 to the nearest 10000.
-110000
What is -0.0242760546 rounded to 5 dps?
-0.02428
What is -96798.37 rounded to the nearest ten thousand?
-100000
Round -0.00053461389 to four dps.
-0.0005
What is 5.096128088 rounded to one dp?
5.1
What is 0.0000014553911 rounded to seven dps?
0.0000015
What is -0.00100896237 rounded to three dps?
-0.001
What is -5745723.28 rounded to the nearest one thousand?
-5746000
What is 0.000033084017179 rounded to 6 dps?
0.000033
What is 23.120736 rounded to the nearest integer?
23
Round -619382.987 to the nearest ten thousand.
-620000
Round 0.01298939204 to four dps.
0.013
What is -2252028.8 rounded to the nearest 100000?
-2300000
What is -471.5179 rounded to zero dps?
-472
Round -0.044467645 to five dps.
-0.04447
Round 25942275050 to the nearest one million.
25942000000
What is -4240.89055 rounded to the nearest integer?
-4241
Round -0.149054039 to one dp.
-0.1
What is 0.00001121135639 rounded to six dps?
0.000011
What is 3313.95997 rounded to 1 decimal place?
3314
Round -1750.27944 to the nearest one hundred.
-1800
Round -5412125880 to the nearest one million.
-5412000000
What is 0.0064255395 rounded to four decimal places?
0.0064
What is 2.05112633 rounded to 3 decimal places?
2.051
What is 0.0250253988 rounded to 6 dps?
0.025025
What is 0.000005705883136 rounded to seven decimal places?
0.0000057
Round 60573.206 to the nearest one thousand.
61000
Round -1120431.168 to the nearest one thousand.
-1120000
Round 7.9749058 to 3 dps.
7.975
What is -694167859.9 rounded to the nearest one million?
-694000000
Round -0.4026771826 to four decimal places.
-0.4027
Round -0.0000355539177 to 5 dps.
-0.00004
What is -0.0040943435 rounded to five dps?
-0.00409
Round -0.0001493890773 to 5 dps.
-0.00015
Round 379.2116198 to the nearest one hundred.
400
What is -1181126690.4 rounded to the nearest 10000?
-1181130000
What is -95658.2827 rounded to the nearest 10?
-95660
What is 1322836.908 rounded to the nearest ten?
1322840
Round 0.00082515094 to five decimal places.
0.00083
Round -3524.46955 to one decimal place.
-3524.5
What is -395454.92 rounded to the nearest 100000?
-400000
What is -639643.546 rounded to the nearest one thousand?
-640000
Round -931.0592 to the nearest one hundred.
-900
Round -4536242 to the nearest 1000000.
-5000000
What is 70.6951778 rounded to 0 dps?
71
What is 4.2247907 rounded to 2 decimal places?
4.22
What is 6.6227065 rounded to one dp?
6.6
Round -0.0006563383931 to 5 decimal places.
-0.00066
Round -0.02380227011 to 3 dps.
-0.024
What is 0.001340410827 rounded to four decimal places?
0.0013
What is 94005301 rounded to the nearest 10000?
94010000
What is 8.021989795 rounded to 4 decimal places?
8.022
What is 5216700.69 rounded to the nearest 100?
5216700
What is 67267.5183 rounded to the nearest 10?
67270
Round 0.319165911 to 5 decimal places.
0.31917
Round -776948.07 to the nearest 1000.
-777000
What is -0.000062889823 rounded to seven decimal places?
-0.0000629
What is -2111082.373 rounded to the nearest one thousand?
-2111000
What is 3879937800 rounded to the nearest one million?
3880000000
Round 26447.88311 to the nearest 10000.
30000
What is 16973.8385 rounded to zero decimal places?
16974
Round 768458.53 to the nearest one hundred thousand.
800000
Round 0.0000012323503 to six decimal places.
0.000001
What is 365618.35 rounded to the nearest 10000?
370000
What is -967.65378 rounded to the nearest 1000?
-1000
Round -11.5506994 to two dps.
-11.55
Round -6.1193115 to 2 decimal places.
-6.12
What is 0.000095316525 rounded to 5 decimal places?
0.0001
Round -4.496491289 to one decimal place.
-4.5
Round -0.008850760322 to four decimal places.
-0.0089
What is -302.0460763 rounded to zero decimal places?
-302
Round -0.164928294 to four dps.
-0.1649
What is -0.00085240719 rounded to 6 dps?
-0.000852
What is -0.0016416844 rounded to 4 decimal places?
-0.0016
Round -0.00367690481 to six dps.
-0.003677
What is 1.226447736 rounded to 1 dp?
1.2
What is 0.000000255600514 rounded to seven dps?
0.0000003
Round 16868.148 to the nearest ten thousand.
20000
What is 31422.43 rounded to the nearest one thousand?
31000
Round 9450929.604 to the nearest ten thousand.
9450000
Round -55103.213 to the nearest 10.
-55100
What is 20331914.9 rounded to the nearest one million?
20000000
What is -1028410.79 rounded to the nearest 10000?
-1030000
Round 10.346352486 to zero dps.
10
Round -0.0000000888898386 to 7 dps.
-0.0000001
Round 1424812845.7 to the nearest 10000.
1424810000
What is 2713867.8 rounded to the nearest ten thousand?
2710000
Round -1811457.89 to the nearest 1000.
-1811000
Round -8753453.193 to the nearest one hundred thousand.
-8800000
What is -0.0001033653368 rounded to 5 decimal places?
-0.0001
What is 27006.742941 rounded to the nearest one thousand?
27000
What is -23.7931669 rounded to one dp?
-23.8
What is -0.46917925 rounded to four dps?
-0.4692
Round 0.01324713274 to four decimal places.
0.0132
What is 0.0446711584 rounded to 4 dps?
0.0447
Round 2489.163345 to 0 dps.
2489
What is -25375.74183 rounded to 0 decimal places?
-25376
What is 0.00011472188 rounded to five decimal places?
0.00011
What is 87835.2018 rounded to the nearest 10?
87840
What is 85164.96 rounded to the nearest 100?
85200
Round -0.000098796946 to 6 decimal places.
-0.000099
Round 0.0464660104 to 2 decimal places.
0.05
Round -0.13093963907 to two dps.
-0.13
Round -0.00358374121 to five decimal places.
-0.00358
Round -844448.092 to the nearest 10000.
-840000
Round -2178.74793 to the nearest ten.
-2180
Round 5804624 to the nearest 1000000.
6000000
Round -0.2535474341 to 2 decimal places.
-0.25
What is -10380.3612 rounded to the nearest ten?
-10380
Round 18796188.8 to the nearest one million.
19000000
Round -1424607886.5 to the nearest one million.
-1425000000
What is -2935.684312 rounded to zero dps?
-2936
What is -6041.46541 rounded to 0 dps?
-6041
What is 5.54854 rounded to the nearest integer?
6
What is -774.8321715 rounded to zero dps?
-775
What is 0.00002389125335 rounded to seven decimal places?
0.0000239
What is 0.000611136715 rounded to four decimal places?
0.0006
Round -0.02980664 to five decimal places.
-0.02981
Round -0.00004684268954 to seven decimal places.
-0.0000468
What is -0.00000241236704 rounded to 7 dps?
-0.0000024
What is -55713.85566 rounded to the nearest ten thousand?
-60000
Round -352340.326 to the nearest 100.
-352300
What is 4887.3861 rounded to zero decimal places?
4887
Round -3.32269211 to 2 dps.
-3.32
Round 0.00170078452 to four decimal places.
0.0017
Round -0.0169740019 to 4 dps.
-0.017
What is 63936207.9 rounded to the nearest 100000?
63900000
Round 0.00539113603 to 5 dps.
0.00539
What is -10.38532503 rounded to four decimal places?
-10.3853
Round 6.5530931 to 0 decimal places.
7
Round -258161.8814 to the nearest 1000.
-258000
What is 0.000001501244511 rounded to 6 decimal places?
0.000002
What is -2.14084636 rounded to two dps?
-2.14
Round -0.05774247 to two dps.
-0.06
Round -871629357 to the nearest ten thousand.
-871630000
Round -4.332396426 to 2 decimal places.
-4.33
Round -1.55991896 to three decimal places.
-1.56
Round 0.000430022463 to six decimal places.
0.00043
Round 3170917.8 to the nearest 1000.
3171000
Round 60247730 to the nearest one million.
60000000
What is -0.0000066111405 rounded to six decimal places?
-0.000007
What is -0.0000564160784 rounded to five dps?
-0.00006
Round 0.05422984398 to five decimal places.
0.05423
Round -67.621929 to the nearest ten.
-70
What is 0.001909309187 rounded to 4 decimal places?
0.0019
Round -305201.9589 to the nearest one thousand.
-305000
Round 0.00007216138 to 5 decimal places.
0.00007
What is -65059061.07 rounded to the nearest 100000?
-65100000
Round -3.2207581 to two dps.
-3.22
What is -0.1184106704
|
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ROME (TheBlaze/AP) — Once again, Pope Francis has shocked supporters and critics, alike. The pontiff washed and kissed the feet of a dozen inmates at a juvenile detention center in a Holy Thursday ritual that he celebrated for years as archbishop and is continuing now that he is pope.
And here’s what really turned heads : Two of the 12 were young women, a remarkable choice given that the church’s current liturgical law says only men should participate.
The mass was held in the Casal del Marmo facility in Rome, where 46 young men and women currently are detained. Many of them are Gypsies or North African migrants, and the 12 selected for the foot-washing rite included Orthodox and Muslim detainees, news reports said.
Pope Francis kisses the feet of a prisoner at the Casal Del Marmo Youth Detention Centre during the mass of the Lord’s Supper on March 28, 2013 in Rome, Italy. During the mass, commemorating Christ’s Last Supper, Pope Francis washed the feet of prisoners in the Casal Del Marmo youth detention centre in observance of the Bible’s account of Jesus Christ’s gesture towards his 12 apostles on the night before he was crucified. Credit: Getty Images
Because the inmates were mostly minors — the facility houses inmates aged 14-to-21 — the Vatican and Italian Justice Ministry limited media access inside. But Vatican Radio carried the Mass live, and Francis told the detainees that Jesus washed the feet of his disciples on the eve of his crucifixion in a gesture of love and service.
“This is a symbol, it is a sign — washing your feet means I am at your service,” Francis told the youngsters. “Help one another. This is what Jesus teaches us. This is what I do. And I do it with my heart. I do this with my heart because it is my duty, as a priest and bishop I must be at your service.”
Later, the Vatican released a limited video of the ritual, showing Francis washing black feet, white feet, male feet, female feet and even a foot with tattoos. Kneeling on the stone floor as the 12 youngsters sat above him, the 76-year-old Francis poured water from a silver chalice over each foot, dried it with a simple cotton towel and then bent over to kiss each one.
As archbishop of Buenos Aires, the former Cardinal Jorge Mario Bergoglio would celebrate the ritual foot-washing in jails, hospitals or hospices – part of his ministry to the poorest and most marginalized of society. It’s a message that he is continuing now that he is pope, saying he wants a church “for the poor.”
Pope Francis washes the feet of a prisoner at the Casal Del Marmo Youth Detention Centre during the mass of the Lord’s Supper on March 28, 2013 in Rome, Italy. During the mass, commemorating Christ’s Last Supper, Pope Francis washed the feet of prisoners in the Casal Del Marmo youth detention centre in observance of the Bible’s account of Jesus Christ’s gesture towards his 12 apostles on the night before he was crucified. Credit: Getty Images
Previous popes would carry out the foot-washing ritual on Holy Thursday in Rome’s grand St. John Lateran basilica. The 12 people chosen for the ritual would always be priests to represent Christ’s 12 apostles.
That Francis would include women in this re-enactment is remarkable given current liturgical rules that restrict the ritual to men.
Canon lawyer Edward Peters, who is an adviser to the Holy See’s top court, noted in a blog that the Congregation for Divine Worship in 1988 said in a letter to bishops that “The washing of the feet of chosen men … represents the service and charity of Christ who came `not to be served, but to serve.’”
Peters noted that bishops over the years have successfully petitioned Rome for an exemption to allow women to participate, but that the law on the issue is clear.
“By disregarding his own law in this matter, Francis violates, of course, no divine directive,” Peters wrote Thursday. “What he does do, I fear, is set a questionable example.”
Others welcomed the example he set.
Credit: Getty Images
“The pope’s washing the feet of women is hugely significant because including women in this part of the Holy Thursday Mass has been frowned on — and even banned — in some dioceses,” said the Rev. James Martin, a Jesuit priest and author of “The Jesuit Guide.”
“It shows the all-embracing love of Christ, who ministered to all he met: man or woman, slave or free, Jew or Gentile,” he said.
After the Mass, Francis greeted each of the inmates and gave each one an Easter egg.
“Don’t lose hope,” he said. “Understand? With hope you can always go on.”
One of the inmates then asked him why he had come to visit them. Francis said it was to “help me to be humble, as a bishop should be.” He said he wanted to come “from my heart. Things from the heart don’t have an explanation,” he said.
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Fiorentina closer to Jese?
By Football Italia staff
Paris Saint-Germain have reportedly given the all-clear for Fiorentina to sign Jese Rodriguez on loan.
According to L’Equipe and Marca, the Ligue 1 giants are open to letting their Spanish talent leave on a temporary basis.
The 24-year-old only moved to PSG in a €25m deal from Real Madrid last summer, but after six months went back to Spain on loan for Las Palmas.
It’s suggested the Viola will take Jese on loan, but the left-sided winger still has to work out personal terms.
Fiorentina cannot shoulder his entire salary for one season and need help from Paris Saint-Germain.
Watch Serie A live in the UK on Premier Sports for just £9.99 per month including live LaLiga, Eredivisie, Scottish Cup Football and more. Visit: https://www.premiersports.com/subscribenow
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France and Germany have scolded President Trump for making a sudden U-turn after he rejected the key document of the G7 summit, jointly adopted just a day earlier. Trump’s move came after clashing with Canadian PM on trade.
Upon leaving the summit in Charlevoix, Canada, the US president had publicly lashed out at Canada’s prime minister Justin Trudeau on Twitter. Trump called him “meek” and “mild” during the G7 talks, and said he asked Congress not to endorse the joint final communiqué adopted on the meeting.
Based on Justin’s false statements at his news conference, and the fact that Canada is charging massive Tariffs to our U.S. farmers, workers and companies, I have instructed our U.S. Reps not to endorse the Communique as we look at Tariffs on automobiles flooding the U.S. Market! — Donald J. Trump (@realDonaldTrump) June 9, 2018
Trump’s outburst quickly raised eyebrows in Europe. “In a matter of seconds, you can destroy trust with 280 twitter characters,” German foreign minister Heiko Maas said on Sunday. He added that Trump behavior is “not a real surprise”, given his previous decisions to back out of the 2015 Iran nuclear deal and the 2015 Paris climate accord.
France were also disappointed with the US leader’s rejection of the G7 joint communiqué. "International cooperation cannot be dictated by fits of anger and throwaway remarks," the office of the French president Emmanuel Macron told AFP in a statement on Sunday. It added that recanting the endorsement of the main document adopted by all G7 members showed "incoherence and inconsistency".
Read more
The meeting itself proved to be quite contentious, with Trump arriving late and leaving early, as the partners clashed with him on free trade and tariffs.
In January 2018, Trump imposed tariffs on steel and aluminum imported from the EU, Canada and Mexico, citing the need to protect American businesses. His move was met with wide criticism abroad, with European Union accusing the White House of inciting a “trade war”.
Justin Trudeau called Trump’s tariffs “insulting” to the history of US-Canada relations. As “retaliatory measures” his government decided to impose their own tariffs on more than 80 types of American goods, from ketchup and strawberry jam to washing machines and plywood, effective on July 1.
The European Union branded the US tariffs “unacceptable”. During a speech in late May, the head of the European Commission Jean-Claude Juncker vowed to launch a complaint to the World Trade Organization and later unveiled a series of “trade defense rules”, including an option to impose higher duties on certain goods.
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Regional Newspapers ABC Circulation July-Dec 2012
The decline in the number of Regional Papers being part of the ABC process is falling at a pace. Two years ago there were nearly 45 papers (paid for) certified by the ABC, now only 24 decide to confess annually or bi-annually.
The only papers to record an increase are the Echo in Dublin and the Donegal News Monday edition. Monday edition.. most likely still living off the special edition the Monday after the All Ireland Final in September. I don’t joke, sales up 25% in September for the Monday edition of the News!
Elsewhere in the parishes things are bleak, as bleak as they are nationally. They collectively are down 8% – mirroring the national picture. The big faller is the Leinster and Offaly Express but that because of the closure of one of the titles and the comparison is unkind at best.
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Spontaneous parathyroid adenoma hemorrhage.
We report a case of spontaneous parathyroid adenoma hemorrhage. A 50-year-old man with a sore throat, and swelling and ecchymosis of the entire anterior neck was found in cervical and chest computed tomography revealed to have a low-density area extending from the parapharyngeal region to below the carina, Suspecting descending necrotizing mediastinitis secondary to a peritonsillar abscess, we conducted mediastinal and cervical drainage, but found no abscess. No evidence was found, either, in bacteriological culture of sputum and pleural effusion. After the hematoma disappeared, cervical ultrasonography indicated parathyroid adenoma. Serum calcium was marginally increased, indicating that serum calcium should be determined if cervical or mediastinal hematoma develops without an obvious cause.
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Depuis un long moment, la DreamHack souhaitait ajouter plus d'étapes internationales à son circuit, en passant notamment par la France. Avec l'aide de Jean-Christophe Arnaud, fondateur de Tours Évènements, ce souhait a été rendu possible et réalisé ce week-end dans le centre international de congrès Vinci à Tours. Il a fallu une longue préparation pour mettre en place un tel évènement, mais les premières discussions avec les Suédois de la DreamHack avaient débouché sur un partenariat pendant plusieurs années, le passage de la DreamHack à Tours n'était donc pas qu'un one-shot ce week-end.
Lorsque l'accord était officiel entre Tours Évènements et la DreamHack, ce n'est pas un seul évènement qui a été prévu d'organiser, mais bien un total de trois. Le premier de cette série s'étant déroulé ce week-end, SekYo a eu l'occasion d'aller interviewer Jean-Christophe Arnaud, ancien membre de Turtle Entertainment plus connu sous le pseudonyme de LOBO, qui nous a révélé tout un tas d'informations dont le fait que la DreamHack reviendra à Tours en 2016 puis 2017.
Maintenant que nous savons que la DreamHack reviendra l'année prochaine, la question qui se pose concerne l'emplacement de la LAN. En effet, comme l'indique LOBO, le but est d'augmenter le nombre de joueurs présents chaque année afin de se rapprocher de ce qui se fait actuellement à Jönköping en Suède lors de la DreamHack Winter et Summer, c'est-à-dire accueillir environ 10 000 joueurs. Or, cette année, la DreamHack Tours accueillait seulement 1 000 joueurs sur le weekend et le centre des congrès ne pourra pas en accueillir beaucoup plus.
En parallèle à cela, les spectateurs s'étaient déplacés en nombre pour suivre leurs joueurs préférés dans les différents tournois, les différents amphithéâtres ont fait salle comble la majeure partie du temps et certaines personnes ont été obligées de suivre les matchs sur des téléviseurs installés dans les couloirs autour des amphis. Néanmoins, les spectateurs aussi bien que les joueurs aient été globalement heureux par rapport à cet évènement et la communauté attendra le prochain avec impatience désormais, mais en attendant, il y aura pas mal de réflexion à avoir pour Jean-Christophe et son équipe.
|
Q:
Serialize a custom transformer using python to be used within a Pyspark ML pipeline
I found the same discussion in comments section of Create a custom Transformer in PySpark ML, but there is no clear answer. There is also an unresolved JIRA corresponding to that: https://issues.apache.org/jira/browse/SPARK-17025.
Given that there is no option provided by Pyspark ML pipeline for saving a custom transformer written in python, what are the other options to get it done? How can I implement the _to_java method in my python class that returns a compatible java object?
A:
As of Spark 2.3.0 there's a much, much better way to do this.
Simply extend DefaultParamsWritable and DefaultParamsReadable and your class will automatically have write and read methods that will save your params and will be used by the PipelineModel serialization system.
The docs were not really clear, and I had to do a bit of source reading to understand this was the way that deserialization worked.
PipelineModel.read instantiates a PipelineModelReader
PipelineModelReader loads metadata and checks if language is 'Python'. If it's not, then the typical JavaMLReader is used (what most of these answers are designed for)
Otherwise, PipelineSharedReadWrite is used, which calls DefaultParamsReader.loadParamsInstance
loadParamsInstance will find class from the saved metadata. It will instantiate that class and call .load(path) on it. You can extend DefaultParamsReader and get the DefaultParamsReader.load method automatically. If you do have specialized deserialization logic you need to implement, I would look at that load method as a starting place.
On the opposite side:
PipelineModel.write will check if all stages are Java (implement JavaMLWritable). If so, the typical JavaMLWriter is used (what most of these answers are designed for)
Otherwise, PipelineWriter is used, which checks that all stages implement MLWritable and calls PipelineSharedReadWrite.saveImpl
PipelineSharedReadWrite.saveImpl will call .write().save(path) on each stage.
You can extend DefaultParamsWriter to get the DefaultParamsWritable.write method that saves metadata for your class and params in the right format. If you have custom serialization logic you need to implement, I would look at that and DefaultParamsWriter as a starting point.
Ok, so finally, you have a pretty simple transformer that extends Params and all your parameters are stored in the typical Params fashion:
from pyspark import keyword_only
from pyspark.ml import Transformer
from pyspark.ml.param.shared import HasOutputCols, Param, Params
from pyspark.ml.util import DefaultParamsReadable, DefaultParamsWritable
from pyspark.sql.functions import lit # for the dummy _transform
class SetValueTransformer(
Transformer, HasOutputCols, DefaultParamsReadable, DefaultParamsWritable,
):
value = Param(
Params._dummy(),
"value",
"value to fill",
)
@keyword_only
def __init__(self, outputCols=None, value=0.0):
super(SetValueTransformer, self).__init__()
self._setDefault(value=0.0)
kwargs = self._input_kwargs
self._set(**kwargs)
@keyword_only
def setParams(self, outputCols=None, value=0.0):
"""
setParams(self, outputCols=None, value=0.0)
Sets params for this SetValueTransformer.
"""
kwargs = self._input_kwargs
return self._set(**kwargs)
def setValue(self, value):
"""
Sets the value of :py:attr:`value`.
"""
return self._set(value=value)
def getValue(self):
"""
Gets the value of :py:attr:`value` or its default value.
"""
return self.getOrDefault(self.value)
def _transform(self, dataset):
for col in self.getOutputCols():
dataset = dataset.withColumn(col, lit(self.getValue()))
return dataset
Now we can use it:
from pyspark.ml import Pipeline
svt = SetValueTransformer(outputCols=["a", "b"], value=123.0)
p = Pipeline(stages=[svt])
df = sc.parallelize([(1, None), (2, 1.0), (3, 0.5)]).toDF(["key", "value"])
pm = p.fit(df)
pm.transform(df).show()
pm.write().overwrite().save('/tmp/example_pyspark_pipeline')
pm2 = PipelineModel.load('/tmp/example_pyspark_pipeline')
print('matches?', pm2.stages[0].extractParamMap() == pm.stages[0].extractParamMap())
pm2.transform(df).show()
Result:
+---+-----+-----+-----+
|key|value| a| b|
+---+-----+-----+-----+
| 1| null|123.0|123.0|
| 2| 1.0|123.0|123.0|
| 3| 0.5|123.0|123.0|
+---+-----+-----+-----+
matches? True
+---+-----+-----+-----+
|key|value| a| b|
+---+-----+-----+-----+
| 1| null|123.0|123.0|
| 2| 1.0|123.0|123.0|
| 3| 0.5|123.0|123.0|
+---+-----+-----+-----+
A:
I am not sure this is the best approach, but I too need the ability to save custom Estimators, Transformers and Models that I have created in Pyspark, and also to support their use in the Pipeline API with persistence. Custom Pyspark Estimators, Transformers and Models may be created and used in the Pipeline API but cannot be saved. This poses an issue in production when the model training takes longer than an event prediction cycle.
In general, Pyspark Estimators, Transformers and Models are just wrappers around the Java or Scala equivalents and the Pyspark wrappers just marshal the parameters to and from Java via py4j. Any persisting of the model is then done on the Java side. Because of this current structure, this limits Custom Pyspark Estimators, Transformers and Models to living only in the python world.
In a previous attempt, I was able to save a single Pyspark model by using Pickle/dill serialization. This worked well, but still did not allow saving or loading back such from within the Pipeline API. But, pointed to by another SO post I was directed to the OneVsRest classifier, and inspected the _to_java and _from_java methods. They do all the heavy lifting on the Pyspark side. After looking I thought, if one had a way to save the pickle dump to an already made and supported savable java object, then it should be possible to save a Custom Pyspark Estimator, Transformer and Model with the Pipeline API.
To that end, I found the StopWordsRemover to be the ideal object to hijack because it has an attribute, stopwords, that is a list of strings. The dill.dumps method returns a pickled representation of the object as a string. The plan was to turn the string into a list and then set the stopwords parameter of a StopWordsRemover to this list. Though a list strings, I found that some of the characters would not marshal to the java object. So the characters get converted to integers then the integers to strings. This all works great for saving a single instance, and also when saving within in a Pipeline, because the Pipeline dutifully calls the _to_java method of my python class (we are still on the Pyspark side so this works). But, coming back to Pyspark from java did not in the Pipeline API.
Because I am hiding my python object in a StopWordsRemover instance, the Pipeline, when coming back to Pyspark, does not know anything about my hidden class object, it knows only it has a StopWordsRemover instance. Ideally, it would be great to subclass Pipeline and PipelineModel, but alas this brings us back to trying to serialize a Python object. To combat this, I created a PysparkPipelineWrapper that takes a Pipeline or PipelineModel and just scans the stages, looking for a coded ID in the stopwords list (remember, this is just the pickled bytes of my python object) that tells it to unwraps the list to my instance and stores it back in the stage it came from. Below is code that shows how this all works.
For any Custom Pyspark Estimator, Transformer and Model, just inherit from Identifiable, PysparkReaderWriter, MLReadable, MLWritable. Then when loading a Pipeline and PipelineModel, pass such through PysparkPipelineWrapper.unwrap(pipeline).
This method does not address using the Pyspark code in Java or Scala, but at least we can save and load Custom Pyspark Estimators, Transformers and Models and work with Pipeline API.
import dill
from pyspark.ml import Transformer, Pipeline, PipelineModel
from pyspark.ml.param import Param, Params
from pyspark.ml.util import Identifiable, MLReadable, MLWritable, JavaMLReader, JavaMLWriter
from pyspark.ml.feature import StopWordsRemover
from pyspark.ml.wrapper import JavaParams
from pyspark.context import SparkContext
from pyspark.sql import Row
class PysparkObjId(object):
"""
A class to specify constants used to idenify and setup python
Estimators, Transformers and Models so they can be serialized on there
own and from within a Pipline or PipelineModel.
"""
def __init__(self):
super(PysparkObjId, self).__init__()
@staticmethod
def _getPyObjId():
return '4c1740b00d3c4ff6806a1402321572cb'
@staticmethod
def _getCarrierClass(javaName=False):
return 'org.apache.spark.ml.feature.StopWordsRemover' if javaName else StopWordsRemover
class PysparkPipelineWrapper(object):
"""
A class to facilitate converting the stages of a Pipeline or PipelineModel
that were saved from PysparkReaderWriter.
"""
def __init__(self):
super(PysparkPipelineWrapper, self).__init__()
@staticmethod
def unwrap(pipeline):
if not (isinstance(pipeline, Pipeline) or isinstance(pipeline, PipelineModel)):
raise TypeError("Cannot recognize a pipeline of type %s." % type(pipeline))
stages = pipeline.getStages() if isinstance(pipeline, Pipeline) else pipeline.stages
for i, stage in enumerate(stages):
if (isinstance(stage, Pipeline) or isinstance(stage, PipelineModel)):
stages[i] = PysparkPipelineWrapper.unwrap(stage)
if isinstance(stage, PysparkObjId._getCarrierClass()) and stage.getStopWords()[-1] == PysparkObjId._getPyObjId():
swords = stage.getStopWords()[:-1] # strip the id
lst = [chr(int(d)) for d in swords]
dmp = ''.join(lst)
py_obj = dill.loads(dmp)
stages[i] = py_obj
if isinstance(pipeline, Pipeline):
pipeline.setStages(stages)
else:
pipeline.stages = stages
return pipeline
class PysparkReaderWriter(object):
"""
A mixin class so custom pyspark Estimators, Transformers and Models may
support saving and loading directly or be saved within a Pipline or PipelineModel.
"""
def __init__(self):
super(PysparkReaderWriter, self).__init__()
def write(self):
"""Returns an MLWriter instance for this ML instance."""
return JavaMLWriter(self)
@classmethod
def read(cls):
"""Returns an MLReader instance for our clarrier class."""
return JavaMLReader(PysparkObjId._getCarrierClass())
@classmethod
def load(cls, path):
"""Reads an ML instance from the input path, a shortcut of `read().load(path)`."""
swr_java_obj = cls.read().load(path)
return cls._from_java(swr_java_obj)
@classmethod
def _from_java(cls, java_obj):
"""
Get the dumby the stopwords that are the characters of the dills dump plus our guid
and convert, via dill, back to our python instance.
"""
swords = java_obj.getStopWords()[:-1] # strip the id
lst = [chr(int(d)) for d in swords] # convert from string integer list to bytes
dmp = ''.join(lst)
py_obj = dill.loads(dmp)
return py_obj
def _to_java(self):
"""
Convert this instance to a dill dump, then to a list of strings with the unicode integer values of each character.
Use this list as a set of dumby stopwords and store in a StopWordsRemover instance
:return: Java object equivalent to this instance.
"""
dmp = dill.dumps(self)
pylist = [str(ord(d)) for d in dmp] # convert byes to string integer list
pylist.append(PysparkObjId._getPyObjId()) # add our id so PysparkPipelineWrapper can id us.
sc = SparkContext._active_spark_context
java_class = sc._gateway.jvm.java.lang.String
java_array = sc._gateway.new_array(java_class, len(pylist))
for i in xrange(len(pylist)):
java_array[i] = pylist[i]
_java_obj = JavaParams._new_java_obj(PysparkObjId._getCarrierClass(javaName=True), self.uid)
_java_obj.setStopWords(java_array)
return _java_obj
class HasFake(Params):
def __init__(self):
super(HasFake, self).__init__()
self.fake = Param(self, "fake", "fake param")
def getFake(self):
return self.getOrDefault(self.fake)
class MockTransformer(Transformer, HasFake, Identifiable):
def __init__(self):
super(MockTransformer, self).__init__()
self.dataset_count = 0
def _transform(self, dataset):
self.dataset_count = dataset.count()
return dataset
class MyTransformer(MockTransformer, Identifiable, PysparkReaderWriter, MLReadable, MLWritable):
def __init__(self):
super(MyTransformer, self).__init__()
def make_a_dataframe(sc):
df = sc.parallelize([Row(name='Alice', age=5, height=80), Row(name='Alice', age=5, height=80), Row(name='Alice', age=10, height=80)]).toDF()
return df
def test1():
trA = MyTransformer()
trA.dataset_count = 999
print trA.dataset_count
trA.save('test.trans')
trB = MyTransformer.load('test.trans')
print trB.dataset_count
def test2():
trA = MyTransformer()
pipeA = Pipeline(stages=[trA])
print type(pipeA)
pipeA.save('testA.pipe')
pipeAA = PysparkPipelineWrapper.unwrap(Pipeline.load('testA.pipe'))
stagesAA = pipeAA.getStages()
trAA = stagesAA[0]
print trAA.dataset_count
def test3():
dfA = make_a_dataframe(sc)
trA = MyTransformer()
pipeA = Pipeline(stages=[trA]).fit(dfA)
print type(pipeA)
pipeA.save('testB.pipe')
pipeAA = PysparkPipelineWrapper.unwrap(PipelineModel.load('testB.pipe'))
stagesAA = pipeAA.stages
trAA = stagesAA[0]
print trAA.dataset_count
dfB = pipeAA.transform(dfA)
dfB.show()
A:
I couldn't get @dmbaker's ingenious solution to work using Python 2 on Spark 2.2.0; I kept getting pickling errors. After several blind alleys I got a working solution by modifying his (her?) idea to write and read the parameter values as strings into StopWordsRemover's stop words directly.
Here's the base class you need if you want to save and load your own estimators or transformers:
from pyspark import SparkContext
from pyspark.ml.feature import StopWordsRemover
from pyspark.ml.util import Identifiable, MLWritable, JavaMLWriter, MLReadable, JavaMLReader
from pyspark.ml.wrapper import JavaWrapper, JavaParams
class PysparkReaderWriter(Identifiable, MLReadable, MLWritable):
"""
A base class for custom pyspark Estimators and Models to support saving and loading directly
or within a Pipeline or PipelineModel.
"""
def __init__(self):
super(PysparkReaderWriter, self).__init__()
@staticmethod
def _getPyObjIdPrefix():
return "_ThisIsReallyA_"
@classmethod
def _getPyObjId(cls):
return PysparkReaderWriter._getPyObjIdPrefix() + cls.__name__
def getParamsAsListOfStrings(self):
raise NotImplementedError("PysparkReaderWriter.getParamsAsListOfStrings() not implemented for instance: %r" % self)
def write(self):
"""Returns an MLWriter instance for this ML instance."""
return JavaMLWriter(self)
def _to_java(self):
# Convert all our parameters to strings:
paramValuesAsStrings = self.getParamsAsListOfStrings()
# Append our own type-specific id so PysparkPipelineLoader can detect this algorithm when unwrapping us.
paramValuesAsStrings.append(self._getPyObjId())
# Convert the parameter values to a Java array:
sc = SparkContext._active_spark_context
java_array = JavaWrapper._new_java_array(paramValuesAsStrings, sc._gateway.jvm.java.lang.String)
# Create a Java (Scala) StopWordsRemover and give it the parameters as its stop words.
_java_obj = JavaParams._new_java_obj("org.apache.spark.ml.feature.StopWordsRemover", self.uid)
_java_obj.setStopWords(java_array)
return _java_obj
@classmethod
def _from_java(cls, java_obj):
# Get the stop words, ignoring the id at the end:
stopWords = java_obj.getStopWords()[:-1]
return cls.createAndInitialisePyObj(stopWords)
@classmethod
def createAndInitialisePyObj(cls, paramsAsListOfStrings):
raise NotImplementedError("PysparkReaderWriter.createAndInitialisePyObj() not implemented for type: %r" % cls)
@classmethod
def read(cls):
"""Returns an MLReader instance for our clarrier class."""
return JavaMLReader(StopWordsRemover)
@classmethod
def load(cls, path):
"""Reads an ML instance from the input path, a shortcut of `read().load(path)`."""
swr_java_obj = cls.read().load(path)
return cls._from_java(swr_java_obj)
Your own pyspark algorithm must then inherit from PysparkReaderWriter and override the getParamsAsListOfStrings() method which saves your parameters to a list of strings. Your algorithm must also override the createAndInitialisePyObj() method for converting a list of strings back into your parameters. Behind the scenes the parameters are converted to and from the stop words used by StopWordsRemover.
Example estimator with 3 parameters of different type:
from pyspark.ml.param.shared import Param, Params, TypeConverters
from pyspark.ml.base import Estimator
class MyEstimator(Estimator, PysparkReaderWriter):
def __init__(self):
super(MyEstimator, self).__init__()
# 3 sample parameters, deliberately of different types:
stringParam = Param(Params._dummy(), "stringParam", "A dummy string parameter", typeConverter=TypeConverters.toString)
def setStringParam(self, value):
return self._set(stringParam=value)
def getStringParam(self):
return self.getOrDefault(self.stringParam)
listOfStringsParam = Param(Params._dummy(), "listOfStringsParam", "A dummy list of strings.", typeConverter=TypeConverters.toListString)
def setListOfStringsParam(self, value):
return self._set(listOfStringsParam=value)
def getListOfStringsParam(self):
return self.getOrDefault(self.listOfStringsParam)
intParam = Param(Params._dummy(), "intParam", "A dummy int parameter.", typeConverter=TypeConverters.toInt)
def setIntParam(self, value):
return self._set(intParam=value)
def getIntParam(self):
return self.getOrDefault(self.intParam)
def _fit(self, dataset):
model = MyModel()
# Just some changes to verify we can modify the model (and also it's something we can expect to see when restoring it later):
model.setAnotherStringParam(self.getStringParam() + " World!")
model.setAnotherListOfStringsParam(self.getListOfStringsParam() + ["E", "F"])
model.setAnotherIntParam(self.getIntParam() + 10)
return model
def getParamsAsListOfStrings(self):
paramValuesAsStrings = []
paramValuesAsStrings.append(self.getStringParam()) # Parameter is already a string
paramValuesAsStrings.append(','.join(self.getListOfStringsParam())) # ...convert from a list of strings
paramValuesAsStrings.append(str(self.getIntParam())) # ...convert from an int
return paramValuesAsStrings
@classmethod
def createAndInitialisePyObj(cls, paramsAsListOfStrings):
# Convert back into our parameters. Make sure you do this in the same order you saved them!
py_obj = cls()
py_obj.setStringParam(paramsAsListOfStrings[0])
py_obj.setListOfStringsParam(paramsAsListOfStrings[1].split(","))
py_obj.setIntParam(int(paramsAsListOfStrings[2]))
return py_obj
Example Model (also a Transformer) which has 3 different parameters:
from pyspark.ml.base import Model
class MyModel(Model, PysparkReaderWriter):
def __init__(self):
super(MyModel, self).__init__()
# 3 sample parameters, deliberately of different types:
anotherStringParam = Param(Params._dummy(), "anotherStringParam", "A dummy string parameter", typeConverter=TypeConverters.toString)
def setAnotherStringParam(self, value):
return self._set(anotherStringParam=value)
def getAnotherStringParam(self):
return self.getOrDefault(self.anotherStringParam)
anotherListOfStringsParam = Param(Params._dummy(), "anotherListOfStringsParam", "A dummy list of strings.", typeConverter=TypeConverters.toListString)
def setAnotherListOfStringsParam(self, value):
return self._set(anotherListOfStringsParam=value)
def getAnotherListOfStringsParam(self):
return self.getOrDefault(self.anotherListOfStringsParam)
anotherIntParam = Param(Params._dummy(), "anotherIntParam", "A dummy int parameter.", typeConverter=TypeConverters.toInt)
def setAnotherIntParam(self, value):
return self._set(anotherIntParam=value)
def getAnotherIntParam(self):
return self.getOrDefault(self.anotherIntParam)
def _transform(self, dataset):
# Dummy transform code:
return dataset.withColumn('age2', dataset.age + self.getAnotherIntParam())
def getParamsAsListOfStrings(self):
paramValuesAsStrings = []
paramValuesAsStrings.append(self.getAnotherStringParam()) # Parameter is already a string
paramValuesAsStrings.append(','.join(self.getAnotherListOfStringsParam())) # ...convert from a list of strings
paramValuesAsStrings.append(str(self.getAnotherIntParam())) # ...convert from an int
return paramValuesAsStrings
@classmethod
def createAndInitialisePyObj(cls, paramsAsListOfStrings):
# Convert back into our parameters. Make sure you do this in the same order you saved them!
py_obj = cls()
py_obj.setAnotherStringParam(paramsAsListOfStrings[0])
py_obj.setAnotherListOfStringsParam(paramsAsListOfStrings[1].split(","))
py_obj.setAnotherIntParam(int(paramsAsListOfStrings[2]))
return py_obj
Below is a sample test case showing how you can save and load your model. It's similar for the estimator so I omit that for brevity.
def createAModel():
m = MyModel()
m.setAnotherStringParam("Boo!")
m.setAnotherListOfStringsParam(["P", "Q", "R"])
m.setAnotherIntParam(77)
return m
def testSaveLoadModel():
modA = createAModel()
print(modA.explainParams())
savePath = "/whatever/path/you/want"
#modA.save(savePath) # Can't overwrite, so...
modA.write().overwrite().save(savePath)
modB = MyModel.load(savePath)
print(modB.explainParams())
testSaveLoadModel()
Output:
anotherIntParam: A dummy int parameter. (current: 77)
anotherListOfStringsParam: A dummy list of strings. (current: ['P', 'Q', 'R'])
anotherStringParam: A dummy string parameter (current: Boo!)
anotherIntParam: A dummy int parameter. (current: 77)
anotherListOfStringsParam: A dummy list of strings. (current: [u'P', u'Q', u'R'])
anotherStringParam: A dummy string parameter (current: Boo!)
Notice how the parameters have come back in as unicode strings. This may or may not make a difference to your underlying algorithm that you implement in _transform() (or _fit() for the estimator). So be aware of this.
Finally, because the Scala algorithm behind the scenes is really a StopWordsRemover, you need to unwrap it back into your own class when loading the Pipeline or PipelineModel from disk. Here's the utility class that does this unwrapping:
from pyspark.ml import Pipeline, PipelineModel
from pyspark.ml.feature import StopWordsRemover
class PysparkPipelineLoader(object):
"""
A class to facilitate converting the stages of a Pipeline or PipelineModel
that were saved from PysparkReaderWriter.
"""
def __init__(self):
super(PysparkPipelineLoader, self).__init__()
@staticmethod
def unwrap(thingToUnwrap, customClassList):
if not (isinstance(thingToUnwrap, Pipeline) or isinstance(thingToUnwrap, PipelineModel)):
raise TypeError("Cannot recognize an object of type %s." % type(thingToUnwrap))
stages = thingToUnwrap.getStages() if isinstance(thingToUnwrap, Pipeline) else thingToUnwrap.stages
for i, stage in enumerate(stages):
if (isinstance(stage, Pipeline) or isinstance(stage, PipelineModel)):
stages[i] = PysparkPipelineLoader.unwrap(stage)
if isinstance(stage, StopWordsRemover) and stage.getStopWords()[-1].startswith(PysparkReaderWriter._getPyObjIdPrefix()):
lastWord = stage.getStopWords()[-1]
className = lastWord[len(PysparkReaderWriter._getPyObjIdPrefix()):]
stopWords = stage.getStopWords()[:-1] # Strip the id
# Create and initialise the appropriate class:
py_obj = None
for clazz in customClassList:
if clazz.__name__ == className:
py_obj = clazz.createAndInitialisePyObj(stopWords)
if py_obj is None:
raise TypeError("I don't know how to create an instance of type: %s" % className)
stages[i] = py_obj
if isinstance(thingToUnwrap, Pipeline):
thingToUnwrap.setStages(stages)
else:
# PipelineModel
thingToUnwrap.stages = stages
return thingToUnwrap
Test for saving and loading a pipeline:
def testSaveAndLoadUnfittedPipeline():
estA = createAnEstimator()
#print(estA.explainParams())
pipelineA = Pipeline(stages=[estA])
savePath = "/whatever/path/you/want"
#pipelineA.save(savePath) # Can't overwrite, so...
pipelineA.write().overwrite().save(savePath)
pipelineReloaded = PysparkPipelineLoader.unwrap(Pipeline.load(savePath), [MyEstimator])
estB = pipelineReloaded.getStages()[0]
print(estB.explainParams())
testSaveAndLoadUnfittedPipeline()
Output:
intParam: A dummy int parameter. (current: 42)
listOfStringsParam: A dummy list of strings. (current: [u'A', u'B', u'C', u'D'])
stringParam: A dummy string parameter (current: Hello)
Test for saving and loading a pipeline model:
from pyspark.sql import Row
def make_a_dataframe(sc):
df = sc.parallelize([Row(name='Alice', age=5, height=80), Row(name='Bob', age=7, height=85), Row(name='Chris', age=10, height=90)]).toDF()
return df
def testSaveAndLoadPipelineModel():
dfA = make_a_dataframe(sc)
estA = createAnEstimator()
#print(estA.explainParams())
pipelineModelA = Pipeline(stages=[estA]).fit(dfA)
savePath = "/whatever/path/you/want"
#pipelineModelA.save(savePath) # Can't overwrite, so...
pipelineModelA.write().overwrite().save(savePath)
pipelineModelReloaded = PysparkPipelineLoader.unwrap(PipelineModel.load(savePath), [MyModel])
modB = pipelineModelReloaded.stages[0]
print(modB.explainParams())
dfB = pipelineModelReloaded.transform(dfA)
dfB.show()
testSaveAndLoadPipelineModel()
Output:
anotherIntParam: A dummy int parameter. (current: 52)
anotherListOfStringsParam: A dummy list of strings. (current: [u'A', u'B', u'C', u'D', u'E', u'F'])
anotherStringParam: A dummy string parameter (current: Hello World!)
+---+------+-----+----+
|age|height| name|age2|
+---+------+-----+----+
| 5| 80|Alice| 57|
| 7| 85| Bob| 59|
| 10| 90|Chris| 62|
+---+------+-----+----+
When unwrapping a pipeline or pipeline model you have to pass in a list of the classes that correspond to your own pyspark algorithms that are masquerading as StopWordsRemover objects in the saved pipeline or pipeline model. The last stop word in your saved object is used to identify your own class's name and then createAndInitialisePyObj() is called to create an instance of your class and initialise its parameters with the remaining stop words.
Various refinements could be made. But hopefully this will enable you to save and load custom estimators and transformers, both inside and outside pipelines, until SPARK-17025 is resolved and available to you.
|
Marie Diron, Moody’s associate managing director, Sovereign Risk Group, commenting Wednesday on Moody’s Chinese downgrade (Bloomberg Television): “It is likely to be a very medium-term and gradual erosion of credit metrics and we are looking at the policies that the government is implementing. The authorities have recognized the risks that come with high leverage and have a very broad agenda of structural reforms and we take that into account to the point that we think leverage will increase more slowly than it has in the past. But still these measures will not be enough to really reverse the increase in leverage.”
I’ve always felt the rating agencies got somewhat of a bum rap after the mortgage finance Bubble collapse. Sure, their ratings methodologies were flawed. In hindsight, Trillions of so-called “AAA” MBS were anything but pristine Credits. And, again looking back, it does appear a case of incompetence - if not worse. Yet reality at the time was one of home prices that had been inflating for years with a corresponding long spell of low delinquencies and minimal loan losses, along with GDP and incomes seemingly on a steady upward trajectory. The GSEs had come to dominate mortgage finance, while the Fed had market yields well under control. Washington surely wouldn’t allow a housing crisis, which ensured that markets were absolutely enamored with anything mortgage related. So the mortgage market enjoyed bountiful liquidity conditions, and it was just difficult for anyone – including the ratings firms – to see what might upset the apple cart.
The ratings agencies were basically oblivious to the key issue of deepening structural maladjustment throughout the mortgage finance Bubble period. They were inattentive to what a major de-leveraging episode could unleash. But so were the Federal Reserve, Wall Street and the world. Analysis and models did not incorporate latent (financial and economic) fragilities that had compounded from years of rapid credit growth and asset inflation. These days there’s a similar inability to comprehend the myriad global risks associated with the runaway Chinese Bubble.
The Moody’s downgrade spurred a bevy of articles this week examining China’s debt issues (i.e. “Total outstanding credit climbed to about 260% of GDP by the end of 2016, up from 160% in 2008”; “$9 trillion local bond market”; “debt has been increasing lately by an amount equal to about 15% of the country’s output each year”). Interestingly, I saw no mention that Chinese debt growth this year will likely approach $3.5 TN. Not only will this exceed U.S. 2017 debt growth, it will significantly surpass even peak annual U.S. debt expansion from the mortgage finance Bubble period.
May 23 – New York Times (Keith Bradsher): “China has gone on a spending spree, borrowing money to build cities, create manufacturing giants and nurture financial markets — money that has helped drive the economic powerhouse in recent years. But the debt-fueled binge now threatens to sap the energy of the world’s second-largest economy. With its economy maturing, China has to pile on ever more debt to keep its growth going, at a pace that could prove unsustainable. And the money is increasingly flowing through opaque channels that operate outside the regulated banking system, leaving China vulnerable to blowups. A major credit agency sounded the alarm on Wednesday, saying the steady buildup of debt would erode China’s financial strength in the years ahead… China’s debt has been increasing lately by an amount equal to about 15% of the country’s output each year, to keep the economy growing from 6.5% to 7%.”
The world has never witnessed such a Credit expansion. Moody’s noted the Chinese economy’s ongoing dependency on stimulus measures. I would argue that the key issue has evolved into China’s systemic addiction to ever-increasing expansions of “money” and Credit. The almost singular focus on debt to GDP ratios understates Chinese fragilities. They succumbed to the debt trap: massive ongoing expansion of Credit - or bust. How sound is this Credit? How stable is the Chinese financial sector? And, perhaps most pressing, how vulnerable is their currency?
May 24 – New York Times (Keith Bradsher): “Moody’s… downgraded its rating of China’s sovereign debt one notch on Wednesday, citing concerns over growing debt in the country, which has the world’s second-largest economy. In recent years, as China’s stunning economic performance of past decades has become difficult to sustain, the country has used debt to fuel growth… When it comes to pumping money into a financial system, China has made the Federal Reserve in the United States and the European Central Bank look almost lackadaisical. It has expanded its broadly measured money supply by more than the rest of the world combined since the global financial crisis. Now it has 70% more money sloshing around its economy than the United States does, even though the American economy is bigger… China has accumulated its towering debt remarkably quickly. Goldman Sachs looked last year at how fast debt had accumulated relative to the size of the economy in 55 countries since 1960. It found that by the end of 2015, China was already in the top 2% of all credit expansions — and its debt shot up even higher last year. All of the other large expansions occurred in very small economies, some of which essentially lost control of their finances.”
Moody’s report focused on the risk of further leveraging. This is clearly an issue. Corporate debt is at very high levels ($18 TN, or 170% of GDP) and corporations (many with earnings and cash-flow issues) continue to pile on additional borrowings. Much of this debt is “non-productive,” as companies borrow to meet rising debt service and to plug expanding cash-flow deficits. Even more alarming, the bloated financial sector continues to balloon, issuing risky loans while creating new deposit “money”. From the NYT (Keith Bradsher) article above, China “has 70% more money sloshing around its economy than the United States.” Even more than “leverage,” China’s Wild West Risk-Intermediation Mayhem has created momentous systemic risk. Much of the risky “Terminal Phase” debt growth – financing inflated apartment values, uneconomic enterprises, economic maladjustment and chicanery – is being transformed into perceived safe and liquid “money” and money-like financial instruments.
The bulls were quick to downplay the importance of Moody’s action, stating both that China has minimal dependence on external financing and that the country still enjoys $3.0 TN of international reserve assets. I would view the issue differently. Yes, China has an extraordinarily large international reserve cushion, though holdings have declined $1.0 TN from June 2014. Most importantly, this large hoard has allowed authorities to prolong the Bubble and delay the type of harsh measures required to rein in Credit, speculation and now deeply imbedded boom-time psychology. Chinese savers are accumulating wealth they never dreamed of, backed by an economy with serious deficiencies and a financial sector of dubious standing.
Chinese authorities have backed away from needed reforms. The late-2015/early-2016 scare forced Beijing to effectively impose capital controls. Rather than promoting open and effective market-based mechanisms, the game has turned to only more zealous interventions: stabilize financial markets and promote rapid Credit growth necessary to sustain 6-7% GDP expansion, while cajoling and controlling to limit the capacity of all this Chinese “money” to flow out of the country.
Chinese authorities have also been pressing Chinese corporations and financial institutions to borrow in overseas markets. This kills two birds... China can offload some high-risk, late-cycle Credit to international investors, while also attracting needed financial inflows. The problem is that foreign investors fear capital control measures and don’t trust the renminbi. So much of this borrowing is done in dollar-denominated debt. And the large issuance of dollar-denominated debt only exacerbates systemic vulnerability to an abrupt renminbi devaluation.
May 24 – Reuters (Adam Jourdan and Samuel Shen): “The decision by Moody's… to downgrade China's credit rating is ‘illogical’ and overstates the levels of government debt, a commerce ministry researcher said in an editorial in the official People's Daily newspaper… Mei Xinyu, a researcher at China's Ministry of Commerce, wrote in a front page editorial of the paper's overseas edition the downgrade… overstated China's reliance on stimulus and the country's debt levels. Moody's downgraded China's credit ratings… for the first time in nearly 30 years, saying it expects the financial strength of the economy will erode in coming years as growth slows and debt continues to rise. China's Finance Ministry said… the downgrade overestimated the risks to the economy and was based on ‘inappropriate methodology’. China's state planner said debt risks were generally controllable.”
I’ve closely monitored China for years now. I recall reading some years back how Chinese officials had studied and learned from the Japanese Bubble experience. I’ve been waiting patiently for China to wrestle control of a precarious Credit Bubble. They have instead repeatedly taken tepid steps to curb various sectoral excesses – real estate, local government debt, stock market, corporate debt and, of late, shadow banking and insurance. Attempts to tamp down excess in one spot have only ensured it pops out elsewhere. The gravest policy misstep has been their failure to take a more systemic approach to Credit growth and asset inflation.
Basically, whenever tightening policies began to bite, Beijing would in short-order reverse course and stimulate. After a while, Chinese tightening measures lacked credibility. Moreover, the greater the inflation of Credit, financial institutions and perceived wealth, the more confident the Chinese population (including investors in real estate and financial assets, bankers, and corporate CEOs) became that Beijing would never tolerate a bust. Beijing these days essentially backs local government debt, the big state banks, corporate debt and apartment prices, not to mention $22 TN of “money” (“M2) and trillions more of money-like “wealth management products” and such. The scope of Beijing’s contingent liabilities is unparalleled.
The Moody’s executive stated that “It is likely to be a very medium-term and gradual erosion of credit metrics.” The Credit “metric” that matters most is my hypothetical chart of systemic risk that turned parabolic with the rapid acceleration of Credit of rapidly deteriorating quality. This “Terminal Phase” Dynamic unfolds during a period of momentous structural maladjustment, with government policies invariably exacerbating already deep structural impairment. It’s worth recalling that the Japanese enjoyed incredible economic growth and restructuring for more than three decades before blowing up their Credit system during the final four years of the boom. The Chinese situation is much more precarious.
I found myself this week thinking back to Dallas Fed President Robert McTeer’s 2001 comment, “Let's all hold hands and buy an SUV.” It was at the time a rather ridiculous central banker prescription for recovery from recession. Things, however, turned only more outrageous the following year, with the arrival of the Bernanke Doctrine at the Federal Reserve (and central banking more generally). Since then policy floodgates have been thrown wide open. What passes these days for reasonable policy would have been unimaginable fifteen years ago.
Chinese authorities apparently believe they can grow out of debt and structural issues. No matter what, they can always stimulate. And no need to dig holes and then refill them. Just tear down old apartments and structures and fabricate glossy tall new ones. Throw “money” at any problem, always plenty freely available. And there’s always endless new enterprises and technologies to support. Lend money around the world so buyers can afford to buy Chinese products. The quantity of debt doesn’t really matter all that much; just keep growing.
May 21 – Bloomberg (Alfred Liu, Moxy Ying, and Enda Curran): “In 1997, the Asian financial crisis touched off a six-year property bust in Hong Kong that shaved more than two-thirds off prices and saddled the city with a stagnant economy and deflation. As Hong Kong gets ready to celebrate the 20th anniversary of its handover to China, which happened just as Asia’s crisis began to unfold, that pain seems all but forgotten. Prices are at all-time highs. Mortgage borrowing is booming. Developers are bidding up the cost of land to records. People young and old are lining up to buy newly built apartments. In short, the kind of fervor that preceded the last bust is back. That’s got experts fretting about the potential fallout should the city of about 7.4 million people experience another crash. By several measures, Hong Kong looks more vulnerable this time around.”
The global government finance Bubble has “gone to unimaginable extremes - and then doubled.” And there are various elements of previous Bubbles that have coalesced into something that somehow masks inherent fragilities and the risk of devastating collapse. I think back to the commercial real estate Bubbles, junk bonds and LBOs from the late-eighties. Bond market leverage (“government carry trade”) and derivatives (mortgage IOs and POs) from the early-nineties. There was Mexico, SE Asia and EM from the mid-nineties. Russia and LTCM fiascos later in the decade. The “tech” and corporate debt Bubbles, followed by the great mortgage finance Bubble. Individually, we’ve seen these kinds of things before and we know they end badly. But as one gigantic, comprehensive, almost all-inclusive Bubble garnering the attention and support from policymakers around the world, it’s different enough this time that risks are dismissed or downplayed. Greed trumps fear.
I look around the world and see an unprecedented Bubble in Chinese Credit and investment. EM more generally has borrowed enormous amounts of debt, much of it in dollars and foreign currencies. European securities markets have inflated into historic Bubbles. Bond markets around the global are mispriced like never before. Almost everything providing a yield – from commercial real estate to corporate debt to dividend stocks – trades today at inflated values. Especially considering the Trillions that have been issued – and Trillions more in the offing – Treasury prices are detached from market pricing mechanisms.
The Trillions of central bank “money” that has spurred a historic Bubble in “risk free” securities has worked similar magic on risk assets, notably corporate Credit, equities and EM debt. The reckless abandon that took derivatives markets by storm during the mortgage finance Bubble period has gone to even greater extremes, this time on a global basis.
Everywhere, it seems market perceptions are more detached than ever from reality. I continue to see confirmation that China is a major global Bubble weak link.
May 26 – Bloomberg (Chris Anstey and Enda Curran): “Chalk up another win for the visible hand in China’s markets over the principle of the private sector determining prices. A move by authorities to smooth out daily changes in the yuan’s fixing versus the dollar, taken on its own, suggests a shift away from any eventual float of the currency. The news comes in a week when officials were suspected of having intervened in the stock market to limit damage to sentiment after Moody’s… downgraded China’s sovereign credit rating. Both developments underscore the importance the Communist Party leadership places on specific outcomes, rather than the embrace of free markets that Western nations once pressed on China. President Xi Jinping has every interest in avoiding turmoil in the currency and equity markets this year as he oversees a critical reshuffle of top officials. While relatively minor, the change ‘is surely a negative step for financial openness,’ said George Magnus, an associate at Oxford University’s China Centre and former adviser at UBS Group AG. It’s ‘another step by Xi Jinping and the leadership to exert control where the deference to market forces was making at least limited headway.’”
May 25 – Wall Street Journal (Lingling Wei and Saumya Vaishampayan): “China’s central bank is effectively anchoring the yuan to the dollar, a policy twist that has helped stabilize the currency in a year of political transition and market jitters about China’s economic management. The yuan weakened more than 6% against the dollar in 2016; this year, it is up roughly 1%, and the expectation that the currency will fluctuate—a gauge known as implied volatility—is around its lowest in nearly two years.”
After a brief bout of selling in Chinese and Asian equities, there was little market reaction to the Moody’s downgrade. Perhaps telling, Chinese authorities revalued the renminbi higher both Thursday and Friday, with the Chinese currency gaining a notable 0.43% for the week.
With my belief that China’s currency may prove their system’s weak link, I find it intriguing that officials would be compelled to move immediately to manipulate its value higher. I believe Beijing prefers a weaker currency to support its massive export sector and to stoke moderately higher inflation. And while their currency policy may be somewhat posturing to the new U.S. administration, I suspect they are more fearful of an unwind of foreign-financed leveraged “carry trades” that have accumulated in higher-yielding Chinese Credit. In the past I’ve referred to the Chinese renminbi as a “currency peg on steroids.” There’s never been an EM currency with the potential for such massive outflows from domestic savers and international speculators alike.
May 26 – Bloomberg: “For ever yuan that the People’s Bank of China injects into the nation’s financial system, it’s up to the banks to decide how far they stretch it in the form of loans to the economy. Right now, they’re working overtime. China’s money multiplier -- the ratio between the broadest measure of money in use, M2, and base money created by the central bank -- has climbed to the highest on records that date to 1997, data compiled by Bloomberg show. Each yuan of base money is being turned into more than 5 in the real economy. The turbocharged multiplier is helping compensate for the drainage of cash caused by Chinese savers and companies venturing abroad. It’s also helping economic growth…”
For all the sound and fury, the president is governing like a traditional Republican
by: Martin Wolf
The first 100 days of Donald Trump’s presidency have brought some good news and some bad news. The good news is that, albeit chaotically, he is governing more as an orthodox post-Reagan Republican than most expected. The bad news is that he is governing more as an orthodox Republican than most expected. This now seems true in all the main policy areas, both domestic and international. It is clearly true in economic policy. The idea of rebuilding US infrastructure has faded. The trade protectionism looks halfhearted. But deregulation is still an objective. So is tax reform, with the familiar combination of unfunded giveaways and magical thinking on deficits. Mr Trump’s policies look ever more like Reagan’s, but from a more unfavourable starting point.In announcing the tax plan, the White House did in an essential respect reinforce experience with this administration. It is hard to think of another government that would announce radical reforms of the tax system in a one-page document as sketchy as this one. It would be laughable if it were not so damaging to the US reputation for competent policymaking. The plan must be dead on arrival in Congress, in large part because it is not alive in the first place.
The single page released by the White House last week does, however, contain very similar ideas to those announced by candidate Trump. This makes it possible for us to go back to the analysis published by the Tax Policy Center in October. While we have little reason to expect a plan just like this to be enacted, that earlier analysis does help us understand how far the administration’s starting point remains from common sense on fiscal policy.Start with the effects on the fiscal deficit. According to the TPC, the plan would raise the federal deficit (even after allowing for beneficial macroeconomic effects) by a little under 3 per cent of gross domestic product for as long as it remains in place. But, according to the International Monetary Fund, the US is already running a general government structural deficit of 4 per cent of GDP, forecast to rise to just under 6 per cent of GDP in the early 2020s.
With the addition of the proposed tax cuts, a structural general government deficit of well over 8 per cent of GDP might emerge in the 2020s. This would cause an explosive rise in debt. That could not be allowed to happen, particularly since US general government net debt is now more than 80 per cent of GDP, up from 45 per cent before the crisis and far lower when Reagan came to office. The structural deficit needs to be reduced, not increased. Yet this fiscal boost is not intended to be temporary and would also occur when unemployment is at 4.5 per cent of the labour force. It would be of the wrong kind, at the wrong time. Defenders suggest, in response, that the plan might pay for itself, via increased activity. Given the low unemployment rate, this seems quite unlikely. Yet US Treasury secretary Steven Mnuchin has even suggested that, in combination with other administration policies, tax cuts could raise US trend growth to 3 per cent, from the current trend of slightly below 2 per cent.
Such a rise in growth would help. But it is very unlikely, for reasons explained by Jason Furman, former chairman of the Council of Economic Advisers. For it to happen, he argues, it would be far from sufficient for the decline in labour force participation to reverse. There would also be a need for a rise in the growth of output per hour from the 1.2 per cent achieved in the last decade to 2.8 per cent. That rate of productivity growth has been extremely rare in the past, over any extended time period. It would be mad for policymakers simply to assume this will happen (See charts.)The question then is whether these huge tax cuts could be offset elsewhere. The border tax adjustment to corporation tax now seems to be a dead idea. So the only solution would be huge cuts in spending. To reduce spending by, say, 2.5 per cent of GDP would mean a cut in federal spending of about 12 per cent. But nearly 90 per cent of that spending goes on defence, health, income security, veterans’ benefits, social security and interest. On the assumption that these items will be protected, every other item of federal spending would have to be eliminated. The federal government would, in many areas, vanish.The tax proposals also look astoundingly regressive. According to the TPC’s analysis, the top 0.1 of the income distribution might receive an average tax cut approaching 14.2 per cent of after-tax income, while middle-income households would receive an average tax cut of 1.8 per cent. Among the startlingly regressive changes would be repeal of the alternative minimum tax, repeal of estate taxes and huge reductions in corporate tax rates, including on so-called pass-through businesses. To those that have it shall be given. That is the doctrine of Mr Trump. It is also the old Republican trickle-down doctrine in purest form.Mr Trump won the nomination by promising to be a different sort of Republican. He is not. What he has achieved is to make the “bait and switch” yet more obvious. Post-Reagan Republicans reached out to the base by campaigning on cultural issues, while legislating for the upper 1 per cent. That is “pluto-populism”. Mr Trump added infrastructure spending, trade protectionism and support for Medicare and social security. But he too plans to deliver for the top 1 per cent. Pluto-populism is highly politically effective. But it works by making the base ever angrier and more desperate. That is playing with political fire. The republic may survive Mr Trump. But what comes after?
Donald Trump has made good on one of his most audacious campaign promises by submitting what he describes as the biggest tax cut in U.S. History. For once, at least, this does not appear to be Trumpian braggadocio. It really may be the mother of all tax cuts. But if passed, what may this bunker buster do to the economy? While I have rarely met a tax cut I didn’t like, this one just may be more likely to send the economy into a downward spiral than it is to send up to orbit.As I mentioned in my January commentary, Donald Trump’s big-spending, tax-cutting campaign rhetoric threatened to make him the biggest borrower in presidential history. He comes to office at a particularly vulnerable time for budget dynamics. After contracting by nearly two thirds from 2010 to 2015 (from the mind-bending $1.3 trillion to the merely enormous $438 billion), the Federal deficit started expanding again in 2016, moving up to $587 billion (Govt. Publishing Office, Office of Management & Budget (OMB). Current projections have it going up nearly every year over the next two decades. The Congressional Budget Office expects it to permanently surpass $1 trillion annually by 2021 or 2022. But these ominous forecasts were made well before anyone thought Trump had a snowball’s chance of ever becoming president. Now that he is in the office, those projections will be the floor. The ceiling is anyone’s guess.The forecasts assume that the taxing and spending laws in place during the Obama Administration won’t change. The steep increase in projected deficits towards the end of this decade and into the next is largely driven by the retirement of the Baby Boom generation, which will lead to simultaneous increases in entitlement spending and decreases in tax revenue. This brick wall has been hiding in plain sight for decades but the can-kickers in Washington have serially failed to do anything to avert the inevitable collision. (These forecasts also optimistically assume that the economy never again enters recession, inflation never again rears its ugly head, and that our creditors never get concerned enough about our growing debt to demand a premium for the risk of financing it.)But now that Trump occupies the Oval office, this date with destiny may come much sooner…and she will definitely be ordering the lobster.Before I go negative, let me give credit to Trump for picking the right taxes to cut. He kills the estate tax, an ugly beast that should have been euthanized years ago. Some may see this simply as a gift to the very rich. But legal wizards have long since devised strategies that offer almost complete protection from the death tax. None of these structures offer any real benefit to the businesses these millionaires typically own, or to the economy in general. Killing the tax will cost the government almost nothing, but it will remove tremendous impediments that have prevented family-run companies from growing over generations. He also kills the Alternative Minimum Tax, a complex parallel system of taxation that few understand but somehow manages to ensnare more and more taxpayers every year.Most importantly, he brings down the corporate tax rate from the globally non-competitive rate of 35% to the much more manageable 15%. Taxing corporations has always been a bad way to raise revenue. Corporations, after all, don’t pay taxes, which are simply treated as a cost of doing business. The real costs are borne by customers, who must pay higher prices, and employees, who must suffer with lower wages. But high domestic corporate taxes have hamstrung U.S. corporations and greatly contributed to the decline of American manufacturing. A more competitive corporate sector will shower benefits on all manner of consumers and employees.On the individual tax side, his decisions are much more problematic. Although Trump makes the sensible decision of compressing the seven individual tax brackets into just three (10%, 25%, and 35%), and doubles the standard personal deductions (thereby saving many people from the hassles of itemization), the headline-grabbing component of the proposals has to do with the lowering of the “pass-through” tax rate to the same 15% level that applies to corporations. This means that wealthy business owners, highly paid freelancers, and partners at law firms, medical groups, and management consultancies, will qualify for the 15% rate. This will be a huge windfall to some of the richest people in the country, who typically pay the highest marginal tax rate (currently 39%). And since the top one percent account for nearly 50% of tax revenue, this one provision promises to cost Uncle Sam plenty and to dramatically shake up the corporate landscape.Small business owners and independent contractors will in fact receive the benefit of the 15% pass through rate. But “Mom and Pop” entrepreneurs rarely have income that is high enough to be taxed at the higher rates. These smaller earners will likely be be trading a 15% tax for a 15% tax. All the big benefits will go to the really big fish. Whereas the vast majority of Tom Cruise’s income would have been taxed at the 39% rate, it will now be taxed at just 15%. His taxes will be reduced by nearly 60% from current law. The same holds true, in lesser degree, to lawyers, doctors, and consultants making more than a few hundreds of thousands of dollars annually.Is there any reason that could justify why a hedge fund manager making a million dollars per year should pay 15%, but a full time CEO at a corporation making half that would be subject to the highest marginal rate of 35%? It’s absurd. Now I’m not a big fan of the “progressive” tax system, whereby the tax rate goes up with income. I think a “flat” tax system, in which everyone paid the same rate, would be better. (Ideally I would like to see income taxes replaced by far less onerous and intrusive consumption taxes). But I certainly don’t believe in a “regressive” tax system in which lower-earning citizens pay higher rates than those at the top. But that’s exactly what Trump is trying to do.Given this wide disparity in tax rates, we can assume that the employment landscape will adjust dramatically. We should expect that legions of highly-paid full-time employees will start to form Limited Liability Corporations (LLCs) to work freelance rather than as employees. There are few barriers that would prevent such a shift, and the growth of internet-based work scenarios will continue to break down the traditional barrier between employee and freelancer. Yes, there are some labor rules that seek to separate employees from freelancers, but those rules may be easily circumvented, especially when the reward is so great. Rather than envy the lawyer earning more and paying less, the CEOs of the country will likely incorporate and sell their services freelance to their former employers.This shift will mean that a great many of the country’s highest earners will be paying taxes at the lowest rate. As a result, the reductions in tax revenue would likely be far greater than what is predicted in the standard modeling. But unlike most prior tax cuts, the Trump version does not even make any attempt to balance the cuts with corresponding cuts in government spending. If Trump’s tax cuts don’t immediately generate sustained 4% growth or more, we may be staring down the barrel of $2 annual deficits. Is this an experiment that we really want to try?But even if the reforms can kick the economy into higher gear, thereby creating higher revenues with lower rates (The Laffer Curve), our current low interest rate environment provides significant obstacles to permit that growth to be sustained. If growth kicks up to the 4% range, the Federal Reserve will have to accelerate its rate increase schedule to keep interest rates in line with GDP growth and to prevent inflation, already above its official 2% target, from running out of control. Plus the markets will also act to adjust interest rates higher due to greater demand for credit and rising inflation. These higher rates will act as a stiff headwind to an economy that has grown increasingly dependent on ultra low rates.But increases in rates would also cost the economy in another way. Our current bonded national debt is ready to surge past the $20 trillion mark. The Trump tax cuts will push it beyond that very quickly. If the Fed raises rates to keep pace with higher growth, then the Government will have to pay much more to finance the outstanding debt. At $20 trillion, every point of increase in interest rates will cost the government $200 billion annually. At that level, if interest rates were at 3.75%, instead of the current .75%, then the Federal Government would have to come up with about another $600 billion per year in interest payments. (That number will be much higher when the debt grows past $20 Trillion).But it's not just Uncle Sam that is over-loaded with debt. Corporations and households would see their interest costs surge as well with rising interest rates. So what lower taxes giveth, higher interest rates will taketh away. Consider the housing market. Not only will higher interest rates substantially increase the cost of home ownership (through higher mortgage rates), but Trump’s tax proposals will dramatically increase the cost of ownership for those living in high tax states. Under the proposal, homeowners will no longer be able to deduct property taxes, and a doubling of the standard deduction means a much larger percentage of homeowners will not be able to deduct mortgage interest from their federal income tax. Plus, with the top tax rate reduced from 39.6% to 15%, the mortgage interest deduction will be far less valuable to those higher earners who can still take advantage of it. Higher mortgage rates and lower tax subsidies will increase the cost and decrease the appeal of home ownership. This could lead to a crash in real estate prices, especially in the high end of the market. Falling prices could wipe out what little home equity many Americas have left, and lead to another wave of foreclosures. The losses to Fannie Mae and Freddie Mac could be significant, with the costs falling directly on the Federal government, further driving up annual deficits. The reality is that years of massive deficits, runaway government spending, artificially low interest rates, and three rounds of quantitative easing, have left the economy so sick that any tax cut large enough to revive it may actually kill it instead. If the Fed tries to keep it on life-support a bit longer by suppressing interest rates with a massive QE4 program, we risk run-a-way inflation and a dollar crisis with economic consequences far more profound than those of the financial crisis of 2008. The only silver lining to this cloud may be that the coming fiscal train wreck leaves lawmakers no choice but to slash government spending. If the real Republican agenda is to starve the beast, its success is assured.
NEW YORK – The likely victory of Emmanuel Macron in the French presidential election has elicited a global sigh of relief. At least Europe is not going down the protectionist path that President Donald Trump is forcing the United States to take.
But advocates of globalization should keep the champagne on ice: protectionists and advocates of “illiberal democracy” are on the rise in many other countries. And the fact that an open bigot and habitual liar could get as many votes as Trump did in the US, and that the far-right Marine Le Pen will be in the run-off vote with Macron on May 7, should be deeply worrying.
Some assume that Trump’s poor management and obvious incompetence should be enough to dent enthusiasm for populist nostrums elsewhere. Likewise, the US Rust Belt voters who supported Trump will almost certainly be worse off in four years, and rational voters surely will understand this.
But it would be a mistake to conclude that discontent with the global economy – at least how it treats large numbers of those in (or formerly in) the middle class – has crested. If the developed liberal democracies maintain status quo policies, displaced workers will continue to be alienated. Many will feel that at least Trump, Le Pen, and their ilk profess to feel their pain.
The idea that voters will turn against protectionism and populism of their own accord may be no more than cosmopolitan wishful thinking.
Advocates of liberal market economies need to grasp that many reforms and technological advances may leave some groups – possibly large groups – worse off. In principle, these changes increase economic efficiency, enabling the winners to compensate the losers. But if the losers remain worse off, why should they support globalization and pro-market policies? Indeed, it is in their self-interest to turn to politicians who oppose these changes.
So the lesson should be obvious: In the absence of progressive policies, including strong social-welfare programs, job retraining, and other forms of assistance for individuals and communities left behind by globalization, Trumpian politicians may become a permanent feature of the landscape.
The costs imposed by such politicians are high for all of us, even if they do not fully achieve their protectionist and nativist ambitions, because they prey on fear, inflame bigotry, and thrive on a dangerously polarized us-versus-them approach to governance. Trump has leveled his Twitter attacks against Mexico, China, Germany, Canada, and many others – and the list is sure to grow the longer he is in office. Le Pen has targeted Muslims, but her recent comments denying French responsibility for rounding up Jews during World War II revealed her lingering anti-Semitism.
Deep and perhaps irreparable national cleavages may be the result. In the US, Trump has already diminished respect for the presidency and will most likely leave behind a more divided country.
We must not forget that before the dawn of the Enlightenment, with its embrace of science and freedom, incomes and living standards were stagnant for centuries. But Trump, Le Pen, and the other populists represent the antithesis of Enlightenment values. Without blushing, Trump cites “alternative facts,” denies the scientific method, and proposes massive budget cuts for public research, including on climate change, which he believes is a hoax.
The protectionism advocated by Trump, Le Pen, and others poses a similar threat to the world economy. For three-quarters of a century, there has been an attempt to create a rules-based global economic order, in which goods, services, people, and ideas could move more freely across borders.
To the applause from his fellow populists, Trump has thrown a hand grenade into that structure.
Given the insistence of Trump and his acolytes that borders do matter, businesses will think twice as they construct global supply chains. The resulting uncertainty will discourage investment, especially cross-border investment, which will diminish the momentum for a global rules-based system. With less invested in the system, advocates for such a system will have less incentive to push for it.
This will be troublesome for the entire world. Like it or not, humanity will remain globally connected, facing common problems like climate change and the threat of terrorism. The ability and incentive to work cooperatively to solve these problems must be strengthened, not weakened.
The lesson of all of this is something that Scandinavian countries learned long ago. The region’s small countries understood that openness was the key to rapid economic growth and prosperity. But if they were to remain open and democratic, their citizens had to be convinced that significant segments of society would not be left behind.
The welfare state thus became integral to the success of the Scandinavian countries. They understood that the only sustainable prosperity is shared prosperity. It is a lesson that the US and the rest of Europe must now learn.
On June 4-7, it will be 75 years since the Battle of Midway, the battle in which the United State won the war in the Pacific and prevented the defeat of Britain and Russia. Guadalcanal, El Alamein and Stalingrad followed, all mostly fought in the second half of 1942. Over two years of horror would remain – neither Japan nor Germany was prepared to concede the point – but the war was won by the beginning of 1943.These were extraordinary battles in an extraordinary war. I want to devote some time this year to considering the battles on their anniversaries and, I want to try to explain how these battles were an interlocking whole – really a single, rolling, global battle that collectively decided the war. By the end of the year, my goal is to show that a single global battle, beginning at Midway and ending at Stalingrad, defined the fate of humanity.
Systemic Wars
This is not simply antiquarian interest, although surely June 1942 to February 1943 must rank with Salamis, where the Greeks stopped the Persian surge into Europe; Teutoburg, where the Germans halted the Roman advance; or Lepanto, where Christian Europe halted Muslim Ottoman expansion. These battles defined the future of a civilization; June 1942 to February 1943 defined the future of the entire world.World War II defined the global civilization in which we now live. It ended Europe’s imperial project, opened the door to American global power, created what was called the Third World and set the stage for the emergence of the Asian mainland as a significant global player. The war also bred a distrust of nationalism, gave rise to multinational institutions and turned an interest in technology into an obsession with its redemptive powers. We live in the shadow of World War II and are now in a global revolt against the world it created.All of this must be discussed, but to understand a war, we must understand it on its own terms, its own grammar. Many talk of wars without wanting to understand their logic, from the details of an artillery barrage to the tonnage of supplies that must flow to the battlefield. War, as all things, is a matter of detail, and the detail must be framed by both the logic of a war and its purpose. World War II had a unique logic. Many Americans long for the days when Americans were united in war. They mistake World War II as the way in which Americans once fought wars, with shared values. That was never the case. The American Revolution, the Mexican-American War, of course the Civil War, and the Spanish-American War were all fought with a vocal and angry faction opposing the war while it was underway. The dissent of Vietnam or Iraq was the norm of American warfighting, and World War II (and to a lesser extent World War I) was unique in its unity. That’s because it was a unique war.I divide wars into two types: political wars, of which there are many, and systemic wars, of which there are only a handful. Political wars are those intended to achieve limited ends. The ends may be important but not existential. The loss of the war does not mean disaster for the nation. Most wars are like this, and many have idiosyncratic or diffuse ends. The Korean War was intended to demonstrate the will of the United States in resisting communism. The Vietnam War sought to shore up the U.S. position in Southeast Asia – a significant but not decisive goal – and to maintain the credibility of the U.S. commitment to the alliance system it depended on. Throughout the history of all powerful nations, political wars abound. They are frequently not intended to be won in a conventional sense but to signal resolve or achieve limited political goals. A defeat is manageable. Such wars appear frivolous and unnecessary to segments of the population and therefore breed dissent – which is tolerated, since the wars are not worth the price of silencing dissenters.Systemic wars differ in two ways. First, avoiding them is usually not an option. Second, losing them can be catastrophic. They aren’t rooted in transitory political interests but in tectonic shifts in the global system. The shifts are not driven by the intent of a nation but by the inevitable rise and decline of nations, the imbalances this creates, and the inevitable rebalancing, which frequently leads to wars. These wars are rare because tectonic shifts take a long time to occur, longer to mature, and longer still to lead to changes in power that are both widespread enough and consequential enough to end in war.The Napoleonic Wars in Europe in the 19th century were systemic, as was the Seven Years’ War in the 18th century. Mongol invasions, European imperialism and the like all were systemic events containing decisive wars. World War II was a systemic war. Some argue that it was a continuation of World War I, and in Europe this was true. But World War II was different from World War I in an important way: The Pacific war between the Japanese and Americans added a new dimension.
Rebalancing the System
Yet both world wars flowed from the rise and fall of powers. In the 19th century, three new powers began to emerge: Germany, Japan and the United States. Germany destabilized Europe. Japan destabilized East Asia. The United States destabilized the world. The unification of Germany in 1871 created a power of enormous economic dynamism, but one extremely vulnerable to simultaneous military attack from Russia and France and to blockade by Britain.Japan was also an economic dynamo but, bereft of natural resources, was unable to maintain its industrial base without imports of oil and other industrial minerals. Its access to these minerals depended on the willingness of suppliers to sell and ability to deliver them through waters controlled by the British and American navies. The newly emergent economic powers were both militarily insecure. This compelled them to seek a rectification of the balance of power against older and frequently weaker powers.A U.S. Navy Ceremonial Band bugler salutes during an event to commemorate the 70th anniversary of the Allied forces victory in the Pacific and the end of World War II on Sept. 2, 2015, at the World War II Memorial in Washington, DC. Alex Wong/Getty ImagesThe rise of the United States was the most radical shift. The U.S. had become the leading economic power in the world in a startlingly short time. The United States’ only vulnerability was from the sea, and the major naval powers were the British and Japanese. The United States constructed a massive navy in response, which unsettle the Japanese in the extreme and made the British uneasy. But behind this was a fundamental reality. The European empires, and particularly the British, were built on a balance of power that was no longer in place. The existing system didn’t make room for the Germans and Japanese, but it also had no place for the Americans. The Americans did not seek formal empire, but they rejected the idea that they should be excluded from economic activities in the British and French empires. A system that marginalized the United States, Japan and Germany was unsustainable.Systemic wars are complex. Alliances shift, and the motives of allies diverge. The Japanese fear of a U.S. blockade triggered the attack on Pearl Harbor. U.S. lend-lease to Britain was contingent on the British surrendering their naval bases in the Western Hemisphere to the United States. The British fought to preserve the empire. The U.S. was content to see it collapse. The Soviet Union was intent on fomenting uprising in Britain and the United States, but both supported Soviet military operations against the Germans. I make no attempt here to write the story of World War II but rather to point out that systemic wars involve many nations, tend to be global and are complicated. Their outcome also determines the fate of nations and, for a while, of the world.One measure of a systemic war is the degree to which the geopolitical systems change. The first change resulting from World War II was the collapse of all European empires in the 20 years following the war’s end. The second was the rise of the United States, not only as a major economic power but also as the dominant military power. Both Japan and Germany, the nations that rose along with the United States, collapsed after the war and then re-emerged as primarily economic powers, and as such, were limited forces in the world. The defeat of Japan opened the door for a communist regime in China that was succeeded by a more complex system that allowed China to emerge as a major economic power.The next phase of history consisted of the global confrontation between the United States and the Soviet Union. That confrontation involved both a strategic cordon around the Soviet Union and a major contest between the United States and the Soviet Union for the domination of the remnants of Europe’s empire. It also consisted of a confrontation of nuclear forces, a weapon that emerged from World War II.
The Forces of Chance and Will
Powers rise and fall, but the process doesn’t happen quickly. It’s driven by shifts deep within the structures of societies. It takes generations or even centuries – too long to be decided by individual leaders or elections.What is decisive in the story are wars. War, particularly modern wars, are driven by necessity. Modern wars are wars of industrial production, and the size and creativity of the industrial plant shape the outcomes of wars, as does the ability to destroy the enemy’s industrial capability. At the same time, there appear to be moments in the systemic war that don’t seem tied to the underlying structure of war-making but much more to the durability of a social order, the commitment of warriors and the chances of war.Geopolitics is, as I have argued and tried to show, predictable. If you consider the deep structure and the imperatives and constraints of the nation-states, and ignore personalities and the public opinion of the moment, you can discern the process that is underway and see where it might be going. You can predict who will be in a war and who is likely to win it. But it is in war that the eccentric forces of will and chance coalesce to create outcomes that, if not violating expectations, give it unexpected dimensions.It was from June 1942 to February 1943 that those eccentric possibilities showed themselves. They allow us to be surprised, certainly by how the war turned out, but also by how close it came to not turning out as we might have expected. Seventy-five years after Midway, Guadalcanal, El Alamein and Stalingrad, there are few who fought in those battles who are still alive. That is a good point for us to consider during these months. We now have to gain perspective over what was, in retrospect, a little more than eight months that redefined the world.It is one thing to see the deep structure of a thing. But in systemic wars, you must also master the battles, in the grammar of war itself. So, in contrast to history, which moves slowly from a human standpoint, battles are measured in seconds, minutes, hours and days. The long wars we speak about today are political wars. Systemic wars rip apart the world and redesign it in a matter of years, with the heart of the matter determined frequently in minutes. In two weeks, we will begin with what I regard as the single-most decisive battle of World War II for all combatant powers: Midway, where the allies could have lost but didn’t, all because of events that transpired in mere minutes.
After Last Week's Gold Drop, Speculative Traders Jump Back On Board This Week
by: Hebba Investments.
Summary
- Speculative gold longs rose and gold shorts covered by a large amount this week.- In silver, the action was different as we saw major short-covering but no increase in speculative silver longs.- Next week's big events are US jobs data related and investors can expect volatility in precious metals on Thursday and Friday.- At this point, our short-term position on precious metals remains at neutral as we see no clear reasons to buy or sell here.
The latest Commitment of Traders (COT) report showed that speculative gold traders last week abandoned short positions and jumped into long positions at the highest rate we have seen in 2017. In silver, the action was quite different as almost all the move was attributed to short-covering, with longs actually declining slightly on the week.
The major (scheduled) event for precious metals next week with be the Non-farm Payrolls report. Though, of course, the ADP and jobless claims report on Thursday will also probably move markets in anticipation of a June Fed rate hike - or if the reports are really poor, maybe that hike (or future expected hikes) may be postponed.
We will get more into some of these details, but before that let us give investors a quick overview into the COT report for those who are not familiar with it.
About the COT Report
The COT report is issued by the CFTC every Friday to provide market participants a breakdown of each Tuesday's open interest for markets in which 20 or more traders hold positions equal to or above the reporting levels established by the CFTC. In plain English, this is a report that shows what positions major traders are taking in a number of financial and commodity markets.
Though there is never one report or tool that can give you certainty about where prices are headed in the future, the COT report does allow the small investors a way to see what larger traders are doing and to possibly position their positions accordingly. For example, if there is a large managed money short interest in gold, that is often an indicator that a rally may be coming because the market is overly pessimistic and saturated with shorts - so you may want to take a long position.
The big disadvantage to the COT report is that it is issued on Friday but only contains Tuesday's data - so there is a three-day lag between the report and the actual positioning of traders. This is an eternity by short-term investing standards, and by the time the new report is issued, it has already missed a large amount of trading activity.
There are many ways to read the COT report, and there are many analysts that focus specifically on this report (we are not one of them) so we won't claim to be the experts on it. What we focus on in this report is the "Managed Money" positions and total open interest as it gives us an idea of how much interest there is in the gold market and how the short-term players are positioned.
This Week's Gold COT Report
This week's report showed that after three straight weeks of declines, gold speculative positions rose - and by a significant amount. For the week, they rose 34,696 contracts, which was the largest rise in speculative longs for 2017 and you would have to go all the way back to June 2016 to see a similar rise. This week we also saw shorts close their own positions by 13,042 contracts which completely reversed last week's short rush and brought us back down to a 23% total short position.
The red line represents the net speculative gold positions of money managers (the biggest category of speculative trader), and as investors can see, the net position of speculative traders increased by about 48,000 contracts to 118,000 net speculative long contracts. Based on the last 10 years' worth of data, we are around the average level of trader positioning in gold - so from a COT perspective, gold neither looks overbought or oversold.
The red line, which represents the net speculative positions of money managers, showed an increase in the net-long silver speculator position as their total net position rose by around 12,000 contracts to a net speculative long position of 30,000 contracts.
What is interesting about this move in silver is that it has primarily been driven by short covering - actually all of it was short covering as speculative longs fell during the COT week.
Last week, total ETF/Fund silver holdings fell slightly by around 1 million ounces; we still worry that if ETFs and funds started selling physical silver in the market, it may be hard for the market to absorb especially considering the decline in silver bullion demand we have seen in 2017 compared to 2016.
On the other side of the coin, we do have to note that the total value of all ETF and fund silver holdings is around $16.8 billion. That is fairly low considering that the SPDR Gold Trust ETF (NYSEARCA:GLD) has a total value of $38 billion by itself. Additionally, the all-time value highs we saw in silver in 2011 and 2012 were over $30 billion - thus, from this angle, silver ETFs are not particularly near their all-time highs.
Our Take and What This Means for Investors
The big upcoming events for next week will be the US jobs reports on Thursday and Friday.
These will be key, at least in traders' minds, to determining the trajectory of the Federal Reserve's interest rate rises. A June rise is almost guaranteed, but the question will be whether the Fed will take it slow on future rises or will it move again a few months later.
We think there are clear issues with the real economy, but we really don't know what the data will show and we have little feeling. But what we do know is that the Fed is dead-set on raising rates for the June meeting, so data would have to be really bad for them not to at least meet those market expectations.
At this point, our short-term view is pretty neutral as we see even odds for metals to move in either direction. Thus, we move our short-term view on precious metals to Neutral on both gold and silver.
Due to our neutral position on precious metals but our bullish view for the intermediate and longer terms, we think short-term speculators should sit tight and not be too exposed one way or the other.
But investors with low exposure may want to take the opportunity to nibble away and add to their precious metals positioning in gold and silver positions (SPDR Gold Trust ETF, iShares Silver Trust (NYSEARCA:SLV), Sprott Physical Silver Trust (NYSEARCA:PSLV), and ETFS Physical Swiss Gold Trust ETF (NYSEARCA:SGOL), etc.). For those who already hold large positions in the precious metals, there may be better opportunities to add further at lower prices, so we would not be adding to large positions at this time.
Chinese regulators are cracking down on stock and bond speculation. Real-estate markets are, however, suddenly doing just fine. This is unlikely to be a coincidence.
By Nathaniel Taplin
Talk to any young adult in a big Chinese city and the subject of yali, or pressure, will quickly come up. China is without a doubt a high-pressure society: Inequality is intense, pollution and traffic are often unavoidable and family obligations can be overwhelming. A high-pressure environment is a good metaphor for Chinese markets too. Because of the nation’s capital controls, investment options are limited—and regulatory crackdowns have a tendency to push leverage around rather than get rid of it. The curious resurgence in 2017 of Chinese property prices, which spent most of late 2016 slowing only to shoot upward again in February and March, looks to be another example of this dynamic at play.The property market rebound has coincided with two big domestic policy developments. First, as the economy has improved, regulators have become increasingly vocal about financial market “deleveraging,” though actual reduction or leverage ratios is unlikely. A two-year high in interbank interest rates, engineered by the central bank, has rattled bond markets and cut off an equity rally. Meanwhile, stricter capital controls have helped choke off capital flight: Following two years of declines, China’s foreign-exchange reserves began rising again in February. Domestic credit growth has slowed, but remains elevated. Total financing to the real economy (including local government debt) was up more than 15% on the year in March, just marginally below the 17% peak in 2016.All that money needs somewhere to go. And with stocks and bonds under pressure, and sending money abroad to buy Italian soccer clubs and dollar bonds getting tougher, cash is instead heading back into Chinese investors’ old standby: real estate.If the renewed momentum in the property market were sustainable, that would be a big shot in the arm for China. The problem is that all the money being squeezed into real estate and out of stocks and bonds could just as easily run out once the current crackdown loses steam and regulatory spotlights focus again squarely on curbing real estate speculation—as they did toward the end of 2016.And the fundamentals for Chinese property look more mixed than justified by the recent price rally. Actual real-estate investment ticked up marginally in March to 9.4% growth on the year, but remained well below its October 2016 peak of over 13%. Steel and other commodity prices have also been under pressure in recent weeks, raising questions about the strength of real demand in China, which consumes around half the world’s steel. Weak purchasing managers indexes out this week add to these worries. Too much pressure inevitably leads to cracks.
If you know the other and know yourself, you need not fear the result of a hundred battles.
Sun Tzu
We are travelers on a cosmic journey, stardust, swirling and dancing in the eddies and whirlpools of infinity. Life is eternal. We have stopped for a moment to encounter each other, to meet, to love, to share.This is a precious moment. It is a little parenthesis in eternity.
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Loretto-Hilton Center (LHCT) Windows Labs Fall 2018 Software Titles
The computers in the Loretto-Hilton Center (LHCT) Rooms 19 and 51, have unique software installed, based on the courses that are taught there. The following
table displays Windows software titles that are installed on the computers in both the computer lab in the Loretto-Hilton Center (LHCT) Room 19 (17 stations) and LHCT 51 (4 stations) for Fall 2018. These software titles are in addition to the Windows software that is installed
on ALL computers across the Webster Groves campus. Click here to view that "base" software list. Additionally, computers in the Loretto-Hilton Center (LHCT) provide more software titles available via CampusConnect (VDI), depending on the courses taught.
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Baseline laboratory parameters predicting clinical outcome in melanoma patients treated with ipilimumab: a single-centre analysis.
Overall response rates (ORRs) for ipilimumab in advanced melanoma are only about 10%. Hence, it is important to explore biomarkers predicting ipilimumab responders. We aimed to explore biomarkers to predict therapy outcome in melanoma patients who have undergone standard ipilimumab therapy in a real-world setting. Databases of cutaneous melanoma patients (n = 52) who had received ipilimumab were reviewed and data collected on patient characteristics and diverse laboratory parameters. We performed univariate and multivariate statistics including logistic regression analysis and Cox proportional-hazards regression. Baseline leucocytes, lymphocytes, eosinophils, thrombocytes, neutrophil/lymphocyte ratio, thrombocytes/lymphocyte ratio, eosinophil/lymphocyte ratio and serum vitamin D levels were not significantly associated with ORR, progression-free survival (PFS) and melanoma-specific survival (MSS). Multivariate analysis confirmed anti-PD-1 pretreatment as significant predictor for ORR following ipilimumab therapy. Low-LDH levels and more than two ipilimumab cycles turned out to be significant independent predictors for prolonged PFS. Low-S100B levels and anti-PD-1 treatment before or after ipilimumab were significant independent predictors for improved MSS. All aforementioned parameters and faecal calprotectin did not turn out to be predictors for ipilimumab-induced autoimmune-related adverse events and autoimmune colitis, respectively. Low serum LDH before ipilimumab treatment is an independent predictor for improved PFS. Furthermore, low serum S100B is an independent predictor for MSS. The number of ipilimumab cycles (>2) is significantly associated with prolonged PFS. Pretreatment calprotectin does not predict the occurrence of autoimmune colitis under ipilimumab therapy.
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Q:
Observable chain repeating itself
I have a chain of observables which follow this logic: getStyles() --> getPrices()
For every config.id in configs, _APIService.getStyleByID() returns a style Object called "res", this style Object is passed to getLease() where a price is appended to it and is then pushed an array called "garage"
getStyles(configs: any) {
configs.forEach(config => {
this._APIService.getStyleByID(config.id).subscribe(
res => {
res.config = config;
this.getLease(res);
}
);
});
}
getLease(style: any): void {
this._priceService.getPrice().subscribe(
price => {
style.price = price;
this.garage.push(style);
console.log(this.garage);
});
}
}
The issue I am experiencing is that there is a loop being done on _APIService.getStyleByID. How do I fix my Service method to only be called once per config? (it recurses over the the configs array two or three times more.
A:
By appending take(1) before subscribe, this fixed my issue.
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Stakeholders & Roles in Clinical Research
The clinical research industry is an ever-evolving and ever-changing enterprise. It is continuously achieving advancements that would not be possible without the many key players and stakeholders within the industry. These stakeholders range from a broad spectrum that includes the participants, research team, sponsors, regulators, monitors, government agencies, Contract Research Organizations (CROs), Site Management Organizations (SMOs), academic institutions, ethics committees or Institutional Review Boards (IRBs), and a myriad of other public and private entities whose involvements greatly effect the clinical research process. Indeed, with the added diversity of stakeholders comes added complexity in collaborative efforts and interactions (Johnson, 2005). The focus of this article is to highlight some, if not all, of the various stakeholders and elaborate on their roles and influences, as well as how they interrelate with one another within the research enterprise.
Clinical Research Stakeholders
The Initiator:
Research sponsors are the primary stakeholders who initiate the research process. They are typically pharmaceutical or biotechnology companies in the business of making drugs, biologics, or medical devices. They may also be academic institutions or even government agencies such as the National Institutes of Health. Either way, before they can conduct their studies or introduce any drugs, biologics, or medical devices into the market, they must first gain approval by verification of their safety and efficacy. This is done by going through the clinical investigation process. However, this cannot be achieved by the sponsor alone. Hence they must rely on other stakeholders. This is where the research team, another stakeholder, is involved in performing the clinical investigation. Although the sponsor hires the research team to conduct the clinical study, the sponsor is expected to maintain their responsibilities as well. As noted in 21 CFR 312.50 (2006), some of these responsibilities include: protocol development and IND submission, selecting qualified investigators, providing all information needed to properly conduct the investigation, monitoring and ensuring that the study is conducted in accordance with the protocol, ensuring compliance with federal regulations, and informing the FDA and the participating investigators of any adverse events and risks.
The Researchers:
The investigative site in any trial generally consists of principal investigators, sub-investigators, clinical research coordinators, site managers, laboratory personnel, technicians, analysts, pharmacists, research assistants, recruiters, and many others. This team of professionals is led by the principal investigator. This is the stakeholder hired by the sponsor to conduct their trial or clinical study. Although each member of the research team has certain duties to fulfill, it is ultimately the investigator who is responsible for all aspects of the study. Some of these responsibilities include (21 CFR 312.60):
Ensuring that an investigation is conducted according to the regulations as well as the approved protocol and the signed investigator statement
Obtaining the informed consent of each subject to whom the drug is administered
Protecting the rights, safety, and welfare of subjects under the investigator's care
Maintaining control of drugs under investigation.
Reporting any adverse events to the sponsor and the IRB
As the research team works on the study, there is a certain level of interaction that occurs between them, the sponsor, the IRB, and the FDA. The interrelation between the research team and the sponsor is driven by the common goal of completing the study and obtaining results that may lead to an approval. The interrelation with the IRB is to ensure that the study will be conducted ethically while preserving the safety and wellbeing of subject. Thus, if the research team conducts the study successfully, the sponsor will be able to obtain the information needed to submit the necessary documents to the FDA, bringing them one step closer to gaining approval.
The Enforcer
The FDA is the main regulatory authority stakeholder in charge of protecting the public health by assuring the safety and efficacy of drugs, biologics, and medical devices. The FDA achieves this through an extensive review process. In this process, the sponsor works with the FDA to submit an application or IND/NDA for the new product. The FDA carefully evaluates the submitted documents, which then leads to either an approval or rejection. In addition to the review process, the FDA also performs audits and inspections of any section of clinical research including sites, sponsors, or IRBs. Should the FDA discover any problems of noncompliance or regulatory issues brought on by any of the stakeholders, a warning letter may be sent in which corrective action must be taken immediately by the stakeholder responsible (Allen, 2002).
The Safety Squad:
The Institutional Review Board, or IRB, is the stakeholder that holds the role of protecting human subjects as detailed in the regulations (21 CFR 50, 21 CFR 56, and 45 CFR 46). Before a research team can begin on a study, this specially constituted review body must conduct an initial review to see if the study can be done ethically and safely. The IRB carefully analyzes the study protocol and assesses the risks and benefits, which ultimately decide whether or not the investigator can go on with conducting the study. The IRB may conduct several reviews throughout the study period. If at any point the IRB determines that subjects are exposed to any unreasonable risk, or the study is not ethically sound in any way, they may decide to require changing the protocol or halt the study altogether. No changes or deviations from the protocol can be done without prior approval from the IRB, unless it is necessary to eliminate apparent immediate hazards. Even so, the research team, or namely the investigator, must report such events to the IRB. Most of the interaction occurs between the IRB and the investigator. While the investigator is interested in conducting the study, the IRB is most interested in maintaining subject welfare. Thus, in the case of these stakeholders, the investigator who represents the research team must comply with the IRB’s requirements as well as the FDA’s requirements in order to have an approved, safe, and ethically sound study.
My Role in the clinical research industry:
The role I play in the clinical research industry is generally that of a consumer but also as a coordinator. As a consumer I have a limited view of the market as I take note of what new drugs are available and how drug prices are impacted. On the other hand, as a coordinator, I play a greater role from within the industry since I have a greater knowledge of the stakeholders involved and a deeper understanding of how the clinical research process works along with its complex intricacies.
The clinical research coordinator, or CRC, is an essential member of the research team, the stakeholder who conducts the study as discussed above. This member plays a critical role in organizing a site's participation in the expanding arena of clinical trials. The primary function of the CRC is to manage and coordinate the smooth, accurate progress of clinical protocols from the planning stage through study completion by acting as a liaison to other member stakeholders including the investigator, the subject, the research site, the IRB, and the sponsor. The reason why this role holds such great importance is because the CRC is at the center of the study process. The CRC assists in the development, review, and maintenance of conducting a study in accordance with appropriate SOPs, GCPs, and regulatory guidelines. This includes assisting in the review of protocols, checking for protocol feasibility, preparing documents for IRB submission, recruiting and screening study participants, obtaining informed consent from study subjects, facilitating continued participation of subjects, and tracking study progress while maintaining compliance (Woodin, 2004).
Considering this multi-faceted role and the many responsibilities that it entails, sometimes it can be a struggle to remain afloat. This individual stakeholder holds the task of maintaining efficiency and effectiveness in conducting all trial activities. Since the CRC is heavily relied on by many stakeholders, the CRC must be aware of all activities of the trial and what goes on at the site. Any slip ups may lead to problems. Since the CRC interacts with such a variety of stakeholders, it is likely that conflicts and moments of tension may arise. For instance, one common complaint from some CRCs may be due to having an investigator who leaves all the work for them to do while the investigator hardly ever shows up at the site. This may certainly build tension between the CRC and the investigator and may even lead to CRC burnout (Woodin, 2004). In the worst case scenario the research site may lose the CRC which could be devastating to the study since the CRC maintains much of the workload and streamlines the operations of the study. In another scenario, should the CRC remain at the site, the CRC may use the wrong consent form for a patient and not realize it due to being overworked. This would cause a problem for the investigator and for the subject. The subject would need to be re-consented and the investigator must report the events and actions taken to the IRB and the Sponsor.
Conflicts and Tension among Stakeholders
Regardless of the position or type of stakeholder, anyone who works in clinical research knows it is a very cooperative field. Many aspects of the clinical research process rely on much collaboration, partnerships, and forming alliances. Teamwork is an essential skill for every clinical research professional since their jobs require working with all kinds of people. This explains why the industry has so many stakeholders involved. However, in this vastly interdependent environment, it is important to remember that different stakeholders have different interests and their collaborative efforts are driven by varying motives (Johnson, 2005). Of course, each stakeholder most likely wishes to protect their interests but as a result, there are times when conflicts and tension may arise and stakeholders may not see eye to eye. The following will explore cases which demonstrate this point.
Case Study #1: Discovering and Reporting Falsified Data
A sponsor contracts with a CRO to monitor their study. During an inspection, the FDA discovers falsified records at the site. Both the sponsor and the CRO conduct their own follow-up inspections in which it is later revealed that the CRO’s records contained falsified data. However, this was not known until after the study was completed at the site. This information was then reported to the sponsor, but the sponsor denies ever receiving such information from the CRO. Thus, the falsifications were never reported to the FDA by either party (Woollen, 2000).
When analyzing any situation such as this, it is important to understand each stakeholder’s roles and responsibilities. In this case, the stakeholders involved are the FDA, the sponsor, the investigator and the CRO. Under the FDA’s Code of Federal Regulations (21 CFR 312.56) “the sponsor shall monitor the progress of all clinical investigations being conducted under its IND.” At the same time, 21 CFR 312.52 states that any or all sponsor obligations may be transferred by contract. In other words, the CRO in this case agreed by contract to take responsibility in monitoring the trial progress and all other aspects of the study. Therefore, the CRO and the sponsor would be held accountable since the CRO that assumes any obligation of a sponsor is subject to the same regulatory actions as the sponsor. Although the CRO reported its findings to the sponsor, the sponsor denies ever receiving any report. This would require further investigation as to whether or not the CRO truly did sent in a report or if the sponsor is merely blaming the CRO. Furthermore, the investigator who was involved in the study is also accountable since he is responsible for conducting the study, supervising the study, and for maintaining adequate and accurate records of the study. Thus, the investigator should have been terminated for the falsification of data and for failure to follow the responsibilities as indicated by the regulations and in FDA Form 1572. Nevertheless, the situation could have been avoided or at least minimized if the CRO also reported to the FDA in addition to reporting to the sponsor. That way, even if the sponsor denies receiving the report, the CRO would have still fulfilled its responsibility by reporting to the FDA.
Case Study #2: A Fifteen-Foot Span of Misconduct
In another study, subjects were asked to read an eye chart from a distance of fifteen feet as indicated in the trial’s approved protocol. The subjects stood at the marking point instructed to read the chart and did so during every visit. Upon the time of monitoring, the CRA that arrived at the site decided to measure the distance and discovered it to be only thirteen feet. It was then revealed that the investigator was aware of the discrepancy but he figured it was not that significant. As a result, he did not think it was important to mention and continued to use the shorter distance (Woodin, 2003).
Based on the information in this case, the stakeholders involved are primarily the CRA and the investigator. The investigator clearly failed to conduct the trial in accordance with the approved protocol, failed to follow the agreements in FDA Form 1572, and deliberately continued to use a measurement fully knowing that it was incorrect. Consequently, the data was rendered completely useless which in turn was a waste of time, effort, and resources for those involved in the study. The CRA was vigilant to measure the distance since it may not have been discovered at all. As part of the CRA’s responsibility, he would have to make a report of this situation and inform the sponsor and CRO. The sponsor would then determine what corrective action would be required including the investigator’s termination from the study and make a report to the FDA as well. Unfortunately, this case could have been easily avoided simply by using the correct distance measurement from the beginning. If the CRA had measured the distance before the subjects were enrolled it would have made a great difference in saving the study from being wasted.
Case Study #3: What’s in the flu vaccine?
On June 30, 2006, the FDA issued a warning letter to Sanofi Pasteur Inc., after performing an inspection of one of the company’s facilities in Swiftwater, PA. Inspectors observed several objectionable conditions and discovered issues of sterility failure and general failures of good manufacturing practices in the production of the Fluzone® vaccine and other licensed biological products (Holland-Moritz, 2006). According to the warning letter Sanofi was reported to have significant deviations from current good manufacturing practices including, but not limited to (FDA, 2006):
Failure to keep equipment and supplies used in, work on, or otherwise exposed to any potentially pathogenic agent separated from other equipment and supplies to prevent cross-contamination.
Failure to establish a system for maintaining equipment to control aseptic conditions
Failure to follow appropriate written procedures designed to prevent microbial contamination of drug products purporting to be sterile.
Failure to establish the accuracy, sensitivity, specificity, and reproducibility of test methods established by the firm.
Failure to report any event and relevant information associated with the manufacturing of a licensed biological product that represents a deviation from current good manufacturing practice.
Failure to inform FDA about a change to a licensed product stability testing program.
Among the violations, one of the most serious pertains to the manufacturing of monovalent concentrate, an intermediate derived from one of the three influenza strains used to produce Sanofi’s Fluzone® vaccine. As many as eleven batches of the monovalent concentrate were discarded when they failed the sterility test as a result of bacterial contamination (FDA, 2006). These concerns raised speculation as to how this would impact the production and distribution of the influenza vaccine during the 2006-07 flu season.
Of course, the stakeholders here are Sanofi and the FDA. This is an example of what happens when a stakeholder fails to follow the regulations; a warning letter is typically issued. The reason for the warning letter in this case is due to deficiencies and reasons of noncompliance. When such a letter is received, it should be taken seriously as it indicates the risk of further regulatory action by the FDA. For this reason it is advisable to provide a timely response and take immediate corrective action to rectify the deficiencies or non-compliance described in the warning letter. In this case, Sanofi was fortunate since both the company and the FDA confirmed that the contamination did not reach the finished vaccine and so no recall was required (In-PharmaTechnologist, 2006). Nevertheless, Sanofi was required to take sufficient remedial action in order to avoid license suspension, revocation, seizure, or injunction from the FDA.
Conclusion
The clinical research industry is made up of many stakeholders and each hold varying interests. However, there is a common goal that leads these stakeholders to form alliances and work together to overcome tensions that may arise along the way. Sponsors continue to compete for innovation and to be at the cutting edge of new advancements in medicine. Regulatory agencies are expanding their efforts in ensuring the safety and efficacy of new drugs, biologics, and devices. All the while, patients and consumers watch the changes in market as prices increase and new drugs are introduced. In an industry where many stakeholders are involved and even more are affected, there are many expectations and increased pressures to meet the needs of many sides. Some wish to make a significant discovery, some wish to make a profit, and others merely wish for a cure. Perhaps no other industry can influence so many parties and affect so many lives as remarkably as the clinical research industry.
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Introduction {#s1}
============
The population-level right-handedness in humans (approximately 90% humans preferentially use the right hand to perform complex manual actions [@pone.0097971-Raymond1], [@pone.0097971-Annett1]) raises questions about the evolutionary origins of hand preference, in humans as well as in their phylogenetic relatives, the non-human primates [@pone.0097971-Cashmore1]. Hand preference in non-human primates has been hypothesized to have had evolved owing to functional and morphological adaptations to feeding in arboreal contexts and to be a precursor of the population-level right-handedness in humans [@pone.0097971-MacNeilage1]--[@pone.0097971-Bradshaw1]. Thus, understanding behavioral lateralities in non-human primates is an important first step towards understanding behavioral lateralities in humans. There are two major existing theories that attempt to explain the evolutionary origins of hand preference in non-human primates, namely the task complexity theory [@pone.0097971-Fagot1] and the postural origins theory [@pone.0097971-MacNeilage1]. The postural origins theory proposes that initially the left hand became specialized for visually guided movements, and the right hand became specialized for postural support. Subsequently, in non-human primate species that adopted a relatively more terrestrial lifestyle, the right hand became more specialized for physical manipulation than for postural support, owing to (a) the development of the opposable thumb and (b) the decreasing demands on the right hand to support vertical posture. However, the postural origins theory fails to describe why initially the left-hand (and not the right hand) became specialized for visually guided reaching, and more importantly, how a population-level right-handedness evolved during the transition from monkeys to apes to humans [@pone.0097971-McGrew1]. Acknowledging that hand preference is likely to be task and situation dependent, the task complexity theory advocates that the cognitively more demanding manual actions that are practiced rarely (e.g., complex and/or bimanual food reaching) would elicit stronger hand preference than the cognitively less demanding actions that are practiced frequently (e.g., unimanual food reaching) [@pone.0097971-Fagot1]. However, the task complexity theory lacks an a priori description of a cognitively demanding manual task and, therefore, remains largely contextual. Also, there can be several other factors that are likely to have played a role in the evolution of hand preference in humans and non-human primates, which are beyond the scope of these two theories.
There exists a possibility that hand preference in non-human primates evolved from the pre-existing lateralities in more elementary brain functions and behavior, or alternatively, the two coevolved. For example, common marmosets, *Callithrix jacchus* have been reported to generally display a larger left hemi-mouth while expressing fear and a larger right hemi-mouth while making social contact calls [@pone.0097971-HookCostigan1]. Observations from the studies on primate premotor cortex, particularly, on the mirror neuron system, substantiate the hypothesis that initially a dual hand-mouth command system could have evolved in the context of ingestion, which then could have developed into a common platform for manual and vocal communication [@pone.0097971-Corballis1]--[@pone.0097971-Maurizio1], i.e., the motor-action patterns that were initially associated with feeding involving both hands and mouth, developed into coordinated manual and vocal gestures. Chimpanzees, *Pan troglodyte* have been reported to preferentially use the right hand in gestural communication, and communicate so more efficiently while vocalizing simultaneously [@pone.0097971-Hopkins1].
These observations indicate a strong evolutionary link between laterality in hand usage and laterality in various other elementary brain functions and behavior, describing which can potentially help identifying some general principle(s) underlying behavioral lateralization.
In the present study, we examined the relationship between laterality in the prehension and mastication processes in free-ranging bonnet macaques, *Macaca radiata*. In a previous study on hand usage in bonnet macaques [@pone.0097971-Mangalam1], we reported that the macaques preferentially used one hand--the 'preferred' hand, to maneuver in three-dimensional space, and the other hand--the 'non-preferred' hand, to obtain support. This kind of division of labor is likely to be a more general principle underlying asymmetries in brain functions and behavior with left and right symmetrical components; considering this possibility, we hypothesized that there would be an analogous division of labor in motor-action patterns associated with cheek pouch usage. Bonnet macaques have cheek pouches, which are located in the thickness of the flange on either sides of the mouth within the oral cavity and allow rapid collection and temporary storage/transportation of food. We expected that the macaques would use the cheek pouch corresponding to the preferred hand predominantly and before the other; also, we expected that laterality in hand usage and laterality in cheek pouch usage would be positively related with each other.
Methods {#s2}
=======
Subjects and Study Site {#s2a}
-----------------------
We conducted semi-manipulative experiments on free-ranging bonnet macaques living close to the Chamundeshwari Temple on top of the Chamundi Hills, Mysore, India (2°14′41″N 76°40′55″E). We studied the hand- and cheek-pouch-usage patterns of 14 macaques: 3 adult males, 3 juvenile males, 7 adult females, and 1 juvenile female. Our experiments were completely non-invasive; we placed bananas on the ground within ∼3 m of the macaque and observed their corresponding hand and cheek pouch usage from distance. Our research work adhered to the American Society of Primatologists (ASP) "Principles for the Ethical Treatment of Non-Human Primates." Whereas no authorization from a local authority was required, we conducted the present study as part of a larger study approved by the Institutional Animal Ethics Committee (IAEC) at the University of Mysore.
Experimental Procedure {#s2b}
----------------------
We presented the macaques with bananas that were sufficiently large to fill both the cheek pouches and the mouth, whenever both the cheek pouches were empty. Typically, the macaques picked up the bananas, filled one of the cheek pouches (i.e., either left or right) first, then the other; then they emptied one of the cheek pouches and then the other (which does not require the usage of hands). We recorded the hand used by the macaques in the 21 trials to pick up the bananas lying on the ground, and the chronology of filling and emptying both the cheek pouches, whenever they filled both of them (which allowed us to appropriately determine the laterality in emptying the cheek pouches). To ensure that each data point represented an event, we recorded only one observation corresponding to the act of picking up a banana. And to eliminate the factors that may have influenced hand preference, we presented the macaques with the bananas only when both the hands were free, and discarded those observations in which the presence of conspecific(s) could have conditioned the manual actions.
Statistical Analyses {#s2c}
--------------------
We determined the z-scores for hand and cheek pouch usage for each of the macaque using the formula: z-score = \[R−(R+L)/2\]/√\[(R+L)/4\] (where 'R' and 'L' represent the frequency of usage of the right and left hand respectively), and used the obtained z-scores to determine the preferred hand/cheek pouch (z≤1.96: left; −1.96\<z\<1.96: none; z≥1.96: right).
We determined the direction and strength of lateral bias in hand usage using the formula: handedness index (HI) = (R−L)/(R+L). The obtained HI values ranged from −1 to +1, with positive values indicating a bias towards right-hand use, and negative values indicating a bias towards left-hand use, while the absolute HI values indicating the strength of the bias. Analogously, we determined the direction and strength of lateral bias in cheek pouch usage viz., laterality index (LI).
We used Spearman\'s rank correlation tests to determine the relationship between HI and LI values. We used a binomial test to compare the frequency of the usage of the two cheek pouches in the observations in which the macaques used the 'non-preferred hand' (i.e., the hand used less often) to pick up the bananas (this allowed us to examine whether physical constraints imposed by the combined structural properties of hand, food, and mouth, ergonomically influenced cheek pouch usage).
Results {#s3}
=======
[Table 1](#pone-0097971-t001){ref-type="table"} describes the hand and cheek pouch usage for the macaques (n = 14). As suggested by the z-scores, only eight macaques preferentially used one hand to pick up the bananas lying on the ground and nine macaques used predominantly and before the other, one of the cheek pouches. There was a positive correlation between the HI and LI values for both filling (Spearman\'s rank correlation: r~s~ = 0.825, n = 14, p\<0.001; [Fig. 1A](#pone-0097971-g001){ref-type="fig"}) and emptying (r~s~ = 0.810, n = 14, p\<0.001; [Fig. 1B](#pone-0097971-g001){ref-type="fig"}) the cheek pouches, and even when the macaques used their non-preferred hand to pick up the bananas, they predominantly used the cheek pouch corresponding to the preferred hand (one-tailed binomial test: 46/76, p = 0.042).
{#pone-0097971-g001}
10.1371/journal.pone.0097971.t001
###### Hand and Cheek Pouch Usage by the Macaques (n = 14).
{#pone-0097971-t001-1}
Individuals Hand Usage Cheek Pouch Usage
------------- ------------ ------------------- -------- -------- --- ---- ---- -------- -------- --- ---- ---- -------- -------- ---
AM1 5 16 0.524 2.400 R 0 21 1.000 4.582 R 7 14 0.333 1.527 N
AM2 21 0 −1.000 −4.582 L 19 2 −0.809 −3.710 L 21 0 −1.000 −4.582 L
AM3 11 10 −0.048 −0.218 N 13 8 −0.238 −1.091 N 15 6 −0.428 −1.964 L
JM1 5 16 0.524 2.400 R 8 13 0.238 1.091 N 9 12 0.143 0.655 N
JM2 11 10 −0.048 −0.218 N 3 18 0.714 3.273 R 2 19 0.809 3.710 R
JM3 3 18 0.714 3.273 R 1 20 0.905 4.146 R 0 21 1.000 4.582 R
AF1 11 10 −0.048 −0.218 N 12 9 −0.143 −0.655 N 10 11 0.048 0.218 N
AF2 5 16 0.524 2.400 R 5 16 0.524 2.400 R 10 11 0.048 0.218 N
AF3 3 18 0.714 3.273 R 1 20 0.905 4.146 R 5 16 0.524 2.400 R
AF4 8 13 0.238 1.091 N 9 12 0.143 0.654 N 12 9 −0.143 −0.655 N
AF5 1 20 0.905 4.146 R 7 14 0.333 1.527 N 8 13 0.238 1.091 N
AF6 12 9 −0.143 −0.655 N 18 3 −0.714 −3.273 L 18 3 −0.714 −3.273 L
AF7 14 7 −0.333 −1.527 N 20 1 −0.905 −4.146 L 18 3 −0.714 −3.273 L
JF1 0 21 1.000 4.582 R 0 21 1.000 4.582 R 0 21 1.000 4.582 R
'L' and 'R' indicate left and right respectively;
preferred hand/cheek pouch: z≤1.96: L; −1.96\<z\<1.96: N (none); z≥1.96: R.
Discussion {#s4}
==========
In the present study, we examined the relationship between lateralities (i.e., the direction and strength of preference) in hand and cheek pouch usage in free-ranging bonnet macaques. Lateralities in hand and cheek pouch usage (for both filling and emptying) were positively related with each other, that is, the macaques used the cheek pouch corresponding to the preferred hand predominantly and before the other. Moreover, when the macaques used the non-preferred hand to pick up the bananas, the frequency of contralateral cheek pouch usage was higher than the frequency of ipsilateral cheek pouch usage, that is, the combined structure of hand, mouth, and food did not influence the relationship between laterality in hand usage and laterality in cheek pouch usage. These findings demonstrate laterality in a relatively more involuntary function than those explored previously in any non-human primate species (e.g., facial expressions in rhesus macaques, *Macaca mulatta* [@pone.0097971-Hauser1], [@pone.0097971-Hauser2] and chimpanzees [@pone.0097971-FernndezCarriba1], and manual gestures in baboons, *Papio anubis* [@pone.0097971-Meguerditchian1], bonobos, *Pongo pygmaeus* [@pone.0097971-Hopkins2], [@pone.0097971-Hopkins3], and chimpanzees [@pone.0097971-Hopkins1], [@pone.0097971-Hopkins4]) (here, 'relatively more' refers to the functions that are not entirely involuntary, i.e., they can be voluntary or involuntary to various degrees, but are more involuntary as compared to many other functions).
Asymmetries in elementary brain functions and behavior are turning out to be widespread in both invertebrates and vertebrates [@pone.0097971-Frasnellia1]--[@pone.0097971-Vallortigara1]. For example, studies reported that honeybees, *Apis mellifera* [@pone.0097971-Letzkus1] and bumble bees, *Bombus terrestris* [@pone.0097971-Anfora1] responded to odors (a first step towards feeding) better when they were trained through the right antenna. Studies on side preference in chewing in humans reported the phenomenon to be comparable to lateralities, for example, in limb usage [@pone.0097971-Nissan1], [@pone.0097971-MartinezGomis1]. And above all, a study on gross preferentially distributed striations on the buccal surfaces of permanent anterior teeth of Neanderthals, *Homo neanderthalensis*, as found in archeological remains, suggested lateralization of the brain functions associated with tool use involving mouth [@pone.0097971-deCastro1]. These examples substantiate the possibility of the ubiquitous nature of lateral asymmetries, extending from very elementary functions to complex motor-action patterns, and across taxa.
Our findings on the relationship between lateralities in hand and cheek pouch usage in bonnet macaques substantiate the possibility of a hand-mouth command system that could have evolved in the context of ingestion, but later could have given rise to hemispheric specializations associated with brain functions and behavior, for example, communication, as has been suggested before [@pone.0097971-Hopkins1], [@pone.0097971-Gentiluccia1]. Laterality in cheek pouch usage is likely to be dependent on some endogenous factors that might be related to division of labor or more specifically, the specialization of one cerebral hemisphere for several related/non-related motor-actions. This hypothesis warrants further exploration, more preferably using brain imaging technologies (e.g., magnetic resonance imaging (MRI)) that are now being increasing used in neurophysiological studies on non-human primates (see, for example, studies on capuchins [@pone.0097971-Phillips1]--[@pone.0097971-Phillips3] and chimpanzees [@pone.0097971-Hopkins5]. Lateralities in elementary brain functions could have been the precursor of the evolution of lateralities in relatively more voluntary brain functions and behavior. Thus, studies on the evolution of behavioral asymmetries should investigate motor-action patterns beyond hand usage.
[^1]: **Competing Interests:**The authors have declared that no competing interests exist.
[^2]: Conceived and designed the experiments: MM. Performed the experiments: MM ND. Analyzed the data: MM. Wrote the paper: MM ND MS.
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3/323
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Four letters picked without replacement from ppgoofppffoofog. Give prob of picking 3 p and 1 g.
8/1365
What is prob of picking 2 i when two letters picked without replacement from iiqiqiqqii?
1/3
Calculate prob of picking 3 w when three letters picked without replacement from lmmmwmbmmmwwmmbmlwm.
4/969
Three letters picked without replacement from {u: 2, b: 2, g: 1, m: 1, i: 1}. What is prob of picking 1 m, 1 g, and 1 b?
2/35
Two letters picked without replacement from gpikbibiqkb. What is prob of picking 1 i and 1 g?
3/55
What is prob of picking 1 m and 1 j when two letters picked without replacement from {o: 1, b: 1, m: 1, j: 1, f: 1}?
1/10
Four letters picked without replacement from uuuuuuucuccu. What is prob of picking 3 u and 1 c?
28/55
What is prob of picking 3 p and 1 g when four letters picked without replacement from {p: 6, g: 7, r: 6}?
35/969
Four letters picked without replacement from {r: 4, v: 15}. What is prob of picking 4 v?
455/1292
Four letters picked without replacement from dpodfoppdp. What is prob of picking 1 f, 2 p, and 1 d?
3/35
Three letters picked without replacement from {q: 2, g: 1, n: 1, c: 2, d: 10, l: 2}. What is prob of picking 1 g, 1 n, and 1 l?
1/408
Three letters picked without replacement from {c: 8, m: 4, n: 4}. Give prob of picking 3 c.
1/10
Two letters picked without replacement from {c: 1, h: 3, l: 1, t: 4, z: 4}. Give prob of picking 1 z and 1 t.
8/39
Three letters picked without replacement from {n: 4, y: 1, v: 3, z: 1, x: 2}. Give prob of picking 1 z and 2 x.
1/165
What is prob of picking 2 p when two letters picked without replacement from {s: 4, n: 1, p: 3}?
3/28
Three letters picked without replacement from {c: 5, t: 4, l: 4, v: 3}. What is prob of picking 1 v, 1 t, and 1 l?
3/35
Four letters picked without replacement from swwwwswsswwwwswswws. What is prob of picking 1 s and 3 w?
385/969
Two letters picked without replacement from gghuuuagaegyhyyyegu. What is prob of picking 1 g and 1 h?
10/171
Two letters picked without replacement from {q: 2, o: 1, l: 1, r: 1, t: 2, m: 2}. What is prob of picking 1 q and 1 o?
1/18
Calculate prob of picking 1 y and 1 w when two letters picked without replacement from iywyf.
1/5
Calculate prob of picking 2 s and 1 g when three letters picked without replacement from {s: 3, g: 3}.
9/20
Calculate prob of picking 1 x and 1 l when two letters picked without replacement from {l: 2, g: 1, c: 1, n: 4, x: 3}.
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Two letters picked without replacement from yyyyyyyyyyyyyyyyyhy. What is prob of picking 2 y?
17/19
Three letters picked without replacement from {p: 1, o: 1, n: 2, j: 4}. Give prob of picking 1 n, 1 p, and 1 o.
1/28
Calculate prob of picking 2 t and 1 i when three letters picked without replacement from ytxttxmxtimiytixmmxm.
1/38
Four letters picked without replacement from eeazllanannaen. What is prob of picking 3 e and 1 a?
4/1001
Three letters picked without replacement from ffkxfkzkzkkj. What is prob of picking 2 k and 1 f?
3/22
Calculate prob of picking 1 b and 1 v when two letters picked without replacement from {w: 4, d: 1, c: 2, v: 1, b: 1}.
1/36
Two letters picked without replacement from {y: 1, h: 1, q: 6, l: 5, j: 6}. What is prob of picking 1 q and 1 y?
2/57
What is prob of picking 2 a when two letters picked without replacement from {n: 2, f: 5, a: 6}?
5/26
Two letters picked without replacement from pzyzyk. Give prob of picking 1 p and 1 z.
2/15
What is prob of picking 1 g, 1 p, and 2 k when four letters picked without replacement from {h: 1, f: 2, g: 1, p: 1, u: 4, k: 6}?
1/91
Calculate prob of picking 2 x and 1 g when three letters picked without replacement from {k: 2, x: 3, g: 1, q: 6}.
3/220
Calculate prob of picking 2 z, 1 a, and 1 l when four letters picked without replacement from {b: 2, v: 1, x: 1, z: 1, l: 1, a: 1}.
0
Two letters picked without replacement from jbrvvjbljgv. Give prob of picking 2 b.
1/55
What is prob of picking 2 y when two letters picked without replacement from puyypppyu?
1/12
Four letters picked without replacement from {n: 1, w: 4, j: 3, r: 2}. What is prob of picking 2 w, 1 j, and 1 r?
6/35
Two letters picked without replacement from {q: 3, l: 8, i: 4, c: 2}. What is prob of picking 2 q?
3/136
Three letters picked without replacement from {q: 2, k: 2, u: 1, d: 1}. What is prob of picking 2 q and 1 u?
1/20
Four letters picked without replacement from {m: 3, q: 4}. What is prob of picking 4 q?
1/35
Four letters picked without replacement from vcgugwbuw. Give prob of picking 1 g, 2 w, and 1 b.
1/63
Two letters picked without replacement from {z: 1, e: 2, b: 1, i: 4, s: 1}. Give prob of picking 1 e and 1 z.
1/18
Two letters picked without replacement from zvezeeaedevzed. Give prob of picking 1 z and 1 e.
18/91
Two letters picked without replacement from ypykpzzvt. What is prob of picking 1 k and 1 t?
1/36
Two letters picked without replacement from {m: 6, y: 2}. What is prob of picking 1 m and 1 y?
3/7
Calculate prob of picking 1 w, 1 p, and 2 z when four letters picked without replacement from {u: 7, x: 1, w: 1, p: 2, z: 2, a: 1}.
2/1001
Three letters picked without replacement from {i: 3, r: 1, m: 8, c: 6}. Give prob of picking 3 i.
1/816
Four letters picked without replacement from ppppppupzzuyztz. Give prob of picking 3 p and 1 t.
1/39
What is prob of picking 2 f and 1 j when three letters picked without replacement from frfrrrffbj?
1/20
Calculate prob of picking 1 y and 1 n when two letters picked without replacement from yttythtttyyyytnyyt.
8/153
What is prob of picking 1 g and 2 u when three letters picked without replacement from uuuvguuuuiuvuuu?
11/91
Three letters picked without replacement from kklxgkxkmk. Give prob of picking 1 l, 1 x, and 1 m.
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Three letters picked without replacement from iquitq. Give prob of picking 3 q.
0
Calculate prob of picking 2 l and 1 h when three letters picked without replacement from {h: 2, l: 3, o: 2, u: 2}.
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What is prob of picking 1 v, 1 m, and 1 q when three letters picked without replacement from mqvv?
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Four letters picked without replacement from {p: 2, s: 5, w: 6}. What is prob of picking 1 p, 1 s, and 2 w?
30/143
Two letters picked without replacement from fjwjiijjuiuwjjii. What is prob of picking 2 j?
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What is prob of picking 1 y and 1 c when two letters picked without replacement from rcdyrrrcy?
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Three letters picked without replacement from mmaegmaqbmbeggemme. What is prob of picking 1 q and 2 e?
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Two letters picked without replacement from vnvvnvvnqvvnvvy. What is prob of picking 1 y and 1 v?
3/35
Two letters picked without replacement from qqqqmcckkccqk. What is prob of picking 2 q?
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Calculate prob of picking 1 t and 2 e when three letters picked without replacement from {e: 6, k: 2, i: 1, r: 1, t: 2}.
3/22
Four letters picked without replacement from scoooodovvv. Give prob of picking 1 v, 1 c, 1 o, and 1 d.
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Two letters picked without replacement from {m: 2, d: 2, c: 1, k: 1}. Give prob of picking 1 c and 1 m.
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Four letters picked without replacement from vkvvvvkv. Give prob of picking 1 k and 3 v.
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Calculate prob of picking 1 z and 2 j when three letters picked without replacement from jzzhjh.
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Calculate prob of picking 1 q, 1 l, and 1 g when three letters picked without replacement from {l: 3, f: 1, o: 1, q: 2, g: 5}.
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Calculate prob of picking 3 f when three letters picked without replacement from {f: 5, i: 5}.
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What is prob of picking 3 n when three letters picked without replacement from nuuuuunnnnnnunnu?
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Three letters picked without replacement from {g: 4, v: 7}. What is prob of picking 3 g?
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Two letters picked without replacement from {d: 13, v: 6}. Give prob of picking 1 v and 1 d.
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Two letters picked without replacement from nnnqqn. What is prob of picking 1 q and 1 n?
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Calculate prob of picking 1 a, 1 j, and 1 z when three letters picked without replacement from jzeejjeazzjeeez.
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Calculate prob of picking 3 v and 1 x when four letters picked without replacement from {v: 3, x: 2}.
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Two letters picked without replacement from vvkjhdjsk
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Carl Finamore, Machinist Local Lodge 1781 delegate to the San Francisco Labor Council, AFL-CIO, discusses his article “Military Orchestrates Egypt’s Presidential Elections;” how Tahrir Square protesters won free speech and labor reforms, but failed to change the military-dominated political system; how the West uses Islamic groups to counter secular nationalism in the Arab world; the US’s strategic interests in Egypt; and why Egyptians, fatigued from lengthy protests, are increasingly more concerned with the economy than politics.
Carl Finamore is Machinist Local Lodge 1781 delegate to the San Francisco Labor Council, AFL-CIO. He was in Cairo only hours after Mubarak was deposed and visited again a few months ago for the one year anniversary. He can be reached at [email protected] and his writings viewed on his website.
Great interview, but like many leftists, this guy is grossly ignorant of economics. The idea that neo-liberal economic policies in any way represent a “free-market” or real “privatization” is beyond ridiculous. Furthermore, while well intended, imposing a national minimum wage by force of law will ultimately shrink the economy, create less jobs and put more poor people out of work. Instead of actively seeking to control the levers of state power, they should simply be pushing to diminish and/or eliminate political power and violence all together. Truly free the market and you will free the workers!
Rick “Imposing a national minimum wage by force of law will ultimately shrink the economy.”
Allowing the 51% most educated and wealthy to establish a voter monopoly, such that the uneducated lower half of society has zero wealth, not even the $35 needed to get a sick kid in the doctor’s office, “by force of law will ultimately shrink the economy.”
So, what is this rich man’s brainwash that man’s government functions by “force of law”? For the sole purpose of government is to enslave the uneducated lower half of society, by having a monopoly on the use of force and violence.
Comes now the fundamental principle of natural and organic law and a concept that we have yet to see enforced by democracy, they all being ruled by the 51% most educated and wealthy.
Absolute good
“No one shall enrich themselves upon the misery of another.”
Remember, two years went by between the fall of Portugal's "Estado Novo" regime – due to a coup by (among others) left-leaning veterans of the colonial wars – and the establishment of a new government. No, things have not been ideal since then, but vastly improved.
What is the rush? It takes time to take a country from the brink of disintegration to the point where a parliament is elected, followed by a presidential elections. There is still much work to be done, including constitution adjustments to allow the reforms the new parliament will want.
Egypt is fortunate to have a functioning military to hold thigs together while all of this is being put in place. But there are always naive romantics that love protesting, and will protest for ever — given half the chance. The problem is, much has changed in Egypt for the better. They paid it by damaging their economy and tourism. So, the sooner they can get on with reforms and running the conomy, the better everyone will be. The governance will not work if turned over to the bunch of anarchists. The fact that islamist parties won is not a tragedy. Let them have a hand at governing, and if things do not get better, others will be elected.
If everyone in Egypt knew there was no tomorrow, that this day of life was more then they deserved and that there would be no tomorrow, then everyone would go for happiness which is give all you can give to those who have less then you. True happiness being to enrich yourself upon the enrichment of others.
But quite the reverse is it in the land of the perpetual Kings, for to a man do they imagine that this day of life is less then they deserve. So, feeling they all deserve to be rich they elect for a presidential runoff, the two millionaires best qualified to create a fast-track for getting rich.
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Q:
Why does a domain resolve to private IP
While going through a domain in the format as mentioned below , I did host lookup using the host command and got a private ip address.
auth-ns.auth-ns.workspace.agate.example.com
host auth-ns.auth-ns.workspace.agate.example.com
Why does an agate auth endpoint provide a private ip address ?
When I searched for agate I came to know agate is used to authenticate to obiba software stack.Is this how the obiba works ? Even it works like this why is it resolving to a private IP ?
The ip belongs to 172.16.0.0/12 CIDR
NOTE: I was not able to browse to the respective endpoint , I never got any response
A:
why is it resolving to a private IP ?
Your question seems to be based on the assumption that a DNS record cannot resolve to a "private" IP for some reason. There's no basis for the assumption, so the answer is "because that's what the person who created the record wants it to resolve to".
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Q:
ArcGIS 10.0/10.1 - arcpy - automate projection tool with different datum or projection
I am getting stuck with a task that is slightly different from the posts I found so far on this same website.
Assumption: all layers have a defined coordinate system
Problem: I would like to automate a python script (using arcGIS 10.1 but 10.0 is fine as well) that projects a list of vector layers (some of which with different coordinate systems) to a common coordinate system, given by a target vector layer. The main issue I would need help with is how to automate something this:
1) check if the coordinate system of the current vector layer is the same as the target layer
2) if not, check if the datum is the same
3) if it's the same datum, then project the current layer to the target layer without any datum transformation
4) if, instead, they do not have the same datum, pick a pre-defined transformation and include that in the projection function
Any help would be much appreciated! thanks!
Here is my sample code:
import arcpy
from arcpy import env
arcpy.gp.overwriteOutput = True
env.workspace = 'C:\\Temp'
Target_lyr = 'water_Broward.shp'
try:
desc = arcpy.Describe(Target_lyr)
TargetSR = desc.spatialReference
for inputFC in arcpy.ListFeatureClasses('*'):
if inputFC != Target_lyr:
inputFC_SR = arcpy.Describe(inputFC).spatialReference
if inputFC_SR.Name == TargetSR.Name:
continue
else:
#check if current layer and target layer are the same type
#thus if they are both 'projected' or 'geographic'
if inputFC_SR.type == TargetSR.type:
#HELP STARTING FROM HERE...
#Check if both have same datum..
#if they ARE, then
#outFC = inputFC + '_prj.shp'
#arcpy.Project_management(inputFC, outFC, TargetCS)
#if datum is NOT the same use
#transformation = for example "WGS_1972_To_WGS_1984_1"
#arcpy.Project_management(inputFC, outFC, TargetCS,transformation)
#if current layer and target layer are NOT same kind
else:
#HELP
#repeat as above same steps as above to check the datum
except:
print arcpy.GetMessages()
A:
some relevant functionality below. all of which is new at 10.1.
with projected coordinate system, you have access to the GCS object which is where the datum info lives. if you're working with a GCS object already, just access the relevant datum properties (datumName, datumCode) directly.
from_sr = arcpy.SpatialReference('NAD 1983 HARN UTM Zone 11N')
to_sr = arcpy.SpatialReference('NAD 1927 StatePlane California VI FIPS 0406')
print("from sr datum: " + from_sr.GCS.datumName)
print(" to sr datum: " + to_sr.GCS.datumName)
# list transformations valid for San Diego county
outlist = arcpy.ListTransformations(from_sr, to_sr,
arcpy.Extent(444450.2212, 3599832.1877,
585727.9387, 3707930.3429))
print("valid transformation: " + outlist[0])
The code above will give you these outputs
from sr datum: D_North_American_1983_HARN
to sr datum: D_North_American_1927
valid transformation: NAD_1983_To_HARN_CA_S + NAD_1927_To_NAD_1983_NADCON
The ListTransformation's extent is optional but you could pass in you data's extent for best transformation. This is the same functionality used in gp's Project tool (to pick default transformation) as well as map's data frame. Documentation link
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Friday, July 26, 2013
Spaccanapoli, Crowne Plaza Abu Dhabi
Lately , we have gone to this restaurant. The food is great and the service pretty good too. One of their boasts is that it is the 'home of the one metre pizza'. So, when in Rome (or Hamdan Street)....
You can order them for take away or home delivery too. The have special long boxes to put them in, although I am a little concerned about how the moped rider manages?! I have to say, it was delicious and well worth a try.
About Me
I moved to Abu Dhabi in June 2008 from Eynsford, Kent. Eynsford is a quaint, typical English village where my 250 year old home was nestled between two pubs.
Abu Dhabi was quite a contrast. There is nothing much there that is more than c.50 years old. In summer it is also about 30 degrees hotter!
I went to earn a bit of tax-free money (didn't really have much to show for it by the end!) and to gain some life experience (but came home with bags of this).
This blog is a record of my time there, so I can share some of what I experienced.
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Inhibition of microglial inflammation by the MLK inhibitor CEP-1347.
CEP-1347 is a potent inhibitor of the mixed lineage kinases (MLKs), a distinct family of mitogen-activated protein kinase kinase kinases (MAPKKK). It blocks the activation of the c-Jun/JNK apoptotic pathway in neurons exposed to various stressors and attenuates neurodegeneration in animal models of Parkinson's disease (PD). Microglial activation may involve kinase pathways controlled by MLKs and might contribute to the pathology of neurodegenerative diseases. Therefore, the possibility that CEP-1347 modulates the microglial inflammatory response [tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1)] was explored. Indeed, the MLK inhibitor CEP-1347 reduced cytokine production in primary cultures of human and murine microglia, and in monocyte/macrophage-derived cell lines, stimulated with various endotoxins or the plaque forming peptide Abeta1-40. Moreover, CEP-1347 inhibited brain TNF production induced by intracerebroventricular injection of lipopolysaccharide in mice. As expected from a MLK inhibitor, CEP-1347 acted upstream of p38 and c-Jun activation in microglia by dampening the activity of both pathways. These data imply MLKs as important, yet unrecognized, modulators of microglial inflammation, and demonstrate a novel anti-inflammatory potential of CEP-1347.
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Effervescence Sponsors and Partners
We would like to thank the following sponsors, without whom the smooth running of the Festival would not be possible
Click on the logos below to find out more about our partners & sponsors
Diamond Partners
Truffle & Wine Co
At the heart of Manjimup’s famed Seven Day Road is the home of Western Australia’s first truffière, The Truffle & Wine Co. Surrounded by vineyards, orchards and majestic rolling hills, our estate produces rare and delicious black winter truffles (Tuber melanosporum) and award-winning cool climate wines.
Since its establishment in 1997, passion and dedication, coupled with an extraordinary microclimate, has seen The Truffle & Wine Co. become the largest producer of superior black perigord truffles in the world and a premier truffière
It might be said that Xennox Diamond Story began in 1976 when Wolfgang opened the doors to one of Brisbane’s first jewellery stores that specialized in hand crafting beautifully designed engagement rings. However, the truth is the story began in 1960, as this was when Wolfgang first fell in love with beautiful jewellery. It was then, in Germany, as an apprentice to Europe’s best Master Jewellers that he first learnt the art of creating unique hand crafted pieces
Over the last 41 years the Xennox family has travelled the world in search of latest trends and designs to ensure only the most amazing pieces are featured in their showroom. Designs that have seen them win over ten national design awards including the prestigious DeBeers Supreme Design Award.
Proudly supported by
Ipswich City Council
As Queensland's oldest provincial city, Ipswich has a rich history. It is renowned for its architectural, natural and cultural heritage. Ipswich proudly preserves and still operates from many of its historical buildings and homes, with more than 6000 heritage-listed sites. Ipswich also has a range of charming townships within the western rural areas of the city, each with its own legitimate claims of historical significance. Ipswich City Council is proud to support the Effervescence Champagne Festival - a region with it’s own strong historical significance.
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If you ever imbibe, you may have heard the latest buzzword: Natural wine.
And you may have wondered: Isn't all wine technically natural? Here's the answer to that question, and a few more questions you might have about the newest trend for wine enthusiasts:
How is natural wine different from "regular" wine?
With "regular" wine, the grape is manipulated before it turns into a wine. Conventional winemakers use commercial yeast, filtration systems and preservatives with sulfites in the fermentation process, whereas natural winemakers say they use fewer sulfites and only naturally occurring yeast.
Is natural wine the same thing as organic wine?
Not exactly. Natural wine is made from organic grapes and is minimally processed using little to no additives, but that doesn't mean that natural wine is just another name for certified organic wine.
The U.S. Department of Agriculture regulates organic wine, which dictates the way the grapes are grown, but there are no federal regulations for what classifies a natural wine. There are some non-government organizations like the Demeter Association that do certify biodynamic wineries (an even more strict version of natural wine).
Related:Pumpkin drinks and holiday cocktail recipes for Thanksgiving, fall and beyond
What is natural wine, exactly?
Although the idea of natural wine is relatively new in the U.S., winemakers in France have been making minimally processed wine since the 1980s.
"While natural wine is a somewhat nebulous term, broadly I would say it is wine that comes from grapes farmed with as little intervention as possible, transformed into wine with as little intervention as possible," Marlen Porter, co-founder of Amplify Wines, a winery in Santa Barbara County, told USA TODAY.
Drew Cuddy, founder of Satellite, a farm to table restaurant and wine shop in Santa Barbara that specializes in natural wines describes natural wines as a return to traditional, laborious farming.
"Rather than wine making (natural winemakers) focus on wine growing," Cuddy told USA TODAY. "It’s much more about farming than manipulating the product and sort of letting the fruit lead the fermentation of the wine."
Natural winemakers do this by using naturally occurring yeast on the grapevine instead of a commercial yeast strain which in turn produces distinctive flavors, Cuddy said.
"There’s yeast everywhere -- that’s one thing that comes along with a healthy vineyard is you have healthy yeast in your vineyard," Cuddy said. "With natural yeast you get something that is very dynamic because every year you can get a unique yeast strain."
Related:The latest beers are inspired by booze
Why am I just now hearing about natural wines?
The natural wine craze is an extension of the healthy lifestyle movement, the winemakers said.
"The broad public desire to know where their food comes from has now begun extending to drinks, and people are turning their attention to where their beverages come from not just with wine but beer, spirits, etc. So I think the transparency of natural wine is very appealing," Porter said.
Michael Roth, co-owner of Lo-Fi Wines, a winery in Santa Barbara County, agrees.
"I think people are more concerned about how things are grown and what they put in their bodies and I think people are more interested in knowing how things are made as a consumer," Roth said.
But is natural wine healthier than conventional wine?
"I don’t know if wine in general is healthy, yes I guess there’s health benefits to wine, but to say that it’s healthy? I don't know," Roth said. "Is American cheese healthier than a natural artisan cheese? -- Not to say that conventional wine is American cheese."
While Porter also wouldn't say that natural wine is healthier, she has noticed a pattern when it comes to drinking it.
"While I would love to say it’s healthier, I can’t say that there’s any scientific evidence. I think people experience less headaches, allergies and hangovers which could suggest it’s healthier than conventionally made wine," Porter said.
How should I choose a natural wine?
When it comes to selecting and purchasing a bottle of natural wine, Roth, Porter and Cuddy recommend working with a reputable distributor -- one that sells natural wines or works with natural wineries.
"Find a trusted curator, be that a winery, a local retailer, or a sommelier who can provide direction based on your personal taste and interests is the best place to start," Porter advises.
"Natural wine is such a broad category, with as vast an array of styles, grapes and wines as one would find in conventionally made wine, that you really need to explore it with a guide whose palate you trust."
Roth also suggests being adventurous and not always letting critics guide your choice.
"Listen to your local retailer, just because it has a high rating (from critics) doesn’t mean you’ll like it," Roth said.
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Navajo child's blanket
Navajo child's blanket
0.01
36" wide x 46" log
handspun synthetic-dyed wool
circa 1880-1890s
excellent condition. a few very small spots on one side that may clean out.
SOLD
(mc2118)
Add To Cart
This child's blanket has wonderful abrache, with soft to deeper tone reds. In addition, the stepped design is woven out of handspun white, green wools. It has a classic Transitional blanket-like design, still showing influence from earlier times.
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So the Minnesota legislature held a sexual harassment training for elected officials. How did it go?
SEVERAL WOMEN LEFT PISSED OFF AND AT LEAST ONE OF THEM CRIED! WTF?!
There are at least two women in office that had to deal with sexual harassment by other legislators; on what planet was it ever okay to run a training without at least running it by them for input first? Ugh, men are trash.
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Status quo for Calgary's housing market (CREB Report)
October's housing market conditions closely echoed previous month's trends with easing sales, rising inventories and downward price pressure. Like last month, the monthly activity was not enough to derail gains that occurred earlier in the year.
October sales and inventories totaled 1,467 and 6,463 units for a month of supply of 4.4. Several months of elevated supply in comparison to demand has weighed on pricing over the past several months. The city-wide unadjusted benchmark price in October totaled $438,900, 0.6 per cent below last month, but comparable to last year.
"While economic activity has improved in 2017, it will take some time for this to translate into housing market growth. There have been employment gains, but most of this has occurred in areas with traditionally lower income," said CREB® chief economist Ann-Marie Lurie.
"We also continue to face weak migration, higher lending rates and changes to lending policy. The combination of these factors is impacting housing demand, which is prolonging the pace of recovery."
Resale inventory gains occurred in each product type and across most districts in the city. The largest gains were in districts with substantial new development growth.
In the detached segment, the largest number of units added to inventory occurred in the $300,000 - $500,000 price range. This represents nearly 42 per cent of all detached inventory. 62 per cent of the inventory in the city-wide market is priced below $500,000.
"There is far more product availability in the lower price ranges now compared to several years ago," said CREB® president David P. Brown.
"This provides more options for potential buyers concerned about their purchasing power given all the changes in the lending market."
The largest monthly price change occurred in the apartment condominium sector which recorded an unadjusted monthly decline of 0.8 per cent, resulting in a 13 per cent spread over monthly highs recorded in 2014.
Despite some recent adjustments, prices in the attached and detached segments remain relatively stable compared to last year.
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import React from 'react';
import PropTypes from 'prop-types';
import { Text, Link, Image, Code, Space, Line, Documentation, List, ListItem, Table, TableRaw, TableCell } from './elements';
import * as TYPES from './types';
/**
* Parser - parser component
* @param props
* @return {ReactElement} markup
*/
const Parser = (props) => {
const { data } = props;
const {
type,
children,
items,
href,
alt,
title,
lang,
depth,
file,
} = data;
const content = children || items;
const contentIsString = typeof content === 'string';
const renderContent = () => {
if (content) {
return contentIsString ? (
content
) : (
content.map((c, key) => {
if (typeof c === 'string') return c;
return <Parser data={c} key={key} />; // eslint-disable-line
})
);
}
return null;
};
if (type === TYPES.HEADING) {
return (
<Text type={`h${depth}`}>
{renderContent()}
</Text>
);
}
if (type === TYPES.PARAGRAPH) {
return (
<Text type="b1">
{renderContent()}
</Text>
);
}
if (type === TYPES.CODESPAN) {
return (
<Text type="code">
{renderContent()}
</Text>
);
}
if (type === TYPES.STRONG) {
return (
<Text type="strong">
{renderContent()}
</Text>
);
}
if (type === TYPES.ITALIC) {
return (
<Text type="i">
{renderContent()}
</Text>
);
}
if (type === TYPES.BLOCKQUOTE) {
return (
<Text type="blockquote">
{renderContent()}
</Text>
);
}
if (type === TYPES.LINK) {
return (
<Link
href={href}
title={title}
>
{renderContent()}
</Link>
);
}
if (type === TYPES.IMAGE) {
return (
<Image
href={href}
alt={alt}
title={title}
>
{renderContent()}
</Image>
);
}
if (type === TYPES.CODE) {
return (
<Code
lang={lang}
>
{renderContent()}
</Code>
);
}
if (type === TYPES.LIST) {
return (
<List>
{renderContent()}
</List>
);
}
if (type === TYPES.LIST_ITEM) {
return (
<ListItem>
{renderContent()}
</ListItem>
);
}
if (type === TYPES.TEXT) {
return (
<Text>
{renderContent()}
</Text>
);
}
if (type === TYPES.SPACE) {
return <Space />;
}
if (type === TYPES.LINE) {
return <Line />;
}
if (type === TYPES.TABLE) {
return (
<Table align={props.data.align}>
{renderContent()}
</Table>
);
}
if (type === TYPES.TABLE_HEAD_RAW || type === TYPES.TABLE_RAW) {
return (
<TableRaw>
{renderContent()}
</TableRaw>
);
}
if (type === TYPES.TABLE_HEAD_CELL || type === TYPES.TABLE_CELL) {
return (
<TableCell head={type === TYPES.TABLE_HEAD_CELL} align={props.data.align}>
{renderContent()}
</TableCell>
);
}
if (type === TYPES.DOCUMENTATION) {
return (
<div>
{Object.keys(file).map((f, index) => (
<Documentation data={file[f]} key={index} /> // eslint-disable-line
))}
</div>
);
}
if (type === 'html') {
const html = props.data.children.map(el => el.children || el).join('');
return (
<div dangerouslySetInnerHTML={{ __html: html }} />
);
}
return (
<div>NEED PARSE TYPE - {type}</div>
);
};
/**
* PropTypes
* @type {{
* data: {
* type: string
* children: array|string
* items: array|string
* ordered: boolean
* href: string
* alt: string
* title: string
* lang: string
* depth: number
* file: object
* }
* }}
*/
Parser.propTypes = {
data: PropTypes.shape({
type: PropTypes.string.isRequired,
children: PropTypes.oneOfType([
PropTypes.array,
PropTypes.string,
]),
items: PropTypes.oneOfType([
PropTypes.array,
PropTypes.string,
]),
ordered: PropTypes.bool,
href: PropTypes.string,
alt: PropTypes.string,
title: PropTypes.string,
lang: PropTypes.string,
depth: PropTypes.number,
file: PropTypes.oneOfType([
PropTypes.object,
]),
align: PropTypes.oneOfType([
PropTypes.string,
PropTypes.arrayOf(PropTypes.any),
]),
}),
};
Parser.defaultProps = {
data: {
type: '',
children: '',
align: [],
},
};
export default Parser;
|
A southwest Washington school principal has been put on administrative leave after suggesting former NBA star Kobe Bryant’s death was deserved.
On the day Bryant and several others were killed in a helicopter crash, Camas High School Principal Liza Sejkora posted to her personal Facebook page, "Not gonna lie. Seems to me that karma caught up with a rapist today.”
She apologized Monday.
The Camas School District superintendent said in a message to the school community the next day: “In light of threats to Dr. Sejkora and concern from our community, Dr. Sejkora has been placed on administrative leave today pending the outcome of our investigation.”
According to KGW (8,) students are planning a nine-minute walkout for Thursday — one minute for each helicopter crash victim. The walkout was initially planned for Wednesday.
Bryant, his daughter Gianna and seven other people were killed Jan. 26 in a helicopter crash in suburban Calabasas, California.
Sejkora wrote later Jan. 26 that she deleted her controversial post “because the comments missed my intent. You are free to judge me for the post just as I am free to judge the person the post was about.”
She said in a message to families Monday that she wanted “to apologize for suggesting that a person’s death is deserved. It was inappropriate and tasteless.”
She also apologized for the disruption her post caused at school Monday and referred to it as “a personal, visceral reaction.”
“In education, we remind students to think before they post online, especially when feelings are inflamed,” she said. “We also teach our students about context. My emotions and past experiences got the best of me in that moment. We also teach our students that what we share online has permanency.”
In 2003, Bryant was accused of raping a 19-year-old employee at a Colorado resort. He said the two had consensual sex, and prosecutors later dropped the felony sexual assault charge at the request of the accuser. The woman later filed a civil suit against Bryant that was settled out of court.
-- Jim Ryan; [email protected]; 503-221-8005; @Jimryan015
The Associated Press contributed to this report
Subscribe to Oregonian/OregonLive newsletters and podcasts for the latest news and top stories.
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By 2100, the world’s energy system will be radically different from today’s. Renewable energy like solar, wind, hydroelectricity, and biofuels will make up a large share of the energy mix, and nuclear energy, too, will have a place. Humans will have found ways of dealing with air pollution and greenhouse gas emissions. New technologies will have reduced the amount of energy needed to power buildings and vehicles.
Indeed, the distant future looks bright, but much depends on how we get there. There are two possible routes. Let’s call the first scenario Scramble. Like an off-road rally through a mountainous desert, it promises excitement and fierce competition. However, the unintended consequence of “more haste” will often be “less speed,” and many will crash along the way.
The alternative scenario can be called Blueprints, which resembles a cautious ride, with some false starts, on a road that is still under construction. Whether we arrive safely at our destination depends on the discipline of the drivers and the ingenuity of all those involved in the construction effort. Technological innovation provides the excitement.
Regardless of which route we choose, the world’s current predicament limits our room to maneuver. We are experiencing a step-change in the growth rate of energy demand due to rising population and economic development. After 2015, easily accessible supplies of oil and gas probably will no longer keep up with demand.
As a result, we will have no choice but to add other sources of energy – renewables, yes, but also more nuclear power and unconventional fossil fuels such as oil sands. Using more energy inevitably means emitting more CO2 at a time when climate change has become a critical global issue.
In the Scramble scenario, nations rush to secure energy resources for themselves, fearing that energy security is a zero-sum game, with clear winners and losers. The use of local coal and homegrown biofuels increases fast. Taking the path of least resistance, policymakers pay little attention to curbing energy consumption – until supplies run short. Likewise, despite much rhetoric, greenhouse gas emissions are not seriously addressed until major shocks trigger political reactions. Since these responses are overdue, they are severe and lead to energy price spikes and volatility.
The Blueprints scenario is less painful, even if the start is more disorderly. Numerous coalitions emerge to take on the challenges of economic development, energy security, and environmental pollution through cross-border cooperation. Much innovation occurs at the local level, as major cities develop links with industry to reduce local emissions. National governments introduce efficiency standards, taxes, and other policy instruments to improve the environmental performance of buildings, vehicles, and transport fuels.
Moreover, as calls for harmonization increase, policies converge across the globe. Cap-and-trade mechanisms that put a price on industrial CO2 emissions gain international acceptance. Rising CO2 prices in turn accelerate innovation, spawning breakthroughs. A growing number of cars are powered by electricity and hydrogen, while industrial facilities are fitted with technology to capture CO2 and store it underground.
Against the backdrop of these two equally plausible scenarios, we will know only in a few years whether December’s Bali declaration on climate change was just rhetoric or the start of a global effort to counter it. Much will depend on how attitudes evolve in China, the European Union, India, and the United States.
Shell traditionally uses its scenarios to prepare for the future without expressing a preference for one over another. But, faced with the need to manage climate risk for our investors and our descendants, we believe the Blueprints outcomes provide the best balance between economy, energy, and environment.
Presented without comment.
Wow. Powerful stuff. Wouldn't it be amazing to see the detailed scenario work behind this letter?
Public summaries of previous scenario work at Shell can be found at this site The new ones are in the making.
Posted by: Rene on 28 Jan 08
Biofuels are a non-starter for a number of reasons:
Larger carbon footprint to produce and I suspect that people will not be willing to sacrafice their food supply to scrape the last bit of energy out of a arid mid-west.
And capturing and storing C02 undergraound is a "fairy-tale" without any backing in science. No suprise that a petroleum CEO is touting a fairy-tale. They have been doing it for decades.
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Distribution of ischemic neuronal damage in the dorsal hippocampus of rat.
Selective neuronal death was investigated in dorsal hippocampus of rats subjected to 30 min of four-vessel occlusion (4VO) and recirculation times of 3, 8, 24, 48, and 72 h. Anatomical orientation was achieved in different subsectors by use of histochemical techniques for the enzyme acetylcholinesterase (AChE) and for heavy metals (Timm-stain). A systematic study of subsectors was performed in different section levels from mid-dorsal levels to the septal pole of the hippocampus. In the hilus of the dentate gyrus, there was early neuronal injury accompanied by microvacuolation of the neuropil. Delayed neuronal death occurred in sector CA1 in parallel to CA2 damage. The use of the Timm-stain allowed the first direct documentation of involvement of CA2 in ischemic injury. The CA3 sector was largely spared from lesions at mid-dorsal levels. At the septal extreme, however, there were lesions of CA3 pyramidal cells, and also portions of the dentate gyrus granule cells were affected. These findings demonstrate that all areas of the hippocampus can be involved in ischemic injury, depending on their position along the temporoseptal axis of the hippocampal formation.
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When it comes to break out hits over the past few years, few can look past Payday: The Heist. Launching on PSN, PC and Xbox Live, the game was a downloadable masterpiece that tasked you with grouping up with friends to take down some in-game banks. The beauty of this game came from the team work required - it was not a run and gun game, by any stretch of the imagination, and you really had to strategize against the AI team mates. In fact, the game became such a hit that Starbreeze Studios purchased the developers (Overkill) and tasked them with taking on Payday 2. The game is back as a full retail release and we recently went hands on with a near final version to see how things are shaping up.
For those who haven't played the original Payday, the game basically revolves around you and a team of three taking down banks. There isn't too much of a story to go with it, although that has changed somewhat in Payday 2. Before each mission, you are presented with a small information cut scene to detail what you need to do and how. Aside from that, you are on your own, and in a multiplayer focused game, that isn't surprising.
One of the concerns we have with the game at this near late stage is the single player component. There is zero doubt that this is a game driven by multiplayer, but the single player component is frustrating right now. The key point is that you cannot control your AI comrades to perform tasks. To give you an example, in one mission, it tasked us with grabbing three bags of jewellery from a store and taking it to a van. In multiplayer, this mission is generally a piece of cake, but in single player it was a nightmare.
The reason being you as the single player have to carry each bag back one at a time and dump it in the car. The reason why this is quite frustrating is that the same problem was present in the original game and so not much has changed. The offline component is definitely more for training than a significant single player campaign, but considering how useless the AI is, we wonder if it should even be there at all. Hopefully something changes before the release in this aspect.
However, move onto the multiplayer, and you start to see why Payday 2 is one of the most anticipated games of the year. It takes everything right with the original game and continues it, whilst improving and including some brand new features to really take it to the next level. As you complete heists, you gain experience points, which level your persistent character up and at some point you will need to choose between four specialities. This again makes the single player component hard, but again shines in multiplayer.
One concern we do have is that you cannot (it appears) run multiple characters. So, for example, if you specialize in explosives, you may need to find a group all the time that needs an explosives expert.
This may not necessarily turn out to be a huge problem, but in a game so multiplayer focused and class based, in the longer term, it may be. There is nothing wrong with having four technicians for example, it just makes the missions a tad more difficult to complete.
So, the actual gameplay revolves around levelling up your character and taking missions on from an in-game Crime.net system. The missions are randomly generated and as your characters progress in level, they become more and more difficult, with some taking place over multiple heists and days. Missions we have seen so far including robbing a small bank, stealing some cocaine, taking out a jewellery store and terrorising four stores within a small area. There is a huge variety to the missions we can see already and each has a random level of difficulty set and also has randomly placed items, so whilst you might think you are playing the same mission, in most cases you are not due to the variation.
In each mission there is also a whole bunch of ways to tackle problems and situations that may arise - there is also generally a risk reward element to each one. For example, you can silently knock a guard out and then patch in a radio to be able to communicate with the other guards. The risk is that every so often the guards won't believe you and trigger an alarm. Once an alarm is triggered, the police will arrive and it really does just turn into a shootout at that point... generally not what the game is about.
The whole beauty of Payday 2 is in its intricate detail and planning. This is a game that you need to use your brains and team work to really do well in. This can easily be seen by the three phases in the game - planning, casing and finally the execution phase. In the planning phase, you can use money to unlock items that make the mission easier or customize your load out.
After which you move into the casing phase. Your characters can freely move about the environment figuring out where cameras and other detection devices may be, but there is always the risk that you will be detected and finally the execution phase where it either all goes to crap or runs perfectly, depending on how well you planned.
During the planning phase, you can use money obtained in earlier heists to unlock additional help during the next mission. That help may be something as small as another way to enter the target building, through to something like a camera feed to help you keep an eye on the cops. This takes the strategy and planning to another level in Payday 2, and utilizing this will be the key to success.
In the multi-day missions, your performance is looked at during each mission to see how the heist will progress. If you perform poorly during a mission and alert the cops, you will most likely then encounter an escape mission, but perform well and that will not happen. Dynamic changing of events is a core component of this game and will really add to the replay value.
This is why the game is one of our most anticipated for the year. It really has the potential to be a deep game with incredible gameplay and the version we played definitely has an inkling of that. No two games ever play out the same, and despite the focus on multiplayer gameplay, it's still looking like it could be one of the year's best.
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Q:
Resize Images on the Fly with AWS Lambda and Amazon API Gateway
I followed the tutorial on this page HERE
but when I try to get a resized picture I get an "Access Denied"
Good: https://xxxx.amazonaws.com/mybucket/test.jpg
Error: https://xxxx.amazonaws.com/mybucket/300x300/test.jpg (access denied)
<Error>
<Code>AccessDenied</Code>
<Message>Access Denied</Message>
</Error>
Below my settings:
Bucket policy editor
{
"Version": "2012-10-17",
"Statement": [
{
"Sid": "AddPerm",
"Effect": "Allow",
"Principal": "*",
"Action": "s3:GetObject",
"Resource": "arn:aws:s3:::mybucket/*"
}
]
}
When I created the trigger, I selected Security: OPEN. I'm just confused about the YOUR_API_HOSTNAME_HERE. In the example, the api hostname is h3ll0w0rld?
A:
GetObject action is not enough. You should give lambda permission to list the content as well . Also notice Resources section that I put.
{
"Version": "2012-10-17",
"Statement": [
{
"Sid": "AddPerm",
"Effect": "Allow",
"Action": [
"s3:Get*",
"s3:List*"
],
"Principal": { "Service": "lambda.amazonaws.com" },
"Resource": [
"arn:aws:s3:::mybucket/*",
"arn:aws:s3:::mybucket"
]
}
]
}
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// RUN: %clang_cc1 -triple %itanium_abi_triple -emit-llvm %s -o - | FileCheck %s
#pragma weak zex
int zex;
// GCC produces a weak symbol for this because it matches mangled names.
// Different c++ ABIs may or may not mangle this, so we produce a strong
// symbol.
// CHECK: @zex = global i32
#pragma weak foo
struct S { void foo(); };
void S::foo() {}
// CHECK-LABEL: define {{.*}}void @_ZN1S3fooEv(
#pragma weak zed
namespace bar { void zed() {} }
// CHECK-LABEL: define {{.*}}void @_ZN3bar3zedEv(
#pragma weak bah
void bah() {}
// CHECK-LABEL: define {{.*}}void @_Z3bahv(
#pragma weak baz
extern "C" void baz() {}
// CHECK-LABEL: define weak {{.*}}void @baz(
#pragma weak _Z3baxv
void bax() {}
// GCC produces a weak symbol for this one, but it doesn't look like a good
// idea to expose the mangling to the pragma unless we really have to.
// CHECK-LABEL: define {{.*}}void @_Z3baxv(
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WASHINGTON -- New video released by the Pentagon shows the successful test of a missile defense system meant to protect against an intercontinental ballistic missile (ICBM) under development by North Korea.
The video shows the launch of a target missile from the Kwajalein Atoll in the Marshall Islands on Tuesday, followed by a shot of an interceptor missile launching from a silo at Vandenberg Air Force Base in California.
Infrared footage shows the collision between the missile and the interceptor.
Infrared footage shows a successful intercept of a mock warhead on Tuesday, May 30, 2017. Missile Defense Agency
Vice Adm. Jim Syring, director of the Missile Defense Agency, said the successful test represented a specific real-world scenario, CBS News national security correspondent David Martin reports.
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Pyongyang is understood to be moving closer to the capability of putting a nuclear warhead on such an ICBM and could develop decoys sophisticated enough to trick an interceptor into missing the real warhead. The target missile used in Tuesday's test deployed decoys meant to throw the interceptor missile off its trail.
Syring said in a briefing that the main difference between the test and a North Korean missile launch was the location of the test, which was conducted much further south in the Pacific than the trajectory of a potential North Korean strike. As a result, radar systems in Japan and Alaska weren't in use during the test.
The successful test was hailed as a triumph, with Syring saying the result was "an incredible accomplishment" that marked a critical milestone for a missile defense program hampered by setbacks over the years.
However, Syring's agency also sounded a note of caution after the $244-million test.
"Initial indications are that the test met its primary objective, but program officials will continue to evaluate system performance based upon telemetry and other data obtained during the test," an earlier written statement said.
In Tuesday's U.S. test, the Pentagon's Missile Defense Agency launched an interceptor rocket from an underground silo at Vandenberg Air Force Base in California. The target was an intercontinental-range missile fired from a test range on Kwajalein Atoll in the Pacific.
According to the plan, a 5-foot-long "kill vehicle" released from atop the interceptor zeroed in on the ICBM-like target's mock warhead outside Earth's atmosphere and obliterated it by sheer force of impact, the Pentagon said. The "kill vehicle" carries no explosives, either in testing or in actual combat.
The target was a custom-made missile meant to simulate an ICBM, meaning it flew faster than missiles used in previous intercept tests, according to Christopher Johnson, the Missile Defense Agency's spokesman. It was not a mock-up of an actual North Korean ICBM, and details of its exact capabilities weren't made public.
Officially known as the Ground-based Midcourse Defense system, the Pentagon likens the defensive tactic to hitting a bullet with a bullet. With congressional support, the Pentagon is increasing by the end of this year the number of deployed interceptors, based in California and Alaska, to 44 from the current total of 36.
While Tuesday's test wasn't designed with the expectation of an imminent North Korean missile threat, the military wants progress toward the stated goal of being able to shoot down a small number of ICBMs targeting the United States.
Laura Grego, senior scientist at the Union of Concerned Scientists, which has criticized the missile defense program, called the interceptor an "advanced prototype," meaning it is not fully matured technologically even if it has been deployed and theoretically available for combat since 2004. A successful test Tuesday, she said, could demonstrate the Pentagon is on the right track with its latest technical fixes.
"Overall," she wrote in an analysis prior to the test, the military "is not even close to demonstrating that the system works in a real-world setting."
The interceptors are, in essence, the last line of U.S. defense against an attack by an intercontinental-range missile.
The Pentagon has other elements of missile defense that have shown to be more reliable, although they are designed to work against medium-range or shorter-range ballistic missiles. These include the Patriot missile, which numerous countries have purchased from the U.S., and the Terminal High-Altitude Area Defense, or THAAD, which the U.S. deployed this year to South Korea to defend against medium-range missiles from North Korea.
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Healthy Vegetarian and Vegan Fare in Indianapolis
With the start of the new year, many people are making the resolution to eat healthier by cutting out fat and carbs or choosing to eliminate meat entirely. I’m definitely trying to do my part by moderating what good and bad foods I eat, and so I’m choosing the asparagus and eggplant options at restaurants instead of the New York Strip. These are a few places I’ve found to complement my approach to dining that any vegetarian or vegan would be impressed with.
Gorgonzola Salad with Mushroom Soup
Tulip Noir – Some of the best restaurants are hidden in the most plain and disguising strip malls in town, and Tulip Noir is one of them. Located near 86th and Ditch Road, this small cafe is a treasure of soups, salads and sandwiches that won’t disappoint your need for creative vegetarian options. Enjoy a weekend brunch with their gluten-free, vegan Gingerbread Buckwheat Waffle or go for a weekday lunch and grab a vegetarian Black Bean Quesadilla. Just don’t ask for a Diet Coke – they prefer to sell hot or iced teas than sodas!
ZestExciting Food Creations – This place is perfect for a relaxed lunch or a date night dinner. The cheese board appetizer is full of surprises like… blueberry cheese. It was beautiful and delicious. Pommes frites with white truffle oil and asiago cheese are impossible to resist, but don’t fill up too much because the entrees are of healthy proportions. I ordered the Chiles Rellenos, a vegetarian plate of a roasted poblano with creamy mac and cheese stuffed inside, perfectly seasoned black beans, rice and tortilla crumbles with a slightly sweet tomato sauce. Or, go for something lighter like the Veggie Burger with herbed cashew cream and kale or the Tempeh Bahn Mi with asian pickles and sweet chili aioli.
SoBro Cafe – Known for their various assortments of pancakes, SoBro Cafe has become one of my new favorite lunch spots. I love their take on savory pancakes, with The Mushroom (mushrooms, sweet corn, tomato and cheese) or the The Popeye (spinach, sautéed red pepper and swiss). Have I said before how much I love anything on pretzel rolls? SoBro Cafe won me over with The Good Burger, which has avocado, tomato, sprouts and garlic aioli in between two soft, sweet pretzel rolls. Soon I’m going to go back for dinner so I can try their Bar-B-Q Lentil Stew and the Sweet and Sour Cabbage. Okay, maybe two more visits.
House salad with Creamy Potato Soup
Taste Cafe & Marketplace – Just next door to SoBro Cafe is Taste Cafe, with an equally exciting menu that can be eaten there or taken home for later. I’m always impressed by the amount of items Taste offers for breakfast, lunch and “after-taste” dinner on Wednesday and Thursday. Just like Zest, the Pommes Frites are irresistible and topped with herbs and enjoyed with a basil aioli. I frequent between two sandwiches, The Veggie with roasted portobello and The Erin with asparagus and sprouts, or their sweet creamy potato soup with a house salad packed with fresh veggies.
Yats – I have to admit that one of my favorite things about the cajun creole food at Yats is that it’s fast, good and cheap. Black beans with caramelized corn and spinach and mushroom etouffee are two of my favorites. Got a big appetite or can’t decide what to get? Get a half & half with both! And you absolutely MUST get extra bread. That was the first tip I ever left on Foursquare and it’s the highest rated one with no surprise to me. You just have to get extra pieces to sop it all up.
Duos Truck – My first experience with Duos was at Dig Indiana, and I wasn’t disappointed. The Duos Hoppin John is a hearty dish of black eyed peas, rice and stewed tomatoes, perfect for these rainy Indianapolis winter days. Duos strives to have several vegetarian, vegan and gluten-free dishes, including desserts. Follow them on Twitter to see where they’ll be hanging out next!
What exciting and unique vegetarian or vegan options have you found in Indianapolis?
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Do-it-yourself oil changes are increasing in popularity as auto supply stores provide improved equipment to assist the car owner with expeditious removal of used oil, and service stations accept the used oil. This system relies extensively on the diligence of the consumer, particularly in bringing the used oil and oil filter to a service station or other collection point, a highly inconvenient task. Less reliance on the consumer's diligence will likely result in fewer illegally disposed of filters and simply dumped residual oil. A typical oil change involves from 4 to 6 quarts of oil and a filter which may contain as much as a quart of oil as it is removed from the vehicle. The used oil will contain in addition to the expected hydrocarbons measurable quantities of heavy metals. Disposal of the used oil or oil-containing oil filters in landfills, storm drains, or in public and private places not intended as disposal sites is potentially harmful to ground water, the atmosphere, and the flora and fauna in the area.
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What’s Scarier Than DE-flation?
As early as 2011, our analysis warned that Europe's deflation was coming and here's why. For the economies of Europe, the past few months have felt like one long ice-bucket challenge that never ends: A perpetual state of shock induced by the bone-chilling fact that deflation "...has become a reality in many European countries." (Oct. 24, New York Times)
At last count, eight European nations are now in outright deflation, including:
Italy's -0.1% annual inflation, the country's first descent into deflation since 1959
Spain's -0.3% annual inflation, the most serious deflation of any larger eurozone economy
France's near 0.0% core inflation, the lowest in modern history
And no, in case you were wondering, it's not the warm and fuzzy kind of "good deflation" being touted here in the United States, where the only consequence is lower prices. In Europe, it's the
So, we ask you: What could possibly be scarier than deflation? How about -- not even being able to foresee it?
Yes, deflation was a surprise to the financial authorities. Says one Oct. 12 financial blog post:
"It seems the entire world is cooling off in ways most political leaders and central bankers never saw coming. Global finance ministers are now up against a beast none have known in their professional lives."
That's what should keep adults like you and me up all night -- the "never-saw-it-coming" part. Just how safe is our future if the people whose job it is to keep the world's economies stable lack the tools to predict one of the most dangerous economic conditions?
This recent lack of foresight jives with what former Federal Reserve chairman Alan "The Maestro" Greenspan said in 2008:
"We can tell a bubble only after it burst."
It also jives with what some big wig at the Organization for Economic Co-operation & Development said in 2012:
"The responsibility of the 'latest' financial crisis, which no one saw coming, should be borne by all of us."
But the fact is -- there was -- and is -- a way to see these deflationary economic sea changes coming.
This chart of the UK Consumer Price Index is a reliable bellwether for inflation in Europe. You can see that price expansion peaked in September 2011 at 5.2%:
At the time, the "D" word was completely off the mainstream radar. Soaring oil, grain, and commodity prices, alongside a stimulus-happy European Central Bank fueled widespread fears of runaway inflation.
One month before the top, Elliott Wave International's August 2011European Financial Forecast laid the opposing groundwork:
"We maintain our stance, however, that the looming threat is not inflation but deflation. Far from a sense of relief, the Banks' paramount feelings should soon develop into an unrelenting dread."
Here's what made us take a contrarian stance (among many other reasons):
[In the August 2011 issue,] for instance, we showed a chart of eurozone manufacturing production and British GDP growth. Both were falling, not rising, indicating Europe's likely return to economic contraction.
[This] chart is another key piece of deflationary evidence... It shows the relentless downward trajectory of Swiss, German and British 10-year bond yields, which is one of the thorniest problems for those who take the inflationist worldview.
Bond yields aren't just falling: 10-year Swiss, German and British yields collectively dropped to record lows last month. The unrelenting demand for Europe's safest debt is a smoking howitzer that is blowing the inflationists' case to pieces.
-- The European Financial Forecast, Sept. 2011
However, the widespread call for inflation only continued to intensify in the mainstream finance. In fact, in February 2012, when the U.K. producer price inflation came in higher than expected, it prompted this word of advice from economists:
"PPI: Another wake-up call for apoplithorismosphobes, the clinical term for those who fear deflation. We recommend that sufferers 'seek therapy.'" (March 12, Wall Street Journal)
Yet, our July 2012 European Financial Forecast remained committed to its counter claim:
"Our models say that inflation rates will keep failing until they're again measuring the rate of deflation as they last did briefly in 2009."
So, it's now 2014 and deflation in Europe is no longer a specter or a figment of an unbalanced imagination. Here's a comment from the September2014 European Financial Forecast:
"The central bank's latest deflation-fighting contrivance is a €400 billion package of targeted LTRO loans, which are designed to compel banks to lend to ordinary business owners... The ECB has slashed its main refinancing rate to 0.15% and now charges for banks' overnight deposits. The result? Shown below, Europe's largest economy, Germany, just contracted 0.2%; French economic output has ground to a halt; and Italy just entered its third recession since 2008."
Now that deflation in Europe is a reality, the question is -- will it get better? Is this just a temporary economic condition that will be soon replaced with another one -- the condition that economists are much more familiar with, inflation?
We don't think deflation will surrender quite so easily. Want to learn more about deflation before it could potentially affect your investments?
Today, we invite you to read a free report from Elliott Wave International titled, What You Need to Know About Protecting Yourself from Deflation. This 10-page report will help you understand how you can better prepare yourself for its devastating effects.
This article was syndicated by Elliott Wave International and was originally published under the headline What's Scarier Than DE-flation?. EWI is the world's largest market forecasting firm. Its staff of full-time analysts led by Chartered Market Technician Robert Prechter provides 24-hour-a-day market analysis to institutional and private investors around the world.
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This disclosure relates generally to the field of boiler/furnace deslagging, and particularly, discloses a device, system and method allowing on-line, explosives-based deslagging.
A variety of devices and methods are used to clean slag and similar deposits from boilers, furnaces, and similar heat exchange devices. Some of these rely on chemicals or fluids that interact with and erode deposits. Water cannons, steam cleaners, pressurized air, and similar approaches are also used. Some approaches also make use of temperature variations. And, of course, various types of explosive, creating strong shock waves to blast slag deposits off of the boiler, are also very commonly used for deslagging.
The use of explosive devices for deslagging is a particularly effective method, as the large shock wave from an explosion, appropriately positioned and timed, can easily and quickly separate large quantities of slag from the boiler surfaces. But the process is costly, since the boiler must be shut down (i.e. brought off line) in order to perform this type of cleaning, and valuable production time is thereby lost. This lost time is not only the time during which the cleaning process is being performed. Also lost are several hours prior to cleaning when the boiler must be taken off line to cool down, and several hours subsequent to cleaning for the boiler to be restarted and brought into full operational capacity.
Were the boiler to remain on-line during cleaning, the immense heat of the boiler would prematurely detonate any explosive placed into the boiler, before the explosive has been properly positioned for detonation, rendering the process ineffective and possibly damaging the boiler. Worse, loss of control over the precise timing of detonation would create a serious danger for personnel located near the boiler at the time of detonation. So, to date, it has been necessary to shut down any heat exchange device for which explosives-based deslagging is desired.
Several U.S. patents have been issued on various uses of explosives for deslagging. U.S. Pat. Nos. 5,307,743 and 5,196,648 disclose, respectively, an apparatus and method for deslagging wherein the explosive is placed into a series of hollow, flexible tubes, and detonated in a timed sequence. The geometric configuration of the explosive placement, and the timing, are chosen to optimize the deslagging process.
U.S. Pat. No. 5,211,135 discloses a plurality of loop clusters of detonating cord placed about boiler tubing panels. These are again geometrically positioned, and detonated with certain timed delays, to optimize effectiveness.
U.S. Pat. No. 5,056,587 similarly discloses placement of explosive cord about the tubing panels at preselected, appropriately spaced locations, and detonation at preselected intervals, once again, to optimize the vibratory pattern of the tubing for slag separation.
Each of these patents discloses certain geometric configurations for placement of the explosive, as well as timed, sequential detonation, so as to enhance the deslagging process. But in all of these disclosures, the essential problem remains. If the boiler were to remain on-line during deslagging, the heat of the boiler would cause the explosive to prematurely detonate before it is properly placed, and this uncontrolled explosion will not be effective, may damage the boiler, and could cause serious injury to personnel.
U.S. Pat. No. 2,840,365 appears to disclose a method for introducing a tube into “a hot space such as an oven or a slag pocket for an oven” prior to the formation of deposits in the hot space; continuously feeding a coolant through the tube during the formation of deposits in the hot space, and, when it is time to break the deposits, inserting an explosive into the tube after the formation of the deposits while the tube is still somewhat cooled, and detonating the explosive before it has a chance to heat up and undesirably self-detonate. (See, e.g., col. 1, lines 44-51, and claim 1) There are a number of problems with the invention disclosed by this patent.
First, the hot space according to this patent must be thoroughly prepared and preconfigured, in advance, for the application of this method, and the tubes that contain the coolant and later the explosive, as well as the coolant feeding and discharge system, must be in place on a more or less permanent basis. The tubes are “inserted before the deposits begin to form or before they are formed sufficiently to cover the points where one wishes to insert the tubes” and are “cooled by the passage of a cooling fluid . . . therethrough during operation.” (col. 2, lines 26-29 and col. 1, lines 44-51) It is necessary “to provide sealable holes in several bricks for allowing the tube . . . to be inserted, or . . . to remove the bricks during operation of the furnace so that a hole is formed through which the tube may be inserted.” (col. 2, lines 32-36) The tubes are supported “at the back end of the pocket upon supports made for the purpose, e.g., by a stepped shape of the back of the wall . . . [or] at the front end or in front of and in the wall . . . [or by having] at least the higher tubes . . . rest immediately upon the deposits already formed.” (col. 2, lines 49-55) A complicated series of hoses and ducts are attached for “feeding cooling water . . . and discharging said cooling water.” (col. 3, lines 1-10, and FIG. 2 generally) And, the tubes must be cooled whenever the hot space is in operation to prevent the tubes from burning and the water from boiling. (see, e.g., col. 3 lines 14-16 and col. 1, lines 44-51) In sum, this invention cannot simply be brought onto the site of a hot space after deposits have formed and then used at will to detonate the deposits while the hot space is still hot. Rather, the tubes must be in place and continuously cooled essentially throughout the entire operation of the hot space and the accumulation of deposits. And, significant accommodations and preparation such as tube openings and supports, the tubes themselves, and coolant supply and drainage infrastructure, must be permanently established for the associated hot space.
Second, the method disclosed by this patent is dangerous, and must be performed quickly to avoid danger. When the time arrives to break the slag deposits, “the pipes . . . are drained,” various cocks, hoses, bolts and an inner pipe are loosened and removed, and “explosive charges are now inserted [into the pipe] . . . immediately after termination of the cooling so that no danger of self-detonation exists, because the explosive charges cannot become too hot before being exploded intentionally.” (col. 3, lines 17-28) Then, the “tubes are exploded immediately after stopping the cooling at the end of the operation of the furnace . . . ” (col. 1, lines 49-51) Not only is the process of draining the pipe and readying it to receive the explosive fairly cumbersome, it must also be done in a hurry to avoid the danger of premature explosion. As soon as the coolant flow is ceased, time is of the essence, since the tubes will begin to heat up, and the explosives must be placed into the tubes and purposefully detonated quickly, before the heating of the tube become so great that the explosive accidentally self-detonates. There is nothing in this patent that discloses or suggests how to ensure that the explosive will not self-detonate, so that the process does not have to be unnecessarily hurried to avoid premature detonation.
Third, the pre-placement of the tubes as discussed above constrains the placement of the explosive when the time for detonation arrives. The explosives must be placed into the tubes in their preexisting location. There is no way to simply approach the hot space after the slag accumulation, freely choose any desired location within the hot space for detonation, move an explosive to that location in an unhurried manner, and then freely and safely detonate the explosive at will.
Fourth, it may be inferred from the description that there is at least some period of time during which the hot space must be taken out of operation. Certainly, operation must cease long enough for the site to be prepared and fitted to properly utilize the invention as described earlier. Since one object of the invention is to “prevent the oven . . . to be taken out of operation for too long a time,” (col. 1, lines 39-41, emphasis added), and, since the “tubes are exploded immediately after stopping the cooling at the end of the operation of the furnace or the like” (col. 1, lines 49-51, emphasis added), it appears from this description that the hot space is in fact shut down for at least some time prior to detonation, and that the crux of the invention is to hasten the cooling of the slag body after shutdown so that detonation can proceed more quickly without waiting for the slag body to cool down naturally (see col. 1, lines 33-36), rather than to allow detonation to occur while the hot space is in full operation without any shutdown at all.
Finally, because of all the site preparation that is needed prior to using this invention, and due to the configuration shown and described for placing the tubes, this invention does not appear to be usable across the board with any form of hot space device, but only with a limited type of hot space device that can be readily preconfigured to support the disclosed horizontal tubing structure as disclosed.
Luxemburg patent no. 41,977 has similar problems to U.S. Pat. No. 2,840,365, particularly: insofar as this patent also requires a significant amount of site preparation and preconfiguration before the invention disclosed thereby can be used; insofar as one cannot simply approach the hot space after the slag accumulation, freely choose any desired location within the hot space for detonation, move an explosive to that location in an unhurried manner, and then freely and safely detonate the explosive at will; and insofar as the types of hot space devices to which this patent applies also appear to be limited.
According to the invention disclosed by this patent, a “blasting hole” must be created within the subject hot space before the invention can be used. (translation of page 2, second full paragraph) Such holes are “drilled at the time of need or made prior to the formation of the solid mass.” (translation of paragraph beginning on page 1 and ending on page 2) Since the device for implementing the process of the invention “includes at least a tube that permits feeding the cooling fluid into the bottom of the blasting hole” (translation of page 2, fourth full paragraph) and, in one form of implementation, “a retaining plate . . . positioned at the bottom of the blast hole (translation of paragraph beginning on page 2 and ending on page 3), and since it is a key feature of the invention that the blast hole is filled with coolant prior to and during the insertion of the explosive, it may be inferred from this description that the blast hole is substantially vertical in it orientation, or at least has a significant enough vertical component to enable water to effectively accumulate and pool within the blast hole.
Because the subject hot space must be preconfigured with a blast hole or holes (with implicitly at least a substantial vertical component) before this invention can be used, it is again not possible to simply approach an unprepared hot space at will after deposits have accumulated, and detonate at will. Since the coolant and the explosive must be contained within the blast holes, it is not possible to freely move and position the explosive wherever desired within the hot space. The explosives can only be positioned and detonated within the blast holes pre-drilled for that purpose. Due to the at least partially vertical orientation of the blast holes, the angle of approach for introducing the coolant and the explosive is necessarily constrained. Also, while it is not clear from the disclosure how the blast holes are initially drilled, it appears that at least some amount of boiler shutdown and/or disruption would be required to introduce these blast holes.
Finally, in both of these cited patents, the components which hold the coolant (the tubes for U.S. Pat. No. 2,840,365 and the blast holes for LU 41,977) reside within the hot space, and are already very hot when the time arrives to deslag. The object of both of these patents, is to cool these components down before the explosive is introduced. U.S. Pat. No. 2,840,365 achieves this by virtue of the fact that the tubes are continuously cooled throughout the operation of the hot space, which, again, is very disruptive and requires significant preparation of and modification to the hot space. And LU 41,977 clearly states that “[a]ccording to all its forms of implementation, the device is put in place without a charge for the purpose of cooling the blast hole for a few hours with the injection fluid. (translation of page 4, last full paragraph, emphasis added) It would be desirable to avoid this cool down period altogether and therefor save time in the deslagging process, and to simply introduce a cooled explosive into a hot space at will without any need to alter or preconfigure the boiler, and to then detonate the cooled explosive at will once it has been properly placed in whatever detonation location is desired. And most certainly, the application of LU 41,977 is limited only to hot spaces into which it is feasible to introduce a blast hole, which appears to eliminate many types of heat-exchange device into which it is not feasible to introduce a blast hole.
It would be desirable if a device, system and method could be devised which would allow explosives to safely and controllably be used for deslagging, on-line, without any need to shut down the boiler during the deslagging process. By enabling a boiler or similar heat-exchange device to remain on-line for explosives-based deslagging, valuable operations time for fuel-burning facilities could then be recovered.
It is therefore desired to provide a device, system and method whereby explosives may be used to clean a boiler, furnace, scrubber, or any other heat exchange device, fuel burning, or incinerating device, without requiring that device to be shut down, thereby enabling that device to remain in full operation during deslagging.
It is desired to enable valuable operations time to be recovered, by virtue of eliminating the need for shutdown of the device or facility to be cleaned.
It is desired to enhance personnel safety and facility integrity, by enabling this on-line explosives-based cleaning to occur in a safe and controlled manner.
|
Matsing: Has The Fat Lady Sung For This Tribe
By EvelDanKirby, October 22, 2012
Can Matsing Tribe turn things around and win challenges?
Matsing is an appropriate name as it appears that the fat lady has sung for this tribe.
Malcolm and Denise, both with an interesting story as well as a unique and unexpected alliance formed early on, would have probably done better to start out on a more balanced tribe. Why is it that this tribe cannot win a challenge? Is it because their leader cannot decide whether or not he wants to be leader? Is it because they pray, asking God to win the challenges for them, when He likely has better things to do these days (especially with an election coming up)? Is it because they do not dig deep enough or want it bad enough? Perhaps it is because they do not have the thing that is most needed by any Survivor contestant… “Cookies”. If they had chosen Angie over Russell after that comment, I would have lost all respect for them. Yes, somehow, I do still have some respect for them.
I think the reasons they can’t win a challenge are a combination of all the above. Episode one, Russell said that whoever tries to be a leader will be the first one gone. Then he, himself, was almost eliminated for stepping up and being too demanding as a leader. He told us in the first episode that he knows better than this, and then demonstrated just the opposite. I also think that Matsing Tribe’s minds are not on winning the challenges. Instead, there was all of this discussion about Malcolm and Angie as a couple and the fact that couples are deadly in Survivor. That is talk about strategy, and when you’re not winning; your focus should instead be on how to win challenges. Even more important, the focus should be on what it is going to take to end the losing streak.
After all these years of watching Survivor, it is my educated guess that Matsing Tribe will soon be dispersed amongst the other tribes. This could prove to be good for them. They will likely be the swing vote of whatever is going on in the other tribes at that time. It also bodes well for some of my other favorites who are currently in trouble, i.e. Lisa and Penner. But will they be able to acclimate? It also is possible in this scenario that they would be the next to be voted off. And my question to all is this, which amongst them would be missed? I think some could acclimate depending on what tribe they get into next and who goes along with them.
Strength in numbers only backfires in Survivor when tribes merge and your numbers are less than theirs. In other words, a Malcolm (for example) is easier to feel out and consider allowing him to become a true member of your tribe than a Malcolm and a Denise combined. Even if you substitute Russell for one of them, who have no duo deal with the other, the rest of their new tribe would not necessarily see it that way. Therefore, perhaps the fairest thing to do would be to let them get down to two tribe members, then throw one on each of the other tribes. I actually like all three of them personally and would miss any of them. They are far more interesting to watch than the whiny girls on the yellow tribe.
And who is even on the other tribe? You’ve got a baseball star and my love, Penner. Can anyone even name another person on that tribe because at this moment I cannot. Of course some of this is television editing. I’m just hoping that it’s the only reason.
I had an idea that if they were going to have a famous actress, a successful baseball star, and three previously injured Survivor contestants all come on the same season, perhaps putting them all on the same tribe would have made the most sense. It’s a tricky one, however, because none of them wants to be known for what they are known for. This idea is relevant because I also wonder if the issue with Matsing is the very make-up of that tribe. Essentially, did Survivor put together a tribe full of losers?
What are your thoughts on this? Why do they keep losing? What do you think will happen to them as individuals and as a tribe? Can they turn this around? And do any of them make you want them to?
|
Little Woodham
Little Woodham, also known as "The Living History Village of Little Woodham" or "The Seventeenth Century Village", is a living museum dedicated to recreating life in a rural village in the mid-17th century. It is situated in ancient woodland in Rowner, on the Gosport peninsula, Hampshire.
History
The hamlet of Little Woodham was initially created in 1984 as a temporary reenactment of village life on the eve of the English Civil War by members of The English Civil War Society as part of their enactment of the fictional Battle Of Stokes Bay. Following this, Society volunteers continued the exhibition during the summers of 1984 and 1985.
When the English Civil War Society announced they would be unable to continue, local residents formed the Gosport Living History Society to take over the running of the village to preserve it as an educational resource and tourist attraction. The Gosport Borough Council provided much of the financing and administration until 1995 when the Gosport Living History Society became a registered charity and took on sole responsibility for funding and administration, and in 2007, Little Woodham won the "Best Leisure & Tourism Venue" in the "Go Gosport".
Unique to Little Woodham
Little Woodham has the only 17th century replica pottery kiln in the world, carefully reconstructed using the same materials and techniques. It was fired for the first time in 2015 and has been fired each year since with all the pottery made using the kick wheel turntable in the 17th century Pottery.
The 17th Century coal forge was recreated using evidence gathered from an archaeological dig of a *seventeenth-century blacksmith shop at Ferryland, Newfoundland (built 1622) and from various *paintings and etchings from the period. Although the forge is a recreation, the artefacts anvils and tools used in the forge are hundreds of years old, so the sounds and smell of the coal forge is as close as you will ever get to being in a forge in the 17th century.
Little Woodham also run frequent 17th-Century Forge Experience days for visitors to spend a day working in the 17th century coal forge, guided by Little Woodham's blacksmith to recreate 17th-century iron work and learning traditional techniques and skills using steel and wrought iron, and look at the real 17th-century examples.
There are a number of other trades and crafts throughout the village, including weavers and wool dyers, a wood turner, button maker, apothecarist, scribe, trickster and barber surgeon and many more.
Events in Little Woodham
May Day: May Day during the 17th century was a big festival. Houses were festooned with may blossom, green vegetation and any colourful cloths that were to hand. Mayday marked the coming of spring and new life. Food was becoming plentyful again, a time to eat, drink and be merry.
Join in the celebration with us! Hear stories from the Hagstone story teller, and see the Green Man, the Hobby horse and much more
17th century Kiln firing: A very special day at Little Woodham when our Master Potter will be loading up and firing the 17th century pottery kiln. This kiln is the only working 17th century replica kiln in existence, and all the pottery that will be in the kiln has been made in the 17th century potter's work shop using a kick wheel turn table.
Craft Day: A day where leather workers, walking stick makers, potters, blacksmiths, weavers, woodworkers, quilters work in the village.
Filming at Little Woodham
Little Woodham has worked with a variety of filmcompanies, including BBC, Channel 4, Channel 5 and various independent national and international film companies. Little Woodham is also a favourite location for many 3rd year film students.
External links
The 1642 Living History Village
- The archaeological investigation of a seventeenth-century blacksmith shop at Ferryland, Newfoundland
Gosport.info article
Category:Living museums in England
Category:Museums in Hampshire
Category:Gosport
|
A statement by the Thai Amateur Weightlifting Association (included at the bottom of this article) has revealed that eight Thai athletes who failed anti-doping tests were caught as a result of a sophisticated but time-consuming testing technique.
Gas Chromatography-Combustion Isotope Ratio Analysis (GC-C-IRMS) is an extremely sensitive way to identify chemicals in complex mixtures. In anti-doping, it is used to compare samples collected in competition with an archive of previous samples (the “Athlete Passport”). The technique is not available to all anti-doping laboratories and takes longer than older testing techniques.
The Thai athletes passed initial tests on their samples from the 2018 World Championships but subsequent testing with the new technique led to Adverse Analytical Findings (failed tests). If B samples show the same results, the athletes are almost certain to receive bans.
The fact that the more sensitive test found things that other tests did not raises the possibility that other doping that has thus far gone undetected could be revealed.
|
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|
IntercontinentalExchange
Firm Physical Natural Gas Price Bulletin
For Natural Gas Delivered on Saturday, November 03, 2001 thru Monday, November 05, 2001
(Trade Date of Friday, November 02, 2001)
Click here to access index history .
* volume represents sell-side only *
Region Hub High Low Wtd Avg Index Change ($) Vol (mmBtu) Hub Name
LOUISIANA
ANR SE $2.8850 $2.7800 $2.8382 - .0623 771,000 American Natural Resources Pipeline Co. - SE Transmission Pool
Columbia Onshore $3.0500 $2.8500 $2.8888 - .0694 542,100 Columbia Gulf Transmission Co. - Onshore Pool
Henry Hub $3.0200 $2.9000 $2.9479 - .0531 3,230,400 Henry Hub tailgate - Louisiana
NGPL LA $2.9300 $2.8300 $2.8640 - .0672 755,100 Natural Gas Pipeline Co. of America, Louisiana Pool
Tenn 500L $2.9950 $2.7800 $2.8297 - .0516 552,600 Tennessee Gas Pipeline Co.-Zone L, 500 Leg Pool
Tenn 800L $3.0000 $2.8050 $2.8416 - .0366 553,500 Tennessee Gas Pipeline Co.-Zone L, 800 Leg Pool
TETCO ELA $3.0200 $2.8250 $2.8573 - .0748 570,600 Texas Eastern - East LA
TETCO WLA $2.9200 $2.8000 $2.8252 - .0715 656,100 Texas Eastern - West LA
Transco 65 $2.9500 $2.9000 $2.9307 - .0628 231,000 Transco - Station 65
Trunkline ELA $2.9000 $2.7700 $2.8012 - .0524 440,400 Trunkline Gas Company - East Louisiana Pool
TxGas SL $2.9750 $2.8500 $2.9112 - .0380 367,500 Texas Gas Transmission Corp.-Zone SL FT Pool
MIDCONTINENT
MichCon, citygate $3.0600 $2.9200 $3.0133 - .0691 356,400 Michigan Consolidated
NGPL Midcont $2.8300 $2.6650 $2.7276 - .1115 370,200 Natural Gas Pipeline Co. of America, Mid-Continent Pool
NGPL Nicor, citygate $3.0300 $2.9000 $2.9495 - .0726 1,146,000 Natural Gas Pipeline Co. of America, Nicor Citygate
NGPL NIPSCO, citygate $3.0000 $2.9450 $2.9750 - .0568 120,000 Natural Gas Pipeline Co. of America, Nipsco Citygate
NNG Demarcation $2.8150 $2.7450 $2.7799 - .0936 231,900 Northern Natural Gas, Demarcation Pool
NORTHEAST
Columbia TCO $3.1500 $3.0000 $3.0483 - .0378 848,700 Columbia Gas Co. - TCO Pool
Dominion So.Point $3.2600 $3.0100 $3.1110 - .0044 786,900 Dominion - South Point
TETCO M3 $3.5000 $3.1350 $3.2227 + .0229 668,100 Texas Eastern - M3 Zone
Transco Z-6 (NY) $3.7250 $3.1650 $3.2657 - .0858 508,500 Transcontinental Gas Pipe Line Corp. - Zone 6 (NY)
WEST
El Paso non-Bondad $2.4500 $2.1800 $2.3123 - .3970 597,000 El Paso - San Juan Basin, Blanco Pool
Huntingdon/Sumas $2.4500 $2.3000 $2.3928 - .2428 381,600 Westcoast Energy & Northwest Pipeline Corp.
Opal $2.2000 $2.0700 $2.1272 - .3060 270,000 Opal
PG?Citygate $2.6900 $2.5000 $2.5794 - .4294 327,000 PG?- Citygate
SoCal Border $2.7100 $2.4900 $2.5760 - .3847 505,500 Southern California Border Points (Ehrenberg,Topock,Needles)
WEST TEXAS
El Paso - Keystone $2.6600 $2.4750 $2.5317 - .2669 814,200 El Paso - Keystone Pool
Waha $2.7800 $2.6100 $2.6701 - .1870 543,000 Waha Hub - West Texas
Includes all firm physical fixed price trades done from 7 AM to 11:30 AM Central Prevailing Time on the trade date specified for natural gas delivered on the specified date(s).
IntercontinentalExchange is the world's most liquid trading platform for over-the-counter energy and metals. Active markets include North American power and natural gas, global crude and refined oil products, and precious metals. Traded instruments include forwards, swaps, and options.
In order to receive the proprietary information contained in this email, you acknowledge and agree that you shall not further disseminate the IntercontinentalExchange Market Data contained herein to any person or entity without the express written consent of IntercontinentalExchange. Furthermore, you acknowledge that (1) IntercontinentalExchange has exclusive and valuable property rights in this data; (2) IntercontinentalExchange's data is being made available to you only for your own business or personal activities; and (3) you cannot communicate the data, in any form, to any other person or entity without the express written consent of IntercontinentalExchange.
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|
SOPA Vote Delayed - nextparadigms
http://www.wired.com/threatlevel/2011/12/sopa-vote-delayed/
======
mMark
Delayed... till Wednesday.
I can hear the glass that was the internet shattering from the future.
Mike Masnick: Update.... Or not. Despite the fact that Congress was supposed
to be out of session until the end of January, the Judiciary Committee has
just announced plans to come back to continue the markup this coming
Wednesday. This is rather unusual and totally unnecessary. But it shows just
how desperate Hollywood is to pass this bill as quickly as possible, before
the momentum of opposition builds up even further.
[http://www.techdirt.com/articles/20111216/11102617108/sopa-m...](http://www.techdirt.com/articles/20111216/11102617108/sopa-
markup-runs-out-time-likely-delayed-until-2012.shtml)
~~~
m0nastic
I'm actually trying to get a Congressional Gallery pass for Wednesday, to see
the session in person.
Although it looks like if I do, I can't live-blog/tweet it, as you can't bring
anything electronic into the gallery. That makes watching it on CSPAN a little
more appealing.
------
bane
Or not
[http://www.techdirt.com/articles/20111216/11102617108/sopa-m...](http://www.techdirt.com/articles/20111216/11102617108/sopa-
markup-runs-out-time-likely-delayed-until-2012.shtml) "Or not. Despite the
fact that Congress was supposed to be out of session until the end of January,
the Judiciary Committee has just announced plans to come back to continue the
markup this coming Wednesday. This is rather unusual and totally unnecessary.
But it shows just how desperate Hollywood is to pass this bill as quickly as
possible, before the momentum of opposition builds up even further."
------
SoftwareMaven
Can I express shock for a moment: first, Mike Lee voting against the defense
appropriation bill, then Jason Chaffetz moving to put this on hold. I'm so
used to Utah politicians like Hatch and Bennet that it is incredibly
surprising to be proud of my state's representatives for a change.
------
joe_the_user
Just to note that the provision granting immunity to banks who pre-emptively
blacklist "illegal" sites also breaks the contract law system...
The next step is will be... robbers are allowed to break into anyone's house
and take their money - well as long as the robbers "think" the people are
terrorists/counterfeiters/bad-people... (and as long as the robbers are ...
cops).
~~~
randallsquared
_The next step is will be... robbers are allowed to break into anyone's house
and take their money - well as long as the robbers "think" the people are
terrorists/counterfeiters/bad-people... (and as long as the robbers are ...
cops)._
Uh, that was the previous step:
<https://www.google.com/search?q=asset+forfeiture>
~~~
joe_the_user
Correct... I just couldn't think of any further next-next steps...
------
meanJim
I'm no expert, but this really sucks that we've reached this point. Can we
just come up with a better bill? Why does it have to be this one that every
media corp wants to go through.
~~~
dangrossman
We don't need a better bill. There's no reason to create any new internet
piracy bill. We already have a copyright act, and the DMCA, and international
treaties on intellectual property rights.
SOPA doesn't make anything that isn't already illegal illegal. It just creates
new ways to shut down anyone the film and music industries want to shut down,
without even having to prove infringement. It has no public support because
it's a ridiculous, unneeded proposal.
SOPA should simply be voted down and the congress should move on to some real
business, not creating new laws at the behest of their campaign contributors.
~~~
meanJim
Thank you so much for clearing that up with me. I do agree with corporations
having the copyright act and the DMCA to protect their intellectual property
rights.
------
adamtmca
Is the fact that Google and Facebook alone are worth more than the combined
market capitalization of the entire entertainment sector getting any play in
this discussion?
[http://www.wolframalpha.com/input/?i=entertainment+industry+...](http://www.wolframalpha.com/input/?i=entertainment+industry+market+cap%2F+%28google+market+cap+%2B+80+billion%29)
------
uptown
Did Congress just realize they could manufacture a few extra days for the
media companies to bump up their contributions?
------
firefoxman1
even if the security claims are "overstated," that's about the only argument
that congressmen have paid attention to. If I was a congressman who only
worried about getting re-elected, I certainly wouldn't want to be known as one
of the men who "voted to censor the internet" by my opponents next election.
|
Ý
Collier
Ý
Bƒton en bois
Ý
N‚gatif
Ý
Papier photo
Ý
Revolver
Ý
Shakuhashi
Ý
Manuel photo
Ý
Lunettes
Ý
Couteau
Ý
Appareil photo
Ý
Lettre
Ý
Serviette
Ý
Flacon
Ý
Journal
Ý
Livre de chimie
Ý
Dossier
Ý
Coupure de presse
Ý
Plaquette de bois
Ý
Clef
Ý
Livre
Ý
Barbe postiche
Ý
Marteau
Ý
Hache
Ý
Statuette
Ý
Bol
Ý
Pinces
Ý
Bƒton correctif
Ý
BoŒte
Ý
Peinture
Ý
Rouleau de s–tra
Ý
Balai en plumes
Ý
Fouet … th‚
Ý
Photo
Ý
Furoshiki
Ý
Costume
Ý
Moustache
Ý
Jeu de go
Ý
Stylo
Ý
C‚ramique
Ý
Feuille
Ý
Peigne
Ý
Livre de s–tras
Ý
Roman policier
Ý
Masque No
Ý
Marionnette
Ý
Buvard
Ý
Sak‚
Ý
Boulier
Ý
Carte postale
Ý
Bout de tissu
Ý
Lucky-Strike
Ý
Poup‚e
Ý
Epingle-cheveux
Ý
Jouet
Ý
Encensoir
Ý
Revue
Ý
Coca-cola
Ý
Pipe
Ý
Pipette
Ý
Ver de terre
Ý
Allumettes
Ý
Savon
Ý
M‚daille
Ý
Bout de ficelle
Ý
Cordelette
Ý
Clochette
Ý
PiŠce ancienne
Ý
Bande magn‚tique
Ý
Carnet de notes
Ý
Malette m‚dicale
Ý
Globe-‚lectrique
Ý
Passe-vue
Ý
10 yen
Ý
50 yen
Ý
100 yen
Ý
R‚v‚lateur
Ý
Fixateur
|
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|
A novel digestion method based on a choline chloride-oxalic acid deep eutectic solvent for determining Cu, Fe, and Zn in fish samples.
A novel and efficient digestion method based on choline chloride-oxalic acid (ChCl-Ox) deep eutectic solvent (DES) was developed for flame atomic absorption spectrometry (FAAS) determination of Cu, Zn, and Fe in biological fish samples. Key parameters that influence analyte recovery were investigated and optimized, using the fish protein certified reference material (CRM, DORM-3) throughout the procedure. In this method, 100 mg of the sample was dissolved in ChCl-Ox (1:2, molar ratio) at 100°C for 45 min. Then, 5.0 mL HNO(3) (1.0 M) was added. After centrifugation, the supernatant solution was filtered, diluted to a known volume, and analyzed by FAAS. Under optimized conditions, an excellent agreement between the obtained results and the certified values was observed, using Student's t-test (P=0.05); the extraction recovery of the all elements was greater than 95.3%. The proposed method was successfully applied to the determination of analytes in different tissues (muscle, liver, and gills) having a broad concentration range in a marine fish sample. The reproducibility of the method was validated by analyzing all samples by our method in a different laboratory, using inductively coupled plasma optical emission spectrometry (ICP-OES). For comparison, a conventional acid digestion (CAD) method was also used for the determination of analytes in all studied samples. The simplicity of the proposed experimental procedure, high extraction efficiency, short analysis time, lack of concentrated acids and oxidizing agents, and the use of safe and inexpensive components demonstrate the high potential of ChCl-Ox (1:2) for routine trace metal analysis in biological samples.
|
Rudy Overrated?
ESPN recently looked at the small forwards of the NBA and asked who the best, most underrated, most overrated and most promising small forward in the league are. Rudy Gay’s name came up, but not in a good way.
Raptors Republic’s very own J.M. Poulard was one of five NBA writers (although under the Warriors World banner) who contributed. There were only two unanimous categories: Best small forward (guess which one) and most overrated. This is what they had to say:
Who’s the most overrated small forward in the NBA?
Cavan: Rudy Gay. Few players personify the stats-eye test divide better than the supremely talented — and supremely flawed — Raptors wing. Where proponents point to Gay’s bucket-harvesting prowess and smooth flow, detractors, well, point to the numbers. The good news: after corrective surgery, Gay should actually be able to, like, see the basket. Which is important when you’re shooting a basketball.
Haberstroh: I’ll go with Rudy Gay, one of the last remaining idols of Points Per Game worshipers. Gay has all the tools to be an All-Star and he’s paid like one — did you know he’ll make more than Durant this season? — but his only above-average skill is shot-taking. Though he may be more overpaid than overrated, he’s not the franchise player that many believe he is.
Poulard: Rudy Gay. He will make roughly $17.9 million in 2013-14 and yet does not possess a single elite skill. He can create good shots but one expects a better conversion rate from the Toronto Raptor. His salary technically puts him close to the same level as Carmelo Anthony. But his production? Not so much.
Wade: Rudy Gay. Critics spurned the Memphis Grizzlies for punting on the season last year when they traded away their ballyhooed wing in favor of fiscal prudence. Then the team advanced further than it ever had in franchise history. Despite getting swept by the Spurs, this is damning evidence that Gay was merely an ancillary ingredient in the team’s success.
Young: Rudy Gay. In today’s NBA, small forward has become a position of production, and not just in raw scoring stats, but efficient, well-rounded production. Gay can score, but it’s in a volume manner. He’s a good player, no doubt, but is there one thing he’s really great at?
Latest Web Articles
Rap of the Day
This I can explain. His low usage rate when he is on the floor minimize his impact on team stats, such as team O/D rating and even plus minus (since that stat also accounts for the other members of the rotation. However, when he is being used, his individual stats, or the stats that are only dependant on his contributions, he looks pretty good, pretty great even.
Basically, like what everyone else has been saying, it comes down to usage rate. Involve him enough in the offense and there's no reason why his individual efficiency won't be reflected in the team stats.
Now here's where you might say "but the raptors lose more when he shoots more than average, so the usage rate argument doesn't hold up". That's a fair point, but I would argue that Jonas often gets those extra field goals when A) the guards are putting up a ton of bricks and Jonas is cleaning the glass, or B) he's a last resort after its clear that the other scoring options aren't working. In both scenarios, the team as a whole is playing below average, so it makes sense that they would win a lower percentage of games.
|
Kabul – The fire in the Chaman e Babrak camp began in Nadiai’s home shortly after noon. She had rushed her son, who had a severe chest infection, to the hospital. She did not know that a gas bottle, used for warmth, was leaking; when the gas connected with a wood burning stove, flames engulfed the mud hut in which they lived and extended to adjacent homes, swiftly rendering nine extended families homeless and destitute in the midst of already astounding poverty. By the time seven fire trucks had arrived in response to the fire at the refugee camp, the houses were already burned to the ground.
No one was killed. When I visited the camp, three days after the disaster, that was a common refrain of relief. Nadiai’s home was on the edge of the camp, close to the entrance road. Had the fire broken out in the middle of the camp, or at night when the homes were filled with sleeping people, the disaster could have been far worse.
Even so, Zakia, age 54, said this is the worst catastrophe she has seen in her life, and already their situation was desperate. Zakia had slapped her own face over and over again to calm and focus herself as she searched for several missing children while the fire initially raged. Now, three days later, her cheeks are quite bruised, but she is relieved that the children were found.
(Photo: Abdulai Safarali)
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Standing amid piles of ashes near what once was her home, a young mother smiled as she introduced her three little children, Shuba, age 3 ½, and Medinah and Monawra, twin girls, age 1 ½. They were trapped in one of the homes, but their uncle rescued them.
Now the nine families have squeezed in with their neighbors. “We are left with only the clothes on our body,” said Maragul. She added that all of the victims feel very grateful to their neighbors. “We cook together,” she said, “and they offer us shelter at night.” Three or four families will sleep together in one room. Asked if their neighbors were all from the same clan, Maragul, Nadiai and Zakia immediately began naming the different ethnic groups that are among their neighbors. Some are Turkman, some Uzbek, some from Herat or Kabul, others are Pashtun, and some are Kuchi. The women said that they begin to feel like brothers and sisters, living together in these adverse circumstances.
The Chaman e Babrak refugee camp spills over the grounds of a large field formerly used for sporting events. With 720 families crowded into the camp, it is second in density and size only to the Charahi Qambar refugee camp, on the outskirts of Kabul, which is twice as large and more than twice as full as the Chaman e Babrak camp.
Asked about prospects for their husbands to find work, the women shook their heads. Nadiai said that her husband has occasional work as a porter, carrying materials in a wheelbarrow from one site to another. Sometimes construction projects will hire him, but in the winter months construction projects are closed and already scarce work vanishes altogether. And war, in a sense, brings its own winter along with it: Next to the camp is a construction project that has been dormant since 2008. It had been intended to become an apartment building.
There was never any plan announced to house these families, even before the fire. And since the fire, there has been no offer of aid aside from those seven fire trucks, rushing in to contain an immediate threat not only to the camp but of course to neighboring businesses, several wedding halls and a plastic surgery hospital, up against which, in a city no stranger to glaring contrasts of wealth, the camp finds itself pressed. I came to the camp with young activists of the Afghan Peace Volunteers there to distribute heavy coverlets, (duvets), manufactured with foreign donations by local seamstresses, precisely for distribution free of charge to Kabul’s neediest people in the winter months. The UK sister organization to my own group, Voices for Creative Nonviolence, will distribute food packages in the camp during the coming week.
We’ll never know who the fire might have killed, because when the old or the young die from the pressures of poverty, of homelessness, of war, we can’t know which disaster tipped the balance. We won’t know which catastrophe, specifically, will have taken any lives lost here to this dreadful winter. Many will be consumed by the slow conflagration of widespread poverty, corruption, inequality and neglect.
The vast expenditures of the U.S. government and its client here simply can’t be designated as contributions toward “security.” These funds have contributed to insecurity and danger while failing to address basic human needs. The realpolitik of an imperial power, as utterly disinterested in security here as it seems to be in its own people’s safety at home, will not notice this camp. As we pull together in our communities to enkindle concern, compassion, and respect for creative nonviolence, we are in deep winter hoping for a spring. We are right to work and to hope, but faced with the spectacle of winter in Chaman e Babrak I can’t help remembering Barbara Deming’s lines: “Locked in winter, summer lies; gather your bones together. Rise!”
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Abhyankar's conjecture
In abstract algebra, Abhyankar's conjecture is a 1957 conjecture of Shreeram Abhyankar, on the Galois groups of algebraic function fields of characteristic p. The soluble case was solved by Serre in 1990 and the full conjecture was proved in 1994 by work of Michel Raynaud and David Harbater.
The problem involves a finite group G, a prime number p, and the function field K(C) of a nonsingular integral algebraic curve C defined over an algebraically closed field K of characteristic p.
The question addresses the existence of a Galois extension L of K(C), with G as Galois group, and with specified ramification. From a geometric point of view, L corresponds to another curve C′, together with
a morphism
π : C′ → C.
Geometrically, the assertion that π is ramified at a finite set S of points on C
means that π restricted to the complement of S in C is an étale morphism.
This is in analogy with the case of Riemann surfaces.
In Abhyankar's conjecture, S is fixed, and the question is what G can be. This is therefore a special type of inverse Galois problem.
The subgroup p(G) is defined to be the subgroup generated by all the Sylow subgroups of G for the prime number p. This is a normal subgroup, and the parameter n is defined as the minimum number of generators of
G/p(G).
Then for the case of C the projective line over K, the conjecture states that G can be realised as a Galois group of L, unramified outside S containing s + 1 points, if and only if
n ≤ s.
This was proved by Raynaud.
For the general case, proved by Harbater, let g be the genus of C. Then G can be realised if and only if
n ≤ s + 2 g.
References
External links
A layman's perspective of Abhyankar's conjecture from Purdue University
Category:Algebraic curves
Category:Galois theory
Category:Theorems in abstract algebra
Category:Conjectures that have been proved
|
The subject of this article is from the Pathfinder update.
The information from this article is up-to-date as of 10 August, 2017.
The information from this article is up-to-date as of 10 August, 2017.
HUB-K-11E BF166 Bot's First in Hub Region Rentocniijik Expanse Galaxy Euclid Spectral class G0pf (Yellow) Distance to centre 166,580.4 Light-years light‑years Planet(s) 3 Moon(s) 0 Discovered by BotFodder2 Platform PS4 Release Pathfinder
HUB-K-11E BF166 Bot's First in Hub Region Rentocniijik Expanse Galaxy Euclid Spectral class G0pf (Yellow) Distance to centre 166,580.4 Light-years light‑years Planet(s) 3 Moon(s) 0 Platform PS4 Release Pathfinder
BF166 Bot's First in Hub is a star system.
BF166 Bot's First in Hub is a star system in the universe of No Man's Sky. On PS4, it was BotFodder2s first discovery post-pilgrimage.
Alias names [ edit | edit source ]
Planets & Moons [ edit | edit source ]
This star system contains three planets:
BF166-1 Red Rock
BF166-2 Onsisi II
BF166-3 Purple Rain
Korvax
0469 : 0081 : 0D6D : 011E
Distance to HUB-V-17F Southern Light: 84.2
Distance to HUB-K-74 FistOfTheNorth: 417.5
Distance to HUB-V-79 Black Hole: 366.8
Galactic Hub Project subreddit
PilgrimStarPath
Galactic Hub Interloper Handbook
|
Turbo Air TSD-27CF Specifications
Low Price Guarantee On All Turbo Air Products!
Description:
This Turbo Air ice cream merchandiser will be the perfect addition to any restaurant or convenience store that serves ice cream or other tasty frozen treats. Perfect for impulse buys setup near the register.
|
Q:
Beamer themes cannot be found / Ubuntu / I've tried every folder one can imagine
I would like to use the theme for beamer called amsterdam (\usetheme{amsterdam}). I'm using Ubuntu 14.04 LTS and Tex Live 2014.
I've tried to place that beamerthemeAmsterdam.sty to everywhere, but it gives me error that it cannot be found.
I've tried these:
/usr/local/texlive/texmf-local/tex/latex/
/home/username/texmf/ <--- I created that texmf folder there.
/usr/local/texlive/2014/texmf-dist/tex/latex/beamer/themes/theme/
/usr/local/texlive/texmf-local/tex/latex/local/
What is the problem? Default themes are in here:
/usr/local/texlive/2014/texmf-dist/tex/latex/beamer/themes/theme/
but I cannot use even those; I get the same error!
I'm using Sublime Text as an editor (with latextools). Everything else is working fine.
A:
run in a terminal:
kpsewhich beamerthemedefault.sty
and you'll get the exact position of that file. However, that is the official directory, where personal files schould not go. There is an local texmf tree. You can get that directory by running
kpsewhich -var-value TEXMFLOCAL
On my system I'll get
/usr/local/texlive/texmf-local
In that directory create a subdirectory like
mkdir -p /usr/local/texlive/texmf-local/tex/latex/beamer/
and put your personal file in there. Then run texhash from the command line to update the data base. A following
kpsewhich beamerthemeAmsterdam.sty
should give the complete path.
|
Diabetes mellitus in treated hypertension: incidence, predictive factors and the impact of non-selective beta-blockers and thiazide diuretics during 15 years treatment of middle-aged hypertensive men in the Primary Prevention Trial Göteborg, Sweden.
The objective of this study was to analyse predictive factors for the development of diabetes mellitus during long-term treatment of hypertension and to compare the diabetogenic potential of thiazide diuretics and non-selective beta-adrenoceptor blockers. The study population comprised 686 hypertensive men, aged 47-54 years, who were followed for 15 years. Patients were treated with either thiazide diuretics or beta-adrenoceptor blockers as monotherapy or in combination with one another or alternative other antihypertensive drugs. During the first part of the study, i.e. during the 1970s, only non-selective beta-adrenoceptor blockers were used. The average yearly incidence of the development of diabetes mellitus during follow-up was 1.3%. In univariate analysis body mass index, serum triglyceride level, radiographic heart enlargement and beta-blocker therapy were significantly associated with the development of diabetes mellitus. Predictors selected by stepwise Cox regression were body mass index, radiological heart enlargement and beta-blocker therapy. Two subgroups with patients treated with nonselective beta-adrenoceptor blockers but not with thiazide diuretics during the first five years of follow-up (the beta-blocker group; n = 93) or with thiazide diuretics but not with nonselective beta-adrenoceptor blockers during the first five years of follow-up (the thiazide-group; n = 96) were identified. The relative risk for developing diabetes mellitus was significantly higher in the beta-blocker group being 6.1 after 10 years and 3.5 after 15 years treatment in comparison with the thiazide group.(ABSTRACT TRUNCATED AT 250 WORDS)
|
Tony Ward (model)
Anthony Borden "Tony" Ward (born June 10, 1963) is an American model and actor.
Early life
Tony Ward was born in Santa Cruz, California on June 10, 1963 to Robert Borden Ward, from Kansas and Karen Elizabeth Castro of California. Ward is the second of three sons and spent his childhood mostly in San Jose before moving to Sonora where he graduated from high school. From there he moved to Los Angeles to pursue his dream of being an actor/model/dancer.
Tony was discovered by a scout while attending West Valley College in Saratoga, California and started modeling at age eighteen.
Modeling career
Ward began his modeling career in 1983 and achieved fame as an international supermodel, first for Calvin Klein underwear with images by Herb Ritts. Later he worked with photographers like Karl Lagerfeld, Steven Klein, Steven Meisel, Dimitris Theocharis, Terry Richardson and Rick Castro, (who had initially introduced him to Ritts) and for fashion designers such as Roberto Cavalli, Chanel, Dolce & Gabbana, Diesel, Fendi, H & M and Hugo Boss.
Ward is signed to DNA Model Management in New York City, Why Not Model Agency in Milan, Italy, Premier Model Management in London, Photogenics Model Management in Los Angeles, Unique Models in Copenhagen, and Bananas Models in Paris.
Ward has his own fashion brand SixInTheFace "Hand Ravaged Clothing by Mr. Ward".
Acting career
In 1996, Ward had his first starring role in the movie Hustler White, directed by Bruce LaBruce and Rick Castro. In 1998, he appeared in Sex/Life in L.A. Jochen Hick's adult documentary about the sex lives of the guys who make L.A. adult movies. Ward reunited with LaBruce playing a homeless junkie in the 2010 zombie thriller L.A. Zombie.
Personal life
Ward was Madonna's boyfriend in the beginning of the 1990s and he appeared in some of her music videos as well as the controversial SEX book in 1992. Tony is also a painter and photographer and lives in Los Angeles. He is a father of three.
According to People in April 15, 1991, "Madonna and male model Tony Ward, 27, her last boyfriend of record and one of the objects of her desire in the "Justify" video, are no longer an item. It may be a coincidence, but he seems to have dropped from her arm at about the same time tabloids revealed that he had married an old flame, Greek-Australian photographer Amalia Papadimos, 23, in a quickie ceremony in Las Vegas on Aug. 21, 1990—after he had begun dating Madonna."
Filmography
Movies
1996 - Hustler White by Bruce LaBruce and Rick Castro—Lead role
1998 - Sex Life in L.A. by Jochen Hick
1999 - Out in Fifty by Bojesse Christopher and Scott Leet
2002 - All about the Benjamins by Kevin Bray
2007 - Story of Jen by François Rotger—Lead Role
2010 - L.A. Zombie
2010 - Out Getting Ribs
Videos
1987 ABC - "King Without a Crown" (directors Vaughan Arnell and Anthea Benton)
1988 Belinda Carlisle - "I Get Weak" (director Diane Keaton)
1989 Madonna - "Cherish" (director Herb Ritts)
1989 Taylor Dayne - "With Every Beat of My Heart" (director David Kellogg)
1990 Madonna - "Justify My Love" (director - Jean Baptiste Mondino)
1990 Tommy Page - "I'll Be Your Everything" (director Greg Masuak)
1992 Madonna - "Erotica" (director Fabien Baron)
1995 Rusty - "Misogyny" (director Bruce LaBruce)
1996 George Michael - "Fastlove" (directors Vaughan Arnell and Anthea Benton)
1996 Spice Girls - "Say You'll Be There" (director Vaughan Arnell)
1999 Esthero - "That Girl" (director Patrick Hoelck)
2000 Sinéad O'Connor - "Jealous" (director Mike Lipscombe)
2005 Lisa Marie Presley - "Idiot" (director Patrick Hoelck)
See also
List of male underwear models
References
Category:1963 births
Category:Living people
Category:Male models from California
Category:Bisexual male actors
Category:LGBT models
Category:Male actors from San Jose, California
|
Q:
scope count multiple string names?
I'm trying to do <%= @user.challenges.habit_badge.count %>, but I don't know how I can get the scope to work to include multiple name strings I want to include in the habit_badge count.
scope :habit_badge, -> do
where(name: ('Read 20 Min', 'Run a Mile', 'Meditate 10 Min', etc....))
end
def habit_badge
if name == "Read 20 Min"
ActionController::Base.helpers.image_tag("read.png", class: "gold-star")
elsif name == "Exercise 20 Min"
ActionController::Base.helpers.image_tag("exercise.png", class: "gold-star")
elsif name == "Meditate 10 Min"
ActionController::Base.helpers.image_tag("meditate.png", class: "gold-star")
elsif name == "Stretch 5 Min"
ActionController::Base.helpers.image_tag("stretch.png", class: "gold-star")
elsif name == "Write 500 Words"
ActionController::Base.helpers.image_tag("write.png", class: "gold-star")
elsif name == "Walk 5,000 Steps"
ActionController::Base.helpers.image_tag("walk.png", class: "gold-star")
elsif name == "Eat Fruit & Veg"
ActionController::Base.helpers.image_tag("fruit-and-vegetable.png", class: "gold-star")
elsif name == "Plan Day"
ActionController::Base.helpers.image_tag("plan.png", class: "gold-star")
elsif name == "After Waking, Guzzle Water"
ActionController::Base.helpers.image_tag("water.png", class: "gold-star")
elsif name == "Track Consumption"
ActionController::Base.helpers.image_tag("track-food.png", class: "gold-star")
elsif name == "Random Act of Kindness"
ActionController::Base.helpers.image_tag("random-kindness.png", class: "gold-star")
elsif name == "Write 3 Gratitudes"
ActionController::Base.helpers.image_tag("gratitude.png", class: "gold-star")
elsif name == "Juice Fast"
ActionController::Base.helpers.image_tag("juice.png", class: "gold-star")
elsif name == "Not Smoke"
ActionController::Base.helpers.image_tag("not-smoke.png", class: "gold-star")
elsif name == "Not Drink Alcohol"
ActionController::Base.helpers.image_tag("not-drink.png", class: "gold-star")
else
ActionController::Base.helpers.image_tag("gold-star-maze.png", class: "gold-star")
end
end
A:
Pass an array of names to scope:
scope :habit_badge, -> {
where(name: ['Read 20 Min', 'Run a Mile', 'Meditate 10 Min'])
}
It will be treated as:
SELECT "resources".* FROM "resources" WHERE "resources"."name" IN ('Read 20 Min', 'Run a Mile', 'Meditate 10 Min')
|
# Copyright 1999-2019 Gentoo Authors
# Distributed under the terms of the GNU General Public License v2
EAPI=7
inherit toolchain-funcs
MY_PN=${PN//_/-}
DESCRIPTION="Show hyphenations in DVI files"
HOMEPAGE="https://packages.debian.org/stable/tex/hyphen-show"
SRC_URI="mirror://debian/pool/main/h/${MY_PN}/${MY_PN}_${PV}.orig.tar.gz"
LICENSE="GPL-1+"
SLOT="0"
KEYWORDS="amd64 ~ppc64 x86"
S=${WORKDIR}/${MY_PN}-${PV}
PATCHES=("${FILESDIR}"/${PN}-gcc34.patch)
src_compile() {
$(tc-getCC) ${CFLAGS} ${LDFLAGS} hyphen_show.c -o hyphen_show || die
}
src_install() {
dobin hyphen_show
doman hyphen_show.1
dodoc README.hyphen_show
}
|
/*
* Copyright (c) 2008-2016 Haulmont.
*
* 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 com.haulmont.cuba.web.widgets.client.popupbutton;
import com.google.gwt.core.client.GWT;
import com.google.gwt.core.client.Scheduler;
import com.google.gwt.dom.client.Element;
import com.google.gwt.dom.client.NativeEvent;
import com.google.gwt.event.dom.client.KeyCodes;
import com.google.gwt.user.client.Event;
import com.google.gwt.user.client.ui.FlowPanel;
import com.google.gwt.user.client.ui.Widget;
import com.haulmont.cuba.web.widgets.CubaPopupButton;
import com.haulmont.cuba.web.widgets.client.Tools;
import com.haulmont.cuba.web.widgets.client.addons.popupbutton.PopupButtonConnector;
import com.haulmont.cuba.web.widgets.client.addons.popupbutton.PopupButtonServerRpc;
import com.haulmont.cuba.web.widgets.client.jqueryfileupload.CubaFileUploadWidget;
import com.vaadin.client.WidgetUtil;
import com.vaadin.client.communication.RpcProxy;
import com.vaadin.client.communication.StateChangeEvent;
import com.vaadin.client.ui.VButton;
import com.vaadin.client.ui.VUpload;
import com.vaadin.shared.ui.Connect;
import static com.haulmont.cuba.web.widgets.client.popupbutton.CubaPopupButtonWidget.SELECTED_ITEM_STYLE;
@Connect(CubaPopupButton.class)
public class CubaPopupButtonConnector extends PopupButtonConnector {
protected PopupButtonServerRpc rpc = RpcProxy.create(PopupButtonServerRpc.class, this);
@Override
public CubaPopupButtonState getState() {
return (CubaPopupButtonState) super.getState();
}
@Override
protected CubaPopupButtonWidget createWidget() {
return GWT.create(CubaPopupButtonWidget.class);
}
@Override
public CubaPopupButtonWidget getWidget() {
return (CubaPopupButtonWidget) super.getWidget();
}
@Override
public void onStateChanged(StateChangeEvent stateChangeEvent) {
super.onStateChanged(stateChangeEvent);
if (stateChangeEvent.hasPropertyChanged("customLayout")) {
getWidget().customLayout = getState().customLayout;
}
}
@Override
public void onPreviewNativeEvent(Event.NativePreviewEvent event) {
NativeEvent nativeEvent = event.getNativeEvent();
if (getWidget().getPopup().isVisible()) {
Element target = Element.as(nativeEvent.getEventTarget());
if (getWidget().popupHasChild(target)) {
if (event.getTypeInt() == Event.ONKEYDOWN
&& (nativeEvent.getKeyCode() == KeyCodes.KEY_ESCAPE
|| nativeEvent.getKeyCode() == KeyCodes.KEY_TAB && isLastChild(target))
&& !nativeEvent.getAltKey()
&& !nativeEvent.getCtrlKey()
&& !nativeEvent.getShiftKey()
&& !nativeEvent.getMetaKey()) {
event.cancel();
event.getNativeEvent().stopPropagation();
event.getNativeEvent().preventDefault();
Scheduler.get().scheduleDeferred(() -> {
getWidget().hidePopup();
rpc.setPopupVisible(false);
getWidget().setFocus(true);
});
return;
}
}
}
super.onPreviewNativeEvent(event);
if (isEnabled()) {
Element target = Element.as(nativeEvent.getEventTarget());
switch (event.getTypeInt()) {
case Event.ONCLICK:
handleClick(event, target);
break;
case Event.ONKEYDOWN:
handleKeyDown(event, target);
break;
case Event.ONMOUSEOVER:
handleMouseOver(event, target);
break;
}
}
}
protected void handleClick(@SuppressWarnings("unused") Event.NativePreviewEvent event, Element target) {
if (getState().autoClose && getWidget().popupHasChild(target)) {
Scheduler.get().scheduleDeferred(() -> {
getWidget().hidePopup();
// update state on server
rpc.setPopupVisible(false);
});
}
}
protected void handleMouseOver(@SuppressWarnings("unused") Event.NativePreviewEvent event, Element target) {
if (!getState().customLayout && getWidget().popupHasChild(target)) {
Widget widget = WidgetUtil.findWidget(target, null);
if ((widget instanceof VButton
|| widget instanceof VUpload
|| widget instanceof CubaFileUploadWidget)) {
VButton button;
if (widget instanceof VButton) {
button = (VButton) widget;
} else if (widget instanceof CubaFileUploadWidget) {
button = ((CubaFileUploadWidget) widget).getSubmitButton();
} else {
button = ((VUpload) widget).submitButton;
}
if (!button.getStyleName().contains(SELECTED_ITEM_STYLE)) {
getWidget().childWidgetFocused(button);
button.setFocus(true);
}
}
}
}
protected void handleKeyDown(Event.NativePreviewEvent event, Element target) {
if (!getState().customLayout && getWidget().popupHasChild(target)) {
Widget widget = WidgetUtil.findWidget(target, null);
if (widget instanceof VButton
|| widget instanceof VUpload
|| widget instanceof CubaFileUploadWidget) {
Widget widgetParent = widget.getParent();
if (widgetParent.getParent() instanceof VUpload) {
VUpload upload = (VUpload) widgetParent.getParent();
widgetParent = upload.getParent();
} else if (widgetParent.getParent() instanceof CubaFileUploadWidget) {
CubaFileUploadWidget upload = (CubaFileUploadWidget) widgetParent.getParent();
widgetParent = upload.getParent();
}
FlowPanel layout = (FlowPanel) widgetParent;
Widget focusWidget = null;
int widgetIndex = layout.getWidgetIndex(widget);
int keyCode = event.getNativeEvent().getKeyCode();
if (keyCode == KeyCodes.KEY_DOWN) {
focusWidget = Tools.findNextWidget(layout, widgetIndex);
} else if (keyCode == KeyCodes.KEY_UP) {
focusWidget = Tools.findPrevWidget(layout, widgetIndex);
}
if (focusWidget instanceof VButton
|| focusWidget instanceof CubaFileUploadWidget
|| focusWidget instanceof VUpload) {
VButton button;
if (focusWidget instanceof VButton) {
button = (VButton) focusWidget;
} else if (focusWidget instanceof CubaFileUploadWidget) {
button = ((CubaFileUploadWidget) focusWidget).getSubmitButton();
} else {
button = ((VUpload) focusWidget).submitButton;
}
getWidget().childWidgetFocused(button);
button.setFocus(true);
}
}
}
}
protected boolean isLastChild(Element target) {
Widget widget = WidgetUtil.findWidget(target, null);
Widget widgetParent = widget.getParent();
FlowPanel layout = (FlowPanel) widgetParent.getParent();
int widgetIndex = layout.getWidgetIndex(widget);
return widgetIndex == layout.getWidgetCount() - 1;
}
}
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12 November 2012
Easy Japanese Curry
Even with 5 kids running around, I made this. :)
I have been craving Japanese curry for weeks now. I don't know why but it's been an unsatisfied craving until today. Woo Hoo!! :)
I remember my grandma who use to make this kind of curry all the time. It was always thick, chunky and best of all, yummy! I like the fact that it's a little sweeter then Indian curries. I wanted to make the curry so I can give Kat something a little different for lunch. She loves her onigiri and gyoza, but she must be getting tired of the same thing everyday. So I thought, I could make curry with an onigiri on top. My inspiration came from my this picture my twitter friend, ♥ ღஜღ Michele ღஜღ ♥, posted a little while ago. I decided to make frog onigiri because of Yum Yum Bento. I love that book so much!
Kat's Bento Lunch
I found his recipe online: http://norecipes.com/blog/karei-raisu-japanese-curry-rice/ and love it. It's super easy and pretty fool-proof. I made a couple of changes, only because I can't seem to make a good roux. I know, the simplest thing in the world, but I seem to keep messing it up. :(
1/4 C flour1 Tbsp garam masala 1 Tbsp curry powder1/2 tsp cayenne pepper (add less if you want it mild or more if you want it spicy)fresh ground black pepper1/2 cup water1 Tbs ketchup (or tomato paste)1 Tbs tonkatsu sauce (or worcestershire sauce)2 tsp oil1 large onions sliced thin2 carrots cut into chunks4 cups water2 large yukon gold potatoes; cut into large chunks1 small apple; peeled, cored and pureed (I just put it in my blender with a little water)2 tsp kosher salt (I actually didn't use any salt)1 tsp garam masala (if needed)1/2 cup frozen peas- In a small bowl, mix together flour, garam masala, curry powder, cayenne pepper, black pepper, water, ketchup and tonkatsu sauce. Set aside.- Heat oil in a large pot over medium heat, add onions and cook until translucent. - Add carrots and saute for about 5 mins, making sure not to burn the onions. - Add water, potatoes, apple puree and salt. Increase heat to high and bring to a boil. - Reduce heat, simmer for about 20 mins, or until carrots and potatoes are fork tender. - Increase heat and bring to a boil. Add curry mixture and mix well. Allow to boil for another 10 mins or until curry has thickened. Taste to see if additional garam masala is needed. If the curry is to thick add more water, or coconut milk (to make it creamy). - Remove from heat. Add frozen peas and stir until peas have heated through. Serve with some rice and enjoy.Oh, I made my little frog using a panda bear mold I purchased from Bento USA. This makes the process so easy. I was able to make an army of frogs with little effort. :)
For the frog in the picture, I used Wilton candy eyeballs . All my other frogs, I used white cheese and nori. The nostrils are black sesame seeds. The mouth, I cut from nori as well. I also coloured my rice using some pureed spinach, added to the water and rice before I put it into my rice cooker. Next time, I might try colouring the rice after it's cooked. The spinach did quite the number on my rice cooker. I guess live and learn right? LOL!
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All relevant data are within the manuscript and its Supporting Information files
Introduction {#sec001}
============
Zika virus is an arbovirus (arthropod-borne) of the Flaviviridae family, which like dengue viruses and alphavirus chikungunya virus is transmitted by Aedes mosquitoes. Although discovered in 1947 in Uganda, the first large Zika virus outbreak was reported in Micronesia in 2007 \[[@pntd.0007695.ref001]\] followed by the 2014 French Polynesia outbreak \[[@pntd.0007695.ref002]\] and the massive Latin American outbreak in 2015, which was first reported in Brazil and spread across the Americas \[[@pntd.0007695.ref003]\]. During this outbreak, alarming Zika-associated complications, such as microcephaly and Guillain Barré syndrome (GBS) were reported \[[@pntd.0007695.ref004], [@pntd.0007695.ref005]\].
GBS is an inflammatory neuropathy and the most common cause of neuromuscular paralysis in the world \[[@pntd.0007695.ref006]\]. The etiology of GBS is unknown but its development has been highly associated with post-infection autoimmune responses against gangliosides in peripheral nerves. Gangliosides are sialated glycosphingolipids found in neuronal membranes and are involved in different neuronal functions. Autoimmune antibodies recognizing gangliosides are found in a high proportion of patients with GBS (62% \[[@pntd.0007695.ref012]\]) and are thought to contribute to neuronal pathology inducing complement-mediated axonal injury and demyelination \[[@pntd.0007695.ref006]\]. Molecular mimicry has been proposed as a likely mechanism in infection-induced GBS, where antibodies generated against microbial antigens with structural similarities to specific gangliosides would cross-react with host gangliosides in neuronal membranes. A classic example is GBS associated with *Campylobacter jejuni* infection \[[@pntd.0007695.ref007]\]. Zika virus was added to the list of GBS-associated pathogens due to the high incidence reported during the 2015 Latin America outbreak \[[@pntd.0007695.ref008]\]; however, Zika virus-associated GBS shows anti-gangliosides antibodies (anti-GA1) that cannot be attributed to molecular mimicry \[[@pntd.0007695.ref009]\], as described for *C*. *jejuni* \[[@pntd.0007695.ref007]\], suggesting alternative mechanisms for the generation of autoantibodies as a result of Zika infection.
During many autoimmune disorders, such as rheumatoid arthritis, autoantibodies play an essential pathological role in mediating the disease. Interestingly, increased levels of IgG autoantibodies against the ganglioside GD3 have been observed in patients with acute Zika infection and without neurologic manifestations such as GBS \[[@pntd.0007695.ref010]\]. Some GBS manifestations have also been associated with elevated levels of autoantibodies such as anti-ganglioside antibodies that can target peripheral nerves \[[@pntd.0007695.ref011], [@pntd.0007695.ref012]\], but the association of these antibodies with Zika-induced GBS remains unclear.
In this study we evaluate the antibody reactivity levels against 17 different glycolipids, including mostly gangliosides, presented in single and combination form, in the plasma of Zika-infected patients from one of the locations of the 2015 outbreak in Salvador, Brazil. We observed that Zika-associated GBS patients have significantly higher levels of plasma anti-glycolipid antibodies compared to non-GBS Zika-infected patients. We also observed a broad repertoire of glycolipids, including gangliosides, that were targeted by both IgM and IgG anti-self antibodies. Collectively, these results established a link between anti-ganglioside antibodies and Zika-associated GBS patients.
Methods {#sec002}
=======
Ethics statement {#sec003}
----------------
This study was approved by the institutional review board of Instituto Gonçalo Moniz-Fiocruz--n°1184454/2015. All participants were adults, agreed to participate in the study and signed Informed Consent.
Study design and sample collection {#sec004}
----------------------------------
Cases of GBS and encephalitis associated with arbovirus infection and Zika infection without neurological symptoms were enrolled in a surveillance study in neurological units of two reference hospitals in Salvador, Bahia, Brazil, from May 2015 to April 2016, during the Zika outbreak in this area \[[@pntd.0007695.ref013]\]. The study population were patients with acute neurological syndromes admitted to neurology sectors of participating hospitals. Patients with Zika infections but no neurological signs were recruited as part of a surveillance program for Zika infections in the same hospitals. All patients with neurological syndromes were evaluated by the researcher neurologist and the diagnosis of GBS was established according to international criteria \[[@pntd.0007695.ref014]\]. The inclusion criteria were: (1) Patients with symptoms compatible with GBS and its variants or encephalitis. The diagnosis of GBS, Miller-Fisher syndrome (MFS) and its variants \[[@pntd.0007695.ref014]\]; and encephalitis \[[@pntd.0007695.ref015]\] was predetermined by disease-specific criteria. \[[@pntd.0007695.ref002]\] Patients that reported acute exantemathous or fever illness in the 4 weeks before onset of neurologic symptoms. Electromyography and nerve conduction studies were performed in patients with GBS. See [Table 1](#pntd.0007695.t001){ref-type="table"} for details regarding the timing of neurologic symptoms and sample collection in relations to symptoms of arbovirus infection.
10.1371/journal.pntd.0007695.t001
###### Patient diagnosis and detection of Zika RNA (by RT-PCR) and arbovirus IgM and IgG by ELISA.
{#pntd.0007695.t001g}
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Patient ID Zika GBS Time to neuro\ Time to sample collection (days)[^2^](#t001fn002){ref-type="table-fn"} Chikungunya Dengue
onset\
(days)[^1^](#t001fn001){ref-type="table-fn"}
------------------------------ --------------------------------------------- ------ ----- ---------------------------------------------- ------------------------------------------------------------------------ ------------------------------------------- -------- --------------------------------------------- ---- ---- ---- ---- ---- ----
Acute Zika\ 1 \+ \+ \+ \- 2 \- \- \- \- \- \+
(n = 3)
2 \- \+ \- \- 7 \- \- \- \- \- \-
3 \+ \- \- \- 3 \- \- \- \- \- \-
4 months after Zika (n = 2) 4 \- \- \+ \- 122 \- \- \- \-
5 \- \- \+ \- 146 \- \- \- \+
Zika + encephalitis (n = 3) 6 \- \+ \+ \- 6 7 \- \- \+ \- \+ \+
7 \- \+ \+ \- 6 5 \- \- \- \- \- \-
8 \- \+ \+ \- 5 13 \- \- \- \- \- \+
Zika + GBS\ 9 (2)[^4^](#t001fn004){ref-type="table-fn"} \- \+ \+ BFP[^5^](#t001fn005){ref-type="table-fn"} 10 10/46[^6^](#t001fn006){ref-type="table-fn"} \- \- \- \- \- \+
(n = 7)
10 (2) \- \+ \+ Classic 33 17/57 \- \- \- \- \- \+
11 \- \- \+ Classic 4 6 \- \- \- \- \- \-
12 \- \+ \+ \+ Classic 11 5 \- \- \- \- \- \+
13 \- \+ \+ \+ Classic 10 23 \- \- \- \- \- \+
14 \- \+ \+ \+ MFS[^7^](#t001fn007){ref-type="table-fn"} 33 5 \- \- \- \- \- \+
15 \- \- \+ Classic 3 35 \- \- \- \- \- \+
GBS unknown etiology (n = 1) 16 \- \- \- Classic 14 7 \- \- \- \- \- \+
Chikungunya (n = 2) 17 \- \- \+ Classic 20 \- \+ \+ \- \- \+
18 \- \- \+ Classic 20 \- \+ \+ \- \- \+
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
^1^Days between onset arboviral symptoms (or fever for patient 16) and neurological onset
^2^Days between onset of arboviral symptoms and sample collection
^3^Plaque reduction neutralization test
^4^Number of samples collected from an individual patient
^5^Bifacial weakness with paresthesias (BFP)
^6^Days between onset of arboviral symptoms and sample collection for first and second samples
^7^Miller Fisher syndrome (MFS)
Serological analysis {#sec005}
--------------------
Detection of specific anti-Zika, anti-chikungunya, and anti-dengue IgG antibodies and anti-dengue and anti-chikungunya IgM antibodies were performed using indirect enzyme-linked immunosorbent assays (ELISAs) (Euroimmun, Lüberg, Germany), in accordance with the manufacturer protocol. An IgM antibody-capture ELISA (MAC-ELISA), provided by the Arbovirus Reference Collection division of the Centers for Disease Control and Prevention (CDC), was used in accordance with the established CDC protocol. Detection of RNA for Zika, chikungunya and dengue virus were performed by reverse transcriptase-PCR following published methods \[[@pntd.0007695.ref016]--[@pntd.0007695.ref018]\]. Patient samples positive for Zika plaque reduction neutralization test (PRNT) and/or positive for Zika IgM and negative for dengue IgM by ELISA (CDC) were considered positive for Zika infection. Patient 11 was considered positive for Zika infection because it showed positive Zika IgG and negative dengue IgG. Only in patient 15, which is positive for Zika and dengue IgG, lack of cross-reactivity with anti-dengue antibodies could not be confirmed. Zika infection was considered acute when samples were positive for Zika RNA (by RT-PCR, \[[@pntd.0007695.ref018]\] and/or Zika IgM (by ELISA). Biological samples, including blood, were collected upon hospital admission or 4 months after the onset of symptoms, as indicated. Data management was performed using [REDCap 6.18.1](https://projectredcap.org/) - 2018 Vanderbilt University.
Ganglioside ELISAs {#sec006}
------------------
Costar 3700 384-well ELISA plates were coated with single or mixes of Glycolipids (Matreya, Sigma) at 20 μg/ml in 200 proof Molecular Biology ethanol using an Agilent Bravo system in a BSL-2 hood. The lipids used were: sphingomyelin (SPM), phosphatidylserine (PS), sulfatide (SULF), globoside (GS), Trihexosylceramide (CTH-hydroxi fatty acid) (THCH), Trihexosylceramide (CTH non-hydroxy fatty acid)(THCHN), galactocerebroside (GALC), and the gangliosides GM1, GM2, GM3, GA1, GD1A, GD1B, GD2, GD3, GT1B and GQ1B. Plates were then allowed to evaporate at RT after \>16 h of incubation at 4°C. Plates were washed 3 times with PBS 0.05% tween 20 and then blocked overnight with PBS supplemented with 3% BSA. Plasma from patients was diluted at 1:100 in blocking buffer and incubated for 2 h at 37 °C. Plates were washed again 3 times and incubated with anti-human IgM/IgG-HRP (Abcam) for 1 h at 37 °C. Plates were washed 3 more times and TMB substrate (BD Biosciences) was added until desired color was obtained. Reaction was stopped with Stop buffer (Biolegend) and absorbance was read at 450 nm. The optical density at 450 nm was compared with the same dilution (1:100) of a positive plasma sample (sample ID: 9b) that was used as reference to calculate relative units (RU). Two negative controls were included in each of the ELISA plates run: (1) The plasma of a healthy US control donor was used in duplicated wells in the ELISA for each glycolipid and combinations. The average of the 2 determinations for each glycolipid and combinations was used as background for each glycolipid and subtracted from each value. (2) The reactivity of each plasma sample in wells coated with PBS supplemented with 3% BSA. The value of eight independent wells for each plasma sample was obtained. It was observed that the variation between the eight replicates with each plasma samples was \<0.02 for all samples and the variation between the average values for the different plasma samples was \<0.0002. The reactivity of all plasma samples to BSA was considered constant and was not subtracted from assay values. The reactivity to wells coated with only glycolipids coating buffer (ethanol) was not considered since it results in high unspecific background for all samples. The secondary antibody, TMB and stop solution was added using the peristaltic pump on the Biotek EL406. Washes were also done using the 96-head washer on the EL406. Validation of the automated 384-well ELISAs was performed using a similar protocol in 96-well plates with manual pipetting. Five different plasma samples (9b, 10a, 11, 14 and 16) of GBS patients were tested with five randomly chosen glycolipids (SPM, GS, GM1, GD3 and SULF). The variation between the two assays was found to be lower than 0.008 for each of the glycolipids.
Statistical analysis {#sec007}
--------------------
Data were analyzed using Prism (GraphPad Software). Unpaired t-test was used to identify statistical differences between groups of samples. For determination of number of antigens recognized per sample and number of positive samples recognizing each ganglioside, reactivity of samples was considered positive if the OD value was at least the average of control background wells plus three times the standard deviation.
Results {#sec008}
=======
Zika-associated GBS is one of the most serious complications associated with this infection. Our main goal in this study is to compare the prevalence and specificities of anti-ganglioside antibodies in a cohort of Zika-associated GBS patients (n = 7) compared to Zika-infected patients without GBS (n = 8). Among these, some patients presented with encephalitis (n = 3) or were Zika-infected with no neurological symptoms, either in acute phase (n = 3) or 4 months after the onset of symptoms (n = 2). The median of days between the onset of arboviral and neurological symptoms was 10 days for the Zika-associated GBS patients ([Table 1](#pntd.0007695.t001){ref-type="table"}).
Strong anti-ganglioside antibody response in Zika-associated GBS patients {#sec009}
-------------------------------------------------------------------------
Using a novel high throughput ELISA approach, we assessed the plasma of these patients for their reactivity (IgM and IgG) against different gangliosides. The reactivity to combinations of glycolipids has been described to be higher than the reactivity to single ones, possibly due to the formation of complex antigenic structures \[[@pntd.0007695.ref012]\]. We therefore analyzed reactivity against 17 lipids, mostly glycolipids including gangliosides described to be associated with GBS \[[@pntd.0007695.ref006]\], alone or their 139 double combinations. We first performed an overall analysis of all the patient samples to determine the levels of ganglioside reactivity in their plasma using a high throughput ELISA approach to detect anti-ganglioside IgM and IgG antibodies. These assays showed increased anti-ganglioside reactivity in the plasma of Zika-associated GBS patients compared to Zika patients without GBS ([Fig 1A--1C](#pntd.0007695.g001){ref-type="fig"}). Collectively, these results showed an enriched anti-ganglioside antibody response in the plasma of Zika-associated GBS patients compared to Zika-infected controls.
{#pntd.0007695.g001}
Additionally, we analyzed one sample from a GBS patient of unknown etiology who was negative for Zika, dengue and chikungunya infections, which showed a similar profile to Zika-associated GBS patients.
Since a previous report described that the plasma of GBS patients presented higher antibody reactivity to complex glycolipids compared to individual ones, we analyzed the responses to individual versus 2-by-2 combined glycolipids. We did not find any significant differences between the average reactivity of any of the plasma samples to individual or combined glycolipids ([Fig 2](#pntd.0007695.g002){ref-type="fig"}).
{#pntd.0007695.g002}
We also analyzed the plasma of two GBS patients with active chikungunya virus infection (IgM+) and previous Zika infection (IgG+). The plasma from these patients did not present strong reactivity against gangliosides, in contrast to Zika-associated GBS patients ([Fig 3](#pntd.0007695.g003){ref-type="fig"}).
{#pntd.0007695.g003}
Broad ganglioside specificity in the plasma of Zika-associated GBS patients {#sec010}
---------------------------------------------------------------------------
We further dissected the anti-ganglioside reactivity patterns observed in Zika-infected patients with or without GBS. A detailed analysis of antigen reactivity showed that patients that developed GBS recognized a significantly higher number of antigens (single and combined ganglioside mixes) compared to patients without GBS ([Fig 4A](#pntd.0007695.g004){ref-type="fig"}). The highest number of antigens recognized was found in a GBS patient reacting significantly to \>100 different single gangliosides/combinations while all non-GBS patients reacted significantly against 2 or fewer antigens. When we analyzed which specific gangliosides had an enriched reactivity across the Zika infected patients (either in single or combination form) we observed a broad reactivity to different gangliosides and other glycolipids ([Fig 4B](#pntd.0007695.g004){ref-type="fig"}). These results suggest a broad anti-ganglioside antibody response in Zika-associated GBS patients, independent of combinations.
{#pntd.0007695.g004}
Isotypes of antibodies in the anti-ganglioside response in Zika-associated GBS high responders {#sec011}
----------------------------------------------------------------------------------------------
Our initial screen of anti-ganglioside reactivity evaluated the presence of overall IgM/IgG antibodies in the plasma of the Zika-associated GBS patients. We further analyzed the samples by validating the responses observed in six highly responsive patients, from the Zika-associated GBS group. We also dissected this response by determining IgM and IgG reactivities separately ([Fig 5](#pntd.0007695.g005){ref-type="fig"}). The results of these assays showed high levels of both anti-ganglioside IgM and IgG in the plasma of the patients compared to control plasma. Additionally, these assays validated the strong broad reactivity of the Zika-GBS patient plasma against a high number of gangliosides ([Fig 4](#pntd.0007695.g004){ref-type="fig"}). Collectively, these results confirm the presence of IgM and IgG anti-ganglioside antibodies in the plasma of Zika-associated GBS patients. Our findings demonstrate broad reactivity to glycolipids with stronger responses to specific gangliosides.
{#pntd.0007695.g005}
Discussion {#sec012}
==========
GBS is one of the most serious complications associated with Zika infection. Neurological symptoms appear shortly after a transient Zika infection resulting in the development of GBS \[[@pntd.0007695.ref009], [@pntd.0007695.ref011], [@pntd.0007695.ref019], [@pntd.0007695.ref020]\]. In this study a median of 10 days before the onset of neurological symptoms was observed, which is similar to a previous report (6 days) \[[@pntd.0007695.ref009]\]. Although Zika virus infection has been reported to lead to development of GBS in patients, little is known about the pathogenesis of this syndrome. Different autoantibodies have been identified as mediators of pathology during different autoimmune disorders, such as anti-nuclear antibodies during Systemic Lupus Erythematosus \[[@pntd.0007695.ref021]\]. Indeed, GBS is considered an autoimmune syndrome due to the immune destruction of peripheral nerve components such as gangliosides \[[@pntd.0007695.ref019], [@pntd.0007695.ref022], [@pntd.0007695.ref023]\]. Generation of anti-ganglioside antibodies and other autoantibodies has been reported in non-Zika infection-induced GBS, such as the classical one induced by the bacterium *C*. *jejuni* \[[@pntd.0007695.ref007]\]. Because anti-ganglioside autoantibodies are implicated in the pathogenesis of GBS \[[@pntd.0007695.ref006]\], we sought to determine whether anti-ganglioside antibodies were selectively increased in Zika-infected patients with GBS as opposed to Zika-infected controls with self-limited illness.
Our initials results show a potent broad reactivity against single and combination of 17 different gangliosides compared to non-GBS Zika infected patients. These anti-ganglioside antibodies were both of the IgM and IgG isotypes. Both anti-ganglioside IgG and IgM have been suggested to have a pathological role during different non-Zika infection induced GBS patients \[[@pntd.0007695.ref024]\]. The mechanism by which these anti-gangliosides lead to pathology is poorly understood. The significant increase in anti-ganglioside IgM/IgG antibodies in patients with GBS compared to non-GBS Zika-infected patients suggests a role for these antibodies in mediating the disease.
A recent study assessed a similar relationship of ganglioside reactivity in Zika-associated GBS patients in French Polynesia \[[@pntd.0007695.ref009]\]. This study found an increase in general anti-ganglioside reactivity against a different set of gangliosides tested by a different method of combinatorial glycolipid microarray. Our results show reactivity against different individual and combination of gangliosides hence illustrating the diversity in the anti-ganglioside response induced in a different cohort of Zika-associated GBS patients. We did not observe any enhancement of reactivity whenever specific gangliosides were tested individually or in combination, which may be attributed to the different methods used for detection (microarray versus ELISA).
In addition to Zika virus, other arbovirus infections like dengue and chikungunya have also been reported to lead to autoimmunity and neurological problems such as GBS \[[@pntd.0007695.ref025]--[@pntd.0007695.ref030]\]. A large percentage of the patients in our study had previous, but not active, dengue infections, as indicated by the differential anti-dengue IgM and IgG reactivity. Previous dengue infections are expected in this area of Brazil where prevalence is 86% in adults and where preexisting high antibody titers to dengue virus have been associated with reduced risk of Zika infection \[[@pntd.0007695.ref031]\].
We also assessed the plasma of two GBS patients with active chikungunya virus infection and previous Zika infection (IgG+). When we assessed the plasma of these patients for anti-ganglioside reactivity, our results demonstrated levels of anti-ganglioside antibodies significantly lower than GBS patients with an active Zika infection. It is possible that anti-ganglioside antibodies in the circulation induced during a Zika infection decrease over time and are no longer present in these patients. The role of an active chikungunya infection is unclear.
It is well established that Zika can infect neurons \[[@pntd.0007695.ref032]--[@pntd.0007695.ref034]\], including peripheral motor nerves/nerve roots, which have high abundance of different gangliosides. Direct infection of neurons would target these cells for phagocytosis by antigen presenting cells, enabling presentation of many auto antigens, such as gangliosides, along with virus antigens, resulting in an antibody response against both. Increased immune recognition of virus-infected neuronal cell antigens could be at the basis of Zika--induced GBS. Immune response against direct neural infection would be consistent with the observation that GBS tends to be an early complication of Zika. Accordingly, a recent studied showed how antiviral CD8+ T-cells mediated nerve damage leading to paralysis in Zika-infected mice \[[@pntd.0007695.ref035]\]. Additionally, immune mediated neurological damage was also reported in fatal cases of Zika-induced microcephaly \[[@pntd.0007695.ref036]\], providing additional evidence of an immune component contributing to the neuronal damage leading to GBS. Accordingly, plasma from Brazilian Zika-infected patients recognized GD3 from neurons in retina tissues \[[@pntd.0007695.ref010]\]. These patients were found to have high titers of anti-ganglioside antibodies, mainly anti-GD3 IgG antibodies. Nevertheless, mechanistic studies are needed to test this hypothesis and elucidate the role anti-ganglioside antibodies might have in Zika-induced GBS.
Although we observed wide reactivity to gangliosides, our results also showed differential reactivity to some gangliosides in the plasma of Zika-associated GBS patients. When we dissected these responses by validating them with single ganglioside ELISAs, we confirmed a strong reactivity against specific gangliosides such as GA1. Interestingly, GA1 also had the highest reactivity from the French Polynesia study as assessed by a different method of combinatorial glycolipid microarray \[[@pntd.0007695.ref009]\]. However, in a different study in India with Zika-infected GBS patients, the most commonly recognize ganglioside was GT1b \[[@pntd.0007695.ref037]\]. Collectively, our results suggest that, in a minor subset of infected patients, Zika infection causes neuronal damage that triggers an auto-immune antibody response against neuron-derived ganglioside antigens, which contributes to the pathogenesis of GBS.
We thank the High-throughput Biology Laboratory Core services at NYU Langone Medical Center.
[^1]: The authors have declared that no competing interests exist.
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[2016-2019] I WISH (Kurei)
In 2016, I made another “charaoke” gift, this time for Ooka-chan (she goes by various names on DeviantART, but I first knew her as Nikki-Ash-Ookami). Because the video took more time to make than I’d expected, I didn’t finish the accompanying illustration (which showcases the full outfits) in time for her birthday. At last, I removed my character and finished hers!
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Watchung Hills Takes Second In Districts: Magaldo Named Outstanding Wrestler And Smith Coach Of The Year
By BRENDA A. NEMCEK
February 23, 2014 at 10:40 AM
By BRENDA A. NEMCEK
February 23, 2014 at 10:40 AM
SOUTH PLAINFIELD, NJ - Watchung Hills placed second at the District 12 tournament in South Plainfield led by Mike Magaldo and Max Meyers who recorded the only two pins of the final round.
Magaldo pinned Middlesex's Bob Dinger at 1:39 in the 132-pound final and after an early takedown Meyers went on to pin South Plainfield's Jeff Plungis 35 seconds into the match at 106 with the fastest pin of the day.
NORTH PLAINFIELD, NJ - Did you play football for the North Plainfield Canucks? Want to connect with former teammates and help support current Canucks? Alumni are beginning the process of establishing an alumni association.
“This message is for all former Canuck football players,” alumni Robert Lake posted. “We are in the process of establishing a football alumni association. Our ...
NORTH PLAINFIELD, NJ - Did you play football for the North Plainfield Canucks? Want to connect ...
TRENTON, NJ - Legislation sponsored by Senator Christopher "Kip" Bateman (R-Somerset, Hunterdon, Middlesex, Mercer)appropriating $9.703 million from corporate business tax revenue to the NJ DEP for state capital and park development, preservation, conservation, and recreation projects has been signed into law by Gov. Phil Murphy..
The summer gardening season is in full swing and gardeners have been harvesting their bounty - lettuces, tomatoes, zucchinis, peppers and herbs. Insect activity is also gearing up in the garden. As the growing degree days increase, so does the damaging effects of pests in the garden. Here are a few ways to protect one of the most popular herb in the garden - BASIL. It's loved by children and ...
The summer gardening season is in full swing and gardeners have been harvesting their bounty - ...
PLAINFIELD, NJ - The annual school supply drive conducted by Netherwood Heights Neighbors is now underway, and the collection will benefit elementary students in Plainfield. The fundraiser will run through Aug. 31st.
HILLSBOROUGH, NJ -The brightly lit midway arch is once again expected to welcome an average of 15,000 local residents to the annual six-day Rotary Fair beginning Tuesday, August 14.
Located adjacent to the Hillsborough Promenade, 315 Route 206, the Fair transforms the field into a classic carnival with over 20 amusement rides, games of chance, food vendors and local business displays.
“It’s ...
HILLSBOROUGH, NJ -The brightly lit midway arch is once again expected to welcome an average of ...
BELMAR, NJ — As a fledgling dune planting flourishes near Belmar’s 12th Avenue beach playground, another patch of greenery is planned for the Third Avenue beach.
In addition to the dune grass, native plants and other suitable foliage that will fill this new 1,500-square-foot area, “pollinators” will be part of the mix, according to Belmar Councilman Thomas Brennan, liaison to the Environmental ...
NEW YORK, NY - Commuters into the Port Authority Bus terminal on Monday will be part of a pilot to test a new security system, one that will try and identify suicide vests and other improvised explosive devices.
The Port Authority will launch the pilot test next week on the new security system designed to help law enforcement professionals.
The technology, in partnership with the ...
NEW YORK, NY - Commuters into the Port Authority Bus terminal on Monday will be part of a pilot to ...
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sorry, its been awhile. went back to doc, still won't put son on IV because of mental state, is getting 1 gram Ricophen IV twice week now, is this enough to help? He's still laughing most of the day and still doesn't remember what he has, confusion and mental fog still there, no better after a month on Minocycline and weekly shot of Biciliian. Pysch doc prescribe Abilify and Namenda hoping to get mental state stabilized to start full time IV, been on Abilify for 3 days now, hasn't started Namenda (read bad reviews, don't know if I should put him on it). Has anyone experienced this? My husband and I really want him on IV all the time but doc won't do it until she's comfortable he can mentally understand why he's having it, afraid he'll pull out IV line. Don't really blame her but he doesn't seem to be getting any better.If anyone has any insight I would truly appreciate it, thanksWill try and keep you all updated more frequently, maybe someone can be helped by us.Very stressful and sad.
I am so sorry that you are still going through this. The only other things I can think of that would cause uncontrollable laughing are strokes and ALS. But, he's really young to have either of those. has he been check out thoroughly?**You never know how STRONG you are....until being STRONG is the ONLY choice you have**
yes, had spinal tap, MRI, SPECT scan and complete blood tests, all with off the charts lyme bacteria, even spotted rocky mountain fever. Tested 10 out of 10 on all bands with the first blood test and then had more test from LLMD and found the other bacteria and rocky mountain spotted fever. We're just doing what the doctors say and hopefully he'll begin to get better. Don't know what else to do.thanks for replying
sorry, its been awhile. went back to doc, still won't put son on IV because of mental state, is getting 1 gram Ricophen IV twice week now, is this enough to help? He's still laughing most of the day and still doesn't remember what he has, confusion and mental fog still there, no better after a month on Minocycline and weekly shot of Biciliian. Pysch doc prescribe Abilify and Namenda hoping to get mental state stabilized to start full time IV, been on Abilify for 3 days now, hasn't started Namenda (read bad reviews, don't know if I should put him on it). Has anyone experienced this? My husband and I really want him on IV all the time but doc won't do it until she's comfortable he can mentally understand why he's having it, afraid he'll pull out IV line. Don't really blame her but he doesn't seem to be getting any better.If anyone has any insight I would truly appreciate it, thanksWill try and keep you all updated more frequently, maybe someone can be helped by us.Very stressful and sad.
frikandfrak, could you send me an email so I can respond to you privately? Just click my email icon.
He may need to go the natural route for a while. Email GWB, he knows alot about natural supplements/herbs as he was helped and has been feeling better.**You never know how STRONG you are....until being STRONG is the ONLY choice you have**
At least your doctor is being cautious. and as far as seeing improvement it doesn't happen so fast. my treatment has only been 3times a week of zethromax as far as abx goes. and I get EDTA for 3 hours before even getting the zethro.
I freaked out on pediatric dose of docxy. 50mg 2x a day and really became suicidal. I never crashed so hard in my life.
also how old is your son? when I was younger I had some very crazy times from taking very strong drugs and ended up in psych hospitol. I turned 16 in a psych ward and thinking back I think I had lyme then.
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Q:
Equal height columns jQuery not working in webkit browsers
I tried to use both of these two solutions
1)
jQuery.fn.equalHeights = function() {
return this.height(Math.max.apply(null,
this.map(function() {
return jQuery(this).height()
}).get()
));
};
2)
jQuery.fn.equalHeights = function () {
var height = 0,
reset = jQuery.browser.msie ? "1%" : "auto";
return this.css("height", reset).each(function () {
height = Math.max(height, this.offsetHeight);
}).css("height", height).each(function () {
var h = this.offsetHeight;
if (h > height) {
jQuery(this).css("height", height - (h - height));
}
});
};
to have equal height columns, but I have problems in webkit browsers only.
Here is a screenshot, with the content of the left column overflowing. The columns have actually the same height, but they are all too short...
This is my jQuery call, in the footer:
jQuery(document).ready(
function() {
//Equal columns
jQuery('#center_column, #right_column,#left_column').equalHeights();
}
);
It looks like it is executed before the DOM is completely ready for some reason...
Any suggestion?
A:
I've had problems in the past with Webkit browsers not being able to see the image dimensions until after the document.ready event. To get around this, you can specify the height and width in the tag:
<img src="foo.jpg" alt="Foo" width="500" height="500" />
And if that doesn't work, you might find you need to do a little bit of a hack, using the window.load event rather than $(document).ready.
|
Q:
ItemAdded event running with user permissions (SharePoint 2010)
My understanding is/was that by default asynchronous event receivers ran under system permissions, while synchronous event receivers run under user permissions -- and that ItemAdding is synchronous, ItemAdded is asynchronous. Now I'm encountering a permissions issue using the ItemAdded event and I'm not sure if I've gotten this all wrong.
I have a feature which, amongst other things, deploys an ItemAdded event receiver. It's a super simple event receiver that just takes the listItemId and fills a custom column with that number once the item has been added.
I have several users who have edit permissions on the list, and several who don't. When an item is added under an account with edit permissions, the event receiver does its intended job. When an item is added by a user without edit permissions, it fails. When debugging, the SPItemEventProperties show the UserDisplayName and the UserLoginName. When the code hits properties.ListItem.Update() I get an UnauthorizedAccessException.
If it matters: this list has a custom content type and a custom list definition deployed through the same feature, and is created programmatically when the feature is activated. The items that appear in the list are created programmatically on ItemAdding.
I know I could put in an impersonation step and I might have to in order to get this working quick enough, but I'd really like to understand where I'm going wrong with my train of thought here. Am I completely wrong about how ItemAdded is run, am I missing a setting somewhere, or what?
Things I've tried: explicitly defining my ItemAdded event receiver as asynchronous in the CAML, adding a list item non-programmatically to check it wasn't a quirk of adding items in ItemAdding, debugging as users with and without edit permissions to check it was really the update failing, trying both a visual studio deploy and a wsp deploy.
I'll add code if people request specific bits, but right now I'm not really sure what's relevant and it might just be a problem with my understanding anyway! Feel stupid asking this but I'm stuck :)
A:
Asynchronous events still run in the context of the user that triggered the event, your initial assumption is incorrect.
Hopefully you are actually impersponating and not just using the RunwithElevatedPrivilege delegate to side security.
Take a good read of this and understand the implication of RWEP:http://www.danlarson.com/best-practices-for-elevated-privilege-in-sharepoint/
|
Fred Cone (American football)
Fred Cone (born June 21, 1926 in Pine Apple, Alabama) is a former professional American football fullback and placekicker in the National Football League for the Green Bay Packers and Dallas Cowboys. He played college football at Clemson University.
Early years
Cone grew up in Pine Apple, Alabama, with a population around 100. He attended Moore Academy, a one-room school from kindergarten through high school. He didn't play football because there weren't enough people to field a team.
Before going to college, he enlisted in the U.S. Army to take part of World War II, where he served in the Pacific as part of the 11th Airborne Division.
College career
When he returned to the United States in the summer of 1946, he read a newspaper advertisement about tryouts at Auburn University and decided to attend. His participation was cut short with an ankle injury that forced him to return home.
During his recovery, a family friend turned out to be the sister of Frank Howard, the head coach at Clemson College. She helped Cone get a tryout and eventually he was able to make the team and receive a scholarship.
Cone was the starting fullback in a backfield that included Ray Mathews. The 1948 team finished undefeated and beat the University of Missouri, 24–23, in the 1949 Gator Bowl. He scored two first-quarter touchdowns and had a critical fourth down conversion late in the game. The next year, he registered 703 rushing yards and 8 touchdowns.
As a senior, his 184 carries for 845 rushing yards, 15 touchdowns and 92 points at the time were all school season records. He also was a part of another undefeated season and played in the 1951 Orange Bowl, beating the University of Miami 15–14. He gained 81 rushing yards, scored one of the touchdowns, returned one kickoff and had 4 punts.
He finished his college career with eight 100-yard career rushing games, 31 touchdowns and 189 points. He also was a kickoff specialist.
In 1973, he was inducted into the State of South Carolina Athletic Hall of Fame and the Clemson Athletic Hall of Fame. He is a member of Clemson’s Ring of Honor.
Professional career
Green Bay Packers
Cone was selected by the Green Bay Packers in the third round (27th overall) of the 1951 NFL draft. He was used as a fullback and placekicker.
As a rookie, he led the team with 50 points, and was the second-leading rusher with 56 carries for 190 yards (3.4-yard average). He also made 5 of 7 field goal attempts and 29 of 35 extra points.
Cone led the Packers in scoring in five of the next six seasons, including leading the league with 16 field goals made in 1955. The next year, he announced his retirement, but was eventually convinced by the team to return.
In 1957, he was a part of the inaugural game at Lambeau Field, then known as City Stadium, contributing to an upset of the Chicago Bears 21-17, before a crowd of 32,132 people. He finished the season by leading his team in scoring with 74 points.
He played for the Packers during a low point in the franchise history, never experiencing a winning season, which cost him the opportunity to earn more accolades for his play.
In 1974, he was inducted into the Green Bay Packers Hall of Fame.
Dallas Cowboys
On May 12, 1960, he was signed as a free agent by the Dallas Cowboys after being out of football for two years, while coaching at University Military School in Mobile Alabama. He became the first starter at placekicker in franchise history. He also was a backup fullback and reunited with former college teammate Ray Mathews. He was released on August 28, 1961.
Personal life
In his first two years in the NFL, he worked for the Packers during the offseason promoting season-ticket sales. He later accepted a job promoting beer with the Miller Brewing Company. He also worked for the Clemson athletic department as their chief football recruiter in the 1960s.
Country comedian Jerry Clower, who played football at Mississippi State University, recounted his experience facing Cone on the field in his story "The Time We Played Clemson".
References
External links
Fred Cone was the leading scorer during lean years
Clemson Vault: Fred Cone, a Clemson Great
Category:1926 births
Category:Living people
Category:People from Wilcox County, Alabama
Category:Players of American football from Alabama
Category:American football running backs
Category:American football placekickers
Category:Clemson Tigers football players
Category:Green Bay Packers players
Category:Dallas Cowboys players
Category:American military personnel of World War II
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[Genetics and male infertility].
Infertility is a problem affecting many couples with a child wish. In about half of these couples a male factor is (co-) responsible for the fertility concern. For part of these patients a genetic factor will be the underlying cause of the problems. This paper gives an overview of the studies performed in the Department of Embryology and Genetics of the Vrije Universiteit Brussel and the Centre for Medical Genetics of UZ Brussel in order to gain more insight into the genetic causes of male infertility. The studies, focusing on men with fertility problems, can be subdivided into three groups: studies on deletions on the long arm of the Y chromosome, studies on X-linked genes and studies on autosomal genes. It is obvious that Yq microdeletions should be considered as a cause of male infertility. Only for patients with a complete AZFc deletion, a small number of spermatozoa can be retrieved. However, even for these patients assisted reproductive technologies are necessary. Complete AZF deletions are found in 4.6% of the patients visiting the centres for Reproductive Medicine and Medical Genetics of the UZ Brussel and for whom no other cause of the fertility problems have been detected. Taken into consideration this low prevalence of Yq microdeletions, it is obvious that also other factors, including genetic factors, must be causing fertility problems. Potentially, gr/gr deletions (partial deletions of the AZFc region) might influence the fertility status of the patients. It remains, however, unclear which of the genes located in the deleted regions are important for the progression of spermatogenesis, in case of partial or complete AZF deletions. In our studies we have also investigated mutations in genes located on the X chromosome. In analogy to the Y chromosome, the X chromosome is interesting in view of studying male infertility since men only have a single copy of the sex chromosomes. As a consequence, mutations in genes crucial for spermatogenesis will have an immediate impact on the sperm production. The genes NXF2, USP26 and TAF7L were investigated for the presence of mutations. All observed single nucleotide changes were also present in control samples, questioning their relationship with male infertility. We also studied five autosomal genes: SYCP3, MSH4, DNMT3L, STRA8 and ETV5. Only for the genes STRA8 and ETV5, changes were detected that were absent in a control population existing of men with normozoospermia. Functional analysis of the changes in ETV5 and the localization of the change observed in STRA8 showed that also these alterations were probably not the cause of the fertility problems in these men. It can be concluded that mutations are rarely detected in men with fertility problems. This low frequency of mutations has also been confirmed in several published studies. Therefore, further research is necessary to determine the impact of genetic causes on male infertility.
|
Jobless set to top two million as the UK economy heads for meltdown
The true scale of the jobs disaster facing Britain is revealed today as experts issue dire warnings that up to half a million workers will lose their jobs over the next two years, as companies cut costs and scale back investment plans to survive the economic downturn.
Official figures are widely expected to reveal this week that the number of people out of work and claiming benefits increased for a seventh successive month in August.
Finance companies based in London’s Square Mile have already laid off thousands of workers since the US mortgage crisis unleashed chaos in the world’s markets last summer; and the 5,000 UK-based staff at crisis-hit investment bank Lehman Brothers are awaiting news this weekend about how many of them will be made redundant.
The constant drip of job losses is spreading beyond the City. Karen Ward, chief UK economist at HSBC, calculates that almost a quarter of the workforce – seven million – are employed in the vulnerable retail and leisure industries. Thousands of shopworkers have already lost their jobs this year, as a succession of retail companies have gone into administration. Car manufacturers are also scaling back their production after the latest registration figures showed that last month was the worst August for new car sales since 1966.
Trade unions at Ford’s Transit van plant in Southampton will hold talks with executives tomorrow in the hope of averting layoffs. Roger Madison, national automotive officer for the Unite union, said: ‘There is just no confidence at the moment. All the companies are struggling – everyone is in the same boat.’ There are fears that the Southampton plant, employing 1,100 workers, will be closed if Ford decides to build a new model of the van at its low-cost sites in Turkey or Romania. A decision on where to build the new model is due soon.
Tomorrow union leaders will also meet executives from General Motors over its plans for a ‘down day’ on 26 September when its Vauxhall Vivaro van plant in Luton will cease production.
Last month it emerged that Toyota was cutting production at its Derbyshire plant because of a fall in demand for cars. Unite also reports that Jaguar Land Rover – owned by the Indian firm Tata – is scaling back operations.
Several housebuilders have announced big job losses as they struggle to sell new properties in the tough housing market. Barratt announced that it would cut a quarter of its workforce, and Persimmon said it would lay off 2,000 staff. In total, up to 50,000 construction workers have lost their jobs. On the broader measure favoured by the government, unemployment had already risen by 60,000 between March and June to 1.7 million. Michael Saunders, chief UK economist at Citigroup, believes the figure will continue rising for another two years, as the economy slides into recession, peaking by late 2010 at 2.25 million.
‘The only parts of the economy that have created many jobs over the past few years have been banking, finance and business services, and the public sector, and both of those look like they’re going to get much weaker,’ he said.
But economists believe it will take until at least the end of next year before a sense of optimism begins to return. In the meantime Britain’s consumers are expected to tighten their belts as the value of their homes declines and their spending power is eroded by rising food and fuel bills. That’s bad for business on the high street and across service industries, and is expected to fuel unemployment. After the travel firm XL collapsed last week, British Airways boss Willie Walsh predicted that up to 30 small airlines could go out of business.
Estate agents, too, have been hit hard. In a survey by the Royal Institution of Chartered Surveyors, some agents said they were selling just one property a week: hardly enough to justify employing a large staff. Halifax has announced that it is closing 53 branches, with the loss of up to 100 jobs. Analysts at Merrill Lynch have suggested that a third of all estate agents’ branches could close.
Hugo Sellert, head of research at online recruitment firm Monster, has noticed a decline in the number of new jobs being advertised. ‘This month what emerged most clearly was that employers seemed to be scaling back on casual and temporary recruitment,’ he said. He said the most noticeable weakening of the job market had been in East Anglia, the Midlands and London. ‘Unemployment typically lags other indicators of the health of the economy, and we’re looking at the early stages of the downturn,’ he said, adding that the UK is six to nine months behind the US, where unemployment has risen sharply to 6.1 per cent, the highest rate in five years.
Driving unemployment to a historic low was one of the proudest boasts of Gordon Brown’s decade-long chancellorship and a key element of restoring Labour’s record for economic competence.
During the 1979 election campaign, Conservative campaign posters bearing the slogan ‘Labour Isn’t Working,’ helped to dislodge the Callaghan government. But over the next four years Margaret Thatcher oversaw more than a doubling in unemployment, which shot up above three million in 1983. It hit three million again a decade later, during the painful recession of the early 1990s.
Lai Wah Co, head of economic analysis at the the Confederation of British Industry (CBI), which represents businesses, said it should also help that UK plc is now leaner than it was at the outset of the last recession. ‘Because of globalisation, companies have outsourced most offshore functions. There is not much scope for cutting back jobs. We don’t think job losses will total those of the early Nineties.’
The recent influx of migrant workers to the UK – many of whom are now going home – should also cushion the impact of falling employment. Since 2004, when eight eastern European countries joined the EU, about 845,000 migrant workers were attracted to the UK by the thriving job market. Approximately half have returned and more are following.
However, because the days of mass unemployment are a distant memory to much of today’s workforce, many employees have built up little in the way of a financial safety net, leaving them extremely vulnerable if they do lose their job. ‘Over the past 10 years, people have never had this feeling of fear,’ said a spokeswoman for Citizens’ Advice, which says unemployment is one of the major causes of financial distress. The spokeswoman said: ‘It [unemployment] doesn’t hit for a while; they often borrow more to pay for basic things, so they get themselves deeper into debt.’
As part of the government’s housing package this month, Alistair Darling, the Chancellor, announced that people who lost their jobs would be able to claim financial support to help with mortgage interest payments after 13 weeks, instead of 39 weeks as at present. The Treasury is keen to prevent job losses leading to a wave of repossessions and forced sales in the housing market, driving prices lower in a vicious circle.
Professor David Blanchflower, the US-based economist who sits on the Bank of England’s interest rate-setting committee, told MPs last week he thought two million people could already be out of work by Christmas. He has repeatedly voted for further cuts in interest rates to prevent the downturn from spiralling out of control; but has been outgunned by the majority on the committee, which has left rates on hold since April.
Case study
For Gary, 40, losing his IT job at a leading bank in the City four months ago could not have come at a worse time. ‘I was made redundant a week before my baby was born,’ he said. ‘I’d just moved into a new department and then the funding was withdrawn. I was escorted off the premises. It wasn’t pleasant.’ While he has enjoyed being around to help look after his first child, he is concerned about getting a new job. ‘I don’t think it’s going to be easy. My concern is how long it’s going to take.’ His situation is more urgent because with his wife on maternity leave, the money coming into the home has fallen sharply. ‘I have been in banking for 13 years and this is the biggest downturn. The question is how long will it take to recover?’
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@testset "pointer" begin
# inner constructors
voidptr_a = CuPtr{Cvoid}(Int(0xDEADBEEF))
generic_voidptr_a = CUDAnative.DevicePtr{Cvoid,AS.Generic}(voidptr_a)
global_voidptr_a = CUDAnative.DevicePtr{Cvoid,AS.Global}(voidptr_a)
local_voidptr_a = CUDAnative.DevicePtr{Cvoid,AS.Local}(voidptr_a)
voidptr_b = CuPtr{Cvoid}(Int(0xCAFEBABE))
generic_voidptr_b = CUDAnative.DevicePtr{Cvoid,AS.Generic}(voidptr_b)
global_voidptr_b = CUDAnative.DevicePtr{Cvoid,AS.Global}(voidptr_b)
local_voidptr_b = CUDAnative.DevicePtr{Cvoid,AS.Local}(voidptr_b)
intptr_b = convert(CuPtr{Int}, voidptr_b)
generic_intptr_b = CUDAnative.DevicePtr{Int,AS.Generic}(intptr_b)
global_intptr_b = CUDAnative.DevicePtr{Int,AS.Global}(intptr_b)
local_intptr_b = CUDAnative.DevicePtr{Int,AS.Local}(intptr_b)
# outer constructors
@test CUDAnative.DevicePtr{Cvoid}(voidptr_a) == generic_voidptr_a
@test CUDAnative.DevicePtr(voidptr_a) == generic_voidptr_a
# getters
@test eltype(generic_voidptr_a) == Cvoid
@test eltype(global_intptr_b) == Int
@test addrspace(generic_voidptr_a) == AS.Generic
@test addrspace(global_voidptr_a) == AS.Global
@test addrspace(local_voidptr_a) == AS.Local
# comparisons
@test generic_voidptr_a != global_voidptr_a
@test generic_voidptr_a != generic_intptr_b
@testset "conversions" begin
# between host and device pointers
@test convert(CuPtr{Cvoid}, generic_voidptr_a) == voidptr_a
@test convert(CUDAnative.DevicePtr{Cvoid}, voidptr_a) == generic_voidptr_a
@test convert(CUDAnative.DevicePtr{Cvoid,AS.Global}, voidptr_a) == global_voidptr_a
# between device pointers
@test_throws ArgumentError convert(typeof(local_voidptr_a), global_voidptr_a)
@test convert(typeof(generic_voidptr_a), generic_voidptr_a) == generic_voidptr_a
@test convert(typeof(global_voidptr_a), global_voidptr_a) == global_voidptr_a
@test Base.unsafe_convert(typeof(local_voidptr_a), global_voidptr_a) == local_voidptr_a
@test convert(typeof(global_voidptr_a), global_intptr_b) == global_voidptr_b
@test convert(typeof(generic_voidptr_a), global_intptr_b) == generic_voidptr_b
@test convert(typeof(global_voidptr_a), generic_intptr_b) == global_voidptr_b
@test convert(CUDAnative.DevicePtr{Cvoid}, global_intptr_b) == global_voidptr_b
end
end
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Jurong East Bus Interchange
Jurong East Temporary Bus Interchange is a bus interchange located in Jurong East, Singapore. An open-air single-level bus terminal, it is directly connected to the adjacent Jurong East MRT station.
History
The original facility used for the bus interchange was built on 30 June 1985, west of the present MRT station and opposite the Jurong CPF building at Jurong Gateway Road. Most of the bus services in the bus interchange originated from the Teban Gardens Terminal and some from the former Jurong Bus Interchange, which were re-routed to this interchange when it opened. For years, despite being in the zone marked as Jurong Regional Centre, the bus interchange had a rather low level of passenger flow as compared to the larger Boon Lay Bus Interchange serving Jurong West New Town, the Jurong Industrial Estate, as well as institutions in the west including the Nanyang Technological University. The interchange serves mainly commuters travelling to the various housing estates, schools, religious places, tourist attractions and industrial places in Jurong East and those travelling to Malaysia via Tuas Checkpoint.
Following the redevelopments in Jurong, the original facility had been slated to be rebuilt into an air-conditioned facility as part of a commercial development on the site, which the commercial development and surrounding commercial places, together with the MRT station, will be collectively known as the Jurong East Integrated Transport Hub, similar to the rest of earlier hubs built. The rebuilding plan came along with the other plots of land surrounding the original facility being sold off to developers for commercial developments on 27 October 2010 when the Land Transport Authority released a tender for a "Proposed Jurong East Temporary Bus Interchange" indicating the redevelopment of the bus interchange. The land (MK05-08622X) occupied by the original facility was to be acquired by Singapore Land Authority for development into a commercial centre 10 years later and the original interchange to relocate to a temporary facility. The construction of the temporary facility spanned from middle of 2011 to the end of 2011.
The temporary facility is located at the south of the MRT station along Jurong Gateway Road, roughly 0.2 km South-East from the original facility, opposite JCube at the western end of it and the JTC Corporation headquarters at the eastern end. It has the same colour scheme of red as the original facility and it somewhat resembles the temporary facility used by Boon Lay Temporary Bus Interchange. The temporary bus interchange will soon be relocated to a second temporary bus interchange at the western end near JCube and Jurong Town Hall Road in 2020. The existing temporary bus interchange will be demolished.
The new bus interchange brought about changes in routes. The bus stop outside Block 131 is now being reused after the Jurong East Modification Project. All former end-on bus services (except for Service 98 and 98M) now call at the bus stop outside Jurong Seventh-Day Adventist Church.
Bus Contracting Model
Under the new bus contracting model, all Singaporean run bus routes were split into 7 route packages-52 under Bishan-Toa Payoh, 506 under Bedok, 51 under Sengkang-Hougang, 105 under Serangoon-Eunos, 160 under Bukit Merah, 197 under Clementi and the rest are under Bulim Bus Packages.
In May 2015, the LTA announced Tower Transit the successful tenderer of the Bulim Bus Package. This package comprises 15 services originating from Jurong East Bus Interchange, including the newly-introduced services 41, 143M and the amended service 49. Tower Transit took over operations of these services out of Bulim Bus Depot, and also operates in Clementi Bus Interchange, along with operating and maintaining Bukit Batok Bus Interchange.
There is no change to the operator of cross-border services CW3 and CW4, which continue to be operated by Causeway Link of Malaysia.
References
External links
Category:Bus stations in Singapore
Category:Jurong East
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Role of angiogenesis in the development and growth of liver metastasis.
Cancer metastasis is a highly complex process that involves aberrations in gene expression by cancer cells leading to transformation, growth, angiogenesis, invasion, dissemination, survival in the circulation, and subsequent attachment and growth in the organ of metastasis. Angiogenesis facilitates metastasis formation by providing a mechanism to (1) increase the likelihood of tumor cells entering the blood circulation and (2) provide nutrients and oxygen for growth at the metastatic site. The formation and establishment of metastatic lesions depend on the activation of multiple angiogenic pathways at both primary and metastatic sites. A variety of factors involved in the angiogenesis of liver metastasis have been identified and may serve as prognostic markers and targets for therapy. Vascular endothelial growth factor, interleukin-8, and platelet-derived endothelial cell growth factor are all proangiogenic factors that have been associated with liver metastasis from various primary tumor types. Inhibition of the activity of these factors is a promising therapeutic approach for patients with liver metastases. In addition, inhibition of integrins that mediate endothelial cell survival may also serve as a component of therapeutic regimens for liver metastases. This review focuses on the biology of angiogenesis in liver metastasis formation and growth. Because colorectal carcinoma is the most common tumor to metastasize to the liver, this disease will serve as a paradigm for the study of angiogenesis in liver metastases.
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Need more information about Dog Grooming in Shoal Bay NT?
Regardless of their shape, size, or temparement, your dog deserves to look their best. Beyond mere aesthetics, Dog Grooming also has a major impact on doggy health, mood, and hygiene. Through Mad Paws' Dog Grooming services, your pooch will leave primped, preened, and healthy. Moreover, you can find a local Dog Groomer in Shoal Bay NT for the time of your choosing. Indeed, it's never been easier to groom your pup. When you book a Dog Groomer through Mad Paws, you can reap the below benefits:
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Consistency – Nobody wants a haircut from a hair dresser on an "off-day" - and the same can be said of Dog Groomer. For this simple reason, "off-day" is not a word that exists in the vocabulary of Mad Paws Dog Groomers. You can expect the same consistent service from groom to groom.
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A Safe Environment – For your dog to be comfortable with a stranger touching them, they need to feel safe. This is where our Dog Groomers' dedication to comfort comes in. Through the crafting of a safe ambient, your Dog Groomer will allow your pooch to feel at ease during their session.
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Enjoyment – It's hard to imagine a world in which we humans would enjoy cutting our toenails and plucking our eyebrows. However, with the right Dog Groomer, your dog can have a fun time whilst they are being groomed. This is the chief objective of Mad Paws Dog Grooming providers.
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Confidence – If you don't feel confident in a Groomer's skills, you shouldn't ever need to leave your dog with them. That's why Mad Paws sets the highest standards for our Dog Grooming professionals. Every Dog Groomer we promote is vetted and publicly reviewed by clients, which lets you better assess them.
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Accumulation and lentiviral infection of macrophages within perivascular spaces is a fundamental concept in the pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection of the central nervous system (CNS). In HIV encephalitis (HIVE) and its animal model, SIV encephalitis (SIVE), the development of lesions within the brain is associated with perivascular accumulation (cuffing) of macrophages and multinucleated giant cells (MNGC)[@b1][@b2][@b3][@b4][@b5]. The mechanisms underlying macrophage accumulation in HIVE are not well understood. Much of the previous research aimed at elucidating mechanisms of persistent HIV infection and inflammation in the brain has focused on monocyte trafficking into the brain. Evidence supporting this, however, is lacking in both studies of HIV-infected humans and SIV-infected macaques.
It is conventionally believed that macrophages are terminally differentiated cells that are in the G0 stage of the cell cycle and do not proliferate[@b6][@b7], thereby implying that macrophage accumulation in tissues is solely due to the contribution from infiltrating monocytes. However, recent mouse studies have demonstrated that macrophages do proliferate locally during inflammation[@b8][@b9][@b10][@b11]. These studies, using *in vivo* thymidine analog incorporation and Ki-67 co-localization, found that local macrophage proliferation dominates lesion formation and inflammation, independently of monocyte recruitment, in the pleural cavity, arterial intima, and adipose tissue.
We, therefore, sought to determine whether there are cycling cells of the macrophage lineage in the brains of adult macaques. Using double-label immunohistochemistry and multi-label immunofluorescence microscopy for various markers for macrophages (CD16, CD68, CD163, HLA-DR, or MAC387), non-macrophage lineage cells (GFAP and CNPase), cell cycle (cyclin D1, MCM2, or p16^INK4a^), cell proliferation (Ki-67 and thymidine analogs), and brain endothelial cells (GLUT1), along with SIV Gag protein (SIV p28), we present evidence that proliferating cells exist in the brains of SIV-infected macaques and that they are of a perivascular macrophage (PVM) phenotype, with the proliferation increasing along with (the degree of) encephalitis. MNGC also express these proliferation markers, with a nuclear distribution and shape such that incomplete cell division can be a mechanism other than cellular fusion for giant cell formation. We also found that the majority of these cell populations are productively infected, with an increase in the number of Ki-67+ macrophages correlating with lesion size. HIVE patient samples stained for Ki-67 and CD68 show evidence of proliferating PVM. These findings indicate that local PVM proliferation contributes to macrophage accumulation and lesion growth and may be one of the underlying mechanisms of HIV/SIV persistence in the CNS.
Results
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Macrophage phenotype of the Ki-67+ cells in the brain and increase in Ki-67+ macrophages in macaques with SIVE
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Recent studies demonstrated that local proliferation can contribute to macrophage accumulation during inflammation in the pleural cavity, arterial intima and adipose tissue[@b8][@b9][@b10][@b11]. We sought to investigate if there are cycling cells of the macrophage lineage in the encephalitic brains of SIV-infected adult macaques. As a first step, we examined the expression of cell cycle proteins (Ki-67, cyclin D1, and p16^INK4a^), by immunohistochemistry, in the frontal and/or temporal cortices and brainstems of uninfected control macaques (*n* = 3), SIV-infected macaques without encephalitis (SIVnoE, *n* = 4), and SIV-infected macaques with encephalitis (SIVE, *n* = 4) ([Table 1](#t1){ref-type="table"}). Preliminary results indicated that SIVE animals demonstrated strong nuclear immunoreactivity for these markers in the perivascular space and within encephalitic lesions compared to uninfected controls and SIVnoE animals ([Fig. S1](#S1){ref-type="supplementary-material"}). A very similar pattern of expression of other cell cycle markers including proliferating cell nuclear antigen (PCNA) and minichromosome maintenance complex component 2 (MCM2) was observed ([Fig. S2](#S1){ref-type="supplementary-material"}). Based on their association with inflammatory perivascular cuffs and encephalitic lesions, we suspected that cells positive for these cell cycle proteins were of the macrophage lineage. To better define this phenotype, we further explored the expression of one of these markers for cycling cells, Ki-67, along with expression of CD68, a marker useful for identifying various macrophage lineage cells. Double-label immunohistochemistry for these two markers revealed that the vast majority of cycling Ki-67+ cells were located within cells positive for CD68 in both uninfected and SIV-infected macaques ([Fig. 1](#f1){ref-type="fig"}). These CD68/Ki-67 double-positive cells had the morphology of PVM (elongated, flattened, and found only directly adjacent to CNS vasculature) in uninfected, SIVnoE, and SIVE animals ([Fig. 1a](#f1){ref-type="fig"}--c). Comparing uninfected and SIVnoE animals with encephalitic animals, there seemed to be an increase in double-positive cells in the encephalitic group, even when ignoring increases contributed by lesions. To quantify the difference in Ki-67+ macrophages among uninfected, infected, and encephalitic animals, we counted the number of CD68 single-positive, Ki-67 single-positive, and CD68/Ki-67 double-positive cells, enumerated in random low-power fields, while excluding any lesions, in each of the nine animals examined ([Fig. 1d](#f1){ref-type="fig"}). The changes in CD68+ macrophages and Ki-67+ cells showed an increasing trend going from uninfected to SIVnoE to SIVE animals, but were only significant for CD68+ macrophages between uninfected and SIVE animals; however, compared to both uninfected and SIVnoE animals, the number of CD68+Ki-67+ cells in SIVE animals was significantly higher, indicating an increase in Ki-67+ macrophages in SIVE.
Ki-67+ macrophages co-express CD163, exhibiting a PVM phenotype
---------------------------------------------------------------
To confirm that these Ki-67+ cells were PVM and not recently infiltrated monocytes, we also examined expression of a more specific macrophage lineage marker, CD163, known to be expressed in PVM in the brain, along with MAC387, commonly used to identify infiltrated monocytes/macrophages[@b3][@b4]. We counted the number of CD68+Ki-67+, CD163+Ki-67+, and MAC387+Ki-67+ cells in four SIVE animals using double-label immunohistochemistry in a similar manner as for [Fig. 1d](#f1){ref-type="fig"}. The number of both CD68+Ki-67+ and CD163+Ki-67+ PVM were significantly higher than that of MAC387+Ki-67+ cells in these encephalitic animals ([Fig. 2a](#f2){ref-type="fig"}). Multi-label immunofluorescence for CD163 and Ki-67 with a DAPI nuclear counterstain indeed revealed that the majority of Ki-67+ cells were CD163+ macrophages found both in the perivascular cuffs ([Fig. 2b](#f2){ref-type="fig"}) and encephalitic lesions ([Fig. 2c](#f2){ref-type="fig"}) of SIV-infected macaques. The minor subset of CD68−CD163−MAC387+Ki-67+ were within perivascular spaces and lesions with a morphology similar to infiltrated monocytes, previously described elsewhere[@b4] ([Fig. S3a,c](#S1){ref-type="supplementary-material"}). Interestingly, scattered MAC387+Ki-67+ cells were also found in both the brain parenchyma and the lumen of vessels. These cells displayed the morphology of polymorphonuclear leukocytes and represented the majority of MAC387+Ki-67+ cells found ([Fig. S3b](#S1){ref-type="supplementary-material"}). These cells were almost exclusively Ki-67+ and may represent a population of infiltrating granulocytes. We additionally examined other brain cell types to determine if there were any other minor subsets of Ki-67+ cells ([Table 2](#t2){ref-type="table"}; [Fig. 3](#f3){ref-type="fig"}). Double-label immunohistochemistry or immunofluorescence for HLA-DR, GFAP, or CNPase and Ki-67 revealed that activated microglia ([Fig. 3a](#f3){ref-type="fig"}) represented a small subset of Ki-67+ cells found in the parenchyma, but that oligodendrocytes and astrocytes did not ([Fig. 3b](#f3){ref-type="fig"},c). Altogether, while the vast majority of Ki-67+ cells are CD68+CD163+ PVM, there are minor populations of other cell types, most noticeably recently infiltrating monocytes, polymorphonuclear cells, and activated microglia, which are also positive for Ki-67.
*In vivo* incorporation of thymidine analogs confirms the proliferative state of Ki-67+ macrophages
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Having shown that a population of Ki-67+ PVM exists in the brains of adult macaques, we sought to confirm that this was an actively proliferating population. Since Ki-67 is present during all active phases of the cell cycle[@b12], expression of Ki-67 does not necessarily indicate that a cell is undergoing cell division, but rather that it has the ability to proliferate. Indeed, when DNA synthesis is blocked, cells remain positive for Ki-67 even though the cell division cycle has been arrested, as measured by BrdU incorporation[@b13]. Therefore, we used multi-label immunofluorescence on tissues from animals which had received BrdU and EdU injections to test whether Ki-67+ cells were co-labeled with these thymidine analogs. Typically, SIV-infected macaques had received one single i.v. injection of BrdU early between day 5 and day 10 post infection and the other single injection of EdU 2 days prior to euthanasia, which is between 55 and 300 days post infection (see [Table S1](#S1){ref-type="supplementary-material"} for experimental injection timeline).
When we examined BrdU incorporation, we found evidence of BrdU+Ki-67+ double-labeled nuclei restricted to areas surrounding vasculature in both SIVnoE and SIVE animals ([Fig. 4](#f4){ref-type="fig"}). Occasionally, we observed double-labeled mitotic figures associated with CNS vessels and within the lesions of SIVE animals. In all tissues examined, the amount of both Ki-67 expression and co-labeling of BrdU appeared to increase in SIVE compared to SIVnoE animals, consistent with our previous findings ([Fig. 4a](#f4){ref-type="fig"}, left versus middle columns). Quantitative analysis of the BrdU+ cells in the cortical areas of these animals revealed that, while not all of the Ki-67+ cells were labeled with BrdU, the vast majority of BrdU+ cells were stained for Ki-67 ([Fig. 4b](#f4){ref-type="fig"}). This followed our expectations, as BrdU was administered by a 30-min infusion and is specific to the S phase, while Ki-67 is expressed in all but the resting phase. Co-labeling was also observed in lesions of SIVE animals ([Fig. 4a](#f4){ref-type="fig"}, right column). Animals which had received EdU injections displayed a similar pattern of expression ([Fig. S4](#S1){ref-type="supplementary-material"}). Incorporation of these two thymidine analogs in cells which co-express Ki-67 suggests that not only does a population of PVM and meningeal macrophages with a proliferative potential exist, but that at least a portion of these cells are actively dividing, or at least undergoing chromosomal replication in preparation for cellular division. Additionally, we found a rare subpopulation of BrdU/EdU double-labeled cells around the vasculature in animals that had received injections of BrdU and EdU at different time points ([Table S1](#S1){ref-type="supplementary-material"}; [Fig. S5](#S1){ref-type="supplementary-material"}), indicating that some of these proliferating cells may be long-lasting and capable of self-renewal.
SIV-infected MNGC express proliferation markers
-----------------------------------------------
Besides perivascular accumulation of macrophages, one of the defining features of HIVE/SIVE is the formation of MNGC. We were curious, then, whether these cells, traditionally held to form from the fusion of macrophages, also expressed markers of proliferation. Upon close examination, we noted that almost all nuclei inside CD68+ MNGC located perivascularly and within encephalitic lesions were positive for Ki-67 ([Fig. 5a](#f5){ref-type="fig"}). This same expression pattern was found in MNGC stained for CD163 ([Fig. 5b](#f5){ref-type="fig"}). When examined for BrdU incorporation, MNGC within lesions ([Fig. 5c](#f5){ref-type="fig"}) and around vessels ([Fig. 5d](#f5){ref-type="fig"}) contained some nuclei labeled with BrdU, as expected. In [Fig. 5c](#f5){ref-type="fig"}, a MNGC expressing CD16 (Fc gamma receptor III) was packed with DAPI-positive nuclei, some of which were co-labeled with BrdU. In addition, mitotic figures in MNGC were infrequently found. Interestingly, the distribution of BrdU-positive nuclei within these MNGC was not around the perimeter of the cell as would be expected if they formed from the fusion of distinct macrophages; instead, almost all of the MNGC showed proliferating nuclei within the center, sometimes spreading to the perimeter. Altogether, this strongly suggests that MNGC of encephalitic brains may form from nuclear division without cell division rather than by cell-to-cell fusion. MNGC are known to harbor significant amounts of HIV/SIV[@b14], and so expression of the structural protein SIV Gag p28 was examined within these cells, revealing that the majority were both productively infected and proliferating ([Fig. 5e](#f5){ref-type="fig"}).
PVM proliferation is correlated with increased size of encephalitic lesions
---------------------------------------------------------------------------
With evidence of productively infected, proliferating MNGC in hand, we next tackled the question of whether or not proliferating PVM in general are productively infected. As has been shown before, macrophages are a major reservoir for latent and productive HIV/SIV infection in the CNS[@b15][@b16][@b17]; additionally, encephalitic lesions consist predominantly of macrophages[@b3]. We thus speculated that the population of proliferating macrophages may contribute to SIVE lesion formation. Multi-label immunofluorescence for Ki-67 and SIVp28 revealed that a majority of Ki-67+ cells were indeed infected ([Fig. 6](#f6){ref-type="fig"}). In particular, we found evidence of productively infected, proliferating macrophages both around vessels ([Fig. 6a](#f6){ref-type="fig"}) and within lesions ([Fig. 6b--d](#f6){ref-type="fig"}). Not all of the Ki-67+ cells were positive for SIV, nor were all of the SIV p28+ macrophages Ki-67-positive, although we noted that as lesions grew in size, there seemed to be a corresponding increase in Ki-67+SIV-p28+ cells. Quantifying this relationship, we indeed found that the number of Ki-67+ cells within a lesion significantly correlated with lesion size ([Fig. 6e](#f6){ref-type="fig"}; *n* = 127, *r* = 0.9292, *p* \< 0.0001, Spearman correlation). This suggests that proliferation of macrophages plays a significant role in the formation of encephalitic lesions. In support of this notion, when comparing mild and severe cases of SIVE, we noted a large increase in Ki-67+ cells and thus, as expected, lesion sizes in severe SIVE tissues. Taken together, these results suggest proliferating macrophages may serve as a reservoir for SIV in the CNS, accounting for the persistence of the virus in the brain, leading to encephalitis.
CD68+ macrophages display increased expression of Ki-67 in HIVE subjects
------------------------------------------------------------------------
To better solidify our findings in the monkey model, we investigated whether Ki-67+ cells were also positive for CD68 in subjects diagnosed with HIVE, the pathological correlate of HIV dementia ([Table 3](#t3){ref-type="table"}). Cortical tissues from HIV seronegative subjects (*n* = 4) and HIV-infected subjects with HIVE (*n* = 3) were stained for Ki-67 and CD68 using double-label immunohistochemistry ([Fig. 7](#f7){ref-type="fig"}). Staining revealed a similar occurrence to the monkey model, previously stated, where the majority of Ki-67+ cells were also positive for CD68 in HIVE brain samples. These cells appeared to be flat, elongated, and the majority of them were found adjacent to CNS vasculature, which is characteristic of the PVM. Quantitative analysis was performed by counting the number of CD68 single-positive, Ki-67 single-positive, and CD68/Ki-67 double-positive cells, enumerated in 20 random, low-power fields per subject, avoiding lesions ([Fig. 7c](#f7){ref-type="fig"}). When comparing CD68 single-positive and Ki-67-single positive, there appeared to be little difference between the HIVE ([Fig. 7b](#f7){ref-type="fig"}) and uninfected ([Fig. 7a](#f7){ref-type="fig"}) subjects. However, when comparing the number of CD68/Ki-67 double-positive cells, the HIVE subjects had significantly higher numbers of Ki-67+ macrophages than the uninfected subjects. Interestingly, in a subject diagnosed with cerebral amyloid angiitis (CAA) we found a similar increase in Ki-67+ macrophages ([Fig. 7d](#f7){ref-type="fig"}). In summary, these findings confirm that there are cycling cells of the macrophage lineage in the human brain, as suggested by our SIV/macaque model, which may contribute to various brain pathologies including HIVE and CAA.
Discussion
==========
Determining the exact mechanisms behind perivascular accumulation of macrophages leading to a potential reservoir for persistent infection would be a major step in understanding AIDS neuropathogenesis. Infection of the CNS by HIV remains one of the most pressing problems in HIV research and treatment. Both human and macaque models support the notion of the brain as a reservoir for persistent infection[@b18][@b19]. The existence of a CNS viral reservoir presents a twofold problem: viral persistence even with highly active antiretroviral therapy (HAART) leading to viral rebound once treatment is stopped, as well as continued cognitive decline related to HIV infection. Two distinct populations of brain macrophages are thought to comprise the majority of this viral reservoir: PVM and parenchymal microglia, both of which have been shown to play key roles in the neurologic manifestations of AIDS[@b15][@b16][@b20][@b21]. In particular, PVM are the major cell type productively infected with HIV and its nonhuman counterpart, SIV, in the brain[@b15][@b16][@b20][@b22][@b23][@b24][@b25][@b26]. HIVE, the pathological correlate of HIV-associated dementia (HAD), is characterized by a perivascular accumulation of macrophages and MNGC in the brain. The earliest uses of antiretroviral therapy showed that the symptoms of HIV encephalopathy could be reversed in some patients with treatment that reduced the plasma viral load[@b27]. However, even with HAART, while the incidence of HAD has decreased, the prevalence of milder forms of cognitive impairment has increased[@b28]. To go along with this, even after HAART, levels of microglial/macrophage activation remain comparable with levels seen, pre-HAART, in HIVE and AIDS cases[@b29].
It is commonly held that bone marrow-derived blood monocytes continuously traffic to the CNS and become PVM under normal conditions, with acceleration of traffic taking place during inflammation and infection, which leads to immune activation of monocytes/macrophages[@b30][@b31]. The importance of monocyte trafficking is highlighted by the fact that, in the SIV macaque model of AIDS, use of BrdU, an analog of thymidine that is incorporated in DNA during replication, revealed that increased monocyte turnover correlates with the severity of SIVE[@b32]. Additionally, using genetically modified CD34+ hematopoietic stem cells, Williams and colleagues showed that a population of brain PVM are slowly renewed by CD34+ hematopoietic stem cell-derived precursors in rhesus macaques that received total-body gamma-irradiation before transplantation[@b33]. Conversely, past studies examining PCNA expression in SIV and HIV encephalitis found evidence of infected perivascular macrophages that were PCNA-positive[@b2][@b34]. As its name suggests, PCNA is often used as a marker for cellular proliferation; however, it is also expressed in non-dividing cells undergoing DNA synthesis and repair[@b35][@b36][@b37]. In these studies, a lack of Ki-67/MIB-1 expression and BrdU labeling, then, were used to suggest that alterations in monocyte/macrophage trafficking and turnover but not macrophage proliferation play the most significant role in the pathogenesis of SIVE/HIVE.
Despite these findings, and encouraged by recent evidence of proliferating macrophages in other pathophysiological settings, we set out to determine whether proliferation plays any role in HIV/SIV infection of the brain. By employing a new rabbit monoclonal antibody against Ki-67, clone SP6, which has been shown to have an enhanced sensitivity and intensity when compared to mouse monoclonal antibody MIB-1[@b38][@b39][@b40], and which we ourselves found to have better immunoreactivity in macaque tissue samples ([Fig. S6](#S1){ref-type="supplementary-material"}), we were able to show the existence of Ki-67+ macrophages in the brain. Using this as a launching point, we conducted further immunohistochemical imaging of these cells using macrophage, proliferation, and SIV markers to investigate if macrophage proliferation is a mechanism for macrophage accumulation and viral persistence in SIVE. Quantification of the CD68+Ki-67+ macrophages revealed a significant increase in the population size of these cells in SIVE animals. The majority of these cells were confirmed, using fluorescent microscopy, to be PVM via their co-expression of CD163 and by their location around Glut1+ CNS vessels. Further phenotyping with MAC387 and numerical comparison with the CD68+ and CD163+ macrophage populations confirmed that PVM represented the majority of the Ki-67-positive population, with the minority being CNS-infiltrating monocytes and polymorphonuclear leukocytes. *In vivo* labeling assays with BrdU and EdU confirmed that Ki-67 expression represented a true proliferative population. This population includes MNGC, a specific feature of encephalitis. Importantly, this proliferating population of PVM and MNGC were shown to be productively infected, expanding along with the degree of encephalitis and as lesions grew in size. Finally, evidence of this Ki-67+ PVM population was found in HIVE patient samples. HIV/SIV infection per se does not seem to directly drive macrophage proliferation since proliferating brain macrophages were also found in the brain of a CAA patient who was HIV-negative. It was previously shown that IL-4, favoring M2 macrophage polarization, directly activates tissue-resident macrophages to proliferate *in vivo*[@b8][@b41]. Very interestingly, IL-4 was also previously shown as a biomarker for simian-human immunodeficiency virus encephalitis[@b42][@b43][@b44][@b45]. It is thus possible that IL-4-driven neuroinflammation is responsible for proliferation of perivascular macrophages.
Previous studies have hinted that recruitment of monocytes from the periphery might not be the dominant mechanism underlying encephalitic lesion formation. For example, Soulas *et al*. found that few MAC387+ cells, representing recently infiltrated monocytes, were in the CNS of acutely infected macaques (day 21 post infection) while they were present in SIVE animals, thereby indicating that infiltration of MAC387+ monocytes into the CNS occurs only late in disease progression[@b4]. Furthermore, characterizing the cellular makeup and macrophage phenotype of encephalitic lesions, the authors revealed that in animals with mild encephalitis the percentage of MAC387+ cells is increased, whereas in severe encephalitis CD68+ cells, representing resident macrophages, were instead relatively more numerous. As another example, Clay *et al*. found that when examining the migration of adoptively transferred dye-labeled monocytes, acutely SIV-infected macaques averaged only about one labeled CD16+ monocyte per section examined[@b46]. Even more direct evidence comes from a recent study which clearly demonstrated that around 82% of CD163+ macrophages found later in SIVE lesions were already present in the CNS at day 20 post infection (the time of the first intracisternal injection of dextran dyes to selectively label pre-existing perivascular macrophages), a time point when no significant monocyte infiltration was found, and well before the development of encephalitis[@b5]. These data, along with the results presented here, support a notion of early seeding of resident PVM followed by proliferation, rather than recruitment of monocytes from the periphery as the primary mechanism of late encephalitic lesion formation and persistence of the viral reservoir in the brain.
While future studies, including *in vitro* proliferation assays and further immunohistology of HIVE tissue samples will be necessary, our data presented here serves as a first step towards illustrating that macrophage proliferation may be critically important to a better understanding of the mechanisms responsible for macrophage accumulation and the formation of encephalitic lesions.
Methods
=======
Animals
-------
A total of 13 adult, male rhesus macaques (*Macaca mulatta*) were used in the study. All animals were housed at the Tulane National Primate Research Center (TNPRC). All procedures of this study were approved by the Tulane University Institutional Animal Care and Use Committee, and were carried out in accordance with the National Institutes of Health "Guide for the Care and Use of Laboratory Animals" and the recommendations of the Weatherall report, "The use of non-human primates in research". All possible measures were taken to minimize discomfort of the animals. For all routine procedures such as blood collection and physical examination, animals were fully anesthetized with ketamine HCl under the direction of a veterinarian. Animals were humanely euthanized by the veterinary staff at the TNPRC in accordance with its endpoint policy. The criteria for euthanasia include 15% weight loss in two weeks, unresponsive opportunistic infection, persistent anorexia, severe intractable diarrhea, progressive neurological signs, significant cardiac and/or pulmonary signs, or any other serious illness. Euthanasia was conducted by anesthesia with ketamine HCl (10 mg/kg) followed by an overdose with sodium pentobarbital. This method is consistent with the recommendation of the American Veterinary Medical Association Guidelines on Euthanasia. Archived tissues from 3 uninfected rhesus macaques were included as normal, uninfected controls. The animals used in the present study are listed in [Table 1](#t1){ref-type="table"}.
Macaque tissue samples
----------------------
Formalin-fixed, paraffin-embedded necropsy brain tissues sections (5 μm thick) of the frontal, parietal, and temporal cortices, as well as brainstem, from adult, male rhesus macaques (*Macaca mulatta*) were used. Several of these archived specimens were from previous studies involving *in vivo* labeling with thymidine analogs. In total, tissues from thirteen monkeys, three uninfected control monkeys and nine monkeys intravenously infected with SIVmac251 virus (20 ng of SIV p27), were used. They were not perfused at necropsy. Evidence of SIVE in six of the infected monkeys was defined by the presence of SIV proteins in the brain and the accumulation of macrophages and MNGC.
Human tissue samples
--------------------
Formalin-fixed, paraffin-embedded sections of parietal, temporal and occipital cortices were obtained from the Manhattan HIV Brain Bank (MHBB), a member of the National NeuroAIDS Tissue Consortium. A total of 3 adult HIVE cases, and 4 seronegative controls were examined ([Table 3](#t3){ref-type="table"}).
*In vivo* BrdU/EdU labeling and detection
-----------------------------------------
The thymidine analogs 5-bromo-2′-deoxyuridine (BrdU; Sigma-Aldrich, St. Louis, MO) and 5-ethynyl-2′ deoxyuridine (EdU; Molecular Probes, Eugene, OR), were used to pulse-label cells undergoing DNA synthesis as previously described[@b47]. [Supplementary Table 1](#S1){ref-type="supplementary-material"} describes the infusion schedule for each animal. Dual-pulse labeling in brain tissues was assessed by immunofluorescence using an anti-BrdU monoclonal antibody that did not cross-react with EdU. EdU was detected using the Click-iT EdU Alexa Fluor 488 Imaging Kit (see below for details).
Immunohistochemistry
--------------------
Immunohistochemistry was performed using the antibodies listed in [Table 2](#t2){ref-type="table"}, as previously described[@b47]. After incubation for 1 h at 58--60 °C, sections were deparaffinized and rehydrated. Sections were then pretreated for antigen retrieval with a citrate-based Antigen Unmasking Solution (Vector Laboratories, Burlingame, CA) in a microwave (900 W) for 20 min. After cooling for 20 min, sections were washed with Tris-buffered saline (TBS) containing 0.05% Tween-20 for 5 min, followed by incubation with a peroxidase blocking solution (Bloxall, Vector Laboratories) for 5 min. After washing again, sections were incubated with either 5% normal horse or goat serum in TBS for 15 and 30 min, respectively, followed immediately by primary antibody incubation for 1 h at room temperature or overnight at 4 °C. After washing, sections were incubated with a biotinylated secondary antibody (Vector Laboratories) for 30 min. Dako Antibody Diluent (Dako, Carpinteria, CA) was used for both primary and secondary antibody dilution. Following another wash, sections were incubated for 30 min with an avidin-biotin peroxidase complex (Vectastain ABC Elite kit, Vector Laboratories) and developed with diaminobenzidine (DAB; Dako) with Mayer's Hematoxlyin (Dako) used as a nuclear counterstain. Sections were dehydrated and mounted using VectaMount (Vector Laboratories). To examine the phenotype of Ki-67+ brain cells, double-label immunohistochemistry for CD68, CD163, HLA-DR, MAC387, GFAP or CNPase with Ki-67 was performed using both Vectastain Elite ABC and ABC-alkaline phosphatase kits, according to the manufacturer's instructions. For these sections, Ki-67 was developed using NBT/BCIP (Roche, Basel, Switzerland) with DAB being used for the cell type-specific markers. Sections were visualized using a Nikon Coolscope digital microscope and, for CD68, CD163, or MAC387 and Ki-67 counting, analyzed using a computer-assisted image processing and analysis software (ImageJ, NIH).
Immunofluorescence microscopy
-----------------------------
Double- or triple-label immunofluorescence was done to further phenotype proliferating cells in the brain, to examine co-labeling with thymidine analogs, and to determine whether proliferating cells were productively infected. As described above, sections were deparaffinized and rehydrated, followed by antigen retrieval. After washing with phosphate-buffered saline (PBS) containing 0.2% fish skin gelatin (FSG; Sigma-Aldrich), sections were permeabilized with PBS containing 0.2% FSG and 0.1% Triton X-100 for 1 h. Following another wash, sections were incubated with 5% normal goat serum in PBS for 30 min at room temperature before incubation for 1 h at room temperature or overnight at 4 °C with primary antibodies diluted in PBS/FSG. After primary antibody incubation, the sections were washed in PBS/FSG and incubated with an Alexa Fluor 350-, 488-, 555-, or 594- conjugated secondary antibody (Molecular Probes; diluted at 1:1000 in PBS/FSG) for 1 h at room temperature. The sections were washed with PBS/FSG before the addition of the next primary antibody. Animals which had received intravenous (i.v.) infusions of BrdU (60 mg/kg) and/or EdU (50 mg/kg) were also assessed for labeling by immunofluorescence. Detection of EdU was done using a Click-iT EdU Alexa Fluor 488 kit (Molecular Probes) according to the manufacturer's instructions. After immunofluorescence staining, the sections were treated with 10 mM CuSO~4~ in 50 mM ammonium acetate buffer for 45 min to quench autofluorescence. The sections were rinsed in distilled water, and cover slipped with Aqua-Mount aqueous mounting medium (Thermo Scientific, Waltham, MA). A Zeiss Axio Observer.Z1 fluorescence microscope was used to analyze the fluorescent labeled sections. Zeiss AxioVision Release 4.8.2 was used to capture and merge fluorescence images. Adobe Photoshop CS12.1 was also used to merge layers into a single image. ImageJ was used for quantification of BrdU/Ki-67 and Ki-67/SIVp28 double-labeling. For the latter, SIVE lesions were measured and the Ki-67+ cells were counted within each lesion. A total of 127 lesions were included in the analysis.
Statistical analysis
--------------------
Newman-Keuls test in conjunction with one-way ANOVA or two-tailed, unpaired t-test with Welch's correction were used to determine significance in the quantification of CD68+Ki-67+ cells (enumerated in at least twenty to thirty random fields of each tissue used at a magnification of 100X) in SIVE and HIVE, respectively. Two-tailed, paired t-test was used to compare Ki-67 expression in different myeloid populations. The Spearman correlation coefficient was calculated to determine the relationship between lesion size and the number of Ki-67+ cells in the lesion. A two-tailed *p*-value was presented.
Additional Information
======================
**How to cite this article**: Filipowicz, A. R. *et al*. Proliferation of Perivascular Macrophages Contributes to the Development of Encephalitic Lesions in HIV-Infected Humans and in SIV-Infected Macaques. *Sci. Rep.* **6**, 32900; doi: 10.1038/srep32900 (2016).
Supplementary Material {#S1}
======================
###### Supplementary Information
This study was supported by Virginia's Commonwealth Health Research Board Grant \#11-09 (to W.-K.K) and in part by National Institutes of Health Grants R21MH108458 and R01MH107333 (to W.-K.K.), as well as by Grants R21AI110163 and R01AI097059 (to M.J.K). We thank Dr. Susan Morgello, of the Manhattan HIV Brain Bank (R24MH59724), for facilitating access to HIVE brain autopsy samples.
**Author Contributions** W.-K.K. conceived the work. A.R.F., C.M.M., G.E.H. and A.A.L. performed immunohistochemistry and immunofluorescent staining. A.R.F. and A.A.L. carried out quantification. E.M.J. reviewed and revised the manuscript. C.S. and M.J.K. performed all the animal experiments. W.-K.K., A.R.F. and A.A.L. prepared the manuscript.
{#f1}
{ref-type="fig"} using double-label immunohistochemical images. Triple-label immunofluorescence for Ki-67 (red), CD163 (green), and DAPI (blue) in the perivascular space (**b**) and in lesions (**c**) of SIVE macaques revealed that the majority of Ki-67+ cells also expressed CD163.](srep32900-f2){#f2}
{ref-type="fig"}, double-label immunohistochemistry for Ki-67 (blue/NBT-BCIP) and HLA-DR (brown/DAB) demonstrated a minor but noticeable population of un-ramified microglia which co-expressed Ki-67 and HLA-DR (**a**). Triple-label immunofluorescence for Ki-67 (green), CNPase (**b**; red) or GFAP (**c**; red), and DAPI (blue) in SIVE macaques showed no expression of Ki-67 in oligodendrocytes (**b**) or astrocytes (**c**).](srep32900-f3){#f3}
{#f4}
{#f5}
{#f6}
{ref-type="fig"}, double-label immunohistochemistry confirmed the presence of Ki-67+ CD68+ macrophages (blue nuclear staining and brown cytoplasm) in the adult human brain (**a,b,d**). The number of Ki-67+ brain PVM in HIVE patients (**b**) was significantly higher than in HIV seronegative controls (**a**) (\*p \< 0.05; two-tailed, unpaired t-test; *n* = 3 per group; (**c**). Data expressed as mean ± SEM. In a human subject with CAA the number of Ki-67+ macrophages also demonstrated a similar increase (**d**).](srep32900-f7){#f7}
###### Animals Used in the Present Study.
Monkey group (size) Animal number Age at euthanasia (years) Survival after infection (days) Degree of SIV-induced encephalitis
------------------------------------------- --------------- --------------------------- --------------------------------- ------------------------------------
Uninfected controls (n = 3)
EC61 8.99 n/a n/a
GI53 5.02 n/a n/a
GI84 5.41 n/a n/a
SIV-infected without encephalitis (n = 4)
DR28 8.84 114 n/a
DR67 9.16 49 n/a
GL96 3.35 49 n/a
EM89 8.19 70 n/a
SIV-infected with encephalitis (n = 6)
CN66 20.88 68 Mild
CV39 10.68 147 Severe
DG09 10.28 98 Mild
FG54 5.70 168 Moderate/severe
GN24 5.15 69 Mild
HD42 5.62 91 Severe
n/a, not applicable.
###### Antibodies Used in the Present Study.
Antigen Clone Isotype Reactivity Manufacturer Application
-------------- ------------ ------------- -------------------- --------------------- -------------
BrdU BU1/75 Rat IgG2a n/a Serotec IF
BrdU Bu20a Mouse IgG1 n/a BioLegend IF
BrdU MoBu-1 Mouse IgG1 n/a BioLegend IF, FC
BrdU ZBU30 Mouse IgG1 n/a Invitrogen IF
CD16 2H7 Mouse IgG2a Hu, Mk Novocastra IF
CD68 KP1 Mouse IgG1 Hu, Mk NeoMarkers IHC, IF
CD163 10D6 Mouse IgG1 Hu, Mk NeoMarkers IHC, IF
CD163 EDHu-1 Mouse IgG1 Hu, Mk Serotec IF
CNPase 11-5B Mouse IgG1 Hu, Mk, Rb, Rt, Ms Millipore IF
Cyclin D1 SP4 Rabbit IgG Hu, Mk NeoMarkers IHC
GFAP 5C10 Mouse IgG1 Hu, Mk, Rt, Ms BioLegend IF
Glut1 Polyclonal Rabbit IgG Hu, Mk, Rt NeoMarkers IF
HLA-DR+DP+DQ CR3/43 Mouse IgG1 Hu, Mk Invitrogen IHC
Ki-67 MIB-1 Mouse IgG1 Hu, Mk Santa Cruz IHC
Ki-67 SP6 Rabbit IgG Hu, Mk Vector Laboratories IHC, IF
MCM2 D7G11 Rabbit IgG Hu, Mk Cell Signaling IHC
MRP8/MRP14 MAC 387 Mouse IgG1 Hu, Mk NeoMarkers IF
p16 JC8 Mouse IgG2a Hu, Mk Santa Cruz IHC
PCNA PC10 Mouse IgG2a Rt, Ms, Hu, Mk Santa Criz IHC
SIV p28 3F7 Mouse IgG1 n/a Fitzgerald IF
n/a, not applicable; Hu, human; Mk, monkey; Rb, rabbit; Rt, rat; IHC, immunohistochemistry; IF, immunofluorescence; FC, flow cytometry.
###### Human Subjects.
PID HIV-1 status CNS pathology Age/gender Risk factor
---------- -------------- --------------------------- ------------ --------------
MHBB 76 \+ HIVE 38 F IVDU
MHBB 87 \+ HIVE 31 M Heterosexual
MHBB 537 \+ HIVE 45 F IVDU
MHBB 101 − None 59 F None known
MHBB 104 − None 56 F None known
MHBB 109 − None 56 M None known
A06-28 − Cerebral amyloid angiitis 57 F None known
IVDU, intravenous drug user.
|
RECOMMENDED FOR FULL-TEXT PUBLICATION
Pursuant to Sixth Circuit I.O.P. 32.1(b)
File Name: 18a0056p.06
UNITED STATES COURT OF APPEALS
FOR THE SIXTH CIRCUIT
UNITED STATES OF AMERICA, ┐
Plaintiff-Appellant, │
│
> No. 17-5893
v. │
│
│
WILLIAM EUGENE HINES, │
Defendant-Appellee. │
┘
Appeal from the United States District Court
for the Western District of Kentucky at Louisville.
No. 3:16-cr-00005-1—Joseph H. McKinley Jr., Chief District Judge.
Argued: March 8, 2018
Decided and Filed: March 22, 2018
Before: MOORE, COOK, and McKEAGUE, Circuit Judges.
_________________
COUNSEL
ARGUED: Amanda B. Harris, UNITED STATES DEPARTMENT OF JUSTICE, Washington,
D.C., for Appellant. Michael R. Mazzoli, COX & MAZZOLI PLLC, Louisville, Kentucky, for
Appellee. ON BRIEF: Amanda B. Harris, UNITED STATES DEPARTMENT OF JUSTICE,
Washington, D.C., Terry M. Cushing, UNITED STATES ATTORNEY’S OFFICE, Louisville,
Kentucky, for Appellant. Michael R. Mazzoli, COX & MAZZOLI PLLC, Louisville, Kentucky,
for Appellee.
_________________
OPINION
_________________
COOK, Circuit Judge. Not all search warrant affidavits include the same ingredients.
It is the mix that courts review to decide whether evidence generated from the search may be
No. 17-5893 United States v. Hines Page 2
used or must be suppressed. Some affidavits describe in fine detail a confidential informant’s
reliability, whereas others emphasize the tipster’s basis of knowledge. Some discuss controlled
drug buys by police officers looking to corroborate a tip, and others spotlight a suspect’s criminal
history. There isn’t a singular formula; we consider the affidavit proper if, in its totality, it
sufficiently demonstrates probable cause for that search warrant.
Finding the affidavit in this case insufficient to establish probable cause, the district court
suppressed evidence recovered during a search. We decide that the totality of the circumstances
dictates otherwise, however, and REVERSE.
I.
A.
On December 15, 2015, Louisville Metropolitan Police Department Detective Daniel
Evans submitted to Kentucky Circuit Court Judge McKay Chauvin an affidavit for a search
warrant of the single-family residence at 668 Eastlawn Avenue in Louisville. The affidavit set
forth the following information.
In July 2015, Louisville law enforcement officers learned from a “reliable confidential
informant”—referred to as “CS1” throughout the affidavit, without any other identifying
information—that William Hines was “selling large amounts of heroin” out of 668 Eastlawn.
Surveillance of that house, owned by Hines’s mother, over the ensuing months tracked Hines’s
regular comings and goings.
On December 14, 2015, CS1 informed Detective Evans that CS1 “had seen an amount of
heroin at” 668 Eastlawn that day. Also on December 14, Detective Evans received further
information about Hines “from another reliable confidential source”—referred to as “CS2” in the
affidavit. CS2 said Hines had contacted him that day and proposed that they meet at a club
called Legends to discuss an incoming heroin shipment. After he met with Hines, CS2 informed
Detective Evans that Hines wanted CS2 to meet him at 668 Eastlawn the following day, where
Hines would provide CS2 with heroin. According to CS2, he had received heroin from Hines
numerous times and was always instructed to meet at 668 Eastlawn.
No. 17-5893 United States v. Hines Page 3
Owing to the information from CS1 and CS2, and prior to the meeting at Legends,
officers set up surveillance around 668 Eastlawn. They saw Hines leave the house, stop briefly
at a liquor store, and then drive to the club. When Hines left the liquor store, surveilling officers
observed him “drive in a manner consistent with narcotics traffickers”—“he drove opposite of
traffic down a one-way street before entering a dark, narrow alley” where officers believed Hines
was looking for any tailing law enforcement.
Detective Evans also independently investigated Hines’s history as a drug trafficker and
summarized it in the affidavit. Hines had been on the Louisville DEA’s radar since at least 2007,
when wire intercepts identified Hines as a kilogram-quantity cocaine trafficker. Additional
wiretaps in 2012 helped the Louisville DEA peg Hines as a significant heroin trafficker. That
summer, officers seized $33,500 from Javier Rodriguez outside 668 Eastlawn, which they
believed to be payment from Hines for a kilogram of cocaine. In a 2015 interview with officers,
Rodriguez said that he had previously provided Hines with kilogram-quantities of cocaine and
heroin.
B.
The state judge signed a search warrant for 668 Eastlawn early in the afternoon of
December 15, which Detective Evans and other officers executed later that day. They recovered,
among other things, 3.72 pounds of cocaine, 2.08 pounds of heroin, $16,085 in cash, and a
digital scale with plastic baggies.
Based on the fruits of the search, a federal grand jury charged Hines with possession with
intent to distribute at least 100 grams of heroin and at least 500 grams of cocaine, in violation of
21 U.S.C. § 841(a)(1), (b)(1)(B). Hines moved to suppress the evidence recovered at
668 Eastlawn. His arguments supporting suppression shifted but ultimately converged on two:
the affidavit did not establish probable cause for the search warrant, and the good-faith exception
to the exclusionary rule did not apply.
The district court granted Hines’s motion to suppress. The court found that “the search
warrant affidavit does not establish the reliability of the confidential informants in this case, and
as such, it lacks probable cause.” It held that the affidavit’s assertion that both CS1 and CS2
No. 17-5893 United States v. Hines Page 4
were “reliable” was “clearly insufficient” to establish the informants’ reliability, noting the
conclusory nature of the description and that Detective Evans neither provided the informants’
identities to the state judge nor indicated in the affidavit that either informant had previously
supplied reliable information. The court also found no independent police corroboration of the
confidential informants’ statements placing drugs at 668 Eastlawn; “[t]he only information
police were able to independently corroborate was that Hines did in fact go to the night club CS2
specified they would meet at,” which, according to the court, was the “least significant part of
CS2’s story.”
Next, the court determined the good-faith exception to the exclusionary rule to be
inapplicable because “the officer who wrote the search warrant affidavit and applied for and
received the warrant was the same officer who executed it.” Because, the court explained,
the warrant lacked the necessary indicia that the statements by CS1 or CS2 were
reliable . . . , it was unreasonable for Detective Evans to have relied on the search
warrant affidavit that he himself prepared, as he was aware of its contents and
should have known that more information was required to establish the reliability
of the confidential informants . . . .
The Government timely appealed. We first address whether the affidavit established
probable cause, and then proceed to the good-faith inquiry.
II.
A.
The Fourth Amendment requires warrants to be supported by probable cause. “In order
to demonstrate probable cause sufficient to justify a search warrant, the proponent must submit
an affidavit that ‘indicate[s] a fair probability that evidence of a crime will be located on the
premises of the proposed search.’” United States v. Dyer, 580 F.3d 386, 390 (6th Cir. 2009)
(quoting United States v. Jenkins, 396 F.3d 751, 760 (6th Cir. 2005)) (alteration in original).
“A court must look to the ‘totality of the circumstances,’ including a confidential informant’s
‘veracity, reliability, and basis of knowledge,’ in order to answer ‘the commonsense, practical
question’ of whether an affidavit is sufficient to support a finding of probable cause.” United
States v. May, 399 F.3d 817, 822 (6th Cir. 2005) (quoting Illinois v. Gates, 462 U.S. 213, 230
No. 17-5893 United States v. Hines Page 5
(1983)). Although the court is “limited to examining the information contained within the four
corners of the affidavit,” Dyer, 580 F.3d at 390, line-by-line scrutiny of the underlying affidavit
is improper when reviewing the issuing judge’s probable cause determination, United States v.
Allen, 211 F.3d 970, 973 (6th Cir. 2000) (en banc).
We assess the district court’s decision to suppress evidence by reviewing the court’s
factual findings for clear error and its legal determinations—including whether probable cause
existed—de novo. United States v. Dunning, 857 F.3d 342, 346 (6th Cir. 2017); United States v.
Lazar, 604 F.3d 230, 232–33 (6th Cir. 2010). “Given the de novo standard of review, where, as
here, the district court reviewed the [issuing judge’s] probable cause determination, we owe
the district court’s conclusion no particular deference.” United States v. Brown, 732 F.3d 569,
572–73 (6th Cir. 2013) (citing United States v. Leake, 998 F.2d 1359, 1362–63 (6th Cir. 1993)).
“In reviewing a state magistrate’s determination of probable cause, this court pays great
deference to a magistrate’s findings, which should not be set aside unless arbitrarily exercised.”
United States v. Washington, 380 F.3d 236, 240 (6th Cir. 2004) (quoting Leake, 998 F.2d at
1363).
B.
The Government argues that the district court’s ruling flouts the totality-of-the-
circumstances approach to determining the affidavit’s sufficiency. We agree.
Although the affidavit neither named the confidential informants nor offered how they
previously provided accurate information, it described both informants’ bases of knowledge for
their tips about Hines’s trafficking drugs out of 668 Eastlawn. At least as of July 2015, CS1
knew that Hines “was actively selling large amounts of heroin from” 668 Eastlawn and informed
law enforcement as much. Then, on December 14, Detective Hines learned from CS1 that CS1
saw heroin at 668 Eastlawn that very day. The basis of CS2’s knowledge is even stronger. CS2
received heroin from Hines “on numerous occasions in the past, and stated that he is always
instructed to come to 668 Eastlawn.” On December 14, CS2 told Detective Evans that Hines had
contacted him earlier in the day “regarding [Hines] receiving a shipment of heroin” and to say
“that he would like to speak with CS2 at Legends Nightclub to discuss the shipment.” After CS2
No. 17-5893 United States v. Hines Page 6
met with Hines, CS2 contacted Detective Evans “and informed that [Hines] wanted CS2 to come
to his residence, 668 Eastlawn Avenue, at [sic] on December 15, where [Hines] will provide CS2
with a large amount of heroin.”
The district court dismissed these statements as “merely creat[ing] a circle of
speculation.” Instead, it should have credited them as illustrating CS1’s and CS2’s bases of
knowledge regarding drug trafficking at 668 Eastlawn. For example, compare this affidavit to
the one upheld in United States v. Moore, 661 F.3d 309 (6th Cir. 2011). The Moore affidavit
contained one paragraph noting that an unnamed informant “stated that he/she has been at the
above described residence within the past five (5) days . . . and has seen the above described
storing and selling cocaine at the above named address.” 661 F.3d at 311. Here, the two
informants had as much or more knowledge of Hines’s heroin stash at 668 Eastlawn. CS1 saw
heroin at 668 Eastlawn the day before the search; Hines contacted CS2 to discuss a shipment of
heroin and later told him to come to 668 Eastlawn for a hand-off. The district court discredited
this information as devoid of details like quantity or location in the house. But the Moore
informant likewise never specified the quantity of drugs or their location within the residence to
be searched. Id. And even though CS2 did not say that he saw heroin at Hines’s residence
immediately before the search, he admitted that he had always picked up heroin from Hines at
668 Eastlawn in the past—the same place Hines told CS2 to visit on December 15.
So even though the affidavit did not address in detail the reliability of CS1 and CS2, it
gave appreciable attention to the bases of their knowledge. See United States v. Coffee, 434 F.3d
887, 895 (6th Cir. 2006) (crediting an affidavit that “contains no averments that the informant
was reliable based on prior contacts” but “does state that the CI had made several purchases in
the past from [the suspect] at the specified address”). We do not evaluate an informant’s
veracity, reliability, and basis of knowledge independently; more of one compensates for less of
the others. United States v. Ferguson, 252 F. App’x 714, 721 (6th Cir. 2007). Fatally faulting
this affidavit for failing to name the informants or explain that they previously gave accurate
information frustrates the totality-of-the-circumstances review we must conduct. See United
States v. Martin, 526 F.3d 926, 936 (6th Cir. 2008) (explaining that we review the totality of the
No. 17-5893 United States v. Hines Page 7
circumstances to make a commonsense, rather than “hyper-technical, determination of whether
probable cause is present”).
Granted, the district court didn’t end its analysis there; it reviewed the affidavit for
independent police corroboration of the tips. The court declared that “[t]he only information
police were able to independently corroborate was that Hines did in fact go to the night club CS2
specified they would meet at.” Calling this “the least significant part of CS2’s story,” the court
concluded that the affidavit lacked substantial independent police corroboration to support the
probable-cause determination. We disagree.
For one, given the informants’ bases of knowledge, substantial independent police
corroboration was unnecessary. See Dyer, 580 F.3d at 392 (“[O]nly when no substantial
supporting evidence exists within the four corners of the affidavit as to the informant’s reliability
do courts require substantial independent police corroboration.”). In any event, officers
independently—and sufficiently—corroborated the tips. After CS1 informed officers in July
2015 that Hines was selling large quantities of heroin out of 668 Eastlawn, DEA and police
officers “conducted surveillance at the residence on occasion” and saw Hines “arrive and depart
the residence with regularity.” Moreover, per the tips from CS1 and CS2 on December 14,
officers re-established surveillance around 668 Eastlawn. They witnessed Hines leave the house
and drive to Legends that evening—the club at which CS2 said Hines wanted to meet to discuss
a shipment of heroin. The district court brushes this aside as mere corroboration that Hines went
to a location mentioned by CS2, but that misses a key point: CS2 specified that Hines wanted to
meet at Legends to discuss a shipment of heroin. And if “an informant is right about some
things, he is more probably right about other facts” regarding the suspect’s illegal activity.
Gates, 462 U.S. at 244 (quoting Spinelli v. United States, 393 U.S. 410, 427 (1969) (White, J.,
concurring)). True, as the district court implies, the officers did not set up a controlled buy or
see drugs in the house. But our precedent does not require independent corroboration of criminal
activity. Corroboration of specific nonobvious information that, although innocent on its own,
meshes with an informant’s tips is similarly relevant. See, e.g., Dyer, 580 F.3d at 392–93
(crediting police corroboration of informant’s descriptions of suspect’s cars and physical
appearance); May, 399 F.3d at 825 (crediting as independent police corroboration the affidavit’s
No. 17-5893 United States v. Hines Page 8
averment that surveillance team saw a particular individual involved in unrelated investigation
entering suspect’s residence).
In addition, Detective Evans independently investigated law enforcement’s previous
dealings with Hines, learning that Hines had “a prior criminal history for narcotics possession
and trafficking.” And Detective Evans laid it out in the affidavit—that 668 Eastlawn served as a
drug distribution point for Hines since 2012, that Javier Rodriguez admitted to officers that he
previously provided drugs to Hines, that “[s]ource information as recently as December of 2015”
indicated Hines to be selling kilos of heroin in Louisville—thereby providing the issuing judge
with further independent corroboration of the informants’ leads. See Dyer, 580 F.3d at 392
(“Although a defendant’s criminal history is not dispositive, it is relevant to the probable cause
inquiry.” (internal citation omitted)); Martin, 526 F.3d at 937 (noting that defendant’s criminal
history—included in the affidavit—constituted “independent corroboration” that “provided other
indicia of reliability”).1
***
At bottom, we judge an affidavit “on the adequacy of what it does contain, not on what it
lacks, or on what a critic might say should have been added.” Allen, 211 F.3d at 975. Here, the
mix of ingredients passes muster. The totality of the circumstances convinces us that this
affidavit demonstrated a specific and concrete nexus between 668 Eastlawn and the evidence
sought, and thus established probable cause for the search.
III.
Even if the affidavit was defective, the district court should have denied Hines’s
suppression motion because the officers “seized [the evidence] in reasonable, good-faith
reliance” on the search warrant. United States v. Leon, 468 U.S. 897, 905 (1984).
1
The affidavit additionally informed that the surveillance team “observed [Hines] drive in a manner
consistent with narcotics traffickers” upon departing the liquor store for Legends by driving the wrong way down a
one-way street before entering an alleyway. The district court correctly noted that this observation has limited
corroborative effect because CS2 didn’t inform officers that Hines would drive like this. Still, that officers observed
Hines drive in a manner consistent with drug traffickers on the way to discuss a possible heroin shipment with CS2
is something we consider in our totality-of-the-circumstances approach to determining the sufficiency of the
affidavit.
No. 17-5893 United States v. Hines Page 9
A.
The Supreme Court created an exception to the exclusionary rule because “[c]ourts
should not . . . suppress ‘evidence obtained in objectively reasonable reliance on a subsequently
invalidated search warrant.’” United States v. Carpenter, 360 F.3d 591, 595 (6th Cir. 2004)
(en banc) (quoting Leon, 468 U.S. at 922). “Following Leon, courts presented with a motion to
suppress claiming a lack of probable cause must ask whether a reasonably well trained officer
would have known that the search was illegal despite the [issuing judge’s] decision. Only when
the answer is ‘yes’ is suppression appropriate.” United States v. White, 874 F.3d 490, 496 (6th
Cir. 2017) (internal quotation marks and citations omitted).
The good-faith exception is inapplicable in four circumstances:
(1) where the issuing magistrate was misled by information in an affidavit that the
affiant knew was false or would have known was false except for his reckless
disregard for the truth; (2) where the issuing magistrate wholly abandoned his
judicial role and failed to act in a neutral and detached fashion, serving merely as
a rubber stamp for the police; (3) where the affidavit was nothing more than a
“bare bones” affidavit that did not provide the magistrate with a substantial basis
for determining the existence of probable cause, or where the affidavit was so
lacking in indicia of probable cause as to render official belief in its existence
entirely unreasonable; and (4) where the officer’s reliance on the warrant was not
in good faith or objectively reasonable, such as where the warrant is facially
deficient.
United States v. Hython, 443 F.3d 480, 484 (6th Cir. 2006) (citing Leon, 468 U.S. at 923).
We review de novo the applicability of the good-faith exception. United States v. Abernathy,
843 F.3d 243, 257 (6th Cir. 2016).
B.
Neither the district court nor Hines suggests that Detective Evans misled the issuing
judge by including in the affidavit information he knew to be false. Nor do they contend that the
issuing judge simply rubber-stamped the affidavit out of a favorable predisposition toward law
enforcement. Rather, the district court eschewed applying the good-faith exception because
Detective Evans both wrote the underlying affidavit and executed it. According to the court,
“it was unreasonable for Detective Evans to have relied on the search warrant affidavit that he
No. 17-5893 United States v. Hines Page 10
himself prepared, as he was aware of its contents and should have known that more information
was required to establish the reliability of the confidential informants.” We conclude otherwise.
First, that Detective Evans both wrote the underlying affidavit and executed the search
warrant is not enough, standing alone, to preclude application of the good-faith exception. See,
e.g., United States v. Kinison, 710 F.3d 678, 686–87 (6th Cir. 2013). As the Government notes,
in past cases this court applied the good-faith exception where the affiant executed the search
warrant. E.g., Moore, 661 F.3d at 311, 314–15; United States v. McCraven, 401 F.3d 693, 695,
698 (6th Cir. 2005).
Second, this was not a bare-bones affidavit because it was not a conclusory affidavit.
White, 874 F.3d at 496. A bare-bones affidavit “asserts only the affiant’s belief that probable
cause existed. It provides nothing more than a mere guess that contraband or evidence of a crime
would be found, either completely devoid of facts to support the affiant’s judgment that probable
cause exists, or so vague as to be conclusory or meaningless.” Id. (internal quotation marks and
citations omitted). Both informants offered concrete information that tied drug-dealing to
668 Eastlawn in the days immediately preceding the warrant’s execution. CS1 saw heroin inside
668 Eastlawn the day before the search; CS2 told Detective Evans about his conversation with
Hines regarding a large quantity of heroin to be provided at 668 Eastlawn; and every time CS2
previously received heroin from Hines, it was at 668 Eastlawn. Such details make this affidavit
different from the one at issue in Mills v. City of Barbourville, 389 F.3d 568, 575–76 (6th Cir.
2004), which failed to state “why [the address] is being searched” or indicate that officers
“performed any investigation to determine whether plaintiff lived at” the address. United States
v. Baxter, 889 F.2d 731 (6th Cir. 1989), on which the district court relied, is similarly
distinguishable. There, the affidavit relied on a confidential informant who was simply an
anonymous caller. 889 F.2d at 733. This court would not apply the good-faith exception
because it found the affidavit to be bare-bones and determined that the officer “had to realize that
the source of the information against defendant was an unknown party who was unavailable and
could not be demonstrated to be ‘reliable.’” Id. at 734.
None of those problems plagues the affidavit or affiant in the instant case. Detective
Evans’s affidavit was not “so lacking in indicia of probable cause that, despite a judicial officer
No. 17-5893 United States v. Hines Page 11
having issued a warrant, no reasonable officer would rely on it.” White, 874 F.3d at 497 (citing
United States v. Helton, 314 F.3d 812, 824 (6th Cir. 2003)). And even if it did fall short of
establishing probable cause, this affidavit was not “completely devoid of any nexus” connecting
Hines’s house with illegal activity. Carpenter, 360 F.3d at 595. Indeed, this affidavit contained
more facts connecting 668 Eastlawn with evidence of drug trafficking than did the affidavit
upheld in Carpenter connecting a residence with marijuana patches. See id. at 593, 596
(affidavit based on pilot’s observation of road connecting marijuana plants and a residence
satisfied Leon good-faith exception).
The only precedent on which Hines relies to argue the unavailability of the good-faith
exception is the distinguishable United States v. Weaver, 99 F.3d 1372 (6th Cir. 1996). The
affiant-officer in Weaver used a “preprinted affidavit” that “was composed of boilerplate text
with a few open spaces for” individuals’ names, a brief description of the house to be searched,
the word “marijuana,” and the date of the affidavit—in total, a classic bare-bones affidavit.
99 F.3d at 1375–76. Turning to the good-faith exception, the Weaver court explained that the
affiant-officer “should have realized that he needed to do more independent investigative work to
show a fair probability that this suspect was either possessing, distributing, or growing
marijuana,” given that he had “little firsthand information and no personal observations.” Id. at
1380. Here, however, Detective Evans corroborated these informants’ tips by independently
investigating Hines’s lengthy trafficking history and observing Hines leave 668 Eastlawn to meet
CS2 at Legends as CS2 said would happen.
***
“[T]he exclusionary rule is designed to deter police misconduct rather than to punish the
errors of judges and magistrates.” Leon, 468 U.S. at 916. The facts here do not engender fears
of police misconduct. Even if this affidavit did not establish probable cause, therefore, the fruits
of the search would nevertheless survive suppression through application of the good-faith
exception.
No. 17-5893 United States v. Hines Page 12
IV.
For these reasons, we REVERSE the district court’s grant of Hines’s suppression motion
and REMAND for proceedings consistent with this opinion.
|
Former TV comedy writer Lamar Sally has told of the awful moment he discovered that his now ex-wife, The View's Sherri Shepherd, was secretly plotting to get out of being a mother - while the baby was still in the womb.
The pair met at an LA party in 2009 and hit it off straightaway agreeing in their first phone conversation that they wanted a baby, said Sally.
Single dad: Lamar Sally (pictured, holding baby LJ) 'fell in love hard' with The View star Sherri Shepherd and the couple agreed to have a baby using a surrogate mother - but Shepherd backed out before LJ was born
Two years later they were married in a half-million-dollar ceremony and living in New York, and soon Shepherd, then 43, was footing a $100,000 bill for a surrogate mother.
But their happiness was not to last.
One month after the first sonogram, Sherpherd gave Sally and ultimatum: 'She said, "I can’t be the wife and mother you need,"' he recalled. '"You can take the kid and go to LA."'
Trust: Sally says Shepherd (pictured) had 'trust issues,' but was shocked when he discovered she had a secret lawyer who said she could get out of paying child support for LJ
Sally told Page Six he went into shock. 'I said, "I love you. We don’t have that many problems, but the ones you do have you need to confront. We have a baby on the way and he needs a mother. I’ll meet you halfway."'
Shepherd just told him they would work out visitation and child support.
But Sally stuck with it, sleeping in the guest room and trying to persuade his wife that they should raise their child together.
He says that things appeared to be getting better for about two weeks, until The View threw Shepherd an on-air birthday party - and Sally wasn't invited.
What he discovered shook him to his core: an email from a lawyer that Shepherd had already put on retainer. It read: ‘We will get you out of the surrogacy contract. We don’t think it’s enforceable.'
'My stomach dropped, I burst into tears,' Sally said. 'This is someone I love. How can you get out of being a mother to this child?'
A mother's touch: Though LJ is happy, Sally wants him to 'feel a mother's touch,' but says his much-publicized history with Shepherd means dating again is out of the question. He hopes Shepherd will return to AJ someday
Surrogate: Jessica Bartholomew was sued by the state of California after Sally was forced to go on welfare to support his son. She and Sally succeeded in making sure Shepherd would pay child support instead
Sally says that Shepherd had 'trust issues' after her previous husband, Jeffrey Tarpley - with whom she had a son also called Jeffrey - fathered a child with his mistress.
Nevertheless, it came as a shock to him when, the day after he discovered her secret lawyer, Shepherd told him to leave. Sally, who had moved to New York to be with Shepherd, returned to LA.
That was where he was living when their son, Lamar Jr. - or LJ - was born in August 2014. But the happiness of holding his son was 'tainted' for Sally by Shepherd's absence - and the discovery that LJ had a rare blood disorder, G6PD deficiency.
Worse, LJ had no health insurance - and Shepherd refused to put the boy on her own.
Sally, who was struggling to find work as a writer ('I would set meetings up with agents and managers, and they would cancel - I think after they found out who I was,' he told Page Six) applied for welfare to help his son.
However, that resulted in the state suing the surrogate mother, Jessica Bartholomew, for child support.
Sally and Bartholomew entered a legal battle to get Shepherd to pay child support and came out on top, although Shepherd appealed all the way up to the Supreme Court of Pennsylvania. It ultimately cost Sally $100,000 in legal fees.
And, says Sally, his name was ruined on national TV. 'I got painted as a gold digger, that I used Sherri,' he said. 'Sherri’s friends in the media - Wendy Williams dogged me out every chance, Steve Harvey talked about me.'
That, he adds, has made it impossible to date - one quick Google and it's all over.
So it's a positive thing that LJ gives Sally a focus to his life - and it is clear that he dearly loves his son.
But until Shepherd accepts LJ as her own, there will always be a sadness in Sally's life. 'I waited 40 years until I found someone,' he told Page Six. 'I didn’t want to be a single father. I didn’t want my son to not know his mother’s touch.”
|
Q:
Confusing step in WolframAlpha integration
The problem was: ∫2e^(-x/4)dx
And the steps WolframAlpha used were:
1.) Take the integral ∫2e^(-x/4)dx
2.) Factor out constants 2∫e^(-x/4)dx
3.) For the integrand e^(-x/4), substitute u = (-x/4) and du = -1/4 dx : -8∫e^(u)du
The rest I understand, but where does the -1/4 dx come from?
A:
From the Fundamental Theorem of Calculus.
$F(x) = \int_a^{u(x)} f(t) dt\\
F'(x) = f(u(x)) u'(x)$
Operating in reverse.
If you want to integrate some function that has the right "shape."
$\int f(u(x)) u'(x) dx$
i.e $\int e^{-\frac {x}{4}}(-\frac 14 dx)$
then you can say $u(x) = -\frac {x}{4}, u'(x) = -\frac {1}{4}$
although we usually write it as $du = -\frac 14 dx$
$\int e^{u} du = e^u + C$
and then reverse the substitution.
$e^{-\frac x4} + C$
But sometimes you get something that is not so perfect.
$\int e^{-\frac {x}{4}} dx$
then you do a little trickery to get the right form
$\int e^{-\frac {x}{4}}(-4)(-\frac 14) dx\\
-4\int e^{-\frac {x}{4}}(-\frac 14 dx)\\$
and substitute.
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