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tomekkorbak

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[ "Saturday, May 22, 2010\n\nPennsylvania's Own Caucus Scandal Spawns Twitter Anonymity Concerns\n\nThe State of Pennsylvania has recently concluded its own version of the caucus scandal that rocked Wisconsin politics several years ago (and hit the news again recently with the ruling that Scooter Jensen can move his retrial to Waukesha County, where the DA seems to have no enthusiasm for taking it up).", "\n\nShortly after the Democrats took control of Pennsylvania's state house (in November of 2006), Republican Attorney General Tom Corbett began investigating the practice of taxpayer-compensated legislative aides working on political campaigns. ", "However, it was mainly Democrats who were prosecuted. ", "Three (one Rep. and two staffers) were convicted in March. ", "The first sentence, against legislative aide Brett Cott, was just handed down this week (21 to 60 months in prison).", "\n\nIn September of 2008, an anonymous blog called CasablancaPA began posting criticisms of Corbett's investigation and prosecutory choices. ", "Corbett asserted that he investigated both Democrats and Republicans. ", "The blog pointed out that, during the second half of 2007, Republican legislative offices (both in Harrisburg and in the District) replaced all of their computers.", "\n\nBefore Brett Cott's sentencing hearing, Attorney General Corbett subpoenaed Twitter, in an attempt to prove that CasablancaPA is authored by Cott (h/t Capper). ", "The subpoena raised a hue and cry around the country, with accusations that Corbett is trying to chill critical speech and also accusations that he is abusing the grand jury process to obtain evidence to use in a sentencing hearing rather than to investigate a crime. ", "After the sentencing hearing, Corbett dropped the Twitter subpoena. ", "However, the ACLU has not dropped the issue.", "\n\nCott plans to appeal the sentence. ", "His attorney, Bryan Walk, said his client already has suffered greatly by being convicted of three crimes and will find it difficult to get a job. ", "Maybe he should move to Wisconsin after he completes his sentence and ask Chuck Chvala for another job, in one of Chvala's private-sector businesses.", "\n\n1 comment:\n\nThe sentence seems to be very extreme, unless he been actually stealing money. ", "What he did was wrong, but as his lawyer, everybody does it. ", "I think, Cott's case was pretty extreme but not worth 21 months. ", "Maybe 6mo in jail with work release would have been more appropriate.", "If he is getting 21 months, then his employer, whoever that was, should be 4 years, minimum." ]

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[ "Abar Khabo\n\nAbar Khabo (English: Eat Again) is a sweet originating in West Bengal that consists of two concentric spheres containing pistachios, cashews, raisins and kheer.", "\n\nHistory \nAbar khabo was invented by Nobin Chandra Das when requested by the Maharani Swarnamoyee Devi of Cossimbazar to create a new kind of sweet. ", "Upon eating the abar khabo the Maharani exclaimed \"আবার খাবো\" (Abar Khabo) which became its name.", "\n\nKolkata-based sweet shops of the Gupta Brothers and Bhim Chandra Nag are known for making abar khabo.", "\n\nSee also \n Rasgulla\n\nReferences \n\nCategory:Sweets of West Bengal" ]

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[ "books.google.com - \"The Orthodox Church, presented here in a newly revised edition, has become an indispensable classic on the history of the Orthodox Church and the unique position it holds in today's world. ", "Fr. ", "Meyendorff reviews the great events and the principle stages in a history of nearly two thousand years, its...http://books.google.com/books/about/The_Orthodox_Church.html?id=E16XzwPdJtsC&utm_source=gb-gplus-shareThe Orthodox Church" ]

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[ "Wednesday, September 21, 2011\n\nWould you like to get your organization or neighborhood more involved in NYC sustainability? ", "We’re setting up video screenings that will expand how New Yorkers think about sustainability, and encourage attendees to plug into existing initiatives.", "Yes, New York City is making progress in lowering carbon emissions and becoming greener. ", "But sustainability is more than just responding to climate change and preparing for extreme weather events - neither of which we’re doing as quickly as the science requires, by the way. ", "As supplies of natural resources and fossil fuels deplete, rising costs will cause permanent economic changes. ", "Urban planners and community activists are increasingly striving not just for sustainability, but resilience, so we can adapt as things change. ", "Raising awareness about the interdependence of energy, environment and economy will encourage smart choices. ", "By conserving energy, turning to mass transit and renewable power while relocalizing production of goods and services, we can assure better quality of life in NYC neighborhoods while moving toward real sustainability. ", "The Transition community organizing method accelerates this process. ", "It starts by educating residents about the full scope of sustainability issues. ", "Then participants envision their community successfully adapted by 2030, brainstorm what steps they need to take, and pick a few to start with (http://www.transitionus.org/). ", "Hundreds of communities around the world have begun Transition initiatives. ", "Many other communities have been influenced by the methods, such as Brooklyn’s Sustainable Flatbush (http://sustainableflatbush.org/).Step up sustainability action in your neighborhood or organization by co-sponsoring a Transition video screening. ", "After each short video, audience members can share their reactions, with a longer facilitated open discussion at the end of the screenings.", "You’re invited to see how this works at the next screening on Wednesday, October 19, 7 – 9 PM. ", "Join us at the Seafarer’s and International House, 123 East 15th Street in Manhattan, just east of Union Square. ", "There is no charge to attend, but a $5 donation is requested to cover costs.", "\n\nTuesday, September 20, 2011\n\nIf you're around this Saturday, consider joining the 15 or so walks and bike rides in NYC that will converge at a climate change rally at the UN. ", "It's one of thousands of climate change actions around the world, organized through 350.org.", "\n\nWhile the City did not agree to a permit for a single unified march to the rally site, individuals will be bicycling, rollerblading and walking to the UN from meeting sites throughout the City. ", "Find the one you prefer at:http://movingplanetnyc.blogspot.com/p/find-ride-or-march.htmlI will be representing Beyond Oil NYC and helping to lead the march from Merchants's Gate at Columbus Circle, 59th Street and Central Park West. ", "Look for me with several 350.org signs. ", "I'll need some help in carrying the signs, so if you get there by 11:30 you may get one. ", "Or make your own sign and bring it.", "\n\nGather at noon and at 12:30, we'll set out down Broadway to 48th Street east to First Avenue, and make our way to the rally at 2 PM at the United Nations' Dag Hammarskjold Plaza on 47th Street between 1st and 2nd Avenues in Manhattan. ", "More from the press release below.", "\"The UN General Assembly will be in session at that time debating important resolutions just 2 months before the UN climate summit in Durban and in the critical run-up to Rio +20. ", "The NYC event has attracted a wide array of support from student groups, climate change activists, faith and environmental justice leaders, bicycling proponents, and opponents to hydrofracking of natural gas and nuclear power.", "The dozens of sponsors of the NYC rally include 350.0rg, NYPIRG, Beyond Oil NYC, Carbon Tax Center, Climate Week NYC, Climate Reality Project, Conversations with the Earth, Earth Day New York, Earth Matters, Environment Action Association, Food and Water Watch, Frack Action, Green Maps System, Green Cents Solutions, Human Impacts Institute, Manhattan Greens (Manhattan Local of the Green Party, No Impact Project, NYC Friends of Clearwater, NYC Climate Coalition, NY Society for Ethical Culture, Oxfam Action Corps, Physicians for Social Responsibility, Sane Energy Project, Small Planet Institute, Slow Food NYC, Solar 1, Time's Up!, ", "Transportation Alternatives, United for Action, Water Defense, We Act/Faith Leaders for Environmental Justice.", "\n\n350.org recently helped coordinate several weeks of civil disobedience protests at the White House in opposition to the Tar Sands pipeline from Canada.", "\n\nThe demands of the global day of action include: relying upon science-based policies to get us back to 350 ppm of carbon dioxide in the atmosphere; rapid, just transition to zero carbon emissions; ensuring adequate funding to assist third world countries with the climate change transition; and lifting the rights of people over the rights of polluters. ", "To preserve our planet, scientists tell us we must reduce the amount of CO2 in the atmosphere from its current level of 392 parts per million to below 350 ppm.", "The local events are part of a worldwide day of action on September 24 calling for a fossil fuel-free world. ", "Hundreds of thousands of people are expected to participate by moving their bodies towards solutions to climate change in nearly 2,000 events across the globe ranging from 5 mile hikes to 350 hour bike rides.\"" ]

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[ "In the thermal treatment of coal under the exclusion of air in a coke oven, coke oven crude gas is produced which is cooled by means of water droplets [trickling water] in a crude gas condenser to about 80° C. and is saturated with water vapor. ", "As a result, about 20% of the naphthalene entrained with the coke oven crude gas is bound up in tar in the liquid phase. ", "The remaining 80% of the naphthalene is then condensed in an indirect crude gascooling together with tarry aqueous components in a precooler. ", "This condensate is initially fed to the crude gas condenser, there heated to about 80° C. and supplied to a tar separation in which the separation of crude tar from cooled water is effected. ", "The naphthalene contained in the crude tar is recovered from the crude tar in highly expensive processes from a process technology view point. ", "Initially in a distillation of the tar a naphthalinol is produced is then subjected to crystallization in which the crude naphthalene is deposited out to recover pure naphthalene, further processes like chemical reactions, (for example with sodium hydroxide and sulfuric acid) are required or the raw naphthalene is distilled again." ]

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[ "Q:\n\nArtifactory host name resolution to docker registry\n\nI am trying to push a docker image into a newly created docker repo in Artifactory. ", "For this I tag the image as follows,\ndocker tag ubuntu mNginxLb.mycompany.com/artifactory/api/docker/<repo_key>\n\nand then push the image but get the following error \ndocker push mNginxLb.mycompany.com/artifactory/api/docker/<repo_key>/ubuntu\n\nThe push refers to a repository [mNginxLb.mycompany.com/artifactory/api/docker/<repo_key>/ubuntu] (len: 1)\nunable to ping registry endpoint https://mNginxLb.mycompany.com/v0/\nv2 ping attempt failed with error: Get https://mNginxLb.mycompany.com/v2/: x509: certificate signed by unknown authority\n v1 ping attempt failed with error: Get https://mNginxLb.mycompany.com/v1/_ping: x509: certificate signed by unknown authority\n\nIs this a problem with the certificate signing authority or with the hostname resolution? ", "I checked to see if other repositories work well with the SSL certificate so I am not sure if the problem is of the certificates. ", "\nHere is my nginx conf:\nupstream artifactory_lb {\n server mNginxLb.mycompany.com:8081;\n server mNginxLb.mycompany.com backup;\n }\n\n log_format upstreamlog '[$time_local] $remote_addr - $remote_user - $server_name to: $upstream_addr: $request upstream_response_time $upstream_response_time msec $msec request_time $request_time';\n\n server {\n listen 80;\n listen 443 ssl;\n\n ssl_certificate /etc/nginx/ssl/my-certs/myCert.pem;\n ssl_certificate_key /etc/nginx/ssl/my-certs/myserver.key;\n client_max_body_size 2048M;\n location / {\n proxy_set_header Host $host:$server_port;\n proxy_pass http://artifactory_lb;\n proxy_read_timeout 90;\n }\n access_log /var/log/nginx/access.log upstreamlog;\n location /basic_status {\n stub_status on;\n allow all;\n }\n }\n\n # Server configuration\n\n server {\n listen 2222 ssl;\n\n server_name mNginxLb.mycompany.com;\n if ($http_x_forwarded_proto = '') {\n set $http_x_forwarded_proto $scheme;\n }\n\n rewrite ^/(v1|v2)/(.*) ", "/api/docker/my_local_repo_key/$1/$2;\n client_max_body_size 0;\n chunked_transfer_encoding on;\n location / {\n proxy_read_timeout 900;\n proxy_pass_header Server;\n proxy_cookie_path ~*^/.* /;\n proxy_pass http://artifactory_lb;\n proxy_set_header X-Artifactory-Override-Base-Url $http_x_forwarded_proto://$host;\n proxy_set_header X-Forwarded-Port $server_port;\n proxy_set_header X-Forwarded-Proto $http_x_forwarded_proto;\n proxy_set_header Host $http_host;\n proxy_set_header X-Forwarded-For $proxy_add_x_forwarded_for;\n }\n }\n\nUPDATE:\nAfter updating the certificate to one by CA, this error goes away , although I still cant push images and get a 403 forbidden error. ", "The command I use is\n docker push host:port/The push refers to a repository [host:port/image_name] (len: 1)\nSending image list\nError: Status 403 trying to push repository ubuntu: \"<!", "DOCTYPE html><html><head><title>Apache Tomcat/8.0.22 - Error report</title><style type=\\\"text/css\\\">H1 {f\nont-family:Tahoma,Arial,sans-serif;color:white;background-color:#525D76;font-size:22px;} H2 {font-family:Tahoma,Arial,sans-serif;color:white;background-color:#5\n25D76;font-size:16px;} H3 {font-family:Tahoma,Arial,sans-serif;color:white;background-color:#525D76;font-size:14px;} BODY {font-family:Tahoma,Arial,sans-serif;c\nolor:black;background-color:white;} B {font-family:Tahoma,Arial,sans-serif;color:white;background-color:#525D76;} P {font-family:Tahoma,Arial,sans-serif;backgro\nund:white;color:black;font-size:12px;}A {color : black;}A.name {color : black;}.line {height: 1px; background-color: #525D76; border: none;}</style> </head><bod\ny><h1>HTTP Status 403 - </h1><div class=\\\"line\\\"></div><p><b>type</b> Status report</p><p><b>message</b> <u></u></p><p><b>description</b> <u>Access to the speci\nfied resource has been forbidden.</u></p><hr class=\\\"line\\\"><h3>Apache Tomcat/8.0.22</h3></body></html>\"image_name\n\nThe docker client gives the following error \n While the artifactory logs show the following \n\"GET /v2/ HTTP/1.1\" 404 466 \"-\" \"docker/1.9.1 go/go1.4.2 git-commit/a34a1d5 kernel/3.13.0-24-generic os/linux arch/amd64\"\n172.28.144.202 - - [22/Dec/2015:11:06:00 -0500] \"GET /v2/ HTTP/1.1\" 404 466 \"-\" \"docker/1.9.1 go/go1.4.2 git-commit/a34a1d5 kernel/3.13.0-24-generic os/linux arch/amd64\"\n \"GET /v1/_ping HTTP/1.1\" 404 470 \"-\" \"docker/1.9.1 go/go1.4.2 git-commit/a34a1d5 kernel/3.13.0-24-generic ] \"PUT /v1/repositories/ubuntu/ HTTP/1.1\" 403 449 \"-\" \"docker/1.9.1 go/go1.4.2 git-commit/a34a1d5 kernel/3.13.0-24-generic os/linux arch/amd64\"\n\nA:\n\nThe problem was that I had configured artifactory with the V1 docker API but was trying to push an image that supported the v2 API\n\n" ]

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[ "Q:\n\nChirpy tutorial or documentation\n\nI want to use Chirpy to minify my js files. ", "Unfortunately, I can't find any documentation. ", "The only link given is down.", "\nEDIT: if someone knows of a better tool, feel free to propose it.", "\n\nA:\n\nFrom the comments on the page you linked: dotnetchunks tutorial\n\n" ]

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[ "SIRT1 longevity factor suppresses NF-kappaB -driven immune responses: regulation of aging via NF-kappaB acetylation?", "\nThe aging process involves changes in immune regulation, i.e. adaptive immunity declines whereas innate immunity becomes activated. ", "NF-kappaB signaling is the master regulator of the both immune systems. ", "Two recent articles highlight the role of the NF-kappaB system in aging and immune responses. ", "Adler et al showed that the NF-kappaB binding domain is the genetic regulatory motif which is most strongly associated with the aging process. ", "Kwon et al studying HIV-1 infection and subsequent immune deficiency process demonstrated that HIV-1 Tat protein binds to SIRT1 protein, a well-known longevity factor, and inhibits the SIRT1-mediated deacetylation of the p65 component of the NF-kappaB complex. ", "As a consequence, the transactivation efficiency of the NF-kappaB factor was greatly potentiated, leading to the activation of immune system and later to the decline of adaptive immunity. ", "These observations support the scenario where immune responses and aging process can be enforced by the potentiation of NF-kappaB transactivation efficiency. ", "Longevity factors, such as SIRT1 and its activators, might regulate the efficiency of the NF-kappaB signaling, the major outcome of which is inflamm-aging via proinflammatory responses." ]

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[ "Hosts: Ash, Scott, and Matt: We’re joined this week by Rahul Kohli, who plays everyone’s favorite forensic pathologist Ravi on The CW’s hit series iZombie. ", "Tune in to hear all about the games he loves, his insane origin story and so much more! ", "Oh yeah, make sure you stick around for Rahul’s lightning round answers, because they’re pretty incredible.", "\n\nListen now! ", "Or, download this episode to listen offline.", "\n\nSupport Rated NA…" ]

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[ "Hold Congress Accountable\n\nAbout FreedomConnector\n\nFind activists, groups, and events right in your own neighborhood. ", "Join FreedomConnector to get involved and learn more about key issues threatening our economic freedom. ", "Whether you’re looking for like-minded people, trying to boost your existing group’s impact, or simply trying to stay up on current events, FreedomConnector is the place to start. ", "See what’s happening in your state today!", "\n\nSearch FreedomWorks\n\nResources\n\nBlog\n\nOwn Your Retirement\n\nThat all Men are born equally free and independent, and have certain inherent natural Right…; among which are the Enjoyment of Life and Liberty, with the Means of acquiring and possessing Property, and pursuing and obtaining Happiness and Safety. —", "Virginia Declaration of Rights (1776)\n\nIndispensable to personal freedom is the liberty for each person to choose how to allocate and invest their time, labor and money as well as to own the gains made by these investments.", "\n\nOwn Your Retirement\n\nRecently, public workers have become more aware their pensions and healthcare programs are in very serious jeopardy. ", "Elected city, county and state officials have made contracts with their employees, but are unable to fund their promises. ", "Sadly, this is the great flaw of democracies. ", "Politicians buy votes to get elected - for example promising great retirements to government union workers - but do not tax, invest or provide adequate resources to pay for their promises. [", "Read: Detroit & Stockton Bankruptcies Expose Democracy's Great Flaw - Short-term Politics Trumps Long-term Planning]\n\nUnforeseen at the time of their elections, government workers in Detroit, Stockton, Chicago and many other cities are learning they have been duped by long-gone politicians. ", "Clearly, this is immoral governance.", "\n\nThen, compare the plight of government workers in Detroit, Chicago and Stockton to those employees in three counties in Texas, who opted out of Social Security by creating personal retirement accounts. [", "Read: Three Texas Counties Opted Out of Social Security]. ", "In 30 years, the county workers in these three counties will retire with more money and better death and disability supplemental benefits than the public employees of Stockton, Detroit and Chicago.", "\n\nMost importantly, the government workers of Galveston, Matagorda and Brazoria Counties own their retirement, and immoral, corrupt governance will not reduce or take away their nest eggs. ", "These Texas counties chose private accounts and used professional money managers competing for the opportunity to invest their money. ", "As a result, the employees are guaranteed a minimum rate of return.", "\n\nMerrill Mathews in the Wall Street journal cites the better returns provided by professional money managers:\n\nThose who retire under the Texas counties' Alternate Plan do much better than those on Social Security. ", "According to First Financial's calculations, based on 40 years of contributions:\n\n• A lower-middle income worker making about $26,000 at retirement would get about $1,007 a month under Social Security, but $1,826 under the Alternate Plan.", "\n\n• A middle-income worker making $51,200 would get about $1,540 monthly from Social Security, but $3,600 from the banking model.", "\n\n• And a high-income worker who maxed out on his Social Security contribution every year would receive about $2,500 a month from Social Security versus $5,000 to $6,000 a month from the Alternate Plan.", "\n\nAs Galveston County Judge Mark Henry says, \"The plan works great. ", "Anyone who spends a few minutes understanding the plan becomes a huge proponent.\" ", "Judge Henry says that out of 1,350 county employees, only five have chosen not to participate.", "\n\nA saving and investing system has enormous benefits to all Americans, and ownership stops immoral and corrupt governance because investors protect and preserve their property as well as that of their fellow workers. ", "In the three Texas counties, employees are receiving more money in retirement, which is obviously good. ", "However, what's most important to every American is saving and investing – as opposed to taxing and redistributing by government – provides seed money which propels commerce and industry.", "\n\nPersonal accounts for retirement is absolutely essential for personal freedom and a vibrant society. ", "America’s critical task is to end our corrupt political system and create personal accounts.", "\n\nSan Antonio spokesman for the Texas Department of Transportation, Josh Donat has said that a planned $15.1 million highway underpass project begun in April is now “highly unlikely...we’ve been asked to avoid further excavation if we can.” ", "The project, which is currently underway will have to be halted. ", "Why? ", "Because of a spider.", "\n\nDemocracy and Power 106: A politician receives no financial gain for good policy or punishment for bad policy.", "It is hard to imagine a more stupid or more dangerous way of making decisions than by putting those decisions in the hands of people who pay no price for being wrong. – ", "Thomas Sowell\n\nPersonal Freedom and Power 105: Freedom and Governance \"A wise and frugal government, which shall restrain men from injuring one another, shall leave them otherwise free to regulate their own pursuits of industry and improvement, and shall not take from the mouth of labor the bread it has earned. ", "This is the sum of good government.\"", "\n\nThe House GOP budget proposal for the coming decade (2013-2022), released yesterday, is a mixture of boldness and caution, principle and compromise.", "\nResembling and building on last year's House-passed \"Ryan budget,\" the Path to Prosperity version 2.0 reads very much like a preview of a Romney Administration budget version 1.0.", "\nWhile not nearly as bold and principled as these debt-drenched times require, it would still be a major improvement over the status quo, and much better than what President Obama and congressional Democrats envision, namely, ever-bigger government.", "\n\nDemocracy and Power 107: Counting votes Successful … politicians are insecure and intimidated men. ", "They advance politically only as they placate, appease, bribe, seduce, bamboozle or otherwise manage to manipulate the demanding and threatening elements in their constituencies. – ", "Walter Lippmann (1889-1974), American Journalist and Author\n\nWelcome to the new Broadway hit: The Phantom of America, starring America’s debt. ", "The premise of the story is that America, falling just short of $15 trillion in debt, is being dragged down the path of unsustainability. ", "The role of the Phantom is played by Social Security. ", "Its true identity—massive unfunded liabilities and unsustainable growth—is masked by the rosy depiction of “security” for all generations that pay into the system.", "\n\nFor young people, Social Security is a misnomer. ", "The generations that follow the Baby Boomers are anything but “secure” in the Social Security program.", "The premise of Social Security is that American citizens who pay taxes out of their paychecks into the program will get their money back at retirement. ", "However, current retirees, who have not paid enough into the system for what they are collecting, are supported by younger generations." ]

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[ "[Therapeutic results in children with acute non-lymphoblastic leukemia treated with modified BFM-87 protocol].", "\nThe effectiveness of modification of the BFM-87 schedule of treatment received by 32 children with different forms of acute non-lymphoblastic leukemia since April, 1991, has been studied. ", "Complete remission was recorded in 90% and 5-year recurrence-free survival--in 47%. ", "Although the complication rate was higher as compared with the \"7 + 3\" schedule, mortality rates were relatively lower due to application of adjuvant therapy." ]

{ "pile_set_name": "PubMed Abstracts" }

[ 0.004691825248301029, 0.0010060813510790467, 0.0006307271542027593, 0.0005892357439734042 ]

[ "RRR-alpha-tocopheryl succinate induces MDA-MB-435 and MCF-7 human breast cancer cells to undergo differentiation.", "\nRRR-alpha-Tocopheryl succinate (vitamin E succinate, VES) is a potent antitumor agent, inducing DNA synthesis arrest, differentiation, and apoptosis. ", "Because little is known about VES-induced differentiation, studies reported here characterize VES effects on the differentiation status of human breast cancer cell lines and investigate possible molecular mechanisms involved. ", "VES-induced differentiation of human MCF-7 and MDA-MB-435 breast cancer cells was characterized by morphological changes, induction of lipid droplets, induction of beta-casein mRNA expression, and down-regulation of Her2/neu protein. ", "In contrast, VES treatment of normal human mammary epithelial cells, MCF-10A cells, and T-47D cells did not induce differentiation. ", "Studies addressing mechanisms showed that neither antibody neutralization of the transforming growth factor-beta signaling pathway nor expression of a dominant-negative mutant of c-Jun N-terminal kinase blocked the ability of VES to induce differentiation; however, treatment of cells with PD 98059, a chemical inhibitor of mitogen-activated protein kinase kinase (MEK1/2), blocked the ability of VES to induce differentiation." ]

{ "pile_set_name": "PubMed Abstracts" }

[ 0.0012148728128522635, 0.003927372395992279, 0.0006282610702328384, 0.0006825582240708172, 0.001160662854090333, 0.0006650621653534472 ]

[ "Introduction {#s1}\n============\n\nA range of disorders from isolated organ defects like blindness or nephronophthisis to multi-system disorders like Joubert (JS), Bardet--Biedl, or Meckel--Gruber syndromes are correlated with mutations in genes involved in formation or stability of the primary cilium ([@bib22]; [@bib44]; [@bib9]). ", "JS is characterized by a distinctive midbrain--hindbrain malformation, named the 'molar tooth sign' on brain magnetic resonance imaging, and clinically by developmental delay, oculomotor apraxia and hypotonia. ", "Currently, 25 genes are known to cause JS when mutated in a bi-allelic or X-linked fashion ([@bib1]; [@bib6]; [@bib34]). ", "Most of the encoded proteins from these genes localize to the primary cilium or are involved in ciliary-related transport and commonly result in defective ciliation in patient cells or in animal models ([@bib39]; [@bib41]; [@bib1]). ", "Importantly, still about half of cases studied by exome sequencing remain genetically unsolved, suggesting many as yet unidentified causes ([@bib1]).", "\n\nAlthough traditional homozygosity mapping or exome sequencing has uncovered many genes for these conditions, these approaches may fall short for genes under strong selective pressure or for genes in which homozygous loss-of-function mutations are embryonic lethal. ", "One approach to identify new human disease genes is to intersect cell biological, genomic, or protein interaction data in order to prioritize candidates for closer inspection. ", "For instance, a protein interaction network derived from genes previously implicated in the ciliopathies identified mutations in *TCTN2* in JS patients ([@bib36]). ", "Similarly, comparing gene content from species with and without cilia led to identification of *BBS5* in Bardet--Biedl syndrome patients ([@bib31]).", "\n\nThere have been few systematic approaches towards characterization of genes required for ciliogenesis. ", "A small interfering RNA (siRNA) screen of 7784 pharmacologically relevant genes identified 36 positive and 13 negative ciliogenesis modulators ([@bib27]), and a study of 815 'kinome' genes identified 9 candidates affecting ciliary signaling ([@bib20]), but neither study was genome-wide. ", "A recent phylogenetic co-occurrence study identified 206 core cilia components ([@bib15]), but no link with disease was shown. ", "Given defective ciliogenesis in patient cells, we reasoned that a genome-wide siRNA screen to identify ciliogenesis factors could help prioritize candidates, especially for families in which traditional exome-sequencing approaches have not yet yielded a cause.", "\n\nOne of the caveats of screening for such genes is that ciliogenesis is intimately linked with mitosis ([@bib28]; [@bib32]), and thus, genes arresting the cell cycle prior to ciliogenesis might be inadvertently flagged as affecting ciliogenesis. ", "Recent live cell cycle imaging markers make it possible to separately flag cell cycle genes, which could greatly increase the specificity of ciliogenesis screens.", "\n\nOur focus was to identify novel genes involved in JS, by applying a functional genomics approach, then intersecting the data with a cohort of unsolved exome-sequencing results from JS patients. ", "We conducted a high-throughput genome-wide siRNA knockdown study for 18,045 human genes in a 'two-color' cell line engineered to report ciliary-localized EGFP and cells in G2/M phase using mCherry-tagged Geminin. ", "A range of cellular features were measured for all genes, and compared with a positive and negative training set, resulting in a prioritized list of 591 ciliary candidates. ", "This list was used to prioritize variants from 145 JS patients on whom exome sequencing had not revealed a cause. ", "We identified deleterious variants *KIAA0586* in a total of 15 families. ", "This gene was previously missed by exome sequencing, most likely due to a high-carrier frequency of a common allele in a predominantly compound heterozygous inheritance, thus, precluding a homozygosity mapping approach or filtering focused on rare variants. ", "Together with a lethal phenotype in other species ([@bib5]), the data suggest that humans may have redundancy or compensation that preclude lethality or that the *KIAA0586* mutations only partially inactivate protein function. ", "The results also support a cell-based screening approach to complement exome sequencing in human mutation identification.", "\n\nResults {#s2}\n=======\n\nGeneration of SEMG cell line {#s2-1}\n----------------------------\n\nThe ciliated stable cell line, human telomerase reverse transcriptase (hTERT)-retinal pigment epithelial 1 (RPE1) Smo-EGFP ([@bib27]), in which Smoothened--tagged EGFP is stably integrated in the polarized human RPE1 cells, reliably reports a single primary cilium upon serum withdrawal in 60--80% of cells. ", "This line was stably transfected with mCherry-tagged Geminin ([@bib35]), a nuclear marker for S/G2/M cell cycle phases, to produce the Smo-EGFP-mCherry-Geminin/hTERT-RPE1 (SEMG) line, enabling differential analysis of ciliogenesis as a function of the cell cycle. ", "Cells lacking a cilium (i.e., absent ciliary-localized EGFP fluorescence) were divided into those in G2/M phase (should normally not display a cilium) and those in G0/G1 (most should display a cilium; [Figure 1A,B](#fig1){ref-type=\"fig\"}). ", "The incorporation of mCherry-Geminin increased the specificity of the screen by filtering siRNAs leading to cell cycle arrest as the primary reason for absent cilia.10.7554/eLife.06602.003Figure 1.Schematic representation, validation and enrichment of genome-wide siRNA cell screen for machine learning approach.(**A**) High-content small interfering RNA (siRNA) cell-based screen using reverse transfection of the library in media containing serum for 72 hr, followed by 24 hr serum starvation, fixation and DAPI staining. ", "Subsequent fluorescent imaging and algorithmic analysis performed for all pooled siRNAs. ", "To assess ciliary candidates for the positive training, we used SYSCILIA gold standard (SCGSv1) and for the negative training the human metabolome database (HMDB 3.0) as well as a manually curated housekeeping gene data set. ", "FDR, false discovery rate. (**", "B**) Segmentation algorithm for cytoplasm and cilia detection: (1) detected nuclei from DAPI channel, (2) nuclear automated segmentation, (3) cell outline automated using cytoplasm_detection_D of the program Acapella, and (4) cilia automated detection and segmentation. ", "Images have been modified for illustration purposes. ", "Scale bar: 10 μm. (**", "C**) Representative images of serum-starved SEMG cells without siRNA showing basal ciliation (small green rods in EGFP channel). ", "Red (mCherry) marks cells in S/G2/M phase of the cycle, green (EGFP) marks cilia, blue (DAPI) marks nuclei. ", "siRNAs used as positive controls: KIF3A interferes with ciliation but not cell cycle. ", "ACTR3 shows increased length of cilia ([@bib27]). ", "CRNKL1 implicated in cell cycle progression ([@bib48]) and showed increased mCherry nuclei and reduced ciliation. ", "Scale bar: 10 μm. (**", "D**) Receiver operating characteristic (ROC) for the classifier, which used features from three data sources. ", "Dashed line: theoretical random classifier. (**", "E**) Precision-recall curve for the final classifier. (**", "F**) Median value (red center bar) and interquartile ranges (blue box) box plot of the classifier scores for the corresponding number of supporting number of evidences (NOEs) in Cildb and the genes used as negative and positive training examples. ", "The indicated contrasts were found significant(\\*) with a highest value of p \\< 1.03 × 10^−4^ (one-tailed Wilcoxon\\'s Rank sum test). (**", "G**) Same as (**F**), limited to the NOEs from humans only. ", "The indicated contrasts were found significant(\\*) with a highest value of p \\< 1.43 × 10^−10^ (one-tailed Wilcoxon\\'s Rank sum test). ", "See [Figure 1---figure supplement 1, 2](#fig1s1 fig1s2){ref-type=\"fig\"} for the prediction score on the gold standard and candidates as well as the visible improvement of the ROC curve and precision--recall curve.**DOI:** [http://dx.doi.org/10.7554/eLife.06602.003](10.7554/eLife.06602.003)10.7554/eLife.06602.004Figure 1---figure supplement 1.Prediction score on Gold standard and Gold standard candidates.(**A**--**C**) Box plot reporting median value (red center bar) and interquartile ranges (blue box) of the classifier scores for gold standard positive and negative genes (out of bag performance, that is, for every gene the score excludes trees where the gene was used for training), also included are boxes for a set of ciliopathy candidate genes (SYSCILIA candidate genes) and genes not annotated to be ciliopathy related (Unknown), which were not used in the training. (**", "A**) Classifier based on cilia siRNA screen features only. (**", "B**) Classifier based on cilia siRNA screen and centriole siRNA screen features only. (**", "C**) Classifier including all siRNA and GTex project expression signature based features. ", "In all cases, the median value for positive set or candidate genes differed significantly from the negative set or unknown set of genes (One-tailed Wilcoxon rank sum test).**DOI:** [http://dx.doi.org/10.7554/eLife.06602.004](10.7554/eLife.06602.004)10.7554/eLife.06602.005Figure 1---figure supplement 2.Visible improvement of ROC curve and precision-recall curve.(**A**) ROC for classifiers trained on different partitions of the feature space (blue: final set, magenta: excluding centriole biogenesis siRNA based features, red: including only features from the whole genome siRNA screen performed in this study). ", "The dashed black line corresponds to a theoretical random classifier. (**", "B**) As in **A** but showing precision-recall curve for each classifier.**DOI:** [http://dx.doi.org/10.7554/eLife.06602.005](10.7554/eLife.06602.005)\n\nUsing this approach, we first optimized seeding density, serum withdrawal conditions, and imaging parameters using a siRNA positive control for cilia (i.e., no known effect on the cell cycle but blocking ciliogenesis) of KIF3A, and for cell cycle (i.e., no direct effect on ciliogenesis but traps cells in G2/M phase of the cell cycle or the effect described above) of ACTR3 and CRNKL1, and verified reporters were robust ([Figure 1C](#fig1){ref-type=\"fig\"}).", "\n\nCell-based screen and validation of whole-genome siRNA data set {#s2-2}\n---------------------------------------------------------------\n\nWe conducted a high-throughput siRNA knockdown study for 18,045 genes of the human genome performed in duplicate, using 4--5 unique pooled siRNAs per gene. ", "After siRNA transfection, ciliation was induced by serum starvation, then fixed and imaged in 384-well plates in three channels (see 'Materials and methods'). ", "18 non-overlapping cellular features reflecting nuclear, cytoplasm and ciliary state, combined into 31 parameters ([Supplementary file 1](#SD2-data){ref-type=\"supplementary-material\"}), yielding 559,395 values across the screen ([Supplementary file 2](#SD3-data){ref-type=\"supplementary-material\"}).", "\n\nDevelopment of the CILIOGENESIS data set {#s2-3}\n----------------------------------------\n\nThe rationale of our whole-genome siRNA screen with SEMG cells was to obtain data allowing for identification of genes as potential candidates as a cause of JS by using a supervised learning approach. ", "We trained a Random Forest classifier using known 'ciliary genes' as a positive training set, derived from the SYSCILIA consortium gold standard (SCGSv1) composed of 303 confirmed factors ([@bib43]). ", "The negative set incorporated genes not involved in any currently known ciliary processes and included 5445 genes annotated in the human metabolome database (HMDB 3.0) ([@bib45]), as well as a manually curated set of 666 housekeeping genes. ", "To ensure accurate annotation of gene sets used in the classifier training, all genes were cross checked with Cildb V3.0, a database of 'ciliary genes' (i.e., genes with presumed ciliary function) based on high-throughput studies across multiple species ([@bib3], [@bib2]). ", "Based on this resource, we removed genes with conflicting annotation from both the positive and negative sets, leaving a final list of high-confidence positive (n = 244) and negative (n = 1802) cilia candidates.", "\n\nWe evaluate the performance of the trained classifier on cilia candidates from the SCGSv1, which included an additional list of 419 ciliary gene candidates, not used to train the classifier. ", "Of these, 21% were flagged by the classifier as likely ciliary. ", "Furthermore, there was significant enrichment compared to the negative set of metabolomics and housekeeping genes not included in the classifier training set (p \\< 1.08 × 10^−25^, one-tailed Wilcoxon rank sum).", "\n\nNext, classifier performance was evaluated by examination of the area under the receiver operating characteristic-curve (AUC). ", "Along with both replicates of the whole-genome siRNA screen, we included data from a siRNA screen designed to identify regulators of centriole biogenesis ([@bib4]) and gene expression signatures derived from the Genotype-Tissue expression (GTEx) tissue specific RNAseq data ([Figure 1D,E](#fig1){ref-type=\"fig\"}, [Figure 1---figure supplement 1](#fig1s1){ref-type=\"fig\"}, [Figure 1---figure supplement 2](#fig1s2){ref-type=\"fig\"}) ([@bib23]). ", "Of the 16,431 genes screened in all three data sets, the classifier predicted 1299 genes (7.9%) as likely ciliary, which we call the CILIOGENESIS database ([Ci]{.ul}liary [Li]{.ul}st [o]{.ul}f Candidate [Gene]{.ul}s using an [si]{.ul}RNA [S]{.ul}trategy, [Supplementary file 3A,B](#SD4-data){ref-type=\"supplementary-material\"}). ", "We also define a high-confidence subset of 591 ciliary genes by controlling for the false discovery rate (FDR \\< 0.1), which is estimated based on the classifier score and training set labels calculated. ", "This high-confidence list includes many established ciliopathy genes such as *TTC26*, *CEP83*, *IFT88*, and *SPATA7*, as well as 14 of 25 known JS causative genes. ", "Of the remaining JS causative genes, two others were included when FDR scores were loosened to 0.21 and 0.25. ", "The remaining eight other JS causative genes (32%) were all found well above the genome-wide median classifier score (lowest ranked gene observed at 58th percentile), but not in the top list, possibly as a result of their activity outside the cilium. ", "Of the high-confidence genes included in the CILIOGENESIS database, 26% were previously included in the SCGCv1, yielding 438 novel candidates.", "\n\nCildb is a multispecies knowledge base constructed through integration of high-throughput screens aimed at identifying ciliary or ciliary-related genes. ", "Cildb outputs two integers for each gene in the knowledge base, referring to independent experimental 'number of evidences' (NOEs, i.e., publications) indicating ciliary association, with one for NOE in human studies and one for NOE in 'any species'. ", "We compared gene-specific classifier score (excluding any genes used in training) with the Cildb NOE output. ", "Significant positive trends were observed when comparing to increasing NOE in both the multi-species and human-only sets (Jonckheere--Terpstra test, see methods, p \\< 3.04 × 10^−29^ and p \\< 6.50 × 10^−42^, [Figure 1F,G](#fig1){ref-type=\"fig\"}). ", "Moreover, we also observed a significant difference when comparing scores in any of the NOE bins to the zero NOE bin in both the multi-species and human sets (p *\\<* 1.03 × 10^−4^ and p *\\<* 1.43 × 10^−10^, respectively, one-tailed Wilcoxon rank sum).", "\n\nEnrichment analysis of the CILIOGENESIS data set {#s2-4}\n------------------------------------------------\n\nTo identify possible candidates for ciliopathies, we performed a gene ontology (GO)-term enrichment analysis on the high-confidence gene list, with functional annotation clustering using DAVID ([@bib24]; [@bib25]). ", "We used a GO-enrichment cutoff of FDR \\<0.05 (Benjamini--Hocheberg test). ", "To ascertain the novelty of genes included in the CILIOGENESIS data set, we excluded SCGSv1 genes used in the training, leaving 1,177 genes. ", "GO enrichment resulted in several significant terms including non-membrane bound organelle, microtubule cytoskeleton/centrosome, spermatogenesis, and microtubule cytoskeleton organization demonstrating an agreement with previous annotations for cilia associations ([Supplementary file 3C](#SD4-data){ref-type=\"supplementary-material\"}). ", "The involvement of ciliary processes in the CILIOGENESIS data set was supported by MsigDB analysis showing gene enrichment among others for the recruitment of mitotic centrosome proteins and complexes, microtubule/cytoskeleton and centrosome ([Supplementary file 3D,E](#SD4-data){ref-type=\"supplementary-material\"}) ([@bib40]). ", "Enrichment validation suggested that the CILIOGENESIS data set may be enriched for ciliopathy disease genes.", "\n\nIntersection of CILIOGENESIS with unsolved JS cases highlights KIAA0586 {#s2-5}\n-----------------------------------------------------------------------\n\nPrevious whole-exome sequencing in 287 cases of JS left ∼50% without a genetic explanation ([@bib1]), suggesting additional causes remain to be identified. ", "Of these, 75% displayed parental consanguinity, suggesting that causative variants might be homozygous. ", "In about half of the remaining cases, sequencing on at least one parent was available, enabling phasing of identified alleles. ", "From these 145 individuals, we tabulated 5485 variants containing 2348 homozygous variants and 3137 potentially compounds heterozygous variant pairs. ", "We prioritized variants occurring within the coding region and canonical splice sites of any of the 591 CILIOGENESIS genes, and identified 179 variants including 106 homozygous and 73 potentially compound heterozygous variant pairs, or a 96.7% reduction in variants to be considered. ", "Collectively, variants were identified in 112 of the 591 CILIOGENESIS genes, respectively. ", "The only gene with more than two families displaying variants was *KIAA0586*, prompting further analysis.", "\n\n*KIAA0586* (i.e., the orthologue of chicken and mouse *Talpid3*) is composed of 34 exons with at least six major transcripts ([Figure 2A](#fig2){ref-type=\"fig\"}). ", "From these 145 sequenced probands (written informed consent provided), there were four displaying putative compound heterozygous and two displaying homozygous potentially deleterious variants. ", "Interestingly, in each of the four compound heterozygous probands, there was a shared frameshift mutation, (chr14:58899157del; c.428del, p.Arg143Lysfs\\*4), which we refer to as M1 (mutation 1). ", "Each of the four carried a single additional potentially deleterious variant, including mutations in a canonical acceptor splice site (chr14:58915212G\\>A; c.1120+1G\\>A, p.Thr323Hisfs\\*3; M2), a canonical donor splice site (chr14:58923419G\\>C; c.1413-1G\\>C; p.Phe472Alafs\\*5; M3), and a missense affecting the start codon of two transcripts (chr14:58896138T\\>C; c.293T\\>C; p.Met98Thr; M4; T1; or c.2T\\>C; p.Met1?; ", "T4-T5, where T refers to transcript number). ", "Implementing an algorithm to identify copy number variants from exome-sequencing data ([@bib21]), we additionally identified a deletion of 15.5 kilobases (Kb) spanning exon 10--17 (chr14:?\\_58923420_58938997\\_?del; c.1413-?\\_2793+?del; p.?; ", "M5) in one patient. ", "These mutations were all confirmed with Sanger sequencing or quantitative PCR, and all segregated according a strict recessive mode of inheritance in all available family members ([Figure 2B](#fig2){ref-type=\"fig\"}, [Figure 2---figure supplement 1](#fig2s1){ref-type=\"fig\"}, [Figure 2---figure supplement 2](#fig2s2){ref-type=\"fig\"}). ", "We conclude that compound heterozygous variants in *KIAA0586* contribute to JS. ", "Each patient carrying the M1 mutation had a demonstrable second mutation on the other allele, suggesting a recessive mode of inheritance.10.7554/eLife.06602.006Figure 2.Pedigrees and schematic representation of *KIAA0586*.(**A**) Genomic structure and mRNA transcripts of *KIAA0586*. ", "Transcript 1 (T1): full-length isoform with 34 exons. ", "T2--T4 have different initiation sites, lack exon 5, and T3 lacks exon 14. ", "T5 starts at the same position as T4 and incorporates exon 6. ", "The shortest transcript (T6) initiates in exon 7, lacks exon 32 and 33, and terminates using an alternative exon, which is not incorporated in the other transcripts. ", "Gray boxes represent alternative exons. ", "UTR\\'s are represented by half-height boxes. ", "The location of the mutations is indicated by M1--M7. (**", "B**) Pedigrees of the Joubert syndrome (JS) families with ancestries of USA (MTI-233 and MTI-103), Mexico (MTI-165), Turkey (MTI-1944 and COR354), and Syria (MTI-505), respectively, demonstrating the segregation of the compound heterozygous mutations in non-consanguineous families and homozygous mutations in consanguineous families. ", "Inferred genotype is italicized. ", "M, mutation; T, transcript. ", "See [Figure 2---figure supplement 1](#fig2s1){ref-type=\"fig\"} for the chromatograms of the mutations in *KIAA0586*. [", "Figure 2---figure supplement 2](#fig2s2){ref-type=\"fig\"} shows the results of the quantitative PCR confirming the large heterozygous mutation in MTI-1944.**DOI:** [http://dx.doi.org/10.7554/eLife.06602.006](10.7554/eLife.06602.006)10.7554/eLife.06602.007Figure 2---figure supplement 1.Chromatograms of mutations in the *KIAA0586* gene.", "The chromatograms of the mutations in identified in *KIAA0586* of individuals with JS. **", "A**) M1, **B**) M2, **C**) M3, **D**) M4, **E**) M6, **F**) M7.**DOI:** [http://dx.doi.org/10.7554/eLife.06602.007](10.7554/eLife.06602.007)10.7554/eLife.06602.008Figure 2---figure supplement 2.Quantitative PCR confirmed heterozygous mutation in MTI-1944.Using quantitative PCR on genomic DNA of the large deletion with unknown specific boundaries was confirmed to segregate in MTI-1944. ", "By analyzing two primer sets outside the presumed heterozygous deletions spanning exon 12 to 20 and two within the deletion absence of approximately half the product in the mother and affected child was shown. ", "Input of genomic DNA was normalized against *GAPDH*. ", "C, control; F, father; M, Mother; A, affected child.**DOI:** [http://dx.doi.org/10.7554/eLife.06602.008](10.7554/eLife.06602.008)\n\nTwo consanguineous families each showed a homozygous mutation in *KIAA0586*. ", "One was predicted to alter splicing in a constitutively incorporated exon (c.2414-1G\\>C; p.?; ", "M6). ", "The other was a single base-pair deletion (c.74del; p.Lys25Argfs\\*6; M7), in an exon incorporated into only three of the six annotated transcripts, all of which are ubiquitously expressed. ", "We conclude that homozygous mutations in *KIAA0586* can also contribute to JS.", "\n\nThe common frameshift variant M1 was identified in all four families with compound heterozygous mutations. ", "Evaluation of M1 in the Exome Variant Server (NHLBI GO Exome Sequencing Project (ESP), Seattle, WA, URL: <http://evs.gs.washington.edu/EVS/> \\[May, 2015\\]) identified in 25/7,757 European American alleles and 3/3511 African American alleles, all in a heterozygous state, presumably all in healthy individuals. ", "Exome Aggregation Consortium (ExAC, Cambridge, MA, URL: <http://exac.broadinstitute.org> \\[May, 2015\\]) showed an overall frequency of 244/120,680 M1 alleles. ", "Combining these with the 1000 Genomes data suggests an allele frequency of 0.0036 in the general population. ", "We conclude that M1 is a relatively common allele in the general population, found in about 1/300 individuals. ", "The M1 variant was found in individual of varying ancestry, but we cannot exclude a common founder mutation.", "\n\nEvaluation of KIAA0586 as a candidate gene in other JS cohorts {#s2-6}\n--------------------------------------------------------------\n\nWe speculated that M1 was likely to represent a common mutation among JS patients. ", "Thus, we screened an additional cohort of 163 classical JS patients with a proven 'molar tooth sign' collected primarily from Mediterranean regions. ", "The M1 allele was surprisingly identified in 17 of 326 alleles (5.21%), of which one was homozygous ([Figure 3](#fig3){ref-type=\"fig\"} individual NG2872). ", "Ethnically matched Mediterranean controls showed 2/536 M1 alleles (0.37%, p \\< 0.0001, odds ratio 13.51). ", "In the remaining 15 individuals, we attempted comprehensive Sanger sequencing of the entire *KIAA0586* transcript, eventually identifying a pathogenic variant in eight individuals (57%), all leading to predicted splice, stop or frameshift changes, again consistent with recessive inheritance. ", "In the other seven JS patients, a second mutation was not yet identified ([Table 1](#tbl1){ref-type=\"table\"}, [Table 1---source data 1](#SD1-data){ref-type=\"supplementary-material\"}). ", "Although it is possible that one or more of these individuals carries M1 by chance, it is most likely that a second mutation exists, not yet uncovered.10.7554/eLife.06602.009Figure 3.MRI scans from patients with *KIAA0586* mutations.", "Magnetic resonance imaging (MRI) in a healthy individual and patients with *KIAA0586* mutations showing thickened and mal-oriented superior cerebellar peduncle (upper, red 'arrowheads'), deepened interpeduncular fossa and constituting the 'molar tooth sign' (red circle). ", "In COR-354-2-3, the molar tooth sign was very mild, possibly due to suboptimal image averaging. [", "Figure 3---figure supplement 1](#fig3s1){ref-type=\"fig\"} shows the imaging phenotype of affected JS individual MTI-1944-2-1.**DOI:** [http://dx.doi.org/10.7554/eLife.06602.009](10.7554/eLife.06602.009)10.7554/eLife.06602.010Figure 3---figure supplement 1.Imaging phenotype of affected JS individual MTI-1944-2-1 with *KIAA0586* mutations.", "MRI of individual MTI-1944 affected by *KIAA0586* mutations causing JS. ", "For the affected individuals, the diagnosis of JS was confirmed by the deepened interpeduncular fossa and abnormal superior cerebellar peduncles, showing the 'molar tooth sign' (red circle).**DOI:** [http://dx.doi.org/10.7554/eLife.06602.010](10.7554/eLife.06602.010)10.7554/eLife.06602.011Table 1.All alleles identified in *KIAA0586* causative for Joubert syndrome**DOI:** [http://dx.doi.org/10.7554/eLife.06602.011](10.7554/eLife.06602.011)10.7554/eLife.06602.012Table 1---source data 1.Chromatograms of mutations in the *KIAA0586* gene identified in the additional cohort of Mediterranean individuals with Joubert syndrome.**DOI:** [http://dx.doi.org/10.7554/eLife.06602.012](10.7554/eLife.06602.012)Allele 1 (based on T1)Allele 2 (based on T1)Patient IDGenotypeGenomicDNAProteinGenomicDNAProteinMTI-233M1/M2g.58899157delc.428delp.", "Arg143Lysfs\\*4g.58915212G\\>Ac.1120+1G\\>Ap.", "Thr323Hisfs\\*3MTI-103M1/M3g.58899157delc.428delp.", "Arg143Lysfs\\*4g.58923419G\\>Cc.1413-1G\\>Cp.", "Arg472Serfs\\*2MTI-165M1/M4g.58899157delc.428delp.", "Arg143Lysfs\\*4g.58896138T\\>Cc.2T\\>C (based on T4-T5)p.", "Met1? (", "based on T4-T5)MTI-1944M1/M5g.58899157delc.428delp.", "Arg143Lysfs\\*4g.?\\_58923420_58938997\\_?delc.1413-?\\_2793+?delp.?MTI-505M6/M6g.58934452G\\>Cc.2414-1G\\>Cp.?g.58934452G\\>Cc.2414-1G\\>Cp.?COR354M7/M7g.58895020delc.74delp.", "Lys25Argfs\\*6g.58895020delc.74delp.", "Lys25Argfs\\*6Mediterranean cohort analysisNG2872M1/M1g.58899157delc.428delp.", "Arg143Lysfs\\*4g.58899157delc.428delp.", "Arg143Lysfs\\*4NG4158M1/M8g.58899157delc.428delp.", "Arg143Lysfs\\*4g.58909503C\\>Tc.649C\\>Tp.", "Gln217\\*NG2326M1/M9g.58899157delc.428delp.", "Arg143Lysfs\\*4g.58910790_58910791delc.863_864delp.", "Gln288Argfs\\*7NG1776M1/M9g.58899157delc.428delp.", "Arg143Lysfs\\*4g.58910790_58910791delc.863_864delp.", "Gln288Argfs\\*7NG3928M1/M10g.58899157delc.428delp.", "Arg143Lysfs\\*4g.58915097C\\>Tc.1006C\\>Tp.", "Gln336\\*NG2458M1/M11g.58899157delc.428delp.", "Arg143Lysfs\\*4g.58924613_58924616delinsAAAc.1658_1661delinsAAAp.", "Val553Glufs\\*79NG2286M1/M12g.58899157delc.428delp.", "Arg143Lysfs\\*4g.58925263G\\>Ac.1815G\\>Ap.= / p.?NG1485M1/M13g.58899157delc.428delp.", "Arg143Lysfs\\*4g.58927869C\\>Tc.2209C\\>Tp.", "Arg737\\*NG3758M1/M14g.58899157delc.428delp.", "Arg143Lysfs\\*4g.58953883delc.3462delp.", "Gly1155Glufs\\*40[^2]\n\nTo evaluate the effect of predicted splicing mutations in *KIAA0586,* we generated mRNA from cultured fibroblasts of an affected and unaffected member of family MTI-233 and MTI-103, displaying an M1 compounded with a splice mutation (M2 or M3, respectively). ", "Sanger sequencing of poly-A primed mRNA showed that the mutation M2 led to the skipping of exon 9 and mutation M3 led to utilization of a cryptic splice acceptor located 16 bp downstream (i.e., 3′), resulting in a frameshifted transcript ([Figure 2---figure supplement 1B,C](#fig2s1){ref-type=\"fig\"}), suggesting partial or complete loss-of-function.", "\n\nLoss-of-function mutations in *Talpid3* result in a short-rib polydactyly-like phenotype in chicken and mouse, with a vascular defect and early lethality, all attributable due to defective ciliogenesis ([@bib5]; [@bib12]). ", "Our patients presented classical features of JS including the MTI of varying severity ([Figure 3](#fig3){ref-type=\"fig\"}, [Figure 3---figure supplement 1](#fig3s1){ref-type=\"fig\"}), without lethality or demonstrable excessive fetal wasting in affected families. ", "Most cases displayed hypotonia, ataxia, developmental delay, and intellectual disability without skeletal or limb malformations. ", "Breathing abnormalities, seizures, macrocephaly, and ophthalmological defects were found in a subset of the cases ([Supplementary file 4A](#SD5-data){ref-type=\"supplementary-material\"}). ", "The affected child of MTI-165 passed away at the age of 18 months from apnea, and no imaging was available. ", "The results support the involvement of *KIAA0586* in the pathogenesis of JS.", "\n\nMutated KIAA0586 results in absence of detectable protein in patient cells {#s2-7}\n--------------------------------------------------------------------------\n\nRT-PCR analysis with primers spanning various transcripts showed ubiquitous *KIAA0586* expression in various tissues ([Figure 4---figure supplement 1A](#fig4s1){ref-type=\"fig\"}). ", "To determine the effect of mutations on KIAA0586 protein level, we analyzed patient fibroblasts of family MTI-103 and MTI-233 by Western analysis using a KIAA0586-specific antibody ([@bib30]). ", "The level of KIAA0586 protein in patient samples was below detection, whereas both carriers showed reduced but detectable expression compared with control ([Figure 4](#fig4){ref-type=\"fig\"}). ", "In human RPE1 cells transfected with KIAA0586 siRNA, we documented reduced protein levels, supporting antibody specificity.10.7554/eLife.06602.013Figure 4.Absent KIAA0586 protein in patient fibroblasts.", "Immunoblot analysis of KIAA0586 in fibroblasts from family MTI-103 and MTI-233. ", "Lysates from RPE1 cells transfected with scrambled or KIAA0586 siRNA were used as control. ", "M, unaffected carrier (mother); A, affected child. ", "RPE1, retinal pigment epithelial-1 cell line. [", "Figure 4---figure supplement 1A](#fig4s1){ref-type=\"fig\"} represents an expression analysis of the *KIAA0586* gene.**DOI:** [http://dx.doi.org/10.7554/eLife.06602.013](10.7554/eLife.06602.013)10.7554/eLife.06602.014Figure 4---figure supplement 1.Expression analysis of the *KIAA0586* gene.", "RT-PCR analysis showing differential expression levels of the *KIAA0586* transcripts amongst various ciliated and non-ciliated tissues was observed. ", "Co, colon; Ce, cerebellum; K, kidney; L, liver; MQ, MilliQ; T, testis; T1-T5 transcript number corresponding to [Figure 2A](#fig2){ref-type=\"fig\"}.**DOI:** [http://dx.doi.org/10.7554/eLife.06602.014](10.7554/eLife.06602.014)\n\nDiscussion {#s3}\n==========\n\nHere, we identify *KIAA0586* mutations in JS using a combination of cell-based screening and exome sequencing. ", "By training of a classifier to prioritize ciliary candidate genes based upon shared loss-of-function phenotypes, we generated a data set we called CILIOGENESIS consisting of 591 prioritized genes. ", "Intersecting these genes with WES data of genetically unexplained JS individuals led to the discovery of mutations in *KIAA0586*, which we found to be a relatively common cause (i.e., about 5%) in unsolved JS cases. ", "In patient cells, there was undetectable KIAA0586 protein supporting its role in JS pathogenesis. ", "It remains to be determined whether mutations in *KIAA0586* can lead to other ciliopathies like Meckel--Gruber syndrome or nephronophthisis, which are often allelic to JS.", "\n\nOur siRNA screen incorporated several improvements over previously published but similar screens. ", "As the first genome-wide siRNA high-content screen for defective ciliogenesis, we evaluated nearly each of the annotated human genes with at least four siRNAs per gene. ", "Second, we incorporated a specific cell phase marker, mCherry-Geminin, to exclude false-positives that might result from cell cycle defects. ", "Third, we incorporated a machine learning approach with positive and negative training sets, which enhanced the predictability of measured cellular features as they relate to ciliogenesis.", "\n\nIt is noteworthy that including features in the classifier from multiple sources, while improving performance of the classifier, caused a reduction from 18,045 targets to 16,431 targets due to missing values (n = 798 targets lost by the biogenesis siRNA screen; n = 786 targets lost by the GTEx RNAseq data). ", "It is possible that some ciliary factors were not correctly classified as such due to incomplete data in these comparative screens. ", "Inevitability, our machine learning approach will be biased towards currently known ciliary factors, and as more knowledge is gained, the power of such approaches will improve. ", "Even by combining the CILIOGENESIS data set with exomes from 145 individuals identified only a single recurrently mutated gene, leaving the majority of families still unexplained ([@bib1]). ", "This observation leads us to postulate that there are probably few commonly mutated genes remaining to be discovered in JS.", "\n\nOur siRNA screen is probably underpowered to detect JS genes primarily involved in effects like signaling through Sonic hedgehog or Wnt pathways. ", "Gene set enrichment analysis of the true positive SCGCv1 genes (SCGCv1 genes ranked within the CILIOGENESIS data set genes) with MsigDB ([@bib40]) showed enrichment for cytoskeletal genes as expected ([Supplementary file 3F](#SD4-data){ref-type=\"supplementary-material\"}), whereas analysis on false negative genes (SCGCv1 genes ranked outside the CILIOGENESIS data set genes) showed significant enrichment for photoreceptor cell maintenance, sensory perception, Sonic hedgehog pathway, and post-chaperonin tubulin folding pathway ([Supplementary file 3G](#SD4-data){ref-type=\"supplementary-material\"}). ", "This suggests that the CILIOGENESIS data set may be enriched for genes involved in the process of ciliogenesis, whereas genes involved in signaling functions are less likely to be detected. ", "Moreover, this is in agreement with analysis of candidate targets involved in Hedgehog signaling from screens described in literature for which we observe no enrichment in the CILIOGENESIS data set ([Supplementary file 3A,B](#SD4-data){ref-type=\"supplementary-material\"}) ([@bib20]; [@bib26]). ", "It is possible that extending the CILIOGENESIS data set to include factors regulating the ciliary responsiveness to Hedgehog or Wnt activators or suppressors could further improve sensitivity.", "\n\nTalpid3 participates in the earliest stages of ciliation, including centriolar satellite dispersal and plasma membrane docking of the basal body ([@bib12]; [@bib30]). ", "Although *Cep290* and *Talpid3* share some similarities in ciliary phenotypes, there are distinct cellular functions ([@bib30]). ", "Talpid3 forms a ring-like structure at the distal end of both centrioles and is involved in the initiation of ciliary vesicle formation and docking, whereas Cep290 functions in the maturation of these vesicles. ", "Moreover, Talpid3 is localized asymmetrically in mother and daughter centrioles and is crucial for limiting the levels of Cep120 at the mother centriole ([@bib46]). ", "In *Talpid3* mutant mouse embryos, centrosomes fail to dock at the plasma membrane and cilia are absent in various tissues ([@bib47]), associated with embryonic lethality.", "\n\n*KIAA0586* might have been identified as mutated in JS even without the CILIOGENESIS data set, but was missed, probably for several reasons. ", "First, the difference in names of the human and mouse genes made it difficult to link the two in automated curation of exome variants. ", "Second, the majority of mutations were compound heterozygous, precluding homozygosity mapping analysis. ", "Third, the higher frequency of the common allele M1 in the general population reduced its priority as a candidate, since the rarest alleles are prioritized over common alleles. ", "Thus, we foresee the CILIOGENESIS data set and other orthogonal approaches as potentially beneficial in gene discovery.", "\n\nThe 1/300 calculated carrier frequency of M1 in the population is comparable to the deep intronic founder mutation of ∼1/500 (c.2991+1655A\\>G) in *CEP290* as the most common cause of Leber congenital amaurosis in Caucasians, but less than the ∼1/100 in *TMEM216* as a cause for JS in the Ashkenazi population ([@bib13]; [@bib42]). ", "Of the 15 patients with heterozygous M1 in the Mediterranean cohort, we identified a second truncating allele in *KIAA0586* in 57%, and the remaining are still under investigation for non-coding or deletion mutations. ", "We screened a cohort of 800 individuals with nephronophthisis with retinopathy, and found four carrying the M1 mutation, close to the predicted 0.0036 expected carrier frequency and no convincing second mutations were documented in this cohort. ", "Thus, it remains to be determined if *KIAA0586* mutations are associated with other ciliopathy phenotypes or can lead to embryonic lethality.", "\n\nBecause the mutations affect only exons incorporated in a subset of transcripts or affect splicing (which can be leaky) and because of embryonic lethality in mouse and chick with homozygous null mutations, we speculate that humans surviving with *KIAA0586* mutations may retain partial function. ", "The M4 allele was predicted to cause loss of the initiator methionine in transcript T4 and T5, potentially leaving other transcripts intact. ", "M4 was encountered in public sequence databases ESP and ExAC with a frequency of 0.002 (322/132,340 alleles), including three homozygous cases with unknown health status. ", "The M7 allele affects three of six transcripts, while no protein was detected on Western blot from patient cells. ", "It will be important to model these alleles or check for complementation of two null alleles with the patient alleles.", "\n\nMaterials and methods {#s4}\n=====================\n\nCell culture {#s4-1}\n------------\n\nhTERT-transformed RPE1 cells were cultured in DMEM/F12 medium supplemented with 10% fetal bovine serum (FBS), under standard conditions (37°C, 5% CO^2^). ", "Plasmid DNAs harboring mouse Smo-EGFP and mCherry-Geminin (1--110aa) fusion genes were transfected to hTERT-RPE1 cells and the stable cell line; Smo-EGFP-mCherry-Geminin/hTERT-RPE1 (SEMG) was established by G418 selection. ", "To induce ciliogenesis, the cells were serum starved on serum-free DMEM/F12 media for 24--48 hr prior to fixation.", "\n\nWhole-genome siRNA library screen {#s4-2}\n---------------------------------\n\n### Primary screen {#s4-2-1}\n\nAn arrayed library containing pooled siRNAs targeting 18,045 human genes (Dharmacon, Lafayette, CO) was screened in duplicate. ", "Assay plates (384-well plate with optical bottom; Greiner Bio-One, Monroe, NC) were spotted with 1 μl of 0.5 μM siRNA using the Velocity 11-Bravo Pipette with a 384 ST head. ", "Reverse transfection was performed using Lipofectamine RNAiMAX: final siRNA concentration was 10 nM. SEMG cells were suspended in DMEM/F12 supplemented with 10% FBS and seeded onto assay plates using the Matrix-Well Mate (2,000 cells in 40 μl medium for each well). ", "Culture medium was replaced with DMEM 24 hr after transfection using the TiterTek-MAP-C, and cells were incubated for additional 48 hr before fixation in 4% PFA and subsequent staining with DAPI.", "\n\n### Imaging and image analysis {#s4-2-2}\n\nImage acquisition of the siRNA screen was performed on the Opera QEHS system (PerkinElmer, Waltham, MA). ", "All cells were imaged with a 20× objective in a standardized manner using the Opera QEHS system (Perkin Elmer, Waltham, MA). ", "The nuclei were stained with DAPI and exposed for ∼10 ms using the non-confocal light path at 365-nm excitation with an and a 450/50-nm emission filter. ", "The green fluorescence for expression of Smo was acquired at 488-nm excitation using the confocal system. ", "The expression of Geminin was measured at 561-nm laser line using the confocal system. ", "Each well was imaged in triplicate. ", "Acapella 2.0 software (PerkinElmer, Waltham, MA) was used to perform image segmentation and cytometry with similar algorithms previously described ([@bib27]). ", "31 output parameters were obtained by an algorithm generated for segmentation of the nucleus, cytoplasm, and primary cilium in the SEMG cells ([Figure 1A--C](#fig1){ref-type=\"fig\"}, [Supplementary file 1](#SD2-data){ref-type=\"supplementary-material\"}). ", "The algorithm applied for segmentation of the nucleus, cytoplasm, and primary cilium in SEMG was confirmed by the manual imaging analysis in both serum positive and negative conditions.", "\n\n### Random Forest classification of cilia genes {#s4-2-3}\n\nData generated by whole-genome siRNA high-content screen were quantile normalized across batches to facilitate cross validation. ", "The SYSCILIA gold standard (SCGSv1) of known ciliary components ([@bib43]) was used as positive training examples. ", "The SCGSv1 included 303 genes curated by the SYSCILIA consortium associated to a ciliopathy, ciliary localization, or function in ciliogenesis ([@bib43]). ", "An additional list which included 419 candidate ciliopathy associated genes, which accompanied the gold standard, was used to benchmark the performance of our classifier and was excluded from training. ", "As non-ciliary examples, we used two non-ciliary sets, the metabolome consisting of 5,445 genes ([@bib45]) and a manually created list of housekeeping genes of 666 genes. ", "To further hone the positive and negative training sets, we use Cildb (V3.0) a comprehensive resource aggregating experimental evidence from 15 model organisms including humans ([@bib3], [@bib2]). ", "Genes appearing in the Cildb list with any evidence of involvement in ciliary related processes were excluded (n = 9,073) from our negative training set, and in similar ways, genes in the positive training set were removed if evidence of ciliary involved was not seen in Cildb. ", "The final positive training set composed of 244 genes, whereas in the negative training sets 1,802 genes remain. ", "To prioritize candidate genes for ciliopathies, a Random Forest classifier was trained to accurately classify positive from negative samples based on features from data generated by our whole-genome siRNA screen, data from centriole formation from Balestra et al., ", "and patterns of gene expression signatures across tissue from the GTEx project ([@bib23]).", "\n\nFirst, the classifier was trained on the first replicate data set of the whole-genome siRNA experiment and tested on the second replicate and vice versa where a modest AUC of 0.63 and 0.64 was observed. ", "Combining the features from the two batches, the classifier reached an AUC of 0.65 in test set performance ([Figure 1---figure supplement 1A](#fig1s1){ref-type=\"fig\"}, [Figure 1---figure supplement 2](#fig1s2){ref-type=\"fig\"}). ", "Next, the classifier was trained with additional features collected in a centriole siRNA screen, which was a whole-genome siRNA study, was designed to identify regulators of centriole biogenesis and provide background on cilia, flagella, and centrosome formation ([@bib4]). ", "Centriole data were downloaded from <http://centriolescreen.vital-it.ch>, to aggregate the effects of multiple siRNA, we use the weighted median method as in the ATARiS approach ([@bib38]), which improved the AUC to 0.70 ([Figure 1---figure supplement 1B](#fig1s1){ref-type=\"fig\"}, [Figure 1---figure supplement 2](#fig1s2){ref-type=\"fig\"}). ", "Subsequently, the GTExs ([@bib23]) data, which enables evaluation between genetic variation and gene expression in post-mortem human tissues, were used. ", "We excluded 80 samples with low-RNA quality scores (RIN \\< 0.6), leaving 2,788 RNAseq samples from 52 tissues for further analysis. ", "Reads per kilobase per million (RPKM) scores are quantile normalized across all samples. ", "Next, for each tissue separately, we calculate the median expression RPKM score and principle component gene loading values for a set of leading principle components chosen to capture 95% of the total variance in each tissue (2--7 principle component, median 4 per tissue). ", "By including these expression features derived from the GTEx RNAseq data in the classifier, an improvement to an AUC of 0.86 was reached ([Figure 1---figure supplement 1C](#fig1s1){ref-type=\"fig\"}, [Figure 1---figure supplement 2](#fig1s2){ref-type=\"fig\"}).", "\n\nClassification was performed using the Random Forest approach ([@bib8]); trees were grown from bootstrapped samples of genes selected with replacement such that the number of negative samples matches the number of positive ones (randomized under sampling) ([@bib37]). ", "In each iteration, the square root the number of features was used (*mtry*, as suggested by Brieman et al.). ", "Each forest is comprised of 5,000 trees trained as above (*ntree*). ", "All predicted scores reported throughout our analysis are based on out-of-bag prediction scores (i.e., Random-Forest cross-validation scores).", "\n\n### Gene set functional annotation clustering with DAVID {#s4-2-4}\n\nFunctional annotation clustering of the CILIOGENESIS data set was performed with the online web tool DAVID ([@bib25]). ", "A set of 591 high scoring genes from the final joined classifier are used for the analysis (FDR \\< 0.1). ", "CILIOGENESIS was tested for enrichment of GO FAT, KEGG, and Reactome pathway categories using the medium stringency setting of DAVID. ", "As a background set, we use all genes, which have a full feature sets in all three data sources (16,810 genes; [Supplementary file 3C](#SD4-data){ref-type=\"supplementary-material\"}).", "\n\n### Gene set enrichment analysis with MsigDB {#s4-2-5}\n\nGene set enrichment was performed by comparison against a collection of gene sets selected from the MsigDB (v5.0) database (Hallmark set, GO set, KEGG set, and Reactome set) ([@bib40]). ", "As a background set, we used all genes, which have a full feature sets in all three data sources (16,431). ", "Sets larger than 400 or smaller than 5 were excluded, and only sets with a minimal overlap of three genes were included from the tested list in the p-value calculation. ", "Enrichment p-value was calculated using a hypergeometric test of enrichment, and are only sets with FDR \\<0.1 are reported (estimated with B&H procedure).", "\n\n### Jonckheere--Terpstra test of trend {#s4-2-6}\n\nWhen considering any type of evidence, the trend is tested for each individual bin (0, 1, 2, 3, 4, 5, 6, 7, \\>8). ", "For 'human only' evidence, the trend was tested for bins of (0, 1, 2, 3, \\>4) ([@bib7]).", "\n\nGenetic analysis {#s4-3}\n----------------\n\n### Patient Recruitment {#s4-3-1}\n\nFamilies were recruited for study based upon the presentation of JS in at least one member of the family. ", "This study was approved by the institutional review boards of the participating centers. ", "All subjects provided written informed consent (including consent to publish) prior to participation in the study. ", "Sampling of blood for this study was performed on the proband and all affected and unaffected available genetically informative siblings and parents consistent with IRB guidelines or for skin biopsies from the proband and one parent when available. ", "All patients were evaluated directly by one of the co-authors with specialty training in neurology, child neurology and/or clinical genetics, and in accordance with local medical practices. ", "Detailed pedigree information, symptomatology, detailed general and neurological evaluations, brain/spine imaging and electrodiagnostic workup were performed in all affected members as well as clinically suspected members of each family, along with videos documenting the neurological examination in most cases.", "\n\n### Exome sequencing {#s4-3-2}\n\nWe performed WES in 145 families with affected(s) displaying features consistent with JS. ", "Blood was acquired from informed, consenting individuals according to institutional guidelines, and DNA extracted using established protocols. ", "In solution, exome capture was performed using the SureSelect Human All Exome 50 Mb Kit (Agilent Technologies, Santa Clara, CA) with 150-bp paired-end read sequences generated on a HiSeq2000 (Illumina, San Diego, CA). ", "Sequences were aligned to hg19 and variants identified through the GATK pipeline ([@bib14]). ", "Variations were annotated with in-house software and the SeattleSeq server ([@bib16]).", "\n\n### Systematic whole exome data analysis and variant identification {#s4-3-3}\n\nInitially, we systematically filtered for segregating (when WES of family member was present) autosomal variants with a total allele frequency \\<1% in Exome Variant Server (EVS; version ESP6500SIV2). ", "Furthermore, all variants (except frame shifts variants) had a combined annotation dependent depletion_phred score ≥10 (CADD) ([@bib29]). ", "All possible single nucleotide variants CADD scores were downloaded and provide a score to prioritize functional, deleterious and pathogenic variants across many functional categories, effect sizes and genetic architectures was unmatched by any current single-annotation method. ", "Frameshift variants were included with a GERP-score ≥4.0 ([@bib10]). ", "Homozygous variants were filtered out when present in unaffected individuals from our in-house database (n = 1,081), and compound heterozygous variants were removed when both were present in unaffected individuals. ", "After performance of this script, we focused on the gene set of 591 genes of FDR \\<0.1 by applying a filter on the previous analysis. ", "Variants in *KIAA0586* were analyzed for pathogenesis on the six largest transcripts ([Supplementary file 4B](#SD5-data){ref-type=\"supplementary-material\"}) and segregation with disease within family members by regular PCR reaction. ", "Primers for variant analysis and whole-gene scanning were designed using Primer3 (<http://biotools.umassmed.edu/bioapps/primer3_www.cgi>) ([Supplementary file 5A](#SD6-data){ref-type=\"supplementary-material\"}).", "\n\n### mRNA and gDNA analysis by RT-PCR {#s4-3-4}\n\nQuantitative PCR on genomic DNA was performed to confirm a the large deletion of unknown specific boundaries in MTI-1944. ", "By analyzing two primer sets outside the deletion spanning exon 12 to 20 and two primer sets within the deletion quantity of PCR product was analyzed. ", "Quantitative PCRs were performed using the C1000 Touch Thermocycler (Bio-Rad, Hercules, CA) in 96 micro-well plates. ", "All samples were run in triplicate using iTaq Universal SYBR Green Supermix (Bio-Rad, Hercules, CA) mastermix, exonic primers ([Supplementary file 5B](#SD6-data){ref-type=\"supplementary-material\"}) and template DNA. ", "Input of genomic DNA was normalized against internal control gene *GAPDH*.", "\n\nTotal RNA was isolated from cultured fibroblasts from affected individual MTI-233-2-1 and MTI-103-2-2 and unaffected MTI-233-1-2 and MTI-103-1-2 according to manufacturer\\'s protocol (Invitrogen, Carlsbad, CA). ", "Reverse transcription with SuperScript III First-Strand Synthesis System (Invitrogen, Carlsbad, CA) was performed on 1 μg of total RNA. ", "RT-PCR experiments were performed using 2.5 μl cDNA with primers in exons 8 and 10 (M2) and 10 and 12/13 (M3; intron spanning) ([Supplementary file 5B](#SD6-data){ref-type=\"supplementary-material\"}) (35 cycles) followed by Sanger sequencing using a 3730 ABI DNA Analyzer.", "\n\n### RNAi {#s4-3-5}\n\nSynthetic siRNA oligonucleotides were obtained from Dharmacon. ", "Transfection of siRNAs using Lipofectamine 2000 or Lipofectamine RNAiMAX (Invitrogen, Carlsbad, CA) was performed according to the manufacturer\\'s instructions. ", "The 21-nucleotide siRNA sequence for the non-specific control was 5′-AATTCTCCGAACGTGTCACGT-3′. The 21-nucleotide siRNA sequence for human Talpid3 is 5′-CAAAGTTACCTACGTGTTATT-3′.\n\n### Western blotting {#s4-3-6}\n\nFibroblasts were grown in DMEM supplemented with 10% FBS, grown to confluence, and subsequently serum starved for 72 hr to induce cilium growth. ", "Cells were lysed with ELB buffer (50 mM Hepes pH 7, 150 mM NaCl, 5 mM Ethylenediaminetetraacetic acid (EDTA)/pH 8, 0.1% NP-40, 1 mM Dithiothreitol (DTT) DTT, 0.5 mM 4- benzenesulfonyl fluoride hydrochloride (AEBSF), 2 μg/ml leupeptin, 2 μg/ml aprotinin, 10 mM NaF, 50 mM ß-glycerophosphate, and 10% glycerol) at 4°C for 30 min. ", "100 μg of lysate per sample in sample buffer was loaded on SDS-PAGE gels. ", "Proteins were transferred to a polyvinylidene difluoride (PVDF) membrane (GE Healthcare, Little Chalfont, UK) and blocked in 3% non-fat milk in Phosphate-buffered saline (PBS). ", "Rabbit polyclonal antibody against Talpid3 (dilution 1:1,000) ([@bib30]) and a mouse monoclonal antibody against α-tubulin (Sigma--Aldrich, dilution 1:5,000) were incubated overnight at 4°C.", "\n\nFunding Information\n===================\n\nThis paper was supported by the following grants:\n\n- http://dx.doi.org/10.13039/100000002National Institutes of Health (NIH) R01NS041537 to Joseph G Gleeson.", "\n\n- http://dx.doi.org/10.13039/501100000781European Research Council (ERC) 260888 to Enza Maria Valente.", "\n\n- http://dx.doi.org/10.13039/100000011Howard Hughes Medical Institute (HHMI) to Joseph G Gleeson.", "\n\n- http://dx.doi.org/10.13039/100000893Simons Foundation (SF) to Joseph G Gleeson.", "\n\n- http://dx.doi.org/10.13039/501100002426Fondazione Telethon (Telethon Foundation) to Enza Maria Valente.", "\n\n- http://dx.doi.org/10.13039/100000002National Institutes of Health (NIH) 1R01HD069647-03 to Sehyun Kim, Brian D Dynlacht.", "\n\n- http://dx.doi.org/10.13039/100000002National Institutes of Health (NIH) P03NS047101 to Joseph G Gleeson.", "\n\n- http://dx.doi.org/10.13039/100000002National Institutes of Health (NIH) P01HD070494 to Joseph G Gleeson.", "\n\n- http://dx.doi.org/10.13039/100000002National Institutes of Health (NIH) R01NS052455 to Joseph G Gleeson.", "\n\n- http://dx.doi.org/10.13039/100000002National Institutes of Health (NIH) R01NS048453 to Joseph G Gleeson.", "\n\n- http://dx.doi.org/10.13039/100000002National Institutes of Health (NIH) R01DK068306 to Friedhelm Hildebrandt.", "\n\nWe thank the affected children and their families for their invaluable contributions to this study, supported by National Institutes of Health grants (R01NS041537, R01NS048453, R01NS052455, P01HD070494, P30NS047101 to JG Gleeson; 1R01HD069647-03 to S Kim and BD Dynlacht and R01DK068308 to F Hildebrandt), the Howard Hughes Medical Institute, and Simons Foundation (JG Gleeson). ", "We thank the Broad Institute (U54HG003067 to E Lander), the Yale Center for Mendelian Disorders (U54HG006504 to R Lifton and M Gunel) for sequencing support. ", "This work was also partly supported by grants from the Italian Ministry of Health (Ricerca Corrente 2015 to EM Valente), the Telethon Foundation Italy (Grant GGP13146 to E Bertini and EM Valente), and the European Research Council (ERC Starting Grant 260888 to EM Valente).", "\n\nAdditional information {#s5}\n======================\n\nJGG: Reviewing editor, *eLife*.", "\n\nThe other authors declare that no competing interests exist.", "\n\nSR, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents.", "\n\nMH, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents.", "\n\nSK, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents.", "\n\nJGG, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents.", "\n\nES, Acquisition of data, Analysis and interpretation of data.", "\n\nBC, Acquisition of data, Analysis and interpretation of data.", "\n\nJLS, Acquisition of data, Analysis and interpretation of data.", "\n\nROR, Acquisition of data, Analysis and interpretation of data.", "\n\nJS, Acquisition of data, Analysis and interpretation of data.", "\n\nTM, Acquisition of data, Analysis and interpretation of data.", "\n\nEM, Acquisition of data, Analysis and interpretation of data.", "\n\nMSZ, Acquisition of data, Analysis and interpretation of data.", "\n\nKJS, Acquisition of data, Analysis and interpretation of data.", "\n\nJM-D, Acquisition of data, Analysis and interpretation of data.", "\n\nWBD, Acquisition of data, Analysis and interpretation of data.", "\n\nMAM, Acquisition of data, Analysis and interpretation of data.", "\n\nFİ, Acquisition of data, Analysis and interpretation of data.", "\n\nMA, Acquisition of data, Analysis and interpretation of data.", "\n\nRB, Acquisition of data, Analysis and interpretation of data.", "\n\nRR, Acquisition of data, Analysis and interpretation of data.", "\n\nR-MB, Acquisition of data, Analysis and interpretation of data.", "\n\nCLC, Acquisition of data, Analysis and interpretation of data.", "\n\nSD\\'A, Acquisition of data, Analysis and interpretation of data.", "\n\nPS, Acquisition of data, Analysis and interpretation of data.", "\n\nEB, Acquisition of data, Analysis and interpretation of data.", "\n\nFS, Acquisition of data, Analysis and interpretation of data.", "\n\nMM-B, Acquisition of data, Analysis and interpretation of data.", "\n\nIM, Acquisition of data, Analysis and interpretation of data.", "\n\nEB, Acquisition of data, Analysis and interpretation of data.", "\n\nFE, Acquisition of data, Analysis and interpretation of data.", "\n\nMS, Acquisition of data, Analysis and interpretation of data.", "\n\nFH, Acquisition of data, Analysis and interpretation of data.", "\n\nMF, Acquisition of data, Analysis and interpretation of data.", "\n\nKKV, Acquisition of data, Analysis and interpretation of data.", "\n\nSBG, Acquisition of data, Analysis and interpretation of data.", "\n\nMR, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article.", "\n\nCAJ, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article.", "\n\nBDD, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article.", "\n\nEMV, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article.", "\n\nPA-B, Conception and design, Acquisition of data, Analysis and interpretation of data.", "\n\nSH-G, Conception and design, Acquisition of data, Analysis and interpretation of data.", "\n\nTI, Conception and design, Acquisition of data.", "\n\nJEL, Conception and design, Acquisition of data.", "\n\nJK, Conception and design, Acquisition of data.", "\n\nHuman subjects: Consenting and sampling was performed on both parents and all available genetically informative siblings to include affected and unaffected members, as well as extended family members if appropriate, consistent with IRB guidelines approved by the ethical committee (JGE-0853) and according to the Declaration of Helsinki.", "\n\nAdditional files {#s6}\n================\n\n10.7554/eLife.06602.015\n\n###### \n\nParameter output genome-wide siRNA analysis screen. ", "Table listing all parameters used in the analysis of the genome wide siRNA screen.", "\n\n**DOI:** [http://dx.doi.org/10.7554/eLife.06602.015](10.7554/eLife.06602.015)\n\n10.7554/eLife.06602.016\n\n###### \n\nsiRNA experimental output based on 31 parameters. ", "Table listing all raw measurements based on the 31 parameters used in the analysis of the genome-wide siRNA screen in duplicate.", "\n\n**DOI:** [http://dx.doi.org/10.7554/eLife.06602.016](10.7554/eLife.06602.016)\n\n10.7554/eLife.06602.017\n\n###### \n\nThe CILIOGENESIS data set. (", "A) Whole genome table listing the rank of predicted ciliary genes and non-ciliary genes. (", "B) The CILIOGENESIS data set containing the genes predicted by the classifier to be ciliary. (", "A--B) Genes predicted by the classifier to be ciliary are color coded. ", "Green rows represents the genes with an FDR \\<0.01, yellow with FDR \\<0.1, orange with FDR \\<0.2, and the remainder (until FDR \\<0.267) is colored in dark orange. (", "C) Enrichment analysis by performing enrichment analysis with DAVID on the CILIOGENESIS database (excluding SCGCv1 genes). (", "D) Enrichment analysis with MsigDB (v4.0, gene sets from GO, KEGG and Reactome) on the CILIOGENESIS database (excluding SCGCv1 genes). (", "E) Enrichment analysis by performing enrichment analysis with MsigDB on the genes with FDR \\<0.01 within the CILIOGENESIS database (excluding SCGCv1 genes). (", "F) Enrichment analysis of hypergeometric gene set on MsigDB onto the true positive genes (SCGCv1 genes ranked within the CILIOGENESIS data set genes). (", "G) Gene set enrichment on MsigDB onto false negative genes (SCGCv1 genes ranked outside the CILIOGENESIS data set genes).", "\n\n**DOI:** [http://dx.doi.org/10.7554/eLife.06602.017](10.7554/eLife.06602.017)\n\n10.7554/eLife.06602.018\n\n###### \n\nClinical features and *KIAA0586* mutations. (", "A) Clinical features of individuals with *KIAA0586* mutations. (", "B) Nomenclature per isoform of the identified *KIAA0586* mutations.", "\n\n**DOI:** [http://dx.doi.org/10.7554/eLife.06602.018](10.7554/eLife.06602.018)\n\n10.7554/eLife.06602.019\n\n###### \n\nPrimers. (", "A) Primers for *KIAA0586* mutation confirmation and segregation analysis. (", "B) Primers for *KIAA0586* mRNA and expression analysis.", "\n\n**DOI:** [http://dx.doi.org/10.7554/eLife.06602.019](10.7554/eLife.06602.019)\n\nMajor datasets {#s6-1}\n--------------\n\nThe following previously published datasets were used:\n\nvan Dam TJ, Wheway G, Slaats GG, SYSCILIA Study Group, Huynen MA, Giles RH, 2013,The SYSCILIA gold standard (SCGSv1),<http://www.syscilia.org/goldstandard.shtml>,Publicly available at SYSCILIA (Accession no: 23725226).", "\n\nWishart DS, Jewison T, Guo AC, Wilson M, Knox C, Liu Y, Djoumbou Y, Mandal R, Aziat F, Dong E, Bouatra S, Sinelnikov I, Arndt D, Xia J, Liu P, Yallou F, Bjorndahl T, Perez-Pineiro R, Eisner R, Allen F, Neveu V, Greiner R, Scalbert A, 2013,HMDB 3.0--The Human Metabolome Database,[www.hmdb.ca](http://www.hmdb.ca),Publicly available at Human Metabolome Database (Accession no:23161693).", "\n\nBalestra FR, Strnad P, Flückiger I, Gönczy P, 2013,Centriole screen,<http://centriolescreen.vital-it.ch>,Publicly available at Centiole Screen (Accession no: 23769972).", "\n\nConsortium, 2013,The Genotype-Tissue Expression (GTEx) project,<http://www.gtexportal.org/home/>,Publicly available at Genotype-Tissue Expression (Accession no: 23715323).", "\n\n10.7554/eLife.06602.020\n\nDecision letter\n\nDietz\n\nHarry C\n\nReviewing editor\n\nJohns Hopkins University School of Medicine\n\n,\n\nUnited States\n\neLife posts the editorial decision letter and author response on a selection of the published articles (subject to the approval of the authors). ", "An edited version of the letter sent to the authors after peer review is shown, indicating the substantive concerns or comments; minor concerns are not usually shown. ", "Reviewers have the opportunity to discuss the decision before the letter is sent (see [review process](http://elifesciences.org/review-process)). ", "Similarly, the author response typically shows only responses to the major concerns raised by the reviewers.", "\n\nThank you for sending your work entitled \"A functional genome-wide siRNA screen identifies *KIAA0586* as mutated in Joubert syndrome\" for consideration at *eLife*. ", "Your article has been evaluated by Stylianos Antonarakis (Senior editor) and two reviewers, one of whom, Harry Dietz, is a member of our Board of Reviewing Editors.", "\n\nOverall, the manuscript was very favorably reviewed. ", "However, a number of points were raised that need to be addressed by reformatting or in the Discussion before final acceptance can be offered.", "\n\nThe Reviewing editor and the other reviewer discussed their comments before we reached this decision, and the Reviewing editor has assembled the following comments to help you prepare a revised submission.", "\n\nGiven the creative and seemingly focused nature of the primary functional screen, one is left wondering whether the application of the supervised learning approaches and training datasets has exacted too high a cost. ", "It seems notable that these filters resulted in exclusion of many known JS causative genes (that were present in the 1,952 candidates) from the prioritized dataset (235 genes). ", "In theory, these genes are indeed involved in ciliogenesis, but were excluded due to excessive filtering, a practice that might also limit or preclude the identification of genes with entirely novel ciliogenesis-related functions. ", "It is also notable that many other JS causative genes were not represented in the broader (functionally-determined) dataset. ", "While, in theory, this may relate to a contribution to ciliary function (as opposed to biogenesis), this is never specifically addressed. ", "There should be a more comprehensive and detailed consideration of both the apparently false-negative and false-positive inclusions in both the broader and restricted CILIOGENESIS datasets. ", "In this light, it is notable that the Discussion ends on a somewhat bland note. ", "There should be more about limitations and strengths of the CILIOGENESIS dataset and anticipated efforts toward improvement.", "\n\n10.7554/eLife.06602.021\n\nAuthor response\n\n*Given the creative and seemingly focused nature of the primary functional screen, one is left wondering whether the application of the supervised learning approaches and training datasets has exacted too high a cost. ", "It seems notable that these filters resulted in exclusion of many known JS causative genes (that were present in the 1,952 candidates) from the prioritized dataset (235 genes). ", "In theory, these genes are indeed involved in ciliogenesis, but were excluded due to excessive filtering, a practice that might also limit or preclude the identification of genes with entirely novel ciliogenesis-related functions. ", "It is also notable that many other JS causative genes were not represented in the broader (functionally-determined) dataset. ", "While, in theory, this may relate to a contribution to ciliary function (as opposed to biogenesis), this is never specifically addressed. ", "There should be a more comprehensive and detailed consideration of both the apparently false-negative and false-positive inclusions in both the broader and restricted CILIOGENESIS datasets. ", "In this light, it is notable that the Discussion ends on a somewhat bland note. ", "There should be more about limitations and strengths of the CILIOGENESIS dataset and anticipated efforts toward improvement*.", "\n\nWe would like to thank the reviewers for this careful comment. ", "To address this concern we have made concerted efforts at improving our overall classifier performance, which we are pleased to report proved extremely fruitful.", "\n\nThe improvement to our classifier is the result of a careful reanalysis of our feature processing approach. ", "First we removed multiple normalization steps, which negatively impacted the classifier performance and were the result of choices made early in the classifier development process. ", "These choices were appropriate when using supervised learning approaches, e.g. 'support vector machines', but were unnecessary and degraded performance when using random-forest a method based on scale invariant decision rules. ", "We observed a further improvement in classifier precision by retaining tissue specific expression information from GTex. ", "We excluded from analysis expression samples with low RNA quality score (RIN\\<6) leaving 2785 samples from 52 tissue types, including tissues from 10 different brain regions. ", "Processing each of these tissues in the same manner as was originally applied globally to the entire set we extracted a variable number of features from each tissue in order to capture 95% of variance in each tissue (median 4 features). ", "Finally, we included known JS candidate genes as positive examples in addition to the SCGSv1 set. ", "Overall these changes resulted in a modest improvement of AUC (0.84 to 0.86), but a substantial improvement to classifier precision and FDR: The improved CILIOGENESIS dataset consists of fewer overall genes flagged (1299 vs. 1925), but a larger set (591 vs. 204) high confidence ciliary genes (FDR \\<0.1). ", "This set includes 16 of the currently known JS genes, of which 5 are observed with a FDR\\<0.01, and 14 with FDR \\<0.1. ", "Furthermore, the revised set now includes over 26% of SCGSv1 genes in this list (up from 7%). ", "We note that in the previous version of our manuscript this number was incorrect.", "\n\nNext, to better understand the limitation of the supervised analysis we examined the set of true-positive (TP) and false-negative (FN) genes based on this classifier (i.e. the classifier recall performance). ", "The TP set of genes included all successfully detected examples, i.e. positive training samples (high confidence SCGCv1 and known JS) that were successfully detected by the classifier. ", "The FN set included the remaining positive examples that the classifier was unable to detect. ", "To characterize these sets we performed enrichment analysis of GO-terms as well as KEGG and Reactome pathways. ", "We observed that in the TP set significant terms included microtubule organizing center, centrosome organization and biogenesis, microtubule motor activity, and gamete generation. ", "Similar analysis on the FN set showed significant GO term enrichment for photoreceptor cell maintenance, sensory perception, Sonic hedgehog pathway and post-chaperonin tubulin folding pathway ([Supplementary file 3](#SD4-data){ref-type=\"supplementary-material\"}, sheet C and D). ", "This suggested that the CILIOGENESIS dataset was better able to detect genes involved in the process of ciliogenesis, whereas genes involved in ciliary function such as signaling were not as well represented. ", "Moreover, we performed an analysis of candidate targets involved in Hedgehog and WNT signaling from screens described in the literature and observed no statistically significant overlap with either the TP, FN or the CILIOGENESIS dataset ([Supplementary file 3](#SD4-data){ref-type=\"supplementary-material\"}, column O and P).", "\n\nUsing the newly created high confidence candidate set (FDR \\<0.1) we performed the same stringent analysis of the WES data. ", "While we observed new CILIOGENESIS candidate genes in which unexplained JS patients have exome variants, we believe that the careful interrogation of these new candidates is beyond the scope of this manuscript. ", "We are pleased that the revised process led to this improved methodology in flagging ciliary genes for the benefit of the field of ciliopathy research.", "\n\n[^1]: Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.", "\n\n[^2]: M; mutation; T; transcript. [", "Table 1---Source data 1](#SD1-data){ref-type=\"supplementary-material\"} shows chromatograms belonging to the identified mutations in the Mediterranean cohort.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "The technology platform has been provided by eye tracking expert SensoMotoric Instruments at CITEC.", "\n\nKai Essig , the Faculty of Psychology and Sports Research and also the Faculty of Technology and the initiative Bielefeld 2000plus STUDIES for the Region are also participating in the task. ", "Furthermore, the Institute for KNOW-HOW, GENERAL MARKET TRENDS, and Entrepreneurship , linked to the Faculty of Business Administration and Economics will provide advice in economic issues, conduct market analysis and prepare a marketing concept for the merchandise. ", "The v. Bodelschwingh Foundation Bethel, particularly proWerk Bethel and Altenhilfe Bethel, provides their know-how in diagnostics, actions assistance, and inclusion to the task. ", "The Foundation's strength in providing look after the elderly and handicapped, and also in integrating disabled people into the workforce produces an optimal research setting.", "Studies show that inadequate sleep is connected with declines in mental and physical health, decreased cognitive function and elevated obesity, she said in a university information release. ", "This new study shows that exposure to a natural environment can help people get the sleep they need. ", "More than 255,000 adults from over the USA were surveyed on the subject of their quality of rest in the last month. ", "Most said they slept fewer than seven nights during the month poorly. ", "But those that said they slept poorly on 21 to 29 nights were less likely to get access to green areas or other natural areas than those who said they slept poorly on fewer than seven nights." ]

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[ "[Postpartum mania induced by Bromocriptine: a case report].", "\nThe postpartum period is a high-risk period for occurrence of mood disorders (depression, mania) particularly for women with a history of bipolar disorder. ", "We report the case of a woman with a postpartum mania episode with psychotic features induced by bromocriptine. ", "This case report highlights the need to systematically explore the personal history of pregnant women in search of mood disorder which may proscribe use of bromocriptine." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "---\ntitle: Destinos de implementaciones\ndescription: Destinos de implementaciones\nposition: 2\ncategory: features\n---\n\n## Alojamiento Estático\n\nPara alojamiento estático (Alojamiento donde no se necesita un servidor) el destino de estatico tiene que ser añadido a tu archivo nuxt.config.", "\n\n```js{}[nuxt.config.js]\nexport default {\n target: 'static' // default is 'server'\n}\n```\n\nEjecutando nuxt dev con el destino estático va a mejorar la experiencia de desarrollo:\n\n- Remueve `req` & `res` de `context`\n- Fallback to client-side rendering on 404, errors and redirects [see SPA fallback](./guides/concepts/static-site-generation#spa-fallback)\n- `$route.query` will always be equal to `{}` on server-side rendering\n- `process.static` is true\n\n<base-alert type=\"info\">\nTambien estamos exponiendo `process.target`para los autores de módulos para añadir lógica dependiendo del destino.", "\n</base-alert>\n\n## Alojamiento de servidor\n\nPara el alojamiento en servidor el target server es usado, cual es el valor por defecto.", "\n\n```js{}[nuxt.config.js]\nexport default {\n target: 'server'\n}\n```\n" ]

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[ "Each Thursday we present a significant excerpt, usually from a recently published book or journal article. ", "In every case the proper permissions have been obtained. ", "If you are a publisher who would like to participate in this feature, please let us know via the site’s contact form.", "\n\nWhen the end came for the storied national law firm of Heenan Blaikie, it came abruptly. ", "On 5 February 2014, the firm issued an understated three-paragraph Press Release that tersely announced that its partners ‘have decided to proceed with an orderly wind-up of the Firm’s operations’.(1) The announcement came after a frenetic week with failed talks of restructuring, a proposed merger with DLA Piper and lawyers fleeing the firm. ", "Such a thing simply had never happened before in the history of the Canadian legal profession. ", "Yes, respected local firms like Goodman & Carr (Toronto) and Freeman and Company (Vancouver) had perished before, but never a national firm like Heenan Blaikie.", "\n\nHeenan Blaikie was an iconic Canadian law firm. ", "In many ways, it represented the Canadian ideal: bilingual and national with pretensions of an international presence. ", "Founded in 1973 in Montreal (2), it quickly established itself as one of the top law firms in Canada, although it was never able to break in to the inner echelon of the ‘Seven Sisters’, the premier Toronto-based law firms that hold the lion’s share of coveted corporate work in Canada. ", "However, Heenan Blaikie (often simply referred to as ‘Heenan’ or ‘Heenans’) was home to former Prime Ministers, a former Quebec Premier and retired judges of the highest courts including the Supreme Court of Canada.", "\n\nNear its peak, Heenan was the sixth largest law firm in Canada with over 500 lawyers in eight Canadian cities as well as an office in Paris (3). ", "It started to experience problems in 2012 with some partners leaving in dribs and drabs, but the collapse of the firm appears to be have been triggered by the announcement in early 2014 that income per partner had dropped by approximately 10 to 15 per cent. ", "This reportedly sparked a ‘run on the bank’ as more than 30 senior partners cashed in their partnership equity and moved to other law firms with their clients (4). ", "As one former Heenan partner so aptly put it, ‘The issue isn’t that Heenan was not profitable; the issue seems to be that it was not profitable enough for some … And that’s crazy.’ (", "5)\n\nIn this sense, the demise of Heenan Blaikie could be characterised as a tale of greed and of the death of law firm loyalty, both of lawyers to each other and of clients to the firm. ", "In the clash between law as a profession and law as business, does the death of Heenan Blaikie show that the idea of law as a profession is simply an anachronism from an age long past? ", "Perhaps. ", "But the acts of certain Heenan lawyers in the dying days show that it is not that easy. ", "By all accounts, while many partners took an ‘every man for himself ’ approach, some firm leaders like Kip Daechsel and Norm Bacal were desperately working to save the firm. ", "They and others stayed behind to ensure an ‘orderly wind-up’ of operations which translated into ensuring that clients, lawyers and staff were dealt with properly. ", "And here too the story is of varied shades of grey. ", "The Toronto office ensured that all current articling students and those scheduled to start articling in the summer found work at other law firms. ", "It is rumoured that partners at some other Heenan offices showed less concern for students. ", "And there were grumblings among staff, suddenly out of their jobs. (", "6)\n\nUltimately the answer as to why Heenan collapsed is complicated. ", "There are so many different explanations and potentially multiple contributing causal factors: the inability of a mid-tier large firm to compete in the Canadian legal market; the failure of the partnership model (7); a clash of cultures between the Toronto and Montreal offices (8); a failure in succession planning (9), etc. ", "In a bizarre turn, one commentator blamed law schools for Heenan’s fall, apparently on the theory that the market cannot absorb the number of Canadian legal graduates. (", "10)\n\nReferences:\n\n* Vice Dean Research and Associate Professor, Faculty of Law, University of Ottawa, Canada (Common Law Section). ", "Thanks to Malcolm Mercer and Alice Woolley for reading an earlier draft of this commentary and providing helpful comments. ", "All websites accessed April 2014." ]

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[ "Q:\n\nmondrian dimension cache not getting flushed\n\nI am trying to flush the mondrian dimension cache by following code - \n org.olap4j.metadata.", "Schema OlapSchema = olapConnection.getOlapSchema();\n NamedList<org.olap4j.metadata.", "Cube> cubeList = OlapSchema.getCubes();\n org.olap4j.metadata.", "Member m = null;\n for(org.olap4j.metadata.", "Cube cube: cubeList) {\n m = cube.lookupMember(IdentifierNode.parseIdentifier( \"[Time].[2013].[Jul2013]\").getSegmentList());\n final CacheControl cacheControl = olapConnection.getCacheControl(null);\n CacheControl.", "MemberSet regionTime = cacheControl.createMemberSet(mondrian.olap.", "Member)m, false);\n cacheControl.flush(regionTime);\n\n }\n\nBut this code is throwing a runtime error \"MondrianOlap4jMember and mondrian.olap.member are incompatible\"\n\nA:\n\nLooks like you need to do the following to flush the cache - \nunwrap the member object returned by lookupMember function using Olap wrapper class like so -\nm = cube.lookupMember(IdentifierNode.parseIdentifier( \"[Time].[2013].[Jul2013]\").getSegmentList());\nOlapWrapper wrapper = (OlapWrapper)m;\nmondrian.olap.", "Member MondrianMember = wrapper.unwrap(mondrian.olap.", "Member.class);\nAnd now call the flush method - \ncacheControl.flush(MondrianMember);\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "The spectroscopic (FT-IR, FT-Raman), MESP, first order hyperpolarizability, NBO analysis, HOMO and LUMO analysis of 1,5-dimethyl napthalene by density functional method.", "\nThe Fourier-transform infrared and FT-Raman spectra of 1,5-Dimethyl Napthalene (15DMN) was recorded in the region 4000-400cm(-1) and 3500-50cm(-1) respectively. ", "Quantum chemical calculations of energies, geometrical structure and vibrational wavenumbers of 6M2C were carried out by density functional theory (DFT/B3LYP) method with 6-311++G(d,p) basis set. ", "The difference between the observed and scaled wavenumber values of most of the fundamentals is very small. ", "The values of the total dipole moment (μ) and the first order hyperpolarizability (β) of the investigated compound were computed using B3LYP/6-311++G(d,p) calculations. ", "The calculated results also show that 15DMN might have microscopic non-linear optical, MESP, NBO analysis with non-zero values. ", "A detailed interpretation of infrared and Raman spectra of 15DMN is also reported. ", "The calculated HOMO7-LUMO energy gap shows that charge transfer occur within the molecule. ", "The molecular electrostatic potential map shows that the negative potential sites are on the electronegative atoms as well as the positive potential sites are around the hydrogen atoms." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Sampson Estwick\n\nSampson Estwick or Eastwick (c. 16571739), was an English musician.", "\n\nBirth\nEstwick was born about 1657, or earlier, if it be true that he was one of the first set of children of the Chapel Royal under Cooke, after the Restoration, and a chorister at St. Paul's Cathedral at the same early date.", "\n\nEducation\nHe proceeded B.A. at Christ Church, Oxford, in 1677, M.A. in 1680, and B.D. in 1692.", "\n\nBackground\nHis intimacy with Henry Aldrich, dean of Christ Church, gave rise to the line: ‘I prithee, Sam, fill,’ in Aldrich's famous Smoking Catch. ", "Estwick was probably too sympathetic and constant a frequenter of the rehearsals of music held weekly in the Dean's lodgings, to fall under the extreme penalty dealt unto delinquents by the genial host, namely; the restriction for the one evening to small beer, and exclusion from the next meeting.", "\n\nAldrich's management of the cathedral choir was excellent; Estwick is described by William Hayes, author of the Remarks on Mr Avison's Essay on Musical Expression (London, 1753), as a ‘remarkable instance of the effect of such a training. ", "He was not only an excellent and zealous performer in the choral duty until extreme old age rendered him incapable of it, but a remarkable fine reader also.’ ", "He became sixth Minor Prebend at St. Paul's Cathedral in 1692; senior cardinal, or Superintendent of the Choir, in November 1698, and Sacrist on the death of James Clifford in February 1698-9.", "\n\nEstwick was appointed vicar of St. Helen's, Bishopsgate, in 1701, and rector of St. Michael's, Queenhithe, in 1712, but he continued to perform his choral duty at the cathedral till near the time of his decease, ‘when little short of ninety years of age. . . . ", "Bending beneath the weight of years,’ Hawkins goes on to say, ‘but preserving his faculties, and even his voice, which was a deep bass, till the last, he constantly attended his duty at St. Paul's, habited in a surplice, and with his bald head covered with a black satin coif, with grey hair round the edge of it, exhibited a figure the most awful that can well be conceived.’", "\n\nDeath\nHe died on 16 February 1738-9. ", "The ‘reverend and truly venerable Mr. Estwick’ was regretted by the author of the Remarks as a ‘good man and worthy clergyman,’ while the ‘London Evening Post’ of 20 February bears witness to his ‘exemplary piety and orthodox principles.’ ", "Estwick was said by Hawkins to have been an unsuccessful candidate for Gresham Professor of Music. ", "He attended all the early meetmgs (from the first held in January 1725-6) of the Academy of Vocal Musick, and his name heads the list of contributors.", "\n\nHis sermon on ‘The Usefulness of Church Musick,’ preached at Christ Church, 27 November 1696, upon the occasion of the anniversary meeting of the lovers of music on St. Cecilia's day, was published in the same year by request of the stewards. ", "In the dedicatory letter, Estwick deplores the tendency of the age to ‘a neglect, if not a disuse, of church musick.’ ", "Another sermon delivered at St. Paul's, was published in 1698. ", "His manuscript music is preserved at the Music School, and at Christ Church Library, Oxford; it includes a motet, songs, and odes to be performed at the Acts.", "\n\nReferences\n\nCategory:1657 births\nCategory:1739 deaths\nCategory:17th-century English musicians\nCategory:18th-century English musicians\nCategory:English Christian religious leaders\nCategory:Alumni of Christ Church, Oxford\nCategory:Choristers" ]

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[ "Maha Amer\n\nMaha Amer (born 27 March 1999) is an Egyptian diver. ", "She competed in the women's three metre springboard event at the 2016 Summer Olympics.", "\n\nReferences\n\nCategory:1999 births\nCategory:Living people\nCategory:Egyptian female divers\nCategory:Olympic divers of Egypt\nCategory:Divers at the 2016 Summer Olympics\nCategory:Place of birth missing (living people)" ]

{ "pile_set_name": "Wikipedia (en)" }

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[ "All posts tagged carolina panthers\n\nAll of Reliant Stadium got into the red act for the Texans victory over the Jaguars on Sunday. ", "Photo by Getty Images\n\nThis week’s action in the NFL was a rare instance of more excitement with uniforms than their college counterparts.", "\n\nIt starts with the Houston Texans who used their alternate red in a victory over the Jacksonville Jaguars. ", "The best part of this was not the jersey itself, but the fact that the rest of the stadium went along with this red revolution.", "\n\nHouston must have gotten the word out to its fanbase of the uniform change because just about every fan in Reliant Stadium was going right along with their Texans in their red jerseys. ", "Even the end zones had a red shadow to the letters instead of the usual blue.", "\n\nOther teams, like the Jets, go with their alternate uniforms without changing anything else about their surrounding area. ", "The Texans got it right in this case with a total feeling of red throughout Reliant Stadium.", "\n\nThe look isn’t good or bad, but just average. ", "I prefer the normal blue uniform to this red look, but was very happy to see the rest of Houston going along with their team in the alternative direction.", "\n\nUsually this color coordination is seen in the NHL and NBA playoffs. ", "It seemed like just about every team in the NBA decided to go with this cool television effect this past postseason. ", "The Heat are known for their white outs including the white drapes over the empty courtside seats.", "\n\nWith that, time for the quick hits:\n\nA.J. Feeley and the rest of the Rams looked good and played even better against the Saints on Sunday. ", "Photo by Getty Images\n\nThe Rams went back to their glory days in the uniform department and on the field as they went to throwbacks for an upset of the Saints. ", "These uniforms are the best the Rams have ever worn, it was great to see them used again.", "\n\nCarolina continued to employ its powder blue home jerseys. ", "It makes me wonder if these have become the primary uniforms for the Panthers.", "\n\nThe Broncos also went with their alternate orange uniforms. ", "The orange harkens back to the Orange Crush and John Elway days. ", "The look is a bit jarring at first, but I think it definitely works for Denver.", "\n\nSunday’s NFL slate was billed as one of the least exciting of the season, and it lived up to the hype. ", "While Tim Tebow might have led another fourth-quarter comeback in Miami and the Jets and Chargers entertained us for a bit early on, it was a good thing the World Series was on that night.", "\n\nThe lack of excitement on the field was matched in the uniforms department. ", "With that said, we will immediately move to the quick hits:\n\nJonathan Stewart and the rest of the Panthers had a very good day against the Redskins in these light blue alternates. ", "Photo by Getty Images\n\nThe Panthers went with their alternate light blue jerseys in a victory against the Redskins. ", "This look works and certainly brings out the light blue outline on the silver helmets. ", "It also matches another football team that plays in North Carolina.", "\n\nMinnesota chose a throwback look for the second time this season in a close loss to the Packers, which is always nice to see.", "\n\nThe Saints dominated the Colts in white at home. ", "I had a sneaking suspicion New Orleans might go this route before the game, but was hoping it wouldn’t be right. ", "There was certainly no getting in the Saints way as their offense soared and Drew Brees ruined my perfect record in fantasy football.", "\n\nQuarterback Mark Sanchez and the Jets rolled in over the Jaguars yesterday in these stellar throwback New York Titans uniforms. ", "Photo by The Star-Ledger\n\nThis week in the NFL did not have too much action in the way of bold fashion statements. ", "The NFL has restrictions on uniforms, keeping teams to only two games in their alternate uniforms per season. ", "This makes sure there are no teams like Maryland or Oregon in the league where they play ……. ", "for pay (thanks, Mike Francesa).", "\n\nThe one team that did make people notice them for more than just their stellar play on the field in a dominant performance over the putrid Jacksonville Jaguars was the New York Jets. ", "As they have done in the past, the Jets went with these New York Titans throwback uniforms.", "\n\nOverall, these uniforms are pretty solid considering they are throwbacks. ", "I would not like them as permanent uniforms for any team.", "\n\nI am always a fan of stripes along the shoulders, which adds some solid detail to this otherwise simple uniform. ", "The same could be said for the white and blue stripes along the side of the gold/yellow pants (I really can’t decide what color they are).", "\n\nThe best feature here is the decidedly gold numbers. ", "They are simple and effective. ", "The absence of any kind of outline on the number helps it almost fade into the blue of the shirt and makes it clear these are throwbacks.", "\n\nLooking at the helmet also makes it clear the Jets have become the Titans for this particular game. ", "Again, the stripe is definitely gold which helps with the helmet. ", "Also, the lack of any writing on the sides of the helmets gives a clear indication it is a throwback.", "\n\nWhile the uniforms were stellar, the look of the field at MetLife Stadium and the surroundings all pointed to this being a Jets home game. ", "While I understand the New York Jets were actually the ones facing the Jaguars, I wish the people at the Meadowlands would have changed the end zone from the usual green coloring with white letters to a blue coloring with gold letters saying “Titans”. ", "It would have completed the day and made everything about the uniforms work.", "\n\nThe Chargers make some changes to their end zone when they go with the powder blues and it completes the entire look of the game. ", "The difference here is the Chargers play on natural grass while the Jets are on FieldTurf, which I imagine might cause some problems for a brand new end zone for just one game, but it would help immensely.", "\n\nBills running back Fred Jackson had a strong game and looked good while doing it in Buffalo's new home uniforms. ", "Photo by Getty Images\n\nThat’s all for the New York Titans, a few other teams made some uniform news so here are a few quick hits:\n\nThe Tennessee Titans went with white uniforms at home in their victory over the Ravens, one of my major pet peeves if you’re not the Dallas Cowboys or Miami Dolphins.", "\n\nThe Saints and Panthers also went with white at home. ", "I understand the move for the Panthers because it can be hot in North Carolina this time of year, but I still prefer the usual black uniforms or their alternate light blues. ", "However, the Saints choice just bothers me. ", "They play in a climate-controlled dome, why do you have to wear white at home?", "\n\nThe Bills debuted their new home uniforms in a thrilling victory over the Raiders that saw them score a touchdown on every possession in the second half. ", "I really like these uniforms for the most part, the only thing I could do without is how the stripe on the helmet gets wider at the back. ", "Why is it like that? ", "It ruins a nearly perfect uniform.", "\n\nAll right, enough for today. ", "Here’s a little preview of what is coming for the rest of the week, including what I hope to be a usual Tuesday staple of reviewing the uniform history of the teams featured on Monday Night Football:\n\nTuesday: A look at the Rams and Giants uniform transformations\n\nWednesday: End Zones, the chance for freedom in field design\n\nThursday: What’s Maryland wearing this week?", "\n\nFriday or Saturday: What uniforms have to do with the Red Sox collapse" ]

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[ "I[NTRODUCTION]{.smallcaps} {#sec1-1}\n==========================\n\nMetastatic carcinoma to the testes was first reported in the United States of America in 1938 and up until 2006, fewer than 200 cases have been reported globally.\\[[@ref1]\\] In Nigeria, three cases of metastatic carcinoma to the testes have so far been documented in the southern parts of the country following review of testicular tumors.\\[[@ref2][@ref3]\\] Metastatic carcinomas to the testes are rare with large autopsy series reporting an incidence of 0.06%.\\[[@ref4]\\] Common tumors metastasizing to the testes in adults are tumors of the prostate, lungs, gastrointestinal tract, melanomas, and kidneys.\\[[@ref5][@ref6]\\] Of these tumors, prostate adenocarcinoma is by far the most common tumor metastasizing to the testis in adults.\\[[@ref7]\\] Majority of the reports on testicular metastasis from prostatic adenocarcinoma have shown coexistence with metastasis to other sites. ", "However, a few authors reported isolated testicular metastasis from prostatic adenocarcinoma.\\[[@ref8]\\] We report a rare case of an isolated unilateral testicular metastasis from prostatic adenocarcinoma incidentally discovered following bilateral orchiectomy as part of hormonal treatment in an 84-year-old man with prostatic adenocarcinoma. ", "This is aimed to add to the few cases so far reported and to emphasize the need for proper evaluation of testes and paratesticular structures to exclude metastasis.", "\n\nC[ASE]{.smallcaps} R[EPORT]{.smallcaps} {#sec1-2}\n=======================================\n\nAn 82-year-old, presented with irritative and obstructive lower urinary tract symptoms for 1 year. ", "He had no other systemic symptoms or symptoms suggestive of metastasis. ", "Digital rectal examination revealed a hard, nodular, and asymmetrically enlarged prostate. ", "Other system examinations were all normal. ", "Serum prostate-specific antigen (PSA) was 25.78 ng/mL. Prostatic ultrasound shows an enlarged suspicious prostate with heterogeneous echo pattern; the prostatic capsule was irregular with obliterated median groove. ", "Chest and lumbosacral X-rays did not show evidence of metastasis as an abdominal ultrasound scan was also normal. ", "Tru-cut biopsy of the prostate gland reported prostatic adenocarcinoma with Gleason 2 + 3 \\[[Figure 1](#F1){ref-type=\"fig\"}\\]. ", "He was counseled and offered bilateral sub capsular orchiectomy as a form of androgen deprivation therapy. ", "Grossly, the left testis was fairly circumscribed and measure 4.5 cm × 3.5 cm × 2 cm cut surfaces were gray white-to-brown. ", "The right testicular biopsy was a spongy tissue flap measuring 7 cm × 6 cm × 2 cm. ", "Microscopically, the left testis showed infiltrating acini and glands lined by a single layer of atypical cells having hyperchromatic nuclei, infiltrating ghost of atrophied seminiferous tubules \\[[Figure 2](#F2){ref-type=\"fig\"}\\]. ", "The right testis showed seminiferous tubules containing cells of spermatogenic series at different stages of maturation having mildly hyalinized basement membranes. ", "Foci of unremarkable interstitial cells of Leydig were also present. ", "A diagnosis of the left testicular metastatic adenocarcinoma from prostatic adenocarcinoma with the right unremarkable testis was made.", "\n\n{#F1}\n\n{#F2}\n\nD[ISCUSSION]{.smallcaps} {#sec1-3}\n========================\n\nProstatic cancer is one of the most common cancer in men and the most common primary malignancy that metastasize to the testis. ", "Secondaries to the testis from prostatic adenocarcinoma are usually seen in the sixth and seventh decade, unlike primary testicular tumors which presents at relatively young age. ", "The case reported is an 84-year-old and was diagnosed with adenocarcinoma of the prostate before the orchiectomy. ", "In consonance with the observation in the index patient, studies have shown that metastatic tumor to the testis is usually unilateral and are discovered incidentally during autopsy or after therapeutic orchiectomies with some even presenting several years after prostatectomy.\\[[@ref9][@ref10]\\] However some patients may present with scrotal swelling and pain.", "\n\nThe mechanism of spread for prostatic carcinoma to the testis is not fully understood; however, suggested mechanisms include as follows: retrograde venous extension, arterial embolism, lymphatic extension, and endocanalicular spread.\\[[@ref11]\\] In cases of testicular metastasis coexisting with bony or visceral metastasis, a hematogenous pattern of spread can be speculated. ", "The index case, the lymphatic extension is perhaps the mechanism of spread due to the unique lymphatic connection between the prostate and the testis and the absence of other metastatic deposit. ", "The microscopic morphology of metastatic disease affecting the testicle usually affects the interstitium, sparing the seminiferous tubules. ", "Occasionally, atrophic seminiferous tubules may, however, be partially or completely invaded. ", "These features were all demonstrated in the index case.", "\n\nMost cases of prostatic carcinoma metastasizing to the testis are usually advanced. ", "They are associated with multiple metastatic deposits and high Gleason score of ≥8. ", "Few reported cases of isolated testicular metastasis from the prostate also have reported high Gleason score of ≥8. ", "On the contrary, the index case had an isolated testicular metastasis from prostatic carcinoma but with a Gleason score of 5.", "\n\nThe entire clinical workup for this patient did not suggest metastasis to any site. ", "Bone scintigraphy would have been more ideal to exclude bone metastasis; however, it is not available in our center and X-ray is used instead. ", "The chest and lumbosacral region are common sites for secondaries form prostatic adenocarcinomas. ", "X-rays of these regions have so far been worthy for patients presenting with advanced disease.", "\n\nThe prognostic value of testicular metastasis from prostatic carcinoma has been investigated in some few publications. ", "Some have suggested that it portends poor prognosis, while some other authors have reported otherwise. ", "The prognostic value of testicular metastasis from prostatic carcinoma has been investigated in some few publications. ", "Some have suggested that it portends poor prognosis. ", "However, some authors have reported otherwise, in a particular report of an isolated testicular metastasis from prostatic carcinoma patient had \\>5 years disease-free interval with undetectable PSA levels after orchiectomy.\\[[@ref12]\\] The prognostic value of testicular metastasis from prostatic carcinoma need to be evaluated further putting in to consideration confounding factors.", "\n\nC[ONCLUSION]{.smallcaps} {#sec1-4}\n========================\n\nTesticular metastasis is very rare with prostatic cancer as the most common primary malignancy. ", "Proper physical examination through specimen sampling and imaging of all the possible sites of metastasis are indispensable in the process of identifying metastasis.", "\n\nDeclaration of patient consent {#sec2-1}\n------------------------------\n\nThe authors certify that they have obtained all appropriate patient consent forms. ", "In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. ", "The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.", "\n\nFinancial support and sponsorship {#sec2-2}\n---------------------------------\n\nNil.", "\n\nConflicts of interest {#sec2-3}\n---------------------\n\nThere are no conflicts of interest.", "\n" ]

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[ "A few months ago, opening a mixed-gender literary cafe in Iraq's second city would have been unthinkable -- punishable by flogging or\n\nOpposite, the only wall not covered with bookshelves is instead host to a gallery of portraits -- medieval Iraqi poet Al-Mutanabbi is pictured alongside Palestinian Mahmoud Darwish and a series of abstract paintings.", "\n\nDrinking tea, coffee and juice, some smoke nargileh water pipes while an oud player takes the stage to accompany a poet about to read from his work.", "\n\nAt the \"Book Forum\" cafe, men and women, young and old, sit passionately debating literature, music, politics and history.", "\n\nLiterary cafes, poetry readings and pavement bookstalls -- Mosul's cultural scene is back in business, months after Iraqi forces ousted the Islamic State group from the city following three years of jihadist rule.", "\n\ndeath under IS rule.", "\n\nBut with the jihadists gone, Fahd Sabah and his partner have set about realising their dream.", "\n\n(photo by: Ahmad MUWAFAQ/AFP)\n\n\"While we lived under the yoke of IS, I told myself that it was an absolute must to open this place,\" Sabah said. \"", "There was a need to inform people, to enlighten minds, to bring new ideas.\"", "\n\nLike many young graduates in Iraq, the 30-year-old engineer had few prospects of finding employment.", "\n\nSo as soon as the jihadists were driven out of Mosul, he set about finding a venue and preparing to open a cafe, putting his savings into the venture. ", "Within a month, it was up and running.", "\n\nIt was worth the sacrifice, he said. ", "His project aims to create \"a new consciousness to overcome this terrible period and the damage left by the war\".", "\n\n'Reforming spirits'\n\nIraqis are renowned in the Arab world for their literary culture. ", "Mosul, capital of Nineveh province and sitting at the crossroads of ancient trading routes, long boasted a parade of booksellers along its famous Al-Nujaifi Street.", "\n\nBut IS methodically destroyed and burned books and destroyed libraries.", "\n\nAfter the jihadists were evicted six months ago, a handful of activists set up the \"Book Pavement\" market outside the city's battle-scarred university.", "\n\nAli Najam, 23, comes every Friday to scour the stalls of second-hand booksellers next to the concrete carcass of a building disemboweled by bombs.", "\n\nToday, he has picked up an English edition of \"Love in the Age of Cholera\" by Colombian Nobel Laureate Gabriel Garcia Marquez.", "\n\n\"People badly need culture and to build their consciousness after the hardships they went through,\" Najam said.", "\n\n(photo by: Ahmad MUWAFAQ/AFP)\n\n\"There's a need to rebuild people's spirits, which is even more important than rebuilding the houses and the city.\"", "\n\nYunis Mohammad, a 33\n\n-year-old writer, said that despite the destruction, \"Mosul will be rebuilt thanks to the brains of its young people, its intellectuals\".", "\n\nAbdelmonim al-Amir, head of Nineveh province's writers' union, said he wants the world, which associates Mosul with \"blood, destruction and desolation\", to know that the city has another face.", "\n\n\"Inhabitants and artists must make the human, cultural and academic dimensions of Mosul shine,\" he said.", "\n\nSo far, everything is being done on limited means, in a city devastated by war, crippled by unemployment and held back by the slow pace of reconstruction.", "\n\n(photo by: Ahmad MUWAFAQ/AFP)\n\n\"The public authorities in charge of culture must now do their duty,\" said writer Hamed al-Zubaidi.", "\n\nHind Ahmed, a 31-year-old engineer, said the mission was important to Iraq, which in December announced the \"liberation\" of the country and the \"end of the war\" against IS.", "\n\n\"Now the land has been liberated we must free minds and ideas,\" she said, dressed in a white veil dotted with butterflies over a beige coat.", "\n\nIraqis must \"give everyone the opportunity to participate,\" she added. \"", "Men and women.\"" ]

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[ "1. ", "Introduction\n===============\n\nSevere acute pancreatitis (SAP) is one of the most common acute severe diseases in clinical practice.^\\[[@R1]\\]^ At the early stage, an enormous release of inflammatory cytokines and toxins in the blood results in systemic inflammatory response syndrome (SIRS), which is the major cause of multiple organ dysfunction syndrome (MODS).", "\n\nAccording to the studies, SAP is a devastating disease that is associated with mortality ranging from less than 10% to as high as 85%.^\\[[@R2]--[@R9]\\]^ The main causes of this disease include gallbladder and biliary stone,^\\[[@R10]\\]^ hypertriglyceridemia, alcohol,^\\[[@R11]\\]^ pancreatic structure,^\\[[@R12]\\]^ and secondary AP.^\\[[@R13],[@R14]\\]^\n\nTherefore, efficacious clinical therapies to prevent disease progression and improve prognosis are urgently needed.", "\n\nIn recent years, with the increasing understanding of SAP disease mechanism, multiple studies have considered SAP as a severe SIRS resulting from pancreatic autodigestion; that is, inflammatory cells are activated to release significant amounts of cytokines, and its downstream reactions are critical to SAP progression.^\\[[@R15],[@R16]\\]^ SAP-induced ischemia, injury, necrosis and endotoxemia lead to increased levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (L-1β) in the circulation; and further induce IL-6 and IL-8 production. ", "This sequentially results in hypercytokinemia, SIRS, shock, loss of inner homeostasis, and organ dysfunction. ", "Therefore, preventing and blocking SIRS initiation and progression is a key in the treatment of SAP, and plays a critical role in the prevention and control of MODS initiation and development.^\\[[@R17]\\]^ At present, the therapeutic strategy for SAP has switched the priority from surgery to comprehensive treatment with nonsurgical methods, with use of short-term high-volume veno-venous hemofiltration, which has a beneficial impact on the management of SAP.^\\[[@R18]\\]^ High-volume hemofiltration (HVHF) can selectively eliminate serum molecules smaller than the pore size of the filter membrane used. ", "Indeed, important amount of cytokines released during SAP can be filtered out by HVHF. ", "In using HVHF to treat pig models of septic shock, it was found that hemofiltration at 6 L/h improved arterial pressure, cardiac output, and left and right ventricular diastolic function. ", "Some recent clinical reports have shown that HVHF relieves SAP symptoms, shortens the disease course, lowers mortality, and reduces hospitalization time.^\\[[@R19]\\]^\n\n2. ", "Materials and methods\n========================\n\n2.1. ", "Patients\n-------------\n\nPatients were recruited from December 2011 to December 2013 in this perspective, nonrandomized controlled trial, which was carried out in the First Affiliated Hospital of Xinjiang Medical University, Urimqi, China. ", "The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University, and informed consent was signed by patients and their families before the examination and treatment.", "\n\nInclusion criteria were as follows: SAP patients who were 25 to 77 years of age, duration from disease onset to hospitalization was within 48 hours, and disease progression to MODS with an APACHE II ranking of 7--34 and Balthazar CT staging between D and E. Exclusion criteria were as follows: acute renal failure before disease onset, pregnant women, and subjects with malignant tumors or immune defects. ", "Patients with chronic kidney disease requiring regular hemofiltration or those with known biliary obstruction were also excluded.", "\n\n2.2. ", "Diagnostic criteria\n------------------------\n\nSAP diagnosis in all patients was in line with the SAP diagnostic standards in the Draft criteria for diagnosis and treatment of acute pancreatitis in China (2014), which was established by The Academic Group of Pancreatic Disease, Branch Association of Digestive Disease, Chinese Medical Academic Association,^\\[[@R20]\\]^ and Atlanta classification of Acute Pancreatitis.^\\[[@R21]\\]^\n\nDuring hospitalization, MODS was evaluated based on the widely recognized Multiple Organ Dysfunction Score by Marshall et al.^\\[[@R22]\\]^ In brief, the functions of 5 major organs (lung, liver, kidney, hemodynamics, and awareness) were evaluated on a daily basis. ", "Scores ranged from 0 (no dysfunction) to 4 (severe dysfunction). ", "Scores 3 and 4 were considered to reflect organ dysfunction.", "\n\nThe diagnostic standards of biliary pancreatitis established by Fölsch et al. ", "were as follows: abdominal beta ultrasound and CT scan calculus were found; 2 of the statements (1) ALP ≥125 U/L, (2) ALT ≥75 U/L, and (3) TBIL ≥2.3 mg/dL were verified.^\\[[@R23]\\]^\n\n2.3. ", "Grouping\n-------------\n\nAccording to the parity of the hospitalization number, patients were prospectively divided into 2 groups. ", "The control group comprised of 22 patients. ", "Among these patients, 11 were male and 11 were female; and the average age of these patients was 50.55 ± 14.99 years. ", "The HVHF group comprised of 18 patients. ", "Among these patients, 14 were males and 4 were females; and the average age of these patients was 53.94 ± 16.46 years.", "\n\n2.4. ", "Treatment\n--------------\n\nThe patients in the control group underwent fasting, decompression, and continuous intravenous perfusion of somatostatin during their hospitalization. ", "Somatostatin (Stilamin, Serono Co., Ltd. Switzerland; 3000 μg in 48 mL of 5% glucose) was infused intravenously using a micropump at 4 mL/h, qd.^\\[[@R20]\\]^ For gastric acid neutralization, lansoprazole (Ao Wei Jia, Jiangsu Aosaikang Pharmaceutical Co., Ltd, China; 30 mg) + 0.9% sodium chloride (100 mL) were intravenously infused, bid. ", "For effective blood volume supplementation, lactated Ringer\\'s solution was chosen with priority. ", "Recovery standards were referred to the International Association of Pancreatology (IPA)/American Pancreatic Association (APA) evidence-based guidelines for the management of acute pancreatitis (2013).^\\[[@R24]\\]^ Patients orally took food together with nasogastric and enteral feeding for nutrition support. ", "Supplementary nutrition indices were according to the IPA/APA evidence-based guidelines for the management of acute pancreatitis (2013).^\\[[@R24]\\]^ The nutrition supply was evaluated and provided by specialized nutritionists of the Nutrition Department of our hospital. ", "These comprised of the following: fat emulsion, amino acids, and glucose injection (1440 mL) + vitamin C injection (2 g) + vitamin B6 injection (0.2 g) + 10% potassium chloride injection (40 mL) + 10% calcium gluconate injection (40 mL) + 10% sodium chloride injection (40 mL) + N(2)-L-alanyl-L-glutamine injection (10 g) + 2 fat-soluble vitamin II. ", "Enteral nutrition emulsions (TPF-D, 500 mL) were fed through nasogastric and enteral tubing, bid. ", "Antibiotic use was according to the IPA/APA evidence-based guidelines for the management of acute pancreatitis (2013)^\\[[@R24]\\]^ and the Draft criteria for the diagnosis and treatment of acute pancreatitis in China (2014), established by The Academic Group of Pancreatic Disease, Branch Association of Digestive Disease, Chinese Medical Academic Association.^\\[[@R20]\\]^ Antibiotic use was decided after consultation with clinical pharmacists in our hospital. ", "The antibiotics used included latamoxef sodium (Hainan Hailing Pharmaceutical Co. Ltd, China, 1.5 g, intravenous infusion, bid), imipenem (Merck and Dohme Corp.; 1 g, intravenous infusion, q8h), and cefotiam hydrochloride (Harbin Pharmaceutical Group; 2 g, q12h). ", "For the abdominal mirabilite pack, 500 g of mirabilite (Sichuan Chuanmei Mirabilite Co., Ltd., China) was packed in a special bag and placed on the surface of the projection of the pancreas. ", "The pack was changed every 8 to 12 hours.^\\[[@R20]\\]^\n\nPatients in the HVHF group received bedside HVHF treatment in addition to the treatment described for the control group. ", "HVHF therapy was performed using an IQ hemofiltration machine (Japan). ", "A double-lumen indwelling catheter was placed in the right femoral or subclavian vein to establish cardiopulmonary bypass. ", "The high-volume continuous veno-venous hemofiltration mode was selected, with a blood flow rate set to 200 to 300 mL/min. ", "The filter and tubules were preperfused with heparin saline (4000 U/L) for 20 minutes before hemofiltration using the set program. ", "Replacement fluid was pumped in at 3.0 to 4.0 L/h using the postdilution mode. ", "The electrolyte content and sodium bicarbonate amount used in the replacement fluid were adjusted according to blood gas analysis data and blood biochemistry tests. ", "The hemofiltration volume was determined through the load capacity of the patients, which varied between 2000 and 3500 mL, daily. ", "The hemofiltration lasted for ≥6 h/d, and the treatment between 4 and 9 days, with an average of 7 days. ", "HVHF was terminated when the heart rate dropped below 100/min, respiration rate dropped below 25/min, abdominal symptoms or signs disappeared, or when organ intubation was removed, or renal function restored.", "\n\n2.5. ", "Outcomes\n-------------\n\nPatient body temperature, heart rate, respiration rate, blood pressure, and SaO~2~ were monitored daily. ", "Body temperature of \\<37°C, respiration rate of \\<25/min, heart rate of \\<100/min, and SaO~2~ at \\>90% were considered normal. ", "Routine blood test, blood and urine amylase, electrolyte levels, hepatic and renal functions, and C-reactive protein (CRP) amounts were examined before HVHF, and at days 3 and 7 during treatment. ", "Abdominal signs in patients were carefully monitored daily. ", "For patients with severe SAP, especially in case of disease worsening, intra-abdominal pressure should be considered. ", "Intra-abdominal hypertension refers to the persistent or recurrent elevation of intra-abdominal pressure to \\>12 mm Hg. ", "This was measured by intravesical perfusion with saline. ", "In case of nonimprovement or worsening of clinical manifestations of SAP, beta-ultrasound, CT and MR examinations should be repeated when invasive operation is planned. ", "Changes in patient\\'s vital signs were recorded to monitor the progression process of disease, and the occurrence of complications and death. ", "Surgery and mortality rates, length of hospitalization, and procedure cost were evaluated.", "\n\n2.6. ", "Follow-ups\n---------------\n\nWhen patients were discharged, they were given heath related education and informed about the follow-ups, which were performed by phone, outpatient visit, and inpatient re-examination. ", "Patient follow-up included 3 aspects: the prevention of recurrence, and the evaluation and treatment of local and general complications. ", "Phone follow-ups were conducted by the authors once every other week for the first 3 months from discharge, and monthly thereafter. ", "Outpatient visits were performed once every 3 months. ", "Patients were followed-up for 2 years.", "\n\n2.7. ", "Statistics\n---------------\n\nData were presented as mean ± standard deviation (SD), and were analyzed using SPSS 17.0 software (SPSS, Chicago, IL). ", "Differences between both groups were assessed by *t*-test. ", "Count data were evaluated by *X*^*2*^-test. *", "P* \\< .05 was considered statistically significant.", "\n\n3. ", "Results\n==========\n\n3.1. ", "Patient baseline characteristics\n-------------------------------------\n\nThere were no significant differences between both groups in terms of age, gender, ethnicity, CT staging, and etiology parameters such as gall stone and alcohol rates, WBC, serum and urine amylase levels, and CRP, BUN, Cr, ALT, and AST amounts (all *P* \\> .05, Table [1](#T1){ref-type=\"table\"}).", "\n\n###### \n\nComparison of baseline information between the 2 groups.", "\n\n![](", "medi-97-e9417-g001)\n\n3.2. ", "HVHF treatment results in improved clinical outcomes\n---------------------------------------------------------\n\nHVHF treatment significantly reduced abdominal pain (49 ± 15 hours vs 74 ± 36 hours, *P* \\< .05) and abdominal tenderness (67 ± 19 hours vs 105 ± 37 hours, *P* \\< .05) relief times in patients, compared with the control group, as summarized in Table [2](#T2){ref-type=\"table\"}. ", "A similar trend was obtained for intubation times (123 ± 34 hours vs 165 ± 43 hours, *P* \\< .05), complication rates (11.1% vs 40.9%), surgery rates (16.7% vs 86.4%), death incidences (16.7% vs 31.8%), and average hospital stay (17.45 ± 6.32 days vs 25.32 ± 7.67 days), with all values markedly reduced in HVHF, compared with controls (all *P* \\< .05). ", "However, average hospitalization costs were similar between both groups (*P* \\> .05, Table [2](#T2){ref-type=\"table\"}).", "\n\n###### \n\nComparison of clinical outcomes between the 2 groups.", "\n\n![](", "medi-97-e9417-g002)\n\n3.3. ", "HVHF treatment results in improved clinical and grading indices\n--------------------------------------------------------------------\n\nBefore treatment, APACHE II scores in the 2 groups were not significantly different. ", "On day 3 of treatment, APACHE II scores of HVHF-treated patients were significantly lower than controls (6.3 ± 1.7 vs 9.2 ± 2.1, *P* \\< .05). ", "Although APACHE II scores decreased with time in both groups, the values obtained for HVHF-treated patients were still significantly lower than those of controls (3.3 ± 0.8 vs 6.2 ± 1.7, *P \\< *.05; Table [3](#T3){ref-type=\"table\"}).", "\n\n###### \n\nComparison of clinical data on day 3 and day 7 between the 2 groups.", "\n\n![](", "medi-97-e9417-g003)\n\nNormal body temperature, respiration, heart and SaO~2~ rates between both the groups were similar before treatment. ", "However, these values were all significantly higher in the HVHF group than in the control group at days three and 7 (*P \\< *.05), with sharper differences obtained at day 3 compared to day 7 (Table [3](#T3){ref-type=\"table\"}).", "\n\n3.4. ", "Dynamic changes of serum and urine amylase levels after treatment\n----------------------------------------------------------------------\n\nHVHF-treated patients and controls had similar serum amylase levels before treatment (*P \\> *.05). ", "On day 3, serum amylase levels of 243.1 ± 42.0 and 477.8 ± 117.7 U/L were obtained for patients in the HVHF and control groups, respectively; indicating a significant decrease after HVHF treatment (*P \\< *.05). ", "These values dropped in both groups at day 7 of treatment. ", "However, HVHF-treated patients revealed even lower serum amylase levels compared with controls (169.5 ± 84.3 vs 311.5 ± 13.4 U/L, *P \\< *.05). ", "Similarly, no significant differences were noted in urine amylase levels between HVHF-treated patients and controls (*P \\> *.05) before treatment. ", "On day 3 of treatment, urine amylase levels in the HVHF group were reduced compared with the control group; but the difference was not statistically significant (*P \\> *.05). ", "These values also decreased with time, but a more pronounced decrease occurred after treatment with HVHF, which resulted in a statistically significant difference between both groups (440.4 ± 390.4 vs 840.3 ± 227.0 U/L) at day 7 (Table [3](#T3){ref-type=\"table\"}).", "\n\n3.5. ", "Dynamic changes in white blood cells and CRP after treatment\n-----------------------------------------------------------------\n\nThere were no significant differences in white blood cell and CRP amounts between both groups before treatment (*P \\> *.05). ", "On day 3 of treatment, HVHF-treated patients revealed less white blood cells (9.57 ± 5.53 × 10^9^/L vs 10.97 ± 5.03 × 10^9^/L) and decreased CRP levels (157.9 ± 35.6 mg/L vs 172.3 ± 38.5 mg/L), than controls; but the differences were not statistically significant (*P \\> *.05). ", "However, these values dropped considerably in HVHF-treated patients, unlike the values in controls. ", "Indeed, compared with the control group, the HVHF group revealed significantly lower WBC amounts (7.71 ± 3.47 × 10^9^/L vs 10.12 ± 5.07 × 10^9^/L) and CRP levels (41.3 ± 22.1 mg/L vs 183.6 ± 42.5 mg/L) at day 7.", "\n\n3.6. ", "Dynamic changes of renal function after treatment\n------------------------------------------------------\n\nThere were no differences in renal function indicators such as BUN and Cr levels between controls and HVHF-treated patients before treatment. ", "On days 3 and 7 of the treatment period, HVHF-treated patients revealed significantly lower BUN (day 3, 7.1 ± 1.9 mM vs 11.6 ± 2.3 mM; day 7, 4.9 ± 0.7 mM vs 8.7 ± 1.4 mM; all *P \\< *.05) and Cr (day 3, 93 ± 23 mM vs 201 ± 43 mM; day 7, 79 ± 21 mM vs 175 ± 47 mM; all *P \\< *.05) than controls (Table [3](#T3){ref-type=\"table\"}).", "\n\n3.7. ", "Dynamic changes of hepatic function after treatment\n--------------------------------------------------------\n\nThere were no significant differences in ALT and AST levels between both groups before treatment (*P \\> *.05). ", "On day 3 of treatment, HVHF-treated patients revealed reduced ALT (109.27 ± 89.76 U/L vs 131.00 ± 21.07 U/L) and AST (102.79 ± 88.38 U/L vs 137.50 ± 28.65 U/L) levels compared with controls, but the differences were not statistically significant (*P \\> *.05). ", "However, these values markedly declined at day 7 in the HVHF group, unlike the values in control group. ", "This resulted in significant differences between both groups in ALT (51.69 ± 41.32 U/L vs 125.55 ± 22.89 U/L) and AST (69.75 ± 58.76 U/L vs 129.18 ± 19.33 U/L) levels.", "\n\n4. ", "Discussion\n=============\n\nSeveral parameters were used to compare controls with patients that received treatment supplemented with HVHF: APACHE II scores, serum, and urine amylase levels, WBC and CRP amounts, and hepatic and renal functions, mortality and complication rates, abdominal pain relief duration, abdominal tenderness relief duration, and hospitalization length. ", "We found that these indices all significantly improved in the HVHF group. ", "Meanwhile, no significant difference was found in treatment costs between both the groups.", "\n\nAfter HVHF, respiration, heart rate, and SaO~2~ worsening were controlled. ", "Among the 18 HVHF-treated patients, \\>11 patients recovered to normal levels in terms of body temperature, heart, respiration, and SaO~2~ rates at day 3 of treatment. ", "At day 7, almost all patients revealed normal values for these parameters in the HVHF group. ", "It is noteworthy to mention that these values were significantly higher compared with the values obtained for patients in the control group at both time points.", "\n\nIn addition, mortality and complication rates were very low in the HVHF group, while 2 to 3 patients' complications or death in the control group. ", "It was recently demonstrated that both somatostatin and octreotide appear to significantly reduce the mortality rate without any effect on the incidence of complications in SAP patients.^\\[[@R25]\\]^ In a large study that compared conservative treatment (with somatostatin) and surgical intervention, a cure rate of 82.29% and a mortality rate of 13.54% were obtained in the conservative group, with no statistically significant difference between both treatment groups.^\\[[@R26]\\]^\n\nAPACHE II scores are widely used for risk stratification of patients newly admitted to ICU. ", "While APACHE II has the problem of being less useful beyond 24 hours of admission, it is still closely related to the severity of SAP. ", "It has been reported that APACHE II scores may be evaluated daily to monitor the disease course and the response to therapy.^\\[[@R27]\\]^ In another study, researchers also pointed out that because SAP is a disease process in evolution, deteriorating APACHE II scores can identify patients who are highly likely to develop complications or a fatal outcome.^\\[[@R28]\\]^ Moreover, Khanna et al^\\[[@R29]\\]^ suggested that APACHE II score was a specific and accurate method to predict organ failure and mortality, with an accuracy of 83.3% for organ failure, and 100% sensitivity and NPV for mortality. ", "Therefore, we included APACHE II scores in the current study as an index to evaluate and compare outcomes of the patients in different groups. ", "In addition, HVHF alleviates local inflammatory response in lungs, reduces the permeability of epithelial cells in lung capillaries and alveolus, and ameliorates cardiac, pulmonary and renal functions. ", "Consequently, HVHF significantly lowered the APACHE II scores in SAP patients.", "\n\nCRP is a pentameric protein with a molecular weight of 120 kDa synthesized by the liver. ", "It promotes the production of inflammatory cytokines and enhances inflammatory response. ", "Hence, CRP level reflects the strength of the inflammatory response induced by various factors (injury, infection and necrosis) in vivo, and serves as a sensitive and reliable index for the diagnosis, treatment, and monitoring of inflammatory responses. ", "CRP is considered one of the key parameters for evaluating the severity of SAP.^\\[[@R30]\\]^ After 3 days, CRP did not significantly decline after HVHF. ", "However, at day 7, it significantly decreased and was close to normal values. ", "This could be related to the elimination of inflammatory cytokines such as IL-1β and TNF-α, as well as the alleviation of inflammatory responses. ", "The insignificant decrease observed at day 3 may be associated with the CRP peak after the initial insult.", "\n\nIt was reported that 50.9% to 76.3% of SAP cases die from MODS within 2 weeks of disease onset. ", "Among these cases, 33.3% to 49.1% were due to concurrent infections.^\\[[@R31]\\]^ Despite the great progress in intensive care and treatment during the past decades,^\\[[@R32]\\]^ the incidence of SAP death remains high.^\\[[@R33]\\]^ Blocking the reaction cascade by inflammatory mediators at the early stage and preventing infection has become the key in nonsurgery therapies to reduce death rates. ", "As shown above, hemofiltration can help SAP patients undergo the acute phase smoothly, increase the treatment success rate, reduce surgical intervention rate, and shorten the length of hospitalization. ", "Therefore, HVHF should be considered an important, effective, and safe treatment in the early stage SAP.", "\n\nAs for HVHF timing, once SAP is diagnosed, it should be performed as early as possible if no contraindications such as low blood pressure or severe bleeding tendency are present.^\\[[@R34]\\]^ We believe that it is necessary to perform HVHF within 48 hours of SAP diagnosis in line with SIRS standards, in order to control inflammatory response, improve disease progression, prevent organ dysfunction or its progression, increase success rate of rescue, and reduce complications.", "\n\nFinally, we compared the costs between both the control and HVHF groups, and found that there was no statistically significant difference; indicating that hemofiltration increases treatment value while maintaining its affordability.", "\n\nDue to clinical trial and ethics limitations, the sample size of this trial was small; and we were unable to conduct a randomized controlled study. ", "In addition, all patients were recruited and treated in the same center, with inherent bias. ", "Therefore, these findings need to be confirmed in larger and multicenter studies.", "\n\nIn summary, the comparison between control and HVHF-treated patients revealed that hemofiltration is a promising supplement for the treatment of SAP. ", "Indeed, HVHF efficacy and safety was demonstrated in this study, as well as its affordable cost. ", "Therefore, further studies should assess the possibility of broadly using HVHF in clinic to better tackle SAP and similar pathologies.", "\n\nAbbreviations: APA = American Pancreatic Association, CRP = C-reactive protein, HVHF = high-volume hemofiltration, IPA = International Association of Pancreatology, L-1β = interleukin-1β, MODS = multiple organ dysfunction syndrome, SAP = severe acute pancreatitis, SD = standard deviation, SIRS = systemic inflammatory response syndrome, TNF-α = tumor necrosis factor-α.", "\n\nThe authors have no funding and conflicts of interest to disclose.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Thrombolysis for acute ischaemic stroke with alteplase in an Asian population: results of the multicenter, multinational Safe Implementation of Thrombolysis in Stroke-Non-European Union World (SITS-NEW).", "\nSafe Implementation of Thrombolysis in Stroke-Non-European Union World was a multinational, prospective, open, monitored, observational study of intravenous alteplase as thrombolytic therapy in clinical practice. ", "Safe Implementation of Thrombolysis in Stroke-Non-European Union World was required to assess the safety of alteplase in an Asian population by comparison with results from the European Safe Implementation of Thrombolysis in Stroke-Monitoring Study and pooled results from randomized controlled trials. ", "To evaluate the efficacy and safety of intravenous alteplase (0·9 mg/kg) as thrombolytic therapy within three-hours of onset of acute ischaemic stroke in an Asian population. ", "The 591 patients included were treated at 48 centers in four countries (South Korea, China, India, and Singapore) between 2006 and 2008. ", "Primary outcomes were symptomatic (deterioration in National Institutes of Health Stroke Scale score ≥4 or death within the first 24 h) intracerebral haemorrhage type 2 22-36 h after the thrombolysis and mortality at three-month follow-up. ", "The secondary outcome was functional independence (modified Rankin Scale score 0-2) at three-months. ", "Results were compared with those from Safe Implementation of Thrombolysis in Stroke-Monitoring Study (n = 6483) and pooled results of patients (n = 415) who received intravenous alteplase (0·9 mg/kg) zero- to three-hours from onset of stroke symptoms in four randomized controlled trials (National Institute of Neurological Disorders and Stroke A and B, Altephase Thrombolysis for Acute Noninterventional Therapy in Ischaemic Stroke, and European Cooperative Acute Stroke Study II). ", "Results are presented as Safe Implementation of Thrombolysis in Stroke-Non-European Union World vs. Safe Implementation of Thrombolysis in Stroke-Monitoring Study vs. pooled randomized controlled trials. ", "Median age was 64 vs. 68 vs. 70 years, National Institutes of Health Stroke Scale score at baseline was 12 vs. 12 vs. 13, time from stroke onset to treatment was 130 vs. 140 vs. 135 mins, and females were 36·4% vs. 39·8% vs. 41·2%. ", "Main outcomes (proportion of patients and 95% confidence intervals) were symptomatic intracerebral haemorrhage: 1·9% (1·1-3·3) vs. 1·7% (1·4-2·0) vs. 3·1% (1·8-5·3); mortality: 10·2% (8·0-12·9) vs. 11·3% (10·5-12·1) vs. 16·4% (13·1-20·3); and functional independence: 62·5% (58·5-66·4) vs. 54·8% (53·5-56·0) vs. 50·1% (45·3-54·9) at three-months. ", "Adjusted odds ratio (95% confidence intervals) between Safe Implementation of Thrombolysis in Stroke-Non-European Union World and Safe Implementation of Thrombolysis in Stroke-Monitoring Study, and between Safe Implementation of Thrombolysis in Stroke-Non-European Union World and the pooled trials were 1·83 (0·89-3·77; P = 0·1156) and 0·63 (0·19-2·07; P = 0·4470) for symptomatic intracerebral haemorrhage, 0·90 (0·64-1·25; P = 0·5092) and 0·93 (0·52-1·64; P = 0·7915) for mortality at three-months, and 1·57 (1·25-1·96; P < 0·0001) and 1·35 (0·91-2·00; P = 0·1325) for functional independence. ", "These data demonstrate the safety and efficacy of the standard dose of intravenous alteplase (0·9 mg/kg) in an Asian population, as previously observed in the European population studied in Safe Implementation of Thrombolysis in Stroke-Monitoring Study and the populations in pooled randomized controlled trials, when used in routine clinical practice within three-hours of stroke onset. ", "The findings should encourage wider use of thrombolytic therapy in Asian countries for suitable patients treated in stroke centers." ]

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[ "The U.S. National Security Agency has lost the legal authority to collect telephone records after the Senate failed to agree Sunday on an extension of several provisions put in place following the September 11, 2001 terror attacks.", "\n\nThe once-secret program that collected information such as the phone numbers, date and duration of calls to try to thwart suspected terrorists drew criticism from Americans who said it violated their privacy.", "\n\nA new law, already passed by the House of Representatives, would modify the program to allow the NSA to request that data from phone companies on a case-by-case basis, but not collect it on its own. ", "The Senate did not approve the measure before the surveillance program expired at midnight Sunday, but could still pass the bill later this week.", "\n\nWhite House spokesman Josh Earnest said late Sunday that the Senate needs to act quickly to address what he called an \"irresponsible lapse.\" ", "He said the new program is a \"reasonable compromise balancing security and privacy.\"", "\n\nWithout the new bill, the NSA has also been forced to at least temporarily shut down two other programs, including a \"lone wolf\" tracking provision that has never been used and a roaming wiretap program.", "\n\nEarlier Sunday, Central Intelligence Director John Brennan urged the Senate to pass the new authorization, warning that terrorists were looking to take advantage of any gap in the spying effort.", "\n\n\"Terrorist elements have watched very carefully what has happened here in the United States,\" Brennan said in an appearance on CBS's Face the Nation. \"", "Whether or not it’s disclosures of classified information, or whether it’s changes in the law and policies, they’re looking for the seams to operate within. ", "This is something that we can’t afford to deal with right now, because if you look at the horrific terrorist attacks and violence that’s being perpetrated around the globe, we need to keep our country safe.”", "\n\nSenator Rand Paul, who is running for president in 2016, led the opposition against the surveillance program, using the Senate's rules to delay a final vote for several days and thus allow the provisions to expire.", "\n\nBut other lawmakers accused him of exploiting the issue for political gain, including Senator John McCain, who said Paul places a \"higher priority on his fundraising and his ambitions than on the security of the nation.", "\n\nObama urges Senate to approve USA Freedom Act\n\nPresident Barack Obama strongly urged the Senate to approve the House-passed USA Freedom Act, which he said was being blocked by \"a handful of senators.\"", "\n\nWATCH: President Barack Obama discusses USA Freedom Act in weekly address\n\n\"I don't want us to be in a situation in which, for a certain period of time, those authorities go away and suddenly we're dark,\" Obama said. \"", "And, heaven forbid we've got a problem where we could have prevented a terrorist attack or apprehended someone who was engaged in dangerous activity but we didn't do so simply because of inaction in the Senate.\"", "\n\nSurveillance Provisions to Expire Sunday\n\nUnusual alliances\n\nThe debate over whether to renew some of the NSA surveillance powers is cutting across the usual political divides between Democrats and Republicans, creating rare alliances.", "\n\nOn Friday, the American Civil Liberties Union joined with the Tea Party Patriots conservative group to call for the Senate to let the provisions expire, saying the government had overreached with its data collection and had violated Americans’ right to privacy.", "\n\nVOA's Cindy Saine contributed to this report from Capitol Hill.", "\n\nWATCH: Debate over surveillance measures comes down to the wire" ]

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[ "Image copyright Getty Images Image caption Deutsche Bank boss John Cryan is looking for ways to return the firm to profitability\n\nChinese conglomerate HNA has overtaken Blackrock to become Deutsche Bank's biggest shareholder after increasing its stake in the firm to nearly 10%.", "\n\nHNA became a major shareholder in Europe's largest investment bank after acquiring a 4.8% stake in March.", "\n\nIts financial unit, HNA Capital, reportedly has ambitions of becoming a global investment bank.", "\n\nDeutsche Bank has been looking to raise funds after incurring major losses due to legal probes and misconduct charges.", "\n\nEarlier this year, the German lender abandoned plans to sell its Postbank unit and sold 8bn euros ($8.8bn) of shares instead.", "\n\nHNA, which is privately run by billionaire Chen Feng, has been on a major acquisition spree in recent years.", "\n\nThe Chinese group owns stakes in a range of companies including Hainan airlines, hotel operator Hilton Worldwide and Singapore-listed logistics firm CWT." ]

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[ "The US Air Force (USAF) has successfully integrated F-22 Raptors with F-16 Fighting Falcons during a live, virtual and constructive (LVC) training event.", "\n\nFour live F-16s and two virtual F-22 Raptors were connected by Northrop Grumman's LVC experimentation, integration and operations suite (LEXIOS) system.", "\n\nThrough LEXIOS, virtual aircraft operated by actual aircrew members participate in the same airspace alongside their live counterparts via networked simulators at full security levels, Northrop said in a statement.", "\n\nNorthrop Grumman Mission Systems satellite and network operations director Martin J. Amen said: \"No aircraft goes to war alone.", "\n\n\"With our increasingly joint and networked approach, fighter integration training is extremely consequential to effective execution in combat.", "\n\n\"Although Distant Frontier is a small-scale training event, with this achievement Northrop Grumman has demonstrated that we can provide full-spectrum combat training and truly transform the way pilots train to fight.\"", "\n\nThe air-to-air combat training exercise was conducted at the USAF's Joint Pacific Alaska Range Complex.", "\n\nThe F-16 aircraft were from the Air Force's 80th Fighter Squadron based at Kunsan Air Base, Korea, operating out of Eielson Air Force Base, while F-22s were operated by 90th Fighter Squadron members from simulators at Joint Base Elmendorf–Richardson in Anchorage.", "\n\n\"With our increasingly joint and networked approach, fighter integration training is extremely consequential to effective execution in combat.\"", "\n\nEielson Air Force Base 354th Operations Group commander colonel Brian E. Toth said: \"The 353rd Combat Training Squadron with great support from Northrop Grumman is spearheading efforts to integrate LVC elements into day-to-day training.", "\n\n“As adversaries continually improve their capabilities, the ability to add LVC is critical to best train and prepare F-22 pilots for dealing with the full complement and degree of threats.”", "\n\nNorthrop Grumman is the prime contractor for the USAF's distributed mission operations network (DMON), which allows dissimilar aircraft platforms located across the globe to seamlessly interoperate and train together in a realistic virtual environment.", "\n\nImage: A F-22 Raptor tactical fighter aircraft in flight. ", "Photo: courtesy of Rob Shenk." ]

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