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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." ]

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[ "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." ]

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[ "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." ]

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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" ]

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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." ]

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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)" ]

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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." ]

{ "pile_set_name": "PubMed Abstracts" }

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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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[ "1. ", "Field of the Invention\nThe invention relates to clamping and/or transporting of paper, particularly stacks of paper in which, after a printing or copying operation, the stack of paper is to be transported to a treatment station, such as stapling or binding device. ", "The invention is particularly desirable in the context of a copying or printing machine, in which, after copying, a stack of sheets are received in a bin, with the stack then clamped and transported to a binding device in the clamped condition.", "\n2. ", "Discussion of Background\nOften, a copying machine or printing apparatus will include a suitable device for binding or attaching a stack of sheets to one another after completion of the copying or printing process. ", "For example, a stapling device or a perforating/binding device can be provided, with a clamp holding the stack of sheets during the binding operation.", "\nFIG. ", "7 shows an example of a paper clamping arrangement as disclosed in Japanese Laid-Open Patent Publication No. ", "2-23154/1990. ", "The clamping apparatus includes a fixed support portion 100, with a clamping assembly designated generally at 110. ", "The clamping assembly 110 can be reciprocated forwardly and backwardly in the direction indicated by arrows and A and B. Mounted upon the support 100 is a motor 101, a pair of gears 102, 103 for reducing the rotational speed of the motor 101 and changing the direction of rotation, as well as a screw or threaded shaft 105 for transmitting the rotation of the motor 101 to the clamping assembly 110 via an intermediate movable bar 104 having a threaded hole therein. ", "As the motor rotates, the shaft 105 causes the bar 104 to translate, thereby causing translation of the clamping assembly 110 connected thereto.", "\nAs also shown in FIG. ", "7, the clamping assembly 110 includes a pair of clamp levers 111, 112 for clamping a stack of sheets which are discharged onto the bin 120 in the direction indicated by arrow C. The upper clamp lever 111 is mounted upon the assembly 110 such that it is movable to effect a clamping operation, while the lower clamp lever 112 is fixed. ", "Further, the upper clamp lever 111 is resiliently biased into a release position via spring 113, with the clamp 111 driven to effect clamping by a solenoid 114. ", "Thus, during actuation of the solenoid, the clamp 111 is moved downwardly, and upon release of the solenoid, the spring 113 causes a release of the clamp.", "\nIn operation of the clamping arrangement shown in FIG. ", "7, the motor 101 rotates in order to rotate the threaded shaft 105, thus moving the bar 104 and clamping assembly 110 to a forward grasping position. ", "Power is then supplied to the solenoid 114, and a stack of sheets located on the bin 120 is clamped by the clamp levers 111, 112. ", "Thereafter, the motor 101 rotates in a reverse direction to retract the clamping assembly to a treatment position at which a stapling or binding operation takes place. ", "The binding apparatus (not shown in FIG. ", "7) is disposed at the side of the clamp apparatus, and performs the binding operation when the clamping assembly is in the retracted and clamped condition. ", "Thereafter, the motor 101 rotates to advance the clamping assembly, with the solenoid 114 then released, thereby returning the bound stack of sheets to the bin. ", "The clamping assembly 110 then retreats to a waiting position for the next binding operation.", "\nAlthough only a single bin 120 is shown in FIG. ", "7, typically, plural bins are arranged which are parallel to one another, and which are stacked vertically. ", "The clamping apparatus and the subsequent treatment unit (e.g., a binding apparatus) are movable up and down to service the plural bins.", "\nIn the arrangement as shown in FIG. ", "7, a cumbersome design is required since the mounting of the binding apparatus must accommodate for the clamping assembly. ", "The arrangement becomes more inconvenient when it is desirable to bind a stack of sheets at more than one location, since the binding apparatus is required to move from a first binding location to a second binding location, and such movement can be obstructed by the clamping assembly. ", "Accordingly, the clamping arrangement as shown in FIG. ", "7 severely limits the flexibility of subsequent treatment operations, such as binding operations, or at least, greatly complicates such binding operations. ", "Moreover, the clamping assembly as shown in FIG. ", "7 is generally only suitable for carrying the stack of sheets in forward and backward reciprocating movement, thereby limiting the options available for placement of the binding apparatus. ", "For example, if the FIG. ", "7 arrangement were utilized to transport a stack of sheets in a direction perpendicular to arrows A-B, the sheets can become skewed, resulting in an unacceptable bound stack.", "\nAccordingly, an improved clamping and transporting arrangement is needed which can conveniently and reliably transport a stack of sheets from a first location, such as in a bin, to a second location at which a binding operation can be easily effected. ", "Such an arrangement should be capable of securely clamping and moving a stack of sheets, without allowing the sheets to move relative to one another or become jumbled, while being able to present the stack of sheets to a variety of subsequent treatment apparatus, such as a binding device which can bind the stack of sheets at one or more locations. ", "In addition, the clamping and transport assembly should be relatively simple, without requiring numerous driving arrangements and/or control systems to synchronize the various movements required for moving the clamping assembly, effecting a clamping operation, and transporting a clamped stack of sheets to a binding device. ", "Further, the clamping assembly should be capable of sustaining moment forces as the stack of sheets are transported, without allowing any of the sheets of the stack to become skewed which would result in an unsatisfactory binding operation." ]

{ "pile_set_name": "USPTO Backgrounds" }

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[ "The safety observer effect: the effects of conducting safety observations.", "\nSome research suggests that conducting safety observations of another's safety performance may serve as an effective tool in increasing the safety performance of the observer. ", "The primary purpose of the present study was to assess the effects of conducting safety observations on the postural safety performance of observers engaging in an assembly task for short time periods. ", "The secondary objectives of the study were: (a) to measure productivity, and (b) to measure the accuracy of participant safety observations. ", "An ABC (A: baseline, B: information, C: observation) multiple-baseline design counterbalanced across postural behaviors (back, shoulder, and feet position) was implemented with six participants. ", "Substantial improvements in postural safety occurred after participants conducted safety observations, and these improvements did not appear to negatively affect productivity. ", "Results also suggest that there is no relation between the accuracy of an observer's safety observation and their subsequent safety performance. ", "This research provides evidence that a safety observation process can function to increase safe postural behavior of observers. ", "Thus, the implementation of such a process may contribute to the prevention of musculoskeletal disorders and related costs in the workplace." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Don Roach\n\nDonald Vivian Roach (31 July 1940 – 3 July 2011) was an Australian rules footballer who played for in the Victorian Football League (VFL) and for West Adelaide and Norwood Football Clubs in the South Australian National Football League (SANFL).", "\n\nRoach, a left footed flanker, played his early football at SANFL club West Adelaide, for whom he debuted in 1958 and won the SANFL premiership in 1961. ", "He moved to Melbourne in 1964 VFL season and joined Hawthorn but only stayed for two seasons playing 33 games for the Hawks.", "\n\nIn 1966 he returned to West Adelaide and was appointed captain-coach. ", "That same year he represented South Australia at the Hobart Carnival, his second interstate carnival having competed in the 1961 Brisbane Carnival. ", "He was selected into the All-Australian team for his efforts in Brisbane.", "\n\nAfter taking a break from the game in 1969 Roach returned to action the following season at his new club Norwood where he would finish his career. ", "When Roach retired in 1972 his final tally of games in the SANFL amounted to 204 and he also represented South Australia on nine occasions. ", "He went on to serve the league as an administrator.", "\n\nDon Roach was an inaugural member of the South Australian Football Hall of Fame in 2002, and he is also a member of the West Adelaide Football Club Hall of Fame.", "\n\nReferences\n\nHolmesby, Russell and Main, Jim (2007). ", "The Encyclopedia of AFL Footballers. ", "7th ed. ", "Melbourne: Bas Publishing.", "\n\nExternal links\n\nCategory:1940 births\nCategory:Australian rules footballers from South Australia\nCategory:Hawthorn Football Club players\nCategory:West Adelaide Football Club players\nCategory:West Adelaide Football Club coaches\nCategory:Norwood Football Club players\nCategory:All-Australians (1953–1988)\nCategory:South Australian Football Hall of Fame inductees\nCategory:2011 deaths" ]

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[ "So why the name Blupela? ", "Actually it is just a cool name we came up with. ", "But it also means Blue Bird of Paradise in Papua New Guinea. ", "It is a bird that is endangered and protected and it serves thus to show you our values here at One World Blue, LLC. ", "Blupela is the brand name and One World Blue is the corporation. ", "We work for good things in and around the world. ", "Protecting the environment is one thing we believe in.", "\nSo why One World Blue? ", "Well what do you see when looking from the moon at the Earth? ", "Does that answer your question? ", "Originally founded in 2005, One World Blue, LLC, has been building something online that is different from all the rest because we care and we are bringing goodness to the Earth with the quality projects and profiles you will see on our network.", "\nBlupela.com is the Social Network for Social Change of The One World Blue Good Network. ", "We are a revolutionary social media and crowdfunding platform that promotes initiatives and profiles for changing and healing the world one good deed at a time. ", "We also serve as a global, moderated forum to promote the sharing of ideas related to peace in our world, the betterment of our planet and its ecosystems, and the celebration and appreciation of cultural diversity.", "\nOne World Blue will become the go to destination for anyone wanting to do good online and in the marketplace. ", "Blupela.com is a site where users can put their Good Initiatives and Profiles online and accept funding, time, and goods as well as allow people the ability to communicate and chat about the initiatives, projects and profiles.", "\nOne World Blue is committed to social harmony, the support and education of wholesome and healthy ecosystems, protection of wildlife and the Earth's resources, and the appreciation and celebration of diversity. ", "One World Blue believes in equality for all human beings and we may be branded The One World Blue Good Network, the Social Network for Social Change.", "\n\nStandPart with One World Blue, LLC to connect and show activity on your Nest\n\nShow on your Nest when One World Blue, LLC: Funds an Initiative Each Comment (on a Cause or a Profile) Summary of Comments (1 notification per Cause or Profile per day) Summary of Recieved comments on Profile (1 notification per day) Lifts (Votes) Creates a Cause Connects with someone Is Connected by someone\n\nHide this Connection (not recommened).What's this?The list of who you connected to, and who connected with you, is normally public. ", "This can help you and others find like minded or interesting people to connect with. ", "But if necessary you can hide this connection, and it will not be visible to anyone, not even the person you are connecting to.", "\n\n\"I take the Kassam, the instrument of death and I change it, I transfer it into something of beauty.\"", "\n\n\"...And they shall beat swords into plowshares...\" (Isaiah 2:4)\n\nYaron Bob, is an art teacher and blacksmith who lives in Yated, a small Israeli community near the border with the Gaza strip.", "\n\nYaron Bob, a teacher and a part-time metal sculptor in Moshav Yated, Israel, makes roses out of Kassam rockets fired out of Gaza.", "\n\nMr. Bob had two close calls with rockets and he knew he needed to react to the terror that he and his community were facing.", "\n\nYaron wanted to create something that speaks of growth and prosperity and to make something out of the destruction and of the ruin of the Kassam.", "\n\nThe truth is because the rocket is an instrument of death he really didn't want to handle it.", "\n\nHowever, his frustration was intensifying with so many missiles falling on Israel and so many alarms.", "\n\nThe situation was very stressful on him and his family. \"", "It finally struck me that I need to make a rose from the Kassam\", Yaron says. ", "Now. ", "Bob collects the spent rockets, most given to him by the police, after they have been checked by the bomb squad.", "\n\nIsraeli Artist Creates Beauty from War Materials\n\nEach rose takes about three to four hours of turning and twisting the steel. ", "Then, hand sculpting intricate petals and leaves on the rose. ", "The sculpture's base is a map of Israel with the rose growing out of the border with Gaza.", "\n\nAlthough the rose, stem and base are made of Kassam remains, there is no sign the flower comes from rocket metal.", "\n\n\"I take the Kassam, the instrument of death and I change it, I transfer it into something of beauty.\"", "\n\nBob is not a pacifist, but he would like Hamas to know talking is better than firing rockets and starting a war.", "\n\nHis goal is to somehow let the world know people in Israel are not hungry for war and what they really want is a bright and beautiful future.", "\n\nTo learn more or to purchase a menorah and Stand with Sderot, please visit:" ]

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[ "Idiotypic and immunochemical differences of anti-DNA antibodies of a lupus patient during active and inactive disease.", "\nIgG anti-DNA antibodies of a lupus patient during active and inactive stages of her disease were studied. ", "There were no significant differences in the amounts, in double-stranded DNA-binding activity, or in complement-fixing ability between purified IgG anti-DNA antibodies of both stages. ", "However, their idiotype (Id) expressions were different as revealed by binding to rabbit anti-Ids raised against each of the anti-DNA antibodies. ", "Moreover, the active stage anti-DNA antibodies had higher activity and less cross-reactivity with polynucleotides. ", "Dominant anti-DNA populations during the active and inactive stages of systemic lupus erythematosus are clonally and qualitatively different." ]

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[ "Michael Jordan's longtime personal residence in suburban Chicago is for sale for $29 million. ", "That includes nine bedrooms, 15 baths and five fireplaces. ", "There's also a three-bedroom guesthouse, pool area, outdoor tennis court and three climate-controlled multi-car garages.", "\nFull story...\n\nAuthorities say a 35-year-old male runner who collapsed during the Chicago Marathon is dead. ", "Race medical director Dr. George Chiampas says the North Carolina man collapsed about 500 yards from the finish line. ", "He says medical personnel were able to get his heart beating again but he died 1 hour, 45 minutes after he was attended to at the race.", "\nFull story..." ]

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[ "Midwest Swing with Brandon Warne\n\nMidwest Swing takes a look at baseball from a flyover country perspective. ", "With up-and-coming baseball writer Brandon Warne and a cast of different characters, Midwest Swing will look to keep it light, but still informative and interesting as it pertains to this great game\nFollow Brandon on Twitter @Brandon_Warne https://twitter.com/Brandon_Warne\nPart of the Cold Omaha Podcast Network\nVisit http://coldomaha.com/podcasts for more Minnesota-Centric Sports Audio Goodness.", "\n\nCategories\n\nCold Omaha's Brandon Warne and Tom Schreier get Drew Rucinski, a recent minor-league signing, on the line to talk about his major league experience, growing up in Wisconsin, playing at Ohio State and more -- plus some Twins offseason talk.", "\n\nMike Berardino (Pioneer Press) joins Cold Omaha's Brandon Warne to discuss happenings at the Winter Meetings and what a potential Brian Dozier trade would look like before going over Brandon's list of potential veteran suitors for the Twins.", "\n\nDustin Nosler (@DustinNosler) of Dodgers Digest joins to discuss a potential Brian Dozier trade from the L.A. side of things, then Brandon Warne breaks down Winter Meetings news with Tom Schreier to end the show.", "\n\nMike Berardino (Pioneer Press) joins Cold Omaha's Brandon Warne and Tom Schreier to talk about the Minnesota Twins adding Torii Hunter, Michael Cuddyer and LaTroy Hawkins as special assistants, plus what Minnesota would have to receive in a Brian Dozier deal and other offseason moves they could make.", "\n\nBrandon Warne is joined by Josh Kusnick, MLB agent who represents Michael Brantley of the Cleveland Indians, Seth Lugo of the New York Mets and many others to discuss the day in the life of a typical agent, Winter Meetings procedures and many other topics.", "\n\nChris from Cleveland joins Cold Omaha's Brandon Warne and Tom Schreier to discuss the World Series from an Indians fan's perspective, then Mike Berardino of the Pioneer Press jumped on to break down the Falvey and Lavine hires and the Minnesota Twins offseason.", "\n\nChris from Cleveland calls in to discuss the Indians' chances in the World Series and what the city is like now that the Cavaliers have won a championship, then Mike Berardino of the Pioneer Press gets on the horn (15:00) to talk about what the Twins can do to turn things around in the offseason.", "\n\nFollow Brandon on Twitter (@Brandon_Warne) https://twitter.com/Brandon_Warne Visit the Website: http://www.brandonwarne.com/ Subscribe to Podcast on iTunes: https://itunes.apple.com/us/podcast/midwestswing2s-podcast/id1073026341?mt=2 Get the Show on Stitcher! ", "http://stitcher.com/s?fid=81063&refid=stpr\n\nMusic for Midwest Swing is created by & produced by deeB. To hear more of his tracks, check out http://soundcloud.com/deeb\n\nMike Berardino of the Pioneer Press calls in from Detroit where he's covering the Twins series against the Tigers, but due to some technical difficulties it sounds like he's calling in from space.", "\n\nHe and Brandon talk about Dozier's 40th home run, the Twins GM search and more.", "\n\nAll that and more on this edition of Midwest Swing!", "\n\nA Cold Omaha Podcast Network Production\n\nFollow Brandon on Twitter (@Brandon_Warne) https://twitter.com/Brandon_Warne Visit the Website: http://www.brandonwarne.com/ Subscribe to Podcast on iTunes: https://itunes.apple.com/us/podcast/midwestswing2s-podcast/id1073026341?mt=2 Get the Show on Stitcher! ", "http://stitcher.com/s?fid=81063&refid=stpr\n\nMusic for Midwest Swing is created by & produced by deeB. To hear more of his tracks, check out http://soundcloud.com/deeb\n\nMike Berardino of the Pioneer Press returns for a second straight week to break down Brian Dozier, Jose Berrios, September call ups and the Twins executive search.", "\n\nAll that and more on this edition of Midwest Swing!", "\n\nA Cold Omaha Podcast Network Production\n\nFollow Brandon on Twitter (@Brandon_Warne) https://twitter.com/Brandon_Warne Visit the Website: http://www.brandonwarne.com/ Subscribe to Podcast on iTunes: https://itunes.apple.com/us/podcast/midwestswing2s-podcast/id1073026341?mt=2 Get the Show on Stitcher! ", "http://stitcher.com/s?fid=81063&refid=stpr\n\nMusic for Midwest Swing is created by & produced by deeB. To hear more of his tracks, check out http://soundcloud.com/deeb\n\nBrandon and Tom talk to Mike Berardino of the Pioneer Press about the Twins 11 game losing streak, whether Paul Molitor's future is in jeopardy and how the roster might look down the stretch of what has been an underwhelming season.", "\n\nAll that and more on this edition of Midwest Swing!", "\n\nA Cold Omaha Podcast Network Production\n\nFollow Brandon on Twitter (@Brandon_Warne) https://twitter.com/Brandon_Warne Visit the Website: http://www.brandonwarne.com/ Subscribe to Podcast on iTunes: https://itunes.apple.com/us/podcast/midwestswing2s-podcast/id1073026341?mt=2 Get the Show on Stitcher! ", "http://stitcher.com/s?fid=81063&refid=stpr\n\nMusic for Midwest Swing is created by & produced by deeB. To hear more of his tracks, check out http://soundcloud.com/deeb\n\nFollow Brandon on Twitter (@Brandon_Warne) https://twitter.com/Brandon_Warne Visit the Website: http://www.brandonwarne.com/ Subscribe to Podcast on iTunes: https://itunes.apple.com/us/podcast/midwestswing2s-podcast/id1073026341?mt=2 Get the Show on Stitcher! ", "http://stitcher.com/s?fid=81063&refid=stpr\n\nMusic for Midwest Swing is created by & produced by deeB. To hear more of his tracks, check out http://soundcloud.com/deeb\n\nMike Berardino (Pioneer Press) joins Cold Omaha's Brandon Warne and Tom Schreier to talk about players that could be traded either at the wavier deadline or in the offseason.", "\n\nAll that and more on this edition of Midwest Swing!", "\n\nA Cold Omaha Podcast Network Production\n\nFollow Brandon on Twitter (@Brandon_Warne) https://twitter.com/Brandon_Warne Visit the Website: http://www.brandonwarne.com/ Subscribe to Podcast on iTunes: https://itunes.apple.com/us/podcast/midwestswing2s-podcast/id1073026341?mt=2 Get the Show on Stitcher! ", "http://stitcher.com/s?fid=81063&refid=stpr\n\nMusic for Midwest Swing is created by & produced by deeB. To hear more of his tracks, check out http://soundcloud.com/deeb\n\nJeremy Nygaard, minor league and draft contributor to Twins Daily, joins Cold Omaha's Brandon Warne and Tom Schreier to break down the top prospects in the Minnesota Twins minor league system.", "\n\nAll that and more on this edition of Midwest Swing!", "\n\nA Cold Omaha Podcast Network Production\n\nFollow Brandon on Twitter (@Brandon_Warne) https://twitter.com/Brandon_Warne Visit the Website: http://www.brandonwarne.com/ Subscribe to Podcast on iTunes: https://itunes.apple.com/us/podcast/midwestswing2s-podcast/id1073026341?mt=2 Get the Show on Stitcher! ", "http://stitcher.com/s?fid=81063&refid=stpr\n\nMusic for Midwest Swing is created by & produced by deeB. To hear more of his tracks, check out http://soundcloud.com/deeb\n\nMike Berardino of the Pioneer Press joins the program to break down big nights from Jose Berrios, Jorge Polanco and of course, Max Kepler. ", "There's also a ton of trade deadline fallout, not only from deals that did get done, but also those that did not.", "\n\nAll that and more on this edition of Midwest Swing!", "\n\nA Cold Omaha Podcast Network Production\n\nFollow Brandon on Twitter (@Brandon_Warne) https://twitter.com/Brandon_Warne Visit the Website: http://www.brandonwarne.com/ Subscribe to Podcast on iTunes: https://itunes.apple.com/us/podcast/midwestswing2s-podcast/id1073026341?mt=2 Get the Show on Stitcher! ", "http://stitcher.com/s?fid=81063&refid=stpr\n\nMusic for Midwest Swing is created by & produced by deeB. To hear more of his tracks, check out http://soundcloud.com/deeb\n\nBen Duronio (@Ben_Duronio) of Rotographs joins the program to talk all things Atlanta Braves as they're in town to start a quick two-game set with the Twins. ", "They also sneak in a little Aroldis Chapman talk as well as some trade deadline chatter.", "\n\nAll that and more on this edition of Midwest Swing!", "\n\nA Cold Omaha Podcast Network Production\n\nFollow Brandon on Twitter (@Brandon_Warne) https://twitter.com/Brandon_Warne Visit the Website: http://www.brandonwarne.com/ Subscribe to Podcast on iTunes: https://itunes.apple.com/us/podcast/midwestswing2s-podcast/id1073026341?mt=2 Get the Show on Stitcher! ", "http://stitcher.com/s?fid=81063&refid=stpr\n\nMusic for Midwest Swing is created by & produced by deeB. To hear more of his tracks, check out http://soundcloud.com/deeb\n\nMike Berardino (Pioneer Press) joins Brandon Warne and Tom Schreier to discuss the Minnesota Twins decision to relieve Terry Ryan of his duties and who should replace him.", "\n\nAll that and more on this edition of Midwest Swing!", "\n\nA Cold Omaha Podcast Network Production\n\nFollow Brandon on Twitter (@Brandon_Warne) https://twitter.com/Brandon_Warne Visit the Website: http://www.brandonwarne.com/ Subscribe to Podcast on iTunes: https://itunes.apple.com/us/podcast/midwestswing2s-podcast/id1073026341?mt=2 Get the Show on Stitcher! ", "http://stitcher.com/s?fid=81063&refid=stpr\n\nMusic for Midwest Swing is created by & produced by deeB. To hear more of his tracks, check out http://soundcloud.com/deeb\n\nChris Cwik (@Chris_Cwik) of Big League Stew (Yahoo! ", "Sports) joins to program to talk his White Sox fandom, the Home Run Derby and break down the hottest -- and not so hot -- teams at the All-Star Break.", "\n\nAll that and more on this edition of Midwest Swing!", "\n\nA Cold Omaha Podcast Network Production\n\nFollow Brandon on Twitter (@Brandon_Warne) https://twitter.com/Brandon_Warne Visit the Website: http://www.brandonwarne.com/ Subscribe to Podcast on iTunes: https://itunes.apple.com/us/podcast/midwestswing2s-podcast/id1073026341?mt=2 Get the Show on Stitcher! ", "http://stitcher.com/s?fid=81063&refid=stpr\n\nMusic for Midwest Swing is created by & produced by deeB. To hear more of his tracks, check out http://soundcloud.com/deeb\n\nBrandon is joined by ColdOmaha.com's Zach Wright and Tom Schreier in the studio, and Mike Berardino calls in from the Pioneer Press to chat about the flurry of moves made by the Twins over the last 48 hours or so. ", "The guys also get into some T-Wolves and Wild offseason talk at the end.", "\n\nBe sure to follow Brandon (@Brandon_Warne), Tom (@tschreier3) and Mike (@MikeBerardino) on Twitter, as well as the whole Cold Omaha Crew (@ColdOmahaMN).", "\n\nAll that and more on this edition of Midwest Swing!", "\n\nA Cold Omaha Podcast Network Production\n\nFollow Brandon on Twitter (@Brandon_Warne) https://twitter.com/Brandon_Warne Visit the Website: http://www.brandonwarne.com/ Subscribe to Podcast on iTunes: https://itunes.apple.com/us/podcast/midwestswing2s-podcast/id1073026341?mt=2 Get the Show on Stitcher! ", "http://stitcher.com/s?fid=81063&refid=stpr\n\nMusic for Midwest Swing is created by & produced by deeB. To hear more of his tracks, check out http://soundcloud.com/deeb\n\nBrandon and Tom are joined by Dan Hayes of CSN Chicago for the first half of the program to talk about the upcoming series between the Twins and the White Sox, and in the second half #oldfriend Matt Trueblood of Baseball Prospectus and BP Wrigleyville joined the program to talk about the world-beating Cubs team.", "\n\nMike Berardino of the Pioneer Press joins the program to talk all things Twins, with a little bit of NBA Finals talk mixed in.", "\n\nAll that and more on this edition of Midwest Swing!", "\n\nA Cold Omaha Podcast Network Production\n\nFollow Brandon on Twitter (@Brandon_Warne) https://twitter.com/Brandon_Warne Visit the Website: http://www.brandonwarne.com/ Subscribe to Podcast on iTunes: https://itunes.apple.com/us/podcast/midwestswing2s-podcast/id1073026341?mt=2 Get the Show on Stitcher! ", "http://stitcher.com/s?fid=81063&refid=stpr\n\nMusic for Midwest Swing is created by & produced by deeB. To hear more of his tracks, check out http://soundcloud.com/deeb" ]

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[ "September 2014\n\nCBS46 News has confirmed the Centers for Disease Control has issued guidelines to U.S. funeral homes on how to handle the remains of Ebola patients. ", "If the outbreak of the potentially deadly virus is in West Africa, why are funeral homes in America being given guidelines? ", "The three-page list of recommendations include instructing funeral workers to wear protective equipment when dealing with the remains since Ebola can be transmitted in postmortem care. ", "It also instructs to avoid autopsies and embalming. ", "Alysia English is Executive Director of the Georgia Funeral Directors Association, the oldest and largest funeral association in Georgia. ", "Georgia is comprised of 700 funeral homes and 2,000 funeral directors. ", "CBS46 asked English if Georgians should be alarmed by these guidelines. “", "Absolutely not. ", "In fact, if they weren’t hearing about it, they should be a whole lot more concerned,” said English. ", "She said Georgia has one of the country’s most thorough public health plans. ", "That includes detailed planning for all hazards such as floods and the flu. “", "If you were in the middle of a flood or gas leak, that’s not the time to figure out how to turn it off. ", "You want to know all of that in advance. ", "This is no different,” said English. – ", "CBS46" ]

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[ "Atty. ", "Paul King\n\n(Editor's note: The following information was released by Tewksbury Police and the Office of Middlesex DA Marian Ryan.)", "\n\nTEWKSBURY – Middlesex District Attorney Marian Ryan, Tewksbury Chief of Police Timothy Sheehan and Billerica Chief of Police Daniel Rosa have confirmed that a 15-year-old male has been arrested and charged with threatening use of a dangerous weapon and threatening to commit a crime in connection with allegedly distributing a snapchat video that depicted him holding a weapon that looked like an assault rifle and threatening to commit a school shooting.", "\n\nThat weapon was later determined by police to be an airsoft rifle that shoots BBs.", "\n\nMonday, at approximately 10:34 p.m. police responded to a Tewksbury home at the request of the juvenile’s mother who had located a video that depicted the male showing the airsoft rifle in an attempt to make it appear real and making threatening remarks. ", "Police located the video and subsequently located the airsoft rifle and another airsoft handgun and took possession of them. ", "No firearms were located in the home.", "\n\nThe juvenile is a student at Shawsheen Valley Regional Vocational Technical High School. ", "The preliminary investigation suggests the video was distributed to four students at the school.", "\n\nInvestigators do not believe this video was circulated beyond these students; however they encourage anyone with information or who may have seen the video to contact Tewksbury Police at (978-851-7373).", "\n\nInvestigators are not aware of any existing threat to the school. ", "The community may notice an increased police presence at the school today. ", "This is out of an abundance of caution and to ensure police are available to address any remaining concerns of students, parents, school officials and the community. ", "The student is in a supervised situation today and is not on the Shawsheen Valley Regional Vocational Technical High School campus.", "\n\nThe student will be arraigned in Lowell Juvenile Court today. ", "With the exception of youthful offender cases, juvenile court proceedings are closed to the public.", "\n\nAl Fresca Ristorante\n\n\n\n" ]

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[ "Structural basis for the carbohydrate recognition of the Sclerotium rolfsii lectin.", "\nThe crystal structure of a novel fungal lectin from Sclerotium rolfsii (SRL) in its free form and in complex with N-acetyl-d-galactosamine (GalNAc) and N-acetyl- d -glucosamine (GlcNAc) has been determined at 1.1 A, 2.0 A, and 1.7 A resolution, respectively. ", "The protein structure is composed of two beta-sheets, which consist of four and six beta-strands, connected by two alpha-helices. ", "Sequence and structural comparisons reveal that SRL is the third member of a newly identified family of fungal lectins, which includes lectins from Agaricus bisporus and Xerocomus chrysenteron that share a high degree of structural similarity and carbohydrate specificity. ", "The data for the free SRL are the highest resolution data for any protein of this family. ", "The crystal structures of the SRL in complex with two carbohydrates, GalNAc and GlcNAc, which differ only in the configuration of a single epimeric hydroxyl group, provide the structural basis for its carbohydrate specificity. ", "SRL has two distinct carbohydrate-binding sites, a primary and a secondary. ", "GalNAc binds at the primary site, whereas GlcNAc binds only at the secondary site. ", "Thus, SRL has the ability to recognize and probably bind at the same time two different carbohydrate structures. ", "Structural comparison to Agaricus bisporus lectin-carbohydrate complexes reveals that the primary site is also able to bind the Thomsen-Friedenreich antigen (Galbeta1-->3GalNAc-alpha- glycan structures) whereas the secondary site cannot. ", "The features of the molecular recognition at the two sites are described in detail." ]

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[ "A pilot study on early versus delayed hypertonic saline dextran resuscitation in a porcine model of near-lethal liver injury: early hemodynamic response and short-term survival.", "\nWe studied the effects of early versus delayed fluid resuscitation on hemodynamic response and short-term survival in a porcine model of severe hepatic injury associated with hemorrhagic shock. ", "Eighteen anesthetized swine were randomized after standardized liver injury into two groups: early resuscitation (ER, n = 9) and delayed resuscitation (DR, n = 9). ", "The ER and DR groups were resuscitated with hypertonic saline dextran (HSD) 20 min and 40 min after the injury, respectively. ", "Mean arterial pressure (MAP), cardiac output (CO), and arterial blood gases were measured in addition to vascular blood flow rates in the aorta, hepatic artery and portal vein. ", "The duration of follow-up was 100 min. ", "MAP decreased from 112 +/- 4 to 23 +/- 2 mmHg (P < 0.05) during 20 min after the injury. ", "Bolus infusion of HSD significantly elevated MAP, CO, and flow rates in the aorta, portal vein and common hepatic artery in both groups. ", "Portal vein flow remained relatively high during the shock. ", "Intra-abdominal bleeding (ER, 701 +/- 42 mL; DR 757 +/- 78 mL) and the mortality rate (ER 44%; DR 33%) did not differ between the groups 100 min after injury (P > 0.05). ", "Aortic flow, portal vein flow, common hepatic artery flow, MAP, CO, PaO(2), PaCO(2), base deficit, pH, hemoglobin measurements, and the volume of blood shed into the intraperitoneal cavity did not affect survival in the Cox regression analysis. ", "Early versus delayed fluid infusion with HSD resulted in a comparable hemodynamic response and survival 100 min after injury. ", "No rebleeding was observed." ]

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[ "From Hipster Bonfire Portraits to Inspirational Quote Posters\n\nBy: Courtney Scharf - Published: Jan 29, 2013\n\nToday's trends were dominated by products and creations that were something to behold. ", "Visually striking posters, editorials and architecture all found a place in the top 20, and seemed to really resonate with readers.", "\n\nTwo innovative poster series were popular today. ", "Dope Prints, a series of cleverly designed move posters, featured symbolic icons to represent quotes from movies like The Social Network and The Godfather. ", "Each print had somewhat of a gritty feel, adding to the appeal of these creative designs. ", "Ben Fearley, on the other hand, uses his typographical skills to create incredibly inspirational posters with popular quotes.", "\n\nThe Przelany Armchair, which looks like it's made of spilled liquid, grabbed the attention of many readers for its odd design, showing that the desire for unusual interiors is still very much alive. ", "If you're looking for insights into interesting design products, check out Trend Hunter's Design Trend Report.", "\nStats for Top Trends of the Day Trending: Older & BuzzingTraction:5,509 clicks in 130 w Interest: 1.5 minutes Concept: Inspirational QuoteRelated: 224 examples / 172 photosSegment: Neutral, 18-55+\nComparison Set: 82 similar articles, including: inspirational quote posters, sublime mod portraits, and iconic film quote posters." ]

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[ "**Apoptosis** is molecularly regulated and genetically programmed cell death. ", "A range of environmental, physical or chemical stresses can induce it. ", "It is characterised by a sequence of precisely regulated events that culminate in self-destruction of a cell. ", "Apoptosis is a common phenomenon in developmental processes and in normal physiological conditions when unnecessary cells have to be eliminated. ", "Apoptosis is also the predominant form of cell death triggered by cytotoxic drugs in tumour cells. ", "There are many biochemical and genetic parallels between cell death pathways in different animal species.", "\n\nMethods of cellular survival under the stressful environmental conditions are also genetically programmed and mediated by the activity of physiological defence mechanisms. ", "That is another, even more conserved and evolutionarily ancient cellular response. ", "This response is mediated by the **heat shock proteins (Hsp).**", "\n\n**Hsp** is a highly conserved family of proteins that play a major role in cytoprotection. ", "However, apoptosis that is induced to eliminate unwanted, damaged or old cells may be understood as another way of protecting tissues, from the great changes in the environment. ", "Consequently, there are many functional interactions between these two, mechanistically opposing, mechanisms that regulate cellular decision to live or to die. ", "Recent studies have established that the survival-promoting effects of Hsp can be partially attributed to the suppression of apoptosis. ", "Therefore there is a great potential in pharmacological applications of Hsp inhibitors that may help inducing apoptosis when that may be beneficial, as in various tumours.", "\n\n2.1 Heat shock proteins {#sec1-1}\n=======================\n\nThe eukaryotic stress response is highly conserved and involves the induction of **Hsp**. ", "Cellular protection against harmful insults relies on transient increase in **Hsp** production. ", "Many vital functions of the cell, such as maintenance of cell cycle and proliferation are under regulatory control of **Hsp**. ", "In mammalian cells, the stress response involves the induction of 5 major classes of **Hsp** families, the small **Hsp** 27, **Hsp** 60, **Hsp**70, **Hsp**90, and **Hsp**104. **", "Hsp** synthesis is tightly regulated at the transcriptional level by heat shock factors, HSF1 and HSF2. ", "In resting cells, HSF1 is a monomer but active HSF1 exists as a trimer and binds to the heat shock elements, the consensus sequence at DNA.", "\n\n**Hsp** function as molecular chaperones in regulating cellular homeostasis and promoting cell survival. ", "The main function of Hsp is helping in folding of nascent proteins, refolding of denatured proteins, inter-organellar transport of proteins and prevention of illegitimate aggregations. ", "Cells failing to respond to stress are sensitive to induced cell death via apoptosis.", "\n\n2.2 Cellular senescence, apoptosis, and necrosis: chaperon overload as a potential regulator {#sec1-2}\n============================================================================================\n\nCells typically die either by **apoptosis or necrosis.** ", "During necrosis, cell membrane looses its integrity and cell content is released causing an inflammatory response. ", "In apoptosis, however, cell content remains \"well-packed\" in the **apoptotic bodies** and inflammation does not develop. ", "Nevertheless, these two forms of cell death share some common features. ", "Both processes could be: caused by the same pathophysiological conditions,prevented by antiapoptotic mechanisms andtransformed from one form to another.", "\n\nThere is another cellular state that is seen in some cell types - a **nondividing-senescent--state.** ", "These cells exhibit only a limited number of replications in cell culture. ", "Morphological and functional properties of a cell change until it reaches a senescent-state. ", "These cells are unable to undergo apoptosis and are shifted to necrosis upon DNA damage.", "\n\nThe **Hsp** play an extremely complex role in the regulation of apoptosis. ", "The principal role is maintaining the physiological homeostasis needed for the cell survival. ", "However, by chaperoning the active structure of key apoptotic signalling proteins **Hsp may directly promote apoptosis** and act as chaperones of the death.", "\n\nOn the other hand, the **protein folding capacities of Hsp may be exhausted** due to massive stress, during ageing, or in chronic diseases. ", "In these conditions protein misfolding and aggregation are prevailing. ", "Various levels of **chaperone overload** may have an important contribution to the signals directing the cell to senescence, necrosis or apoptosis.", "\n\n2.3 Major elements in the mechanism of apoptosis {#sec1-3}\n================================================\n\nApoptosis is an **energy-dependent, ubiquitous and genetically controlled physiological process**.", "\n\n- **It is morphologically** well characterised with nuclear condensation, cell shrinkage, and membrane blebbing.", "\n\n- The **physiological changes** involve fragmentation of nuclear DNA into 80-200 oligo-nucleosomal fragments. ", "The DNA fragments are produced by the specific caspase-activated endonucleases.", "\n\n This highly regulated process develops as the response to some initial stimulus followed by a specific cascade of events. ", "Apoptosis proceeds in three phases:\n\n- **The initiation - signalling phase,** which involves the activation of surface death receptors, or the mitochondrial pathway;\n\n- **The signal transduction - preparation phase** where activation of initiator caspases and certain kinases/phosphatases takes place and\n\n- **The execution -- death phase** involving activation of effector caspases ([Table 2](#table002){ref-type=\"table\"}).", "\n\n2.4 Sites of initial signalling events {#sec1-4}\n======================================\n\n2.4.1 Plasma membrane {#sec2-1}\n---------------------\n\nActivation of the **TNF** and the **Fas** receptor, the so-called death receptors on the plasma membrane activates factors that promote cell death. ", "The superfamily of TNF receptors is implicated in the inflammatory and immune response. **", "Death receptors** contain an intra-cytoplasmic domain called death domain. ", "Through this domain receptors interact with the cytosolic proteins and propagate the death signal by activating caspases. ", "They are the final executioners in a stereotyped cascade leading to cell death.", "\n\nIn the late execution phase, apoptosis is characterised by marked changes in cell morphology, including **membrane blebbing,** loss of the membrane phospholipid asymmetry and **exposure of phosphatidylserine** on the surface. ", "The phosphatidylserine can be recognised by the immune system. **", "Hsp** can help translocate phosphatidylserine to the cell surface making cells more vulnerable to immune lysis.", "\n\nThe role of **Hsp70** is pleiotropic to cellular life and in some cases over-expression of **Hsp70** is protecting from apoptosis, but in other cases it may promote the cell death. **", "Hsp90** is helping in propagation of the apoptotic signal from plasma membrane.", "\n\n2.4.2 Cytosol {#sec2-2}\n-------------\n\nIn the cytosol **stress kinases** are important elements of signal transduction pathway in inducing and/or modulating the apoptotic response. ", "Among the **mitogen-activated protein kinases,** the activation of the signal-regulated protein kinase **ERK** is associated with mitogenic stimulus, whereas the **JNK** and **p38** kinases are stress responsive.", "\n\nThe small **Hsp27** is activated by **p38**-activated phosphorylation. ", "The phosphorylated dimers of **Hsp27** interact with **Daxx,** a protein that contains the death domain. ", "Association with **Hsp27** prevents Daxx from interaction with another serine/threonine kinase. ", "That is the way of inhibiting the Fas--mediated apoptosis.", "\n\n**Hsp70** has a general inhibitory role in stress kinase pathways. **", "Hsp72** also interacts with peptide binding domain of **JNK** and is necessary for **JNK** down-regulation.", "\n\n2.4.3 Nucleus {#sec2-3}\n-------------\n\nThe biochemical signature of apoptosis is **DNA damage** and **nucleosomal fragmentation of DNA** that is resulting from activation of specific **endonucleases.** ", "These enzymes cleave the chromatin to shorter, oligo-nucleosomal DNA fragments.", "\n\n**Hsp** play a major role in protecting the cells from DNA damage induced by various agents. ", "Members of the **Hsp27** and **Hsp70** families have a protective role for the DNA integrity against oxidative stress. ", "Nuclear **Hsp72** suppresses the appearance of apoptosis after DNA damage.", "\n\nThe specific form of DNA damage occurs with **telomere** shortening. ", "At the critical length of the telomere regions, around 7kb, cells go to the state of senescence, which may further proceed to apoptosis. ", "Telomere regions are maintained by enzyme telomerase and **Hsp90** is necessary for the enzyme activity.", "\n\n2.4.4 Mitochondria and reactive oxygen species {#sec2-4}\n----------------------------------------------\n\nThe mitochondrion appears to be the central coordinator of apoptotic events. ", "Many proapoptotic and signal transduction pathways converge on the mitochondria to induce the membrane permeabilisation. ", "Rupture of the outer membrane and formation of the **mega-channel, permeability transition pore** (PTP) is the starting event. ", "The **adenine nucleotide translocator** present in the inner mitochondrial membrane and the voltage-dependent anion channel at the outer membrane are the major components of PTP. ", "These proteins are responsible for the lethal changes in mitochondrial membrane potential and release of certain molecules from intermembrane space to cytosol. ", "The reaction is controlled by **Bcl-2** and Bcl-2 related proteins. ", "The PTP formation is connected with the Bax protein and physical disruption of the outer membrane. ", "Changes in membrane permeability lead to matrix swelling and finally to leakage of **cytochrome c**, and this is a starting signal for the execution phase of apoptosis.", "\n\nThe second mitochondrial protein involved in apoptosis is **activator of caspases (Smac/DIABOLO).** ", "This protein inhibits inhibitor of apoptosis **(IAP),** that blocks processing of effector caspases --3 and -- 9. ", "The release of cytochrome c from mitochondria drives the assembly of the high molecular weight caspase-activating complex -- **apoptosome.** ", "The apoptosome contains oligomerised **Apaf-1,** which in the presence of **dATP** and **caspase-9** helps auto-activating cleavage of caspase --3, an executioner of apoptosis.", "\n\n**Hsp27** may decrease caspase activity by binding to cytochrome c and down-regulate mitochondria pathway of caspase dependent cell death. **", "Hsp70** and **Hsp90** suppress apoptosis by directly associating with Apaf-1 and blocking formation of apoptosome.", "\n\nThere is another role of mitochondria in the development of apoptosis. ", "Mitochondria are primary sites of **reactive oxygen species (ROS) formation.** ", "ROS have a major role in mediation of cellular damage. ", "ROS can be generated in the electron transport chain, xanthine and other flavoprotein oxidases, auto-oxidation of catecholamines, thiols, intracellular xenobiotics, haemoglobin and NADP(H) oxidase. ", "In normal cells there is a balance between pro- and anti-oxidant pathways. ", "Upon stress stimuli an imbalance in redox system develops that leads to accumulation of ROS. ", "ROS may induce damage to cell by **oxidizing the membrane lipids, proteins and DNA.** ", "The overproduction of ROS is associated with many forms of apoptosis and necrosis. ", "ROS-induced apoptosis is associated with up-regulation of **Fas death receptor.** ", "Anti-apoptotic protein Bcl-2 prevents generation of ROS.", "\n\nSmall **Hsp27** and **Hsp 70** appear to be protective agents against oxidative stimuli, by **elevating reduced gluthatione** level, or stimulating glucose-6-phosphate dehydrogenase activity, or inhibiting lipid peroxidation.", "\n\n**Nitric oxide (NO)** is an important signalling molecule regulating a number of diverse physiological processes and is produced by **nitric oxide synthases (NOS).** ", "There are three types of NOS in the cell: **neuronal, endothelial and inducible.** ", "NO inhibits apoptosis, through up-regulation of survival kinases, and inhibition of caspase-3.", "\n\n2.4.5 Endoplasmic reticulum {#sec2-5}\n---------------------------\n\nThe ER plays important function in intracellular calcium homeostasis. ", "Conditions leading to alteration of ER intraluminal oxidative status can also induce stress. ", "Participation of ER in induction and progression of apoptosis involve the disturbed Ca++ signalling and accumulation of unfolded proteins. **", "Glucose regulated proteins (Grp)** belong to the **Hsp70** family and could be induced by ER stress. ", "After translocation across ER membrane they act as apoptotic regulators by protecting the host cell against stress-induced death.", "\n\n2.5 Effector molecules {#sec1-5}\n======================\n\n2.5.1 Caspases {#sec2-6}\n--------------\n\nCaspases represent the family of **proteases** that hydrolyse proteins at **aspartate residues.** ", "There are 14 types of caspases that are classified into 3 major groups, which are: **initiator,inflammatory,** and**effector caspases**\n\nThe activation of caspases is organised through an apoptotic cascade pathway. ", "The **TNF-induced apoptosis** involves activation of initiator **caspases -8 and -10.** ", "The **mitochondrial pathway** involves **initiator caspase --9** and **effector caspases -3, -6.**", "\n\n**Hsp27** inhibits mitochondrion -- dependent caspase activation. ", "The small **Hsp** α- and β- crystallines, inhibit both mitochondrial and death receptor pathways. **", "Hsp-70** binds to caspase-3 and inhibits its activity.", "\n\n2.5.2 Nucleases {#sec2-7}\n---------------\n\nThere are various endonucleases expressed in the cell. ", "The deoxyribonuclease (DNase) implicated in apoptosis is an Mg++ endonuclease called **caspase--activated DNase (CAD). ", "Hsc**70, with its cofactor **Hsp**40 is involved in folding of CAD.", "\n\n2.5.3 Transglutaminases {#sec2-8}\n-----------------------\n\n**Tissue transglutaminase (TGase)** is a member of a family of enzymes that catalyse protein cross-linking by **transdamidation.** ", "Transamidation has an important role in packing the cells in the tissue. ", "At the late phase of apoptosis this protein cross-linking is important for preventing the massive inflammatory processes. ", "TGase binds and hydrolyses ATP and GTP. ", "The enzyme is inhibited by NO and is activated by increased intracellular Ca++ concentration. ", "TGase expression is inversely correlated with the expression of antiapoptotic protein Bcl-2, and inhibition of TGases confers protection against apoptosis.", "\n\n2.6 Heat shock proteins and caspase independent apoptosis {#sec1-6}\n=========================================================\n\nIt has been shown that the signalling pathways are interrelated and that **caspase-independent pathways** may interconverge with caspase-dependent pathways in induction of apoptosis. ", "The therapeutic use of **Hsp** modulation in anti-cancer protocols points to the importance of caspase-independent apoptotic pathways, which are predominant pathways of apoptosis in tumour cells. ", "A number of enzymes and lipid molecules participate in the development of caspase-independent apoptosis.", "\n\n**Serine proteases** are participating in amplification of apoptosis. **", "Granzyme,** which is a serine protease, is an activator of caspases, and activator of cytochrome c release. ", "The surface--expressed **Hsp**70 mediates the apoptosis of tumour cells by binding of granzyme B. **Cathepsins** are a class of proteolytic enzymes involving 3 major groups: **cysteine proteases, aspartyl proteases and serine proteases** (B, C, L, H, K, S, and O). ", "The enzymes are of lysosomal origin and are involved in peptide formation and protein degradation. ", "They are involved in autophagy-associated apoptosis and in oxidative stress-induced apoptosis. ", "In tumour cells cathepsin-B is the most important mediator of cell death.", "\n\nThe **Hsp**70/**Hsp**90 chaperone plays an important role in lysosomal proteolytic pathways. ", "Hsc70 is involved in uptake of cytosolic proteins into the lysosomal lumen.", "\n\n2.6.1 Calpains {#sec2-9}\n--------------\n\nCalpains are calcium-dependent proteases involved in cytoskeletal reorganisation and muscle protein degradation. ", "The enzymes are heterodimers composed of small regulatory and large catalytic subunit. ", "Calpains and caspases often act in a synergistic way in promotion of apoptosis.", "\n\n2.6.2 Ceramide induced apoptosis {#sec2-10}\n--------------------------------\n\nCeramide is a lipid mediator in induction of apoptosis. ", "It activates stress activated protein kinase signalling pathway. **", "Hsp**70 protects cells from ceramide-induced apoptosis\n\n2.6.3 Apoptosis inducing factor {#sec2-11}\n-------------------------------\n\nApoptosis inducing factor (AIF) is a mediator of caspase-independent apoptosis. ", "AIF translocates from mitochondria to both cytosol and nucleus. ", "Bcl-2 and **Hsp**P70 can inhibit AIF translocation.", "\n\n2.6.4 Anoikis {#sec2-12}\n-------------\n\nAnoikis is a type of cell death where cells fail to find substratum and connection with other cells or extracellular matrix. ", "The lack of integrin-mediated interactions with extracellular matrix induces apoptosis. ", "It mainly occurs at epithelial cells and it assures proper opmental positioning in specialized structures. ", "Failure of anoikis contributes substantially to tumour progression and facilitates metastasis. ", "It is possible that cytoskeletal alterations and cell-matrix detachment could release death receptors leading to death domain induced apoptosis.", "\n\nThe phosphorylated form of **Hsp**27 helps the stability of integrin. ", "It was shown that **Hsp**27 inhibit metastatic potential in melanoma cells.", "\n\n2.6.5 Heat shock proteins and antiapoptotic mediators {#sec2-13}\n-----------------------------------------------------\n\n**Hsp** are involved in negative regulation of pro-apoptotic pathways, but also in activation of anti-apoptotic mediators. **", "Hsp** 70 acts in helping Bcl-2 activation.", "\n\nApoptosis itself inhibits Hsp synthesis by down-regulating the respective transcription factor HSF-1. ", "In that manner apoptosis stops one of the important surviving signals.", "\n\n2.6.6 Molecular mechanisms of Hsp action {#sec2-14}\n----------------------------------------\n\n**Hsp** act as molecular chaperones preventing protein aggregation and promoting protein folding. **", "Hsp** function as oligomers and often form chaperone complexes with each other. ", "The biological role of Hsp is mediated by their ability to interact with protein or polypeptide substrates. ", "The peptide binding activity of Hsp70 is mediated through interactions between its C-terminal peptide binding domain and hydrophobic residues exposed in unfolded substrates. ", "Association of Hsp70 with its target peptides is further regulated by the activity of its N-terminal ATPase domain ([Figure 2](#fig002){ref-type=\"fig\"}.)", "\n\n**Hsp** may function in **\"passive mode\"** when they behave as ATP-independent **\"holders\"** of damaged proteins, sequestering them and preventing their fatal aggregation. ", "In ATP dependent **\"active mode\"** chaperones are working as **\"folders\"** helping in the folding, transport and ATP-dependent degradation of unfolded or misfolded proteins. ", "The passive mode is typical during stress when cellular ATP level is low. ", "The active mode prevails when cells have recovered and the ATP level is increased again. ", "Many proteins, such as protein kinases and nuclear hormone receptors, require the continuous help of **Hsp** chaperone complex to keep them in activation competent state. ", "However, **Hsp** have no priority or selection between substrates and hence the chaperone function is extended to pro-apoptotic factors, too. **", "Hsp 60** promotes apoptosis by helping in the maturation of procaspase-3.", "\n\n2.6.7 Heat shock proteins and cellular homeostasis {#sec2-15}\n--------------------------------------------------\n\n**Hsp** have essentially a dual function in the cell. ", "They are **eliminating misfolded** and damaged proteins produced by stress and other insults. ", "However, they also play a critical role in the maintenance of cellular homeostasis by **continuously chaperoning** of a number of cellular proteins.", "\n\n- Redox homeostasis\n\n**Hsp** act as antioxidants, and **haem oxygenase** is one of the **Hsp** members that are responsible for the production of antioxidants biliverdin and bilirubin. ", "The redox state of the cell influences **Hsp** synthesis and a decreased gluthatione level may lead to direct activation of HSF-1. ", "On the contrary, strong oxidative agents block activation of HSF-1 and its binding to DNA. ", "It has been shown that mild changes of redox homeostasis lead to activation of HSF-1. ", "However, large changes cause HSF-1 inhibition.", "\n\n- Cell organisation\n\n**Hsp** help in stabilising the cytoskeleton and cytoarchitecture by direct interactions with cytoskeletal proteins. ", "Inhibition of major cytoplasmic **Hsp, Hsp90** leads to increased cellular lysis and disruption of cytoplasmic organisation. ", "Small **Hsp** protect actin filaments and help cell survival in apoptosis.", "\n\n2.7 Heat shock proteins as pharmacological targets in apoptosis modulation {#sec1-7}\n==========================================================================\n\n2.7.1 Heat shock protein inhibition -- an efficient way to induce apoptosis of tumour cells {#sec2-16}\n-------------------------------------------------------------------------------------------\n\n### Apoptosis in tumour cells {#sec3-1}\n\nFrom the various mouse models and cultured cells it becomes evident that acquired resistance to apoptosis is hallmark of most, if not all, types of cancers. ", "Although tumour cells are resistant to apoptosis, they are not completely devoid of death. ", "Cell death in tumour cells is mostly associated with cellular senescence and mostly involves **caspase-independent routes** of apoptosis or necrosis. ", "A tumour cell may escape from caspase-mediated apoptosis either by **over expressing antiapoptotic** proteins or by severe **mutations in proapoptotic factors.** ", "The antiapoptotic Bcl-2 is known to be over-expressed in many tumours. ", "In Hodgkin's lymphoma, mutations of Fas receptor were found and caspase-8 is frequently mutated in neuroblastoma. ", "Tumour cells also have ways to escape caspase-dependent apoptosis, by expressing **survivin**, an inhibitor of apoptosis. ", "The survivin expression is associated with poor prognosis. ", "Mutations in the tumour-suppressor p53 gene are one of the major mechanisms of the tumour escape from apoptosis. **", "Hsp** regulates the function of p53.", "\n\n2.7.2 Heat shock proteins in tumour cells {#sec2-17}\n-----------------------------------------\n\nIt was found that members of the **Hsp** family, such as **Hsp**70, **Hsp**27, and **Hsp**90 are over-expressed in several tumour cells. ", "It has been shown that **Hsp**90 can inhibit apoptosis by direct physical interaction with apoptotic molecules. ", "There are numerous examples of **Hsp** involvement in tumourigenicity; **Hsp**27 is over expressed in colon carcinoma cells, **Hsp**90 in prostate cancer and **Hsp**70 in breast tumours where it is found to be necessary for the progression.", "\n\nHsp bind to caspases inhibiting their activation, but they are also efficient in blocking caspase independent apoptosis. ", "These characteristics make inhibition of **Hsp** an efficient tool in inducing a cell-specific apoptosis. ", "Depletion of **Hsp70** and **Hsp90** in tumour cells induces their apoptosis.", "\n\nAging and various degenerative diseases induce accumulation of damaged/misfolded proteins that are produced by the oxidative stress and proteotoxic insults. ", "At the same time the essential chaperone functions of Hsp are also impaired. ", "Increased demands of chaperone function may exceed the available chaperone capacity leading to imbalance of cellular homeostasis.", "\n\nOn the other hand tumours undergo facilitated evolution due to increased proliferation. ", "Conventional antitumour therapies (chemotherapy, radiotherapy, hyperthermia) all induce **Hsp** in surviving cells. ", "The over-expression of **Hsp** may help the accumulation of mutations in tumours, which can help their further progression to more aggressive types of malignant cells. ", "Use of **Hsp** inhibitors may affect this process and release some of mutations that have been rescued by **Hsp** before.", "\n\n2.7.3 Enforced apoptosis of tumour cells {#sec2-18}\n----------------------------------------\n\nInhibitors of **Hsp** can suspend the **Hsp**-dependent block of both caspase-mediated and caspase-independent apoptosis of tumour cells. ", "It is well known that **Hsp** are not selective in their chaperoning function. ", "They assist in the folding of a variety of cellular proteins. ", "Consequently, **Hsp** inhibitors will target a number of different molecules. ", "That makes inhibition of **Hsp** potentially very effective in induction of tumour cells apoptosis.", "\n\nAlthough there are efficient inhibitors of **Hsp**60 and **Hsp**70, targeting of **Hsp**90 represents a central attraction in **Hsp**-related tumour inhibition. ", "Inhibition of **Hsp**90 induces apoptosis in various tumour cells and also leads to a defect in number of proliferative signals. ", "The most important **Hsp**90 inhibitor is *geldanamycin* and its derivatives. **", "Hsp**90 inhibition leads to dissociation of various **Hsp**90 client proteins from chaperone complex and to their consecutive **degradation by the proteasome.** ", "Some drugs interact with **Hsp90,** like cisplatin, taxol and the antibactericide, novobiocin, and influence its function.", "\n\nIt appears that applying low doses of **Hsp**90 inhibitors together with conventional chemotherapeutic represents an effective way to target various cancers. ", "Cytoprotective effects of **Hsp** come from the inhibition of stress-induced apoptosis. ", "Rescue from apoptosis may also be helpful in anticancer protocols, where by-stander non-malignant cells are also damaged by the therapy.", "\n\nAt some point **Hsp** inhibitors may act as **Hsp** inducers. **", "Hsp** synthesis is regulated at transcriptional level by HSF-1. **", "Hsp**90 and **Hsp**70 have been shown to bind to HSF-1 and keep it repressed in the absence of stress. ", "During stress, misfolded proteins occupy both chaperones, which results in dissociation, nuclear translocation and activation of HSF-1. ", "Pharmacological Hsp inhibition may therefore paradoxically lead to an increase in their amount.", "\n\nIncreased **Hsp** may lead to tumour cell sensitisation against immune attacks, providing a simultaneous protection of bystander cells in various cancer therapies, such as chemotherapy, radiotherapy, hyperthermia etc. ", "Tumour cells may express **Hsp** on their surface, which leads to their enhanced recognition by the natural killer cells of the native immune system, and a specific anti-tumour immunity may develop. ", "Extracellular **Hsp**, released as a result of cell death and taken up by antigen-presenting cells through **Hsp** receptors, are involved in the cross presentation of chaperoned peptides.", "\n\nProteasome inhibitors up-regulate **Hsp** synthesis by increasing amounts of misfolded proteins that compete for **Hsp** with HSF-1. ", "The level of various **Hsp**, as well as, the amount of **Hsp**, which are not occupied by damaged, misfolded proteins, can be critical in cytoprotection and cell survival.", "\n\n2.7.4 Therapeutic use of heat shock protein up regulation {#sec2-19}\n---------------------------------------------------------\n\nA number of clinical applications can be derived from the general cytoprotective / antiapoptotic role of **Hsp**. ", "It could be applied in cardioprotection, in cellular defence against stroke and in various neurodegenerative diseases, as well as, for the improvement of efficacy in tissue transplantation. **", "Hsp** induction eases the deleterious consequences of chronic diseases, such as diabetes, and conditions like Alzheimer's, Parkinson's or prion disease, where the accumulation of misfolded proteins is the major cause of neurodegeneration. ", "These conditions may gain beneficial effects from the Hsp over expression.", "\n\nCell life and proliferation, as well as, cell death involves regulation through the dynamic conformational changes of a number of apoptotic molecules, involving various oligomerisation and autoactivation steps. ", "These suggest an extensive need for molecular chaperones. **", "Hsp** are capable of assisting in all these processes. ", "Their proapoptotic role is usually balanced, and very often overwhelm by their participation in cytoprotection. ", "Therefore, finely tuned balance of **Hsp** function is a key point for regulation of cell death, or survival, and also for making switch between two forms of cell death, apoptosis and necrosis.", "\n\n{#fig001}\n\n{#fig002}\n\n###### \n\nMain families of mammalian Hsps\n\n -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n FAMILY CHAPERONS LOCATION FUNCTION\n ------------ ---------------------------- ----------------- -----------------------------------------------------------------------------------------------------------------------------------\n **sHsp** **Hsp27, α- β-crystallin** **cytosol** stabilisation against aggregation\n\n **Hsp60**\\ **chaperonin**\\ mitochondria\\ prevents agregation of denatured proteins folding of nascent proteins, interorganellar transport, refelding of denatured proteins\n **Hsp70** **Hsp70**\\ cyt/nucleus\\ \n **Hsc70** cyt/nucleus \n\n   **mHsp70 GRP78** mitochondria ER  \n\n **Hsp90** **Hsp90α** cytosol conformational maturation of steroid hormone receptors and signal transducing kinases\n\n   **Hsp90β** cytosol  \n\n   **Grp94** ER  \n -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n\n###### \n\nThe most important members of the apoptotic machinery\n\n ---------------------------- --------------------------------------------------------------------\n   **Mediators¶**\n **SIGNALLING PHASE**  \n **Death receptors** TNF-α, Fas (Apol/CD95), FADD\n **Physiological inducers** RCS, Ca2+, JNK/SAPK activation\n **Protease activators** granzymes, calpains, cathepsins, proteasome\n **PREPARATIONPHASE**  \n **Initiator caspases** caspase-8, -9, -10, -12\n **Physiological inducers** **Bax, ROS, MMPT, cytochrome c, apoptosome**\n **Nucleases** **AIF,**\n **EXECUTIONPHASE**  \n **Effector caspases** **caspase-3, -6, and -7**\n **Physiological factors** **membrane blebbing, apoptotic body formation, DNA fragmentation**\n ---------------------------- --------------------------------------------------------------------\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "I took these shoes out for a spin today, and at 4\", they're a pretty comfortable height, but after wearing them for several hours, my toes were beginning to get squished. ", "You know when your feet slide forward a little every time you take a step? ", "There are no words to adequately convey how much I absolutely loathe that feeling! ", "The sad thing is, to me, these shoes are worth it and I'll happily brave the pain. ", ":D\n\nThe other day while I was walking to class, I caught a girl trying to surreptiously take a picture of me on her phone. ", "The operative word here is 'trying,' because she was being pretty obvious about it. ", "Look back on it now, I should've taken advantage of the potential advertising opportunity: \"If you want pictures of me, you can visit my blog, notwithoutincident.net! ", "New posts daily!\" ", "Haha, oh wow, if I could redo that moment... :D" ]

{ "pile_set_name": "Pile-CC" }

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[ "Improving Tibial Component Coronal Alignment During Total Knee Arthroplasty with the Use of a Double-Check Technique.", "\nTo compare the efficacy of the restoration of tibial component coronal alignment with a double-check technique and the conventional surgical technique during total knee arthroplasty (TKA) in knee osteoarthritis patients, and to investigate the distribution of the medial proximal tibial angle (MPTA) after TKA. ", "A retrospective review was performed of 151 patients (179 knees) with knee osteoarthritis undergoing primary TKA in Beijing Chaoyang Hospital, Capital Medical University from February 2013 to January 2015 to evaluate the differences in MPTA in patients undergoing the conventional TKA and those undergoing a modified TKA with a double-check technique after the surgery. ", "All patients were evaluated by MPTA, range of motion (ROM), Knee Society Clinical Rating System (KSS) clinical scores, and KSS functional scores. ", "An MPTA deviation of 3° or greater was considered malalignment. ", "A total of 130 TKA procedures in 119 patients were included in the study: 64 knees treated with conventional TKA and 66 knees treated with the double-check technique TKA. ", "The mean postoperative MPTA was 88.6° ± 2.2° in the conventional TKA group and 89.1° ± 1.5° in the double-check TKA group. ", "The mean postoperative MPTA between the two groups was not significantly different. ", "In the conventional TKA group, 79.7% (51 knees) had a postoperative MPTA deviation within 3° and 20.3% (13 knees) had a MPTA deviation greater than 3°. ", "In the double-check TKA group, 93.9% (62 knees) had a postoperative MPTA deviation within 3°and 6.1% (4 knees) had a MPTA deviation greater than 3°. ", "The postoperative MPTA deviation within 3° showed a statistically significant difference between the two groups. ", "In the double-check TKA group, a 21.2% (14 knees) tibial malalignment was detected after the first check and a 9.1% (6 knees) tibial malalignment was detected after the second check. ", "The mean postoperative ROM was 118.1° ± 9.2° in the conventional TKA group and 115.7° ± 10.1° in the double-check TKA group. ", "The mean postoperative KSS clinical score was 89.3 ± 3.5 in the conventional TKA group and 89.0 ± 3.7 in the double-check TKA group. ", "The mean postoperative KSS functional score was 84.8 ± 10.0 in the conventional TKA group and 84.9 ± 9.0 in the double-check TKA group. ", "The mean postoperative ROM, KSS clinical scores, and KSS functional scores between the two groups were not statistically significantly different. ", "Malalignment of the tibial component can occur after conventional TKA, and the double-check technique is an effective method to improve tibial component coronal alignment." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "YouTube's most watched blogger PewDiePie will lose his preferred status on the Google-owned video service after posting several videos containing anti-Semitic remarks and Nazi references, the tech firm said Tuesday.", "\n\nYouTube said it was canceling a popular program from the 27-year-old Swede, whose real name is Felix Kjellberg, the same day Disney said it was cutting its ties with the social media star.", "\n\nPewDiePie—known for posting humorous clips to his more than 53 million followers on YouTube—will be sanctioned for violating the platform's guidelines on hate speech, Google said Tuesday.", "\n\n\"We've decided to cancel the release of 'Scare PewDiePie Season 2' and we're removing the PewDiePie channel from Google Preferred,\" a statement from the US tech giant said.", "\n\n\"Scare PewDiePie\" was program that YouTube ordered for its online subscription service.", "\n\nGoogle Preferred is a program that allows advertisers to direct their messages to the key 18- to 34-year-old demographic, with an implicit guarantee that the participation won't hurt their brand.", "\n\nThe moves won't keep PewDiePie off YouTube but will likely limit his audience and could sharply curtail his revenue from advertising.", "\n\nSeparately Disney indicated it was ending its business relationship with the Swedish media star.", "\n\n\"Although Felix has created a following by being provocative and irreverent, he clearly went too far in this case and the resulting videos are inappropriate,\" according to a statement to AFP by Disney's Maker Studios.", "\n\nPewDiePie, who had editorial independence under the terms of the arrangement with Disney, reportedly paid two Indian men five dollars to hold the banner reading \"Death to all Jews\" while they laugh and dance in the January 11 video.", "\n\n\"I was trying to show how crazy the modern world is, specifically some of the services available online,\" Kjellberg said in a Tumblr blog post on February 12.", "\n\n\"I picked something that seemed absurd to me—that people on Fiverr would say anything for 5 dollars,\" referring to a website that helps freelancers receive part-time work.", "\n\nThe Wall Street Journal reported PewDiePie had posted nine videos that display anti-Semitic jokes and Nazi references since August.", "\n\nOne of them shows a man dressed as Jesus Christ, saying \"Hitler did absolutely nothing wrong.\"", "\n\n\"I think it's important to say something and I want to make one thing clear: I am in no way supporting any kind of hateful attitudes,\" the YouTube star said in the blog post.", "\n\nKjellberg is a top earner on YouTube, making roughly $14.5 million (13.6 million euros) last year, according to reported estimates from social media data firm NeoReach.", "\n\nThat amount includes splitting ad revenue with YouTube, as well as sponsorships and appearance fees.", "\n\nIn December, PewDiePie accused YouTube of trying to \"kill\" his channel and has threatened to shut it down, a move that turned out to be a publicity stunt.", "\n\nExplore further PewDiePie threatens to shut down YouTube channel\n\n© 2017 AFP" ]

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[ "Q:\n\nRblpapi - bdh function returns NULL with certain fields\n\nDoes bdh() only work with certain Bloomberg fields on Rblpapi? ", "The following returns NULL:\nlibrary(Rblpapi)\nblpConnect()\nbdh(\"IBM US Equity\", \"RR906\", start.date = Sys.", "Date()-22)\n\nand so does using the mnemonic for the field:\nbdh(\"IBM US Equity\", \"TRAIL_12M_EPS\", start.date = Sys.", "Date()-22)\n\nI can get the current value through bdp() but that's it. ", "bdh() seems to be working fine for Real-time fields but not so for Static ones even though Bloomberg says historical values are available for those through the API.", "\nHas anyone run into this problem? ", "And more importantly, are there any solutions for this? ", "Not sure if I'm missing something obvious. ", "\nEDIT:\nI figured out a solution. ", "Using the following option returns the correct values:\nbdh(\"IBM Equity\", \"TRAIL_12M_EPS\", Sys.", "Date()-22, options = c(\"nonTradingDayFillOption\"=\"ALL_CALENDAR_DAYS\"))\n\nDepending on user requirements the value of nonTradingDayFillOption can also be set to ACTIVE_DAYS_ONLY (returns only days when field value changes). ", "\n\nA:\n\nUsing the following option returns the correct values:\nbdh(\"IBM Equity\", \"TRAIL_12M_EPS\", Sys.", "Date()-22, options = c(\"nonTradingDayFillOption\"=\"ALL_CALENDAR_DAYS\"))\n\nDepending on user requirements the value of nonTradingDayFillOption can also be set to ACTIVE_DAYS_ONLY (returns only days when field value changes).", "\nGoing through the full API documentation does help, I guess...\n\n" ]

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[ "Ce mouton vit au Japon à Kobe et sourit tout le temps. — ", "KYODOWC/NEWSCOM/SIPA\n\nUn troupeau de moutons a semé la zizanie dans les rues de Rhydypandy, petite commune du Pays-de-Galles, rapporte le Daily Mail.", "\n\n« Il y a un troupeau de moutons qui se balade dans les villages et crée une forte nuisance » a prévenu Ioan Richard, conseiller régional. « ", "Ils entrent dans les jardins des particuliers, ils ont même réussi à entrer dans un bungalow et ont semé la pagaille dans une chambre » détaille-t-il.", "\n\nLes restes d’une plantation de cannabis en cause\n\nA l’origine de ces incidents, un dépôt de plants de cannabis sur lequel seraient tombés les ovins. ", "Quelques jours avant les faits, les habitants de Rhydypandy avaient en effet découvert les restes d’une plantation de cannabis à proximité de la ville.", "\n\nMercredi, le conseil municipal de Swansea, ville toute proche, avait pourtant assuré dans les colonnes du Metro britannique que les autorités s’étaient débarrassées des plants.", "\n\nLaon Richard a fait savoir qu’un certain nombre de moutons avaient été tués dans le village alors qu’ils erraient, « confus et hébétés » dans les rues.", "\n\nLe porte-parole du conseil municipal ajoutait : « nous enquêtons aussi dans le cadre de différents cas de décharges sauvages et nous prendrons des mesures si nous avons suffisamment d’éléments »." ]

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[ "Car Park Attendant Long Sleeve T-Shirts are an Idakoos specialtiy! ", "Idakoos has many things to offer. ", "Whether you want to get a Car Park Attendant Long Sleeve T-Shirt for a special occasion, give a Car Park Attendant Long Sleeve as a present or need to represent with a funny Car Park Attendant Long Sleeve Tee during Holidays or Family and Friends get-togethers, Idakoos is sure to have the right Car Park Attendant Long Sleeve T-Shirt for you! ", "Even if it turns out you can't find the right Car Park Attendant Long Sleeve Shirt with the perfect design for your mother, father or children (or friends!); ", "Idakoos offers all of its men's women's and children's Car Park Attendant Long Sleeve T-Shirts as Custom Car Park Attendant T-Shirts. ", "Personalize any Car Park Attendant Long Sleeve T-Shirt the way you want to ensure the perfect gift." ]

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[ "/*\n * Copyright (c) 2010 The DragonFly Project. ", " All rights reserved.", "\n *\n * This code is derived from software contributed to The DragonFly Project\n * by Alex Hornung <ahornung@gmail.com>\n *\n * Redistribution and use in source and binary forms, with or without\n * modification, are permitted provided that the following conditions\n * are met:\n *\n * 1. ", "Redistributions of source code must retain the above copyright\n * notice, this list of conditions and the following disclaimer.", "\n * 2. ", "Redistributions in binary form must reproduce the above copyright\n * notice, this list of conditions and the following disclaimer in\n * the documentation and/or other materials provided with the\n * distribution.", "\n * 3. ", "Neither the name of The DragonFly Project nor the names of its\n * contributors may be used to endorse or promote products derived\n * from this software without specific, prior written permission.", "\n *\n * THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS\n * ``AS IS'' AND ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT\n * LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS\n * FOR A PARTICULAR PURPOSE ARE DISCLAIMED. ", " IN NO EVENT SHALL THE\n * COPYRIGHT HOLDERS OR CONTRIBUTORS BE LIABLE FOR ANY DIRECT, INDIRECT,\n * INCIDENTAL, SPECIAL, EXEMPLARY OR CONSEQUENTIAL DAMAGES (INCLUDING,\n * BUT NOT LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES;\n * LOSS OF USE, DATA, OR PROFITS; OR BUSINESS INTERRUPTION) HOWEVER CAUSED\n * AND ON ANY THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY,\n * OR TORT (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT\n * OF THE USE OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF\n * SUCH DAMAGE.", "\n */\n#include <sys/types.h>\n#include <sys/device.h>\n#include <sys/wait.h>\n#include <sys/stat.h>\n#include <sys/socket.h>\n#include <sys/un.h>\n\n#include <err.h>\n#include <errno.h>\n#include <fcntl.h>\n#include <libgen.h>\n#include <regex.h>\n#include <signal.h>\n#include <stdarg.h>\n#include <stdio.h>\n#include <stdlib.h>\n#include <string.h>\n#include <syslog.h>\n#include <unistd.h>\n\n#include <libprop/proplib.h>\n#include <sys/udev.h>\n#include \"udevd.h\"\n\nint\nsend_xml(int s, char *xml)\n{\n\tssize_t r,n;\n\tsize_t sz;\n\n\tsz = strlen(xml) + 1;\n\n\tr = send(s, &sz, sizeof(sz), 0);\n\tif (r <= 0)\n\t\treturn r;\n\n\tr = 0;\n\twhile (r < (ssize_t)sz) {\n\t\tn = send(s, xml+r, sz-r, 0);\n\t\tif (n <= 0)\n\t\t\treturn n;\n\t\tr += n;\n\t}\n\n\treturn r;\n}\n\nint\nread_xml(int s, char **buf)\n{\n\tchar *xml;\n\tsize_t sz;\n\tint n, r;\n\n\t*buf = NULL;\n\n\tn = recv(s, &sz, sizeof(sz), MSG_WAITALL);\n\tif ((n <= 0) || (sz > 12*1024*1024)) /* Arbitrary limit */\n\t\treturn n;\n\n\txml = malloc(sz+2);\t\n\tr = 0;\n\twhile (r < (ssize_t)sz) {\n\t\tn = recv(s, xml+r, sz-r, MSG_WAITALL);\n\t\tif (n <= 0) {\n\t\t\tfree(xml);\n\t\t\treturn n;\n\t\t}\n\t\tr += n;\n\t}\n\n\t*buf = xml;\n\treturn r;\n}\n\nint\nunblock_descriptor(int s)\n{\n\tint flags, ret;\n\n\tflags = fcntl(s, F_GETFL, 0);\n\tret = fcntl(s, F_SETFL, flags | O_NONBLOCK);\n\treturn ret;\n}\n\nint\nblock_descriptor(int s)\n{\n\tint flags, ret;\n\n\tflags = fcntl(s, F_GETFL, 0);\n\tret = fcntl(s, F_SETFL, flags & ~O_NONBLOCK);\n\treturn ret;\n}\n\nint\ninit_local_server(const char *sockfile, int socktype, int nonblock)\n{\n\tmode_t msk;\n\tint s;\n\tstruct sockaddr_un un_addr;\n\n\tif ((s = socket(AF_UNIX, socktype, 0)) < 0)\n\t\treturn -1;\n\n\tmemset(&un_addr, 0, sizeof(un_addr));\n\tun_addr.sun_family = AF_UNIX;\n\tstrncpy(un_addr.sun_path, sockfile, SOCKFILE_NAMELEN);\n\tun_addr.sun_path[SOCKFILE_NAMELEN - 1] = '\\0';\n\n\t/*\n\t * DO NOT change `un_addr.sun_path' to `sockfile' here,\n\t * since `sockfile' may have been truncated by above strncpy(3).", "\n\t */\n\tunlink(un_addr.sun_path);\n\n\tif (nonblock && unblock_descriptor(s) < 0) {\n\t\tclose(s);\n\t\treturn -1;\n\t}\n\n\tmsk = umask(S_IXUSR|S_IXGRP|S_IXOTH);\n\tif (bind(s, (struct sockaddr *)&un_addr, sizeof(un_addr)) < 0) {\n\t\tclose(s);\n\t\treturn -1;\n\t}\n\tumask(msk);\t /* Restore the original mask */\n\n\tif (socktype == SOCK_STREAM && listen(s, LOCAL_BACKLOG) < 0) {\n\t\tclose(s);\n\t\treturn -1;\n\t}\n\n\treturn s;\n}\n" ]

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[ "Innovation Systems\n\nCompany Profile\n\nInnovation Systems is a professional company for last 16 years in the field of photocopier MFD's. ", "Scanner, Services & Rental Basis quality basis with cost effective world class products and brands like CANON, XEROX, KYOCERA, KONICA MINOLTA, RICHO​." ]

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[ "In the latest installment of our new (semi)regular segment, Wow! ", "Really?, ", "we examine little-known or unexpected facts about Hungary and Hungarian culture.", "\n\nYou may know the saying “Hungarians can be found everywhere in the world”. ", "That’s fine it is not a surprise you can find Hungarians in the member states of the European Union, or overseas in Canada and the United States. ", "It can be unexpected to meet Hungarians in China, Japan and other far eastern places but did you know there are Hungarian villages in the middle of the rainforest of Latin-America? ", "Now, you may say; wow! ", "really?", "\n\nIn the north-eastern part of Argentina, you can find the Province of Chaco. ", "This territory with its subtropical climate has historically been among Argentina’s poorest regions. ", "Here in the eastern part of the province, the summers are hot with temperatures that can reach up to 38 to 41°C (100 to 106 °F). ", "What the hell are the Hungarians doing here, in the hell of Chaco? ", "It is a hard story how they arrived but it may be more tough how they survived…\n\nHungarian immigrants began arriving in the province of Chaco in the mid 1920s. ", "They escaped after World War I and wanted to reach North-America but they transported to South-America. ", "Here besides contending with drought in the dry season, settlers had to endure heavy rainfall and even the periodic flooding of the Bermejo River during the long rainy season. ", "Cotton was introduced around this times. ", "The Hungarian farmers after cutting space from the rainforest decided to make it on their own and they started growing cotton. ", "In time, out of the several pioneer communities that Hungarian settlers had helped populate, two grew into towns: Villa Ángela and Coronel du Garaty.", "\n\nAlthough, Villa Ángela is a small town with a mixed population of German, Polish, Hungarian and Argentinian habitants but Coronel du Garaty is a real kind of Hungarian village where the people speak Hungarian with a Transylvanian dialect; even the Mayor is Hungarian! ", "What’s more, nowadays there are strong and active Hungarian communities in Argentina.", "\n\n*If you speak Hungarian here, you can watch this documentary about the Hungarians of Chaco;\n\nvia: Friends of Hungary Magazine; wikipedia.com; mno.hu; kulsomagyarok.blogspot.hu; Church and Society in Hungary and in the Hungarian Diaspora\n\nphotos: friendsofhungary.hu; index.hu; pinterest.com" ]

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[ "Michael Flynn, President Trump's national security advisor, resigned last night over a controversy about a phone call he made to the Russian ambassador to the U.S. in December. ", "In his resignation letter, Flynn said he \"inadvertently\" provided \"incomplete information\" about phone calls to the ambassador—specifically, Flynn told Vice President Mike Pence and Reince Priebus, the White House chief-of-staff, he did not discuss sanctions with the ambassador even though he did. ", "In its last days, the Obama administration imposed new sanctions on Russia over its alleged interference in the 2016 presidential election—Russia did not respond, and Trump called that a \"great move\" and Putin \"very smart.\"", "\n\nLate last month, the Department of Justice reportedly informed the Trump White House that Flynn had misled it about his call to the ambassador—the Washington Post reports that the message was delivered by Sally Yates, who Trump fired after she said she was not convinced the DOJ should defend Trump's travel ban executive order in court. ", "It's unclear how the DOJ concluded Flynn was not being truthful about his phone call with the ambassador.", "\n\nThe Daily Wire's Ben Shapiro notes two possibilities for Flynn's deceit—that he misled Pence, Priebus, and Trump, or that he withheld the nature of his call to the ambassador from Pence and Priebus because Trump had not authorized him to disclose that information to others.", "\n\nCongressional Democrats insist Flynn is \"just the beginning\" and are calling for hearings on the phone call. \"", "It defies reason,\" Rep. Peter Welch (D-Vt.) ", "said, according to The Hill. \"", "People in that position don't do things without authorization.\" ", "The House and Senate intelligence committees are already probing allegations of Russian interference in last year's election.", "\n\nRussian policy makers and political elites, meanwhile, are growing more concerned about the Trump administration and U.S.-Russia relations, as Foreign Policy reports. ", "Ivan Krastev and Stephen Holmes write that Russia's leadership is worried about trade wars, and that the Trump presidency also meant \"Putin has lost his monopoly over geopolitical unpredictability.\" ", "The two also report that Kremlin insiders may be most worried about Trump resigning, being removed from office, or even being killed, which would be \"bound to unleash a virulent and bipartisan anti-Russian campaign\" in the U.S. \"Putin has become a hostage to Trump's survival and success,\" the two conclude, saying that that reality has restricted Russia's options on the international stage.", "\n\nIt's a far cry from November, when Russian leaders reportedly cheered the results of the U.S. presidential election. ", "Russia preferred the unpredictability of Trump to the predictably aggressive stance Clinton had staked as secretary of state and was campaigning for president on. ", "The hysteria whipped up by the American political elite over Russia's alleged influence on the election may yet exert enough pressure on the U.S. to keep its relations with Russia frosty. ", "Russia's political elite, too, may be working toward that goal—Russia reportedly deployed a cruise missile in violation of a 1987 arms control treaty. ", "It had test fired the missile back in 2014." ]

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[ "Antigen presentation is an obligatory step in the development of specific antibody and cellular immune responses that protect individuals from infection. ", "Understanding this process should lead to novel approaches to control immune responses including the development new and more effective vaccines. ", "The theme of this project remains the analysis of how antigens (Ags) are processed and presented to T lymphocytes. ", "The central hypothesis of this project is that class I Ag processing involves the cleavage of Ags into peptides through the action of intracellular proteanases. ", "There are 3 specific Aims: 1. ", "What is the role of ubiquitin and the 265 proteasome in class I Ag presentation? ", "The goals of this Aim are: (i) To evaluate whether and to what extent Ub and the 26S proteasome play a role in the processing of endogenous Ags for class I presentation; and, (ii) To test the hypothesis that the rate of degradation of Ags in the cytosol is a critical parameter that influences the efficiency of class I presentation. ", "The experimental approach is to analyze whether blocking or enhancing degradation by the Ub-proteasome pathway of degradation affects class I-restricted Ag presentation. ", "These studies will define the role of a major catabolic pathway in Ag processing. ", "In addition, these experiments will define how degradation may control the immunogenicity of intracellular Ags and could provide a rationale strategy for designing more active vaccines. ", "2. ", "Does a form of the proteasome generate appropriate peptides for class I presentation? ", "The goal of this Aim is to examine whether the proteasome generates antigenic peptides and whether its activity/specificity is immunologically-regulated. ", "The experimental approach will be to analyze in cell free systems the activity and specificity of the various forms of the proteasome from normal, mutant or interferon-stimulated cells. ", "These experiments will define whether the 205 or 265 proteasome produce one or both appropriate cleavages for immunogenic peptides and what role the MHC- encoded subunits may play in this process. ", "3. ", "How does a subset of APCs process exogenous Ags for MHC class I presentation? ", "The goal of this Aim is to define the apparently novel pathway through which some APCs processes exogenous Ag. ", "The experimental approach will use mutant (targeted gene disruption) and cloned-lines of these APCs in studies that will directly follow the fate of Ag and in experiments using modified-Ags and selective inhibitors to probe the key steps in this pathway." ]

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[ "The president is tweeting again.", "\n\nHe’s mad at the “negative (Fake)” coverage of TV network news. ", "And he’s using Twitter to float a new idea for striking back — which, if it actually happened, would be very worrisome indeed.", "\n\nThe Fake News is working overtime. ", "Just reported that, despite the tremendous success we are having with the economy & all things else, 91% of the Network News about me is negative (Fake). ", "Why do we work so hard in working with the media when it is corrupt? ", "Take away credentials? — ", "Donald J. Trump (@realDonaldTrump) May 9, 2018\n\nTrump’s tweet is based on a right-wing “watchdog” study — via Fox News, of course\n\nAt this point, when Trump tweets that something was “just reported,” it practically goes without saying that it was reported on Fox & Friends, the Fox News morning show that has all but supplanted the president’s daily intelligence briefing.", "\n\nMatt Gertz of the progressive media watchdog Media Matters pegged the exact Fox & Friends segment Trump was referring to — presumably watching on tape delay on his “super TiVo” an hour and a half after it aired:\n\nThe \"91% negative\" data that spurred Trump to float pulling media credentials is a Media Research Center report aired on Fox & Friends this morning.", "\n\n\n\nLeft, Fox & Friends, 6:09 am\n\nRight, Trump, 7:38 am pic.twitter.com/f3M2l5hvdg — Matthew Gertz (@MattGertz) May 9, 2018\n\nThe Fox report, in turn, is based on a study by the Media Research Center, a right-wing media watchdog group. ", "Fox’s graphic isn’t quite right: The most recent Media Research Center report on network coverage, from January 1 to April 30 of this year, shows that 90 percent of Trump coverage was negative, not 91 percent. ", "Previous Media Research Center reports, issued last fall and this March, showed that 91 percent coverage was negative.", "\n\nIt’s not clear how the Media Research Center determines whether coverage is positive or negative, and the consistency of their findings — with multiple studies showing the exact same 9 percent/91 percent split of positive versus negative coverage — might raise some questions as to the rigor of their methods.", "\n\nBut other analysts agree that network coverage of Trump has been more negative than positive. ", "The Shorenstein Center on Media, Politics, and Public Policy at the Harvard Kennedy School found that over Trump’s first 100 days in office, network coverage of Trump that expressed a position was more than 90 percent negative on CNN, CBS, and NBC — though that doesn’t include a large share of coverage that was deemed neutral.", "\n\nDear Donald Trump: negative coverage doesn’t mean “Fake” news\n\nIt’s nice of Trump to admit, explicitly, what many skeptics have suspected all along: When he complains about “fake news,” he doesn’t actually mean “news that is untrue”; he means news that is personally inconvenient to Donald Trump.", "\n\nThe Media Research Center didn’t say 91 percent of Trump coverage was fake. ", "Trump himself conveniently drew the connection.", "\n\nAnd having conflated “negative” with “Fake,” he proceeded to float the idea of punishing the press for its perceived transgressions — in particular, revoking their credentials (presumably their White House credentials).", "\n\nIf this actually happened, it would be an unprecedented attack on the freedom of the press. ", "Revoking White House credentials for major news outlets simply because the president doesn’t like them wouldn’t technically be censorship, but it would certainly put a thumb on the scale of White House coverage.", "\n\nBut it’s also worth noting that at this point, President Trump has done a lot of Twitter saber rattling about the press having too much freedom and hasn’t spent a lot of energy acting on it.", "\n\nTrump’s White House has reduced access to the president in official Oval Office press gaggles, and his press secretaries call on explicitly pro-Trump and conservative outlets more than their predecessors (and nonpartisan outlets, by extension, less often). ", "But when the White House actually tried to restrict some outlets from accessing a press briefing in February 2017, other outlets refused to attend in solidarity — and two of the outlets that did send reporters clarified after the fact that if they’d known some journalists would be barred, they wouldn’t have gone.", "\n\nThe White House hasn’t tried to pull that trick in the past several months. ", "Sarah Huckabee Sanders complains about the press corps, but she talks to them.", "\n\nIt’s reasonable to worry about reporters changing their behavior due to Trump’s threats, and becoming more obedient. ", "But if it hasn’t happened after the past several gripes and threats, it’s not clear why it would start now." ]

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[ "Dixon, Illinois\n\nDixon is a city and the county seat of Lee County, Illinois, United States. ", " The population was 15,733 as of the 2010 census, down from 15,941 in 2000. ", "The city is named after founder John Dixon, who operated a rope ferry service across Rock River, which runs through the city. ", "The Illinois General Assembly designated Dixon as \"Petunia Capital of Illinois\" in 1999 and \"The Catfish Capital of Illinois\" in 2009.", "\n\nDixon is the boyhood home of former U.S. President Ronald Reagan. ", "The city is also the site of the Lincoln Monument State Memorial, marking the spot where Abraham Lincoln joined the Illinois militia at Fort Dixon in 1832 during the Black Hawk War. ", "The memorial is located on the west side of Dixon's main north-south street, Galena Avenue, (U.S. Route 52, also Illinois Route 26), north of the Rock River.", "\n\nHistory\nAround 1828, Joseph Ogee, a man of mixed French and Native American descent, established a ferry and a cabin along the banks of the Rock River. ", "In 1829, an employee of Ogee was named postmaster at the newly constructed post office. ", "John Dixon, the eponymous founder, bought Ogee's Ferry in the spring of 1830 and brought his family to his newly purchased establishment on April 11 of that year. ", "Shortly after, the name of the post office was changed to Dixon's Ferry.", "\n\nOn May 4, 1873, the Truesdell Bridge collapsed resulting in the deaths of 45 people. ", " A large number of people were on the bridge in order to watch a baptism ceremony in the river below.", "\n\nRunning by Interstate 88 is a road named Bloody Gulch Road. ", "The road is named after a murder and body disposal. ", "On September 12, 1885, two young men walked along a county road south of Dixon, one a farm hand named Joseph M. Mosse and the other, Frank C. Thiel, a traveling salesman from Elgin, IL. ", "The unemployed farmhand told the salesman of a place he could sell his Bibles and proceeded to take him to a farm where he had worked. ", "As the two men passed a gulch the farmhand struck and killed the salesman with a knife and a walnut baluster he was seen carrying under his arm. ", "He then buried the body in the culvert. ", "The body was later discovered when cattle refused to use the underpass en route to a milking barn. ", "An overnight rain had washed away some of the dirt exposing a limb. ", "When the sheriff arrived to question the farm hand, since he was seen leaving Dixon with the deceased, he pretended to get a drink while throwing a watch chain taken from the salesman in the bushes. ", "The evidence was found and the farmhand was eventually put in jail for life, while the road over the underpass began to be called Bloody Gulch Road.", "\n\nIn April 2012, Dixon Municipal Comptroller Rita Crundwell was indicted by a Federal Grand Jury for embezzlement. ", "She used the embezzled funds to pay for her lavish lifestyle and what became one of the nation's best-known quarter horse-breeding programs, among other things. ", "Crundwell's crimes, thought to be the most substantial municipal theft in U.S. history, impacted Dixon's finances severely. ", "Federal prosecutors estimated the amount embezzled at $53 million since 1990. ", "The city sued the auditors who had failed to detect the embezzlement and the bank at which Crundwell maintained a secret account, and received $40 million in settlements. ", "In February 2013, Crundwell was sentenced to almost 20 years in prison.", "\n\nOn May 16, 2018, Matthew Milby, a 19-year-old student entered Dixon High School and fired shots during graduation practice. ", "He was pursued by School Resource Officer Mark Dallas, of the Dixon Police Department. ", "After firing shots at the officer, the shooter was wounded by Dallas as he returned fire. ", "He was taken into custody. ", "There were no additional injuries.", "\n\nRonald Reagan\nDixon is the boyhood home of the 40th President of the United States, Ronald Reagan. ", "Reagan was born in nearby Tampico and moved to Dixon, aged nine. ", "In his teen years, he lifeguarded along the banks of the Rock River. ", "His family house is preserved at 816 South Hennepin Avenue, and authorized by Congress to become the Ronald Reagan Boyhood Home. ", " In 1984, during his first term as president, Reagan returned to Dixon to celebrate his 73rd birthday. ", "He toured his boyhood residence and the city held a parade in his honor.", "\n\nGeography\nAccording to the 2010 census, Dixon has a total area of , of which (or 94.51%) is land and (or 5.49%) is water.", "\n\nDemographics\n\nAs of the census of 2000, 15,941 people, 5,681 households, and 3,488 families resided in the city. ", "The population density was 2,519.8 people per square mile (972.3/km²). ", "The city consisted of 6,138 housing units at an average density of 970.3 per square mile (374.4/km²). ", "The city's racial makeup included 86.33% White, 10.48% African American, 0.14% Native American, 0.82% Asian, 0.05% Pacific Islander, 1.10% from other races, and 1.09% from two or more races. ", "Hispanic or Latino of any race comprised 4.30% of the population.", "\n\nOf 5,681 households out of which 29.8% had children under the age of 18 living with them, 45.7% were married couples living together, 11.8% had a female householder with no husband present, and 38.6% were non-families. ", "32.6% of all households were made up of individuals and 14.7% had someone living alone who was 65 years of age or older. ", "The average household size was 2.32 and the average family size was 2.94.", "\n\nIn the city, the population was spread out with 20.9% under the age of 18, 8.9% from 18 to 24, 34.6% from 25 to 44, 20.7% from 45 to 64, and 14.9% who were 65 years of age or older. ", "The median age was 37 years. ", "For every 100 females, there were 110.5 males. ", "For every 100 females age 18 and over, there were 112.6 males.", "\n\nThe median income for a household in the city was $35,720, and the median income for a family was $45,088. ", "Males had a median income of $32,511 versus $21,777 for females. ", "The per capita income for the city was $16,630. ", "About 5.7% of families and 10.1% of the population were below the poverty line, including 10.7% of those under age 18 and 12.0% of those age 65 or over.", "\n\nEconomy\n\nDixon is a regional employment hub and is part of two fast growing distribution and warehousing and food processing districts: one is I-88 West and the other, the I-39 Logistics Corridor. ", "The biggest industries are healthcare and government. ", "Healthcare employs over 1,700, while government jobs approach 1,500. ", "The Dixon Correctional Center employs over 600 workers, as does the Department of Transportation. ", "KSB Hospital has nearly 1,000 employees. ", "Dixon has many industries employing thousands of the region's residents. ", "The largest are Raynor Garage Doors, Donaldson Inc., Borg Warner, and Spectrum Brands. ", "Fifteen miles away in Ashton, Crest Foods employs over 600.", "\n\nArts and culture\n\n The city of Dixon has numerous art venues including: a downtown art gallery, 2 galleries held in museums, and several private business galleries. ", "Dixon also has a performing arts theatre called Dixon Stage Left, and a musician and visual arts co-op called Rosbrook Studio. ", "The city has numerous festivals throughout the year including: Gardenstock Arts & Music Fest, Venitian Night on the Riverfront, a downtown wine festival, Blues-Brews-and BBQ, Reagan Trail Days, and the fall Scarecrow Festival.", "\n\nEvery summer Dixon holds the annual Petunia Festival featuring a parade, carnival (Farrow shows), country concert, fireworks show, and a 5K race—the Reagan Run. ", "The parade features a multitude of floats from surrounding businesses, politicians, and other area groups. ", "A carnival is also held in Dixon during this time, and the festival ends with the Fourth of July fireworks. ", "The Downtown district has become a National Historic District. ", "The Rock River which runs through the center of Dixon has been designated a National Waterway by the Federal Government. ", "Dixon residents have supported a variety of large-scale projects that have created several aspects to their rural community. ", "One aspect of this small town is that an individual can kayak the Rock River to the city's downtown docks and join a public Yoga session on the riverfront.", "\n\nThe Petunia Festival was conceived after Dutch Elm Disease and highway expansion wiped out the trees along the major roads in the late 1950s. ", "In response to the dramatic change the streetscape underwent, the Dixon Men's Garden Club planted petunias along Galena Avenue to regain some sort of streetscape identity once again in the early 1960s. ", "Before this annual festival, volunteers plant thousands of pink petunias along the main streets. ", "The flowers are watered and maintained by the combined efforts of city workers and volunteers.", "\n\nAn iconic arch along Galena Avenue, just south of the Rock River, features the word \"Dixon\" in neon glasswork. ", "Though commonly referred to as the Dixon Arch, the proper name for the structure is the War Memorial Arch. ", "The Northwest Territory Historic Center is a History Research and Learning Center housed in President Ronald Reagan's boyhood South Central School. ", "Restored with the dedicated support of the townspeople and Reagan colleagues, the Center is proudly affiliated with the Smithsonian Institution.", "\n\nThe Center houses the Veterans History Project Regional Center, auditorium, research library, historical exhibits, art gallery, surround-sound theater, and museum store.", "\n\nParks and recreation\n\nThe Dixon Park District owns more than of land including two historic parks platted in 1842. ", "The parks range from Lowell Park's which is listed on the National Register of Historic Places; rural Meadows Park which encompasses of recreational opportunities with natural areas and farm land; to neighborhood parks located throughout the city. ", "Lee County, of which Dixon is the County Seat, offers many recreational areas and campgrounds; over 7,000 campsites are located within 17 miles of the city. ", "Tourists from nearby Chicago take advantage of Lee County's recreational opportunities, particularly during summer weekends, adding approximately 20,000 people to the area's population.", "\n\nInfrastructure\n\nHealth care\nDixon is a regional center for healthcare. ", "The community has KSB Hospital which is a medical student teaching facility, 4 adult clinics, a children's clinic, 2 dialysis centers, 2 urgent care clinics, and is home to Sinnissippi Mental Health Center and the Northern Illinois Cancer Center. ", "There is also a hospital, an infirmary, and a clinic for the mentally ill at the Dixon Correctional Center. ", "The Mabley State Mental Health complex is also located in Dixon.", "\n\nNotable people\n\nWilliam Conger: painter and educator\nHubert D. Considine: Illinois state representative and businessman.", "\nRita Crundwell: breeder of quarterhorses; embezzled approximately $53 million while Dixon comptroller in what is believed to be the largest municipal fraud in American history.", "\nJohn Dement: 19th century politician and military commander.", "\nJohn Deere: industrialist, manufacturer, invented first commercially successful steel plow; born in Vermont, lived in Grand Detour.", "\nJohn Devine: professional bicycle racer.", "\nJohn P. Devine: Speaker of the Illinois House of Representatives.", "\nSherwood Dixon: politician, 36th Lieutenant Governor of Illinois.", "\nJames K. Edsall: politician, Illinois Attorney General.", "\nSamuel Cook Edsall: Episcopal Bishop of Minnesota.", "\nDaniel G. Garnsey: United States Congressman.", "\nJerry Hey: five-time Grammy winner.", "\nDavid Klamen: artist and academic\nJeanie Linders: writer and producer of Menopause: The Musical.", "\nWilliam H. McMaster: South Dakota state representative, state senator, lieutenant governor, governor, US senator, later banker in Dixon.", "\nWard T. Miller: professional baseball player in early 1900s for Pittsburgh Pirates, Cincinnati Reds, Chicago Cubs, St. Louis Terriers (FL) and St. Louis Browns.", "\nLouella Parsons (born Louella Rose Oettinger): influential newspaper columnist; born in Freeport and grew up in Dixon.", "\nRonald Reagan: 40th President of the United States, 33rd Governor of California, noted actor; born in Tampico and grew up in Dixon.", "\nRondi Reed: Tony Award-winning actress and singer.", "\nFred E. Sterling: politician.", "\nCharles Rudolph Walgreen: founder of drugstore chain; he grew up in Dixon and began his career there as a pharmacist.", "\nLarry Young: MLB umpire.", "\nIsaiah Roby: NBA Oklahoma City Thunder\n\nSee also\nDixon High School\nSauk Valley Community College\nIllinois Central Stone Arch Railroad Bridges\nNachusa House\nWilliam H. Van Epps House\nLincoln Highway\nRonald Reagan Trail\nNachusa Grasslands\n\nReferences\n\nExternal links\n\nDixon Chamber of Commerce\n Town Dixon- Newspaper\n\nCategory:Cities in Illinois\nCategory:Cities in Lee County, Illinois\nCategory:County seats in Illinois\nCategory:Dixon, Illinois\nCategory:Micropolitan areas of Illinois\nCategory:Populated places established in 1828\nCategory:Ronald Reagan Trail" ]

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[ "\n636 F.Supp. ", "1453 (1986)\nPROJECT BASIC TENANTS UNION, Plaintiff,\nv.\nRHODE ISLAND HOUSING AND MORTGAGE FINANCE CORPORATION, et al., ", "Defendants.", "\nCiv. ", "A. No. ", "85-0131.", "\nUnited States District Court, D. Rhode Island.", "\nJune 5, 1986.", "\n*1454 *1455 John W. Dineen, Michael V. Milito, Providence, R.I., for plaintiff.", "\nWilliam P. Robinson III, Michael DiBiase, Edwards & Angell, Providence, R.I., for defendant R.I. Housing.", "\nElizabeth A. Del Padre, Office of Atty. ", "Gen., Providence, R.I., for defendant State of R.I.\nHerbert DeSimone, Sr., ", "Providence, R.I., for defendant DiPrete.", "\nFaith A. LaSalle, Asst. ", "City Sol., ", "Providence, R.I., for defendant City of Providence.", "\nDonald S. Ianazzi, Providence, R.I., for defendant Cianci.", "\n*1456 John Tramonti, Providence, R.I., for defendant Ralph Pari.", "\nMichael T. Robinson, HUD Office of Litigation, Washington, D.C., for defendant Dept. ", "of Housing and Urban Development.", "\nMichael P. Iannotti, Asst. ", "U.S. Atty., ", "Providence, R.I., for U.S.\n\nOPINION\nFRANCIS J. BOYLE, Chief Judge.", "\nPlaintiff, Project Basic Tenants Union, sues Rhode Island Housing Mortgage Finance Corporation (\"RIHMFC\"), the City of Providence, the State of Rhode Island, the United States Department of Housing and Urban Development (\"HUD\"), and certain named City and State officials and ex-officials. ", "It alleges that Defendants have violated federal law by adopting and promulgating racially discriminatory housing practices, in the City of Providence generally and in the Silver Lake area specifically. ", "Defendants have moved to dismiss the action on the ground that Plaintiff lacks both the capacity and standing to sue. ", "The Court heard argument and reserved decision. ", "For reasons detailed below, the Court holds that Plaintiff has the capacity to sue and has standing as to some Defendants. ", "The Plaintiff lacks standing as to other Defendants. ", "The motions of Defendants RIHMFC, State of Rhode Island, City of Providence and HUD are denied. ", "Those of the individual Defendants, Mayor Paolino, Governor DiPrete, Councilman Stravato, Commissioner Pisaturo, former Mayor Cianci and Ralph Pari, are granted.", "\n\nI.\nPlaintiff is an association of individuals who seek to rectify perceived inequalities in Providence housing.[1] It has two self appointed chairpersons, and no set number of members. ", "Membership in the association generally consists of lessees in public and private housing. ", "Membership is voluntary, based on consistent attendance at association meetings. ", "Project Basic Tenants Union operates under the umbrella of the John Hope Settlement House, a neighborhood community center which provides certain social services. ", "The Tenants Union has no budget or bank account apart from that of the Settlement House. ", "In fact, it is an association under the group known as Project Basic, an apparently more formal association within the Settlement House. ", "Project Basic is also financially dependent upon the larger association. ", "Project Basic Tenants Union is not incorporated and was not formed pursuant to any statutory authority.", "\nIn 1976, a development group known as Hillside Associates sought and received from RIHMFC financing for a federally subsidized housing project to be constructed in the Silver Lake area of Providence. ", "As of the 1980 census, Silver Lake was the least integrated tract of the 36 Providence census tracts. ", "At that time, the development group, through the efforts of RIHMFC, also received a commitment from HUD for federal rental subsidy for the project.", "\nShortly thereafter, Hillside Associates retained a builder who sought a building permit from the City of Providence. ", "At this time, however, public objection to the Hillside Project was mounting. ", "It is alleged that then Mayor Cianci and City Councilman Louis R. Stravato, both named Defendants, were among those speaking out against the project, and that they vowed to stop it. ", "In 1978, the City changed its zoning in the Silver Lake area so that the project could not proceed.", "\nVincent J. Mesolella, owner of the targeted land in Silver Lake and organizer of Hillside Associates, challenged the City zoning change in the state courts. ", "The Rhode Island Supreme Court ultimately sustained a Superior Court ruling which invalidated the zoning change and removed any zoning barrier to the Hillside Project. *", "1457 Mesolella v. City of Providence, 439 A.2d 1370 (R.I.1982).", "\nWhile the zoning issue was being resolved, HUD and RIHMFC had not terminated their financing commitments, but had held them in abeyance. ", "Opponents of Hillside Village learned of this fact and in February of 1985 \"renewed their efforts to terminate the development or have it moved to South Providence.\" ", "Former Mayor Cianci allegedly rejoined the effort, and Governor DiPrete and the State allegedly urged RIHMFC and its Executive Director Ralph Pari to withdraw their financing commitment. ", "On March 1, 1985, RIHMFC did in fact withdraw its financing commitment. ", "HUD has confirmed that, from its standpoint, the project is still feasible.", "\nPlaintiff alleges in substance that the policies and practices of the Defendants both generally and in relation to Hillside Village have, in a racially discriminatory manner, denied low income minorities access to open and integrated housing in the City of Providence. ", "With respect to all non-federal Defendants, Plaintiff alleges violations of the Fair Housing Act, 42 U.S.C. § 3601, Title VI of the Civil Rights Act of 1964, 42 U.S.C. § 2000d, the civil rights laws of 42 U.S.C. §§ 1981 and 1982, the Thirteenth and Fourteenth Amendments, and the United States Housing Act, 42 U.S.C. § 1437. ", "It alleges that the federal Defendant, HUD, in violation of the Fair Housing Act, has provided funds to Providence and Rhode Island despite known Title VIII non-compliance by the City. ", "Plaintiff seeks damages, declaratory relief, and injunctive relief including but not limited to:\n1. ", "a direction that RIHMFC rescind its announcement withdrawing financing for Hillside Village and seek the necessary extensions of its financing commitment and HUD's reservation of funds;\n2. ", "an injunction against further opposition to the Hillside project against the named City and State officials and former Mayor Cianci;\n3. ", "a direction that the City, State and RIHMFC develop a plan to alleviate a general \"imbalance in terms of geographical location and elderly-family proportionality\" in Providence housing; and\n4. ", "a direction that HUD withhold federal funding earmarked for Providence until the City establishes its compliance with its Title VIII obligations.", "\nPlaintiff seeks to raise and protect the rights of certain named members of its association. ", "By way of affidavit, Plaintiff certifies that two members, Mary-Lou Tetreault and Cassandra Plummer, are income eligible for Section 8 housing, would like to live in Silver Lake, and would apply for admission to Hillside Village if it were built. ", "The depositions of these two individuals reveal that neither has sought any housing, let alone Section 8 housing, in at least two years, and the eligibility of each for Section 8 housing is questionable—Ms. ", "Tetreault, because of a lack of credit worthiness, and Ms. Plummer, due to income in excess of the maximum requirement.", "\nAll Defendants question Plaintiff's standing to sue in either its own right as an organization or as representative of its members. ", "Defendant RIHMFC raises a more basic concern—whether the Plaintiff is a legal entity capable of bringing suit at all. ", "The Court will first address this capacity concern and then the standing questions.", "\n\nII.", "\nAt common law, an unincorporated association had no capacity to sue or be sued. ", "See Puerto Rico v. Russell & Co., 288 U.S. 476, 480, 53 S.Ct. ", "447, 448, 77 L.Ed. ", "903 (1933). ", "However, two exceptions to this rule have developed. ", "First, an unincorporated association may sue or be sued if the law of the forum state recognizes such capacity. ", "3A Moore's Federal Practice ¶ 17.25. ", "Secondly, \"a partnership or other unincorporated association ... may sue or be sued in its common name for the purpose of enforcing for or against it a substantive right existing under the Constitution or laws of the United States.\" ", "Fed. ", "R.Civ.", "P. 17(b); see 3A Moore's Federal Practice ¶ 17.25. ", "Here, Plaintiff association clearly seeks to raise federal rights *1458 and, therefore, has capacity to sue if it in fact can be characterized as an \"unincorporated association.\"", "\nAn unincorporated association is generally defined as \"a body of persons acting together and using certain methods for prosecuting a special purpose or common enterprise.\" ", "Motta v. Samuel Weiser, Inc., 768 F.2d 481, 485 (1st Cir.), ", "cert. ", "den., ___ ", "U.S. ___, 106 S.Ct. ", "596, 88 L.Ed.2d 575 (1985). \"", "The common purpose or interest affords a court objective criteria by which it may ascertain the membership.\" ", "Motta v. Samuel Weiser, Inc., 598 F.Supp. ", "941, 950 (D.Me.1984), aff'd, 768 F.2d 481 (1st Cir.), ", "cert. ", "den., ___ ", "U.S. ___, 106 S.Ct. ", "696, 88 L.Ed.2d 575 (1985). ", "Associations that are not actual assemblages of people, but rather are \"amorphous and attenuated ...\" groups or \"the most informal or transitory of organizations,\" have been held not to constitute unincorporated associations. ", "See Motta, 768 F.2d at 486; California Clippers, Inc. v. United States S.F. Ass'n., ", "314 F.Supp. ", "1057, 1067 (N.D.Cal.1970).", "\nProject Basic Tenants Union lacks structure. ", "It has no elected officers, no budget, no by-laws and apparently no set group of members. ", "Yet, it has a distinct purpose and performs specific functions toward that end. ", "Its purpose is to aid low income residents of Providence in their search for decent and affordable housing, and in addition, to assist tenants, who are or who become housed, with various problems that arise amongst tenants. ", "The Union, through sub-committees, meet once every two months to discuss Union action. ", "Its members knock on doors and make phone calls to make known their views and concerns, and the concerns of other members. ", "Union members have met with City officials in an effort to improve the plight of tenants. ", "The Union's membership is indefinite; any one willing to meet and work toward the Union's goal may join. ", "Yet, in light of its very definite purpose and activities, the Union is clearly an actual assemblage of people, and is far from an amorphous or transitory group.", "\nThe Court is not persuaded by the case law cited by Defendant RIHMFC in its reply brief in support of its contention that Plaintiff lacks capacity. ", "In California Clippers Inc. v. United States S.F. Ass'n, supra, the court, in finding that the International Games Committee was not an unincorporated association, noted that the committee had no office or place of business, had no mailing address and had not transacted any business. ", "In Trustees of Huntington v. Environmental Protection Agency, 55 F.R.D. 445, 454 (E.D.N.Y.1972), the court found that the plaintiff, a group of trustees, was a \"non-existent body with non-existent members.\" ", "Unlike the plaintiff in California Clippers, Plaintiff has office space, indeed a full-time staff person; it has funding and presumably does business on its own behalf. ", "A finding that Plaintiff or its members are \"non-existent\" can hardly be made here. ", "The Court holds that the Tenants' Union is an \"unincorporated association\" capable of bringing suit.", "\nIt is necessary therefore to proceed to the issue of Plaintiff's standing.", "\n\nIII.", "\n\nA.\nThe standing doctrine is one of a number of doctrines which define the \"case and controversy\" requirement of Article III of the Constitution. ", "See Allen v. Wright, 468 U.S. 737, 104 S.Ct. ", "3315, 3324, 82 L.Ed.2d 556 (1984). ", "It, along with the other \"case and controversy\" doctrines, ensures that federal courts hear actual controversies rather than deciding legal questions in the abstract. ", "If a plaintiff lacks standing to redress a claimed wrong, he has not presented a \"case or controversy,\" and an Article III court lacks subject matter jurisdiction over the suit presented. ", "See Valley Forge Christian College v. Americans United for Separation of Church and State, Inc., 454 U.S. 464, 471-476, 102 S.Ct. ", "752, 757-760, 70 L.Ed.2d 700 (1982).", "\nTo have constitutional standing a plaintiff must allege three elements. ", "He must allege: 1) that he has suffered personal injury; 2) that the injury is fairly traceable to the defendant's allegedly unlawful *1459 conduct; and 3) that the injury is likely to be redressed by the requested relief. ", "Allen, supra, 104 S.Ct. ", "at 3325 (citing Valley Forge, supra, 454 U.S. at 472, 102 S.Ct. ", "at 758). ", "An organization has standing on its own behalf if it can allege that it has suffered the requisite injury. ", "See Havens Realty Corp. v. Coleman, 455 U.S. 363, 378-79, 102 S.Ct. ", "1114, 1124, 71 L.Ed.2d 214 (1982). ", "An organization may sue on behalf of one or more of its members if the members would themselves have standing to sue. ", "See Warth v. Seldin, 422 U.S. 490, 511, 95 S.Ct. ", "2197, 2211, 45 L.Ed.2d 343 (1975).", "\nA second component of standing, the so-called \"prudential component,\" is comprised of a number of judicially imposed limitations on the exercise of federal jurisdiction. ", "Allen, supra, 104 S.Ct. ", "at 3324-25. ", "Among these are the rules that a party generally lacks standing to raise the rights of third parties, that a federal court will not exercise jurisdiction over a generalized grievance, and that a plaintiff must raise rights that are within the zone of protection of the statute he invokes. ", "Allen, supra, at 3324-25. ", "The Supreme Court has held that in a suit brought under the Fair Housing Act these prudential concerns need not be considered; a plaintiff need only meet the constitutional requirements. ", "Havens Realty Corp. v. Coleman, supra, 455 U.S. at 372, 102 S.Ct. ", "at 1120. ", "Since Plaintiff's claim is based in part on the Fair Housing Act, the Court need only concern itself with the constitutional standing requirements.", "\nPlaintiff claims both organizational injury and injury suffered by its members. ", "Plaintiff alleges that Defendants, through their discriminatory practices, both generally and in relation to Hillside Village, have adversely affected its ability to provide effective housing assistance to its members. ", "It alleges that its members have: 1) suffered a nine year deprivation of subsidized housing in the Silver Lake area, 2) have suffered the loss of open housing opportunities throughout the City, 3) have, through the deprivation of open housing, lost the benefits of living in an integrated community, and 4) have suffered stigmatic injury which flows from \"forcing [Union members] to interact on a daily basis under the weight of the badge of inferiority.\" ", "The Court finds that Plaintiff has alleged an organizational injury, which is causally related to Defendants' alleged activities, and which the Court can redress through the requested relief. ", "Plaintiff has standing on this basis. ", "Therefore, the Court need not address Plaintiff's claims of injury to its members in deciding this motion.", "\n\nB.\nAs for Plaintiff's claimed organizational injury, the Supreme Court case of Havens Realty Corporation v. Coleman, supra, is controlling. ", "In that case, a nonprofit organization, the claimed purpose of which was \"to make equal opportunity in housing a reality in the Richmond Metropolitan area,\" sued a realty company alleging racial steering in violation of the Fair Housing Act. ", "The challenge was to exclusionary practices with respect to one housing complex. ", "Plaintiff's members were identified simply as \"multiracial and includ[ing] 600 individuals.\" ", "Three named plaintiffs were renters and residents of Richmond, Virginia. ", "The Supreme Court held that the injury the organization alleged, namely, that defendant's steering practices had frustrated the organization \"in its efforts to assist equal access to housing through counseling and other referral services,\" was a sufficient allegation of injury for standing purposes. ", "Havens Realty, supra, at 379, 102 S.Ct. ", "at 1124.", "\nPlaintiff in this case alleges precisely the same type of injury. ", "It alleges harm to its \"efforts and interests ... in ... advocating for more affordable housing and more open housing opportunities throughout the City ...,\" Complaint ¶ 70, and interference with \"its encouragement of others in the enjoyment of ... the benefits of open housing.\" ", "Complaint ¶ 76. ", "Like the plaintiff organization in Havens, Plaintiff alleges that the practices involving one housing complex hurt its efforts on behalf of its Citywide members. ", "The Court finds this case and the Havens case indistinguishable and *1460 holds that Plaintiff on its own behalf has alleged \"distinct and palpable injury\".", "\nIn opposition to Plaintiff's claim of organizational injury, Defendant RIHMFC relies on the Supreme Court's statement in Havens that \"[w]e have not suggested that discrimination within a single housing complex might give use to `distinct and palpable injury' ... throughout a metropolitan area.\" ", "Havens, at 377, 102 S.Ct. ", "at 1123. ", "The reliance is misplaced. ", "In making this statement, the Court was specifically addressing the ability of individuals who lived in the general area to allege sufficient injury. ", "Similarly, the Court does not accept Defendant RIHMFC's suggestion that the rule established in Simon v. Eastern Kentucky Welfare Rights Organization, 426 U.S. 26, 96 S.Ct. ", "1917, 48 L.Ed.2d 450 (1976), is controlling. ", "The Simon court held that standing of an organization can not be based on an abstract concern. ", "Based on its allegations, Plaintiff's concern is not abstract, but rather stems from the delay of a specific housing project. ", "Defendant RIHMFC also argues that the loss of forty-two units in Silver Lake is insignificant and therefore cannot support \"distinct and palpable injury\" to Plaintiff. ", "The effect of the lost units at this early stage must be resolved in Plaintiff's favor. ", "Finally, the suggestion of the federal, state and municipal Defendants that no organizational injury is alleged is clearly in error. ", "See Complaint ¶ 70, 76.", "\n\nC.\nIn addition to alleging the requisite injury, Plaintiff must allege causation and redressability. ", "Plaintiff satisfies the causation element of standing as to RIHMFC by alleging that RIHMFC's decision to withhold funds prevented the construction of Hillside Village. ", "A direction that RIHMFC rescind its withdrawal, relief which Plaintiff seeks, would remove this impediment to construction. ", "Thus redressability as to RIHMFC is satisfied. ", "RIHMFC argues that it has recently resolved to do all it can to reinstate the mortgage loan to Hillside Associates. ", "It argues therefore that this action, as to them, is moot. ", "The Court has not heard the parties on mootness and therefore declines to reach this issue at this point.[2]\nThe Court finds causation and redressability as to the City and State. ", "Plaintiff has alleged that its injury is fairly traceable to the conduct of the City and State because it has alleged that the City and State through their officials lobbied for RIHMFC's withdrawal of its financing commitment. ", "If the Court were to order the City and State to affirmatively act to ensure that Hillside Village is built, see Resident Advisory Bd. ", "v. Rizzo, 564 F.2d 126, 138 (3rd Cir.1977), cert. ", "den., ", "Whitman Area Improv. ", "Council v. Resident Adv. ", "Bd., ", "435 U.S. 908, 98 S.Ct. ", "1457, 55 L.Ed.2d 499 (1978), there is a substantial likelihood that it will be built, for Hillside Associates have indicated their willingness to proceed. ", "The City argues that Plaintiff has no standing as to it because it was RIHMFC and HUD which stopped financing and also because the success of the project in the future depends upon the actions of RIHMFC, HUD, and the developer. ", "The State makes similar arguments. ", "Plaintiff's complaint, however, alleges that the actions of RIHMFC and HUD are traceable to the lobbying efforts of the City and State, and as noted, the developer is ready to proceed. ", "Standing to challenge a denial of housing does not require certainty that a proposed development will be built. ", "See Arlington Heights v. Metropolitan Housing Corp., 429 U.S. 252, 261-62, 97 S.Ct. ", "555, 561, 50 L.Ed.2d 450 (1977).", "\nDefendant HUD's alleged involvement is a bit more attenuated than that of the City, the State or RIHMFC. ", "Plaintiff alleges that HUD failed to condition its provision of federal funds to the City on the City's Title VIII compliance. ", "This inaction allegedly promulgated a discriminatory housing policy in the City. ", "It is this policy which in turn allegedly prompted City action *1461 toward Hillside Village. ", "The First Circuit has recognized standing against HUD where HUD's failure to condition the giving of funds, and thereby its failure to meet its affirmative obligation to ensure fair housing, allegedly caused a discriminatory municipal practice. ", "See NAACP, Boston Chapter v. Harris, 607 F.2d 514 (1st Cir.1979). ", "In NAACP, the court recognized that injury to minority plaintiffs in being unable to locate decent, low-cost housing in an integrated neighborhood was fairly traceable to HUD's failure to perform its affirmative obligation—that is, condition disbursement of funds on city compliance with fair housing mandates. ", "NAACP, supra, at 525. ", "Plaintiff organization alleges the same injury as was alleged in NAACP. ", "It, like the NAACP plaintiffs, seeks better housing, the only distinction being that Plaintiff seeks housing opportunities on behalf of others. ", "Therefore, the Court concludes that causation as to HUD is properly alleged.[3] As for redressability, the NAACP plaintiff sought an order compelling HUD to condition grants on City compliance with housing standards. ", "The court concluded that this relief was substantially likely to redress the housing shortage the minority plaintiffs confronted. ", "NAACP, supra, at 526. ", "This Court similarly finds that Plaintiff's complaint as to HUD meets the redressability prong. ", "If this Court were to order HUD to condition its future disbursement of funds to Providence on city Title VIII compliance, city support for Hillside Village is more likely.", "\nDefendant HUD raises some specific arguments against redressability. ", "It claims in substance that the Court lacks power to grant relief against HUD and therefore that Plaintiff lacks standing. ", "It argues first that sovereign immunity bars a grant of relief against HUD. ", "The Supreme Court case of Hills v. Gautreaux, 425 U.S. 284, 96 S.Ct. ", "1538, 47 L.Ed.2d 792 (1976), holds, however, that a district court has authority to require HUD to carry out the duties mandated by Title VI and Title VIII. ", "425 U.S. at 301-06, 96 S.Ct. ", "at 1548-50: see NAACP, Boston Chapter v. Pierce, 624 F.Supp. ", "1083, 1085 (D.Mass.1985). ", "The Hills court did not discuss sovereign immunity. ", "HUD's second argument is that because Title VIII implies no private cause of action, Plaintiff's claim can be based solely on the Administrative Procedure Act (hereinafter \"APA\"). ", "It then cites the case of Heckler v. Chaney, 470 U.S. 821, 105 S.Ct. ", "1649, 84 L.Ed.2d 714 (1985), for the proposition that a refusal of an agency to take enforcement action is committed to agency discretion by law and thus non-reviewable by a court under the APA. ", "Assuming Plaintiff's only claim against HUD is under Title VIII, this Court need not decide the reviewability issue at this point. ", "Under Hill, the Court has subject matter jurisdiction. ", "Pierce, 624 F.Supp. ", "at 1085-86. ", "Indeed, the standing question goes to the Court's subject matter jurisdiction. ", "The rule of Chaney is concerned with whether a plaintiff has stated a cause of action upon which relief can be granted. ", "Railway Labor Exec. ", "Ass'n v. Dole, 760 F.2d 1021, 1023 (9th Cir.1985); see Chaney, supra, 105 S.Ct. ", "at 1659 (agency decision not to institute proceedings not judicially reviewable under APA). ", "No 12(b)(6) motion is currently before the Court.", "\nThe final question this Court must address is causation and redressability with respect to the individuals named in the Complaint. ", "The following are named: Ralph Pari, former director of RIHMFC, Mayor Paolino, City Councilman Stravato, City Public Safety Commissioner Pisaturo, *1462 Governor DiPrete, and former Mayor Cianci. ", "In essence, Plaintiff's contention is that each individual at one time or another spoke out against the Hillside Village project thereby contributing to its being halted. ", "It further alleges that the individuals fueled a pattern or practice of discrimination which caused housing shortages and therefore its organizational injury. ", "The Court must at this juncture accept the allegation that the individuals involved opposed the project. ", "The Court, however, can not accept the further allegation that the outcries of these individuals caused the Hillside Village delay. ", "Housing in the City of Providence and the State of Rhode Island is presumably controlled by bodies of individuals, such as the City Council, RIHMFC and the State legislature, not individuals themselves. ", "Plaintiff cites no legal authority which empowers the governor, the mayor or individual government officials to effectuate or halt housing plans. ", "Moreover, if discriminatory policy and practices pervaded the City, State and RIHMFC, the City, State and RIHMFC are the proper parties. ", "The Court finds a lack of causation as to all individual Defendants. ", "The Court further notes that Plaintiff cites no authority which would exclude from First Amendment protection public speeches against proposed housing projects. ", "Having found no causation as to the individual Defendants, the redressibility concerns with respect to these Defendants need not be addressed.", "\n\nIV.", "\nIn sum, the Court finds standing as to Defendants City of Providence, State of Rhode Island, RIHMFC, and HUD. ", "It finds no standing as to Mayor Paolino, Governor DiPrete, Councilman Stravato, Commissioner Pisaturo, former Mayor Cianci or Ralph Pari. ", "The Court holds that Plaintiff has alleged sufficient organizational injury to support Article III standing. ", "It holds that both the causation and redressability elements of standing are satisfied only as to the City, the State, RIHMFC, and HUD. ", "Thus, the Motions to Dismiss of Defendants City of Providence, State of Rhode Island, RIHMFC, and HUD are denied. ", "The motions of Mayor Paolino, Governor DiPrete, Councilman Stravato, Commissioner Pisaturo, former Mayor Cianci and former RIHMFC director Ralph Pari are granted, and Plaintiff's Complaint as to these Defendants is dismissed.", "\nNOTES\n[1] For purposes of this Motion to Dismiss on standing grounds, the Court must accept as true allegations of the Complaint and supplemental allegations by way of affidavit, and it must view the Complaint in Plaintiff's favor. ", "Warth v. Seldin, 422 U.S. 490, 501-02, 95 S.Ct. ", "2197, 2206-07, 45 L.Ed.2d 343 (1975).", "\n[2] Indeed, mootness may be a non-issue since Plaintiff, in addition to injunctive and declaratory relief, seeks monetary relief. ", "See Havens Realty Corp., supra, 455 U.S. at 371, 102 S.Ct. ", "at 1120.", "\n[3] Defendant HUD cites the recent case of Ohio Fair Housing Congress v. Pierce, 639 F.Supp. ", "215 (D.Ohio 1986), a case in which the district court found no injury or causation as to HUD or the State of Ohio. ", "The court ruled that because the plaintiff had not alleged that a discriminatory practice of HUD or the State had caused a drain on plaintiff organization's resources, it had not alleged that its organizational injury was fairly traceable to defendants' actions. ", "Pierce at 218-19. ", "The Pierce court refused to find that a failure to enforce housing regulations could cause injury in fact to plaintiff organization. ", "The Court finds this decision inconsistent with the First Circuit's ruling in Harris and therefore declines to follow it. ", "The Harris court specifically ruled that the requisite injury can result from a failure to enforce fair housing regulations.", "\n" ]

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[ "Q:\n\nHandling mobile images in responsive theme\n\nSorry for the open-handed nature of the question, but I don't know where else to get an answer to this. ", "I'm deciding whether or not go full-force into a responsive Drupal 7 theme, probably the Omega framework. ", "\nOne issue that keeps nagging at me is that the mobile devices have to download all the large images (not to mention everything else...). ", "\nIs there an easy way to serve up smaller images for mobile devices?", "\n\nA:\n\nThere are many modules to handle responsive images, including; \n\nResponsive Images\nClient-side adaptive image\nAdaptive Image Styles (ais)\nAdaptive Image\nBorealis \n\n" ]

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[ "At the same time, she said, the idea behind the word plays into something deeply American: “Our individualism. ", "We want everything made special for us. ", "Even when it comes to salad bars.”", "\n\nAlso, the word “sounds old-fashioned and traditional,” Ms. Tannen said, naming two qualities common to the hipsterish faith that earlier generations did things in a more natural, and so, more righteous, way.", "\n\n“It’s part of the authenticity hoax,” Mr. Riccio said.", "\n\nAlong the way, the term’s meaning has become muddled. ", "For a party hosted by the music public relations firm Shore Fire Media, the invitation advertised “bespoke cocktails.” ", "But the drinks weren’t tailored to the individual. ", "Guests could choose from several predetermined concoctions.", "\n\nA popular new restaurant in the West Village, Bespoke Kitchen, may allow diners to choose their own protein and flavor profile (rich or light), but from there, the chef makes most of the decisions. ", "Diners also have the option of leaving the composition of their meal entirely up to the chef — the exact opposite of a bespoke experience.", "\n\nWith so elastic a definition, it’s small wonder one British food blogger wryly identified Burger King as the first “bespoke” restaurant, because it has allowed special orders for decades. (“", "Hold the pickles, hold the lettuce,” went its jingle.)" ]

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[ "Closed reduction, open reduction, and endoscopic assistance: current thoughts on the management of mandibular condyle fractures.", "\nThe management of fractures of the mandibular condyle continues to be controversial. ", "This is in part attributable to a misinterpretation of the literature from decades prior, a lack of uniformity of classification of the various anatomical components of the mandibular condyle, and a perceived potential to cause harm through the open approach based in part on the surgeon's lack of a critical examination of the literature. ", "This review explores the key historical articles that deal with the management of mandibular condyle fractures, and those modern-day contributions that represent the state of the art. ", "The authors' intention was to provide the reader with an objective summary of the management of this form of injury, to place its management into a modern-day perspective, and perhaps to minimize the perception of controversy." ]

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[ "This week, thoughts turn to love and disappointment.", "\n\nValentine’s Day has a special place in the underwhelming calendar, ranking slightly above taking the Christmas tree to the skip.", "\n\nAs is traditional, we would like to see how you are spending this special day - provided it’s not very good. ", "If you have old photos of previous, terrible Valentine’s Day experiences, so much the better.", "\n\nThe kind of thing we’re interested in seeing:\n\n\n\nRomantic walks ruined by drizzle\n\n\n\nBeautiful meals left in the oven too long\n\n\n\nAwful cards\n\n\n\nHeartfelt (but in hindsight, slightly weird) gestures that seemed like a good idea at the time\n\n\n\nThings we are not interested in seeing:\n\n\n\nAnything actually romantic\n\nOnce we’ve gazed longingly at all your submissions, we’ll put the best together in a gallery to make single people feel better about themselves.", "\n\nHow to contribute\n\nShare your underwhelming Valentine’s Day related photos and stories by clicking on the blue “Contribute” button on this article. ", "You can also use the Guardian app and search for “GuardianWitness assignments”.", "\n\n\n\nAny problems? ", "You can always email your pictures to guardian.witness@theguardian.com instead.", "\n\n" ]

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[ "One of the most sophisticated murder investigations in Italian history concluded on Friday with the key suspect jailed for life after being caught through a combination of DNA evidence and the revelation of family secrets.", "\n\nMassimo Bossetti, 46, was found guilty of killing Yara Gambirasio in November 2010 and dumping her body in a field where she was found three months later. ", "The 13-year-old had been on her way home from a gym class in Brembate di Sopra, a town close to Milan, when she was abducted and suffered multiple injuries.", "\n\n\n\nItaly gripped as trial begins over murder of 13-year-old Yara Gambirasio Read more\n\nBossetti, a local construction worker, was sentenced by the Bergamo court to life in prison for the girl’s murder. ", "Judges said he would lose parental rights over his three children, though they did not grant the prosecutor’s request to put him in isolation for six months.", "\n\n\n\nHis DNA had been found on Gambirasio’s body and fibres from his van were on her clothes, but, ahead of the verdict, Bossetti professed his innocence and challenged the scientific evidence. “", "I might be stupid, an idiot, ignorant, but I’m not a killer,” he told the court.", "\n\n\n\nThe Gambirasio family responded to the verdict in a statement released through their lawyers, Enrico Pelillo and Andrea Pezzotta. “", "Now we know who it was, even if we know that no one will bring Yara back to us,” her parents said.", "\n\n\n\nThe conclusion of the year-long trial follows the testing of 18,000 DNA samples in the wake of Gambirasio’s body being found, in an unprecedented operation mounted on the back of public pressure to find her killer.", "\n\n\n\nThrough a sample given by a relative of Giuseppe Guerinoni, who had died in 1999, police found the DNA evidence was a close match to the deceased and in 2013 decided to exhume his body.", "\n\n\n\nThe murder that obsessed Italy | Tobias Jones Read more\n\nFurther tests confirmed the suspected killer was Guerinoni’s illegitimate son, sparking a hunt throughout the area to discover who had borne him a child decades earlier. ", "It wasn’t until June 2014 that police pinpointed Bossetti as the chief suspect, through a DNA match with his mother, Ester Arzuffi, who was married and has denied the affair with Guerinoni.", "\n\n\n\nThe breadth of the police investigation revealed a number of other illegitimate children and affairs, including allegations by two men who claimed to have had affairs with Bossetti’s wife.", "\n\n\n\nThe massive operation came to a head with the arrest of Bossetti in June last year, after he was stopped at a fake roadblock where police took his DNA sample under the guise of a breathalyser test. ", "Bossetti, who has been in custody since his arrest, will be able to appeal the guilty verdict.", "\n\n" ]

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[ "Alterations induced by lithium in gfap expression and in the proteinic composition of glial cells in vitro.", "\nIn the adult brain, astrocytes account for about 40% of the cell population in the central nervous system. ", "Normal, reactive and neoplastic astrocytes can be identified in immunohistochemical preparations by means of glial fibrillary acid proteins (GFAP) expression. ", "This protein is considered to be a sensitive indicator of xenobiotics toxicity. ", "Previous studies have demonstrated that 2 mM LiCl induce alterations of astrocyte morphology after 18-20 days of treatment in vitro. ", "We have decided to study GFAP expression under such conditions. ", "Immunodetection and Western blotting assays have shown 2 mM of LiCl to induce alterations of GFAP expression both after 12 days of treatment and after 18-20 days. ", "Moreover, 2 mM of LiCl induce an alteration of the proteinic composition of cells." ]

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[ "Q:\n\nHow do we know $b$ is in $G$?", "\n\nI'm having trouble understanding when we can assume that an element is in a group. ", "\nGiven problem\nLet $H$ be a normal subgroup of $G$. Prove that if $ab \\in H$, then $ba \\in H$.\nGiven solution\nLet $H$ be a normal subgroup of $G$ and suppose $ab \\in H$; say $ab = h \\in H$. Since $H$ is normal, $H$ is closed under conjugation by elements of $G$. In particular, $bhb^{-1} \\in H$. Substituting $h=ab$, we see that $babb^{-1} = ba \\in H$.\nQuestion\nWhy can we assume $b \\in G$? ", "\nMy understanding is that even if the product of two elements is in a group, we can't necessarily assume that the individual elements are also in that group. ", "I'd assume that the same goes for large groups also, i.e., $ab \\in G \\nRightarrow a,b \\in G$.\n\nA:\n\nWell, your binary group operation $\\cdot$ is only defined on $G$. That is, its domain is $G \\times G$. When you write $ab$, this a shorthand for $a \\cdot b$. But then for the expression to make sense, $a$ and $b$ must be in $G$. Therefore it's a literature convention to imply that by writing $a\\cdot b \\in H$, we actually mean \"$a \\in G, b \\in G, a \\cdot b \\in H$\".", "\nNote that is very different than saying that \"$a\\cdot b \\in H$\" implies \"$a\\in H, b \\in H, ab \\in H$\", because $\\cdot$ is well-defined on a superset of $H \\times H$. So, usually literature just implies the minimal requirement for the expression to make sense, that is, $a$ and $b$ are in $G$.\n\n" ]

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[ "INTRODUCTION {#sec1-1}\n============\n\nCiprofloxacin, structurally (1-cyclopropyl-6-fluoro-1,4-dihydro 4-oxo-7-\\[1-piperazinyl\\]-3-quinolinecarboxylic acid) \\[[Figure 1a](#F1){ref-type=\"fig\"}\\], is a potent fluoroquinolone chemotherapeutic of the second-generation group of nalidixic acid derivatives. ", "It is faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8 g/mol. ", "Due to the broad spectrum effect, it is widely used both in human and veterinary medicine to treat infectious diseases, caused particularly by Gram-negative and some Gram-positive bacteria. ", "The target of highly selective action of ciprofloxacin is bacterial DNA gyrase, a type of topoisomerase II.\\[[@ref1][@ref2]\\] After peroral administration in human, ciprofloxacin is rapidly absorbed from the gastrointestinal (GI) tract into the systemic circulation and reaches the maximal concentration in 1--2 h. The bioavailability is 56--79%, about 65% of unchanged ciprofloxacin and 10--15% of metabolites is excreted in the urine and about 15% in feces.\\[[@ref3][@ref4]\\] Ciprofloxacin has been available in conventional tablets that require twice-daily administration.\\[[@ref4]\\] Inconvenient regimens, longer duration of therapy, and possible side effects could result in poor patient adherence to the treatment which often leads to sub-therapeutic antibiotic concentrations at sites of infection. ", "This would result in longer persistence of the pathogens, therapeutic failure, and emerging of resistant microorganisms. ", "Therefore, there has been a significant interest in the development of a convenient once-daily formulation of ciprofloxacin. ", "We developed a controlled release floating gastroretentive formulation containing 500 mg ciprofloxacin that could be administered once-daily along with a 500 mg conventional immediate-release tablet to achieve desirable clinical effects.\\[[@ref5]\\] Since the drug is released in a sustained manner from developed floating formulation, lower drug concentrations in the range of 0.025--1 µg/ml in plasma samples are achieved.\\[[@ref5]\\] Thus, the current study details a simple, sensitive, and rapid high-performance liquid chromatography (HPLC) method that we have developed in our laboratory to quantify ciprofloxacin concentrations in human plasma to address pharmacokinetics of ciprofloxacin after ingestion of this novel gastro retentive floating formulation.", "\n\n{#F1}\n\nA literature review revealed that the HPLC method has been the technique of choice for the separation and determination of ciprofloxacin in biological fluids. ", "Thus far, several HPLC methods have been described to analyze ciprofloxacin in various body fluids following oral administration of conventional immediate-release dosage forms using different clean-up procedures including protein precipitation (PP),\\[[@ref6][@ref7][@ref8][@ref9][@ref10][@ref11]\\] filtration,\\[[@ref12][@ref13][@ref14]\\] solid-phase extraction (SPE),\\[[@ref15][@ref16]\\] liquid-liquid extraction (LLE)\\[[@ref17][@ref18][@ref19]\\] either with ultraviolet (UV)\\[[@ref7][@ref11][@ref14][@ref16][@ref17][@ref18]\\] or fluorimetric detection.\\[[@ref6][@ref8][@ref9][@ref10][@ref12][@ref13][@ref15][@ref20]\\] Although direct injection of samples after precipitation of the plasma proteins is a simple and rapid procedure, this method could deteriorate the chromatographic column due to inadequate PP. ", "Endogenous compounds can also overload the column, which interfere with the peak of interest or appear as late eluting peaks and consequently lead to a long run time. ", "In addition, sample dilution, which occurs after deproteinization, reduces the sensitivity of the assay.\\[[@ref21]\\] To increase the column durability and efficiency and to remove the interferents coming from proteins, the use of SPE has been reported. ", "SPE technique is a fairly expensive procedure and suffers from sorbent drying between washing procedures resulting in cracking of the packing materials. ", "Moreover, due to the strong bonding of ciprofloxacin to the sorbent, the use of acidic aqueous extractant\\[[@ref15][@ref16]\\] seems essential reflecting to a decrease in sensitivity of the assay. ", "In most instances, LLE has been considered as the main procedure for the isolation and determination of drug substances from biological matrices. ", "Although some studies have been performed with regard to HPLC determination of ciprofloxacin in plasma after LLE, none of them are appropriately developed and validated to be entirely applicable and reproducible to the pharmacokinetic studies of this drug. ", "Nessem *et al*.\\[[@ref17]\\] proposed a HPLC method for determination of ciprofloxacin in plasma samples using LLE and UV detection. ", "The calibration curve was linear in the range of 1--10 µg/ml and the method was not validated according to the International Conference on Harmonization (ICH) guidelines. ", "In some other similar studies,\\[[@ref18][@ref19]\\] after LLE of plasma samples, the limit of quantitations (LOQs) of ciprofloxacin were reported between 100 and 250 ng/ml. ", "The quantification limits in the aforementioned studies is not sufficiently low to precisely characterize the drug plasma profiles, especially at later time points after oral administration of the drug where the concentration of ciprofloxacin is quite low. ", "To overcome the low sensitivity of the assay procedures, fluorescence detections have been proposed and utilized for analysis of ciprofloxacin. ", "However, fluorescence detectors require extremely pure solvents and are not readily available and affordable at most laboratories.", "\n\nIn the current study, it was of interest to us to develop a reliable HPLC method using UV detection and LLE for determination of ciprofloxacin in human plasma in the range of 0.025--4 μg/ml. ", "The described method does not utilize fluorescent detection and yet more sensitive, making the method rapid, simple, and appropriate for pharmacokinetic and bioequivalence studies of this drug following the oral administration of controlled release and conventional immediate-release tablet formulations. ", "This method can also be utilized in the determination of plasma concentration of this antibiotic when administered concomitantly with divalent and trivalent cations such as aluminum-, magnesium-, or calcium-containing products under which the bioavailability of ciprofloxacin is significantly reduced. ", "This method was developed and validated for its accuracy, precision, limit of detection (LOD), LOQ, robustness, and stability as per ICH guidelines.", "\n\nMATERIALS AND METHODS {#sec1-2}\n=====================\n\nMaterials {#sec2-1}\n---------\n\nCiprofloxacin hydrochloride was provided by Pars Daru (Iran, Tehran). ", "Phenacetin (internal standard \\[IS\\], [Figure 1b](#F1){ref-type=\"fig\"}), HPLC-grade acetonitrile and methanol, potassium dihydrogen phosphate, orthophosphoric acid 85% were purchased from Merck (Germany) 500 mg prolonged-release gastroretentive tablets of ciprofloxacin were prepared in our laboratory.", "\n\nChromatographic conditions {#sec2-2}\n--------------------------\n\nThe apparatus used was a Waters HPLC system model 746 (Milford, US), consisting of a model 515 intelligent solvent delivery pump, a 100 μl injection loop, a computerized system controller, and a Waters 2487 UV detector. ", "HPLC assay was carried out on a μ-Bondapack C~18~ column (250 mm × 4.6 mm, 10 μm, Waters, Ireland). ", "The mobile phase consisted of potassium dihydrogen phosphate (0.1 M)/acetonitrile at 80/20 (pH, 3 ± 0.1) eluted at flow rate 1.5 ml/min. ", "Column effluent was detected at 276 nm with a UV detector. ", "Column temperature was set at 40°C, and 50 µl of samples was injected to the HPLC system.", "\n\nQuantitation was achieved by measurement of the peak area ratios of the drug to the IS.", "\n\nStandard solutions of ciprofloxacin and internal standard {#sec2-3}\n---------------------------------------------------------\n\nA standard stock solution of ciprofloxacin hydrochloride at 100 μg/ml was prepared by dissolving 11.64 mg of the drug (equal to 10 mg ciprofloxacin base) in 100 ml double-distilled water. ", "A series of working solutions at concentrations of 0.25, 0.5, 1, 2.5, 5, 7.5, 10, 20, 30, and 40 μg/ml were prepared by further dilution of the standard stock solution in double-distilled water. ", "Stock solution of phenacetin (IS) at a concentration 100 μg/ml was prepared in methanol.", "\n\nCalibration procedure {#sec2-4}\n---------------------\n\nTo 0.5 ml of blank plasma, 50 µl of ciprofloxacin standard solutions at concentrations of 0.25, 0.5, 1, 2.5, 5, 7.5, 10, 20, 30, 40 µg/ml and 50 µl of IS at fixed concentration of 100 µg/ml were added to obtain ciprofloxacin standard concentrations ranging from 0.025 to 4 µg/ml. ", "A 0.5 ml of 0.1 M phosphate buffer (pH: 7.4), 5 ml of dichloromethane were added, vortexed, and centrifuged at 3000 rpm for 10 min. ", "The upper aqueous layer was removed by aspiration and discarded. ", "The organic layer was evaporated to dryness under nitrogen gas and the residue reconstituted with 75 µl of mobile phase, and 50 µl aliquot was injected to the HPLC system. ", "Two calibration curves were obtained by linear least-squares regression analysis by plotting peak area ratios (ciprofloxacin/IS) versus two different ranges (0.025--0.5 and 0.5--4 μg/ml) of ciprofloxacin plasma concentrations.", "\n\nMethod validation {#sec2-5}\n-----------------\n\n### Linearity {#sec3-1}\n\nCalibration plots were constructed by plotting the ratio of ciprofloxacin peak area to that of IS, using five different concentrations of each sample on five separate days. ", "Distribution of the residuals (% difference of the back-calculated concentration from the nominal concentration) was determined to validate the correlation. ", "The calibration model will be accepted if the residuals are within ± 20% for the lower limit of quantification and within 15% for all other calibration levels and at least 2/3 of the standards should meet this criterion. ", "The calibration curves were evaluated by the correlation coefficient, slope, and intercept.", "\n\nLimit of detection and limit of quantitation {#sec2-6}\n--------------------------------------------\n\nThe parameter LOD was determined using the signal-to-noise ratio by comparing the results of test samples with known concentrations of analyte to the blank samples. ", "The analyte concentration that produced a signal-to-noise ratio of 3:1 was accepted as the LOD. ", "The LOQ was identified as the lowest plasma concentration of the standard curves that could be quantified with acceptable accuracy, precision, and variability.\\[[@ref22]\\]\n\nPrecision, accuracy, and recovery {#sec2-7}\n---------------------------------\n\nThe intra- and inter-day variation of the assay was determined by replicate analysis (*n* = 5) of samples at concentrations within the range of calibration curves in a single analytical run on the same day and at five different days, respectively, using the same stock solutions and plasma batches. ", "Percentage coefficient of variance (% CV) was used as the measure of precision, and percentage accuracy (% accuracy = \\[measured concentration/nominal concentration\\] ×100) was also determined. ", "The extraction recovery of ciprofloxacin was estimated at 0.025, 1, 4 µg/ml concentrations in plasma. ", "Plasma samples (in six replicates) containing ciprofloxacin were extracted and analyzed. ", "Six samples containing similar concentrations of the compound in mobile phase were directly injected, and peak areas were measured. ", "Absolute recovery was calculated by comparing the peak areas for direct injection of pure ciprofloxacin solution with those obtained by plasma containing the same amount of ciprofloxacin.", "\n\nRobustness {#sec2-8}\n----------\n\nThe robustness of the HPLC method was determined by analysis of samples under a variety of conditions such as small changes in the percentage of mobile phase acetonitrile, in the pH, in the mobile phase flow rate and in the temperature. ", "The effect on retention time and peak parameters were studied.\\[[@ref23]\\]\n\nStability {#sec2-9}\n---------\n\nStability of ciprofloxacin was examined by keeping replicates of plasma samples at room temperature for 12 h. Freeze-thaw stability of analyte in human plasma samples were studied over three freeze-thaw cycles, by thawing at room temperature for 2--3 h and refrozen for 12--24 h. Stability of the drug in human plasma was also tested after storage at below − 70°C for 3 months. ", "In all stability studies, plasma samples were spiked with ciprofloxacin at three levels of concentration, low (0.025 µg/ml), medium (1 µg/ml), and high (4 µg/ml). ", "For each concentration and each storage condition, six replicates were analyzed. ", "The concentration of ciprofloxacin after each storage period was related to the initial analyte concentration of freshly prepared samples. ", "Samples were considered stable if the assay values were within the acceptable limits of accuracy and precision.\\[[@ref22]\\]\n\nApplication of the method {#sec2-10}\n-------------------------\n\nThe present method was applied in human pharmacokinetics study of ciprofloxacin after ingestion of 500 mg ciprofloxacin immediate-release tablet as well as the developed gastro retentive controlled release formulation in two separate groups.\\[[@ref5]\\] The study was conducted in accordance with ethical principles and standards described in the Declaration of Helsinki and the ICH/Good Clinical Practice. ", "Guidelines were approved by an independent Medical Bioethics Committee at the Isfahan University of Medical Sciences. ", "Twelve healthy adult volunteers aged between 21 and 26 years and weighted from 56 to 70 kg participated in each group. ", "Clinical examinations and laboratory tests revealed that no subject had an evidence of any acute or chronic disease or drug allergy. ", "The subjects were asked to avoid taking any medication at least 2 weeks prior to and during the study period. ", "No milk or dairy products were served during the study. ", "Each subject was enrolled after signing an informed consent form. ", "After oral administration of dosage forms, in predetermined intervals, the blood samples were collected in heparinized tubes. ", "The blood samples were centrifuged at 3000 rpm for 20 min; plasma was separated and kept frozen at −20°C in glass tubes. ", "For determination of Ciprofloxacin concentration in plasma of volunteers, 50 µl of IS solution, 0.5 ml phosphate buffer (pH, 7.4), and 5 ml of dichloromethane were added to 0.5 ml plasma. ", "All samples were taken through the same extraction procedure described earlier. ", "Final sample concentrations were calculated by determining the peak area ratio of ciprofloxacin related to IS and comparing the ratio with the standard curve, obtained after the analysis of calibration samples.", "\n\nPharmacokinetic analysis {#sec2-11}\n------------------------\n\nThe peak plasma concentration (C~max~) and the corresponding peak time (T~max~) were obtained directly from individual plasma concentration-time profiles. ", "The AUC~0--48~ was calculated by the trapezoidal rule and the total AUC~0--∞~ was calculated according to the following equation.", "\n\n*AUC*~0−∞~ = *AUC*~0~ − ~48~ + *C*~48~/*K*~E~\n\nWhere, C~48~ is the drug concentration after 48 h and K~E~ is the elimination rate constant. ", "The K~E~ value was estimated from the terminal slope of plasma concentration versus time plot through the logarithmic transformation of the concentration values and application of linear regression. ", "We considered four points in the terminal log-linear phase to obtain an accurate estimate of K~E~ from linear regression. ", "The mean residence time (MRT) was also calculated using following equation.", "\n\n![](", "ABR-5-163-g002.jpg)\n\nAUMC~0-∞~ is the area under the first moment of the concentration-time curves and was calculated according to the following equation.", "\n\n*AUMC*~0−∞~ = *AUMC*~0~ −~48~+ (*C*~48~ × t~48~)/*K*~E~ + *C*~48~/*K*~E~^2^\n\nThe AUMC~0-48~ was calculated by the trapezoidal rule\n\n![](", "ABR-5-163-g003.jpg)\n\nRESULTS {#sec1-3}\n=======\n\nCalibration curve {#sec2-12}\n-----------------\n\nThe calibration curves were constructed by plotting the ratio of ciprofloxacin peak areas to that of IS against standard ciprofloxacin concentrations \\[[Figure 2](#F2){ref-type=\"fig\"}\\]. ", "Acceptable linear relationships were found in both low (0.025--0.5 µg/ml) and high ciprofloxacin concentrations (0.5--4 µg/ml). ", "Since the distribution of residuals was within ± 5%, no weight factor was applied. ", "Although blank plasma samples (with zero concentrations) were not selected in constructing the calibration curves, the 95% confidence interval of the intercept encompassed the origin. ", "The linear regression equation for the low concentration range were Y = 0.5573 × (±0.0313) + 0.0028 (±0.0042). ", "The coefficient of the linear regression analysis was 0.996 ± 0.0022. ", "For calibration curves prepared at high ciprofloxacin, concentration range results were as follows: Y =0.6873 × (±0.02025) − 0.0842 (±0.0047) and coefficient of the linear regression analysis of 0.997 ± 0.0013.", "\n\n{#F2}\n\nLimit of detection and limit of quantitation {#sec2-13}\n--------------------------------------------\n\nThe LOD was 15 ng/ml at a signal-to-noise ratio of 3:1, using 0.5 ml of the plasma sample. ", "The LOQ was 25 ng/ml in plasma with precision, expressed as a CV%, of 7.09% and accuracy of 115%. ", "Representative chromatograms of blank human plasma, (a) blank plasma spiked with IS, phenacetin, (b) the lowest standard concentration (0.025 µg/ml), (c) the highest standard concentration (4 µg/ml), (d) and human plasma 6 h after oral ingestion of a 500 mg gastro retentive prolonged-release formulation are shown in [Figure 3](#F3){ref-type=\"fig\"}. ", "All samples were spiked with 50 µl of IS at a concentration of 100 µg/ml. ", "No interfering substances were observed at the retention time of ciprofloxacin and IS, and both compounds were eluted completely and appeared as two separate resolved peaks (resolution factor: 3.2) without peak tailing (tailing factor: 1.05, 1.2, respectively). ", "An optimum flow rate of 1.5 ml/min for the mobile phase resulted in the retention times of 5.15 min for ciprofloxacin and 8.21 min for phenacetin.", "\n\n{#F3}\n\nPrecision, accuracy, and recovery {#sec2-14}\n---------------------------------\n\nThe precision and accuracy of calibration standard concentrations were within acceptable limits as defined in the ICH guidelines. ", "The inter- and intra-day precision and accuracy values of the assay method are presented in [Table 1](#T1){ref-type=\"table\"}. ", "Accuracy % was within 93--115% and the CV% ranged from 0.20 to 12.8, which indicate the method is reproducible within a day and between days. ", "The mean recoveries of ciprofloxacin after plasma extraction were 97.4% ±3.6%.", "\n\n###### \n\nIntra- and inter-day precision and accuracy of the high-performance liquid chromatography assay developed for determination of ciprofloxacin concentrations in plasma\n\n![](", "ABR-5-163-g006)\n\nRobustness {#sec2-15}\n----------\n\nThe results of the robustness of the assay method are listed in [Table 2](#T2){ref-type=\"table\"}. ", "Method robustness that was checked after deliberate alterations of the mobile phase composition, flow, pH, and temperature showed that the changes of the operational parameters did not lead to any essential changes in the performance of the chromatographic system. ", "The tailing factor for ciprofloxacin and phenacetin always ranged from 1 to 1.3, and the eluents were well-separated under all the changes carried out (resolution factor: 3.12--3.26). ", "The percent recoveries of ciprofloxacin were good under most conditions and did not show a significant change when the critical parameters were modified. ", "Considering the result of modifications in the system suitability parameters and the specificity of the method, it would be concluded that the method conditions are robust.", "\n\n###### \n\nInfluence of changes in experimental parameters on the performance of chromatographic system\n\n![](", "ABR-5-163-g007)\n\nStability {#sec2-16}\n---------\n\nThe results of the stability study determined at various storage conditions are summarized in [Table 3](#T3){ref-type=\"table\"}. ", "No tendency of degradation of ciprofloxacin after storage at room temperature was observed. ", "In three freeze-thaw cycles, the drug was stable in plasma, indicating no significant substance loss during repeated thawing and freezing. ", "Acceptable analyte stability was demonstrated for all phases of storage and processing.", "\n\n###### \n\nStability of ciprofloxacin in human samples at different storage conditions (*n*=6)\n\n![](", "ABR-5-163-g008)\n\nPharmacokinetics and tissue distribution in human {#sec2-17}\n-------------------------------------------------\n\nThe method described here was successfully employed to quantify ciprofloxacin in plasma following administration of a conventional tablet formulation and a sustained release GI floating tablet containing 500 mg ciprofloxacin to healthy human volunteers. ", "The concentration-time profile following oral administration of floating gastroretentive formulation was presented in [Figure 4](#F4){ref-type=\"fig\"}. ", "Peak plasma concentrations (C~max~), time taken to reach the maximum concentration (t~max~), area under the plasma concentration-time curve (AUC~0--48~), and MRT of ciprofloxacin following ingestion of floating gastroretentive formulation were 2.1 ± 0.49 µg/ml, 1.4 ± 0.59 h, 8.56 ± 1.87 µg h/ml, and 3.64 ± 0.39 h, respectively.", "\n\n{#F4}\n\nDISCUSSION {#sec1-4}\n==========\n\nThe present study describes a very sensitive, accurate, and reproducible HPLC method for the determination of ciprofloxacin in human plasma. ", "Several HPLC methods have so far been reported for the analysis of ciprofloxacin in biological fluids using various extraction procedures including PP,\\[[@ref6][@ref7][@ref8][@ref9][@ref10][@ref11]\\] filtration,\\[[@ref12][@ref13][@ref14]\\] SPE,\\[[@ref15][@ref16]\\] LLE.\\[[@ref17][@ref18]\\] Some of these methods use UV detection,\\[[@ref7][@ref11][@ref14][@ref16][@ref17][@ref18]\\] whereas others use expensive fluorometric detection.\\[[@ref6][@ref8][@ref9][@ref10][@ref12][@ref13][@ref15][@ref19]\\] A literature review indicated that PP has been the main clean up producer for determination of ciprofloxacin from plasma samples. ", "However, PP will result in low recoveries due to drug precipitation, low sensitivity because of unavoidable dilution, column deterioration, back pressure increment, and late eluting peaks due to endogenous compounds. ", "In different studies conducted by Kamberi *et al*. ", "and Krol *et al*., ", "total chromatography run time was prolonged to 20 min to allow for late eluting peaks.\\[[@ref24][@ref25]\\] Moreover, the interfering peak from plasma in the chromatograms demonstrated inadequate PP, which could diminish peak resolutions and sensitivity of the assays after a long run time. ", "In other similar studies, the plasma sample containing ciprofloxacin was deproteinized with perchloric acid and the supernatant was directly injected to the HPLC column.\\[[@ref26][@ref27]\\] Perchloric or trichloroacetic acid causes PP without significant dilution of the sample, but acidic condition can decrease column durability. ", "To overcome the low sensitivity associated with PP fluorescence detectors have been utilized which are not readily available in most laboratories due to their financial limitations and requires extremely pure HPLC grade solvents. ", "In the study conducted by Sowinski and Kays, the quantification limit of 100 ng/ml was reported by HPLC with UV detection and PP followed by ultrafiltration; however, using fluorescence detection resulted in a sensitivity limit of 20 ng/ml.\\[[@ref7]\\] Similar quantification limits (\\>20 ng/ml) have been reported using PP procedure and fluorescence detection.\\[[@ref8][@ref9][@ref10]\\] These reported quantification limits even by fluorescence detection is very close to 25 ng/ml which was observed in our study.", "\n\nTo overcome the mentioned difficulties associated with PP, LLE may be a potential alternative. ", "Some studies have been published with regard to HPLC determination of ciprofloxacin in plasma samples following LLE. ", "In all of these studies, the quantification limits obtained higher than 100 ng/ml, which could not precisely characterize the drug plasma profiles, especially at later time points after oral administration of the drug where the concentration of ciprofloxacin is quite low or following ingestion of sustained release forms. ", "Therefore, in the current study, we aimed to develop a very sensitive HPLC method using UV detection and LLE for the determination of ciprofloxacin in human plasma which can be applied in pharmacokinetic studies of this drug when lower ciprofloxacin plasma concentrations are attained. ", "During the development of analytical method, short analysis time, and simple procedures are especially important. ", "The retention times of ciprofloxacin and phenacetin achieved in this work were comparable or even much shorter than those have been yet reported. ", "It is generally known that quinolones give tailing peaks in reversed-phase chromatography, which can be prevented by acidic mobile phase as employed in this study.\\[[@ref16]\\] In some previous studies, the mobile phase has been modified by tetrabutylammonium salts or sodium dodecyl sulfate to reduce retention time and peak tailing.\\[[@ref6][@ref9][@ref10][@ref16][@ref18]\\] However, these compounds can be bound to the analytical HPLC column irreversibly and may cause some problems in column maintenance. ", "Ciprofloxacin is an amphoteric compound which due to the presence of two ionizable groups in its molecule, exhibits ionic properties in all ranges of the pH. Only the zwitter ionic form of ciprofloxacin is soluble in organic solvent. ", "As a result, adjustment of the sample pH to the isoelecteric pH of around seven prior to extraction of the drug can improve the recovery of the eluent. ", "Direct extraction with organic extracting solvents from biological fluids may not result in an efficient extraction of the drug from matrix without pH adjustment. ", "The first reported HPLC method for ciprofloxacin analysis involved the direct methylene chloride extraction of ciprofloxacin from serum without prior adjustment of the pH.\\[[@ref17]\\] The percent recovery of ciprofloxacin following LLE with dichloromethane was reported to be around 8.8%.\\[[@ref14]\\] The low recovery of the analyte could be attributed to the pH of the samples which not adjusted to the isoelectric pH of the analyte ciprofloxacin. ", "In spite the pH adjustment, Idowu and Peggins\\[[@ref8]\\] were unable to recover ciprofloxacin from plasma and milk by LLE using dichloromethane.\\[[@ref8]\\] No explanation was provided for such unrealistic observation. ", "In the current study, we adjusted the pH of the samples to about 7.4, which resulted in an efficient recovery of about 97.4%. ", "The very low quantification limit obtained with UV detection (25 ng/ml) which is comparable\\[[@ref6][@ref7][@ref10][@ref18]\\] or even less\\[[@ref9][@ref12][@ref14][@ref15][@ref16][@ref17]\\] than that of most previous reports even when fluorescence detection\\[[@ref6][@ref9][@ref10][@ref12][@ref15]\\] was used allowed us to avoid using fluorometric detection which is more expensive and not available in most laboratories. ", "UV detector produces more reproducible responses in compression with fluorometric detection. ", "Another advantage of our method is the simple composition of mobile phase which reduces the risk of column deterioration associated with the use of ion-pair reagents such as tetrabutylammonium salt and sodium dodecyl sulfate. ", "It is considered that this advantage is favorable for clinical routine applications.", "\n\nCONCLUSION {#sec1-5}\n==========\n\nIn the current study, we developed a very sensitive, precise, accurate, and beneficial HPLC method using LLE and UV detection for determination of ciprofloxacin in human plasma which does not utilize fluorescent detection but still sensitive, making the method rapid, simple and appropriate for pharmacokinetic studies of this drug following oral administration of controlled release formulations for research purposes, conventional immediate-release tablets and when administered concomitantly with divalent and trivalent cations such as aluminum, magnesium, or calcium containing products under which the bioavailability of ciprofloxacin is significantly reduced.", "\n\nFinancial support and sponsorship {#sec2-18}\n---------------------------------\n\nNil.", "\n\nConflicts of interest {#sec2-19}\n---------------------\n\nThere are no conflicts of interest.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "A modified swim-up method reduces polyspermy during in vitro fertilization of porcine oocytes.", "\nThe general method of porcine in vitro fertilization (IVF), involving the co-culture of both gametes in a medium drop, is thought to be the main reason for the high incidence of polyspermy. ", "The aim of this study was to reduce the polyspermic fertilization of porcine embryos during IVF by the modified swim-up method, based on general sperm swim-up technique. ", "Within this design, a 70 microm pore sized cell strainer was used to separate the sperm pellet placed at the bottom of a tube from the mature oocytes placed within the upper region. ", "The separation of gametes using this permeable barrier was to ensure that only motile sperm gained access to the oocytes. ", "It was found that the rate of polyspermy was significantly lowered for the sperm preparations from three boar breeds in modified swim-up method when compared with that of the general microdrop method (p<0.05). ", "However, the penetration rates were found to be similar in both methods for two boar breeds. ", "The average occurrence of blastocysts with more total cell number was higher in the modified swim-up method, while no significant difference in blastocyst rates between the two IVF methods was observed. ", "The frequency of normal diploid embryos was also significantly higher in the modified swim-up method and polyploidy was more frequently observed in microdrop method (p<0.05). ", "Our results demonstrated that the modified swim-up IVF method could reduce polyspermic penetration, and consequently produce better quality and karyotypically normal embryos in porcine IVF." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "A classic crew neck pullover is updated with a modern twist with a suede chest pocket siting atop a space dye print. ", "Pair with your favourite denim for an outfit that easily takes you from day to night out." ]

{ "pile_set_name": "Pile-CC" }

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[ "---\nauthor:\n- 'Luis Caffarelli[^1] and Alessio Figalli[^2]'\ntitle: |\n Regularity of solutions\\\n to the parabolic fractional obstacle problem\n---\n\nIntroduction\n============\n\nIn recent years, there has been an increasing interest in studying constrained variational problems with a fractional diffusion. ", "One of the motivations comes from mathematical finance: jump-diffusion processes where incorporated by Merton [@merton] into the theory of option evaluation to introduce discontinuous paths in the dynamics of the stock’s prices, in contrast with the classical lognormal diffusion model of Black and Scholes [@blsc]. ", "These models allow to take into account large price changes, and they have become increasingly popular for modeling market fluctuations, both for risk management and option pricing purposes.", "\n\nLet us recall that an American option gives its holder the right to buy a stock at a given price prior (but not later) than a given time $T>0$. If $v(\\tau,x)$ represents the rational price of an American option with a payoff $\\psi$ at time $T>0$, then $v$ will solve (in the viscosity sense) the following obstacle problem: $$\\left\\{\n\\begin{array}{l}\n\\min\\{ {\\mathcal{L}}v,v-\\psi\\}=0,\\\\\nv(T)=\\psi.", "\n\\end{array}\n\\right.$$ Here ${\\mathcal{L}}v$ is a (backward) parabolic integro-differential operator of the form $$\\begin{gathered}\n{\\mathcal{L}}v= -v_\\tau - r v + \\sum_{i=1}^n (r-d_i) x_i v_{x_i} - \\frac{1}{2}\\sum_{i,j=1}^n x_i x_j \\sigma_{ij} v_{x_i x_j}\\\\\n - \\int \\Bigl[v\\bigl(\\tau,x_1e^{y_1},\\ldots,x_ne^{y_n}\\bigr) - v(\\tau,x) - \\sum_{i=1}^n(e^{y_i} - 1) x_i v_{x_i}(\\tau,x)\\Bigr]\\,\\mu(dy),\\end{gathered}$$ where $r>0$, $d_i \\in {\\mathbb{R}}$, $\\sigma=(\\sigma_{ij})$ is a non-negative definite matrix, and $\\mu$ is a jump measure. (", "We refer to the book [@conttankov] for an explanation of these models and more references.) ", "When the matrix $\\sigma$ is uniformly elliptic, after the change of variable $x_i \\mapsto \\log (x_i)$ the equation becomes uniformly parabolic (backward in time) and the diffusion part dominates. ", "In particular, if no jump part is present (i.e., $\\mu\\equiv 0$), then the regularity theory is pretty well-understood (see, for instance, [@lawsal]).", "\n\nHere we assume that there is no diffusion (i.e., $\\sigma\\equiv 0$), so all the regularity should come from the jump part. ", "We also assume that the jump part behaves, at least at the leading order, as a fractional power of the Laplacian, so that the equation takes the form $$\\label{eq:tilde LL}\n{\\mathcal{L}}v= -v_\\tau - r v - b\\cdot \\nabla u + {(-\\Delta)^{s}}v + {\\mathcal{K}}v,\\qquad s\\in (0,1),$$ where $b=(d_1-r,\\ldots,d_n-r)$, and ${\\mathcal{K}}v$ is a non-local operator of lower order with respect to ${(-\\Delta)^{s}}v$.\n\nWe now observe that the choice of $s \\in (0,1)$ plays a key role:\n\n1. ", " $s>1/2$: In this case ${(-\\Delta)^{s}}v$ is the leading term, so the regularity theory for solutions to is expected to be the same one as that for the equation $$\\label{eq:frac heat visc back}\n \\left\\{\n \\begin{array}{l}\n \\min\\{- v_\\tau + {(-\\Delta)^{s}}v,v-\\psi\\}=0\\quad \\text{on }[0,T]\\times {\\mathbb{R}}^n,\\\\\n v(T)=\\psi\\quad \\text{on }{\\mathbb{R}}^n.", "\n \\end{array}\n \\right.$$\n\n2. ", " $s\\leq 1/2$: If $s<1/2$ then the leading term becomes $b\\cdot \\nabla v$, and we do not expect to have a regularity theory for . ", "On the other hand, in the borderline case $s=1/2$ one may expect some regularity due to the interplay between $b\\cdot \\nabla v$ and $ - {(-\\Delta)^{s}}v$ (but this becomes a very delicate issue). ", "However, when $b\\equiv 0$, even if the diffusion term is of lower order with respect to the time derivative, the equation is still parabolic and one may hope to prove some regularity for all values of $s$.\n\nThe goal of this paper is to investigate the regularity theory for the model equation . ", "The reason for this is three-fold: first of all, considering this model case allows to avoid technicalities which may obscure the main ideas behind the regularity theory that we will develop. ", "Moreover, since there is no transport term inside the equation, we are able to prove that solutions are as smooth as in the elliptic case [@cafsalsil] *for all* values of $s \\in (0,1)$. Hence, although when $s <1/2$ the time derivative is of higher order with respect to the elliptic part ${(-\\Delta)^{s}}v$, the regularity of solutions is as good as in the stationary case. ", "Finally, as described in Section \\[sect:general eq\\], once the general regularity theory for solutions of is established, the adaptation of these proofs to the more general case when $s>1/2$ should not present any major difficulty.\\\nLet us remark that the fact that the smoothness of solutions of is the same as in the elliptic case may look surprising. ", "Indeed, the optimal regularity for the stationary problem $\\min\\{ {(-\\Delta)^{s}}v,v-\\psi\\}=0$ is $C_{x}^{1+s}({\\mathbb{R}}^n)$ [@athcaf; @silv; @cafsalsil]. ", "On the other hand, as we will show in Remark \\[rmk:C1\\], for any ${\\beta}\\in(0,1)$ one can find a traveling wave solution to the parabolic obstacle problem $\\min\\{- v_\\tau + (-\\Delta)^{1/2} v,v-\\psi\\}=0$ which is $C^{1+{\\beta}}$ both in space and time, but not $C^{1+{\\gamma}}$ for any ${\\gamma}>{\\beta}$. Hence, in order to prove that solutions to are $C^{1+s}$ in space, one has to exploit the crucial fact that $v$ coincides with the obstacle at time $T$.\n\nDescription of the results and structure of the paper\n=====================================================\n\nIn this section we introduce more in detail the problem, and describe our main result.", "\n\nLet us observe that, by performing the change of variable $t=T-\\tau$, all equations introduced in the previous section become forward in time. ", "From now on, we will always work with $t$ in place of $\\tau$, so the payoff $\\psi$ becomes the initial condition at time $0$.\n\nPreliminary definitions {#subsect:prelim}\n-----------------------\n\nThe fractional Laplacian can be defined as $${(-\\Delta)^{s}}f := \\widehat{|\\xi|^{2s}\\hat f}\\qquad \\forall\\,f \\in C^\\infty_c({\\mathbb{R}}^n),$$ so that $\\int f {(-\\Delta)^{s}}g ={\\langle}f,g{\\rangle}_{\\dot H^s}$. There are also two other different ways to define ${(-\\Delta)^{s}}$. The first one is through an integral kernel: there exists a positive constant $C_{n,s}$ such that $$-{(-\\Delta)^{s}}f(x)=C_{n,s}\\int \\frac{f(x')-f(x)}{|x'-x|^{n+2s}}\\,dx' \\qquad \\forall\\, f \\in C^\\infty_c({\\mathbb{R}}^n),$$ where the integral has to be intended in the principal value sense. (", "This can be proved, for instance, by computing the Fourier transform of $|\\xi|^{2s}$.) The second one is through a Dirichlet-to-Neumann operator, as shown in [@cafsil]: given $a \\in (-1,1)$, for any function $f\\in C^\\infty_c({\\mathbb{R}}^n)$ denote by $F:{\\mathbb{R}}^n\\times {\\mathbb{R}}^+ \\to {\\mathbb{R}}$ the $L_a$-harmonic extension of $f$, i.e., $$\\left\\{\n\\begin{array}{ll}\nL_a F(x,y):={\\operatorname{div}}_{x,y}\\bigl(y^a \\nabla_{x,y} F(x,y)\\bigr)=0&\\text{on ${\\mathbb{R}}^n\\times{\\mathbb{R}}^+$},\\\\\nF(x,0)=f(x)&\\text{on ${\\mathbb{R}}^n$}.", "\n\\end{array}\n\\right.$$ Then there exists a positive constant $c_{n,s}$ such that $$\\lim_{y\\to 0^+}y^a F_y(x,y)=-c_{n,s}{(-\\Delta)^{s}}f(x,0),\\qquad s:=\\frac{1-a}{2} \\in (0,1).$$ In the sequel, we will make use of all of the three above characterizations of the fractional Laplacian. ", "However, in order to simplify the notation, we will conventionally assume that $C_{n,s}=c_{n,s}=1$, so that $$\\label{eq:equivalent frac lapl}\n-{(-\\Delta)^{s}}f=\\int \\frac{f(x')-f(x)}{|x'-x|^{n+2s}}\\,dx'=\\lim_{y\\to 0^+}y^a F_y(x,y).$$\n\nWe will also need the notion of semiconvex function: a function $w:{\\mathbb{R}}^n\\to{\\mathbb{R}}$ is said to be $C$-semiconvex for some constant $C \\in {\\mathbb{R}}$ if $w+C|x|^2/2$ is convex.\\\nFinally, to measure the regularity of the solutions we will use space-time Hölder, Lipschitz, and logLipschitz spaces: given ${\\alpha},{\\beta},{\\gamma},{\\delta}\\in (0,1)$, and $[a,b] \\subset {\\mathbb{R}}$, we say that:\\\n$w \\in C_{t,x}^{{\\alpha},{\\beta}} ([a,b] \\times {\\mathbb{R}}^n)$ if $$\\begin{aligned}\n\\|w\\|_{C_{t,x}^{{\\alpha},{\\beta}}([a,b] \\times {\\mathbb{R}}^n)}&:=\\|w\\|_{L^\\infty({[a,b] \\times {\\mathbb{R}}^n})}+[w]_{C_{t,x}^{{\\alpha},{\\beta}}([a,b] \\times {\\mathbb{R}}^n)}\\\\\n&= \\|w\\|_{L^\\infty({[a,b] \\times {\\mathbb{R}}^n})}+\\sup_{[a,b] \\times {\\mathbb{R}}^n} \\frac{|w(t,x)-w(t',x')|}{|t-t'|^{\\alpha}+|x-x'|^{\\beta}} <+\\infty;\\end{aligned}$$ $w \\in {{\\rm Lip}}_tC_{x}^{\\beta}([a,b] \\times {\\mathbb{R}}^n)$ if $$\\|w\\|_{{{\\rm Lip}}_tC_{x}^{\\beta}([a,b] \\times {\\mathbb{R}}^n)}:=\\|w\\|_{L^\\infty({[a,b] \\times {\\mathbb{R}}^n})}+ \\sup_{[a,b] \\times {\\mathbb{R}}^n} \\frac{|w(t,x)-w(t',x')|}{|t-t'| +|x-x'|^{\\beta}} <+\\infty;$$ $w \\in {{\\rm logLip}}_tC_x^{\\beta}([a,b] \\times {\\mathbb{R}}^n)$ if $$\\|w\\|_{{{\\rm logLip}}_tC_{x}^{\\beta}([a,b] \\times {\\mathbb{R}}^n)}:=\\|w\\|_{L^\\infty({[a,b] \\times {\\mathbb{R}}^n})}+ \\sup_{[a,b] \\times {\\mathbb{R}}^n} \\frac{|w(t,x)-w(t',x')|}{|t-t'|\\bigl(1+\\bigl|\\log|t-t'|\\bigr|\\bigr) +|x-x'|^{\\beta}} <+\\infty.$$ We will also use the notation $w \\in C_{t,x}^{{\\alpha}-0^+,{\\beta}} ([a,b] \\times {\\mathbb{R}}^n)$ if $$w \\in C_{t,x}^{{\\alpha}-{\\varepsilon},{\\beta}} ([a,b] \\times {\\mathbb{R}}^n) \\qquad \\forall\\,{\\varepsilon}>0,$$ and $w \\in C_{t,x}^{{\\alpha},{\\beta}} ((a,b] \\times {\\mathbb{R}}^n)$ if $$w \\in C_{t,x}^{{\\alpha},{\\beta}} ([a+{\\varepsilon},b] \\times {\\mathbb{R}}^n) \\qquad \\forall\\,{\\varepsilon}>0$$ (analogous definitions hold for the other spaces).", "\n\nThe main result\n---------------\n\nLet $\\psi:{\\mathbb{R}}^n \\to {\\mathbb{R}}^+$ be a globally Lipschitz function of class $C^2$ satisfying $\\int_{{\\mathbb{R}}^n}\\frac{|\\psi|}{(1+|x|)^{n+2s}}<+\\infty$ and ${(-\\Delta)^{s}}\\psi \\in L^\\infty({\\mathbb{R}}^n)$. Fix $s \\in (0,1)$, and let $u:[0,T]\\times {\\mathbb{R}}^n \\to {\\mathbb{R}}$ be a (continuous) viscosity solution to the obstacle problem $$\\label{eq:frac heat}\n\\left\\{\n\\begin{array}{l}\n\\min\\{ u_t + {(-\\Delta)^{s}}u,u-\\psi\\}=0 \\quad \\text{on }[0,T]\\times {\\mathbb{R}}^n,\\\\\nu(0)=\\psi\\quad \\text{on } {\\mathbb{R}}^n.", "\n\\end{array}\n\\right.$$ Existence and uniqueness of such a solution follows by standard results on obstacle problems[^3]. ", "The main goal of this paper is to investigate the smoothness of solutions to the above equations, planning to address in a future work the regularity of the free boundary.", "\n\nOur main result is the following:\n\n\\[thm:main\\] Assume that $\\psi \\in C^2({\\mathbb{R}}^n)$, with $$\\|\\nabla \\psi\\|_{L^\\infty({\\mathbb{R}}^n)}+\\|D^2 \\psi\\|_{L^\\infty({\\mathbb{R}}^n)}+\\|{(-\\Delta)^{s}}\\psi\\|_{C_x^{1-s}({\\mathbb{R}}^n)} <+\\infty,$$ and let $u$ be the unique continuous viscosity solution of . ", "Then $u$ is globally Lipschitz in space-time on $[0,T]\\times {\\mathbb{R}}^n$, and satisfies $$\\label{eq:opt reg}\n\\left\\{\n\\begin{array}{lll}\nu_t \\in {{\\rm logLip}}_tC_x^{1-s}((0,T]\\times{\\mathbb{R}}^n),&{(-\\Delta)^{s}}u \\in{{\\rm logLip}}_tC_x^{1-s}((0,T]\\times {\\mathbb{R}}^n)&\\text{if }s\\leq 1/3;\\\\\nu_t \\in C_{t,x}^{\\frac{1-s}{2s}-0^+,1-s}((0,T]\\times {\\mathbb{R}}^n),&{(-\\Delta)^{s}}u \\in C_{t,x}^{\\frac{1-s}{2s},1-s}((0,T]\\times {\\mathbb{R}}^n)&\\text{if }s>1/3.\\\\\n\\end{array}\n\\right.$$\n\nLet us make some comments. ", "First of all we recall that, for the stationary version of the obstacle problem, solutions belong to $C_{x}^{1+s}({\\mathbb{R}}^n)$ (or equivalently, ${(-\\Delta)^{s}}u \\in C_{x}^{1-s}({\\mathbb{R}}^n)$), and such a regularity result is optimal [@silv; @cafsalsil]. ", "Hence, at least concerning the spatial regularity, our result is optimal, too.", "\n\nOnce the $C_x^{1-s}$-regularity of ${(-\\Delta)^{s}}u$ is established, the fact that $s=1/3$ plays a special role is not surprising: indeed, the operator ${\\partial}_t+{(-\\Delta)^{s}}$ is invariant under the scaling $(t,x)\\mapsto ({\\lambda}^{2s}t,{\\lambda}x)$. Hence, a spatial regularity $C^{1-s}_x$ naturally corresponds to a time regularity $C^{\\frac{1-s}{2s}}_t$, provided $\\frac{1-s}{2s}< 1$, that is, $s > 1/3$ (see - in the Appendix).", "\n\nFinally, concerning the regularity in time, when $s=1/2$ one can construct traveling wave solutions which are $C^{1+1/2}$ both in space and time, see Remark \\[rmk:C1\\]. ", "Hence our result is almost optimal in time, at least when $s=1/2$ (the result would be optimal if we did not have the $0^+$ in the Hölder exponent). ", "Moreover, the regularity in time is almost optimal also in the limit $s \\to 1$ (since, when $s=1$, it is well-known that solutions are $C^1$ in time and $C^{1,1}$ in space [@brekind; @caffActa; @cafffried-contStefan]). ", "Hence, it may be expected that our result is almost optimal in time for all $s \\in (0,1)$ (or at least for $s> 1/3$).", "\n\nStructure of the paper\n----------------------\n\nThe paper is structured as follows: first, in Section \\[sect:prelim\\] we discuss some basic properties of solutions of , like the validity of a comparison principle, the Lipschitz regularity in space-time, the semiconvexity in space, and the boundedness of ${(-\\Delta)^{s}}u$. Moreover, we will show that solutions are $C^1$ for $s \\geq 1/2$, and, as explained in Remark \\[rmk:C1\\], $C^1$-regularity in space is optimal when $s=1/2$ unless one exploits the additional information that the solution coincides with the obstacle at the initial time.", "\n\nIn Section \\[sect:opt reg\\], we first use an iteration method to show that, for any $t>0$, ${(-\\Delta)^{s}}u(t)$ is $C_{x}^{{\\alpha}}$ near any free boundary point (Subsection \\[sect:general C1a\\]). ", "Then, we prove a monotonicity formula which allows to show that ${(-\\Delta)^{s}}u(t)$ is $C_{x}^{1-s}$ near any free boundary point for all $t>0$ (Subsection \\[subsect:monot\\]). ", "Finally, combining the fact that ${(-\\Delta)^{s}}u(t)$ is $C_{x}^{1-s}$ on the contact set with equation , a bootstrap argument allows to prove Theorem \\[thm:main\\] (Subsection \\[sect:C1s u\\]).", "\n\nIn Section \\[sect:general eq\\] we briefly describe what are the main modifications to perform in order to extend the regularity result in Theorem \\[thm:main\\] to solutions of when $s>1/2$, leaving the details to some future work.", "\n\nFinally, in the appendix we collect some regularity properties of the fractional heat operator ${\\partial}_t+{(-\\Delta)^{s}}$.\n\nBasic properties of solutions {#sect:prelim}\n=============================\n\nHere we discuss some elementary properties of solutions of . ", "Actually, since many of them do not rely on the fact that $u$ coincides with the obstacle at time $0$, we consider solutions to $$\\label{eq:frac heat no initial}\n\\left\\{\n\\begin{array}{ll}\n\\min\\{u_t + {(-\\Delta)^{s}}u,u-\\psi\\}=0\\quad \\text{on }[0,T]\\times {\\mathbb{R}}^n,\\\\\nu(0)=u_0\\quad \\text{on } {\\mathbb{R}}^n,\n\\end{array}\n\\right.$$ where $u_0 \\geq \\psi$ is a globally Lipschitz semiconvex function. ", "Most of the properties of $u$ will be a consequence of the following general comparison principle:\n\n\\[lemma:comparison\\] Let $\\psi,\\tilde\\psi:{\\mathbb{R}}^n\\to {\\mathbb{R}}$ be two continuous functions, and assume that $u,\\tilde u:[0,T]\\times {\\mathbb{R}}^n\\to {\\mathbb{R}}$ are viscosity solutions of $$\\label{eq:gen frac heat 1}\n\\left\\{\n\\begin{array}{l}\n\\min\\{ u_t + {(-\\Delta)^{s}}u,u-\\psi\\}=0\\quad \\text{on }[0,T]\\times {\\mathbb{R}}^n,\\\\\nu(0)=u_0\\quad \\text{on }{\\mathbb{R}}^n,\n\\end{array}\n\\right.$$ and $$\\label{eq:gen frac heat 2}\n\\left\\{\n\\begin{array}{l}\n\\min\\{ \\tilde u_t + {(-\\Delta)^{s}}\\tilde u,\\tilde u-\\tilde \\psi\\}=0\\quad \\text{on }[0,T]\\times {\\mathbb{R}}^n,\\\\\n\\tilde u(0)=\\tilde u_0\\quad \\text{on }{\\mathbb{R}}^n,\n\\end{array}\n\\right.$$ respectively. ", "Assume that $u_0\\leq \\tilde u_0$ and $\\psi \\leq \\tilde\\psi$. Then $u(t) \\leq \\tilde u(t)$ for all $t \\in [0,T]$.\n\nWe use a penalization method: it is well-known that solutions of can be constructed as a limit of $u^{\\varepsilon}$ as ${\\varepsilon}\\to 0$, where $u^{\\varepsilon}$ is smooth solutions of $$\\label{eq:approx frac heat}\n\\left\\{\n\\begin{array}{ll}\nu_t^{\\varepsilon}+{(-\\Delta)^{s}}u^{\\varepsilon}= \\beta_{\\varepsilon}(u^{\\varepsilon}- \\psi_{\\varepsilon})&\\text{on }[0,T]\\times {\\mathbb{R}}^n\\\\\nu^{\\varepsilon}(0)=u_0^{\\varepsilon}\\geq \\psi_{\\varepsilon}\\quad \\text{on } {\\mathbb{R}}^n,,\n\\end{array}\n\\right.$$ with $u_0^{\\varepsilon},\\psi_{\\varepsilon}\\in C^\\infty_c({\\mathbb{R}}^n)$, $\\beta_{\\varepsilon}(s)=e^{-s/{\\varepsilon}}$, $\\psi_{\\varepsilon}\\to \\psi$, ${(-\\Delta)^{s}}\\psi_{\\varepsilon}\\to {(-\\Delta)^{s}}\\psi$, and $u_0^{\\varepsilon}\\to u_0$ locally uniformly as ${\\varepsilon}\\to 0$ (see for instance [@chipotbook Chapter 3] for a proof in the classical parabolic case).", "\n\nHence, it suffices to prove the comparison principle at the level of the approximate equations, assuming $u^{\\varepsilon}(0)\\leq \\tilde u^{\\varepsilon}(0)$ and $\\psi_{\\varepsilon}\\leq\\tilde\\psi_{\\varepsilon}$. Let us observe that, since $\\psi_{\\varepsilon}\\leq \\tilde\\psi_{\\varepsilon}$ and $\\beta_{\\varepsilon}'\\leq 0$, we have $$\\beta_{\\varepsilon}(\\cdot - \\psi_{\\varepsilon})\\leq \\beta_{\\varepsilon}(\\cdot - \\tilde \\psi_{\\varepsilon}),$$ which implies $$u_t^{\\varepsilon}+{(-\\Delta)^{s}}u^{\\varepsilon}= \\beta_{\\varepsilon}(u^{\\varepsilon}- \\psi_{\\varepsilon})\\qquad \\text{on }[0,T]\\times {\\mathbb{R}}^n\\\\$$ $$\\tilde u_t^{\\varepsilon}+{(-\\Delta)^{s}}\\tilde u^{\\varepsilon}=\\beta_{\\varepsilon}(\\tilde u^{\\varepsilon}- \\tilde \\psi_{\\varepsilon}) \\geq \\beta_{\\varepsilon}(\\tilde u^{\\varepsilon}- \\psi_{\\varepsilon})\\qquad\\text{on }[0,T]\\times {\\mathbb{R}}^n.$$ Since $u^{\\varepsilon}(0)\\leq \\tilde u^{\\varepsilon}(0)$, by standard comparison principle for parabolic equations (see for instance the argument in the proof of Lemma \\[lemma:Linfty bound frac heat\\] below) we get $u^{\\varepsilon}\\leq \\tilde u^{\\varepsilon}$, as desired.", "\n\nThe following important properties are an immediate consequence of the above result:\n\n\\[lemma:basic\\] Let $u$ be a solution of , and assume that $u_0$ and $\\psi$ are globally Lipschitz and $C_0$-semiconvex. ", "Then:\n\n1. ", " $u(t)$ is Lipschitz for all $t \\in [0,T]$, with $\\|\\nabla u(t)\\|_{L^\\infty({\\mathbb{R}}^n)} \\leq \\max\\{\\|\\nabla u_0\\|_{L^\\infty({\\mathbb{R}}^n)},\\|\\nabla \\psi\\|_{L^\\infty({\\mathbb{R}}^n)}\\}$.\n\n2. ", " $u(t)$ is $C_0$-semiconvex for all $t \\in [0,T]$.\n\nMoreover, if $u_0=\\psi$ then\n\n1. ", " $[0,T]\\ni t\\mapsto u(t,x)$ is non-decreasing in time.", "\n\n\\(i) Observe that, for every vector $v\\in{\\mathbb{R}}^n$ and any constant $C\\in{\\mathbb{R}}$, $u(t,x+v) + C|v|$ solves starting from $u_0(x+v)+C|v|$ with obstacle $\\psi(x+v)+C|v|$. Moreover, if $C:=\\max\\{\\|\\nabla u_0\\|_{L^\\infty({\\mathbb{R}}^n)},\\|\\nabla \\psi\\|_{L^\\infty({\\mathbb{R}}^n)}\\}$, then $u_0(x+v)+C|v|\\geq u_0(x)$ and $\\psi(x+v)+C|v|\\geq \\psi(x)$. Hence, by Lemma \\[lemma:comparison\\] we obtain $$u(t,x+v) + C|v| \\geq u(t,x)\\qquad \\forall\\, x,v \\in{\\mathbb{R}}^n,\\,t\\geq 0.$$ The Lipschitz regularity of $u(t)$ follows.\\\n(ii) As above, we just remark that $u(t,x+v)+u(t,x-v)+C|v|^2$ solves for every $C \\in {\\mathbb{R}}$. Hence, by choosing $C:=2C_0$ we get $u_0(x+v) +u_0(x-v)+2C_0|v|^2 \\geq 2u_0(x)$ and $\\psi(x+v) +\\psi(x-v)+2C_0|v|^2 \\geq 2\\psi(x)$, and we conclude as above using Lemma \\[lemma:comparison\\].\\\n(iii) We observe that, for any ${\\varepsilon}\\geq 0$, the function $u(t+{\\varepsilon},x)$ solves starting from $u({\\varepsilon},\\cdot)$. Hence, since $u({\\varepsilon},\\cdot) \\geq \\psi$, by the comparison principle we obtain $$u(t+{\\varepsilon},x) \\geq u(t,x)\\qquad \\forall \\,t, {\\varepsilon}\\geq 0.$$\n\nWe now prove the following important bounds:\n\n\\[lemma:Linfty bound frac heat\\] Let $u$ be a solution of . ", "Then $$\\label{eq:Linfty bound frac heat}\n0 \\leq u_t + {(-\\Delta)^{s}}u \\leq \\|{(-\\Delta)^{s}}\\psi\\|_{L^\\infty({\\mathbb{R}}^n)},$$ $$\\label{eq:Linfty bound ut}\n\\|u_t\\|_{L^\\infty([0,T]\\times {\\mathbb{R}}^n)} \\leq \\|{(-\\Delta)^{s}}u_0\\|_{L^\\infty({\\mathbb{R}}^n)} ,$$ In particular ${(-\\Delta)^{s}}u$ is bounded, with $$\\label{eq:Linfty bound Df u}\n\\|{(-\\Delta)^{s}}u\\|_{L^\\infty([0,T]\\times {\\mathbb{R}}^n)} \\leq \\|{(-\\Delta)^{s}}\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}+\\|{(-\\Delta)^{s}}u_0\\|_{L^\\infty({\\mathbb{R}}^n)}.$$\n\nAs in the proof of Lemma \\[lemma:comparison\\], we use a penalization method: we consider solutions $u^{\\varepsilon}$ to , and we prove a uniform (with respect to ${\\varepsilon}$) $L^\\infty$-bound on both $\\beta_{\\varepsilon}(u^{\\varepsilon}- \\psi_{\\varepsilon})$ and $u_t^{\\varepsilon}$.\n\n*$\\bullet$ $L^\\infty$-bound on $\\beta_{\\varepsilon}(u^{\\varepsilon}- \\psi_{\\varepsilon})$.* Since $\\beta_{\\varepsilon}\\geq 0$, we only need an upper bound.", "\n\nAssume that $\\inf_{[0,T]\\times {\\mathbb{R}}^n}(u^{\\varepsilon}- \\psi_{\\varepsilon}) <0$ (otherwise the problem is trivial), and let ${\\varphi}$ be a smooth function which grows like $|x|^s$ at infinity. ", "Then, since $u^{\\varepsilon}$ vanishes at infinity (being a solution to a smooth parabolic equation starting from a compactly supported initial datum), for any $\\delta>0$ small we can consider $(t_{\\varepsilon}^\\delta,x_{\\varepsilon}^\\delta)$ a minimum point for $u^{\\varepsilon}- \\psi_{\\varepsilon}+\\frac{\\delta}{T-t}+\\delta {\\varphi}$ over $[0,T]\\times{\\mathbb{R}}^n$. Of course, $\\min_{[0,T]\\times {\\mathbb{R}}^n}\\left(u^{\\varepsilon}- \\psi_{\\varepsilon}+\\frac{\\delta}{T-t}+\\delta {\\varphi}\\right) <0$ for $\\delta$ sufficiently small, which implies that $(t_{\\varepsilon}^\\delta,x_{\\varepsilon}^\\delta)$ belongs to the interior of $(0,T)\\times {\\mathbb{R}}^n$. Hence $$u_t^{\\varepsilon}(t_{\\varepsilon}^\\delta,x_{\\varepsilon}^\\delta) + \\frac{\\delta}{(T-t^\\delta_{\\varepsilon})^2}=0,\\qquad\n{(-\\Delta)^{s}}u^{\\varepsilon}(t_{\\varepsilon}^\\delta,x_{\\varepsilon}^\\delta) - {(-\\Delta)^{s}}\\psi_{\\varepsilon}(x_{\\varepsilon}^\\delta) +\\delta {(-\\Delta)^{s}}{\\varphi}(x_{\\varepsilon}^\\delta)\\leq 0,$$ which combined with gives $$\\beta_{\\varepsilon}(u^{\\varepsilon}- \\psi_{\\varepsilon})(t_{\\varepsilon}^\\delta,x_{\\varepsilon}^\\delta) \\leq\n{(-\\Delta)^{s}}\\psi_{\\varepsilon}(x_{\\varepsilon}^\\delta)-\\frac{\\delta}{(T-t^\\delta_{\\varepsilon})^2}- \\delta {(-\\Delta)^{s}}{\\varphi}(x_{\\varepsilon}^\\delta)\\leq \\|{(-\\Delta)^{s}}\\psi_{\\varepsilon}\\|_{L^\\infty({\\mathbb{R}}^n)}+O(\\delta).$$ Since $(u^{\\varepsilon}- \\psi_{\\varepsilon})(t_{\\varepsilon}^\\delta,x_{\\varepsilon}^\\delta)\\to \\inf_{[0,T]\\times {\\mathbb{R}}^n}(u^{\\varepsilon}- \\psi_{\\varepsilon})$ as ${\\delta}\\to 0$ and $\\beta_{\\varepsilon}'\\leq 0$ we obtain $$\\sup_{[0,T]\\times {\\mathbb{R}}^n}\\beta_{\\varepsilon}(u^{\\varepsilon}- \\psi_{\\varepsilon}) = \\lim_{{\\delta}\\to 0}\\beta_{\\varepsilon}(u^{\\varepsilon}- \\psi_{\\varepsilon})(t_{\\varepsilon}^\\delta,x_{\\varepsilon}^\\delta) \\leq \\|{(-\\Delta)^{s}}\\psi_{\\varepsilon}\\|_{L^\\infty({\\mathbb{R}}^n)},$$ so that follows letting ${\\varepsilon}\\to 0$.\n\n*$\\bullet$ $L^\\infty$-bound on $u_t^{\\varepsilon}$.* We use the same argument as in [@frikin Lemma 2.1]: differentiating with respect to $t$ we obtain that $w^{\\varepsilon}:=u_t^{\\varepsilon}$ solves $$\\left\\{\n\\begin{array}{ll}\nw^{\\varepsilon}_t +{(-\\Delta)^{s}}w^{\\varepsilon}= \\beta_{\\varepsilon}'(u^{\\varepsilon}- \\psi_{\\varepsilon})w^{\\varepsilon}&\\text{on }[0,T]\\times {\\mathbb{R}}^n\\\\\nw^{\\varepsilon}(0)=-{(-\\Delta)^{s}}u^{\\varepsilon}(0)\\quad \\text{on }{\\mathbb{R}}^n.", "\n\\end{array}\n\\right.$$ Since $\\beta_{\\varepsilon}' \\leq 0$ and $\\|w^{\\varepsilon}(0)\\|_{L^\\infty}=\\|{(-\\Delta)^{s}}u_0^{\\varepsilon}\\|_{L^\\infty}$, using a maximum principle argument (as above), we infer that $$\\|u_t^{\\varepsilon}\\|_{L^\\infty([0,T]\\times{\\mathbb{R}}^n)}=\\|w^{\\varepsilon}\\|_{L^\\infty([0,T]\\times{\\mathbb{R}}^n)}\n\\leq \\|w^{\\varepsilon}(0)\\|_{L^\\infty({\\mathbb{R}}^n)}=\\|{(-\\Delta)^{s}}u_0^{\\varepsilon}\\|_{L^\\infty({\\mathbb{R}}^n)}.$$ Letting ${\\varepsilon}\\to 0$ we get , as desired.", "\n\nThe above result together with Lemma \\[lemma:basic\\](i) gives the following:\n\n\\[cor:Lip\\] Let $u$ be a solution of . ", "Then $$\\|u_t\\|_{L^\\infty([0,T]\\times {\\mathbb{R}}^n)}+\n\\|\\nabla u\\|_{L^\\infty([0,T]\\times {\\mathbb{R}}^n)}\\leq\n\\max\\{\\|\\nabla u_0\\|_{L^\\infty({\\mathbb{R}}^n)},\\|\\nabla \\psi\\|_{L^\\infty({\\mathbb{R}}^n)}\\}+\n\\|{(-\\Delta)^{s}}u_0\\|_{L^\\infty({\\mathbb{R}}^n)}.$$\n\nIn the sequel we will also need the following result:\n\n\\[lem:sign frac lapl\\] Let $u$ be a solution of with $$\\|\\nabla \\psi\\|_{L^\\infty({\\mathbb{R}}^n)}+\\|{(-\\Delta)^{s}}\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}+\\|\\nabla u_0\\|_{L^\\infty({\\mathbb{R}}^n)}+\n\\|{(-\\Delta)^{s}}u_0\\|_{L^\\infty({\\mathbb{R}}^n)}<+\\infty,$$ and fix $t_0>0$. Then $$\\label{eq:frac lapl leq 0}\n0 \\leq {(-\\Delta)^{s}}u(t_0) \\leq \\|{(-\\Delta)^{s}}\\psi\\|_{L^\\infty({\\mathbb{R}}^n)} \\qquad \\text{for a.e. ", "$x \\in \\{u(t_0)=\\psi\\}$},$$ $$\\label{eq:frac lapl geq 0}\n{(-\\Delta)^{s}}u(t_0) \\leq 0 \\qquad \\text{on $\\{u(t_0)>\\psi\\}$}.$$\n\nLet us recall that, thanks to Corollary \\[cor:Lip\\], $u$ is Lipschitz in time. ", "So, Lemma \\[lemma:basic\\](iii) gives $u_t\\geq 0$ a.e.", "\n\nMoreover, since $u_t=0$ a.e. ", "on the contact set $\\{u=\\psi\\}$, $u$ satisfies $$u_t +{(-\\Delta)^{s}}u=0\\quad \\text{in }\\{u>\\psi\\},\n\\qquad\nu_t=0\\quad \\text{a.e. ", "on }\\{u=\\psi\\},$$ which gives $$u_t +{(-\\Delta)^{s}}u=\\bigl({(-\\Delta)^{s}}u\\bigr) \\chi_{\\{u=\\psi\\}}$$ both in the almost everywhere sense and in the sense of distribution. (", "Observe that the above formula makes sense since ${(-\\Delta)^{s}}u$ is a bounded function, see Lemma \\[lemma:Linfty bound frac heat\\]). ", "Hence, $u$ solves the smooth parabolic equation $u_t+{(-\\Delta)^{s}}u =f$, with $f$ globally bounded and vanishing inside the open set $\\{u>\\psi\\}$. So, a simple application of Duhamel formula shows that $u$ is smooth inside $\\{u>\\psi\\}$. In particular, this fact combined with the non-negativity of $u_t$ implies $${(-\\Delta)^{s}}u(t_0)=-u_t(t_0) \\leq 0 \\qquad \\text{on $\\{u(t_0)>\\psi\\}$},$$ that is, .", "\n\nWe now prove . ", "Since $u_t=0$ a.e. ", "on the contact set $\\{u=\\psi\\}$, gives $$\\label{eq:bound space-time}\n0 \\leq {(-\\Delta)^{s}}u \\leq \\|{(-\\Delta)^{s}}\\psi\\|_{L^\\infty}\\qquad \\text{ for a.e. ", "$(t,x) \\in \\{u=\\psi\\}$.}$$ Now, to show that the bound $0 \\leq {(-\\Delta)^{s}}u(t_0) \\leq \\|{(-\\Delta)^{s}}\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}$ holds a.e. ", "on ${\\mathbb{R}}^n$ *for every $t_0 \\in [0,T]$*, we observe that the map $$t \\mapsto u(t) \\in L^2_{{\\rm loc}}({\\mathbb{R}}^n)$$ is uniformly continuous (this is a consequence of the Lipschitz continuity in time, see Corollary \\[cor:Lip\\]), which together with the uniform bound implies that the map $$t \\mapsto {(-\\Delta)^{s}}u(t) \\in L^2_{{\\rm loc}}({\\mathbb{R}}^n)$$ is weakly continuous. ", "Thanks to this fact, we easily deduce the desired estimate. ", "Indeed, fix ${\\varepsilon}>0$, $A\\subset \\{u(t_0)=\\psi\\}$ a bounded Borel set, and test against the function $\\chi_{[t_0-{\\varepsilon},t_0]}\\chi_{A}$. Since the sets $\\{u(t)=\\psi\\}$ are decreasing in time (see Lemma \\[lemma:basic\\](iii)), we have $[t_0-{\\varepsilon},t_0]\\times A\\subset \\{u=\\psi\\}$, which together with gives $$0 \\leq \\int_{t_0-{\\varepsilon}}^{t_0}\\int_{A} {(-\\Delta)^{s}}u \\leq \\|{(-\\Delta)^{s}}\\psi\\|_{L^\\infty}\\,|A|\\,{\\varepsilon}.$$ Dividing by ${\\varepsilon}$ and letting ${\\varepsilon}\\to 0$, by the weak-$L^2$ continuity of $t \\mapsto {(-\\Delta)^{s}}u(t)$ we deduce $$0 \\leq \\int_{A} {(-\\Delta)^{s}}u(t_0) \\leq \\|{(-\\Delta)^{s}}\\psi\\|_{L^\\infty}\\,|A|\\qquad \\forall\\text{ $A\\subset \\{u(t_0)=\\psi\\}$ Borel bounded},$$ so that the desired bound follows.", "\n\nWe now show that the uniform semiconvexity of $u(t)$, together with the $L^\\infty$-bound on ${(-\\Delta)^{s}}u(t)$, implies that solutions are $C^1$ in space when $s \\geq 1/2$ (actually, when $s>1/2$, by elliptic regularity theory the boundedness of ${(-\\Delta)^{s}}u(t)$ implies that $u(t) \\in C^{2s-0^+}_{\\rm loc}({\\mathbb{R}}^n)$). ", "As we will show in Remark \\[rmk:C1\\] below, unless the contact set shrinks in time, this regularity result is optimal for $s=1/2$.\n\n\\[prop:C1x reg\\] Let $u$ be a solution of with $s \\in [1/2,1)$. Assume that $u_0$ and $\\psi$ are semiconvex, and that $\\|{(-\\Delta)^{s}}u_0\\|_{L^\\infty({\\mathbb{R}}^n)}+\\|{(-\\Delta)^{s}}\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}<+\\infty$. Then $u(t) \\in C^1({\\mathbb{R}}^n)$ for all $t \\in [0,T]$. Moreover the modulus of continuity of $\\nabla u$ depends only on $s$, the semiconvexity constant of $u_0$ and $\\psi$, and on $\\|{(-\\Delta)^{s}}u_0\\|_{L^\\infty({\\mathbb{R}}^n)}+\\|{(-\\Delta)^{s}}\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}$.\n\nFirst of all, we claim that, for every fixed $t \\in [0,T]$, the map $x\\mapsto -{(-\\Delta)^{s}}u(t,x)$ is lower semicontinuous. ", "Indeed, recall that if $C_0$ denotes a semiconvexity constant for both $u_0$ and $\\psi$, then $u(t)$ is $C_0$-semiconvex for all $t \\in [0,T]$ (see Lemma \\[lemma:basic\\](ii)). ", "Hence ${(-\\Delta)^{s}}u(t,x)$ is pointwise defined *at every* $x \\in {\\mathbb{R}}^n$, and is given by (see ) $$\\begin{aligned}\n-{(-\\Delta)^{s}}u (t,x)&=\\int_{B_1} \\frac{u(t,x+h)+u(t,x-h)-2u(t,x)}{2|h|^{n+2s}}\\,dh + \\int_{{\\mathbb{R}}^n\\setminus B_1}\n\\frac{u(t,x+h)-u(t,x)}{|h|^{n+2s}}\\,dy\\\\\n&=\\int_{B_1} \\frac{u(t,x+h)+u(t,x-h)-2u(t,x)+2C_0|h|^2}{2|h|^{n+2s}}\\,dh\\\\\n&\\quad-C_0 C(n,s) +\n\\int_{{\\mathbb{R}}^n\\setminus B_1} \\frac{u(t,x+h)-u(t,x)}{|h|^{n+2s}}\\,dy\\end{aligned}$$ where $C(n,s):=\\int_{B_1}|h|^{2-n-2s}\\,dh$. The last integral in the right hand side is continuous as a function of $x$ (since $u$ is continuous). ", "Moreover, since the function inside the first integral is continuous in $x$ and non-negative (by the $C_0$-semiconvexity), the first integral is lower semicontinuous as a function of $x$ by Fatou’s lemma. ", "This proves the claim.", "\n\nNow, we remark that $-{(-\\Delta)^{s}}u(t,x_0)=+\\infty$ whenever $x_0$ is a point such that the subdifferential of $u(t)$ at $x_0$ is not single valued. ", "Indeed, suppose that $$u(t,x) \\geq {\\varphi}_{x_0,p_1,p_2}(x):=\\Big[u(t,x_0)+ \\max\\bigl\\{p_1\\cdot (x-x_0) ,p_2\\cdot (x-x_0) \\bigr\\}-\\frac{C_0}{2}|x-x_0|^2\\Big]\\chi_{B_{1}(x_0)}(x),$$ for some $p_1\\neq p_2$. Then, it is easy to check by a simple explicit computation that $$-{(-\\Delta)^{s}}{\\varphi}_{x_0,p_1,p_2}(x_0)=+\\infty\\qquad \\forall\\,s \\geq 1/2.$$ Hence, since $u(t)\\geq {\\varphi}_{x_0,p_1,p_2}$ with equality at $x_0$, we get $${(-\\Delta)^{s}}u (t,x_0)\\geq {(-\\Delta)^{s}}{\\varphi}_{x_0,p_1,p_2}(x_0)=+\\infty.$$ However, since $-{(-\\Delta)^{s}}u(t)$ is bounded by $\\|{(-\\Delta)^{s}}u_0\\|_{L^\\infty({\\mathbb{R}}^n)}+\\|{(-\\Delta)^{s}}\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}$ (see ) and it is a lower semicontinuous function, the above inequality is impossible. ", "Thus the subdifferential of $u(t)$ at $x$ is a singleton at every point, i.e., $u(t)$ is $C^1$. Finally, the last part of the statement follows by a simple compactness argument.", "\n\n\\[rmk:C1\\]\n\nThe spatial $C^1$-regularity proved in the above proposition is optimal for $s=1/2$. Indeed, consider the case $n=1$ and $\\psi\\equiv 0$, and use the interpretation of the $(1/2)$-fractional Laplacian as the Dirichlet-to-Neumann operator for the harmonic extension, as explained in Subsection \\[subsect:prelim\\] (observe that $L_a=\\Delta_{x,y}$ when $s=1/2$). ", "Then, we look for solutions to the problem $$\\label{eq:Df 12}\n\\left\\{\n\\begin{array}{ll}\n\\min\\{ u_t -u_y,u\\}=0& \\text{on }[0,T]\\times{\\mathbb{R}},\\\\\n\\Delta_{x,y} u(t)=0&\\text{on }[0,T]\\times{\\mathbb{R}}\\times {\\mathbb{R}}^+.\\\\\n\\end{array}\n\\right.$$ Let us try to find traveling waves solutions to the above equation, i.e., solutions of the form $u(t,x,y)=w(a t+x,y)$, with $a \\in {\\mathbb{R}}$. In this case $u_t=a u_x$, so $w(x,y)$ has to solve $$\\label{eq:traveling}\n\\left\\{\n\\begin{array}{ll}\na w_x(x,0)-w_y(x,0)=0 & \\text{when } \\{w(x,0)>0\\},\\\\\n\\Delta_{x,y} w=0 &\\text{on }{\\mathbb{R}}\\times {\\mathbb{R}}^+.", "\n\\end{array}\n\\right.$$ By using the complex variable $z=x+iy$ it is easy to construct $C^1$ solutions to the above equation: if we denote $\\rho=|z|=\\sqrt{x^2+y^2}$ and $\\theta=\\arg(z)$, then $w_{\\beta}(x,y):=-\\rho^{1+\\beta} \\sin((1+\\beta)\\theta)=-{\\rm Im}(z^{1+\\beta})$ is harmonic in the half-space $y>0$ and solves $$\\left\\{\n\\begin{array}{ll}\nw_{\\beta}(x,0)=0 & \\text{on }\\{x\\geq 0\\},\\\\\nw_{\\beta}(x,0)>0,\\,\\frac{(w_{\\beta})_x}{\\tan({\\beta}\\pi)}=(w_{\\beta})_y &\\text{on }\\{x><0\\}.", "\n\\end{array}\n\\right.$$ Observe that $w_{\\beta}$ is of class $C^{1+{\\beta}}$ both in space and time (but not more), and solves with $a=1/\\tan({\\beta}\\pi)$. Since ${\\beta}\\in (0,1)$ is arbitrary, we cannot expect to prove any uniform $C_{x}^{1+{\\alpha}}$-regularity for solutions to . ", "Thus, the $C^1_x$-regularity proved in Proposition \\[prop:C1x reg\\] is optimal.", "\n\nOn the other hand, we observe that the case $u_t\\geq0$ (i.e., the contact set shrinks in time) corresponds to $a \\leq 0$, or equivalently to $\\beta \\geq 1/2$. Hence, in this case the solutions constructed above are at least $C_{t,x}^{1+1/2}$, which is the optimal regularity result for the stationary case [@athcaf; @cafsalsil]. ", "As we will show in the next section, solutions to satisfying $u_t\\geq 0$ are of class $C^{1+1/2}$ in space. ", "In particular, by Lemma \\[lemma:basic\\] this result applies to solutions of .", "\n\nProof of Theorem \\[thm:main\\] {#sect:opt reg}\n=============================\n\nThe strategy of the proof is the following: first in Subsection \\[sect:general C1a\\] we prove a general $C^{{\\alpha}+2s}$-regularity result in space which, roughly speaking, says the following: let $v:{\\mathbb{R}}^n\\to {\\mathbb{R}}$ be a semiconvex function which touches from above an obstacle $\\psi:{\\mathbb{R}}^n\\to {\\mathbb{R}}$ of class $C^2$. Assume that ${(-\\Delta)^{s}}v$ is non-positive outside the contact set and non-negative on the contact set. ", "Then $v$ detaches from $\\psi$ in a $C^{{\\alpha}+2s}$ fashion, for some $\\alpha=\\alpha(s)>0$ universal. ", "In particular, as shown in Corollary \\[cor:unif C1a v\\], this implies that ${(-\\Delta)^{s}}v\\chi_{\\{v=\\psi\\}} \\in C_{x}^{{\\alpha}}({\\mathbb{R}}^n)$.\n\nThen, in Subsection \\[subsect:monot\\] we use a monotonicity formula to prove the optimal regularity in space $${(-\\Delta)^{s}}v\\chi_{\\{v=\\psi\\}} \\in C_{x}^{1-s}({\\mathbb{R}}^n).$$ Finally, in Subsection \\[sect:C1s u\\] we apply the above estimate to any time slice $u(t)$ to prove that ${(-\\Delta)^{s}}u(t)\\chi_{u(t)=\\psi}\\in C_{x}^{1-s}({\\mathbb{R}}^n)$, uniformly in time. ", "Then, exploiting and a bootstrap argument, we get .", "\n\nA general $C^{{\\alpha}+2s}$-regularity result. {#", "sect:general C1a}\n----------------------------------------------\n\nIn order to underline what are the key elements in the proof, in this and in the next subsection we forget about equation , and we work in the following general setting: let $v,\\psi:{\\mathbb{R}}^n \\to {\\mathbb{R}}$ be two globally Lipschitz functions with $v \\geq \\psi$. Assume that[^4]:\n\n1. ", " $\\|D^2 \\psi\\|_{L^\\infty({\\mathbb{R}}^n)}=:C_0 <+\\infty$;\n\n2. ", " $\\|{(-\\Delta)^{s}}\\psi\\|_{C_x^{1-s}({\\mathbb{R}}^n)} <+\\infty $;\n\n3. ", " $v-\\psi,{(-\\Delta)^{s}}v\\in L^\\infty({\\mathbb{R}}^n)$;\n\n4. ", " $v$ is $C_0$-semiconvex;\n\n5. ", " $v$ is smooth and ${(-\\Delta)^{s}}v \\leq 0$ inside the open set $\\{v>\\psi\\}$;\n\n6. ", " $\\|{(-\\Delta)^{s}}\\psi\\|_{L^\\infty({\\mathbb{R}}^n)} \\geq {(-\\Delta)^{s}}v \\geq 0$ a.e. ", "on $\\{v=\\psi\\}$.\n\nUnder these assumptions, we want to show that $v$ is $C^{{\\alpha}+2s}$ at every free boundary point, with a uniform bound. ", "More precisely, we want to prove:\n\n\\[thm:unif C1a v\\] Let $v$ be as above. ", "Then there exist $\\bar C>0$ and ${\\alpha}\\in (0,1)$, depending on $C_0$, $\\|{(-\\Delta)^{s}}\\psi\\|_{C_x^{1-s}({\\mathbb{R}}^n)}$, $\\|v-\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}$, and $\\|{(-\\Delta)^{s}}v\\|_{L^\\infty({\\mathbb{R}}^n)}$ only, such that $$\\label{eq:unif C1a v} \n\\sup_{B_r(x)}|v-\\psi| \\leq \\bar C\\, r^{{\\alpha}+2s},\\quad \\sup_{B_r(x)}|{(-\\Delta)^{s}}v\\chi_{\\{v=\\psi\\}}| \\leq \\bar C\\,\nr^{{\\alpha}}\\qquad \\forall \\,r \\leq 1$$ for every $x \\in {\\partial}\\{u=\\psi\\}$.\n\nBefore proving the above result, let us show how it implies the following:\n\n\\[cor:unif C1a v\\] Let $v$ be as above. ", "Then there exist $\\bar C'>0$ and ${\\alpha}\\in (0,1-s]$, depending on $C_0$, $\\|v-\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}$, and $\\|{(-\\Delta)^{s}}v\\|_{L^\\infty({\\mathbb{R}}^n)}$ only, such that $$\\|{(-\\Delta)^{s}}v \\chi_{\\{v=\\psi\\}}\\|_{C_{x}^{{\\alpha}}({\\mathbb{R}}^n)}\\leq \\bar C'.$$\n\nWithout loss of generality, we can assume that the exponent ${\\alpha}$ provided by Theorem \\[thm:unif C1a v\\] is not greater than $1-s$. Moreover, since ${(-\\Delta)^{s}}v$ is bounded on $\\{v=\\psi\\}$ (see (A6)), it suffices to control $|{(-\\Delta)^{s}}v(x_1)-{(-\\Delta)^{s}}v(x_2)|$ when $x_1,x_2 \\in \\{v=\\psi\\}$ and $|x_1-x_2|\\leq 1/4.$\n\nLet $M:=\\|v-\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}$. Moreover, given $x \\in \\{v=\\psi\\}$, let $d_F(x)$ denote its distance from the free boundary ${\\partial}\\{v=\\psi\\}$.\n\nFix $x_1,x_2 \\in \\{v=\\psi\\}$, with $|x_1-x_2|\\leq 1/4$. Two cases arise.\\\n$\\bullet$ *Case 1:* $\\max_{i=1,2}d_F(x_i) \\geq 4|x_1-x_2|$. Set $\\tilde v:=v-\\psi$. Since $\\alpha\\leq 1-s$ by assumption, thanks to (A2) it suffices to estimate ${(-\\Delta)^{s}}\\tilde v$ inside $\\{\\tilde v=0\\}=\\{v=\\psi\\}$. Now, by Theorem \\[thm:unif C1a v\\] we have $$\\sup_{B_r(x_i)}|\\tilde v| \\leq \\bar C\\, r^{{\\alpha}+2s},\\qquad \\forall\\,r \\leq 1, \\,i=1,2.$$ Hence, since $\\tilde v=0$ inside $B_{4|x_1-x_2|}(x_1)\\cap B_{4|x_1-x_2|}(x_2)$ and $|\\tilde v|\\leq M$ outside $B_1(x_1)\\supset B_{1/2}(x_2)$, we get $$\\begin{aligned}\n&|{(-\\Delta)^{s}}\\tilde v(x_1) - {(-\\Delta)^{s}}\\tilde v(x_2)|\\\\\n&= \\int_{{\\mathbb{R}}^n} \\frac{\\tilde v(x') - \\tilde v(x_1)}{|x'-x_1|^{n+2s}}\\,dx'\n- \\int_{{\\mathbb{R}}^n}\\frac{\\tilde v(x') - \\tilde v(x_2)}{|x'-x_2|^{n+2s}}\\,dx'\\\\\n&\\leq \\int_{{\\mathbb{R}}^n\\setminus [B_{4|x_1-x_2|}(x_1)\\cap B_{4|x_1-x_2|}(x_2)]}\n|\\tilde v(x')|\\,\\biggl|\\frac{1}{|x'-x_1|^{n+2s}}-\\frac{1}{|x'-x_1|^{n+2s}}\\biggr|\\,dx'\\\\\n&\\leq \\bar C\\,|x_1-x_2|\\int_{B_1(x_1)\\setminus [B_{4|x_1-x_2|}(x_1)\\cap B_{4|x_1-x_2|}(x_2)]} |x'|^{{\\alpha}+2s}\n\\biggl[\\frac{1}{|x'-x_1|^{n+2s+1}}+\\frac{1}{|x'-x_2|^{n+2s+1}}\\biggr]\\,dx'\\\\\n&\\qquad+ 2M\\,|x_1-x_2|\\int_{{\\mathbb{R}}^n\\setminus B_1(x_1)}\n\\biggl[\\frac{1}{|x'-x_1|^{n+2s+1}}+\\frac{1}{|x'-x_2|^{n+2s+1}}\\biggr]\\,dx'\\\\\n&\\leq C\\,\\biggl[\\bar C\\int_{|x_1-x_2|}^1 s^{{\\alpha}-2}\\,ds +M\\biggr]\\,|x_1-x_2| \\leq C\\,|x_1-x_2|^{\\alpha},\\end{aligned}$$ as desired.\\\n$\\bullet$ *Case 2:* $\\max_{i=1,2}d_F(x_i) \\leq 4|x_1-x_2|$. For every $i=1,2$, let $\\bar x_i \\in {\\partial}\\{v=\\psi\\}$ denote a point such that $|x_i-\\bar x_i|=d_F(x_i)$. Then, by Theorem \\[thm:unif C1a v\\] we get $$\\begin{aligned}\n|{(-\\Delta)^{s}}v(x_1)-{(-\\Delta)^{s}}v(x_2)| \n& \\leq \\sup_{B_{4|x_1-x_2|}(\\bar x_1)}|{(-\\Delta)^{s}}v|+\\sup_{B_{4|x_1-x_2|}(\\bar x_2)}|{(-\\Delta)^{s}}v|\\\\\n&\\leq 8\\bar C\\,\n|x_1-x_2|^{{\\alpha}}.\\end{aligned}$$\n\n### Proof of Theorem \\[thm:unif C1a v\\]\n\nThe strategy of the proof is analogous to the one used in [@athcaf] to study the stationary fractional obstacle problem with $s=1/2$ (also called “Signorini problem”).", "\n\nWith no loss of generality, we can assume that $0$ is a free boundary point, and we prove at $x=0$. Moreover, by a slight abuse of notation, let us still denote by $v:{\\mathbb{R}}^n\\times {\\mathbb{R}}^+ \\to {\\mathbb{R}}$ the $L_a$-harmonic extension of $v$, i.e., $$L_a v(x,y)={\\operatorname{div}}_{x,y}\\bigl(y^a \\nabla_{x,y} v(x,y)\\bigr)=0\\qquad \\text{for $y>0$},$$ and $v(x,0)=v(x)$, with $v(x)$ as above. ", "Then $$\\lim_{y\\to 0^+}y^a v_y(x,y)=-{(-\\Delta)^{s}}v(x,0),\\qquad a=1-2s$$ (see ). ", "Let us observe that the $C_0$-semiconvexity of $v(x,0)$ (see (A4)) propagates in $y$: since $$v(x+h,0)+v(x-h,0)-2v(x,0)\\geq -2C_0|h|^2 \\qquad\\forall\\,h \\in {\\mathbb{R}}^n,$$ the maximum principle implies $$v(x+h,y)+v(x-h,y)-2v(x,y)\\geq -2C_0|h|^2\\qquad\\forall\\,h \\in {\\mathbb{R}}^n,\\,y>0,$$ that is,\n\n1. ", " $v(\\cdot,y)$ is $C_0$-semiconvex for all $y \\geq 0$.\n\nIn particular, since $L_a v=0$ we get\n\n1. ", " ${\\partial}_y(y^a v_y)\\leq nC_0 y^a.$\n\nIn the sequel, we will informally call the above property “$a$-semiconcavity” in $y$[^5]. ", "Set now $$\\tilde v(x,y):=v(x,y)-\\psi(x),$$ and denote by ${\\Lambda}:=\\{\\tilde v(x,0)=0\\}=\\{v(x,0)=\\psi(x)\\}$ the contact set. ", "Observe that $ \\tilde v_y=v_y$, which together with thanks to (A1)-(A6) gives that the function $\\tilde v$ enjoys the following properties:\n\n1. ", " $\\tilde v(x,0)\\geq 0$ for all $(x,y)\\in {\\mathbb{R}}^n\\times {\\mathbb{R}}^+\\setminus {\\Lambda}\\times\\{0\\}$.\n\n2. ", " ${\\partial}_y(y^a\\tilde v_y(x,y))\\leq 2nC_0y^a$, $\\tilde v(\\cdot,y)$ is $(2C_0)$-semiconvex for all $y \\geq 0$.\n\n3. ", " $\\lim_{y \\to 0^+} y^a\\tilde v_y(x,y) \\leq 0$ for a.e. ", "$x \\in {\\Lambda}$, $\\lim_{y \\to 0^+} y^a\\tilde v_y(x,y)\\geq 0$ for a.e. ", "$x \\in {\\mathbb{R}}^n\\setminus {\\Lambda}$.\n\n4. ", " $\\tilde v(x,y)-\\tilde v(x,0)\\leq \\frac{nC_0}{1+a}\\,y^{2}$ for all $x \\in {\\Lambda}$.\n\n5. ", " if $\\tilde v(x,y)\\geq h$, then $\\tilde v(x,y) \\geq h-C_0\\rho^2$ in the half-ball $$HB_\\rho(x):=\\{z \\in B_\\rho(x)\\subset {\\mathbb{R}}^n\\,:\\,{\\langle}{\\nabla}_x \\tilde v(x,y),z-x{\\rangle}\\geq 0\\}.$$\n\nObserve that the proof of (B1)-(B5) is almost immediate, except for (B4) for which a (simple) computation is needed: using (B2) and (B3), for a.e. ", "$x \\in {\\Lambda}$ we have $$\\tilde v(x,y)-\\tilde v(x,0)=\\int_0^y \\tilde v_y(x,s)\\,ds =\\int_0^y \\frac{s^a\\tilde v_y(x,s)}{s^a}\\,ds \\leq \\int_0^y \\frac{\\int_0^s 2nC_0 \\tau^a\\,d\\tau}{s^a}\\,ds=\\frac{nC_0}{1+a}\\,y^2,$$ and by continuity the above inequality holds for all $x \\in {\\Lambda}$.\n\nWe use the notation ${\\Gamma}_r:=B_r\\times [0,\\eta_{n,a}r]$, where $\\eta_{n,a}=\\sqrt{\\frac{1+a}{2n}}$. We first show a decay result for $y^{a}\\tilde v_y$:\n\n\\[prop: C1a v\\] There exist two constants $K_1>0$, $\\mu \\in (0,1)$, depending on $C_0$, $\\|v-\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}$, and $\\|{(-\\Delta)^{s}}v\\|_{L^\\infty({\\mathbb{R}}^n)}$ only, such that $$\\label{eq:induction}\n\\inf_{{\\Gamma}_{4^{-k}}} y^a\\tilde v_y \\geq -K_1\\,\\mu^k,$$\n\nWe prove the result by induction.\\\n*Case $k=1$:* since $v$ is $L_{a}$-harmonic, $y^a\\tilde v_y=y^a v_y$ solves the “conjugate” equation $L_{-a}(y^a \\tilde v_y)=0$ inside ${\\mathbb{R}}^n\\times {\\mathbb{R}}^+$ (see for instance [@cafsil Subsection 2.3]). ", "Hence, the boundedness of $\\lim_{y\\to 0^+}y^a\\tilde v_y(x,y)={(-\\Delta)^{s}}v(x,0)$ (see (A6) and ) combined with the maximum principle implies the result.\\\n*Induction step:* Assume the result is true for $k= k_0$, i.e., $$\\inf_{{\\Gamma}_{4^{-k_0}}} y^a\\tilde v_y \\geq -K_1\\,\\mu^{k_0}$$ for some constants $K_1>0$ and $\\mu\\in(0,1)$ which will be chosen later, and renormalize the solution inside ${\\Gamma}_1$ by setting $$\\tilde V(x,y):=\\frac{1}{K_1} \\left(\\frac{4^{2s}}{\\mu}\\right)^{k_0} \\tilde v\\left(\\frac{x}{4^{k_0}},\\frac{y}{4^{k_0}}\\right).$$ It will also useful to consider the $L_a$-harmonic function $$\\bar V(x,y):=\\frac{1}{K_1} \\left(\\frac{4^{2s}}{\\mu}\\right)^{k_0} \\bar v\\left(\\frac{x}{4^{k_0}},\\frac{y}{4^{k_0}}\\right),$$ where $\\bar v$ is the $L_a$-harmonic function given by $$\\label{eq:bar v}\n\\bar v(x,y):=v(x,y)-\\psi(0)-{\\nabla}\\psi(0)\\cdot x.$$ Then, thanks to (A1) and (B2):\n\n1. ", " $|\\tilde V(x,y) - \\bar V(x,y)|\\leq \\frac{C_0}{K_1(4^{2(1-s)}\\mu)^{k_0}}|x|^2$ and $\\tilde V_y=\\bar V_y$;\n\n2. ", " $\\inf_{{\\Gamma}_1} y^a \\tilde V_y=\\inf_{{\\Gamma}_1} y^a \\bar V_y\\geq -1$;\n\n3. ", " ${\\partial}_y(y^a\\tilde V_{y})={\\partial}_y(y^a\\bar V_{y})\\leq \\frac{2nC_0}{K_1(4^{2(1-s)}\\mu)^{k_0}}y^a$, $\\tilde V$ and $\\bar V$ are $\\left(\\frac{2C_0}{K_1(4^{2(1-s)}\\mu)^{k_0}}\\right)$-semiconvex inside ${\\Gamma}_1$.\n\nFix $L:=\\bar C_{n,a} C_0$, where $\\bar C_{n,a}\\gg 1$ is a large constant depending on $n$ and $a$ only (to be fixed later), and define $$\\bar W(x,y):=\\bar V(x,y) - \\frac{L}{K_1(4^{2(1-s)}\\mu)^{k_0}}\\biggl[|x|^2 - \\frac{n}{1+a}\\,y^2 \\biggr].$$ Thanks to (B1)-(B3), the function $\\bar W$ satisfies the following properties:\n\n1. ", " it is $L_a$-harmonic in the interior of ${\\Gamma}_{1/8}$;\n\n2. ", " $\\bar W(x,0)< 0$ for $x\\in \\bigl({\\Lambda}\\setminus \\{0\\}\\bigr)\\times\\{0\\}$;\n\n3. ", " $\\lim_{(x,y)\\to (0,0)} \\bar W(x,y)=0$;\n\n4. ", " $\\lim_{y\\to 0^+}y^a\\bar W_y(x,y)\\geq 0$ for $x \\not\\in B_{1/8}\\setminus {\\Lambda}$.\n\nHence, up to replacing $\\bar W$ by $\\bar W+{\\varepsilon}y^{1-a}$ with ${\\varepsilon}>0$ (so that the inequality in 4. ", "becomes strict) and then letting ${\\varepsilon}\\to 0$, by Hopf’s Lemma $\\bar W$ attains its non-negative maximum on ${\\partial}{\\Gamma}_{1/8} \\setminus \\{y=0\\}$.\\\nTwo cases arise:\\\n*Case 1:* *The maximum is attained on ${\\partial}{\\Gamma}_{1/8}\\cap \\{y=\\eta_{n,a}/8\\}$*.\\\nIn this case, there exists $x_0 \\in B_{1/8}$ such that $$\\bar V\\left(x_0,\\textstyle{\\frac{\\eta_{n,a}}{8}}\\right) \\geq -c'_{n,a}\\frac{L}{K_1(4^{2(1-s)}\\mu)^{k_0}},$$ for some constant $c_{n,a}'>0$ depending on $n,a$ only. ", "Thanks to the semiconvexity in $x$ (see property (iii) above) and recalling that $L \\gg C_0$ by assumption, there exists an $n$-dimensional half-ball $HB_{1/2}\\left(x_0,\\textstyle{\\frac{\\eta_{n,a}}{8}}\\right)$ such that $$\\bar V\\left(x,\\textstyle{\\frac{\\eta_{n,a}}{8}}\\right) \\geq -\\frac{c_{n,a}'}2\\frac{L}{K_1(4^{2(1-s)}\\mu)^{k_0}}\\qquad\n\\forall\\, x \\in HB_{1/2}\\left(x_0,\\textstyle{\\frac{\\eta_{n,a}}{8}}\\right)$$ (see property (B5)). ", "Recall now that $\\lim_{y\\to 0^+}y^a\\bar V_y(x,y)=\\lim_{y\\to 0^+}y^a\\tilde V_y(x,y)\\geq 0$ when $\\tilde V(x,0)>0$, while $\\lim_{y\\to 0^+}y^a\\bar V_y(x,y)=\\lim_{y\\to 0^+}y^a\\tilde V_y(x,y)\\leq 0$ when $\\tilde V(x,0)=0$. Hence, by the “$a$-semiconcavity” of $\\bar V$ in $y$ (property (iii) above) and by (i), it is easy to see that $$\\lim_{y\\to 0^+}y^a\\bar V_y\\left(x,y\\right) \\geq -C_{n,a}''\\frac{L}{K_1(4^{2(1-s)}\\mu)^{k_0}}\\qquad\n\\forall\\, x \\in HB_{1/2}\\left(x_0,0\\right),$$ for some universal constant $C_{n,a}''>0$.\\\n*Case 2:* *The maximum is attained on ${\\partial}{\\Gamma}_{1/8}\\setminus \\{y=\\eta_{n,a}/8\\}$*.\\\nLet $(x_0',y_0')$ be a maximum point. ", "Since such a point belongs to the lateral side of the cylinder, recalling the definition of $\\eta_{n,a}$ we have $|x_0'|^2\\ge \\frac{2n}{1+a}|y_0'|^2$, which implies $$\\bar V(x_0',y_0')\\geq \\frac{L}{K_1(4^{2(1-s)}\\mu)^{k_0}}.$$ Again, we recall that $\\lim_{y\\to 0^+}y^a\\bar V_y(x,y)=\\lim_{y\\to 0^+}y^a\\tilde V_y(x,y) \\geq 0$ when $\\tilde V(x,0)>0$, while $\\lim_{y\\to 0^+}y^a\\bar V_y(x,y)=\\lim_{y\\to 0^+}y^a\\tilde V_y(x,y)\\leq 0$ when $\\tilde V(x,0)=0$. Thus, by the half-ball estimate (B5) applied to $\\bar V$, by the “$a$-semiconcavity” of $\\bar V$ in $y$ (property (iii)) and by (i), we obtain $$\\lim_{y\\to 0^+}y^a\\bar V_y\\left(x,y\\right) \\geq 0 \\qquad \\forall\\, x \\in HB_{1/2}\\left(x_0',0\\right).$$\n\nHence, in both case we have reached the following conclusion:\\\n*There exist a constant $C_1>0$, depending on $n,a$, and $C_0$ only, and a point $\\bar x \\in B_{1/8}\\subset {\\mathbb{R}}^n$, such that $$\\lim_{y\\to 0^+}y^a\\bar V_y(x,0) >-\\frac{C_1}{K_1(4^{2(1-s)}\\mu)^{k_0}} \\qquad \\forall\\,x \\in HB_{1/2}\\left(\\bar x,0\\right).$$* Thus, if we choose $K_1$ and $\\mu$ satisfying $K_1>2C_1$ and $\\mu \\geq 1/4^{2(1-s)}$, then we obtain $$\\label{eq:wy 12}\n\\lim_{y\\to 0^+} y^a\\bar V_y(x,y) >-\\frac{1}{2}.$$ Moreover, thanks to (ii), $$\\label{eq:wy 1eps}\ny^a \\bar V_y \\geq -1\\qquad \\text{in }\\Gamma_1.$$ As we already observed before, the fact that $\\bar V$ is $L_{a}$-harmonic implies that $y^a\\bar V_y$ solves the conjugate equation $L_{-a}(y^a \\bar V_y)=0$ inside ${\\mathbb{R}}^n\\times {\\mathbb{R}}^+$. Hence, thanks to and , the Poisson representation formula (see [@cafsil Subsection 2.4]) implies the existence of a constant $\\theta<1$ such that $$y^a\\bar V_y\\left(x,\\textstyle{\\frac{\\eta_{n,a}}{4}}\\right) \\geq -\\theta \\qquad \\forall\\, x\\in B_{1/4}.$$ Therefore, by (i) and the “$a$-semiconcavity” of $\\bar v$ in $y$ (property (iii)), we obtain $$y^a\\tilde V_y(x,y)=y^a\\bar V_y(x,y) \\geq -\\theta - \\frac{2nC_0}{K_1(4^{2(1-s)}\\mu)^{k_0}}=:-\\mu>-1,$$ provided $K_1$ is sufficiently large. ", "Rescaling back, this proves with $k=k_0+1$, which concludes the proof.", "\n\nRecalling that $y^a \\tilde v_y=y^a v_y$, thanks to and (A6) the above proposition implies $$\\sup_{B_r(x)}|{(-\\Delta)^{s}}v\\chi_{\\{v=\\psi\\}}| \\leq \\bar C\\,\nr^{{\\alpha}}\\qquad \\forall \\,r \\leq 1.$$ We now show that a control from below on $y^a\\tilde v_y$ inside ${\\Gamma}_r$ gives a control from both sides on $\\tilde v$ inside ${\\Gamma}_{r/8}$. This will conclude the proof of Theorem \\[thm:unif C1a v\\].", "\n\n\\[lemma:deriv to fct\\] Fix $K>0$, ${\\alpha}\\in (0,1)$, and assume that $$\\label{eq:bound below vy}\n\\inf_{{\\Gamma}_r}y^a\\tilde v_y \\geq -Kr^\\alpha$$ for some $r \\in (0,1]$. Then there exists a constant $M=M(K,\\alpha,C_0)$, independent of $r$, such that $$\\sup_{{\\Gamma}_{r/8}}|\\tilde v| \\leq M r^{1+\\alpha-a}=M r^{\\alpha+2s}.$$\n\nSince $\\tilde v$ is globally bounded, it suffices to prove the result for $r$ small. ", "First of all, let us observe that, thanks to (B1) and , $$\\label{eq:bound below v}\n\\tilde v(x,y) \\geq \\tilde v(x,0) - K\\int_0^y \\frac{r^{\\alpha}}{u^{a}}\\,du \\geq -K\\,\\frac{r^{1+{\\alpha}-a}}{1-a}\\qquad\n\\forall \\,(x,y)\\in {\\Gamma}_r,$$ which proves the lower bound on $\\tilde v$.\n\nTo prove the upper-bound, assume that there exists a point $(\\bar x,\\bar y)\\in {\\Gamma}_{r/8}$ such that $\\tilde v(\\bar x,\\bar y)\\geq Mr^{1+{\\alpha}-a}$ for some large constant $M$. Arguing as above, this implies $$\\label{eq:bound below big v}\n\\tilde v\\left(\\bar x,\\frac{\\eta_{n,a}r}{2}\\right)\\geq \\frac{M}4 \\,r^{1+{\\alpha}-a},$$ provided $M$ is sufficiently large (depending only on $K$). ", "Now, let $B':=B_{\\frac{\\eta_{n,a}r}{2}}'\\left(\\bar x,\\frac{\\eta_{n,a}r}{2}\\right)$ denote the $(n+1)$-dimensional ball of radius $\\frac{\\eta_{n,a}r}{2}$ centered at $\\left(\\bar x,\\frac{\\eta_{n,a}r}{2}\\right)\\in {\\mathbb{R}}^n\\times{\\mathbb{R}}^+$, and set $B'/2:=B_{\\eta_{n,a}r/4}'\\left(\\bar x,\\frac{\\eta_{n,a}r}{2}\\right)$. Then $B'\\subset {\\Gamma}_r$ and $\\left(0,\\frac{\\eta_{n,a}r}{2}\\right)\\in B'/2$.\n\nLet $\\bar v$ be as in . ", "Thanks to (A1), $|\\bar v-\\tilde v|\\leq C_0\\,r^{2}$ inside ${\\Gamma}_r$ (observe that $\\eta_{n,a} \\leq 1$), which together with implies that $w+K\\frac{r^{1+{\\alpha}-a}}{1-a}+C_0r^{2}$ is non-negative inside ${\\Gamma}_r$. Hence we can apply Harnack inequality inside $B'$ (see [@cafsalsil Proposition 2.2] and [@fabkenser]) to obtain $$\\frac{M}8 \\,r^{1+{\\alpha}-a} \\leq \\sup_{B'/2} \\biggl[\\bar v+K\\frac{r^{1+{\\alpha}-a}}{1-a}+C_0r^{2}\\biggr] \\leq C \\biggl[\\bar v\\left(0,\\frac{\\eta_{n,a}r}{2}\\right)+K\\frac{r^{1+{\\alpha}-a}}{1-a}+C_0r^{2}\\biggr],$$ that is $\\bar v(0,\\eta_{n,a}r/2)\\geq c_0Mr^{1+{\\alpha}-a}-K\\frac{r^{1+{\\alpha}-a}}{1-a}-C_0r^{2}$ for some universal constant $c_0>0$, which gives $$\\tilde v\\left(0,\\frac{\\eta_{n,a}r}{2}\\right)\\geq c_0M\\,r^{1+{\\alpha}-a} -K\\frac{r^{1+{\\alpha}-a}}{1-a}-2C_0r^{2}.$$ Since $0\\in {\\Lambda}$, combining the above estimate with property (B4) we get $$0=\\tilde v(0,0)\\geq \\tilde v\\left(0,\\frac{\\eta_{n,a}r}{2}\\right) - \\frac{nC_0}{1+a}r^{2}\\geq\nc_0M\\,r^{1+{\\alpha}-a}-K\\frac{r^{1+{\\alpha}-a}}{1-a} - \n\\left[\\frac{nC_0}{1+a}+2C_0\\right]r^{2},$$ which shows that $M$ is universally bounded, as desired.", "\n\nTowards optimal regularity: a monotonicity formula {#subsect:monot}\n--------------------------------------------------\n\nWe use the same notation as in the previous subsection.", "\n\nWe have proved that ${(-\\Delta)^{s}}v\\chi_{\\{v=\\psi\\}}$ grows at most as $r^{\\alpha}$ near any free boundary point, which implies that ${(-\\Delta)^{s}}v \\chi_{\\{v=\\psi\\}}\\in C_{x}^{{\\alpha}}({\\mathbb{R}}^n)$ (see Corollary \\[cor:unif C1a v\\]). ", "Consider now the function $w:{\\mathbb{R}}^n\\times {\\mathbb{R}}^+\\to {\\mathbb{R}}$ obtained by solving the Dirichlet problem $$\\label{eq:def w}\n\\left\\{\n\\begin{array}{ll}\nL_{-a}w=0 &\\text{on }{\\mathbb{R}}^n\\times {\\mathbb{R}}^+,\\\\\nw(x,0)={(-\\Delta)^{s}}v(x) \\chi_{\\{v=\\psi\\}}(x)&\\text{on }{\\mathbb{R}}^n.", "\n\\end{array}\n\\right.$$ Since $w(x,0)\\geq 0$, the maximum principle implies $w \\geq 0$ everywhere.", "\n\nAssume that $0\\in {\\mathbb{R}}^n$ is a free boundary point. ", "Since ${(-\\Delta)^{s}}v(x)$ is globally bounded (see (A3)), using the Poisson representation formula for $w$ [@cafsil Subsection 2.4] together with the uniform $C_{x}^{{\\alpha}}$-regularity of $w(x,0)$ (Corollary \\[cor:unif C1a v\\]) we get $$\\sup_{|x|^2+y^2\\leq r^2} w(x,y) \\leq C \\,r^{{\\alpha}},$$ for some uniform constant $C$. ", "The goal of this subsection is to show that $$\\label{eq:C1s}\n\\sup_{|x|^2+y^2\\leq r^2} w(x,y) \\leq \\tilde C \\,r^{1-s},$$ for some constant $\\tilde C>0$, depending on $C_0$, $\\|{(-\\Delta)^{s}}\\psi\\|_{C_x^{1-s}({\\mathbb{R}}^n)}$, $\\|v-\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}$, and $\\|{(-\\Delta)^{s}}v\\|_{L^\\infty({\\mathbb{R}}^n)}$ only.", "\n\nThis estimate will imply that ${(-\\Delta)^{s}}v$ grows at most as $|x|^{1-s}$ at every free boundary point, so that the same proof as in Corollary \\[cor:unif C1a v\\] will give that ${(-\\Delta)^{s}}v \\chi_{\\{v=\\psi\\}}\\in C_{x}^{1-s}({\\mathbb{R}}^n)$, with a uniform bound. ", "Then, in the next subsection we will apply this estimate to $v=u(t)$ for every $t \\in (0,T]$, and using we will obtain the desired regularity result for $u$.\\\nAs in the previous subsection, we consider the function $\\tilde v(x,y)=v(x,y) - \\psi(x)$. Thanks to Theorem \\[thm:unif C1a v\\] together with the $(2C_0)$-semiconvexity of $\\tilde v$ (see (B2) in the previous subsection), we can mimic the proof of [@athcaf Lemma 5]:\n\n\\[lem:apply monot\\] Let $\\bar C>0$ and ${\\alpha}\\in (0,1-s]$ be as in Theorem \\[thm:unif C1a v\\], and set $\\delta_{\\alpha}=\\delta_{\\alpha}(s):=\\frac{1}{4}\\left(\\frac{{\\alpha}}{{\\alpha}+2s} -\\frac{{\\alpha}}{2}\\right)$. Then there exists $r_0=r_0({\\alpha},s,\\bar C,C_0)>0$ such that the convex hull of the set $\\{x \\in {\\mathbb{R}}^n\\,:\\,w(x,0)\\geq r^{{\\alpha}+\\delta_{\\alpha}}\\}$ in $B_r\\subset {\\mathbb{R}}^n$ does not contain the origin for $r \\leq r_0$.\n\nThanks to (B3), $$\\tilde v(x,0)=0\\quad \\text{and}\\quad\\lim_{y\\to 0^+}y^a\\tilde v_y(t,x,y)=-w(x,0) \\leq -r^{{\\alpha}+\\delta_{\\alpha}}\n\\qquad \\forall\\,x \\in \\{w(x,0)\\geq r^{{\\alpha}+\\delta_{\\alpha}}\\}.$$ Hence, by the “$a$-semiconcavity” (B2) of $\\tilde v$ in $y$, for any $x \\in \\{w(x,0)\\geq r^{{\\alpha}+\\delta_{\\alpha}}\\}$ we have $$\\label{eq:upper bound tilde v}\n\\begin{split}\n\\tilde v(x,h) &\\leq \\int_0^h \\frac{s^a\\tilde v_y(t,x,s)}{s^a}\\,ds\\\\\n&\\leq -\\int_0^h \\frac{r^{{\\alpha}+\\delta_{\\alpha}}}{s^a}\\,ds+ \\int_0^h \\frac{1}{s^a}\\biggl(\\int_0^s 2nC_0 \\tau^a\\,d\\tau \\biggr)\\,ds\\\\\n&=-\\frac{1}{1-a}r^{{\\alpha}+{\\delta}_{\\alpha}} h^{1-a} + \\frac{nC_0}{1+a}h^2=-\\frac{1}{2s}r^{{\\alpha}+{\\delta}_{\\alpha}}h^{2s} + \\frac{nC_0}{1+a}h^2.", "\n\\end{split}$$ On the other hand, Theorem \\[thm:unif C1a v\\] gives $$\\label{eq:lower bound tilde v}\n\\tilde v(0,h)=\\tilde v(0,h)-\\tilde v(0,0) \\geq -\\bar Ch^{{\\alpha}+2s}.$$ Assume now by contradiction that the convex hull of the set $\\{(x,0)\\,:\\,w(x,0)\\geq r^{{\\alpha}+\\delta_{\\alpha}}\\}\\cap B_r$ contains $(0,0)$. Then, by the $(2C_0)$-semiconvexity of $\\tilde v(\\cdot,h)$ (see (B2)) we get $$\\tilde v(0,h) \\leq \\sup_{x \\in \\{w(x,0)\\geq r^{{\\alpha}+\\delta_{\\alpha}}\\}} \\tilde v(x,h) +C_0r^2,$$ which together with and gives $$\\bar C h^{{\\alpha}+2s} \\geq \\frac{1}{2s}r^{{\\alpha}+{\\delta}_{\\alpha}}h^{2s} - \\frac{nC_0}{1+a}h^2- C_0r^2$$ for all $r,h\\in (0,1)$. To get a contradiction from the above inequality, we want to choose $h=h(r)$ in such a way that $$h^2 \\ll r^2 \\ll h^{{\\alpha}+2s} \\ll r^{{\\alpha}+{\\delta}_{\\alpha}}h^{2s}\\qquad \\text{for $r$ sufficiently small}.$$ To this aim, set $h=r^{1+2{\\delta}_{\\alpha}/{\\alpha}}$. Then $h^{\\alpha}=r^{{\\alpha}+2{\\delta}_{\\alpha}}=o(r^{{\\alpha}+{\\delta}_{\\alpha}})$, and both the first and the third condition above hold. ", "To ensure that also the second one is satisfied, it suffices to have $$({\\alpha}+2s)\\biggl(1+2\\frac{{\\delta}_{\\alpha}}{{\\alpha}}\\biggr) <2,$$ that is $${\\delta}_{\\alpha}< \\frac{1}{2}\\left(\\frac{{\\alpha}}{{\\alpha}+2s} -\\frac{{\\alpha}}{2}\\right).$$ Recalling that ${\\alpha}+2s <2$ (so, the right hand side is positive) and the definition of $\\delta_{{\\alpha}}$, we get the desired contradiction, which concludes the proof.", "\n\nWe now want to use a monotonicity formula to improve the decay of $w(x,y)$ at the origin. ", "We first need some preliminary results:\n\n\\[lemma:prelim for monot\\] (i) There exists a constant $C'$, depending on $C_0$, $\\|{(-\\Delta)^{s}}\\psi\\|_{C_x^{1-s}({\\mathbb{R}}^n)}$, $\\|v-\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}$, and $\\|{(-\\Delta)^{s}}v\\|_{L^\\infty({\\mathbb{R}}^n)}$ only, such that $$\\limsup_{y \\to 0^+} \\int_{B_r} (w^2)_y(x,y) \\frac{y^{-a}}{(|x|^2+y^2)^{(n-1+a)/2}}\\,dx\n\\geq -C'r^{{\\alpha}+1+a}\\qquad \\forall\\,r \\geq 0.$$ (ii) It holds $$\\lim_{y \\to 0^+}\n\\int_{B_r} w^2(x,y) {\\partial}_y \\left( \\frac{1}{(|x|^2+y^2)^{(n-1-a)/2}}\\right)\\,y^{-a}\\,dx=0.$$\n\n*(i)* To show the estimate, let us observe that:\n\n1. ", " Since $w(\\cdot,0)=0$ on ${\\mathbb{R}}^n\\setminus {\\Lambda}$ while $w(\\cdot,0)\\geq 0$ on ${\\Lambda}$ (see (A6)), by the maximum principle we get $w(x,y)\\geq 0$. Hence $$w(x,y)\\geq w(x,0) \\qquad \\forall \\,x \\in {\\mathbb{R}}^n\\setminus {\\Lambda},\\,y>0.$$\n\n2. ", " By the $a$-semiconcavity of $v$ in $y$ (see (A8)), $$y^a v_y(x,y) \\leq \\lim_{s\\to 0^+}s^a v_y(x,s) +\\frac{nC_0}{1+a} y^{1+a}.$$ (Observe that the above limit always exists, since ${(-\\Delta)^{s}}v(x,0)$ is Hölder continuous on the contact set, while $v$ is smooth outside, see (A5).)", "\n\n3. ", " The function $y^a v_y$ solves $$\\left\\{\n \\begin{array}{l}\n L_{-a}(y^a v_y)=0,\\\\\n \\lim_{y\\to 0^+}y^a v_y(x,0)=-{(-\\Delta)^{s}}v(x,0),\n \\end{array}\n \\right.$$ (see [@cafsil Subsection 2.3]). ", "Since $w(x,0)\\geq {(-\\Delta)^{s}}v(x,0)$ by (A5), the maximum principle gives $w\\geq -y^a v_y$ on ${\\mathbb{R}}^n\\times {\\mathbb{R}}^+$. Hence, since $w(x,0)=-\\lim_{y\\to 0^+}y^a v_y(x,0)$ in ${\\Lambda}$, by (2) above we get $$w(x,y) \\geq w(x,0) - \\frac{nC_0}{1+a}y^{1+a}\\qquad \\forall\\, x\\in {\\Lambda},\\,y>0.$$\n\nCombining (1) and (3) we obtain $$\\label{eq:bound below w}\nw(x,y) \\geq w(x,0) - \\frac{nC_0}{1+a}y^{1+a}\\qquad \\forall\\, x\\in {\\mathbb{R}}^n,\\,y>0.$$ This estimate, together with the $C_{x}^{{\\alpha}}$ regularity of $w$ and the fact that $w$ is non-negative, implies that, for all $x \\in B_r$ and $y>0$, $$\\label{eq:bound 1+a}\nw^2(x,y)- w^2(x,0)=[w(x,y)- w(x,0)][w(x,y)+ w(x,0)]\\geq -K y^{1+a} (r+y)^{\\alpha},$$ for some uniform constant $K>0$.\n\nWe now want to estimate from below $$\\limsup_{y \\to 0^+} \\int_{B_r} (w^2)_y(x,y) \\frac{y^{-a}}{(|x|^2+y^2)^{(n-1-a)/2}}\\,dx.$$ To this aim, consider the change of variable $s=s(y):=\\left(\\frac{y}{1+a}\\right)^{1+a}$ and define $\\tilde w(x,s(y)):=w(x,y)$. Then becomes $$\\label{eq:bound 1}\n\\tilde w^2(x,s)- \\tilde w^2(x,0)\\geq -K' s (r+s^{1/(1+a)})^{\\alpha}\\qquad \\forall \\,x \\in B_r,\\,s>0,$$ for some uniform constant $K'>0$. Moreover, since $y^{-a}(w^2)_y(x,y)=(\\tilde w^2)_s(x,s)$, we are left with estimating $$\\limsup_{s \\to 0^+} \\int_{B_r} (\\tilde w^2)_s(x,s) \\frac{1}{(|x|^2+(1+a)^2 s^{2/(1+a)})^{(n-1-a)/2}}\\,dx.$$ To do this, we average the above expression with respect to $s \\in [0,{\\varepsilon}]$ and we use Fubini Theorem to get $$\\begin{aligned}\n\\frac{1}{{\\varepsilon}}\\int_0^{\\varepsilon}ds &\\int_{B_r} (\\tilde w^2)_s(x,s) \\frac{1}{(|x|^2+(1+a)^2 s^{2/(1+a)})^{(n-1-a)/2}}\\,dx\\\\\n&=\\int_{B_r} \\frac{1}{{\\varepsilon}}\\left[\\frac{\\tilde w^2(x,{\\varepsilon})}{(|x|^2+(1+a)^2 {\\varepsilon}^{2/(1+a)})^{(n-1-a)/2}}- \\frac{\\tilde w^2(x,0)}{|x|^{n-1-a}}\\right] \\,dx\\\\\n&\\qquad-\\frac{1}{{\\varepsilon}}\\int_0^{\\varepsilon}ds \\int_{B_r}\\tilde w^2(x,s) \\frac{d}{ds}\\left( \\frac{1}{(|x|^2+(1+a)^2 s^{2/(1+a)})^{(n-1-a)/2}}\\right)\\,dx.\\end{aligned}$$ Now, thanks to , the $C_{x}^{{\\alpha}}$-regularity of $w(x,0)=\\tilde w(x,0)$, and the fact that $$\\frac{d}{ds}\\left( \\frac{1}{(|x|^2+(1+a)^2 s^{2/(1+a)})^{(n-1-a)/2}}\\right)\\leq 0,$$ we obtain that the above expression is bounded from below by $$\\begin{aligned}\n \\int_{B_r} &\\frac{1}{{\\varepsilon}}\\left[\\frac{\\tilde w^2(x,0) - K'{\\varepsilon}(r+{\\varepsilon}^{1/(1+a)})^{\\alpha}}{(|x|^2+(1+a)^2 {\\varepsilon}^{2/(1+a)})^{(n-1-a)/2}}- \\frac{\\tilde w^2(x,0)}{|x|^{n-1-a}}\\right] \\,dx\\\\\n&\\geq -K'(r+{\\varepsilon}^{1/(1+a)})^{\\alpha}\\int_{B_r}\\frac{1}{|x|^{n-1-a}} \\,dx\\\\\n&\\quad+ C\\int_{B_r}\\frac{|x|^{2{\\alpha}}}{{\\varepsilon}}\\left[\\frac{1}{(|x|^2+(1+a)^2 {\\varepsilon}^{2/(1+a)})^{(n-1-a)/2}}- \\frac{1}{|x|^{n-1-a}}\\right] \\,dx\\end{aligned}$$ Concerning the first term in the right hand side, since $a=1-2s<1$ we have $$(r+{\\varepsilon}^{1/(1+a)})^{\\alpha}\\int_{B_r}\\frac{1}{|x|^{n-1-a}} \\,dx \\to C_{n,a}r^{{\\alpha}+1+a}=C_{n,a}r^{{\\alpha}+1+a}\\qquad \\text{as }{\\varepsilon}\\to 0.$$ For the second term, we want to prove that it converges to $0$ as ${\\varepsilon}\\to 0.$ To this aim, we split the integral into two terms: the integral over $B_{{\\varepsilon}^\\beta}$, and the one over $B_r \\setminus B_{{\\varepsilon}^\\beta}$, where $\\beta>0$ has to be chosen. ", "For the first term, we can bound it from below by $$-\\frac{C}{{\\varepsilon}} \\int_{B_{{\\varepsilon}^\\beta}} \\frac{|x|^{2{\\alpha}}}{|x|^{n-1-a}}\\,dx = C {\\varepsilon}^{{\\beta}(2{\\alpha}+ a+1) -1}.$$ Thus, by choosing $\\beta \\in \\left(\\frac1{2{\\alpha}+ a+1},\\frac1{1+a}\\right)$ we ensure that the above expression converges to $0$ as ${\\varepsilon}\\to 0$. Moreover, the fact that $\\beta<1/(1+a)$ implies that $${\\varepsilon}^{2/(1+a)} \\ll |x|^2 \\qquad \\forall\\, |x|\\geq {\\varepsilon}^{\\beta}.$$ Therefore, for estimating the second part we can use polar coordinates and the fact that $$(|x|^2+(1+a)^2 {\\varepsilon}^{2/(1+a)})^{(n-1-a)/2} \\sim |x|^{n-1-a}+C{\\varepsilon}^{2/(1+a)}|x|^{n-3-a} \\qquad \\forall\\, |x|\\geq {\\varepsilon}^{\\beta}$$ to write $$\\begin{aligned}\n\\int_{B_r\\setminus B_{{\\varepsilon}^\\beta}}&\\frac{|x|^{2{\\alpha}}}{{\\varepsilon}}\\left[\\frac{1}{(|x|^2+(1+a)^2 {\\varepsilon}^{2/(1+a)})^{(n-1-a)/2}}- \\frac{1}{|x|^{n-1-a}}\\right] \\,dx\\\\\n&\\sim \\frac{C}{{\\varepsilon}} \\int_{{\\varepsilon}^{\\beta}}^r \\rho^{n-1+2{\\alpha}} \\left[\\frac{1}{\\rho^{n-1-a}+C{\\varepsilon}^{2/(1+a)}\\rho^{n-3-a}}- \\frac{1}{\\rho^{n-1-a}}\\right]\\,d\\rho\\\\\n&=\\frac{C}{{\\varepsilon}} \\int_{{\\varepsilon}^{\\beta}}^r \\rho^{2{\\alpha}+a} \\left[\\frac{\\rho^2}{\\rho^2+C{\\varepsilon}^{2/(1+a)}}- 1\\right]\\,d\\rho\n=-\\frac{C}{{\\varepsilon}} \\int_{{\\varepsilon}^{\\beta}}^r \\rho^{2{\\alpha}+a} \\frac{{\\varepsilon}^{2/(1+a)}}{\\rho^2+C{\\varepsilon}^{2/(1+a)}}\\,d\\rho\\\\\n&\\geq -\\frac{C{\\varepsilon}^{2/(1+a)}}{{\\varepsilon}} \\int_{{\\varepsilon}^{\\beta}}^r \\rho^{2{\\alpha}+a-2}\\,d\\rho\\geq -C {\\varepsilon}^{2/(1+a) - 1}\\bigl[1+{\\varepsilon}^{\\beta(2{\\alpha}+a-1)}\\bigr]. ", "\\\\\\end{aligned}$$ Let us remark that $2/(1+a)>1$, so if $2{\\alpha}+a-1\\geq 0$ the above expression obviously converges to $0$. On the other hand, if $2{\\alpha}+a-1< 0$, since ${\\beta}<1/(1+a)$ we get $$\\frac2{1+a}- 1+\\beta(2{\\alpha}+a-1)> \\frac2{1+a}- 1+\\frac{2{\\alpha}+a-1}{1+a} \\geq \\frac{2-1-a+2{\\alpha}+a-1}{1+a}=\\frac{2{\\alpha}}{1+a}>0,$$ and again the above expression converges to $0$. All in all, we conclude that $$\\int_{B_r}\\frac{|x|^{2{\\alpha}}}{{\\varepsilon}}\\left[\\frac{1}{(|x|^2+(1+a)^2 {\\varepsilon}^{2/(1+a)})^{(n-1-a)/2}}- \\frac{1}{|x|^{n-1-a}}\\right] \\,dx\\to 0 \\qquad \\text{as ${\\varepsilon}\\to 0$},$$ so that combining all our estimates together we obtain $$\\liminf_{{\\varepsilon}\\to 0}\\frac{1}{{\\varepsilon}}\\int_0^{\\varepsilon}ds \\int_{B_r} (\\tilde w^2)_s(x,s) \\frac{1}{(|x|^2+(1+a)^2 s^{2/(1+a)})^{(n-1-a)/2}}\\,dx \\geq -K'C_{n,a}r^{{\\alpha}+1+a}.$$ From this fact we easily deduce that $$\\limsup_{{\\varepsilon}\\to 0} \\int_{B_r} (\\tilde w^2)_s(x,{\\varepsilon}) \\frac{1}{(|x|^2+(1+a)^2 {\\varepsilon}^{2/(1+a)})^{(n-1-a)/2}}\\,dx \\geq -K'C_{n,a}r^{{\\alpha}+1+a},$$ which concludes the proof of (i).\\\n*(ii)* In this case, we use the $C_{x}^{{\\alpha}}$-regularity of $w$ to control the integral by $$y^{1-a}\\int_{B_r} \\frac{1}{(|x|^2+y^2)^{(n+1-a)/2-{\\alpha}}} \\,dx.$$ Using polar coordinates, the above integral is comparable to $$y^{1-a}\\int_0^r \\frac{\\rho^{n-1}}{(\\rho^2+y^2)^{(n+1-a)/2-{\\alpha}}}\\,d\\rho\\sim y^{1-a}\\int_0^r \\frac{\\rho^{n-1}}{(\\rho+y)^{n+1-a-2{\\alpha}}}\\,d\\rho \\sim \\frac{y^{1-a}}{y^{1-a-2{\\alpha}}}=y^{2{\\alpha}},$$ and the above expression converges to $0$ as $y\\to 0$.\n\nWe will also need a result on the first eigenvalue of a weighted Laplacian on the half-sphere. ", "We use ${\\nabla}_\\theta w$ to denote the derivative of $w$ with respect to the angular variables:.", "\n\n\\[lem:eigen\\] Set ${\\mathbb{S}}^{n+1}_+:={\\mathbb{S}}^{n+1}\\cap \\{x_{n+1}\\geq 0\\}$, ${\\mathbb{S}}^{n+1}_0:={\\partial}{\\mathbb{S}}^{n+1}_+\n={\\mathbb{S}}^{n+1}\\cap \\{x_{n+1}=0\\}$, ${\\mathbb{S}}^{n+1}_{0,+}:={\\mathbb{S}}^{n+1}\\cap \\{x_{n+1}=0\\}\\cap \\{x_n \\geq 0\\}$. Then $$\\inf_{h \\in H^{1/2}({\\mathbb{S}}^{n+1}_0),\\,h=0 \\text{ on } {\\mathbb{S}}^{n+1}_{0,+} }\n\\frac{\\int_{{\\mathbb{S}}^{n+1}_+}|{\\nabla}_\\theta h|^2y^{-a}\\,d\\sigma}{\\int_{{\\mathbb{S}}^{n+1}_+} h^2y^{-a}\\,d\\sigma}\n=(1-s)(n-1+s).$$\n\nLet $\\bar h(\\theta)$ denote the restriction to ${\\mathbb{S}}^{n+1}_+$ of $$\\bar H(x,y):=\\bigl(\\sqrt{x_n^2+y^2}-x_n\\bigr)^{1-s},$$ that is $\\bar H=r^{1-s}\\bar h(\\theta)$. As shown in [@cafsalsil Proposition 5.4], $\\bar h$ is the first eigenfunction corresponding to the above minimization problem. ", "Moreover, $\\bar H$ solves $L_{-a} \\bar H=0$ for $y>0$.[^6] Let ${\\lambda}_1$ denote the eigenvalue corresponding to $\\bar h$, so that $$\\inf_{h \\in H^{1/2}({\\mathbb{S}}^{n+1}_0),\\,h=0 \\text{ on } {\\mathbb{S}}^{n+1}_{0,+} }\n\\frac{\\int_{{\\mathbb{S}}^{n+1}_+}|{\\nabla}_\\theta h|^2y^{-a}\\,d\\sigma}{\\int_{{\\mathbb{S}}^{n+1}_+} h^2y^{-a}\\,d\\sigma}=-{\\lambda}_1.$$ In order to explicitly compute ${\\lambda}_1$, we observe that ${\\operatorname{div}}_\\theta(y^{-a} \\nabla_\\theta \\bar h)={\\lambda}_1\\bar h$. In particular, evaluating the above identity at the point $(0,1)\\in {\\mathbb{R}}^n\\times {\\mathbb{R}}^+$ we obtain $$\\Delta_\\theta \\bar h(0,1)={\\lambda}_1 \\bar h(0,1).$$ We now write the equation $L_{-a} \\bar H=0$ in spherical coordinates: $$\\Delta_r \\bar H+\\frac{n}{r} \\bar H_r +\\frac{1}{r^2}\\Delta_\\theta \\bar H-\\frac{a}{y}\\bar H_y=0$$ Evaluating the above expression at $(0,1)\\in {\\mathbb{R}}^n\\times {\\mathbb{R}}^+$ and recalling that $\\bar H=r^{1-s}\\bar h$, we get $$\\begin{aligned}\n0&=\\Delta_r \\bar H(0,1) + n \\bar H_r(0,1) + \\Delta_\\theta \\bar H(0,1) - a \\bar H_r(0,1)\\\\\n&=-(1-s)s \\,\\bar h(0,1) + (1-s)(n-a)\\,\\bar h(0,1) + \\Delta_\\theta \\bar h(0,1).\\end{aligned}$$ Hence $$\\Delta_\\theta \\bar h(0,1)=- (1-s)(n-a-s)\\,\\bar h(0,1)=- (1-s)(n-1+s)\\,\\bar h(0,1).$$ which gives ${\\lambda}_1=- (1-s)(n-1+s)$ as desired.", "\n\nTo simplify notation, we use the variable $z$ to denote a point $(x,y)\\in {\\mathbb{R}}^n\\times {\\mathbb{R}}^+$.\n\n\\[lemma:monotonicity\\] Let $w$ and $r_0$ be as above, set $B_r^+:=\\{z \\in {\\mathbb{R}}^n\\times {\\mathbb{R}}^+\\,:\\, |z| <r\\}$, and define $${\\varphi}(r):=\\frac{1}{r^{2(1-s)}}\\int_{B_r^+} \\frac{|{\\nabla}w(z)|^2y^{-a}}{|z|^{n-1-a}}\\,dz\\qquad \\forall \\,r\\leq 1.$$ There exists a constant $C''$, depending on $C_0$, $\\|{(-\\Delta)^{s}}\\psi\\|_{C_x^{1-s}({\\mathbb{R}}^n)}$, $\\|v-\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}$, and $\\|{(-\\Delta)^{s}}v\\|_{L^\\infty({\\mathbb{R}}^n)}$ only, such that $${\\varphi}(r)\\leq C''\\left[1+r^{2{\\alpha}+{\\delta}_{\\alpha}-a-1}\\right]\\qquad \\forall \\,r\\leq 1.$$\n\nFirst of all, we show that ${\\varphi}(1)$ is universally bounded, so that in particular ${\\varphi}(r)$ is well-defined for all $r \\in (0,1]$.\n\nSet ${\\varphi}_{\\varepsilon}(r):=\\frac{1}{r^{2(1-s)}}\\int_{B_r^+ \\cap \\{y>{\\varepsilon}\\}} \\frac{|{\\nabla}w(z)|^2y^{-a}}{|z|^{n-1-a}}\\,dz$. By the monotone convergence theorem, it suffices to estimate $\\liminf_{{\\varepsilon}\\to 0}{\\varphi}_{\\varepsilon}(1)$. Let $\\chi:{\\mathbb{R}}^n \\to [0,1]$ be a smooth compactly supported function such that $\\chi\\equiv 1$ on $B_1\\subset {\\mathbb{R}}^n$. Then $${\\varphi}_{\\varepsilon}(r) \\leq \\int_{\\varepsilon}^1 \\int_{{\\mathbb{R}}^n} \\frac{|{\\nabla}w(z)|^2y^{-a}}{|z|^{n-1-a}}\\chi(x)\\,dx\\,dy.$$ Since $L_{-a} w=0$ we have $L_{-a}(w^2) =\n2w L_{-a} w + 2|{\\nabla}w|^2y^{-a} = 2|{\\nabla}w|^2y^{-a}$, which implies that the right hand side is equal to $$\\begin{aligned}\n \\int_{\\varepsilon}^1 \\int_{{\\mathbb{R}}^n} \\frac{L_{-a}(w^2)}{2|z|^{n-1-a}}\\chi(x)\\,dx\\,dy&=\n \\int_{\\varepsilon}^1 \\int_{{\\mathbb{R}}^n} \\nabla(w^2)\\cdot \\nabla \\biggl(\\frac{1}{2|z|^{n-1-a}}\\biggr)y^{-a}\\chi(x)\\,dx\\,dy\\\\\n& +\\int_{\\varepsilon}^1 \\int_{{\\mathbb{R}}^n} \\nabla_x(w^2)\\cdot \\nabla_x \\chi(x) \\frac{y^{-a}}{2|z|^{n-1-a}}\\,dx\\,dy\\\\\n &\\quad+ \n \\int_{{\\mathbb{R}}^n} (w^2)_y\\frac{y^{-a}}{2|z|^{n-1-a}}\\chi(x)\\,dx\\bigg|_{y={\\varepsilon}}^{y=1}.", "\n \\end{aligned}$$ Integrating by parts again the first two terms in the right hand side, and using that $L_{-a} \\frac{1}{|z|^{n-1-a}}=C_{n,a} \\delta_{(0,0)}$, we find that the above expression coincides with $$\\begin{gathered}\n -\\int_{\\varepsilon}^1 \\int_{{\\mathbb{R}}^n} w^2 \\nabla_x\\chi(x)\\cdot \\nabla_x \\biggl(\\frac{1}{|z|^{n-1-a}}\\biggr)y^{-a}\\,dx\\,dy -\\int_{\\varepsilon}^1 \\int_{{\\mathbb{R}}^n} w^2\\Delta_x \\chi(x) \\frac{y^{-a}}{2|z|^{n-1-a}}\\,dx\\,dy\\\\\n + \\int_{{\\mathbb{R}}^n} w^2 {\\partial}_y \\biggl(\\frac{1}{2|z|^{n-1-a}}\\biggr)y^{-a}\\chi(x)\\,dx\\bigg|_{y={\\varepsilon}}^{y=1}\n+ \\int_{{\\mathbb{R}}^n} (w^2)_y\\frac{y^{-a}}{2|z|^{n-1-a}}\\chi(x)\\,dx\\bigg|_{y={\\varepsilon}}^{y=1}.", "\n \\end{gathered}$$ Now, since $\\chi\\equiv 1$ inside $B_1$, the first two terms above are immediately seen to be bounded. ", "Concerning the last two terms, the integrals evaluated at $y=1$ are clearly finite (and universally bounded), since $w$ is smooth for $y>0$. Finally, we apply Lemma \\[lemma:prelim for monot\\] to estimate the integrals at $y={\\varepsilon}$, and we obtain $${\\varphi}(1) = \\liminf_{{\\varepsilon}\\to 0} {\\varphi}_{\\varepsilon}(1) \\leq C_{\\varphi},$$ for some constant $C_{\\varphi}$ depending on $C_0$, $\\|{(-\\Delta)^{s}}\\psi\\|_{C_x^{1-s}({\\mathbb{R}}^n)}$, $\\|v-\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}$, and $\\|{(-\\Delta)^{s}}v\\|_{L^\\infty({\\mathbb{R}}^n)}$ only. ", "Observe that, as a consequence of the fact that ${\\varphi}(1)$ is finite (i.e., $ \\frac{|{\\nabla}w(z)|^2y^{-a}}{|z|^{n-1-a}}$ is integrable over $B_1^+$), we deduce that ${\\varphi}_{\\varepsilon}(r)\\to {\\varphi}(r)$ locally uniformly over $(0,1]$.\n\nNow that we have proved that ${\\varphi}(r)$ is well-defined, we want to estimates from below its derivative. ", "Again, we will do our computations with ${\\varphi}_{\\varepsilon}$, and then we let ${\\varepsilon}\\to 0$[^7].", "\n\nLet us assume $r>{\\varepsilon}$, and split ${\\partial}\\left( B_r^+\\cap \\{y>{\\varepsilon}\\}\\right)$ as the union of ${\\partial}B_r^+\\cap \\{y={\\varepsilon}\\}$ and ${\\partial}B_r^+\\cap \\{y>{\\varepsilon}\\}$. Using again that $L_{-a} \\frac{1}{|z|^{n-1-a}}=C_{n,a} \\delta_{(0,0)}$ and recalling that $a=1-2s$, we easily get $$\\begin{aligned}\n{\\varphi}_{\\varepsilon}'(r)&=-\\frac{1-s}{r^{1+2(1-s)}} \\int_{B_r^+ \\cap \\{y>{\\varepsilon}\\}} \\frac{L_{-a}(w^2)}{|z|^{n-1-a}}\\,dz+\n\\frac{1}{r^{n}} \\int_{{\\partial}B_r^+\\cap \\{y>{\\varepsilon}\\}} |{\\nabla}w(z)|^2y^{-a}\\,d\\sigma\\\\\n&=-\\frac{2(1-s)}{r^{1+2(1-s)}}\n\\int_{{\\partial}(B_r^+\\cap \\{y>{\\varepsilon}\\})}-w\\,{\\nabla}w\\cdot \\nu\\, \\frac{y^{-a}}{|z|^{n-1-a}}\\,d\\sigma\\\\\n&\\quad-\\frac{1-s}{r^{1+2(1-s)}} \\int_{B_r^+\\cap \\{y>{\\varepsilon}\\}} {\\nabla}(w^2)\\cdot {\\nabla}\\left( \\frac{1}{|z|^{n-1-a}}\\right)y^{-a}\\,dz\n+\\frac{1}{r^{n}} \\int_{{\\partial}B_r^+\\cap \\{y>{\\varepsilon}\\}} |{\\nabla}w(z)|^2y^{-a}\\,d\\sigma\\\\\n&= \\frac{2(1-s)}{r^{1+2(1-s)}} \\int_{{\\partial}(B_r^+\\cap \\{y>{\\varepsilon}\\})}-w\\,{\\nabla}w\\cdot \\nu\\, \\frac{y^{-a}}{|z|^{n-1-a}}\\,d\\sigma\\\\\n&\\quad+\\frac{1-s}{r^{1+2(1-s)}} \\int_{{\\partial}(B_r^+\\cap \\{y>{\\varepsilon}\\})}\n -w^2 {\\nabla}\\left( \\frac{1}{|z|^{n-1-a}}\\right)\n\\cdot \\nu\\,y^{-a}\\,d\\sigma\\\\\n&\\quad+\\frac{1}{r^{n}} \\int_{{\\partial}B_r^+\\cap \\{y>{\\varepsilon}\\}} |{\\nabla}w(z)|^2y^{-a}\\,d\\sigma\\\\\n&= -\\frac{2(1-s)}{r^{n+1}} \\int_{{\\partial}B_r^+\\cap \\{y>{\\varepsilon}\\}}w\\,w_r\\,y^{-a}\\,d\\sigma\n+\\frac{1-s}{r^{1+2(1-s)}} \n\\int_{B_r^+ \\cap\\{y={\\varepsilon}\\}}(w^2)_y\\,\\frac{y^{-a}}{|z|^{n-1-a}}\\,d\\sigma\\\\\n&\\quad-\\frac{(1-s)(n-1-a)}{r^{n+2}} \\int_{{\\partial}B_r^+\\cap \\{y>{\\varepsilon}\\}} w^2y^{-a} \\,d\\sigma\\\\\n&\\quad+\\frac{1-s}{r^{1+2(1-s)}}\n\\int_{B_r^+ \\cap\\{y={\\varepsilon}\\}} w^2 {\\partial}_y \\left( \\frac{1}{|z|^{n-1-a}}\\right)\\,y^{-a}\\,d\\sigma\n+\\frac{1}{r^{n}} \\int_{{\\partial}B_r^+\\cap \\{y>{\\varepsilon}\\}} |{\\nabla}w(z)|^2y^{-a}\\,d\\sigma.\\end{aligned}$$ Thanks to Lemma \\[lemma:prelim for monot\\], we can estimate from below both the second and the last but one term in the last expression. ", "So, letting ${\\varepsilon}\\to 0$ and using that ${\\varphi}_{\\varepsilon}\\to {\\varphi}$ locally uniformly, we deduce that the distributional derivative $D_r{\\varphi}$ of ${\\varphi}$ is bounded from below by $$\\begin{gathered}\n-\\frac{2(1-s)}{r^{n+1}} \\int_{{\\partial}B_{r,+}}w\\,w_r\\,y^{-a}\\,d\\sigma-C\\,r^{{\\alpha}+1+a}\\\\\n-\\frac{(1-s)(n-1-a)}{r^{n+2}} \\int_{{\\partial}B_{r,+}} w^2y^{-a} \\,d\\sigma\n+\\frac{1}{r^{n}} \\int_{{\\partial}B_{r,+}} |{\\nabla}w(z)|^2y^{-a}\\,d\\sigma ,\\end{gathered}$$ for some universal constant $C$. ", "Now, by Schwartz’s inequality the first term in the above expression can be estimated from below by $$-\\frac{1}{r^{n}} \\int_{{\\partial}B_{r,+}} (w_r)^2y^{-a}\\,d\\sigma- \\frac{(1-s)^2}{r^{n+2}}\\int_{{\\partial}B_{r,+}} w^2y^{-a} \\,d\\sigma.$$ Hence, recalling that $|{\\nabla}w(z)|^2=(w_r)^2+\\frac{1}{r^2}|{\\nabla}_\\theta w_\\theta|^2$ and observing that $n-1-a+1-s=n-1+s$, we obtain $$D_r {\\varphi}\\geq\\frac{1}{r^{n+2}} \\int_{{\\partial}B_{r,+}} |{\\nabla}_\\theta w(z)|^2y^{-a}\\,d\\sigma\n-\\frac{(1-s)(n-1+s)}{r^{n+2}} \\int_{{\\partial}B_{r,+}} w^2y^{-a} \\,d\\sigma\n-C\\,r^{{\\alpha}+1+a}.$$ Consider now the function $\\bar W:=(w-r^{{\\alpha}+{\\delta}_{\\alpha}})^-$. Then $|{\\nabla}_\\theta \\bar W(z)|^2\\leq |{\\nabla}_\\theta w(z)|^2$. Moreover, by Lemma \\[lem:apply monot\\], $\\bar W$ is admissible for the eigenvalue problem in Lemma \\[lem:eigen\\]. ", "Hence $$\\begin{aligned}\nD_r {\\varphi}&\\geq \\frac{1}{r^{n+2}} \\int_{{\\partial}B_{r,+}} |{\\nabla}_\\theta \\bar W(z)|^2y^{-a}\\,d\\sigma\n-\\frac{(1-s)(n-1+s)}{r^{n+2}} \\int_{{\\partial}B_{r,+}} \\bar W^2 y^{-a}\\,d\\sigma\\\\\n&\\qquad+ \\frac{(1-s)(n-1+s)}{r^{n+2}} \\int_{{\\partial}B_{r,+}} \\bigl[(w-\\bar W)^2 +2\\bar W(w-\\bar W)\\bigr]\\,y^{-a}\\,d\\sigma -C\\,r^{{\\alpha}+1+a}\\\\\n&\\geq \\frac{(1-s)(n-1+s)}{r^{n+2}} \\int_{{\\partial}B_{r,+}} \\bigl[(w-\\bar W)^2 +2\\bar W(w-\\bar W)\\bigr]\\,y^{-a}\\,d\\sigma -C\\,r^{{\\alpha}+1+a}.\\end{aligned}$$ Since $|\\bar W|\\leq |w|\\leq C\\,r^{\\alpha}$ and $|w-\\bar W|\\leq r^{{\\alpha}+{\\delta}_{\\alpha}}$ we obtain $$D_r {\\varphi}\\geq -C\\,r^{2{\\alpha}+{\\delta}_{\\alpha}-a-2} - Cr^{{\\alpha}+1+a},$$ which integrated over $[r,1]$ gives $${\\varphi}(r)\\leq {\\varphi}(1)+ C\\,r^{2{\\alpha}+{\\delta}_{\\alpha}-a-1} + C\\qquad \\forall \\,r \\leq 1.$$ (Recall that $1+a>0$.) Since ${\\varphi}(1)$ is universally bounded, this concludes the proof.", "\n\nWe are now ready to prove the optimal decay rate around free boundary points.", "\n\n\\[prop:C1s\\] There exists a constant $\\tilde C>0$, depending on $C_0$, $\\|{(-\\Delta)^{s}}\\psi\\|_{C_x^{1-s}({\\mathbb{R}}^n)}$, $\\|v-\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}$, and $\\|{(-\\Delta)^{s}}v\\|_{L^\\infty({\\mathbb{R}}^n)}$ only, such that holds.", "\n\nDefine $w_{\\varepsilon}=w \\ast \\rho_{\\varepsilon}$, where $\\rho_{\\varepsilon}=\\rho_{\\varepsilon}(x)$ is a smooth convolution kernel. ", "Since $L_{-a}$ commutes with convolution in the $x$ variable, $w_{\\varepsilon}$ is $L_{-a}$-harmonic on ${\\mathbb{R}}^n\\times {\\mathbb{R}}^+$. Moreover, by , $w_{\\varepsilon}(x,y)-w_{\\varepsilon}(x,0) \\geq-\\frac{nC_0}{1+a}y^{1+a}$.\n\nSet $\\bar W_{\\varepsilon}:=(w_{\\varepsilon}-r^{{\\alpha}+{\\delta}_{\\alpha}})^+$. Then it is easily seen that $\\bar W_{\\varepsilon}$ is $L_{-a}$-subharmonic for $y>0$, and $\\bar W_{\\varepsilon}(x,y)-\\bar W_{\\varepsilon}(x,0) \\geq-\\frac{nC_0}{1+a}y^{1+a}$. Consider now the function $$\\tilde w_{\\varepsilon}(x,y):=\n\\bar W_{\\varepsilon}(x,|y|) + \\left(1+\\frac{nC_0}{1+a}\\right)\\,|y|^{1+a}\\qquad \\text{on }{\\mathbb{R}}^n \\times {\\mathbb{R}}.$$ We observe that $\\tilde w_{\\varepsilon}$ is $L_{-a}$-subharmonic outside $\\{y=0\\}$. Moreover, since $\\tilde w_{\\varepsilon}(x,y)-\\tilde w_{\\varepsilon}(x,0) \\geq |y|^{1+a}$ and $\\tilde w_{\\varepsilon}$ is smooth in the $x$ variable, we deduce that it is $L_{-a}$-subharmonic on the whole ${\\mathbb{R}}^n\\times {\\mathbb{R}}$. Letting ${\\varepsilon}\\to 0$ we obtain that $$\\tilde w(x,y):=\n\\bigl(w(x,|y|)-r^{{\\alpha}+{\\delta}_{\\alpha}}\\bigr)^++ \\left(1+\\frac{nC_0}{1+a}\\right)\\,|y|^{1+a}$$ is globally $L_{-a}$-subharmonic. ", "Thanks to Lemma \\[lemma:monotonicity\\], $\\tilde w$ vanishes on more than half of the $n$-dimensional disc $B_r \\times \\{0\\}$. So we can apply a weighted Poincaré inequality (see [@fabkenser]) and the definition of ${\\varphi}$ (see Lemma \\[lemma:monotonicity\\]) to get $$\\begin{aligned}\n\\int_{B_r^+} (\\tilde w)^2y^{-a}\\,dz&\\leq C\\,r^2\\int_{B_r^+} |\\nabla \\tilde w|^2y^{-a}\\,dz\\\\\n&\\leq\nC\\,r^2\\biggl[\\int_{B_r^+} |\\nabla w|^2y^{-a}\\,dz + \\, r^{n+1+a}\\biggr]\\\\\n&\\leq C\\, r^{n+2} \\bigl[{\\varphi}(r)+r^{1+a}\\bigr] \\leq C\\, r^{n+2} \\bigl[{\\varphi}(r)+1\\bigr] \\qquad \\forall \\,r \\leq 1,\\end{aligned}$$ which combined with the $L_{-a}$-subharmonicity of $\\tilde w$ and Lemma \\[lemma:monotonicity\\] gives $$\\begin{aligned}\n\\sup_{B_{r/2}^+} (\\tilde w)^2 &\\leq \\frac{C}{r^{n+1-a}}\\int_{B_r^+} (\\tilde w)^2y^{-a}\\,dz \\\\\n&\\leq C\\,r^{1+a} \\bigl[{\\varphi}(r)+1\\bigr]\n\\leq C\\,\\left[r^{1+a}+r^{2{\\alpha}+\\delta_{\\alpha}}\\right].\\end{aligned}$$ Hence, since $1+a=2(1-s)$ we obtain $$\\sup_{B_{r/2}^+} w \\leq C\\biggl[\\sup_{B_{r/2}^+} \\tilde w +r^{{\\alpha}+{\\delta}_{\\alpha}}+r^{1+a}\\biggr] \\leq C\\left[r^{1-s}+r^{{\\alpha}+\\delta_{\\alpha}/2}\\right] \\qquad \\forall \\,r \\leq 1.$$ Since the above bound holds at every free boundary point, by the very same argument as in the proof of Corollary \\[cor:unif C1a v\\] we obtain that $\\|w\\|_{C_{x}^{\\beta_{\\alpha}}({\\mathbb{R}}^n)} \\leq C$, where $\\beta_{\\alpha}=\\beta_a(s):= \\min\\{{\\alpha}+\\delta_{\\alpha}/2,(1-s)\\}$. Observe now that, by the formula for $\\delta_{\\alpha}$ provided in Lemma \\[lem:apply monot\\], given $\\alpha_0>0$ there exists $\\delta_0>0$ such that $\\delta_{\\alpha}\\geq \\delta_0>0$ for $\\alpha \\in [{\\alpha}_0,1-s]$. Hence, by iterating the above argument $k$ times we get $$\\sup_{B_{r/2}^+} \\tilde w \\leq C\\left[r^{1-s}+r^{{\\alpha}+k\\delta_0/2}\\right] \\qquad \\forall \\,r \\leq 1,$$ and after finitely many iterations we obtain .", "\n\nArguing as in the proof of Corollary \\[cor:unif C1a v\\], gives:\n\n\\[cor:C1s\\] There exists a constant $\\bar C''>0$, depending on $C_0$, $\\|{(-\\Delta)^{s}}\\psi\\|_{C_x^{1-s}({\\mathbb{R}}^n)}$, $\\|v-\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}$, and $\\|{(-\\Delta)^{s}}v\\|_{L^\\infty({\\mathbb{R}}^n)}$ only, such that $$\\|{(-\\Delta)^{s}}v \\chi_{\\{v=\\psi\\}}\\|_{C_{x}^{1-s}({\\mathbb{R}}^n)}\\leq \\bar C''.$$\n\nAlmost optimal regularity of solutions to the parabolic fractional obstacle problem {#sect:C1s u}\n-----------------------------------------------------------------------------------\n\nLet $u$ be a solution of , with $\\psi \\in C^{2}({\\mathbb{R}}^n)$ satisfying assumptions (A1)-(A2) of Subsection \\[sect:general C1a\\]. ", "Let us remark that $u(0)=\\psi$, while for all $t>0$ we can apply the results of the previous subsections with $v=u(t)$. Hence Corollary \\[cor:C1s\\] gives:\n\n\\[prop:unif C1a rhs\\] Let $u,\\psi$ be as above. ", "Then there exists a constant $\\bar C_T>0$, depending on $T$, $\\|D^2\\psi\\|_{L^\\infty(R^n)}$, and $\\|{(-\\Delta)^{s}}\\psi\\|_{C_x^{1-s}({\\mathbb{R}}^n)}$ only, such that $$\\sup_{t\\in [0,T]} \\|{(-\\Delta)^{s}}u(t) \\chi_{\\{u(t)=\\psi\\}}\\|_{C_{x}^{1-s}({\\mathbb{R}}^n)}\\leq \\bar C_T.$$\n\nAs explained at the beginning of Subsection \\[sect:general C1a\\], $u(t)$ satisfies assumptions (A5)-(A6) of Subsection \\[sect:general C1a\\] for every $t>0$ (see Lemma \\[lem:sign frac lapl\\]). ", "Moreover, (A3)-(A4) follow from Lemma \\[lemma:Linfty bound frac heat\\] (since $\\|u(t)-\\psi\\|_{L^\\infty({\\mathbb{R}}^n)} \\leq T \\|u_t\\|_{L^\\infty([0,T]\\times {\\mathbb{R}}^n)} \\leq T \\|{(-\\Delta)^{s}}\\psi\\|_{L^\\infty({\\mathbb{R}}^n)}$). ", "Hence the result is an immediate consequence of Corollary \\[cor:C1s\\] applied to $v=u(t)$ for any $t>0$. (For $t=0$ the result is trivial since $u(0)=\\psi$.)\n\nNow, we want to exploit the fact that $u$ solves the parabolic equation $$\\label{eq:parabolic rhs}\nu_t +{(-\\Delta)^{s}}u=\\bigl({(-\\Delta)^{s}}u\\bigr) \\chi_{\\{u=\\psi\\}}\\qquad \\text{on }(0,T]\\times {\\mathbb{R}}^n.$$ Thanks to Proposition \\[prop:unif C1a rhs\\], the right-hand side of belongs to $L^\\infty([0,T];C_{x}^{1-s}({\\mathbb{R}}^n))$, which by parabolic regularity implies $$\\label{eq:Df C0a}\nu_t,{(-\\Delta)^{s}}u \\in L^\\infty((0,T];C_{x}^{1-s-0^+}({\\mathbb{R}}^n)),$$ see . ", "We now want to use and a bootstrap argument to obtain the desired Hölder regularity in time. ", "We start with a preliminary result:\n\n\\[lemma:bootstrap\\] Let that ${(-\\Delta)^{s}}u \\, \\chi_{\\{u=\\psi\\}}\\in L^\\infty((0,T];C_{x}^{1-s}({\\mathbb{R}}^n))$. Fix ${\\alpha}\\in \\left[0,\\min\\left\\{1,\\frac{1-s}{2s}\\right\\}\\right)$, and assume that:\n\n1. ", " $u_t \\in L^\\infty((0,T]\\times {\\mathbb{R}}^n)$, ${(-\\Delta)^{s}}u \\in L^\\infty((0,T];C_{x}^{1-s-0^+}({\\mathbb{R}}^n))$ if ${\\alpha}=0$;\n\n2. ", " $u_t \\in C_{t,x}^{{\\alpha},1-s} ((0,T]\\times {\\mathbb{R}}^n)$, ${(-\\Delta)^{s}}u \\in L^\\infty((0,T];C_{x}^{1-s}({\\mathbb{R}}^n))$ if ${\\alpha}>0$.\n\nThen $${(-\\Delta)^{s}}u \\, \\chi_{\\{u=\\psi\\}}\\in \n\\left\\{\n\\begin{array}{ll}\nC_{t,x}^{\\frac{1-s}{1+s}-0^+,1-s} ((0,T]\\times {\\mathbb{R}}^n)&\\text{if }{\\alpha}=0,\\\\\n{\\rm {{\\rm Lip}}}_tC_{x}^{1-s}((0,T]\\times {\\mathbb{R}}^n)& \\text{if }{\\alpha}>0,\\,s < 1/3,\\\\\n{\\rm {{\\rm logLip}}}_tC_{x}^{1-s}((0,T]\\times {\\mathbb{R}}^n)& \\text{if }{\\alpha}>0,\\,s = 1/3,\\\\\nC_{t,x}^{(1+{\\alpha})\\frac{1-s}{1+s},1-s}((0,T]\\times {\\mathbb{R}}^n)& \\text{if }{\\alpha}>0,\\,s >1/3,\n\\end{array}\n\\right.$$ with a uniform bound.", "\n\nMoreover, for $s>1/3$ the function $${\\alpha}\\mapsto \\Phi({\\alpha}):=(1+{\\alpha})\\frac{1-s}{1+s}$$ is strictly increasing on $\\left[0,\\frac{1-s}{2s}\\right)$, and $\\Phi\\left(\\frac{1-s}{2s}\\right)=\\frac{1-s}{2s}$.\n\nWe need to estimate $$\\label{eq:holder time rhs}\n|{(-\\Delta)^{s}}u(t,x)\\chi_{\\{u(t)=\\psi\\}}-{(-\\Delta)^{s}}u(s,x)\\chi_{\\{u(s)=\\psi\\}}|,\\qquad 0< s<t.$$ Since $\\{u(t)=\\psi\\}\\subset \\{u(s)=\\psi\\}$ for $s<t$, we can assume that $x \\in \\{u(s)=\\psi\\}$ (otherwise the above expression vanishes and there is nothing to prove). ", "Moreover, since ${(-\\Delta)^{s}}u$ vanishes on the free boundary, if $x \\in\\{u(s)=\\psi\\}\\setminus \\{u(t)=\\psi\\}$ we can alway find a time $\\tau \\in(s,t)$ such that $${(-\\Delta)^{s}}u(\\tau,x)\\chi_{\\{u(\\tau)=\\psi\\}}={(-\\Delta)^{s}}u(t,x)\\chi_{\\{u(t)=\\psi\\}}\\quad \\text{and}\\quad x \\in {\\partial}\\{u(\\tau)=\\psi\\}.$$ Then, if we can estimate with $\\tau$ in place of $t$, then we will also get the desired bound by simply replacing $\\tau$ with $t$. Hence, we only need to consider the case $x \\in \\{u(t)=\\psi\\}$.\n\nWe have to estimate $|{(-\\Delta)^{s}}u(t,x)-{(-\\Delta)^{s}}u(s,x)|$. Let $\\phi$ be a smooth non-negative cut-off function supported in $B_1$ such that $\\int_{{\\mathbb{R}}^n}\\phi=1$, set $\\phi_r(x):=\\frac{1}{r^n}\\phi\\left(\\frac{x}{r}\\right)$, and compute $$\\label{eq:triangle inequality}\n\\begin{split}\n|{(-\\Delta)^{s}}u(t,x)-{(-\\Delta)^{s}}u(s,x)| &\\leq \\left|\\int_{{\\mathbb{R}}^n}[{(-\\Delta)^{s}}u(t,x) - {(-\\Delta)^{s}}u(t,z)]\\phi_r(x-z) \\,dz\\right|\\\\\n&\\qquad+\\left|\\int_{{\\mathbb{R}}^n}[{(-\\Delta)^{s}}u(t,z)-{(-\\Delta)^{s}}u(s,z)]\\phi_r(x-z) \\,dz\\right|\\\\\n&\\qquad+ \\left|\\int_{{\\mathbb{R}}^n}[{(-\\Delta)^{s}}u(s,x) - {(-\\Delta)^{s}}u(s,z)]\\phi_r(x-z) \\,dz\\right|,\n\\end{split}$$ We now distinguish between two cases:\\\n*$\\bullet$ ${\\alpha}=0$.* Thanks to the $C_x^{1-s-0^+}$-regularity of ${(-\\Delta)^{s}}u$ and the fact that ${\\operatorname{supp}}\\, \\phi_r \\subset B_r$, the first and the third term in the right hand side of are bounded by $C\\,r^{1-s-0^+}$. For the second term, we integrate ${(-\\Delta)^{s}}$ by parts, and using that $\\|{(-\\Delta)^{s}}\\phi_r\\|_{L^1({\\mathbb{R}}^n)}=\\|{(-\\Delta)^{s}}\\phi\\|_{L^1({\\mathbb{R}}^n)}/r^{2s} \\sim 1/r^{2s}$ and that $u$ is Lipschitz in time (Corollary \\[cor:Lip\\]), we get $$|{(-\\Delta)^{s}}u(t,x)-{(-\\Delta)^{s}}u(s,x)| \\leq C\\left[r^{1-s-0^+} + \\frac{(t-s)}{r^{2s}}\\right].$$ Choosing $r:=|t-s|^{1/(1+s)}$ we obtain $$|{(-\\Delta)^{s}}u(t,x)-{(-\\Delta)^{s}}u(s,x)| \\leq C(t-s)^{\\frac{1-s}{1+s}-0^+},$$ as desired.\\\n*$\\bullet$ ${\\alpha}>0$.* Arguing as above, the first and the third term in the right hand side of are bounded by $C\\,r^{1-s}$. For the second one, we integrate again by parts and we estimate $$\\begin{aligned}\n\\bigg|\\int_{{\\mathbb{R}}^n}&[{(-\\Delta)^{s}}u(t,z)-{(-\\Delta)^{s}}u(s,z)]\\phi_r(x-z) \\,dz\\bigg|\\\\\n&=\\left|\\int_{{\\mathbb{R}}^n}[u(t,z)-u(s,z)]{(-\\Delta)^{s}}\\phi_r(x-z) \\,dz\\right|\\\\\n&\\leq \\left|\\int_{{\\mathbb{R}}^n}\\bigl[u(t,z)-u(s,z)- u_t(s,z)[t-s]\\bigr]{(-\\Delta)^{s}}\\phi_r(x-z) \\,dz\\right|\\\\\n&\\qquad+ (t-s)\\,\\left|\\int_{{\\mathbb{R}}^n} |u_t(s,z)| \\,|{(-\\Delta)^{s}}\\phi_r(x-z)| \\,dz\\right|.\\end{aligned}$$ Since $\\|{(-\\Delta)^{s}}\\phi_r\\|_{L^1({\\mathbb{R}}^n)} \\sim 1/r^{2s}$ and $u_t\\in C_t^{\\alpha}$, the first term in the right hand side is bounded by $C\\,\\frac{(t-s)^{1+{\\alpha}}}{r^{2s}}$. For the second term, we observe that $u_t$ vanishes at $(t,x)\\in \\{u=\\psi\\}$, so by the $C_{x}^{1-s}$-regularity of $u_t$ we get $$\\left|\\int_{{\\mathbb{R}}^n} |u_t(s,z)| \\,|{(-\\Delta)^{s}}\\phi_r(x-z)| \\,dz\\right|\n\\leq C \\left|\\int_{{\\mathbb{R}}^n} \\min\\left\\{|x-z|^{1-s},1\\right\\} \\,|{(-\\Delta)^{s}}\\phi_r(x-z)| \\,dz\\right|.$$ We now remark that, since $\\phi$ is compactly supported, $|{(-\\Delta)^{s}}\\phi(w)| \\leq \\frac{C}{|w|^{n+2s}}$ for $|w|$ large. ", "So, there exists a constant $C_\\phi$, depending on $\\phi$ only, such that $$|{(-\\Delta)^{s}}\\phi(w)|\\leq \\frac{C_\\phi}{1+ |w|^{n+2s}}\\qquad \\forall \\,w \\in {\\mathbb{R}}^n,$$ which by scaling gives $$|{(-\\Delta)^{s}}\\phi_r(w)|\\leq \\frac{C_\\phi}{r^{n+2s}+ |w|^{n+2s}}\\qquad \\forall \\,w \\in {\\mathbb{R}}^n.$$ Hence $$\\begin{aligned}\n\\int_{{\\mathbb{R}}^n} \\min\\left\\{|w|^{1-s},1\\right\\}|{(-\\Delta)^{s}}\\phi_r(w)|\\,dw &\\leq C\\int_{B_1} \\frac{|w|^{1-s}}{r^{n+2s}+ |w|^{n+2s}}\\,dw\n+ C\\int_{{\\mathbb{R}}^n\\setminus B_1} \\frac{1}{|w|^{n+2s}}\\,dw\\\\\n& \\leq \\frac{C}{r^{n+2s}} \\int_{B_r}|w|^{1-s}\\,dw + C \\int_{B_1\\setminus B_r} |w|^{1-3s - n}\\,dw + C,\\end{aligned}$$ which implies $$\\int_{{\\mathbb{R}}^n} \\min\\left\\{|w|^{1-s},1\\right\\}|{(-\\Delta)^{s}}\\phi_r(w)|\\,dw \\leq \\left\\{\n\\begin{array}{ll}\n C & \\text{if }s<1/3;\\\\\nC (1+|\\log(r)|) & \\text{if }s=1/3;\\\\\nC (1+r^{1-3s}) & \\text{if }s>1/3.", "\n\\end{array}\n\\right.$$ All in all, we have obtained $$|{(-\\Delta)^{s}}u(t,x)-{(-\\Delta)^{s}}u(s,x)| \\leq C\\biggl[r^{1-s} + \\frac{(t-s)^{1+{\\alpha}}}{r^{2s}}+(t-s)\\left\\{\\begin{array}{ll}\n C & \\text{if }s<1/3;\\\\\nC (1+|\\log(r)|) & \\text{if }s=1/3;\\\\\nC (1+r^{1-3s}) & \\text{if }s>1/3.", "\n\\end{array}\n\\right.\\biggr]$$ Choosing $r:=(t-s)^{(1+{\\alpha})/(1+s)}$, the above estimates give:\n\n1. ", " $s<1/3$: $|{(-\\Delta)^{s}}u(t,x)-{(-\\Delta)^{s}}u(s,x)| \\leq C(t-s).$\n\n2. ", " $s=1/3$: $|{(-\\Delta)^{s}}u(t,x)-{(-\\Delta)^{s}}u(s,x)| \\leq C(t-s)\\bigl[1+|\\log(t-s)|\\bigr].$\n\n3. ", " $s>1/3$: Since ${\\alpha}\\leq (1-s)/2s$ by assumption, we have ${\\alpha}\\leq \\frac{(1-s)(1+{\\alpha})}{1+s} \\leq 1+\\frac{(1-3s)(1+{\\alpha})}{1+s},$ so $$\\begin{aligned}\n |{(-\\Delta)^{s}}u(t,x)-{(-\\Delta)^{s}}u(s,x)| &\\leq C\\left[(t-s)^{\\frac{(1+{\\alpha})(1-s)}{1+s}} + (t-s)+(t-s)^{1+\\frac{(1-3s)(1+{\\alpha})}{1+s}}\\right]\\\\\n & \\leq C\\,(t-s)^{\\frac{(1+{\\alpha})(1-s)}{1+s}}.\\end{aligned}$$\n\nThanks to the above lemma, we can use and a bootstrap argument to prove our main regularity result.", "\n\nThe global Lipschitz regularity of $u$ in space-time follows from Corollary \\[cor:Lip\\].", "\n\nBy Proposition \\[prop:unif C1a rhs\\] and , we can apply Lemma \\[lemma:bootstrap\\] with ${\\alpha}=0$ to deduce that the right hand side of belongs to $C_{t,x}^{\\frac{1-s}{1+s}-0^+,1-s}((0,T]\\times {\\mathbb{R}}^n) $. ", "Hence, since $2s<1+s$, by the parabolic regularity theory for ${\\partial}_t+{(-\\Delta)^{s}}$ (see ) we get $u_t,{(-\\Delta)^{s}}u \\in C_{t,x}^{\\frac{1-s}{1+s}-0^+,1-s}((0,T]\\times {\\mathbb{R}}^n)$. We now apply Lemma \\[lemma:bootstrap\\] with ${\\alpha}>0$, and we distinguish between two cases:\n\n1. ", " $s\\leq 1/3$: In this case we get $${(-\\Delta)^{s}}u \\, \\chi_{\\{u=\\psi\\}}\\in {\\rm {{\\rm logLip}}}_tC_{x}^{1-s}((0,T]\\times {\\mathbb{R}}^n),$$ so by and we get ${(-\\Delta)^{s}}u\\in {{\\rm logLip}}_tC_x^{1-s}((0,T]\\times{\\mathbb{R}}^n)$, and we conclude by using $u_t={(-\\Delta)^{s}}u \\, \\chi_{\\{u=\\psi\\}}-{(-\\Delta)^{s}}u$.\n\n2. ", " $s>1/3$: Lemma \\[lemma:bootstrap\\] gives $${(-\\Delta)^{s}}u \\, \\chi_{\\{u=\\psi\\}}\\in C_{t,x}^{\\Phi\\left(\\frac{1-s}{1+s}-0^+\\right),1-s}((0,T]\\times {\\mathbb{R}}^n),$$ which by implies $u_t,{(-\\Delta)^{s}}u \\in C_{t,x}^{\\Phi\\left(\\frac{1-s}{1+s}-0^+\\right),1-s}((0,T]\\times {\\mathbb{R}}^n)$ (recall that $\\Phi({\\alpha})<\\frac{1-s}{2s}$ if ${\\alpha}<\\frac{1-s}{2s}$). ", "Hence, we can use iteratively Lemma \\[lemma:bootstrap\\] and to get $$u_t,{(-\\Delta)^{s}}u\\in C_{t,x}^{\\Phi^n\\left(\\frac{1-s}{1+s}-0^+\\right),1-s}((0,T]\\times {\\mathbb{R}}^n),$$ which together with implies $${(-\\Delta)^{s}}u\\in C_{t,x}^{\\frac{1-s}{2s},1-s}((0,T]\\times {\\mathbb{R}}^n).$$ Finally, since $\\Phi^n\\left(\\frac{1-s}{1+s}-0^+\\right) \\nearrow \\frac{1-s}{2s}$ as $n \\to \\infty$, we obtain $$u_t\\in C_{t,x}^{\\frac{1-s}{2s}-0^+,1-s}((0,T]\\times {\\mathbb{R}}^n),$$ as desired.", "\n\nExtension to more general equations {#sect:general eq}\n===================================\n\nIn this section we give a brief informal description of the main modifications needed to extend the regularity result of Theorem \\[thm:main\\] to solutions of , at least when $s>1/2$. Our aim is only to point out the major differences with respect to the model case treated above, and to explain how to handle them. ", "There will be however to attempt to state a proper theorem, as this would need a careful analysis of the assumptions needed on $\\psi,{\\mathcal{K}}$ (for instance, since the operators are non-local, in all the estimates one should take care of the contribution coming from infinity). ", "We plan to address this issue in a future work.\\\nAssume that $\\psi:{\\mathbb{R}}^n \\to {\\mathbb{R}}^+$ is a smooth globally Lipschitz function, $b \\in {\\mathbb{R}}^n$ a vector, $r\\geq 0$ is a constant and ${\\mathcal{K}}$ a (smooth) non-local translation-invariant elliptic operator of lower order with respect to ${(-\\Delta)^{s}}$, i.e., there exists ${\\kappa}\\in (0,1)$ such that $$[{\\mathcal{K}}{\\varphi}]_{C^{{\\kappa}}_{{\\rm loc}}({\\mathbb{R}}^n)} \\lesssim \\|{(-\\Delta)^{s}}{\\varphi}\\|_{L^\\infty({\\mathbb{R}}^n)}\\qquad \\forall \\, {\\varphi}\\in C_c^\\infty({\\mathbb{R}}^n).$$ We consider $u:[0,T]\\times {\\mathbb{R}}^n \\to {\\mathbb{R}}$ a (continuous) viscosity solution to the obstacle problem $$\\label{eq:general frac heat visc}\n\\left\\{\n\\begin{array}{l}\n\\min\\{ -u_t +ru + b\\cdot \\nabla u - {(-\\Delta)^{s}}u - {\\mathcal{K}}u ,u-\\psi\\}=0 \\quad \\text{on }(0,T]\\times {\\mathbb{R}}^n,\\\\\nu(0)=\\psi,\n\\end{array}\n\\right.$$ When $s >1/2$, existence and uniqueness of such a solution follows again by standard results on obstacle problems.", "\n\nLet us now analyze the properties of solutions, as we did before for .\\\n*$\\bullet$ Basic properties.* ", "We proceed as in Section \\[sect:prelim\\]. ", "First of all, as in Lemma \\[lemma:comparison\\] one can approximate solutions to using a penalization method. ", "In this way, all the results of Section \\[sect:prelim\\] still hold true:\n\n1. ", " $u(t,\\cdot)$ is globally Lipschitz (see Lemma \\[lemma:basic\\]);\n\n2. ", " $u(t,\\cdot)$ is uniformly semiconvex (see Lemma \\[lemma:basic\\]);\n\n3. ", " $u_t$ is globally bounded (see Lemma \\[lemma:Linfty bound frac heat\\]);\n\n4. ", " ${(-\\Delta)^{s}}u + {\\mathcal{K}}u - r u- b \\cdot \\nabla u$ is globally bounded (see Lemma \\[lemma:Linfty bound frac heat\\]).", "\n\nIn particular, by elliptic regularity for the fractional Laplacian, the $L^\\infty$-bound on ${(-\\Delta)^{s}}u + {\\mathcal{K}}u(t) - r u(t)- b \\cdot \\nabla u(t)$ gives\n\n1. ", " $u \\in L^\\infty([0,T],C_{{\\rm loc}}^{2s-0^+}({\\mathbb{R}}^n))$.\n\nHence, since $s>1/2$ and ${\\mathcal{K}}u$ is of order $\\leq 2s-{\\kappa}$, there exists $\\gamma=\\gamma(s,{\\kappa})>0$ such that $$\\label{eq:R}\nR:=- {\\mathcal{K}}u+ru +b \\cdot \\nabla u \\in L^\\infty([0,T],C_{{\\rm loc}}^{{\\gamma}}({\\mathbb{R}}^n)).$$\n\n*$\\bullet$ $C_{x}^{{\\alpha}}$-decay for ${(-\\Delta)^{s}}u(t)$.* In this setting, we have:\n\n1. ", " ${(-\\Delta)^{s}}u(t) -R(t)< 0$ inside the open set $\\{u(t)>\\psi\\}$;\n\n2. ", " ${(-\\Delta)^{s}}u(t)-R(t)\\geq 0$ a.e. ", "on $\\{u(t)=\\psi\\}$.\n\nNow, fixed $t>0$ and given a free boundary point $x_0 \\in {\\partial}\\{u(t)=\\psi\\}$, we consider the $L_a$-harmonic function $v(x,y):=u(t,x,y) -\\frac{R(t,x_0)}{1-a}\\,y^{1-a}$, where $u(t,x,y)$ is the $L_a$-harmonic extension of $u(t)$. Moreover, as in Subsection \\[sect:general C1a\\] we consider the function $$\\tilde v(x,y):=v(x,y)-\\psi(x).$$ Since $u_t$ is globally bounded and $v(\\cdot,0)$ is semiconvex, all estimates (B1)-(B2) and (B4)-(B5) of Subsection \\[sect:general C1a\\] still hold true, while (B3) becomes\n\n1. ", " $\\lim_{y \\to 0^+} y^a\\tilde v_y(x,y)\\leq |R(t,x)-R(t,x_0)| \\leq C|x-x_0|^\\gamma$ for a.e. ", "$x \\in {\\Lambda}$,\\\n $\\lim_{y \\to 0^+} y^a\\tilde v_y(x,y) > -C|x-x_0|^\\gamma$ for $x \\in {\\mathbb{R}}^n\\setminus {\\Lambda}$.\n\nWhile the proof of Lemma \\[lemma:deriv to fct\\] works with no modifications under these assumptions, for the proof of Proposition \\[prop: C1a v\\] we remark that now we do not have $\\lim_{y \\to 0^+} y^a\\tilde v_y(x,y) \\geq 0$ for $x \\in {\\mathbb{R}}^n\\setminus {\\Lambda}$, which was used to apply Hopf’s Lemma. ", "To overcome this difficulty, in the induction step from $k_0$ to $k_0+1$ one should replace $v(x,y)$ with $v(x,y)+\\frac{\\|R(t)\\|_{C^{\\gamma}(B_1(x_0))}}{1-a} (4^{-k_0})^\\gamma y^{1-a}$, and the rest of the proof should go through with minor modifications.", "\n\nHence, one still gets $\\sup_{B_r(x_0)}|u(t) - \\psi| \\leq Cr^{{\\alpha}+2s}$ and $$[{(-\\Delta)^{s}}u(t)-R(t)] \\chi_{u(t)=\\psi}=[{(-\\Delta)^{s}}u(t)+ {\\mathcal{K}}u(t) - r u(t)- b \\cdot \\nabla u(t)] \\chi_{u(t)=\\psi} \\in C_{{\\rm loc}}^{{\\alpha}}({\\mathbb{R}}^n),$$ for some universal exponent ${\\alpha}\\in(0,\\gamma)$.\\\n*$\\bullet$ Monotonicity formula and optimal spatial regularity.* ", "As in Subsection \\[subsect:monot\\], one would like to apply a monotonicity formula. ", "However, first of all one has to do a preliminary step: using the equation $$u_t + {(-\\Delta)^{s}}u=[{(-\\Delta)^{s}}u+ R] \\chi_{u=\\psi} - R \\in L^\\infty([0,T];C_{{\\rm loc}}^{{\\alpha}}({\\mathbb{R}}^n))$$ one deduces (thanks to a local variant of -) that ${(-\\Delta)^{s}}u \\in L^\\infty([0,T];C_{{\\rm loc}}^{{\\alpha}-0^+}({\\mathbb{R}}^n))$. So, by elliptic regularity for the fractional Laplacian, $u \\in C_{{\\rm loc}}^{{\\alpha}+2s-0^+}({\\mathbb{R}}^n)$, which gives $$R \\in L^\\infty([0,T],C_{{\\rm loc}}^{{\\alpha}+\\gamma/2}({\\mathbb{R}}^n)).$$ This allows considering $R$ as a lower order perturbation when applying the monotonicity formula.", "\n\nNow, to apply the monotonicity formula around a free boundary point $x_0 \\in {\\partial}\\{u(t)=\\psi\\}$, one should consider the function $w:{\\mathbb{R}}^n\\times {\\mathbb{R}}^+\\times {\\mathbb{R}}$ obtained by solving the Dirichlet problem $$\\left\\{\n\\begin{array}{l}\nL_{-a}w=0,\\\\\nw(x,0)=[{(-\\Delta)^{s}}u(t,x,0)-R(t,x_0)] \\chi_{\\{u(t)=\\psi\\}}(x).", "\n\\end{array}\n\\right.$$ Since $R(t) \\in C_{{\\rm loc}}^{{\\alpha}+\\gamma/2}({\\mathbb{R}}^n)$, we have $w \\geq -C r^{{\\alpha}+{\\gamma}/2}$ on $B_r(x_0)$. So, by the monotonicity formula one gets $[{(-\\Delta)^{s}}u+R(t,x)] \\chi_{u(t)=\\psi} \\in C_{{\\rm loc}}^{\\beta_{\\alpha}'}({\\mathbb{R}}^n)$, $\\beta_{\\alpha}':=\\min\\{{\\alpha}+{\\delta}_{\\alpha}',1-s\\}$. Then, one can iterate the above strategy, first using the parabolic regularity of ${\\partial}_t+{(-\\Delta)^{s}}$ and the the elliptic regularity of ${(-\\Delta)^{s}}$ to show that $R \\in L^\\infty([0,T];C_{{\\rm loc}}^{{\\beta}_{\\alpha}'+\\gamma}({\\mathbb{R}}^n)$, and then applying again the monotonicity formula. ", "In this way, after finitely many iterations we get $$[{(-\\Delta)^{s}}u+ {\\mathcal{K}}u - r u- b \\cdot \\nabla u] \\chi_{u=\\psi} \\in L^\\infty([0,T],C_{{\\rm loc}}^{1-s}({\\mathbb{R}}^n)),\\qquad R\\in L^\\infty([0,T],C_{{\\rm loc}}^{1-s+{\\gamma}}({\\mathbb{R}}^n)).$$\n\n*$\\bullet$ Parabolic regularity and conclusion.* ", "Using Lemma \\[lemma:bootstrap\\], the argument in Subsection \\[sect:C1s u\\] applied to $${\\partial}_t u +{(-\\Delta)^{s}}u = [{(-\\Delta)^{s}}u+ R] \\chi_{u=\\psi} - R$$ allows to extend the regularity result in Theorem \\[thm:main\\] (at least locally in space-time) to solutions of .", "\n\nRegularity properties of the operator ${\\partial}_t+{(-\\Delta)^{s}}$\n====================================================================\n\nIn this appendix we describe some important properties of the parabolic operator ${\\partial}_t+{(-\\Delta)^{s}}$.\\\nLet us first recall that fractional Laplacian works nicely in Hölder spaces: in $f \\in C^{{\\alpha}}({\\mathbb{R}}^n)$ then $(-{\\Delta})^{-s}f \\in C^{{\\alpha}+2s}({\\mathbb{R}}^n)$, see for instance [@silv Subsection 2.1].", "\n\nAnalogously, the operator ${\\partial}_t + {(-\\Delta)^{s}}$ works nicely in space-time Hölder spaces: if $v_t+{(-\\Delta)^{s}}v=f$ on $[0,T]\\times {\\mathbb{R}}^n$ and $v(0)$ is smooth (for our purposes, we can assume $v(0) \\in C^2({\\mathbb{R}}^n)$, globally Lipschitz, and $\\|D^2 v(0)\\|_{L^\\infty({\\mathbb{R}}^n)}+\\|{(-\\Delta)^{s}}v(0)\\|_{C_x^{1-s}({\\mathbb{R}}^n)} <+\\infty$), by classical results on multipliers on Hölder spaces (see for instance [@madychriviere Theorem 2.3] and the proof of [@madychriviere Theorem 3.1]) we get $$\\label{eq:regularity holder multipliers}\n\\| v_t\\|_{C_{t,x}^{{\\alpha},{\\beta}}((0,T]\\times{\\mathbb{R}}^n)}+\\| {(-\\Delta)^{s}}v\\|_{C_{t,x}^{{\\alpha},{\\beta}}((0,T]\\times{\\mathbb{R}}^n)} \\lesssim 1+ \\|f\\|_{C_{t,x}^{{\\alpha},{\\beta}}((0,T]\\times{\\mathbb{R}}^n)} \\qquad \\forall\\,{\\alpha},{\\beta}\\in (0,1)$$ However, for our purposes, we also need to have some regularity estimates when $f$ is only bounded in time (but Hölder in space).", "\n\nLet us observe that we can write the solution in terms of the fundamental solution ${\\Gamma}_s(t,x)$ of the fractional heat equation. ", "More precisely, using Duhamel formula, we have $$\\label{eq:duhamel}\n\\begin{split}\n-{(-\\Delta)^{s}}v(t,x) &=v_t(t,x)-f(t,x)\\\\\n&=-{\\Gamma}_s(t)\\ast {(-\\Delta)^{s}}v(0)+\\int_0^t \\int_{{\\mathbb{R}}^n}\\partial_t {\\Gamma}_s(t-\\tau,x-y) [f(\\tau,y)-f(\\tau,x)]\\,dy\\,d\\tau.", "\n\\end{split}$$ We now claim that the following estimates hold (the proof of them is postponed to Subsection \\[subsect:proof estimates\\] below): $$\\label{eq:infty regularity holder 1}\n\\left\\|\\int_0^t \\int_{{\\mathbb{R}}^n}\\partial_t {\\Gamma}_s(t-\\tau,x-y) [f(\\tau,y)-f(\\tau,x)]\\,dy\\,d\\tau\\right\\|_{C_{t,x}^{{\\beta}/(2s),{\\beta}-0^+}((0,T]\\times{\\mathbb{R}}^n)} \\lesssim \\|f\\|_{L^\\infty((0,T];C_{x}^{\\beta}({\\mathbb{R}}^n))}$$ if ${\\beta}<2s$, $$\\label{eq:infty regularity holder 2}\n\\left\\|\\int_0^t \\int_{{\\mathbb{R}}^n}\\partial_t {\\Gamma}_s(t-\\tau,x-y) [f(\\tau,y)-f(\\tau,x)]\\,dy\\,d\\tau\\right\\|_{{{\\rm logLip}}_tC_x^{{\\beta}-0^+}((0,T]\\times{\\mathbb{R}}^n)} \\lesssim \\|f\\|_{L^\\infty((0,T];C_{x}^{\\beta}({\\mathbb{R}}^n))}$$ if ${\\beta}\\geq 2s$.\n\nCombining the above estimates with , and using that $-{\\Gamma}_s(t)\\ast {(-\\Delta)^{s}}v(0)$ is smooth in space-time for $t>0$, we get $$\\label{eq:regularity holder 1}\n\\| {(-\\Delta)^{s}}v\\|_{C_{t,x}^{{\\beta}/(2s),{\\beta}-0^+}((0,T]\\times{\\mathbb{R}}^n)} \\lesssim 1+ \\|f\\|_{L^\\infty((0,T];C_{x}^{\\beta}({\\mathbb{R}}^n))} \\qquad \\forall\\, \\beta\\in (0,2s)$$ $$\\label{eq:regularity holder 2}\n\\| {(-\\Delta)^{s}}v\\|_{{{\\rm logLip}}_tC_x^{{\\beta}-0^+}((0,T]\\times{\\mathbb{R}}^n)} \\lesssim 1+ \\|f\\|_{L^\\infty((0,T];C_{x}^{\\beta}({\\mathbb{R}}^n))}\\qquad \\forall\\, \\beta\\in [2s,1)$$ (At $t=0$ the time regularity may degenerate, due to the presence of the term ${\\Gamma}_s(t)\\ast {(-\\Delta)^{s}}v(0)$.) In particular, using that $v_t=f-{(-\\Delta)^{s}}v$, we obtain $$\\label{eq:regularity ut holder}\n\\| v_t\\|_{L^\\infty((0,T];C_x^{{\\beta}-0^+}({\\mathbb{R}}^n))}+ \\| {(-\\Delta)^{s}}v\\|_{L^\\infty((0,T];C_x^{{\\beta}-0^+}({\\mathbb{R}}^n))}\\lesssim 1+ \\|f\\|_{L^\\infty((0,T];C_{x}^{\\beta}({\\mathbb{R}}^n))} \\qquad \\forall\\, \\beta\\in (0,1)$$\n\nProof of and {#subsect:proof estimates}\n-------------\n\nLet us recall that $t \\in [0,T]$, with $T<+\\infty$.\n\nTo prove and , we use that the fundamental solution ${\\Gamma}_s(1,y)$ behaves like $\\frac{1}{1+|y|^{n+2s}}$, which by scaling implies $$\\label{eq:fund sol 1}\n{\\Gamma}_s(t,y) \\sim \\frac{t}{t^{\\frac{n+2s}{2s}}+|y|^{n+2s}},\\qquad |{\\partial}_t{\\Gamma}_s(t,y)| \\lesssim \\frac{1}{t^{\\frac{n+2s}{2s}}+|y|^{n+2s}},$$ $$\\label{eq:fund sol 2}\n|{\\partial}_{tt}{\\Gamma}_s(t,y)| \n\\lesssim \\frac{1}{t}\\frac{1}{(t^{\\frac{n+2s}{2s}}+|y|^{n+2s})}, \\quad |\\nabla_y{\\partial}_{t}{\\Gamma}_s(t,y)| \n\\lesssim \\frac{1}{|y|}\\frac{1}{(t^{\\frac{n+2s}{2s}}+|y|^{n+2s})}$$ We will also make use of the following two basics estimates:\\\n- There exists a constant $C>0$ such that, for all $h \\in (0,1]$, $$\\label{estimate1}\n\\int_{{\\mathbb{R}}^n}\\frac{\\min\\{|z|^{\\beta},1\\}}{h^{\\frac{n+2s}{2s}}+|z|^{n+2s}}\\,dz\n\\leq C \\Bigl(1+ h^{{\\beta}/(2s)-1}\\Bigr).$$ - There exists a constant $C>0$ such that, for all $h >0$, $$\\label{estimate2}\n\\int_0^t\\frac{1}{(t-\\tau)^{\\frac{n+2s}{2s}}+h^{n+2s}}\\,d\\tau \\leq C \\min\\left\\{\\frac{1}{h^n},\\frac{1}{h^{n+2s}}\\right\\}.$$ The proof of both is pretty simple. ", "For instance, to show , one splits the integral into three parts: $$\\int_{B_{h^{1/(2s)}}}\\frac{|z|^{\\beta}}{h^{\\frac{n+2s}{2s}}+|z|^{n+2s}}\\,dz \\leq \\frac{1}{h^{\\frac{n+2s}{2s}}} \\int_{B_{h^{1/(2s)}}}|z|^{\\beta}\\,dz \\lesssim \nh^{{\\beta}/(2s)-1},$$ $$\\int_{B_1\\setminus B_{h^{1/(2s)}}}\\frac{|z|^{\\beta}}{h^{\\frac{n+2s}{2s}}+|z|^{n+2s}}\\,dz \\leq \\int_{B_1\\setminus B_{h^{1/(2s)}}}|z|^{{\\beta}-n-2s} \\,dz \\lesssim 1+ h^{{\\beta}/(2s)-1},$$ $$\\int_{{\\mathbb{R}}^n\\setminus B_1}\\frac{1}{h^{\\frac{n+2s}{2s}}+|z|^{n+2s}}\\,dz \\leq \\int_{{\\mathbb{R}}^n\\setminus B_1}|z|^{-n-2s} \\,dz \\lesssim 1.$$ To prove , we observe that the bound is trivial if $h \\geq 1$, since $\\frac{1}{(t-\\tau)^{\\frac{n+2s}{2s}}+h^{n+2s}} \\lesssim \\frac{1}{h^{n+2s}}$ (recall that $|t-\\tau| \\leq T \\lesssim 1$). ", "On the other hand, if $h \\in (0,1]$, it suffices to split the integral over $[0,t-h^{2s}]$ and $[t-h^{2s},t]$, and argue as above.\\\n$\\bullet$ *Proof of .* ", "Let us observe that, for $u<t$, $$\\begin{aligned}\n\\bigl|{(-\\Delta)^{s}}v(t,x)&-{(-\\Delta)^{s}}v(\\tau,x)\\bigr|\\\\\n&=\\biggl|\\int_0^t \\int_{{\\mathbb{R}}^n}\\partial_t {\\Gamma}_s(t-\\tau,x-y) [f(\\tau,y)-f(\\tau,x)]\\,dy\\,d\\tau\\\\\n&\\qquad- \\int_0^u \\int_{{\\mathbb{R}}^n}\\partial_t {\\Gamma}_s(u-\\tau,x-y) [f(\\tau,y)-f(\\tau,x)]\\,dy\\,d\\tau\\biggr|\\\\\n&\\lesssim \\int_u^t \\int_{{\\mathbb{R}}^n}\\bigl|\\partial_t {\\Gamma}_s(t-\\tau,x-y)\\bigr||f(\\tau,y)-f(\\tau,x)|\\,dy\\,d\\tau\\\\\n&\\qquad+\\int_0^u \\int_{{\\mathbb{R}}^n}\\Bigl|\\partial_t {\\Gamma}_s(u-\\tau,x-y)-\\partial_t {\\Gamma}_s(t-\\tau,x-y)\\Bigr| \\min\\{|x-y|^{\\beta},1\\}\\,dy\\,d\\tau\\\\\n&=(T1)+(T2).\\end{aligned}$$ Now, using , by applied with $h=(t-\\tau)$ we get that (T1) is bounded by $$\\begin{aligned}\n\\int_u^t \\int_{{\\mathbb{R}}^n}\\frac{\\min\\{|x-y|^{\\beta},1\\}}{(t-\\tau)^{\\frac{n+2s}{2s}}+|x-y|^{n+2s}}\\,dy\\,d\\tau&\n\\leq \\int_u^t \\Bigl(1+ (t-\\tau)^{{\\beta}/(2s)-1}\\Bigr)\\,d\\tau\\\\\n&\\lesssim (t-u)+(t-u)^{{\\beta}/(2s)}.\\end{aligned}$$ Concerning (T2), thanks to , , and with $h=(t-\\tau)$, we can control it by $$\\begin{aligned}\n&\\int_0^u \\int_{{\\mathbb{R}}^n} \\min\\left\\{\\frac{t-u}{u-\\tau},1\\right\\}\\frac{1}{((u-\\tau)^{\\frac{n+2s}{2s}}+|x-y|^{n+2s})}\\min\\{|x-y|^{\\beta},1\\}\\,dy\\,d\\tau\\\\\n&\\lesssim \\int_0^u \\min\\left\\{\\frac{t-u}{u-\\tau},1\\right\\} \\int_{{\\mathbb{R}}^n} \\frac{\\min\\{|x-y|^{\\beta},1\\}}{(u-\\tau)^{\\frac{n+2s}{2s}}+|x-y|^{n+2s}}\\,dy\\,d\\tau\\\\\n&\\lesssim \\int_0^{u-(t-u)} \\frac{t-u}{u-\\tau}\\Bigl(1+ (u-\\tau)^{{\\beta}/(2s)-1}\\Bigr) \\,d\\tau+\\int_{u-(t-u)}^u \\Bigl(1+ (u-\\tau)^{{\\beta}/(2s)-1}\\Bigr) \\,d\\tau\\\\\n&\\lesssim (t-u)+(t-u)|\\log(t-u)|+ (t-u)^{{\\beta}/(2s)},\\end{aligned}$$ which proves the time regularity of ${(-\\Delta)^{s}}v$.\n\n$\\bullet$ *Proof of .* ", "The proof of the spatial regularity is analogous: we write $$\\begin{aligned}\n&{(-\\Delta)^{s}}v(t,x)-{(-\\Delta)^{s}}v(t,z)\\\\\n&=\\int_0^t \\int_{{\\mathbb{R}}^n}\\Bigl(\\partial_t {\\Gamma}_s(t-\\tau,x-y) [f(\\tau,y)-f(\\tau,x)]-\\partial_t {\\Gamma}_s(t-\\tau,z-y) [f(\\tau,y)-f(\\tau,z)] \\Bigr)\\,dy\\,d\\tau.\\end{aligned}$$ Then, we split the spatial integral over two sets: the region where $\\bigl\\{|x-z| \\leq |x-y|/2\\bigr\\}$ and the region where $\\bigl\\{|x-z| \\geq |x-y|/2\\bigr\\}$.\n\nOn the first set, since $\\frac{1}{(t-\\tau)^\\frac{n+2s}{2s}+|x-y|^{n+2s}}$ and $\\frac{1}{(t-\\tau)^\\frac{n+2s}{2s}+|z-y|^{n+2s}}$ are comparable, we can estimate the integrand by $$|f(\\tau,y)-f(\\tau,x)|\\Bigl|\\partial_t {\\Gamma}_s(t-\\tau,x-y)-\\partial_t {\\Gamma}_s(t-\\tau,z-y)\\Bigr|\n+ |f(\\tau,x)-f(\\tau,z)|\\Bigl|\\partial_t {\\Gamma}_s(t-\\tau,x-y)\\Bigr|,$$ which thanks to and can be bounded by $$|y-x|^\\beta\\frac{|x-z|}{|x-y|}\\frac{ 1 }{(t-\\tau)^{\\frac{n+2s}{2s}}+|x-y|^{n+2s}}\n+|x-z|^{\\beta}\\frac{1}{(t-\\tau)^{\\frac{n+2s}{2s}}+|x-y|^{n+2s}}.$$ So, using with $h=|x-y|$ we get $$\\begin{aligned}\n&\\int_0^t \\int_{\\{|x-z| \\leq |x-y|/2\\}}\\Bigl|\\partial_t {\\Gamma}_s(t-\\tau,x-y) [f(\\tau,y)-f(\\tau,x)]-\\partial_t {\\Gamma}_s(t-\\tau,z-y) [f(\\tau,y)-f(\\tau,z)] \\Bigr|\\,dy\\,d\\tau\\\\\n& \\lesssim \\int_{\\{|x-z| \\leq |x-y|/2\\}} \\left(\\frac{|x-z|}{|x-y|^{1-{\\beta}}}+|x-z|^{\\beta}\\right)\\int_0^t\\frac{1}{(t-\\tau)^{\\frac{n+2s}{2s}}+|x-y|^{n+2s}}\\,d\\tau \\,dy\\\\\n&\\lesssim \\int_{\\{|x-z| \\leq |x-y|/2\\}} |x-z|^{\\beta}\\min\\left\\{\\frac{1}{|x-y|^n},\\frac{1}{|x-y|^{n+2s}}\\right\\} \\,dy\\\\\n& \\leq |x-z|^{{\\beta}} \\int_{\\{|x-z| \\leq |x-y|/2 \\leq 1\\}} |x-y|^{-n} + |x-z|^{\\beta}\\int_{\\{|x-y|/2 \\geq 1\\}}|x-y|^{-n-2s}\\\\\n&\\lesssim |x-z|^{\\beta}\\bigl|\\log|x-z|\\bigr| \\lesssim |x-z|^{{\\beta}-{\\varepsilon}}\\qquad\\forall \\,{\\varepsilon}>0.\\end{aligned}$$ Concerning the integral over the second set, we simply use to bound the integrand by $$\\frac{|x-y|^\\beta}{(t-\\tau)^\\frac{n+2s}{2s}+|x-y|^{n+2s}}+ \\frac{|x-z|^\\beta}{(t-\\tau)^\\frac{n+2s}{2s}+|x-z|^{n+2s}}$$ and observing that $\\{|x-z| \\geq |x-y|/2\\} \\subset B_{3|x-z|}(x)\\cap B_{3|x-z|}(z)$ we get $$\\begin{aligned}\n&\\int_0^t \\int_{\\{|x-z| \\geq |x-y|/2\\}}\\Bigl|\\partial_t {\\Gamma}_s(t-\\tau,x-y) [f(\\tau,y)-f(\\tau,x)]-\\partial_t {\\Gamma}_s(t-\\tau,z-y) [f(\\tau,y)-f(\\tau,z)] \\Bigr|\\,dy\\,d\\tau\\\\\n&\\lesssim \\int_0^t \\int_{B_{3|x-z|}(x)} \\frac{|x-y|^\\beta}{(t-\\tau)^\\frac{n+2s}{2s}+|x-y|^{n+2s}}\\,dy\\,d\\tau\\\\\n&=\\int_{B_{3|x-z|}(x)} |x-y|^\\beta\\int_0^t \\frac{1}{(t-\\tau)^\\frac{n+2s}{2s}+|x-y|^{n+2s}}\\,d\\tau\\,dy\\\\\n&\\lesssim \\int_{B_{3|x-z|}(x)} |x-y|^{\\beta-n}\\,dy \\lesssim |x-z|^{\\beta},\\end{aligned}$$ where for the last but one inequality we used again with $h=|x-y|$. This concludes the proof of .", "\n\n[99]{}\n\nAthanasopoulos, I.; Caffarelli, L. A. Optimal regularity of lower dimensional obstacle problems. *", "Zap. ", "Nauchn. ", "Sem. ", "S.-Peterburg. ", "Otdel. ", "Mat. ", "Inst. ", "Steklov. (", "POMI)* 310 (2004), *Kraev. ", "Zadachi Mat. ", "Fiz. ", "i Smezh. ", "Vopr. ", "Teor. ", "Funkts. ", "35 \\[34\\]*, 49–66, 226; translation in *J. Math. ", "Sci. (", "N. Y.)* 132 (2006), no. ", "3, 274–284.", "\n\nBlack, F.; Scholes, M. The Pricing of Options and Corporate Liabilities *J. Polit. ", "Econ.* ", "81 (1973), 637–659.", "\n\nBrézis, H.; Kinderlehrer, D. The smoothness of solutions to nonlinear variational inequalities. *", "Indiana Univ. ", "Math. ", "J.* 23 (1973/74), 831–844.", "\n\nCaffarelli, L. A. The regularity of free boundaries in higher dimensions. *", "Acta Math.* ", "139 (1977), no. ", "3-4, 155–184.", "\n\nCaffarelli, L. A.; Friedman, A. Continuity of the temperature in the Stefan problem. *", "Indiana Univ. ", "Math. ", "J.* 28 (1979), no. ", "1, 53–70.", "\n\nCaffarelli, L. A.; Salsa, S.; Silvestre, L. Regularity estimates for the solution and the free boundary of the obstacle problem for the fractional Laplacian. *", "Invent. ", "Math.* ", "171 (2008), no. ", "2, 425–461.", "\n\nCaffarelli, L. A.; Silvestre, L. An extension problem related to the fractional Laplacian. *", "Comm. ", "Partial Differential Equations* 32 (2007), no. ", "7-9, 1245–1260.", "\n\nChipot, M. Variational inequalities and flow in porous media. *", "Applied Mathematical Sciences*, 52. ", "Springer-Verlag, New York, 1984.", "\n\nCont, R.; Tankov, P. Financial modelling with jump processes. *", "Chapman & Hall/CRC Financial Mathematics Series.* ", "Chapman & Hall/CRC, Boca Raton, FL, 2004\n\nFabes, E. B.; Kenig, C. E.; Serapioni, Raul P. The local regularity of solutions of degenerate elliptic equations. *", "Comm. ", "Partial Differential Equations* 7 (1982), no. ", "1, 77–116.", "\n\nFriedman, A.; Kinderlehrer, D. A one phase Stefan problem. *", "Indiana Univ. ", "Math. ", "J.* 24 (1974/75), no. ", "11, 1005–1035.", "\n\nLaurence, P.; Salsa, S. Regularity of the free boundary of an American option on several assets. *", "Comm. ", "Pure Appl. ", "Math.* ", "62 (2009), no. ", "7, 969–994.", "\n\nMadych, W. R.; Rivière, N. M. Multipliers of the Hölder classes. *", "J. Functional Analysis* 21 (1976), no. ", "4, 369–379.", "\n\nMerton, R. Option Pricing when the Underlying Stock Returns are Discontinuous. *", "J. Finan. ", "Econ.* ", "5 (1976), 125–144.", "\n\nSilvestre, L. Regularity of the obstacle problem for a fractional power of the Laplace operator. *", "Comm. ", "Pure Appl. ", "Math.* ", "60 (2007), no. ", "1, 67–112.", "\n\n[^1]: Department of Mathematics, The University of Texas at Austin, 1 University Station C1200, Austin TX 78712, USA. ", "E-mail: `caffarel@math.utexas.edu`\n\n[^2]: Department of Mathematics, The University of Texas at Austin, 1 University Station C1200, Austin TX 78712, USA. ", "E-mail: `figalli@math.utexas.edu`\n\n[^3]: Here, existence of solutions is not the main issue: for instance, one can construct solutions by using probabilistic formulas involving stochastic processes and stopping times [@conttankov]. ", "Another possibility is to approximate the equation using a penalization method (as done in the proof of Lemma \\[lemma:comparison\\]) and then use the a priori bounds on the approximate solutions (see the proofs of Lemmas \\[lemma:basic\\] and \\[lemma:Linfty bound frac heat\\]) to show existence by compactness. ", "The fact that these two notions of solutions (the probabilistic one and the one constructed by approximation) coincide, follows from standard comparisons principle for viscosity solutions.", "\n\n[^4]: The smoothness assumption on $v$ inside the open set $\\{v>\\psi\\}$ (see (A5)) is not essential for the proof of the regularity of $v$ at free boundary points, but it is only used to avoid some minor technical issues. ", "Anyhow this makes no differences for our purposes, since all the following results will be applied to $v=u(t)$ with $t>0$, and $u$ is smooth inside the open set $\\{u>\\psi\\}$ (see the proof of Lemma \\[lem:sign frac lapl\\]).", "\n\n[^5]: Even if we use the names “$a$-semiconcavity” and “$C_0$-semiconvexity” with different meanings, this should create no confusion. ", "Observe also that, when $a=0$, (A8) reduces to the classical notion of semiconcavity.", "\n\n[^6]: A simple way to check this fact is the following: the function $G:=\\bigl(\\sqrt{x_n^2+y^2}-x_n\\bigr)^{1/2}$ is harmonic inside $y>0$, since it is equal to the imaginary part of the holomorphic function $z \\mapsto z^{1/2}$, $z=x_n+iy_n$. Moreover, by a direct computation it is easily checked that $G$ satisfies $$|\\nabla_x G|^2 + (G_y)^2 -\\frac{G G_y}{y}=0\\qquad \\forall \\,(x,y) \\in{\\mathbb{R}}^n \\times {\\mathbb{R}}^+.$$ Thanks to this fact, since $\\bar H=G^{2(1-s)}=G^{1+a}$, we get $$L_{-a}\\bar H=L_{-a}\\bigl(G^{1+a}\\bigr)=(1+a)G^a \\Delta_{x,y}G+(1+a)a\\, G^{a-1} \\left[ |\\nabla_x G|^2 + (G_y)^2 -\\frac{G G_y}{y}\\right]=0,$$ as desired.", "\n\n[^7]: The proof of the monotonicity formula may look a bit tedious, since we always prove the result at the $\\epsilon$ level, and then we show that one can take the limit as ${\\varepsilon}\\to 0$. Let us point out that this level of precision is actually needed: indeed, assume that we had chosen a different operator $L_b$ ($b \\in (-1,1)$) to define $w$ in , and we defined ${\\varphi}(r)$ replacing $-a$ by $b$ (changing, of course, the value of $s$ correspondingly). ", "Then, if one does a “formal” proof of the monotonicity formula, one would obtain (at least in the stationary case, so that $w(x,0)={(-\\Delta)^{s}}v(x)$) that Lemma \\[lemma:monotonicity\\] is true with $b$ in place of $-a$, and this would imply a false Hölder regularity for $w$ (since we know that $w$ should be only $C^{1-s}$). ", "The fact that we have chosen the “right” operator $L_{-a}$ to define $w$ has played a key role in the proof of Lemma \\[lemma:prelim for monot\\], which is now providing to us some fundamental estimates, which are needed to give a rigorous proof of the monotonicity formula.", "\n" ]

{ "pile_set_name": "ArXiv" }

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[ "[The comparative analysis of the clinical and morphological picture of the various forms of chronic suppurative otitis media].", "\nWe present the results of the surgical treatment of 300 patients presenting with chronic suppurative otitis media. ", "The changes in the mucous membrane of the tympanic cavity were revealed in 61% of the patients with mesotympanitis while spreading cholesteatoma occurred in 48% of the cases of «dry» perforations. ", "The cholesteatomic process was documented in 64% of the patients with epitympanitis, the remaining patients presented with the pyo-carious process. ", "The efficiency of the surgical intervention on the «dry» ear of the patients with the tubotympanic form of chronic suppurative otitis media (CSOM) amounted to 91.4% compared with 85% in the case of the altered mucous membrane of the tympanic cavity, 85.5% and 92.9% in the patients with the pyo-carious and cholesteatomic forms of the tympano-antral lesions, respectively. ", "Residual cholesteatomas were found in 7.8% of the patients suffering from epitympanitis during the three year follow-up period. ", "It is concluded that the results of clinical and morphological observations taken together with intraoperative findings give reason to consider mesotympanitis to be a prognosticallyunfavourable form of chronic suppurative otitis media." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "A large portion of the Internet follows a client server model in which client devices request content from server systems across the Internet via a browser or a different client application, e.g., a mobile application. ", "Client devices can receive multimedia content that is unique to specific users or common across multiple users, e.g., from various websites on the Internet. ", "Under current content delivery schemes, network traffic bottlenecks at the server end are generally relieved via content delivery networks that cache content files on cache servers distributed around the Internet nearby large concentrations of users. ", "Network traffic bottlenecks at the client end are generally relieved via browser or other caches on the client devices. ", "Despite the use of cache servers and the browser caches, a large amount of redundant traffic still flows through the current client/server network architecture. ", "For example, redundant traffic may flow between content delivery networks and various servers that service multiple client devices.", "\nReducing redundant network traffic is desirable because it can increase overall network speeds and reduce network infrastructure costs. ", "This can be especially useful in emerging markets where Internet infrastructure is only now improving.", "\nThe figures depict various embodiments of the disclosed technology for purposes of illustration only. ", "One skilled in the art will readily recognize from the following discussion that alternative embodiments may be employed." ]

{ "pile_set_name": "USPTO Backgrounds" }

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[ "package com.crashinvaders.texturepackergui.controllers.projectserializer;\n\nimport com.badlogic.gdx.", "Gdx;\nimport com.badlogic.gdx.files.", "FileHandle;\nimport com.badlogic.gdx.utils.", "Json;\nimport com.badlogic.gdx.utils.", "JsonValue;\nimport com.crashinvaders.texturepackergui.controllers.model.", "InputFile;\nimport com.crashinvaders.texturepackergui.utils.", "PathUtils;\n\nimport java.io.", "File;\n\npublic class InputFileSerializer implements Json.", "Serializer<InputFile> {\n\n private File root;\n\n @Override\n public void write(Json json, InputFile model, Class knownType) {\n String path = PathUtils.relativize(model.getFileHandle().path(), root.getPath());\n\n json.writeObjectStart();\n json.writeValue(\"path\", path);\n json.writeValue(\"type\", model.getType().name());\n\n switch (model.getType()) {\n case Input:\n if (model.isDirectory()) {\n //### Input directory properties\n json.writeValue(\"dirFilePrefix\", model.getDirFilePrefix());\n json.writeValue(\"recursive\", model.isRecursive());\n json.writeValue(\"flattenPaths\", model.isFlattenPaths());\n } else {\n //### Input file properties\n json.writeValue(\"regionName\", model.getRegionName());\n // Ninepatch\n if (model.isProgrammaticNinePatch()) {\n InputFile.", "NinePatchProps npp = model.getNinePatchProps();\n json.writeObjectStart(\"ninepatch\");\n json.writeArrayStart(\"splits\");\n json.writeValue(npp.left);\n json.writeValue(npp.right);\n json.writeValue(npp.top);\n json.writeValue(npp.bottom);\n json.writeArrayEnd();\n json.writeArrayStart(\"pads\");\n json.writeValue(npp.padLeft);\n json.writeValue(npp.padRight);\n json.writeValue(npp.padTop);\n json.writeValue(npp.padBottom);\n json.writeArrayEnd();\n json.writeObjectEnd();\n }\n }\n break;\n case Ignore:\n //### Ignore file properties\n break;\n }\n json.writeObjectEnd();\n }\n\n @Override\n public InputFile read(Json json, JsonValue jsonData, Class clazz) {\n String path = jsonData.getString(\"path\");\n InputFile.", "Type type = InputFile.", "Type.valueOf(jsonData.getString(\"type\"));\n String dirFilePrefix = jsonData.getString(\"dirFilePrefix\", null);\n String regionName = jsonData.getString(\"regionName\", null);\n boolean recursive = jsonData.getBoolean(\"recursive\", false);\n boolean flattenPaths = jsonData.getBoolean(\"flattenPaths\", false);\n\n FileHandle fileHandle;\n if (new File(path).isAbsolute()) {\n fileHandle = Gdx.files.absolute(path);\n } else {\n fileHandle = Gdx.files.absolute(new File(root, path).getAbsolutePath());\n }\n\n InputFile inputFile = new InputFile(fileHandle, type);\n inputFile.setDirFilePrefix(dirFilePrefix);\n inputFile.setRegionName(regionName);\n inputFile.setRecursive(recursive);\n inputFile.setFlattenPaths(flattenPaths);\n\n // Ninepatch\n JsonValue ninepatch = jsonData.get(\"ninepatch\");\n if (ninepatch !", "= null) {\n InputFile.", "NinePatchProps npp = inputFile.getNinePatchProps();\n int[] splits = ninepatch.get(\"splits\").asIntArray();\n int[] pads = ninepatch.get(\"pads\").asIntArray();\n npp.left = splits[0];\n npp.right = splits[1];\n npp.top = splits[2];\n npp.bottom = splits[3];\n npp.padLeft = pads[0];\n npp.padRight = pads[1];\n npp.padTop = pads[2];\n npp.padBottom = pads[3];\n inputFile.setProgrammaticNinePatch(true);\n }\n\n return inputFile;\n }\n\n public void setRoot(File root) {\n this.root = root;\n }\n}\n" ]

{ "pile_set_name": "Github" }

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[ "Top economic adviser of President Donald Trump, Larry Kudlow, incorrectly stated on Friday that the coronavirus “is being controlled in the US.” ", "One more senior Trump official, counselor to the President Kellyanne Conway, made a similar statement. ", "He claimed that they had controlled the virus.", "\n\nFacts First: Professionals say the United States is not close to restricting the coronavirus. ", "They also articulate the little amount of tests conducted in the US so far has prohibited the administration from getting a precise image of how widespread the virus, in fact, is.", "\n\n“It is spreading so quickly in numerous places that it may be hard to bring to an end.”", "\n\nKudlow and Conway said;\n\nKudlow, a member of a coronavirus task force of Trump, said on CNBC’s “Squawk on the Street” that “honestly, so far it seems comparatively controlled.”", "\n\nWhen Kudlow’s statement was challenged by co-hosts David Faber and Carl Quintanilla, he said, “Concerning the containment problem, I will still state to you that this is controlled.", "\n\nConway also made a statement of a victorious inhibition effort. ", "Conway made a statement on Fox News that “speedy, substantive and determined action of the President at the very start of this and task force is operational 24/7; in fact, it has made the dissimilarity in terms of controlling this in this country so far.”", "\n\nWhat is actually happening?", "\n\nThe figure of diagnosed cases of the virus in the United States is going to increase continuously. ", "Since Saturday morning, over 330 people have tested positive. ", "17 people have passed away from the sickness, the majority of them are from Washington State. ", "There are confirmed cases in over 20 states as of early Friday afternoon.", "\n\nLipsitch analyses that the virus is spreading within societies in the US and in other states. ", "According to Horney, the US has been stating crises this week to provide themselves extra flexibility to try to control the spread of the virus.", "\n\nExperts stated that the US showed an insufficient number of tests so far.", "\n\nAccording to Gordon;\n\n“I would mention that we now do not know the size of the eruptions on the West Coast. ", "It is due to restricted testing.” ", "Due to the low testing abilities the US has had and the fact that the government originally compulsory strict limitations on who could get verified.", "\n\nShe stated, “Indeed, we do not know the level of community broadcast.”" ]

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[ "JavaScript's this keyword is confusing at the best of times. ", "But what if I told you that 99% of the time, five simple rules are all you need to use this like a pro?" ]

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[ "VIDEO: We owe a big debt to women like Ita and Dulcie\n\nBy\nIan Horner\n\nJune 7, 2013, 4:17 p.m.\n\nPaper Giants: Magazine Wars concludes on ABC1 on Sunday, June 9. ", "For Rachel Griffiths it was a chance to sink her teeth into an issue close to home -- the role of women in the media, on screen and behind it.", "\n\nPaper Giants: Magazine Wars concludes on ABC1 on Sunday, June 9. ", "For Rachel Griffiths it was a chance to sink her teeth into an issue close to home -- the role of women in the media, on screen and behind it. ", "And the immigration debate: ‘Look, for 10 years I was a migrant in America’ -- where she starred on Brothers & Sisters and Six Feet Under. ", "She talks to IAN HORNER.", "\n\nKerry Packer’s move to push Ita Buttrose to the forefront was groundbreaking. ", "Yes, it was commercialism, not altruism, and it was certainly a first for the media to have Buttrose, Dulcie Boling and Nene King, three strong women, wielding real power. ", "Did that attract you to play Boling in Magazine Wars? ‘‘", "When I first saw the Cleo story about Ita in the original Paper Wars it rocked my perception of the accomplishments of a particular generation of women. ", "When I was a kid we made fun of Ita and Dulcie. ", "We thought they were kind of pre-feminist dinosaurs in a way. ", "This was me as a 15-year-old. ", "Well I was really rocked to my core when I realised until these women became editors of their magazines there weren’t women in executive positions in Australian media. ", "I had a little shame-on-me moment. ", "And I had to really wake up to the extraordinary in-roads they made for generations of journalists who followed them.’’", "\n\nHow was Boling treated by the male executives in her company? ‘‘", "I’m not going to divulge private conversations I had with Dulcie. ", "I think she had kind of a patience and a grit. ", "And I think she was able to take her gains when and how they happened. ", "She’s a very strategic person. ", "Eventually she came right out and asked for what she deserved and she didn’t wait for someone to maybe have the brilliant idea maybe Dulcie should be on the board. ", "She said ‘This is what I’ve achieved, this is how much money I’ve made you’ and I think in that moment Murdoch looked at the ledger and said: ‘You’re right; there’s your seat on the board.’ ", "But had a very reactive, emotional person been on the same career path as her I don’t think she would’ve made it because she wouldn’t have been able to hold the fort without outbursts and female emotions that would have ‘proved’ to the men at the time she wasn’t executive material.’’", "\n\nThe rise of celebrity culture at the time was also running in tandem with the rise of the predatory press. ‘‘", "That’s correct, yeah.’’", "\n\nDid Boling ever feel a twinge of responsibility for what the papparazzi did to Diana? ‘‘", "Can I say I think it’s no coincidence that Dulcie stepped down from the day-to-day running of her magazines fairly shortly after that time. ", "I also have no doubt a young Dulcie these days wouldn’t be attracted to the women’s corner of the media market but at the time that was the only way she was going to be able to consolidate any power and get to flex her muscles at capacity. ", "I think she’s a real journalist and these days would be more likely running the Fin Review than one of these magazines. ", "She could run The Australian. ", "I think she could run a network if one of the stations decided they could have women on the board. ", "The boys are all running the show. ", "It’s still crazy, the lack of women. ", "Given that most media is consumed by at least as many women if not more it’s still madness there’s not a balance of women in programming and setting the direction that different networks might go.’’", "\n\nOn screen at least we’ve had some improvements. ", "Back in the 1950s and 1960s the family sitcoms were built around the father, a classic example was Father Knows Best. ", "But then you come to the point just recently where you can launch what would become a long-running hit TV show, Brothers & Sisters, and kill off Dad in episode one! ‘‘", "Yes, it’s kind of the death of the patriarch. ", "It really started with Alan Ball who did exactly the same thing in Six Feet Under. ", "It’s all about what happens when a woman is running her micro-world.’’", "\n\nBrothers & Sisters broke a lot of ground. ", "It championed gay rights, single working mums and Sally Field was one of the driving forces behind the show. ", "Did she have real power and what sort of battles did she and others have to fight to shape the show into what it was? ‘‘", "We were extremely fortunate on Brothers & Sisters that the writers’ door was always open. ", "Sally probably went in as often as I did, you know, to tell a 22-year-old male writer that a 60-year-old widow would not speak in such a manner and certainly wouldn’t speak to her mother in this way! ", "We were always trying to make the relationships in that show real and it was by how true they felt to our audience that the show lived and died. ", "No one on that show threw their power around. ", "We were all very thankful that the writers’ door was open.’’", "\n\nYou did 63 episodes of Six Feet Under but you did double that of Brothers & Sisters. ", "That’s a huge chunk of your life! ‘‘", "Isn’t that crazy?!’’", "\n\nAnd that’s an awful lot of fake wine to drink! ", "Or was it real? ‘‘", "It was always fake wine, unfortunately. ", "I think the average time in a job for most people over 28 is about five years and it’s just a perfect amount of time to really get to the top of the game in the area you’re working and make some fantastic relationships with the people you’re working with and not get bored. ", "So it wasn’t so much I was making 130 hours of television but I was getting to spend that amount of time with these incredibly talented and wonderful people.’’", "\n\nWhen you got tired did you ever have trouble saying ‘‘prodoose’’ (produce) and ‘‘Mom’’? ‘‘[", "laughs] You’re right! ", "By March we were scraping the barrel.’’", "\n\nJohn Piper-Ferguson, who played your husband for a while, is also from Melbourne. ‘‘", "Yeah, but he identifies as Canadian. ", "It was remarkable. ", "We had two Canadians (Ferguson and Emily VanCamp), a Welshman (Matthew Rhys) and myself and a Frenchman (Gilles Marini) by the end and that was a good 40per cent of the cast. ", "When I was in the canteen I said to some of other actors ‘Do you resent the fact we’re taking your jobs?’ ", "and they’d say: ‘Not at all, it keeps us all at the top of our game.’ ", "It’s a really wonderful, exceptional attitude, I think, the Americans have. ", "They’re not threatened by it. ", "And I think we’ve all got a lot to learn from that.’’", "\n\nDo you find Australia still a little insular in its attitudes? ‘‘", "No, I don’t. ", "But I do think things come up, unfortunately, pre-election time and the immigration thingo becomes a little more politicised than it should. ", "I think I’ve come home to a younger, more multicultural and forward-looking country than the one I left. ", "I personally believe the immigration we’ve had over the last 10 years has had a very big part in keeping us out of recession and keeping us growing and providing a working base to support our older Australians -- who, sure, can get nervous when they see the familiar streets of their childhood, you know, with different cooking smells. ", "I think that generation needs to be reminded the only way we can fully support the retirees who’ve really contributed enormously to this country is by having younger skilled economic immigrants who come with their eyes full of life and hope for their family. ", "And I know having been an immigrant working in America for 10 years, when you come to another country you always want to do good work. ", "When I was there you had to always make the work count and I noticed that with other immigrants. ", "You’re always trying to make it count because at the end of the day when you come home your 10 best friends aren’t there to whine to about how bad your day was. ", "I do think you give 120 per cent because you’re sacrificing such a lot. ", "You’ve left your friends, your homeland and your own family. ", "Immigrants turn the dial up on productivity and passion. ", "We must celebrate and support that and not be threatened.", "’’" ]

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[ "France - Dans son rapport annuel publié mardi dernier, la Cour des comptes accuse l'État d'un manque de détermination face à la pollution des eaux liée aux pratiques agricoles. ", "Évoquant un \"bilan décevant de la politique de l'eau\", la Cour épingle l'État français, dont l'inaction entraîne, selon elle, un gâchis de moyens exposant la France à de lourdes pénalités financières.", "\n\nAppelant l'État à \"adopter une politique plus volontariste\" en matière de pollution agricole, la Cour des comptes dénonce \"la méconnaissance par la France des objectifs communautaires\" de même qu'elle déplore une \"action répressive insuffisante\".", "\n\n\n\nComme tous les États membres de l'Union européenne, la France s'est engagée à réduire la présence de nitrates et d'azote dans les eaux destinées à la consommation, visant un \"bon état\" écologique d'ici à 2015. ", "Or, le manque de respect des règlements européens à déjà valu au pays six condamnations et la Cour des comptes souligne que cette inaction entraîne un véritable gâchis de moyens, tout en conduisant à \"douter de la capacité de la France à atteindre les objectifs\".", "\n\n\n\nEt la Cour de dénoncer une \"approche routinière\" des six agences de l'eau qui préfèrent payer \"1,8 fois plus\" pour réparer les dégâts plutôt que les prévenir.", "\n\n\n\nAlors que le ministère de l'Environnement se défend en précisant que la Cour se base sur des contrôles effectués entre 2002 et 2006, il demande à ce que soit pris en compte \"l'immense mouvement de transformation engagé depuis trois ans\"." ]

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[ "#region License Information (GPL v3)\r\n\r\n/*\r\n ShareX - A program that allows you to take screenshots and share any file type\r\n Copyright (c) 2007-2020 ShareX Team\r\n\r\n This program is free software; you can redistribute it and/or\r\n modify it under the terms of the GNU General Public License\r\n as published by the Free Software Foundation; either version 2\r\n of the License, or (at your option) any later version.", "\r\n\r\n This program is distributed in the hope that it will be useful,\r\n but WITHOUT ANY WARRANTY; without even the implied warranty of\r\n MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. ", " See the\r\n GNU General Public License for more details.", "\r\n\r\n You should have received a copy of the GNU General Public License\r\n along with this program; if not, write to the Free Software\r\n Foundation, Inc., 51 Franklin Street, Fifth Floor, Boston, MA 02110-1301, USA.", "\r\n\r\n Optionally you can also view the license at <http://www.gnu.org/licenses/>.", "\r\n*/\r\n\r\n#endregion License Information (GPL v3)\r\n\r\n// Adapted from https://stackoverflow.com/questions/33569396/correctly-implement-a-2-pass-gaussian-blur\r\n// Filters: http://www.codeproject.com/Articles/2008/Image-Processing-for-Dummies-with-C-and-GDI-Part-2\r\n\r\nusing System;\r\nusing System.", "Drawing;\r\nusing System.", "Drawing.", "Imaging;\r\nusing System.", "Threading.", "Tasks;\r\n\r\nnamespace ShareX.HelpersLib\r\n{\r\n public static class ConvolutionMatrixManager\r\n {\r\n public static Bitmap Apply(this ConvolutionMatrix kernel, Bitmap bmp)\r\n {\r\n Bitmap bmpResult = (Bitmap)bmp.", "Clone();\r\n\r\n using (UnsafeBitmap source = new UnsafeBitmap(bmp, true, ImageLockMode.", "ReadOnly))\r\n using (UnsafeBitmap dest = new UnsafeBitmap(bmpResult, true, ImageLockMode.", "WriteOnly))\r\n {\r\n int originX = (kernel.", "Width - 1) / 2;\r\n int originY = (kernel.", "Height - 1) / 2;\r\n\r\n Parallel.", "For(0, source.", "Height, y =>\r\n {\r\n Parallel.", "For(0, source.", "Width, x =>\r\n {\r\n double r = 0.0;\r\n double g = 0.0;\r\n double b = 0.0;\r\n double a = 0.0;\r\n\r\n // Apply each matrix multiplier to the color components for each pixel.", "\r\n for (int fy = 0; fy < kernel.", "Height; fy++)\r\n {\r\n int fyr = fy - originY;\r\n int offsetY = y + fyr;\r\n\r\n offsetY = offsetY.Clamp(0, source.", "Height - 1);\r\n\r\n for (int fx = 0; fx < kernel.", "Width; fx++)\r\n {\r\n int fxr = fx - originX;\r\n int offsetX = x + fxr;\r\n\r\n offsetX = offsetX.Clamp(0, source.", "Width - 1);\r\n\r\n ColorBgra currentColor = source.", "GetPixel(offsetX, offsetY);\r\n\r\n r += kernel[fy, fx] * currentColor.", "Red;\r\n g += kernel[fy, fx] * currentColor.", "Green;\r\n b += kernel[fy, fx] * currentColor.", "Blue;\r\n if (kernel.", "ConsiderAlpha)\r\n {\r\n a += kernel[fy, fx] * currentColor.", "Alpha;\r\n }\r\n }\r\n }\r\n\r\n r += kernel.", "Offset;\r\n r = r.Clamp(0, 255);\r\n\r\n g += kernel.", "Offset;\r\n g = g.Clamp(0, 255);\r\n\r\n b += kernel.", "Offset;\r\n b = b.Clamp(0, 255);\r\n\r\n if (kernel.", "ConsiderAlpha)\r\n {\r\n a += kernel.", "Offset;\r\n a = a.Clamp(0, 255);\r\n }\r\n\r\n dest.", "SetPixel(x, y, new ColorBgra((byte)b, (byte)g, (byte)r, kernel.", "ConsiderAlpha ? (", "byte)a : source.", "GetPixel(x, y).Alpha));\r\n });\r\n });\r\n }\r\n\r\n return bmpResult;\r\n }\r\n\r\n public static ConvolutionMatrix Smooth(int weight = 1)\r\n {\r\n ConvolutionMatrix cm = new ConvolutionMatrix();\r\n double factor = weight + 8;\r\n cm.", "SetAll(1 / factor);\r\n cm[1, 1] = weight / factor;\r\n return cm;\r\n }\r\n\r\n private static double GaussianFunction(double x, double sigma)\r\n {\r\n double left = 1.0 / (Math.", "Sqrt(2 * Math.", "PI) * sigma);\r\n\r\n double exponentNumerator = -x * x;\r\n double exponentDenominator = 2 * Math.", "Pow(sigma, 2);\r\n double right = Math.", "Exp(exponentNumerator / exponentDenominator);\r\n\r\n return left * right;\r\n }\r\n\r\n public static ConvolutionMatrix GaussianBlur(int height, int width, double sigma)\r\n {\r\n ConvolutionMatrix cm = new ConvolutionMatrix(height, width);\r\n cm.", "ConsiderAlpha = true;\r\n\r\n double sum = 0.0;\r\n double midpointX = (width - 1) / 2.0;\r\n double midpointY = (height - 1) / 2.0;\r\n\r\n for (int y = 0; y < height; y++)\r\n {\r\n for (int x = 0; x < width; x++)\r\n {\r\n sum += cm[y, x] = GaussianFunction(x - midpointX, sigma) * GaussianFunction(y - midpointY, sigma);\r\n }\r\n }\r\n\r\n // Normalise kernel so that the sum of all weights equals 1\r\n for (int y = 0; y < height; y++)\r\n {\r\n for (int x = 0; x < width; x++)\r\n {\r\n cm[y, x] /= sum;\r\n }\r\n }\r\n\r\n return cm;\r\n }\r\n\r\n public static ConvolutionMatrix MeanRemoval(int weight = 9)\r\n {\r\n ConvolutionMatrix cm = new ConvolutionMatrix();\r\n double factor = weight - 8;\r\n cm.", "SetAll(-1 / factor);\r\n cm[1, 1] = weight / factor;\r\n return cm;\r\n }\r\n\r\n public static ConvolutionMatrix Sharpen(int weight = 11)\r\n {\r\n ConvolutionMatrix cm = new ConvolutionMatrix();\r\n double factor = weight - 8;\r\n cm.", "SetAll(0);\r\n cm[1, 1] = weight / factor;\r\n cm[1, 0] = cm[0, 1] = cm[2, 1] = cm[1, 2] = -2 / factor;\r\n return cm;\r\n }\r\n\r\n public static ConvolutionMatrix Emboss()\r\n {\r\n ConvolutionMatrix cm = new ConvolutionMatrix();\r\n cm.", "SetAll(-1);\r\n cm[1, 1] = 4;\r\n cm[1, 0] = cm[0, 1] = cm[2, 1] = cm[1, 2] = 0;\r\n cm.", "Offset = 127;\r\n return cm;\r\n }\r\n\r\n public static ConvolutionMatrix EdgeDetect()\r\n {\r\n ConvolutionMatrix cm = new ConvolutionMatrix();\r\n cm[0, 0] = cm[0, 1] = cm[0, 2] = -1;\r\n cm[1, 0] = cm[1, 1] = cm[1, 2] = 0;\r\n cm[2, 0] = cm[2, 1] = cm[2, 2] = 1;\r\n cm.", "Offset = 127;\r\n return cm;\r\n }\r\n }\r\n}" ]

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[ "Q:\n\nGuidance for how and when to flag a question: declined flags\n\nWhen reviewing first posts in particular, it is my understanding that one should check if the question is a fit for the site, among which if the question makes sufficient sense. ", "I take these tasks fairly seriously, and have recently been confused. ", "What constitutes \"low quality\"?", "\nTo make this concrete, the 2 cases that prompt me to look for guidance. ", "I flagged these 2 for low quality, and add the feedback received after my flag was declined:\nvector operations between a two-dimensional and a three-dimensional vectors (\"flags should only be used if a question demands moderator attention\" - I would understand if a moderator thinks it is \"not low quality\" (although, how, I do not know, but one can disagree); but how am I supposed to understand this?)", "\nhttps://math.stackexchange.com/questions/318792/a-characterization-of-probability-theory (\"moderator found no evidence to support your flag\" - question was closed shortly thereafter, probably as it is not an actionable question, which is why I flagged).", "\nAs said, I take my flags very seriously, and don't want to be on the record as someone who flags many unjustified posts. ", "Reviewing first posts has an answer box \"low quality\", which is a subjective criterion which I took as \"it's low quality, alright, flag, then let a moderator decide what to do\" - but to at least bring it to a moderator's attention I had thought to be encouraged. ", "\nI happened to visit the StackOverflow voting page today, in which candidates underline their number of flags as evidence for how much they care. ", "To understand this properly, I do not consider flagging as preparing a future candidacy (because that will never happen); but it seems at SO flagging is considered a good thing, whereas I cannot help feeling that the most recent feedback sounded as if I was told to not bother the moderators. ", "\nIt seems to tell me that only absurdly bad posts should be flagged (or spam maybe). ", "I feel disinclined to ever flag 'low quality' again, and lean towards just waving through new posts if it just leads to me having a bad flagging record.", "\n\nA:\n\nI'm answering this from a network-wide perspective (I'm a moderator on Skeptics and Biology), the attitude towards moderators using their supervotes is markedly different than on most other SE sites. ", "This might affect also the attitude towards which posts should be flagged.", "\nIn general, I find the most useful way to think about flagging is to think about what you want to happen to the post you flagged. ", "Usually, you flag for a moderator because you want something to happen to the post that you can't do yourself. ", "If you don't have the power to close questions, you can flag them. ", "If you can't delete posts (or even if you can, because on most sites deletion by the community is very hard to achieve), you can flag. ", "\nFlags are not only handled by moderators, flags that request that a question is closed can be seen and handled by the community (10k+ users). ", "If a moderator thinks that the question is at least problematic, but doesn't want to unilaterally decide to close, they can just leave the flag in the queue and let the community handle it.", "\nAnother category of flags are custom flags that inform the moderators about problematic user behaviour, because dealing with such issues is something that regular users can't do, as they don't have the necessary tools to do this.", "\nThe \"very low quality\" is by far the most problematic of all flag reasons. ", "It shouldn't be used for somewhat problematic posts, it is meant for really bad and unsalvageable posts. ", "If you think the post is so bad that a moderator should just outright delete it, then a \"very low quality\" flag would be appropriate.", "\nI personally find that \"very low quality\" flags are unnecessary in most cases, and you usually should use other, more descriptive flags. ", "For questions, I would flag with one of the close reasons, a very low quality question fits into \"not a real question\" most of the time. ", "For answers, very often such a low quality answer is not an answer at all, and should be flagged as \"not an answer\". ", "\n\nA:\n\nI looked at the post about vector operations and could not understand the reason for flagging it. ", " It is a reasonable and natural question, much better than verbatim copies of homework washing up to the shores of Math.", "SE every day. ", " I wish more of my calculus students asked questions like this (not necessarily at Math.", "SE, they can ask me). ", " \nBecause \"low quality\" is a somewhat diffuse notion, it may help to consider a practical aspect before flagging: what would you do if you were the moderator seeing this flag? ", "\n\nWould you close or delete the post at once? (", "Moderators cannot simply vote to close, their decisions go into effect immediately).", "\nWould you suspend the user who asked the question, or destroy their account? ", "\nWould you migrate the question to another site? ", "\n\nIf none of the above actions are called for, perhaps the post indeed does not need moderator's attention. ", "This does not mean it's perfect, but whatever needs to be fixed can be fixed by ordinary users such as yourself. ", "You can edit the post, comment to prompt a clarification from the user, vote to close (not yet, but soon you'll be able to), or simply vote. ", "The first post review queue displays the voting arrows specifically to encourage the reviewers to vote on the newcomers' posts. ", "\n\n" ]

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[ "24:35 Allah is the light of the heavens and the earth. ", "A likeness of His light is as a pillar on which is a lamp — the lamp is in a glass, the glass is as it were a brightly shining star — lit from a blessed olive-tree, neither eastern nor western, the oil whereof gives light, though fire touch it not — light upon light. ", "Allah guides to His light whom He pleases. ", "And Allah sets forth parables for men, and Allah is Knower of all things\n\nIn this Khutba Brother Talha looks at Verse 35 from Chapter 24 of The Holy Quran and in this short verse of the holy Qur’an, Allah has mentioned the important role of divine revelation working for the moral and spiritual advancement of human beings. ", "Allah by taking oath of fig, olive, Mount Sinai and Makkah has provided undeniable historical evidence to vindicate its truth.", "\n\n24:35 Allah is the light of the heavens and the earth. ", "A likeness of His light is as a pillar on which is a lamp — the lamp is in a glass, the glass is as it were a brightly shining star — lit from a blessed olive-tree, neither eastern nor western, the oil whereof gives light, though fire touch it not — light upon light. ", "Allah guides [...]\n\nWhile all other scriptures were revealed for a particular people, Muslims say that the Holy Quran was revealed for the whole of mankind. ", "We look at an extract from Hazrat Mirza Ghulam Ahmad which explains this.", "\n\nWhile all other scriptures were revealed for a particular people, Muslims say that the Holy Quran was revealed for the whole of mankind. ", "We look at an extract from Hazrat Mirza Ghulam Ahmad which explains this.", "\n\nWe continue with the discussion of the traditional belief that the Holy Prophet Muhammad (pbuh) could not read or write. ", "In part I, the traditional belief was explained. ", "In part II, objections to the traditional belief were discussed and in the last part we look at the alternative interpretations.", "\n\nWe continue with the discussion of the traditional belief that the Holy Prophet Muhammad (pbuh) could not read or write. ", "In part I, the traditional belief was explained. ", "In part II, objections to the traditional belief were discussed and in the last part we look at the alternative interpretations.", "\n\nIn order properly to analyse these speeches, it is necessary, to have a basic understanding of Islam, its terminology and its tropes. ", "It is also important to have an understanding of the historical context of the Qur’an (the Revelation) and the Sunna (the practice of the Prophet Muhammad) and the contemporaneous circumstances in which the [...]\n\nIn the Holy Quran the word ummi is used for the Holy Prophet Muhammad (s). ", "Does this mean that he did not know how to read or write? ", "In this and the next two khutbas we consider the use of this word for the Holy Prophet (s).", "\n\nRob Wallace and Lauren Effron from abc news; While some fundamentalist Muslims may declare they follow Muhammad’s instructions to “fight the infidels,” moderate scholars argue the infidels he was referring to have been dead for 1,300 years. “‘", "Infidel’ in the Koran is not just a noun or an adjective, [...]\n\nA lot of people are arguing on television and in print media that the Holy Quran is just filled with violence and misogyny. ", "American conservative Christians talk about the peaceful message of the Bible and seem to forget or are oblivious to what is actually contained in the Bible. ", "A Youtube channel run by a group of Dutch producers called [...]\n\nIn this khutba we will be looking at Chapter 86 of The Holy Quran, verses one to three. ", "Allah seeks of a person who comes by night. ", "Who is this person and what is the point of his coming? ", "These are are the questions we try and answer by looking at these verses.", "\n\nThis khutba carries on in general terms from the speech one of our younger members, Bushra Ahmad, made at the October Community meeting. ", "She discussed the mention in the Holy Quran of an ant speaking to other ants and explained how ants communicate by exchanging chemicals. ", "This khutba looks at the fact that the Holy Quran is a book of guidance [...]\n\nIn Chapter 5 verse 6, the Holy Quran gives us instructions about how to perform the wudhu (physical cleaning) before prayer. ", "In this khutba we look at what the message is of the Call to Prayer and the wudhu. ", "The Call draws our attention to the fact that seeking Allah and His pleasure is better than anything else we may be engaged in. ", "The wudhu [...]\n\nSurah Al-Ikhlas is the 112th Chapter of the Holy Quran. ", "It is the second most important chapter of the Holy Quran after Surah Fatiha – the very first Surah. ", "The Holy Prophet (s) is reported to have said that Surah Al-Iklhas by itself is equal to one third of the Holy Quran. ", "In this Khutba we look at human desires in the light of Surah [...]" ]

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[ "This disclosure relates to improved deicer compositions. ", "More particularly, the disclosure relates to pre-wetted deicer compositions with reduced leaching properties.", "\nPre-wetted deicers are commonly used in winter road maintenance. ", "Pre-wetted deicers can be applied to roads and other surfaces during winter months in areas where snow and/or ice tend to form on those surfaces after precipitation. ", "Pre-wetted deicers typically consist of a solid deicer blended with a liquid deicer. ", "The liquid deicer is sometimes sprayed onto the salt at the moment it is applied onto the road, but this requires special equipment. ", "Thus, it is often desirable to pre-blend the liquid with the solid deicer so that the pre-wetted blend can be applied using the same, standard equipment and trucks used to apply dry salt to roads.", "\nOne of the challenges in producing pre-wetted deicers is leaching during storage. ", "Leaching occurs when liquid migrates within, or flows out of, a mass of pre-wetted deicer. ", "Environmental exposure can sometimes introduce additional moisture to pre-wetted deicers, pushing the deicers past their saturation point and resulting in leaching. ", "Leaching is a nuisance that often requires site clean-ups. ", "Leaching also produces inconsistent and non-uniform deicers, making them less effective, and has potential environmental impacts. ", "There is thus a need to decrease leaching from pre-wetted deicers." ]

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[ "Q:\n\nC++ class in separate file not compiling. ", "Already defined in Class.obj one or more multiply defined symbols found\n\nSo I've done extensive googling and searching on StackOverflow and am unable to find a solution despite several answers with this exact issue.", "\nI am trying to create a test class in an external file called Fpc5.cpp\nIt's contents are:\nFpc5.cpp\n#include \"stdafx.h\"\n#include \"Fpc5.h\";\n#include <iostream>\nusing std::cout;\n\nclass Fpc5 {\n int bar;\npublic:\n void testMethod();\n};\n\nvoid Fpc5::testMethod() {\n cout << \"Hey it worked! \";", "\n}\n\nand my main .cpp file:\nTest.cpp\n// Test.cpp : Defines the entry point for the console application.", "\n//\n\n#include \"stdafx.h\"\n#include \"iostream\"\n//#include \"Fpc5.cpp\"\n#include \"Fpc5.h\";\nusing std::cout;\nusing std::cin;\nusing std::endl;\n\nint main()\n{\n cout << \"Hello\" << endl;\n Fpc5 testObj;\n testObj.testMethod();\n\n system(\"pause\");\n return 0;\n}\n\nall the answers I've read indicate this is caused becaused I used to be including the class in the main file itself which is why I created a header file\nFpc5.h\n#pragma once\nvoid testMethod();\n\nThis changed the error, but still did not fix the issue. ", "Currently my Test.cpp does not recognize a Fpc5 class. ", "I've also tried adding the Fpc5.cpp and Fpc5.h in stdafx.h and that still does not resolve the issue. ", " \nstdafx.h\n// stdafx.h : include file for standard system include files,\n// or project specific include files that are used frequently, but\n// are changed infrequently\n//\n\n#pragma once\n\n#include \"targetver.h\"\n\n#include <stdio.h>\n#include <tchar.h>\n\n// TODO: reference additional headers your program requires here\n\n//#include \"Fpc5.cpp\"\n#include \"Fpc5.h\"\n\nI'm sure this a simple syntax/conceptual understanding error, but I'm quite new to c++ and am not sure what is wrong. ", "\n\nA:\n\nThis is definition of your class and it must be in Fpc5.h\nclass Fpc5 {\n int bar;\npublic:\n void testMethod();\n};\n\nThen, you have Fpc5.cpp where you implement methods of the class:\n#include \"Fpc5.h\" // Compiler needs class definition to compile this file!", "\n\nvoid Fpc5::testMethod()\n{\n}\n\nAnd then you can use Fpc5 class in Test.cpp\n#include \"Fpc5.h\"\n\nint main()\n{\n Fpc5 foo;\n foo.testMethod();\n return 0;\n}\n\nAs an alternative you can pack everything into Test.cpp\n\n" ]

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[ "/*\n * Copyright 2020 Red Hat, Inc. and/or its affiliates.", "\n *\n * Licensed under the Apache License, Version 2.0 (the \"License\");\n * you may not use this file except in compliance with the License.", "\n * You may obtain a copy of the License at\n *\n * http://www.apache.org/licenses/LICENSE-2.0\n *\n * Unless required by applicable law or agreed to in writing, software\n * distributed under the License is distributed on an \"AS IS\" BASIS,\n * WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.", "\n * See the License for the specific language governing permissions and\n * limitations under the License.", "\n */\n\npackage org.optaplanner.test.impl.score.buildin.bendable;\n\nimport org.optaplanner.core.api.domain.solution.", "PlanningSolution;\nimport org.optaplanner.core.api.score.buildin.bendable.", "BendableScore;\nimport org.optaplanner.core.api.score.stream.", "ConstraintStream;\nimport org.optaplanner.core.api.solver.", "SolverFactory;\nimport org.optaplanner.core.impl.score.buildin.bendable.", "BendableScoreDefinition;\nimport org.optaplanner.test.api.score.stream.", "ConstraintVerifier;\nimport org.optaplanner.test.impl.score.", "AbstractScoreVerifier;\n\n/**\n * To assert the constraints of a {@link SolverFactory}\n * that uses a {@link BendableScore}.", "\n * If you're using {@link ConstraintStream}s, use {@link ConstraintVerifier} instead.", "\n *\n * @param <Solution_> the solution type, the class with the {@link PlanningSolution} annotation\n */\npublic class BendableScoreVerifier<Solution_> extends AbstractScoreVerifier<Solution_> {\n\n protected final int hardLevelsSize;\n\n /**\n * @param solverFactory never null, the {@link SolverFactory} of which you want to test the constraints.", "\n */\n public BendableScoreVerifier(SolverFactory<Solution_> solverFactory) {\n super(solverFactory, BendableScore.class);\n hardLevelsSize = ((BendableScoreDefinition) scoreDirectorFactory.getScoreDefinition()).getHardLevelsSize();\n }\n\n /**\n * Assert that the constraint of {@link PlanningSolution}\n * has the expected weight for that score level.", "\n *\n * @param constraintName never null, the name of the constraint\n * @param hardLevel {@code 0 <= hardLevel <} {@code hardLevelSize}.", "\n * The {@code scoreLevel} is {@code hardLevel} for hard levels and {@code softLevel + hardLevelSize} for soft levels.", "\n * @param expectedWeight the total weight for all matches of that 1 constraint\n * @param solution never null, the actual {@link PlanningSolution}\n */\n public void assertHardWeight(String constraintName, int hardLevel, int expectedWeight, Solution_ solution) {\n assertHardWeight(null, constraintName, hardLevel, expectedWeight, solution);\n }\n\n /**\n * Assert that the constraint of {@link PlanningSolution}\n * has the expected weight for that score level.", "\n *\n * @param constraintPackage sometimes null.", "\n * When null, {@code constraintName} for the {@code scoreLevel} must be unique.", "\n * @param constraintName never null, the name of the constraint\n * @param hardLevel {@code 0 <= hardLevel <} {@code hardLevelSize}.", "\n * The {@code scoreLevel} is {@code hardLevel} for hard levels and {@code softLevel + hardLevelSize} for soft levels.", "\n * @param expectedWeight the total weight for all matches of that 1 constraint\n * @param solution never null, the actual {@link PlanningSolution}\n */\n public void assertHardWeight(String constraintPackage, String constraintName,\n int hardLevel, int expectedWeight,\n Solution_ solution) {\n assertWeight(constraintPackage, constraintName,\n hardLevel, Integer.valueOf(expectedWeight), solution);\n }\n\n /**\n * Assert that the constraint of {@link PlanningSolution}\n * has the expected weight for that score level.", "\n *\n * @param constraintName never null, the name of the constraint\n * @param softLevel {@code 0 <= softLevel <} {@code softLevelSize}.", "\n * The {@code scoreLevel} is {@code hardLevel} for hard levels and {@code softLevel + hardLevelSize} for soft levels.", "\n * @param expectedWeight the total weight for all matches of that 1 constraint\n * @param solution never null, the actual {@link PlanningSolution}\n */\n public void assertSoftWeight(String constraintName, int softLevel, int expectedWeight, Solution_ solution) {\n assertSoftWeight(null, constraintName, softLevel, expectedWeight, solution);\n }\n\n /**\n * Assert that the constraint of {@link PlanningSolution}\n * has the expected weight for that score level.", "\n *\n * @param constraintPackage sometimes null.", "\n * When null, {@code constraintName} for the {@code scoreLevel} must be unique.", "\n * @param constraintName never null, the name of the constraint\n * @param softLevel {@code 0 <= softLevel <} {@code softLevelSize}.", "\n * The {@code scoreLevel} is {@code hardLevel} for hard levels and {@code softLevel + hardLevelSize} for soft levels.", "\n * @param expectedWeight the total weight for all matches of that 1 constraint\n * @param solution never null, the actual {@link PlanningSolution}\n */\n public void assertSoftWeight(String constraintPackage, String constraintName, int softLevel, int expectedWeight,\n Solution_ solution) {\n assertWeight(constraintPackage, constraintName,\n hardLevelsSize + softLevel, Integer.valueOf(expectedWeight), solution);\n }\n\n}\n" ]

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[ "The mother congregation of Australia's Jewish community has closed its doors to a visiting extremist Israeli politician who has publicly condemned homosexuals and dubbed Palestinians \"bandits\".", "\n\nThe newly-minted chief minister and rabbi of The Great Synagogue in Sydney, Benjamin Elton, said Moshe Feiglin was not welcome.", "\n\n\"He wouldn't be welcome here,\" Dr Elton said.", "\n\n\"I'm absolutely opposed to any sexism, racism or homophobia.\"" ]

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[ "But all that variety and all those decisions can be quite\nintimidating to the unknowing shopper.", "\n\nWith natural stone, knowledge really pays off. ", "And knowledge\ntoday, before you buy, can be invaluable.", "\n\nIt can help you decide which type of natural stone best fits with\nyour home and its activities, which size tile complements your\nroom size and much more.", "\n\nThus this section.", "\n\nIt’s all about things you should be aware of, keep in mind, and\njust plain know, before your shopping phase leads to purchase\ntime.", "\n\nYou won’t see your floor at the neighbors.", "\n\nThe beauty of natural stone is that no two pieces are ever the\nsame.", "\n\nEach piece has its own natural characteristics such as color,\nveining and markings, as well as hardness and porosity. ", "Your\nfloor is truly unique and completely individual. ", "Exclusive.", "\n\nA natural stone tile floor begins with giant pieces of stone that\nare mined from the earth and transported to factories where they\nare cut into thin slabs.", "\n\nEach slab is different, displaying the affects of the physical\ncourse of its ancient history.", "\n\nThe slabs are then cut into individual tiles. ", "Depending solely on\nMother Nature, and Father Time, each tile cut from the same slab\nmight look completely different from the next.", "\n\nVeining and crystallization may be abundant in one, yet\nnon-existent in another.", "\n\nAppearance may vary from tile to tile, but that only adds to the\nelegance, charm and magic of natural stone.", "\n\nWith natural stone you go with the flow.", "\n\nVariations in natural stone are to be expected and, frankly,\nenjoyed.", "\n\nSo the samples you view at our store can have completely\ndifferent veining patterns or color variations compared to the\nstone installed in your home.", "\n\nAlso, please remember that it is not possible for you to hand\nselect your natural stone.", "\n\nYou should be aware that irregular markings, lines, veins and\ncrystallization are not cracks or imperfections, but rather a\nnatural part of the stone’s beauty.", "\n\nThink of them all as forming the “personality” of your floor.", "\n\nAdditionally, if you select a combination of natural stone\nproducts, of the same color and type of stone, for different\nareas of your home, they will not match.", "\n\nAnd no natural stone tile will have a perfectly smooth surface.", "\nEven after the tiles are polished there may be small chips or\npits that may be apparent in different lighting.", "\n\nBeing a natural product, natural stone tiles will vary more in\nthickness, squareness and length compared to man-made ceramic\ntile.", "\n\nAs a result, once your natural stone tile is installed, it will\nnot be a perfectly smooth surface from tile to tile.", "\n\nFinally, natural stone also varies in hardness, which is the\nscratch resistance of a mineral. ", "Talc is the softest mineral and\ndiamond is the hardest.", "\n\nThis is important when picking a stone. ", "Make sure to consider\nwhat types of activities will be taking place where the stone is\ninstalled in your home.", "\n\nFor example, you would not want to install a soft, porous type of\nstone floor in a high traffic area. ", "Our best advice is to consult\nwith us.", "\n\nHard and fast facts about the popular half dozen.", "\n\nTo help you shop smart for natural stone flooring, here’s a\nrundown on six popular stones: granite, marble, limestone,\ntravertine, slate and tumbled stone.", "\n\nGranite is one of the hardest and densest of all natural stone.", "\n\nIn fact, made up of quartz, feldspar and mica, granite is one\nof the hardest stones next to diamond.", "\n\nIt also resists staining and scratching better than any other\nnatural stone due to its density.", "\n\nGranite makes a powerful impact in kitchens, entryways and\nbathrooms, or as an accent with other natural stone tiles.", "\n\nMarble\nis crystallized limestone that comes in many different color\nvariations and usually displays a veining pattern that adds to\nits uniqueness.", "\n\nMarble is a timeless addition to any home, bearing the signs\nand marks of history from thousands of years.", "\n\nMarble is more porous than granite, making it more\nsusceptible to staining and therefore is more suitable for\nyour foyers, bathrooms, fireplaces, studies or libraries.", "\n\nA note to you on marble color. ", "It is important to know that\ngreen and black marbles are not recommended for wet areas of\nthe home, such as a shower.", "\n\nGreen marbles will absorb water and then curl and warp.", "\n\nBlack marbles, when wet, can exhibit “spalling” at veins,\nwhich means small pieces of the stone may break away.", "\n\nLimestone\nhas a more subtle look and is often offered in a “honed” or\nmatte finish.", "\n\nLimestone is created by the accumulation of organic\nmaterials such as shells and coral.", "\n\nThis stone will require preventative maintenance over time,\nas it is very porous.", "\n\nAs it is a softer and more porous stone it may not be\nsuitable for all areas in the home because it will stain\neasily.", "\n\nYou should know that this stone should be sealed to protect\nthe stone’s natural beauty and performance. (", "More on\nsealing below.)", "\n\nTravertine\nis a unique looking stone due to the “fill process”. ", "In its\noriginal form, travertine has thousands of holes running\nthrough it.", "\n\nThese holes are filled and then the stone is polished.", "\nThe stone polishes to a high sheen and the fill areas\nremain dull offering you a unique and beautiful floor.", "\n\nHowever, like limestone, travertine will require you to\nhave preventative maintenance performed over time, due to\nits porosity.", "\n\nSlate,\na rustic-looking stone, has become increasing popular\nover the years.", "\n\nIt comes in various colors and shades in the warm and\nearthy tones.", "\n\nSlate has some of the most dramatic color variations\nfrom tile to tile.", "\n\nColors range from rich reds, oranges and golds, to\nmauve, lavender, green, blue, black, rust and brown.", "\nImagine the possibilities in your home!", "\nSlate tile is extremely durable and can be used in\nindoor and outdoor installations.", "\n\nAll slate has a natural clefting along the surface that\ngives this stone its unique textural look of layers.", "\n\nTumbled Stone has an\nantique look. ", "These tiles come in numerous sizes and\nare many times used in borders or decorative strips.", "\n\nTheir Old World look is recreated through modern means.", "\nPieces of marble, travertine and limestone are tumbled\nand distressed to evoke a timeworn look of stone from\ncenturies past. ", "Perhaps this is the look you’re after.", "\n\nTumbled Stone is often times created into accent\nstrips, mosaics and smaller sizes such as 4” x 4” and\n6” x 6”.", "\n\nThis type of stone is a design element that is both\nrustic and elegant at the same time.", "\n\nKnow this about grout.", "\n\nNatural stone tile grout lines are typically filled\nwith un-sanded grout and are usually much thinner than\nceramic tile installations.", "\n\nGrout can match, contrast or coordinate with your stone\ntile.", "\n\nRemember that grout will outline each tile creating a\nvisual picture frame.", "\n\nIf you want the grout to be less noticeable, select a\ngrout that is close in color to the stone.", "\n\nA contrasting grout color, either darker or lighter,\nwill make the grout lines more visible and thereby will\ncreate a checkerboard effect.", "\n\nGrout colors installed in your home can be slightly\ndifferent from the sample you viewed in our store.", "\n\nThis is due to differences in temperature and humidity\nduring installation.", "\n\nEven when the same grout color is used, it is also\ncommon to see slight differences between the grout used\nfor floor tile in one room and the grout used in an\nadjacent room.", "\n\nExact layouts, type of grout and grout joint widths are\ndetermined by the tile setter at the time of\ninstallation and are governed by the actual size and\nshape of the tile, and the exact dimensions of the\nareas to be covered.", "\n\nSealing is recommended.", "\n\nIt is important to note that sealing of natural stone\nis highly recommended, and that it be performed by a\nseasoned professional.", "\n\nSealing your natural stone flooring makes it less\nporous, more stain resistant, and protects the stone’s\noriginal beauty.", "\n\nThere are different types of sealer depending on your\ntype of stone. ", "We recommend consulting with us about\nsealing your flooring.", "\n\nYou should also be aware that, once your flooring is\ninstalled, you are responsible for maintaining all\ncaulked areas to guard against water damage.", "\n\nGet on top of the bottom line. ", "Know the entire cost of\nownership.", "\n\nThe “cost per square foot” of your natural stone floor\nis just one component of the entire project cost. ", "To\nensure there are no surprises, and the natural stone\nyou select fits within your overall project budget, be\nsure to ask us to calculate the total cost of your\nfloor covering project.", "\n\nHere’s a list of potential additional expenses you may\nincur:\n\nFurniture removal/replacement.", "\n\nDemolition/disposal of old floor covering.", "\nDepending on the existing floor covering, this can be\nan expensive item; also, be sure to include the cost to\ndispose of the old floor covering.", "\n\nSubfloor preparation. ", "Depending on the condition of\nthe subfloor, it may require additional work.", "\n\nCreating Your Space. ", "All Rights Reserved.", "All content and images are the property of Creating Your Space and may not be reproduced or used in any way without the written consent of the owner.", "\nPrivacy Policy" ]

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[ "1.0µg of E.coli in a standard sandwich ELISA. ", "Assay by immunoelectrophoresis resulted in a single precipitin arc against purified and partially purified E.coli beta-galactosidase.", "\n\nGeneral notes\n\nApplication Note: This antibody shows inconsistent results between batches in ICC/IF, IF, IHC-P, IHC-Fr and IHC-FoFr. ", "We have received several good Abreviews on these applications, however, we are unable to guarantee positive results. ", "If the antibody is used for IHC, please try fixing with methanol and block with gelatine instead with BSA or NGS. ", "After each antibody incubation, please wash 5x with TBS instead of PBS.We would recommend ab4761 or ab12081 as alternatives.", "\n\nProperties\n\nForm\n\nLiquid\n\nStorage instructions\n\nShipped at 4°C. ", "Store at +4°C short term (1-2 weeks). ", "Upon delivery aliquot. ", "Store at -20°C or -80°C. ", "Avoid freeze / thaw cycle.", "\n\nApplications\n\nThe application notes include recommended starting dilutions; optimal dilutions/concentrations should be determined by the end user.", "\n\nApplication\n\nAbreviews\n\nNotes\n\nELISA\n\n1/10000.", "\n\nsELISA tested against 1ug E.coli beta galactosidase.", "\n\nWB\n\n1/5000 - 1/10000. ", "Detects a band of approximately 116 kDa.", "\n\nThis antibody shows inconsistent results between batches in ICC/IF, IHC-P, IHC-Fr and IHC-FoFr. ", "We have received several good Abreviews on these applications, however, we are unable to guarantee positive results. ", "If the antibody is used for IHC, please try fixing with methanol and block with gelatine instead with BSA or NGS. ", "After each antibody incubation, please wash 5x with TBS instead of PBS. ", "We would recommend ab4761 or ab12081 as alternatives.", "\n\nIP\n\n1/500 - 1/5000.", "\n\nApplication notes\n\nIs unsuitable for ICC/IF,IHC-FoFr,IHC-Fr or IHC-P.\n\nTarget\n\nRelevance\n\nBeta galactosidase is coded by a gene (lac z) in the lac operon of Escherichia coli. ", "It is a metalloenzyme that splits lactose into glucose and galactose. ", "It hydrolyzes terminal, non-reducing beta-D-galactose residues in beta-D-galactosides.", "\nActivation by cations seems to be substrate dependent. ", "K+, Na+, NH4+, Rb+, Cs+ and Mn++ all activate enzyme activity based upon the substrate used.", "\n\nWestern blotting using ab616. ", "Lane 1 shows 80 ng and lane 2 shows 20 ng loaded onto gel. ", "Results for non-reducing conditions of SDS-PAGE prior to transfer to nitrocellulose are shown on the left side of the figure; results obtainined under reducing conditions are shown on the right. ", "The membrane was probed with ab616 at 1/10,000 dilution.", "\n\nI am very pleased to hear you would like to accept our offer and testab616 and ab15580in ICE. ", "These codes will give you: 1 free primary antibody per code before the expiration date. ", "To redeem this offer, please submit an Abreview for ICE for each antibody and include this code in the “Additional Comments” section so we know the Abreview is for this promotion. ", "Please remember that submission of the Abreview is sufficient for the discount code to become active.", "For more information on how to submit an Abreview, please visit the site: https://www.abcam.com/Abreviews.", "\n\nRemember, we publish both positive and negative Abreviews on our datasheets so please submit the results of your tests. ", "The code will be active once the Abreview has been submitted and can be redeemed in one of the following ways: 1) Call to place your order and mention the code to our customer service department; 2) Include the code in your fax order; 3) Place your order on the web and enter the promotional code.", "\n\nAny feedback that you can provide will be greatly appreciated, whether positive or negative. ", "If you have any further questions, please do not hesitate to contact us. ", "We look forward to receiving your Abreview and wish you luck with your research.", "\n\nThe terms and conditions applicable to this offer can be found here: https://www.abcam.com/collaborationdiscount.", "\n\nThank you for submitting an Abreview for ab616. ", "As you may have noticed, your review has now been published on our website.", "Since you obtained poor results using the antibody in an untested species, we would like to follow up on this to see if we can possibly improve the results you are seeing with this antibody.", "Based on the information in your review, I have a few more questions:1) Did you use the antibody to detect human beta Galactosidase ?", "2) If not, for which application or species was the discount code given?In terms of suggestions:- It might be helpful to compare the resuts obtained with human beta Galactosidase with E.coli beta Galactosidase. ", "If you decide to follow these suggestions, please let me know if they are helpful.", "I wish you good luck with your research.", "\n\nI am sorry to hear you are experiencing difficulties with one of our products. ", "As discussed over the phone, I'd like to try and help you to improve the results currently obtained. ", "In order to do this, could you please fill out the questionnair I have attached to this email. ", "If you could also include some images of the blots obtained that would be very helpful. ", "I understand that you have already performed a lotof optimisation but if you could just briefly outline what you have tried to optimise that would be very helpful.", "\n\nI think it would be worthwhile to try and use the beta Galactosidase protein (ab7981) which you have just to check that there is not a problem with the antibody itself thatare contributing to the poor results.", "\n\nIn answer to you questions in regards to how to use this protein as a control. ", "We recommend reconstituting the protein in a minimum concentration of 1 mg/mL in 0.1 M Sodium/potassium phosphate buffer, pH 7.0. ", "This can be performed as follows:\n\nThe lypolised powder the protein is provided as can be stored at2-8°C but once dissolved it is best to aliquot and freeze stocks at -20C or -80C. We do not have any reconstituted stability data andwould therefore recommend to reconstitute the amount needed for the assay fresh just prior to performing the assay.", "\n\nI would recommend initially loading 0.1 ug in a well to see how well the antibody performs next to your samples. ", "This value may need to be reduced if the signal observed is too strong compared to your lysates.", "\n\nI hope this information has been of help. ", "I look forward to receiving your reply." ]

{ "pile_set_name": "Pile-CC" }

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[ "Q:\n\nSignalR with Self-Signed SSL and Self-Host\n\nTried my luck at research, but so far no joy.", "\nI would like to connect a SignalR javascript client to a self-hosted SignalR Windows Service binding to a self-signed SSL certificate.", "\nMy application works quite well over http, but the client repetitively disconnects when the Owin WebApplication starts using https.", "\nHere is what I've done to configure SignalR with SSL.", "\n\nCreated a Self-Signed certificate using IIS\nImported the certificate into the Trusted Root Certification Authorities in the mmc (not sure if that helped)\nRan NETSH command to bind SSL to port 8080 \nnetsh http add sslcert ipport=0.0.0.0:8080 certhash=123456f6790a35f4b017b55d09e28f7ebe001bd appid={12345678-db90-4b66-8b01-88f7af2e36bf}\n\nAdded code in self-hosted HubConnection instances to add exported SSL like this (though this shouldn't matter because it's the client that cannot connect): \nif (File.", "Exists(\"MyCert.cer\") \n && Settings.", "GetSetting(Settings.", "Setting.", "SrProtocol).Equals(\"https\", StringComparison.", "InvariantCultureIgnoreCase))\n connection.", "AddClientCertificate(X509Certificate.", "CreateFromCertFile(\"MyCert.cer\"));\n\nStarting Owin WebApplication using https (this should create the binding in http.sys)\nstring registerUrl = string.", "Format(\"{0}://SOME.WHERE.COM:{1}\", Service.", "Server.", "SrProtocol, Service.", "Server.", "SrPort);\nWebApp.", "Start<StartUp>(registerUrl);\n\nIn the SignalR 2.0 documentation, it says:\n\nTo start the web server, call WebApplication.", "Start(endpoint). ", "You should now be able to navigate to endpoint/signalr/hubs in your browser.", "\n\nWhen I browse to the URL http://SOME.WHERE.COM:8080/signalr/hubs I am successful receiving the javascript that drives SignalR.\nWhen I browse to the URL https://SOME.WHERE.COM:8080/signalr/hubs I am unsuccessful and I receive \"The connection to the server was reset\" using FF.", "\nSome additional points I've considered:\n\nNETSH SHOW indicates the url is registered\nURL group ID: E300000240000022\nState: Active\nRequest queue name: Request queue is unnamed.", "\nProperties:\n Max bandwidth: inherited\n Max connections: inherited\n Timeouts:\n Timeout values inherited\n Number of registered URLs: 1\n Registered URLs: HTTPS://SOME.WHERE.COM:8080/\n\nNETSH SHOW indicates the SSL certificate is bound to 8080:\nIP:port : 0.0.0.0:8080 \nCertificate Hash : 123456f6790a35f4b017b55d09e28f7ebe001bd\nApplication ID : {12345678-db90-4b66-8b01-88f7af2e36bf} \nCertificate Store Name : (null) \nVerify Client Certificate Revocation : Enabled\nVerify Revocation Using Cached Client Certificate Only : Disabled\nUsage Check : Enabled\nRevocation Freshness Time : 0 \nURL Retrieval Timeout : 0 \nCtl Identifier : (null) \nCtl Store Name : (null) \nDS Mapper Usage : Disabled\nNegotiate Client Certificate : Disabled\n\nAny help is greatly appreciated!", "\n\nA:\n\nI believe its all working for me now. ", " Here is a run down of the steps I took to get things flowing:\nSSL NOTES\nSSL & SignalR (Owin WebApplication) requires binding a certificate to a port.", "\n\nUse IIS to generate an self-signed cert, this should place the certificate into the LOCAL COMPUTER > Personal > Certificates folder in CERTMGR\nIn CERTMGR shift+drag certificate to LOCAL COMPUTER > Trusted Root Certification Authorities > Certificates folder, which should make a copy of it there\nRun the following command to bind the SSL certificate to 0.0.0.0:8080 \nnetsh http add sslcert ipport=0.0.0.0:8080 certhash=123456f6790a35f4b017b55d09e28f7ebe001bd appid={12345678-db90-4b66-8b01-88f7af2e36bf} \nnetsh http show urlacl > D:\\urlacl.txt\n\nOutput:\nReserved URL : https://*:8080/ \nUser: SOMEWHERE\\Administrator\nListen: Yes\nDelegate: No\nSDDL: D:(A;;GX;;;S-1-5-21-138209071-46972887-2260295844-1106) \n\nRun the following NETSH command to reserve all IP addresses for port 8080 to the My Service application ID and service account\nnetsh http add urlacl url=https://*:8080/ user=SOMEWHERE\\Administrator listen=yes\nnetsh http show sslcert > D:\\sslcert.txt\n\nOutput:\nIP:port : 0.0.0.0:8080 \nCertificate Hash : 123456f6790a35f4b017b55d09e28f7ebe001bd\nApplication ID : {12345678-db90-4b66-8b01-88f7af2e36bf} \nCertificate Store Name : (null) \nVerify Client Certificate Revocation : Enabled\nVerify Revocation Using Cached Client Certificate Only : Disabled\nUsage Check : Enabled\nRevocation Freshness Time : 0 \nURL Retrieval Timeout : 0 \nCtl Identifier : (null) \nCtl Store Name : (null) \nDS Mapper Usage : Disabled\nNegotiate Client Certificate : Disabled\n\nUpdate the MyServices.exe.config file to use https protocol (These are appSetting keys used to dynamically set the protocol and port of SignalR when My Service starts)\n<add key=\"SrProtocol\" value=\"https\" />\n<add key=\"SrPort\" value=\"8080\" />\n\nStart the My Service using the NETSTAT START command\nRun the following NETSH command to show the service state is occupying the registered url\nnetsh http show servicestate > D:\\servicestate.txt\n\nOutput:\nServer session ID: C300000320000039\nVersion: 2.0\nState: Active\nProperties:\n Max bandwidth: 4294967295\n Timeouts:\n Entity body timeout (secs): 120\n Drain entity body timeout (secs): 120\n Request queue timeout (secs): 120\n Idle connection timeout (secs): 120\n Header wait timeout (secs): 120\n Minimum send rate (bytes/sec): 150\nURL groups:\nURL group ID: C600000340000138\n State: Active\n Request queue name: Request queue is unnamed.", "\n Properties:\n Max bandwidth: inherited\n Max connections: inherited\n Timeouts:\n Timeout values inherited\n Number of registered URLs: 1\n Registered URLs:\n HTTPS://*:8080/\n\nMy application does NOT depend on IIS, but once I used IIS to temporarily create a port binding to my SSL certificate, my application started to work, and I was able to inspect the NETSH servicestate to see how IIS does it. ", " I have since dropped the IIS binding and ran through the setup notes, and still have success.", "\nMy Owing startup looks somethign like this:\nprivate void configureMessaging()\n{\n string registerUrl = string.", "Format(\"{0}://*:{1}\", Service.", "Server.", "SrProtocol, Service.", "Server.", "SrPort);\n\n try\n {\n#if DEBUG\n //System.", "Diagnostics.", "Debugger.", "Launch();\n#endif\n // Starts an owin web application to host SignalR, using the protocol and port defined.", "\n WebApp.", "Start<StartUp>(registerUrl);\n }\n catch (Exception ex)\n {\n Logger.", "Logs.", "Log(string.", "Format(\"Failed to configure messaging. ", " Exception: {0}\", ex.", "RecurseInnerException()), LogType.", "Error); \n\n if (ex is HttpListenerException || ex.", "InnerException is HttpListenerException)\n {\n try\n {\n Process p = new Process();\n p.StartInfo.", "UseShellExecute = false;\n p.StartInfo.", "RedirectStandardOutput = true;\n p.StartInfo.", "FileName = \"netsh.exe\";\n p.StartInfo.", "Arguments = string.", "Format(\"netsh http delete urlacl url={0}\"\n , registerUrl\n );\n p.Start();\n p.StandardOutput.", "ReadToEnd();\n p.WaitForExit();\n }\n catch (Exception exP)\n {\n Logger.", "Logs.", "Log(string.", "Format(\"Failed to delete urlacl {0}. ", " Exception: {1}\"\n , registerUrl\n , exP.RecurseInnerException()\n )\n , LogType.", "Error\n )\n ;\n\n retries = 5;\n }\n }\n\n if (retries < 5)\n {\n retries++;\n\n Logger.", "Logs.", "Log(string.", "Format(\"Attempting to configure messaging again. ", " Attempt No. {", "0}\", retries), LogType.", "Warn);\n\n Thread.", "Sleep(1000);\n\n configureMessaging();\n }\n else\n Logger.", "Logs.", "Log(string.", "Format(\"Exceeded total number of retries to configure messaging.\", ", "retries), LogType.", "Error);\n\n }\n\n}\nAnd self-hosted HubConnetion instances look like this:\n public IHubProxy MyHubProxy\n {\n get\n {\n if (this._MyHubProxy == null)\n {\n var connection = new HubConnection(string.", "Format(\"{0}://{1}:{2}/\"\n , Settings.", "GetSetting(Settings.", "Setting.", "SrProtocol)\n , MyHub.", "GetLocalhostFqdn(null)\n , Settings.", "GetSetting(Settings.", "Setting.", "SrPort)\n )\n )\n ;\n this._MyHubProxy = connection.", "CreateHubProxy(\"MyHub\");\n\n if (File.", "Exists(\"My.cer\")\n && Settings.", "GetSetting(Settings.", "Setting.", "SrProtocol).Equals(\"https\", StringComparison.", "InvariantCultureIgnoreCase))\n connection.", "AddClientCertificate(X509Certificate.", "CreateFromCertFile(\"My.cer\"));\n\n connection.", "Start().Wait();\n }\n\n return this._MyHubProxy;\n }\n }\n\nThere is a little more code here than relevant, but hopefully it may be of help!", "\n\n" ]

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[ "Story highlights Republican Party's platform is against same-sex marriage\n\nLog Cabin Republicans invited to take part in convention for first time\n\nSome GOP groups that support LGBT community emphasize other issues\n\nA man hurrying to catch the light at a corner in muggy downtown Tampa carries a book with a rainbow of color on its cover.", "\n\nIts title stands out, especially here, where the Republican National Convention has officially accepted a platform that a New York Times editorial called \"more aggressive in its opposition to women's reproductive rights and to gay rights than any in memory.\"", "\n\nThe book is \"A Fundamental Freedom: Why Republicans, Conservatives, and Libertarians Should Support Gay Rights.\"", "\n\nTed McCormac is a precinct committee person for the GOP in Bradenton, Florida, and the father of a gay son. ", "He picked up the book at a brunch co-hosted by the Young Conservatives for the Freedom to Marry and the Log Cabin Republicans -- two of a small number of visible LGBT-supportive Republican groups at this year's convention.", "\n\nPhotos: Unconventional: Postcards from Tampa Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Confetti remains on the floor of the Republican National Convention after presidential nominee Mitt Romney delivered his acceptance speech on Thusday, August 30. ", "Photographer Zoran Milich wandered around Tampa this week during the convention. ", "Look back at his view of the action. ", "Hide Caption 1 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A reflection of the National Debt Clock is seen as Mitt Romney speaks on the last night of the convention. ", "Hide Caption 2 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Balloons and confetti drop after Romney's speech. ", "Hide Caption 3 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A Mitt Romney cutout rides in the front seat of a van advertising a \"nude lounge\" during the Republican National Convention on Thursday. ", "Hide Caption 4 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Texas delegate Read King kisses his son Benjamin on Thursday. ", "Hide Caption 5 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Californian Kaden Tollestrup, great-nephew of Mitt Romney, strikes a pose for his family on the floor of the convention. ", "Hide Caption 6 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – DeLeon Sheffield photographs balloons set to fall from the roof during Thursday night's closing performance with her ensemble with BeBe Winans. ", "Hide Caption 7 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A worker cleans the convention hall on Thursday, the morning after Paul Ryan's speech. ", "Hide Caption 8 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – The debt clock is on display in the convention hall. ", "Hide Caption 9 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A sign marking the Ohio delegation sits on empty seats on the floor of the convention hall. ", "Hide Caption 10 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Former Minnesota Gov. Tim Pawlenty's speech at the convention is televised at a pizza bar in Tampa's Ybor City district on Wednesday, August 29. ", "Hide Caption 11 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – People try on hats at Riverside Park in Tampa on Wednesday, August 29. ", "Hide Caption 12 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A protester sits in his car in Ybor City. ", "During a summer road trip, Republican presidential nominee Mitt Romney once put his family dog in a cage and perched it atop the family car. ", "Hide Caption 13 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Alfred Moreno rolls a cigar in Ybor City, a historic neighborhood in Tampa known for its nightlife. ", "Hide Caption 14 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A Romney cutout is wrapped with the American flag on the floor of the convention. ", "Hide Caption 15 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Romney cookies are sold outside the convention center where protesters are gathered. ", "Hide Caption 16 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A new sign is brought in to be set up in the convention center. ", "Hide Caption 17 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A phone labeled \"Moscow\" sits in the press center at the Republican National Convention. ", "Hide Caption 18 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Texas delegates sit on the floor of the Republican National Convention on Tuesday, August 28. ", "Hide Caption 19 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A Mitt Romney supporter rests her feet after a long day at the Republican National Convention. ", "Hide Caption 20 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – California delegate Don Genhart shows off his American flag cowboy boots. ", "Hide Caption 21 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Lighters are confiscated during security checks at the Republican National Convention. ", "They can be reclaimed upon exiting. ", "Hide Caption 22 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Washington state delegates Trin Wilbur and Jeff McMorris dance on the convention floor. ", "Hide Caption 23 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Jaclyn Tupek wears a Lady Liberty hat at a Ron Paul gathering a few blocks from the Tampa Bay Times Forum. ", "Hide Caption 24 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Ron Paul supporters hold hands at a rally for the only challenger to Mitt Romney who has not conceded. ", "Hide Caption 25 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Mitt Romney's motorcade arrives in Tampa as the Republican National Convention gets under way. ", "Hide Caption 26 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A painting of former President Ronald Reagan sits in a hallway at the Embassy Suites in Tampa, where many Republicans are staying during the convention. ", "Hide Caption 27 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – New Jersey Gov. Chris Christie casts a shadow on a Romney/Ryan campaign sign while speaking to delegates from Michigan. ", "Christie will deliver the convention's keynote address Tuesday night. ", "Hide Caption 28 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Tampa security forces line up to block a small group of demonstrators on Monday, August 27. ", "Hide Caption 29 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Texas delegates Jason Kute and Stephanie Traska hang on to their hats in the windy Florida city. ", "Hide Caption 30 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Riot police walk through the rainy streets of Tampa on Monday. ", "Hide Caption 31 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A shirtless protester stands in the rain in front of a police line. ", "Hide Caption 32 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – One of many message-covered vehicles drives through the streets of Tampa. ", "Hide Caption 33 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Images of Romney appear on the podium Monday at the gavel opening of the RNC. ", "Hide Caption 34 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Actor and active Republican Jon Voight arrives at the Tampa Bay Times Forum on Monday. ", "Hide Caption 35 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – An electrician at the Tampa Bay Times Forum fixes a light as a limo driver awaits Republican delegates. ", "Hide Caption 36 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Republicans attend the gavel opening Monday. ", "The full proceedings of the first day were canceled because of Tropical Storm Isaac. ", "Hide Caption 37 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Republican Allen Johnson of Texas watches the gavel opening. ", "The seven-minute session went into recess until Tuesday. ", "Hide Caption 38 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A billboard opposing Mitt Romney stands among palm trees Monday. ", "Hide Caption 39 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Former Republican presidential candidate Herman Cain, left, with support from his assistant, signs a photograph of himself for political fan Kieth Klickna. ", "Hide Caption 40 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Hand puppets of Mitt Romney, Newt Gingrich and Ron Paul are for sale in Tampa. ", "Hide Caption 41 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Christine Gill from Alaska poses for a picture at a party Sunday, August 26, at Tampa's Tropicana Field. ", "Hide Caption 42 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Convention-goers gather at Tropicana Field for a convention opening party Sunday night. ", "Hide Caption 43 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Larry Mazza of the local carpenters union cleans up wood chips at the Tampa Bay Times Forum. ", "Hide Caption 44 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Mark Anthoney sells buttons for Mitt Romney supporters on Sunday, August 26. ", "Hide Caption 45 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A T-shirt bashing President Barack Obama and the Democratic Party mimics the logo of \"The Sopranos,\" a television series revolving around a fictional Mafia family. ", "Hide Caption 46 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – The teleprompter is tested Sunday at the Tampa Bay Times Forum. ", "Hide Caption 47 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Storm clouds brew Saturday over the Lightning statue in Tampa. ", "As Tropical Storm Isaac (now a hurricane) drew closer, officials decided to push back Monday's scheduled start of the RNC by one day. ", "The storm took a westward path, however. ", "Hide Caption 48 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Mounted police horses from across Florida gear up for the convention. ", "Hide Caption 49 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A pro-Ron Paul Corvette cruises the streets of Tampa. ", "Hide Caption 50 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A Great Dane, Dora, is held back as she jumps for the table during a Dogs Against Romney protest on Sunday. ", "Hide Caption 51 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Young men visiting the convention center run in the rain. ", "Hide Caption 52 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – A chalk message is left by protesters a few blocks from the Tampa Bay Times Forum. ", "Hide Caption 53 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – House band leader G.E. Smith arrives at the convention center Saturday with a pair of guitars. ", "Hide Caption 54 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Conversion tech Kevin Losier carries a recycling bin shaped like a bottle of Coke. ", "Hide Caption 55 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – As Tropical Storm Isaac loomed on Saturday, laborers awaited a decision on whether to tear down tents or continue building them. ", "Hide Caption 56 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Motorcyclists roll into Tampa on Saturday. ", "Hide Caption 57 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Brett Burge removes the vision block on a fence Saturday because of the threat of Tropical Storm Isaac. ", "Hide Caption 58 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – Pro-Democratic Party advertisements move through Tampa ahead of the Republican National Convention. ", "Hide Caption 59 of 60 Photos: Unconventional: Postcards from Tampa Unconventional: Postcards from Tampa – The Original Hooters restaurant welcomes the RNC. ", "Hide Caption 60 of 60\n\nIndividual members of the Log Cabin Republicans have attended previous conventions, but this year marks a first for the group: It was invited by the Republican National Convention committee to participate in the convention itself. ", "In addition, there are many high-profile, gay-themed events this year, including the brunch McCormac attended. \"", "I've never been to an event of theirs, but people clearly went out of their way to be nice to me,\" McCormac said, with a catch in his voice. \"", "It means so much since I'm kind of new at this.\"", "\n\nPhotos: Republican convention: The best photos Photos: Republican convention: The best photos Republican convention: The best photos – Presidential candidate Mitt Romney delivers his acceptance speech on the final day of the Republican National Convention at the Tampa Bay Times Forum on Thursday, August 30. ", "See the best photos from the Democratic National Convention. ", "Hide Caption 1 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Attendees celebrate as confetti and balloons drop after Romney's speech. ", "Hide Caption 2 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Romney and vice presidential candidate Paul Ryan take the stage with their families at the end of the night. ", "Hide Caption 3 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – People bow their heads for the benediction to wrap up the GOP convention. ", "Hide Caption 4 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Romney and Ryan wave to the audience after Romney's speech, which described a future of opportunity and promise for the nation. ", "Hide Caption 5 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Romney greets supporters as he enters the arena Thursday. ", "Hide Caption 6 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Florida Sen. Marco Rubio introduces Romney after his speech. ", "Hide Caption 7 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Delegates wave signs on the final day of the RNC. ", "Hide Caption 8 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Actor Clint Eastwood speaks as a surprise guest. ", "Hide Caption 9 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Mitt Romney's wife, Ann, and son Josh sit in the VIP box. ", "Hide Caption 10 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Former Florida Gov. Jeb Bush speaks on stage. ", "Hide Caption 11 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A man holds an American flag in the audience. ", "Hide Caption 12 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Pam Finlayson speaks during the convention. ", "Hide Caption 13 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Jane Edmonds, the former Massachusetts secretary of workforce, delivers remarks. ", "Hide Caption 14 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Olympians and gold medalists Michael Eruzione, Derek Parra and Kim Rhode stand on stage at the convention. ", "Hide Caption 15 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A woman clasps her hands during the program. ", "Hide Caption 16 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Former Speaker of the House Newt Gingrich and his wife, Callista, speak during a tribute to former president Ronald Reagan on Thursday. ", "Hide Caption 17 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Callista and Newt Gingrich take the stage during the final day of the Republican National Convention. ", "Hide Caption 18 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Delegates listen to the national anthem at the Tampa Bay Times Forum. ", "Hide Caption 19 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Texas Gov. Rick Perry applauds during the final day of the convention. ", "Hide Caption 20 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – U.S. Rep. Connie Mack, R-Florida, speaks on stage during the final day. ", "Hide Caption 21 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Law enforcement officials work to free protesters with Earth First, who had connected themselves to each other in front of the Big Bend TECO Power Station in Apollo Beach, Florida. ", "Substantially fewer protesters took to the downtown Tampa streets Thursday. ", "Hide Caption 22 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – GOP vice presidential nominee Paul Ryan addresses the Republican National Convention on Wednesday night. ", "Hide Caption 23 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Paul Ryan's wife, Janna, is flanked by her sons Charlie, left, and Sam during Ryan's keynote address Wednesday night. ", "Hide Caption 24 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A woman grasps her hands during speeches on the third day of the GOP convention. ", "Hide Caption 25 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Paul Ryan and his wife and children exit the stage after the biggest speech of his political career. ", "Hide Caption 26 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Former Secretary of State Condoleezza Rice speaks at the Tampa Bay Times Forum on Wednesday. ", "She accused President Barack Obama of yielding the nation's leadership role in the world. ", "Hide Caption 27 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – George Engelbach, dressed as President Abraham Lincoln, attends the GOP convention. ", "Hide Caption 28 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Mike Huckabee, a Republican candidate in the 2008 presidential primaries, backs his one-time rival Mitt Romney. ", "Hide Caption 29 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A woman snaps an image with her iPhone during Wednesday night's events. ", "Hide Caption 30 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Former Minnesota Gov. Tim Pawlenty takes the convention stage. ", "Hide Caption 31 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Delegate Carlos Mendez of Puerto Rico watches Wednesday night's program. ", "Hide Caption 32 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – New Mexico Gov. Susana Martinez delivers remarks. ", "Her speech emphasized her belief in the American Dream. ", "Hide Caption 33 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Delegate Crystal Berg of Hartford, Wisconsin, cries while watching the George H.W. Bush tribute Wednesday night. ", "Hide Caption 34 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Arizona Sen. John McCain, who was the 2008 Republican presidential nominee, speaks to the audience. ", "Hide Caption 35 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – As Sen. John McCain speaks, some audience members display happy birthday posters. ", "Hide Caption 36 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Sen. John McCain, who was a POW during the Vietnam War, addresses the crowd. ", "Hide Caption 37 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Senate Minority Leader Mitch McConnell of Kentucky speaks during the third day of the Republican National Convention. ", "Hide Caption 38 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Col.", "Oscar Poole of Georgia puts his arm around Wisconsin Gov. Scott Walker. ", "Hide Caption 39 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Sen. Rand Paul of Kentucky speaks during the third day of the Republican National Convention. ", "His father, U.S. Rep. Ron Paul of Texas, was one of the hopefuls for the 2012 nomination. ", "Hide Caption 40 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Former President George W. Bush is shown on the giant screens at the Tampa Bay Times Forum. ", "Hide Caption 41 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A woman gestures during the third day of the Republican National Convention. ", "Hide Caption 42 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Rosemary Edwards of Austin, Texas, kisses the face of Texas Gov. Rick Perry. ", "Hide Caption 43 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Sen. John Thune of South Dakota speaks during the third day of the Republican National Convention. ", "Hide Caption 44 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A woman holds a campaign sign. ", "Hide Caption 45 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Sen. Rob Portman of Ohio speaks at the podium. ", "Hide Caption 46 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Delegates from Maine and supporters of Republican presidential candidate Ron Paul chant \"As Maine goes, so goes the nation\" after they staged a walkout at the Tampa Bay Times Forum. ", "Hide Caption 47 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Paul Ryan speaks during a soundcheck Wednesday. ", "Hide Caption 48 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Ryan waves with daughter, Liza Ryan, and sons, Charlie Ryan, right, and Sam Ryan from the stage during a soundcheck. ", "Hide Caption 49 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Republican presidential candidate Mitt Romney exits a vehicle before boarding his campaign plane. ", "As the Republican National Convention continues, Romney will travel to Indianapolis to address the American Legion. ", "Hide Caption 50 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Laura Bowman accepts Bradley Thompson's proposal on the stage. ", "Thompson is a production manager and Bowman is a production coordinator for the convention. ", "Hide Caption 51 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Arizona Sen. John McCain walks the floor. ", "Hide Caption 52 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Bradley Thompson kneels down to propose to Laura Bowman, who accepted, on the stage. ", "Hide Caption 53 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Journalists and media work the third day of the Republican National Convention. ", "Hide Caption 54 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Ryan gives the thumbs-up during a sound check at the Tampa Bay Times Forum. ", "Hide Caption 55 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Ann Romney, Republican presidential candidate Mitt Romney's wife, greets a crowd of supporters on Tuesday. ", "Hide Caption 56 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Mitt Romney joins his wife on stage shortly after she addressed the Republican National Convention at the Tampa Bay Times Forum on Tuesday, August 28. ", "Hide Caption 57 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – New Jersey Gov. Chris Christie delivers the keynote address to wrap up the first full night of the convention. ", "Hide Caption 58 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Republican presidential candidate Mitt Romney sits between his wife, Ann, and former U.S. Secretary of State Condoleezza Rice during Gov. Chris Christie's speech. ", "Hide Caption 59 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Concluding the first night of speech, Chris Christie declared Republicans were willing to face the tough issues and find solutions that work. ", "Hide Caption 60 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Delegates watch Gov. Chris Christie deliver the keynote address. ", "Hide Caption 61 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A delegate snaps a photograph of Chris Christie just before his speech. ", "Hide Caption 62 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – As the crowd cheers, Mitt Romney embraces his wife, Ann, on stage during the convention. ", "Hide Caption 63 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – An excerpt from Ann Romney's speech is displayed on a teleprompter Tuesday. ", "She repeatedly referred to her first date with Mitt Romney in urging Americans to trust him to fix the nation's problems. ", "Hide Caption 64 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A veteran claps during Ann Romney's speech. ", "Hide Caption 65 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Ann Romney addresses the crowd in the biggest political speech of her life. ", "She concluded by declaring \"you can trust Mitt.\" ", "Hide Caption 66 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Former Republican presidential candidate Rick Santorum addresses the crowd Tuesday. ", "Hide Caption 67 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Leslie Jones of Virginia Beach, Virginia, wears a hat with tea bags attached. ", "Hide Caption 68 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Ohio Gov. John Kasich waves as he takes the stage. ", "Hide Caption 69 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Former Speaker of the House Newt Gingrich walks the floor. ", "Hide Caption 70 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – American pop opera singer Neal E. Boyd performs at the Tampa Bay Times Forum. ", "Hide Caption 71 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – American country and gospel vocal quartet Oak Ridge Boys perform. ", "Hide Caption 72 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Texas Solicitor General Ted Cruz, who is running for the U.S. Senate, speaks. ", "Hide Caption 73 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – South Carolina Gov. Nikki Haley waves on stage. ", "Hide Caption 74 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Former U.S. Rep. Artur Davis speaks. ", "He changed his party affiliation from Democrat to Republican earlier this year. ", "Hide Caption 75 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Delegates crowd the floor after the tallying of votes during the roll call for nomination of president of the United States at the Tampa Bay Times Forum. ", "Hide Caption 76 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Delegates display signs in support of Mitt Romney after the tallying of votes during the roll call for nomination of president of the United States. ", "Hide Caption 77 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Scott Romney, brother of Republican presidential candidate Mitt Romney, cheers during the roll call. ", "Hide Caption 78 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – People cheer as the screen displays \"Over The Top\" during the roll call of delegates. ", "Hide Caption 79 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Supporters flash posters supporting Republican presidential candidate Mitt Romney at the Tampa Bay Times Forum. ", "Hide Caption 80 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – People hold signs that say \"Mitt!\" ", "as U.S. Speaker of the House Rep. John Boehner, R-Ohio, speaks. ", "Hide Caption 81 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Delegates from host state Florida face photographers and cameras as they pose for the official convention photograph. ", "Hide Caption 82 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A delegate takes a picture of the floor at the Tampa Bay Times Forum. ", "Hide Caption 83 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Ann Romney, Republican presidential candidate former Massachusetts Gov. Mitt Romney's wife, stands onstage with stage manager Howard Kolins during a soundcheck. ", "Hide Caption 84 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – People from the Texas delegation say the Pledge of Allegiance. ", "Hide Caption 85 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A delegate from Wisconsin sports a cheese hat at the Tampa Bay Times Forum. ", "Hide Caption 86 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Ann Romney leans on a seat aboard the campaign plane en route to Tampa. ", "Hide Caption 87 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Karl Rove, former deputychief of staff and senior policy adviser to President George W. Bush, talks on a phone at the convention hall. ", "Hide Caption 88 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Republican candidate Ron Paul waves to supporters at the Tampa Bay Times Forum. ", "Hide Caption 89 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A woman cheers during the second day of the Republican National Convention. ", "Hide Caption 90 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A delegate checks out the convention floor before other delegates arrive at the Tampa Bay Times Forum. ", "Hide Caption 91 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A convention attendee carries a bag with a Time magazine featuring Mitt Romney on the cover. ", "Hide Caption 92 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A participant walks the convention floor before the start of proceedings Tuesday. ", "Organizers pushed events back a day because of concerns about Isaac. ", "Hide Caption 93 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – The Republican National Convention officially began Monday, August 27, but the bulk of the action was delayed until Tuesday. ", "Hide Caption 94 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A woman captures the goings-on with her phone before the start of the shortened first day of the Republican National Convention. ", "Hide Caption 95 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – The chairman of the Republican National Committee, Reince Priebus, convenes the convention with a bang of a gavel. ", "Hide Caption 96 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Priebus raises the gavel as he convenes the Republican National Convention. ", "Hide Caption 97 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Lynne David walks behind a group of law enforcement officers as they patrol the streets before the convention. ", "Hide Caption 98 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – New Jersey Gov. Chris Christie walks through the convention center before the start of the abbreviated first day. ", "Hide Caption 99 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Last-minute adjustments are made to the main stage at the Tampa Bay Times Forum on the abbreviated first day of the GOP convention. ", "Hide Caption 100 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – An elephant logo is featured on the side of a tent outside of the Republican National Convention at the Tampa Bay Times Forum. ", "Hide Caption 101 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Two convention-goers wear plastic bags as shelter from the rain caused by Tropical Storm Isaac. ", "Hide Caption 102 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A man reads a newspaper in the empty seats of the Tampa Bay Times Forum. ", "Hide Caption 103 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Former New Hampshire Gov. John Sununu, left, stands at the podium with stage manager Howard Kolins before events begin Monday. ", "Hide Caption 104 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Men wearing cowboy hats stand on the arena floor before the start of the abbreviated first day. ", "Hide Caption 105 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Convention staff hang a Romney-Ryan sign at the Tampa Bay Times Forum on Sunday, August 26, in preparation for the Republican National Convention. ", "Hide Caption 106 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A tribute to NASA astronaut Neil Armstrong, who died Saturday, August 25, is displayed at the GOP convention as preparations continue. ", "Hide Caption 107 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Donald Trump, who accepted the Statesman of the Year Award from the Sarasota County Republican Party, answers questions in Sarasota, Florida. ", "Hide Caption 108 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – A microphone is in place at the front of the convention hall in Tampa. ", "Hide Caption 109 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Former Republican presidential candidate Ron Paul speaks in the Sun Dome at the University of South Florida in Tampa on Sunday. ", "Hide Caption 110 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Activists hold signs mocking President Barack Obama at the Tea Party Unity Rally at The River at Tampa Bay Church. ", "Hide Caption 111 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Police officers question protesters carrying an effigy of Republican Party presidential candidate Mitt Romney during a demonstration in downtown Tampa. ", "Hide Caption 112 of 113 Photos: Republican convention: The best photos Republican convention: The best photos – Rachel Bolch Thach tries to shelter herself from the rain in Tampa. ", "Tropical Storm Isaac is expected to bring rain and wind to the area and has caused convention officials to delay the start of the convention until Tuesday. ", "Hide Caption 113 of 113\n\nIn fact, Sarah Longwell, a Log Cabin board member and one of the speakers at the brunch, began her speech by talking about McCormac. ", "She said she teared up when she met McCormac there and he told her how proud he and his wife are of their son, Tony.", "\n\nJUST WATCHED Social issues and the GOP Replay More Videos ... MUST WATCH Social issues and the GOP 01:53\n\nTony McCormac is getting married to Jeff Cook, who was also there working on behalf of American Unity, a political action committee that supports Republican candidates who are gay friendly. ", "Cook is so involved in Republican politics that they've scheduled their ceremony In New York after the November election.", "\n\n\"That's what this is all about -- events where we can talk to Republicans about why marriage matters for our community, conservative to conservative,\" Longwell said.", "\n\nLongwell's own engagement is so new she still stumbles a little when she describes Karen Bencala as her \"fiancee.\" ", "But her message about why conservatives should back same-sex marriage comes through loud and clear. ", "She shared it Wednesday with all the Republicans gathered for the convention in the form of a full-page ad in the Tampa Tribune, paid for by the Log Cabin and Young Conservatives for the Freedom to Marry.", "\n\nThe ad shows several photos of same-sex couples smiling under a quote from Tony Perkins, president of the Family Research Council, a Christian right think tank that is far from gay friendly. ", "In his argument that successfully added anti-same sex marriage language to the party's platform, Perkins said, \"The institution of marriage is the foundation of civil society. ", "Its success as an institution will determine our success as a nation.\"", "\n\nLongwell's ad goes on to say the LGBT Republican groups agree with Perkins, which is why the government should stop denying marriage licenses to gay couples. \"", "The freedom to marry is directly in line with the core ideals and principles of the Republican Party -- less government, more individual freedom, personal responsibility and the importance of freedom,\" it argues.", "\n\n\"What I want to ask Tony Perkins if I see him here is, 'If you believe marriage is the very foundation of society, why would you deny us this right?' \" ", "Longwell said. \"", "I honestly believe it's cruel to deny us this. ", "If you believe we are real people, that is.\"", "\n\nAs she finishes speaking, Longwell recognizes a man from the Family Research Council riding an escalator into the carefully secured convention center and wonders whether she could catch up with him.", "\n\nUntil this year, Longwell may not have had the credentials to follow him into those secured areas, at least not as a Log Cabin Republican. ", "One of the Log Cabin's former directors says this is the first year the RNC has credentialed the group and saved rooms for its members in official hotel space.", "\n\nBob Kabel says the evolution of the roles that openly gay people play at the convention -- and in the party itself -- has been remarkable. ", "Kabel was the chairman of the Log Cabin Republicans from 1993 to 1999. ", "He went on to be elected the first openly gay person in the nation to chair a state Republican Party, in the District of Columbia. ", "Early on, he says, he felt forced to stand up at a public meeting and shame the Republican National Convention chair into an official meeting with Log Cabin.", "\n\n\"The current RNC leadership has been much better. ", "They've been great,\" Kabel said. \"", "We feel so much more welcome, and the voices of the Tony Perkinses in the party will be drowned out as more young people come into the party. ", "This is not a negative issue for young people in our party. ", "And we are more visible than ever.\"", "\n\nProof of his statement was visible Tuesday at a GOProud dance party called \"Homocon,\" where many young gay and straight convention danced in the shadow of buff go-go dancers wearing the LGBT group's \"freedom is fabulous\" T-shirts. ", "At the door on the way out of the event, attendees received a convention collector's item -- a keychain with the GOProud logo.", "\n\nLate into the evening, GOProud co-founder Jimmy LaSalvia hushed the dancing crowd for a moment. ", "He described how proud he was that his was the first gay GOP group to endorse this Republican presidential ticket -- even if he personally disagreed with Mitt Romney and Paul Ryan's stance against same-sex marriage. ", "To him, the gay community is so mainstream within the party that GOProud shouldn't solely be about gay issues.", "\n\n\"As most of you know, I support civil marriage for gay couples,\" LaSalvia said, which drew a smattering of supportive shouts from the crowd. \"", "And marriage is important. ", "But before you get married, you need a date. ", "And everybody knows you can't get a date without a job.\"" ]

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[ "using System;\nusing System.", "Collections.", "Generic;\nusing System.", "Linq;\nusing System.", "Reflection;\nusing System.", "Runtime.", "InteropServices;\n\nusing ILRuntime.", "CLR.TypeSystem;\nusing ILRuntime.", "CLR.Method;\nusing ILRuntime.", "Runtime.", "Enviorment;\nusing ILRuntime.", "Runtime.", "Intepreter;\nusing ILRuntime.", "Runtime.", "Stack;\nusing ILRuntime.", "Reflection;\nusing ILRuntime.", "CLR.Utils;\n\nnamespace ILRuntime.", "Runtime.", "Generated\n{\n unsafe class System_Collections_IDictionary_Binding\n {\n public static void Register(ILRuntime.", "Runtime.", "Enviorment.", "AppDomain app)\n {\n BindingFlags flag = BindingFlags.", "Public | BindingFlags.", "Instance | BindingFlags.", "Static | BindingFlags.", "DeclaredOnly;\n MethodBase method;\n Type[] args;\n Type type = typeof(System.", "Collections.", "IDictionary);\n args = new Type[]{typeof(System.", "Object)};\n method = type.", "GetMethod(\"get_Item\", flag, null, args, null);\n app.", "RegisterCLRMethodRedirection(method, get_Item_0);\n\n\n }\n\n\n static StackObject* get_Item_0(ILIntepreter __intp, StackObject* __esp, IList<object> __mStack, CLRMethod __method, bool isNewObj)\n {\n ILRuntime.", "Runtime.", "Enviorment.", "AppDomain __domain = __intp.", "AppDomain;\n StackObject* ptr_of_this_method;\n StackObject* __ret = ILIntepreter.", "Minus(__esp, 2);\n\n ptr_of_this_method = ILIntepreter.", "Minus(__esp, 1);\n System.", "Object @key = (System.", "Object)typeof(System.", "Object).CheckCLRTypes(StackObject.", "ToObject(ptr_of_this_method, __domain, __mStack));\n __intp.", "Free(ptr_of_this_method);\n\n ptr_of_this_method = ILIntepreter.", "Minus(__esp, 2);\n System.", "Collections.", "IDictionary instance_of_this_method = (System.", "Collections.", "IDictionary)typeof(System.", "Collections.", "IDictionary).CheckCLRTypes(StackObject.", "ToObject(ptr_of_this_method, __domain, __mStack));\n __intp.", "Free(ptr_of_this_method);\n\n var result_of_this_method = instance_of_this_method[key];\n\n object obj_result_of_this_method = result_of_this_method;\n if(obj_result_of_this_method is CrossBindingAdaptorType)\n { \n return ILIntepreter.", "PushObject(__ret, __mStack, ((CrossBindingAdaptorType)obj_result_of_this_method).ILInstance, true);\n }\n return ILIntepreter.", "PushObject(__ret, __mStack, result_of_this_method, true);\n }\n\n\n\n }\n}\n" ]

{ "pile_set_name": "Github" }

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[ "Introduction {#Sec1}\n============\n\nThe fungus *Pseudogymnoascus destructans* (previously named as *Geomyces destructans*) is a psychrophilic (cold-loving) fungus responsible for the white-nose syndrome (WNS) in bat populations in North America^[@CR1]--[@CR3]^. This newly discovered pathogen has directly or indirectly caused the death of more than 5.7 million bats since 2006^[@CR4],[@CR5]^. *P. destructans* was found to infect at least eleven species of bats, of which seven species exhibited disease symptoms upon infection. ", "The infected bat species include the endangered Indiana bat (*Myotis sodalis*) and the grey bat (*Myotis grisescens*) <https://www.whitenosesyndrome.org/about/bats-affected-wns>^[@CR6]^.\n\n*P. destructans* grows as an opportunistic pathogen on bat skin during bat hibernation in caves. ", "It also persists in the cave environment as a saprotroph^[@CR7]--[@CR9]^. The optimal temperature of growth for this fungus is around 15 °C. ", "It produces brown and grey colonies, secretes a brownish pigment, and reproduces asexually via asymmetrically curved conidia when cultured on Sabouraud dextrose agar (SAB)^[@CR3]^. Although *P. destructans* isolates analyzed to date from the US and Canada represent a clonal population, variations were reported among isolates^[@CR10]--[@CR12]^. Despite apparent genetic homogeneity, phenotypic variations were reported among North American *P. destructans* isolates, specifically in the mycelial growth rate, exudate production, pigment formation, and diffusion into agar media^[@CR12]^. The underlying cause(s) for the phenotypic variations remain to be discovered. ", "Viral infection could be a potential reason for the variation in fungal phenotypic expression^[@CR13],[@CR14]^.\n\nViruses that infect fungi (mycoviruses) are rather common and mostly latent^[@CR15],[@CR16]^. The majority of mycoviruses are dsRNA-containing isometric particles, although ssRNA and ssDNA mycoviruses have also been recognized. ", "Three well-studied mycovirus systems include (i) yeast killer toxins in *Saccharomyces cerevisiae* and non-conventional yeasts^[@CR17]^, (ii) hypovirulence in *Cryphonectria parasitica* and *Sclerotinia sclerotiorum*, the causal agents of Chestnut blight and white mold diseases on hundreds of plant species, respectively^[@CR18]--[@CR21]^, and (iii) a symbiotic role in conferring heat tolerance to fungal endophytes of grasses^[@CR22]^. There are reports linking mycovirus infection to phenotypic changes in the fungal host^[@CR23]^.\n\nRecently, dsRNA mycoviruses in the human pathogens *Aspergillus fumigatus* and *Talaromyces marneffei* were found to cause hypervirulence^[@CR24],[@CR25]^. Mycoviruses could also provide a 'phylogenomics window' as their evolution showed a strong co-divergence with their fungal hosts^[@CR26]^. We hypothesized that the origin, evolution, and virulence of *P. destructans* could be investigated by focusing on mycoviruses. ", "The current study summarizes the molecular characterization of a virus \\[named Pseudogymnoascus destructans partitivirus 1 (PdPV-1)\\] that infects *P. destructans*. ", "All US and a few Czech Republic isolates tested positive for PdPV-1. ", "PdPV-1 appears to be host-specific to *P. destructans,* as closely related non-pathogenic fungi *P. appendiculatus* and *P. roseus*^[@CR27]^ tested negative for the mycovirus. ", "The results indicated that PdPV-1 represents a common feature among all US and some Czech Republic isolates of *P. destructans* and could be used to further investigate fungal biogeography and the host--pathogen interactions in bat WNS.", "\n\nMaterials and methods {#Sec2}\n=====================\n\nFungal isolates {#Sec3}\n---------------\n\n*P. destructans* isolate (MYC80251) has been described previously^[@CR3]^. *P. destructans* isolates and other *Pseudogymnoascus* species listed in Table [1](#Tab1){ref-type=\"table\"}, were maintained on SAB agar.", "Table 1Fungal isolates used in this study.", "Fungal isolateLocationSourceViral RNA detectionGenBank accession\\#RdRpCapsid***Pseudogymnoascus destructans***MYC80251Albany, New York*Myotis lucifugus*YesKP128044MK789667\\*KP128045MK789674\\*PESU14Avery, North Carolina*Perimyotis subflavus*YesMN990689MN990699LBB17Lawrence, Ohio*Myotis lucifugus*YesMN990690MN990700PESU8Greenbrier, West Virginia*Perimyotis subflavus*YesMN990691MN990701LBB11Woodward, Pennsylvania*Myotis lucifugus*YesMN990692MN990702M2335Tompkins, New York*Myotis lucifugus*YesMN990693MN990703M2337Erie, New York*Myotis lucifugus*YesMN990694MN990704M2339Ulster, New York*Myotis lucifugus*YesMN990695MN990705HA-8-2Hailes Cave, New YorkCave wall swabYesMN990696MN990706VTG1-5-1Greely Mine, VermontSoilYesMN990697MN990707AC-3-3Aelous Cave, VermontSoilYesMN990698MN990708CCF3937Malá Amerika mine, Czech Republic*Myotis myotis*NoCCF3938Solenice tunnel, Czech Republic*Myotis myotis*YesKY609331MK789668\\*KY609337MK789675\\*CCF3939Solenice tunnel, Czech Republic*Myotis myotis*YesMK789669\\*MK789676\\*CCF3941Malá Amerika mine, Czech Republic*Myotis myotis*YesKY609332MK789670\\*KY609338MK789677\\*CCF3944Nový Knín, Czech Republic*Myotis myotis*NoCCF4103Herlíkovice tunnel, Czech Republic*Myotis myotis*NoCCF4124Albeřická/Bischofova cave, Czech Republic*Plecotus auritus*NoCCF4125Albeřická/Bischofova cave, Czech Republic*Myotis myotis*NoCCF4126Portál tunnel, Czech Republic*Myotis myotis*NoCCF4127Herlíkovice tunnel, Czech Republic*Myotis myotis*YesKY609329MK789671\\*KY609335MK789678\\*CCF4129Pístov cellar, Czech Republic*Myotis myotis*YesMK789672\\*MK789679\\*CCF4130Fučná-Otov tunnel, Czech Republic*Myotis myotis*YesKY609328MK789673\\*KY609334MK789680\\*M3695Malá Morávka mine, Czech Republic*Myotis myotis*YesKY609330KY609336M3696Kateřinská cave, Czech Republic*Myotis bechsteinii*NoM3697Malá Morávka mine, Czech Republic*Myotis emarginatus*NoM3698Kateřinská cave, Czech Republic*Myotis nattereri*YesKY609333KY609339M3699Malá Morávka mine, Czech Republic*Myotis daubentonii*NoM3701Sloupsko-Šošůvské cave, Czech Republic*Myotis myotis*No***Pseudogymnoascus roseus***3-VT-5VermontHibernacular soilNo5-NY-6New YorkHibernacular soilNo5-NY-8New YorkHibernacular soilNo5-NY-9New YorkHibernacular soilNoWSF-3629WisconsinAmorphus peatNoUAMH1658CanadaSphagnum bogNo***Pseudogymnoascus appendiculatus***UAMH10510CanadaWood bait block, Sphagnum bogNo\\*GenBank accession numbers for sequences that were determined in the laboratory in Beijing, China; all other accession numbers are for sequences determined in the Albany, NY laboratory.", "\n\ndsRNA extraction {#Sec4}\n----------------\n\n*P. destructans* was grown in a stationary culture in potato dextrose broth (PDB) at 15 °C for 1--2 months in 500-ml flasks. ", "About 1 g wet weight mycelium was harvested and ground to powder under liquid nitrogen with a mortar and pestle. ", "The powder was collected and suspended in 1 ml extraction buffer (150 mM sodium acetate, pH 5.0, 100 mM LiCl, 4% sodium dodecyl sulfate, 10 mM EDTA, pH 8.0, and 20 mM β-mercaptoethanol) and incubated on ice for 10 min. ", "Total nucleic acids were obtained by standard phenol--chloroform extraction followed by precipitation with LiCl and isopropanol. ", "ssRNA and DNA were removed by treatment with S1 nuclease (Life Technologies; Carlsbad, CA) in buffer containing 30 mM sodium acetate (pH 4.6), 50 mM NaCl, 1 mM zinc acetate, 0.5 mg/ml heat-denatured DNA, and 5% (v/v) glycerol at 37 °C for 10 min, followed by incubation with DNase I (Epicentre; Madison, WI) at 37 °C for 30 min. ", "The reaction was extracted with an equal volume of Tris--EDTA--saturated phenol--chloroform--isoamyl alcohol (25:24:1), followed by extraction with an equal volume of chloroform--isoamyl alcohol (24:1). ", "Undigested nucleic acid was precipitated with 2 volumes of absolute ethanol at − 20 °C overnight and recovered by centrifugation for 15 min at 10,000×*g*. ", "Then the pellet was rinsed with 70% ethanol, air-dried and resuspended in 40 µl of RNase-free water. ", "The extracted material was electrophoresed on a 1% agarose gel, stained with ethidium bromide and visualized by UV transillumination. ", "To confirm the dsRNA nature of the remaining material, a 15-µg sample was treated with RNase III and RNase A (Life Technologies) at 37 °C for 1 h. Denaturing polyacrylamide gel electrophoresis of the purified dsRNA was used to determine the size of the two RNA bands.", "\n\ncDNA synthesis and sequence analysis {#Sec5}\n------------------------------------\n\nPurified dsRNA fractions (1--5 µg) containing 2 segments were denatured in 90% dimethyl sulfoxide (DMSO) at 65 °C for 20 min in the presence of random hexadeoxynucleotide and quickly chilled on ice. ", "The RNA-primer mixture was precipitated with ethanol and resuspended in 11 µl RNase-free water. ", "First-strand cDNA was synthesized using M-MLV reverse transcriptase (Life Technologies), based on the manufacturer's instructions. ", "Briefly, the denatured dsRNA with the random hexadeoxynucleotide were mixed with dNTPs, 5 × First-Strand Buffer, 0.1 M DTT, and RNaseOUT Recombinant Ribonuclease Inhibitor (40 units/µl) and incubated at 37 °C for 2 min. ", "After adding 1 µl (200 units) of M-MLV RT, the mixture was incubated at 25 °C for 10 min, followed by 37 °C for 50 min. ", "The reaction was inactivated by heating at 70 °C for 15 min. ", "The resulting cDNA was amplified with random primers and the variously sized PCR products were cloned in TOPO TA cloning vector. ", "A series of overlapping cDNA clones were obtained from the sequencing of the positive clones ([S1](#MOESM1){ref-type=\"media\"} Table). ", "Determination of the ends of each dsRNA was done using FirstChoice^®^ RLM-RACE Kit (Life Technologies). ", "All the sequence contigs were assembled by Sequencher 4.8 (Gene Codes Co.; Ann Arbor, MI). ", "Conserved sequences in GenBank were identified by searches using the tblastx program. ", "Multiple sequence alignments for the two dsRNA segments were carried out using ClustalW analysis by MacVector 7.2 (Accelrys Inc.; Cary, NC). ", "The maximum likelihood phylogenetic trees were generated by MEGA 6.0^[@CR28]^ ([S2](#MOESM1){ref-type=\"media\"} Table).", "\n\nVirus purification {#Sec6}\n------------------\n\nApproximately 60 g wet weight fungal mycelium were collected and ground to powder as described above. ", "The homogenate was mixed with extraction buffer (0.1 M sodium phosphate, pH 7.4, containing 0.1% β-mercaptoethanol) at a volume of 5 ml/g of wet mycelium. ", "Following the addition of an equal volume of chloroform, the suspension was vortexed extensively, and the resulting emulsion was broken by centrifugation in a Sorvall GSA rotor at 10,000×*g* for 20 min. ", "The upper aqueous layer was then mixed thoroughly with 0.5 volumes of 30% polyethylene glycol 8000 (PEG) in 0.85% NaCl and held on ice for 1 h. The PEG precipitate was pelleted in a Sorvall GSA rotor at 16,000×*g* at 4 °C for 30 min and resuspended in 0.1 M sodium phosphate, pH 7.4. ", "After centrifugation at 23,000×*g* at 4 °C for 20 min to remove unsuspended debris, virus was collected by ultracentrifugation of the supernatant in a Beckman SW41 rotor at 76,000×*g*, 4 °C for 2 h. The pelleted virus was resuspended in a total of 4 ml 0.1 M sodium phosphate buffer and purified by loading the viral suspension onto pre-formed gradients of 10--50% (w/v) sucrose in 0.1 M sodium phosphate buffer and centrifuging at 76,000×*g*, 4 °C overnight. ", "The collected virus fractions were diluted in 0.1 M sodium phosphate buffer and preserved at 4 °C for immediate electron microscopy^[@CR29]--[@CR31]^.\n\nNegatively staining electron microscopy {#Sec7}\n---------------------------------------\n\nTwo µl of the virus solution was placed on a glow-discharged copper grid covered with a continuous carbon film. ", "After 1 min of adsorption, the grid was washed with pure water for several seconds and stained with 3 µl of 2% (w/v) uranyl acetate solution for 1 min. ", "The staining solution was blotted away with Whatman No. ", "1 filter paper. ", "The grid was air-dried completely before it was examined in a JEOL JEM-1400 electron microscope operating at 120 keV. The micrographs were recorded at various magnifications using a 4K × 4K CMOS camera (TVIPS F-416).", "\n\nReverse transcription PCR (RT-PCR) assay {#Sec8}\n----------------------------------------\n\nFirst-strand cDNA synthesis was performed as described earlier and followed by PCR using primer pairs V2085/V2090 (40 cycles of 94 °C for 30 s, 57.5 °C for 30 s, and 72 °C for 1 min) and V2168/V2164 (40 cycles of 94 °C for 30 s, 56.5 °C for 30 s, and 72 °C for 1 min) to amplify partial dsRNA1 and dsRNA2 segments with expected fragment lengths of 828 bp and 613 bp, respectively ([S1](#MOESM1){ref-type=\"media\"} Table). ", "PCR products were sequenced using the same primers and aligned to the prototype PdPV-1 sequence from MYC80251 to verify the identities of the amplicons obtained.", "\n\nIndependent laboratory confirmatory analysis {#Sec9}\n--------------------------------------------\n\nIn order to further confirm our findings, one of us (TZ) imported four of the original six positive Czech *P. destructans* isolates, as well as two isolates not previously tested in the US laboratory, directly from the Czech Republic to China. ", "Additionally, the MYC80251 isolate was imported from the US to China. ", "RNA extraction, RT-PCR, and sequencing analysis of these isolates were carried out with primers, probes, and fresh reagents in a laboratory in Beijing, China that had no prior history of *P. destructans* investigations.", "\n\nResults {#Sec10}\n=======\n\nIsolation and characterization of dsRNA from *P. destructans* {#Sec11}\n-------------------------------------------------------------\n\nTotal nucleic acids extracted from *P. destructans* isolate MYC80251 migrated as multiple bands when analyzed by native agarose gel electrophoresis (Fig.", " [1](#Fig1){ref-type=\"fig\"}, lane 1). ", "The most slowly migrating set of bands was found to be removed by treatment with DNase I, showing that these corresponded to fungal genomic DNA (Fig.", " [1](#Fig1){ref-type=\"fig\"}, lane 2). ", "Conversely, only the high molecular weight fungal genomic DNA bands remained following treatment of total *P. destructans* nucleic acids with a combination of RNase III, a dsRNA-specific endoribonuclease, and RNase A, a pancreatic ribonuclease that cleaves ssRNA (Fig.", " [1](#Fig1){ref-type=\"fig\"}, lane 3). ", "This demonstrated that all of the other bands were RNA species. ", "The two dominant RNA bands were most likely fungal 28S and 18S ribosomal RNAs. ", "Migrating more slowly than the rRNAs were two prominent discrete bands of unknown identities (labeled by an asterisk in lane 1). ", "To determine the nature of these bands, total extracted nucleic acids were digested with a combination of S1 nuclease (a single-strand-specific endonuclease) and DNase I. This treatment abolished all RNA and DNA species except the unknown doublet of bands (Fig.", " [1](#Fig1){ref-type=\"fig\"}, lane 4). ", "Collectively, these results strongly indicated that the unknown bands were double-stranded RNA (dsRNA), most likely derived from a fungal virus. ", "Because the analysis in Fig.", " [1](#Fig1){ref-type=\"fig\"} was carried out in native agarose gels, the mobilities of RNA species were compared to those of dsDNA size markers. ", "To more accurately gauge the sizes of the two dsRNA bands, they were analyzed by denaturing polyacrylamide gel electrophoresis in comparison to ssRNA size markers. ", "In this type of gel, the denatured dsRNAs were almost totally masked by the presence of the 18S rRNA band in a sample of total *P. destructans* RNA (Fig.", " [2](#Fig2){ref-type=\"fig\"}, lane 1). ", "However, removal of rRNAs by RNase A treatment of total RNA prior to reisolation, denaturation and electrophoresis allowed us to estimate that the dsRNA species fell in the size range of 1.5--2.0 kb (Fig.", " [2](#Fig2){ref-type=\"fig\"}, lane 2, labeled by asterisk).Figure 1Analysis of nucleic acids extracted from *P. destructans* by differential endonuclease sensitivity or resistance. ", "Samples were digested with the indicated enzymes, and undigested species were separated by electrophoresis in 1% native agarose gels. ", "Lane 1: total *P. destructans* nucleic acids; the 28 S and 18 S ribosomal RNAs are indicated, and the two unknown, more slowly migrating bands are labeled with an asterisk. ", "Lane 2: total nucleic acids following digestion with DNase I. Lane 3: total nucleic acids following digestion with both RNase III and RNase A. Lane 4: total nucleic acids following digestion with both S1 nuclease and DNase I. Size markers: lanes M1, lambda DNA-HindIII digest; lane M2, 2-log DNA ladder (New England BioLabs).Figure 2Estimation of the size of the dsRNA species in nucleic acids extracted from *P. destructans*. ", "Samples were analyzed by electrophoresis in denaturing polyacrylamide gels. ", "Lane 1: total RNA; the 28 S and 18 S ribosomal RNAs are indicated. ", "Lane 2: total RNA digested with RNase A prior to reisolation and denaturation. ", "Size marker (lanes M): ssRNA ladder (in nucleotides).", "\n\nElectron microscopy (EM) {#Sec12}\n------------------------\n\nThe presence of viral particles in *P. destructans* was confirmed by transmission EM. ", "Viral particles (named as PdPV-1) were purified from mycelia of *P. destructans* MYC80251 by homogenization, PEG precipitation, and sucrose density gradient centrifugation. ", "Large amounts of isometric viral particles were observed under EM. ", "The diameter of the virions was estimated to be about 33 nm (Fig.", " [3](#Fig3){ref-type=\"fig\"}).Figure 3Electron microscopy of purified PdPV-1. ", "Isometric viral particles with an estimated diameter of 33 nm were observed. ", "The bar represents 100 nm.", "\n\nSequence and phylogenetic analysis {#Sec13}\n----------------------------------\n\nThe complete sequences of the two dsRNA genome segments of PdPV-1 were obtained by sequencing of a library of cDNA clones, gap-filling reverse transcription PCR, and RLM-RACE. ", "The large segment dsRNA1 comprised 1,683 bp with 46% GC content. ", "The dsRNA1 segment contains an open reading frame (ORF) that encodes 539 amino acids with a molecular mass of approximately 62.7 kDa (GenBank Accession number: KP128044). ", "The small segment dsRNA2 comprised 1,524 bp with 49% GC content. ", "The dsRNA2 segment contains an ORF that encodes 434 amino acids with a molecular mass of approximately 46.9 kDa (GenBank Accession number: KP128045). ", "Both ORFs were identified on the positive strand of each dsRNA segment. ", "The negative strands did not contain any significant ORFs that are longer than 82 amino acids. ", "The search for similar deduced amino-acid sequences in GenBank revealed that the ORFs of dsRNA dsRNA1 and dsRNA2 have significant similarities to the putative RNA-dependent RNA polymerase (RdRp) and the capsid protein (CP), respectively, of viruses from the family *Partitiviridae* genus *Gammapartitivirus*^[@CR32]^*.* ", "These include Penicillium stoloniferum virus S (PsV-S), Aspergillus fumigatus partitivirus-1 (AfuPV-1), Aspergillus ochraceus virus (AoV), Botryotinia fuckeliana partitivirus 1 (BfPV1), Discula destructiva virus 2 (DdV2), Fusarium solani virus 1 (FusoV), Gremmeniella abietina virus MS1 (GaV-MS1), Ophiostoma partitivirus (OPV1), Ustilaginoidea virens partitivirus (UvPV-1), and Verticillium dahliae partitivirus 1 (VdPV1) (Fig.", " [4](#Fig4){ref-type=\"fig\"} and Fig. [", "S1](#MOESM1){ref-type=\"media\"}). ", "Specifically, the RdRp of PdPV-1 showed 76% identity with PsV-S RdRp, whereas the CP of PdPV-1 showed 67% identity with that of PsV-S. Homologies (amino acid identity in red and consensus match in blue) were much higher within the core motif regions of the RdRp (amino acids 174--491) of PdPV-1, than elsewhere in the molecule (Fig.", " [4](#Fig4){ref-type=\"fig\"}). ", "Phylogenetic analyses were performed by using the RdRp and CP sequences of the various mycoviruses such as alphapartitiviruses, betapartitivirues, deltapartitiviruses, gammapartitiviruses, totiviruses, and chrysoviruses. ", "Phylogenetic trees derived from both RdRp and CP sequences exhibited three major branches and suggested that PdPV-1 is a member of the genus *Gammapartitivirus* in the family *Partitiviridae* (Fig.", " [5](#Fig5){ref-type=\"fig\"} and Fig. [", "S2](#MOESM1){ref-type=\"media\"}). ", "In addition, phylogenetic analyses of the putative RdRp and CP of PdPV-1 showed that PdPV-1 was most closely related to the gammapartitivirus PsV-S.Figure 4Comparison of the amino acid sequences of putative RdRp of the Pseudogymnoascus destructans virus (PdPV-1), Penicillium stoloniferum virus S (PsV-S), Gremmeniella abietina virus MS1 (GaV-MS1), Aspergillus ochraceus virus (AoV), Botryotinia fuckeliana partitivirus-1 (BfPV1), Aspergillus fumigatus partitivirus-1 (AfuPV-1), Ustilaginoidea virens partitivirus 1 (UvPV-1), Verticillium dahliae partitivirus 1 (VdPV1), Ophiostoma partitivirus (OPV1), Discula destructiva virus 2 (DdV2), and Fusarium solani virus 1 (FusoV). ", "Red: 100% identity; Blue: consensus match; Green: mismatch.", "Figure 5Phylogenetic analysis of PdPV-1. ", "Maximum likelihood phylogenetic tree based on RdRp amino acid sequences of representative members of the families *Partitiviridae*(including genera *Alphapartitivirus, Betapartitivirus, Deltapartitivirus,* and *Gammapartitivirus*),*Totiviridae,* and *Chrysoviridae* were constructed using the program MEGA 6 (GenBank accession numbers are in the Table [S2](#MOESM1){ref-type=\"media\"}).", "\n\nWe found that the 5′ untranslated regions (UTRs) of the plus strands of segments dsRNA1 and dsRNA2 were 8 and 60 nucleotides, respectively; whereas the 3′ UTRs of the plus strands of segments dsRNA1 and dsRNA2 were 54 and 159 nucleotides, respectively. ", "In contrast, a separate study of PdPV-1^[@CR33]^ obtained longer RLM-RACE reads than ours and was able to identify conserved 5′-terminal nucleotide sequence motifs in both genome segments, a feature that is common to the majority of partitiviruses^[@CR29],[@CR34]--[@CR36]^. Additionally, as a consequence of the observed longer 5′ end of the dsRNA2 sequence, the deduced CP amino-acid sequence in that study^[@CR33]^ had a 35-residue amino-terminal extension relative to the CP ORF that we determined. ", "If confirmed, such an extension would make the PdPV-1 CP unique among the partitiviruses (Fig. [", "S1](#MOESM1){ref-type=\"media\"}). ", "This apparent discrepancy remains to be resolved in the future by the direct characterization of the CP. ", "Very recently, a PdPV-1 sequence was also assembled in a metagenomic analysis of fungal transcriptomic datasets^[@CR37]^. Notably, other than the amino-terminal CP extension^[@CR33]^, the PdPV-1 sequences obtained in all three studies were 100% identical in the dsRNA1 and dsRNA2 coding regions.", "\n\nReverse transcription PCR (RT-PCR) screening of *P. destructans* isolates for the presence of PdPV-1 {#Sec14}\n----------------------------------------------------------------------------------------------------\n\nRT-PCR was performed to examine whether PdPV-1 exists in various *P. destructans* isolates from diverse sources. *", "P. destructans* isolates listed in Table [1](#Tab1){ref-type=\"table\"} include those collected from fungus-infected bats in the caves from various geographic locations in the US and the Czech Republic, as well as those that were purified from environmental samples collected from caves or mines where bats with WNS hibernated. ", "Closely related strains of *Pseudogymnoascus roseus* that were isolated from soil samples collected in bat hibernacula were also tested. *", "P. roseus* WSF-3629 was collected from Amorphus peat in Wisconsin^[@CR27]^. *P. roseus* UAMH1658 and *P. appendiculatus* UAMH10510 were obtained from the University of Alberta Microfungus Collection and Herbarium. ", "All these bat tissue samples and environmental isolates were subjected to total RNA extraction, followed by virus-specific RT-PCR detection and sequencing of RT-PCR product fragments. ", "Both dsRNA1 and dsRNA2 segments of PdPV-1 were detected in RNA extracts of all *P. destructans* isolates from the US, irrespective of where they were collected, and their partial sequences (GenBank accession numbers: MN990689--MN990708) were 100% identical to those of our original PdPV-1 strain from MYC80251. ", "Six out of sixteen *P. destructans* isolates collected in the Czech Republic were also found to be PdPV-1 positive. ", "dsRNA1 and dsRNA2 segments of these six PdPV-1 positive isolates were partially sequenced (GenBank accession numbers: KY609328--KY609339), and we found that some of these PdPV-1 strains had polymorphisms in both their dsRNA1 and dsRNA2 segments, while others were identical to the sequences of PdPV-1 from the US *P. destructans* isolates. ", "Additionally, examination of the closely related fungi *P. roseus* and *P. appendiculatus* showed no detectable dsRNA1 or dsRNA2 segment of PdPV-1 dsRNA (Table [1](#Tab1){ref-type=\"table\"}).", "\n\nIndependent analysis of *P. destructans* isolates from the Czech Republic {#Sec15}\n-------------------------------------------------------------------------\n\nTo obtain independent verification of some of these findings, four of the Czech Republic isolates (CCF3938, CCF3941, CCF4127, and CCF4130) that had been found to be positive for PdPV-1 by testing in the US were imported directly from the Czech Republic to China and were tested in a laboratory in Beijing that had no prior history of work with *P. destructans*. ", "These isolates, plus two previously untested Czech isolates (CCF3939 and CCF4129), were confirmed by RT-PCR and sequencing to harbor PdPV-1 (GenBank accession numbers: MK789668--MK789673 and MK789675--MK789680) (Table [1](#Tab1){ref-type=\"table\"}).The laboratory in Beijing also confirmed the presence of PdPV-1 in the US *P. destructans* isolate MYC80251 (GenBank accession numbers: MK789667 and MK789674) (Table [1](#Tab1){ref-type=\"table\"}).", "\n\nDiscussion {#Sec16}\n==========\n\nBat WNS continues to devastate the bat populations in the United States and Canada and therefore, there remains an urgent need to understand the origin and spread of this disease. ", "In this study, we characterized mycovirus PdPV-1 infecting the WNS etiological fungus *P. destructans*. ", "The identity of PdPV-1 was confirmed by (i) demonstration of its dsRNA content by differential sensitivity or resistance to DNA and RNA endonucleases; (ii) complete viral genome sequencing; (iii) nucleotide similarities of the dsRNA viral genome segments and phylogenetic alignment of their encoded proteins with mycoviruses from the family *Partitiviridae* genus *Gammapartitivirus*; (iv) TEM confirmation of isometric viral particles, and (v) host specificity of PdPV-1 for *P. destructans* and no detection of this virus in closely related *Pseudogymnoascus* species. ", "Overall, PdPV-1 exhibited size, morphology, and nucleotide sequences typical of the fungal viruses in the family *Partitiviridae* genus *Gammapartitivirus*^[@CR32],[@CR38]^.\n\nThese findings in our study (<https://www.biorxiv.org/content/10.1101/059709v1>) were obtained independently from and prior to a report by Thapa et al*.*^[@CR33]^. In contrast to results contained in that publication, we found that some of the Czech Republic *P. destructans* isolates were infected with PdPV-1. ", "To eliminate the possibility that these results were false-positives, virus testing was repeated separately using four of the original six positive isolates that were shipped directly to China from the Czech Republic. ", "Testing in the laboratory in Beijing verified that these four isolates contained PdPV-1, as did two other isolates not previously tested in the US (Table [1](#Tab1){ref-type=\"table\"}). ", "This confirmation of our results strongly supports our conclusion that PdPV-1 infection is not unique to the North American isolates of *P. destructans*. ", "We do not know the basis for the discrepancy between the results of our laboratories and those of the other report^[@CR33]^; notably, dsRNA1 (GenBank Accession number KP128044 and KY207543) and dsRNA2 (GenBank Accession number KP128045 and KY207544) from the two laboratories have 100% nucleotide identity, respectively. ", "It is possible that it may be attributable to differences in the methods used for dsRNA extraction. ", "Also, we note that the Czech *P. destructans* isolates that we tested were obtained from laboratories in the Czech Republic, whereas those analyzed by Thapa et al*.*^[@CR33]^ were acquired from the Center for Forest Mycology Research in Madison, Wisconsin.", "\n\nBoth *P. destructans* and its closely related species of *P. roseus* have been isolated from the soil of WNS affected caves and mines^[@CR7],[@CR39]^. PdPV-1 was only detected from the randomly selected samples of *P. destructans*, but not from *P. roseus*. ", "The result showed that all US *P. destructans* isolates were infected with PdPV-1, no matter whether the samples were isolated from the bats with WNS or its environment in the US. ", "Virus-free fungal isolates of *P. roseus* were not found on the bats with WNS although this fungal species was found in the same environmental reservoir as the WNS pathogen. ", "The absence of PdPV-1 infection in other *Pseudogymnoascus* species, collected from the same bat hibernacula in the US, suggested a close viral association with *P. destructans*. ", "The observed host-specificity of PdPV-1 was consistent with the narrow host ranges of mycoviruses due to severe bottlenecks in their horizontal transmission^[@CR16]^. The above results raise two questions: (i) If PdPV-1 can infect *P. roseus*, will *P. roseus* with virus cause WNS? (", "ii) Can virus-free isolates of *P. destructans* infect bats to cause WNS? ", "Additional studies are needed to address these questions.", "\n\nThe discovery of a dsRNA mycovirus in *P. destructans* is consistent with the wide occurrence of mycoviruses in fungi^[@CR15],[@CR40]^. Mycovirus infection of fungi is usually asymptomatic^[@CR41]^. However, mycovirus infection could alter the ability of plant-pathogenic fungi to cause diseases^[@CR23],[@CR42]^. In plant-pathogenic fungi, mycovirus infections generally reduce fungal yield, attenuate mycelial growth, abolish female fertility in sexual crosses, decrease asexual sporulation, alter colony morphologies, modulate pigment production, and diminish the accumulation of specific metabolites. ", "These effects lead to hypovirulence, an attenuation of the pathogenic outcome of fungal infection on the plant host^[@CR20]^. The harmful effects of mycoviruses on fungal growth were exploited as beneficial functions in phytopathogen control^[@CR15],[@CR43],[@CR44]^. On the contrary, virus infections of animal pathogenic fungi and protozoan pathogens showed hypervirulence^[@CR45]^. A recent publication suggested that partitivirus infections of the dimorphic human fungal pathogen *Talaromyces marneffei* caused aberrant gene expression and hypervirulence in an animal model^[@CR25]^. More in-depth experiments will be needed to discern the outcome of PdPV-1 infection on *P. destructans* phenotype and virulence. ", "These investigations will be facilitated by the recent availability of a molecular tool kit and experimental infection model of *P. destructans*^[@CR46]--[@CR51]^.\n\nIn conclusion, mycoviruses are ubiquitous in fungi, while the connection between fungal phenotype and mycovirus presence is not always straightforward. ", "In this study, we discovered the existence of the partitivirus PdPV-1 in *P. destructans* isolated from various species of bats with WNS or from their living environment in both the US and the Czech Republic. *", "P. destructans* PdPV-1 could be a valuable tool to investigate fungal biogeography and the host--pathogen interactions in bat WNS.", "\n\nSupplementary information\n=========================\n\n {#Sec18}\n\nSupplementary Information.", "\n\n**Publisher\\'s note**\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.", "\n\nSupplementary information\n=========================\n\nis available for this paper at 10.1038/s41598-020-70375-6.", "\n\nThis study was funded in part by the US Fish and Wildlife Service (F12AP01167), National Science Foundation (1203528), National Natural Science Foundation of China (31872617), and the Fundamental Research Funds for the Central Universities, China (3332018097). ", "DNA sequencing in the US laboratory was performed at the Wadsworth Center Advance Genomics Technologies Core. ", "EM was carried out at the Wadsworth Center EM Core.", "\n\nV.C. conceived the study, obtained initial funding, and supervised experiments. ", "P.R. and S.S.R. carried out experiments described in Figs.", " [1](#Fig1){ref-type=\"fig\"}, [2](#Fig2){ref-type=\"fig\"}, [4](#Fig4){ref-type=\"fig\"}, and [5](#Fig5){ref-type=\"fig\"}. ", "P.R., H.S., and P.S.M. collaborated on Figs.", " [3](#Fig3){ref-type=\"fig\"} and [4](#Fig4){ref-type=\"fig\"}. ", "S.C. advised on the design and interpretation of data in Figs.", " [1](#Fig1){ref-type=\"fig\"}, [2](#Fig2){ref-type=\"fig\"}, [3](#Fig3){ref-type=\"fig\"}, Fig. [", "S1](#MOESM1){ref-type=\"media\"}, and Table [1](#Tab1){ref-type=\"table\"}. ", "N.M., A.K., and J.P. contributed samples and details of isolates from the Czech Republic. ", "T.Z. carried out independent confirmation of major findings and obtained partial funding. ", "V.C., with contributions from P.R., wrote the draft manuscript. ", "P.R., P.S.M., and S.C. edited the draft manuscript. ", "All authors reviewed the final manuscript.", "\n\nAll nucleotide sequences generated in this study are deposited in the NCBI database.", "\n\nThe authors declare no competing interests.", "\n" ]

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[ "Established in 1891, Best Best & Krieger (BBK) is a highly regarded, full-service law firm of over 350 professionals, including more than 200 attorneys across nine offices in California and in Washington, D.C. Maria Casas is the firm’s Operations Manager.", "\n\nFive years ago, Casas engaged Mattern & Associates to streamline the firm’s outsourced facilities management processes. ", "During that initial engagement, Mattern’s consultants were able to achieve savings of close to 23% per month for the firm, while consolidating vendors to a single provider and streamlining equipment platforms and contract expirations. “", "We were very pleased with those results,” says, Casas, “which is why BBK called upon the consultants of Mattern & Associates to spearhead a new project for BBK, tackling our office supplies contract.”", "\n\nPhase I and II Engagement in Office Supplies\nFor the firm’s office supplies, Mattern performed Phase I and II analyses in which there was an in-depth review of BBK’s invoices, contracts in addition to onsite visits to review current workflow processes. ", "These custom analyses were then benchmarked and also provided the basis for Mattern’s recommendations.", "\n\nBBK moved forward with an open RFP in the office supplies situation, selected a new vendor from the field of competitors, Office Max. ", "Mattern & Associates was able to achieve approximately 10% in monthly savings firmwide for their office supplies. ", "Because of these excellent results, BBK decided to move forward with the Mattern Phase III offering.", "\n\nThe Decision to Move Forward with Phase III\nThe Phase III offering from Mattern includes implementation oversight, monitoring and maintenance of a firm’s vendor contracts. “", "Best Best & Krieger wanted to maximize the opportunities in our office supplies contracts; however, our firm doesn’t have the resources to scrutinize contracts on an ongoing basis at this level. ", "Having Mattern & Associates engaged for the Phase III meant our firm would have expert advice at our disposal throughout the lifecycle of the office supplies contract,” says Casas.", "\n\nFor the firm’s contract with Office Max, Phase III entailed oversight of the vendor transition to Office Max, including firm-announcement language, coordinating firm-vendor conference calls and meetings; invoice monitoring and reconciliation specifically to ensure that the pricing was in-line with contract and pricing adjustments.", "\n\n“Simply put, it’s a second pair of eyes looking at these things –an expert second pair of eyes. ", "Mattern’s consultants are so well versed on our particular contract that they are able to suggest strategic recommendations based upon pricing fluctuations, or catch discrepancies very easily. ", "The bottom line is BBK wants to maximize cost-efficiencies and optimize the value of our contracts, and with Mattern in place, we have the expert manpower to do just that.”", "\n\nMattern performs ongoing reviews and reports on accuracy in invoicing; on target run rates, ensuring these are being met to prevent price increases; optimizing contract vs. non-contract spend and making recommendations if supplies lists need calibrated to ensure the most cost-effective purchasing for firm as well as non-contract discounts to monitor for any required adjustments; and finally, reporting on purchasing trends to determine if any action items need to be addressed for budgetary purposes. ", "As with the Phase I & II aspects of the project, the Phase III services cost the firm zero additional dollars due to the fact that Mattern’s fees were reimbursed by the vendor.”", "\n\nThe Results\n“The bottom line goal of having Mattern in the picture is to consolidate, save costs, become more efficient and provide consistencies throughout our nine locations,” Casas continues to say. “", "To be able to do this at no extra cost to our firm is clearly a win-win for Best Best and Krieger.”", "\n\nIn office supplies, Mattern’s consultants regularly review invoices for accurate pricing and, based on the firm’s concern regarding price fluctuations and lower advertised pricing for some of BBK’s core items by other providers, Mattern has additionally conducted a purchasing analysis to determine the impact to the firm’s contractual agreement if certain purchases were made elsewhere versus through Office Max – as well as allowing that data to illustrate what the most advantageous path for the firm would be.", "\n\n“The Mattern team also provides spend per office and spend per attorney analyses—and all of these oversights by their expert consultants are very beneficial strategic tools for the firm’s budgeting,” includes Casas.", "\n\nThe Takeaways\n“At the end of the day, it’s good practice to ensure contractual terms are met—and the consultants at Mattern are really good at that,” says Casas. “", "Their consultants even participate in quarterly vendor presentations—keeping everyone on task.”", "\n\nCasas concludes, “Because of engaging Mattern & Associates for the Phase III, our firm is more pleased with our service contracts, we have also achieved significantly more effective contracts.", "\n\n“Over the lifecycle of the engagement, the consultants of Mattern & Associates bring things to our attention we may have overlooked and act as an expert resource for any questions we may have, whether it be a strategic or price negotiation point in one of our contracts. ", "I consider their team to be an invaluable resource.”", "\n\nOur Unique Approach\n\nContact Us Today\n\nAbout Mattern & Associates\n\nMattern & Associates is the leader in legal business process consulting and cost recovery solutions. ", "We provide law firms with unbiased strategies for measurably improving the efficiency and cost effectiveness of in-house and outsourced back and middle office services." ]

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[ "Address:2622 CAROLINE ST Subdivision: DOWNTOWNBedrooms: 2Bathrooms: Full (1) Half (0)Description: Perfect opportunity to live downtown Fredericksburg in this one of a kind home with exceptional char..." ]

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[ "Q:\n\nCreating a PHP websockets server\n\nI am new in websockets technology. ", "I was trying to create a websockets php server and connect to the server with a javascript client. ", "I am using xampp 1.8.3.", "\nI made this simple PHP server:\n<?", "php \n error_reporting(E_ALL);\n set_time_limit(0);\n\n $address = \"127.0.0.1\";\n $port = 1777;\n $maxConnections = 10;\n\n if(!($sock = socket_create(AF_INET, SOCK_STREAM, 0))){\n $errorCode = socket_last_error();\n $errorMsg = socket_strerror($errorCode);\n die(\"socket_create() failed -> {$errorCode}:{$errorMsg}\\n\");\n }\n echo \"Server created.\\n\";\n\n if(!(socket_bind($sock, $address, $port))){\n $errorCode = socket_last_error();\n $errorMsg = socket_strerror($errorCode);\n die(\"socket_bind() failed -> {$errorCode}:{$errorMsg}\\n\");\n }\n echo \"Server opened on {$address}:{$port}\\n\";\n\n if(!(socket_listen($sock, $maxConnections))){\n $errorCode = socket_last_error();\n $errorMsg = socket_strerror($errorCode);\n die(\"socket_listen() failed -> {$errorCode}:{$errorMsg}\\n\");\n }\n echo \"Waiting for connections...\\n\";\n\n $client = socket_accept($sock);\n if(socket_getpeername($client, $address, $port)){\n echo \"The client {$address}:{$port} is online.\\n\";\n }\n $msg = socket_read($client, 1024000);\n if(!(socket_write($client, $msg, strlen($msg)))){\n $errorCode = socket_last_error();\n $errorMsg = socket_strerror($errorCode);\n die(\"socket_write() failed -> {$errorCode}:{$errorMsg}\\n\");\n }\n echo \"Message sent\\n\";\n\n socket_close($client);\n socket_close($sock);\n\n?", ">\n\nI ran this php file with xampp shell using the following expression: \nphp htdocs/server.php\n\nand I got this message on shell:\nphp htdocs/server.php\nServer created.", "\nServer opened on 127.0.0.1:1777\nWaiting for connections...\n\nThen I opened my client.html on chrome (my supports websockets). ", "\nMy client.html code is:\n<html>\n <head>\n <meta charset=\"UTF-8\" />\n <title>Websockets web-server connection</title>\n </head>\n <body>\n <p>Websockets connection. ", "Status: <span id=\"status\"></span></p>\n <script type=\"text/javascript\">\n var webSockets = new WebSocket(\"ws://127.0.0.1:1777/\");\n webSockets.onopen = function(){\n document.getElementById(\"status\").innerHTML=\"connected\";\n webSockets.send(\"ping\");\n }\n </script>\n </body>\n</html>\n\nAnd I received this message on javascript console log: \nWebSocket connection to 'ws://127.0.0.1:1777/' failed: client.html:9\n\nAnd my shell had this messages:\nphp htdocs/server.php\nServer created.", "\nServer opened on 127.0.0.1:1777\nWaiting for connections...\nThe client 127.0.0.1:64446 is online\nMessage sent\n\nHowever I didn't receive any message on client, I do not even get a connected status.", "\nWhat is happening? ", "Where is my error?", "\nThank you.", "\n\nA:\n\nWebSockets are not raw TCP sockets. ", "They require a rather complex HTTP-like handshake to establish a connection, and require data transferred over them to be encoded and framed in a very particular way. ", "The protocol is defined in RFC 6455.", "\nUnless you are feeling incredibly masochistic, you don't want to try to implement this yourself. ", "Use a library like Ratchet to implement WebSockets in PHP.", "\n\nA:\n\nI had the same problem bro but no need of using Ratchet or other libraries you can write your own simple code . ", "The handshake process,and the masking-unmasking of messages is rather difficult so i copied the code for those \nfunction perform_handshaking($receved_header,$client_conn, $host, $port)\n{\n $headers = array();\n $lines = preg_split(\"/\\r\\n/\", $receved_header);\n foreach($lines as $line)\n {\n $line = chop($line);\n if(preg_match('/\\A(\\S+): (.*)\\z/', $line, $matches))\n {\n $headers[$matches[1]] = $matches[2];\n }\n }\n\n $secKey = $headers['Sec-WebSocket-Key'];\n $secAccept = base64_encode(pack('H*', sha1($secKey . '", "258EAFA5-E914-47DA-95CA-C5AB0DC85B11')));\n //hand shaking header\n $upgrade = \"HTTP/1.1 101 Web Socket Protocol Handshake\\r\\n\" .", "\n \"Upgrade: websocket\\r\\n\" .", "\n \"Connection: Upgrade\\r\\n\" .", "\n \"WebSocket-Origin: $host\\r\\n\" .", "\n \"WebSocket-Location: ws://$host:$port/\\r\\n\".", "\n \"Sec-WebSocket-Accept:$secAccept\\r\\n\\r\\n\";\n socket_write($client_conn,$upgrade,strlen($upgrade));\n return $upgrade;\n}\n\nfunction unmask($text) {\n $length = ord($text[1]) & 127;\n if($length == 126) {\n $masks = substr($text, 4, 4);\n $data = substr($text, 8);\n }\n elseif($length == 127) {\n $masks = substr($text, 10, 4);\n $data = substr($text, 14);\n }\n else {\n $masks = substr($text, 2, 4);\n $data = substr($text, 6);\n }\n $text = \"\";\n for ($i = 0; $i < strlen($data); ++$i) {\n $text .= $data[$i] ^ $masks[$i%4];\n }\n return $text;\n}\n\n//Encode message for transfer to client.", "\nfunction mask($text)\n{\n $b1 = 0x80 | (0x1 & 0x0f);\n $length = strlen($text);\n\n if($length <= 125)\n $header = pack('CC', $b1, $length);\n elseif($length > 125 && $length < 65536)\n $header = pack('CCn', $b1, 126, $length);\n elseif($length >= 65536)\n $header = pack('CCNN', $b1, 127, $length);\n return $header.$text;\n}\n\nInstead of socket_accept user socket_read to get the http header containing request from webpage that it wants to upgrade its http conn to websocket then use the handshake function above to write an accept header message .then your connection will be established .but still on the client side you have to add events like these \nif(\"WebSocket\" in window){\n var a = \"ws://\"+serverip+\":9000\";\n var ws = new WebSocket(a);\n var error = null;\n\n ws.onopen = function(){\n open();\n }\n\n ws.onerror = function(err){\n errorhandler(err);\n\n }\n ws.onmessage = function(e){\n messagehandler(e);\n\n }\n ws.onclose = function(){\n close();\n }\n\n}\n\nfunction open(){\n document.getElementById('logs').innerHTML+='<p>WebSocket Connection OPened</p>';\n\n}\n\nfunction errorhandler(err){\n document.getElementById('logs').innerHTML+='<p>WebSocket Connection Error occured &nbsp'+err.data+'</p>';\n\n}\n\nfunction messagehandler(a){\n document.getElementById('logs').innerHTML+=\"<p>\"+a.data+\"</p>\";\n\n}\n\nfunction close(){\n document.getElementById('logs').innerHTML+='<p>WebSocket Connection Closed</p>';\n ws = null;\n\n}\n\n" ]

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[ "1980 Little League World Series\n\nThe 1980 Little League World Series took place between August 26 and August 30 in Williamsport, Pennsylvania. ", "The Longkuang Little League of Hualien, Taiwan, defeated the Belmont Heights Little League of Tampa, Florida, in the championship game of the 34th Little League World Series.", "\n\nTeams\n\nChampionship Bracket\n\nPosition Bracket\n\nNotable players\nGary Sheffield (Tampa, Florida) – MLB outfielder and third baseman from 1988 to 2009\nDerek Bell (Tampa, Florida) – MLB outfielder from 1991 to 2001\n\nExternal links\n\nCategory:Little League World Series\nLittle League World Series\nLittle League World Series" ]

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

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[ "# Copyright 2013-2020 Lawrence Livermore National Security, LLC and other\n# Spack Project Developers. ", "See the top-level COPYRIGHT file for details.", "\n#\n# SPDX-License-Identifier: (Apache-2.0 OR MIT)\n\nfrom spack import *\n\n\nclass Libffi(AutotoolsPackage, SourcewarePackage):\n \"\"\"The libffi library provides a portable, high level programming\n interface to various calling conventions. ", "This allows a programmer\n to call any function specified by a call interface description at\n run time.\"\"\"", "\n homepage = \"https://sourceware.org/libffi/\"\n sourceware_mirror_path = \"libffi/libffi-3.2.1.tar.gz\"\n\n version('3.3', sha256='72fba7922703ddfa7a028d513ac15a85c8d54c8d67f55fa5a4802885dc652056')\n version('3.2.1', sha256='d06ebb8e1d9a22d19e38d63fdb83954253f39bedc5d46232a05645685722ca37')\n\n patch('clang-powerpc-3.2.1.patch', when='@3.2.1%clang platform=linux')\n # ref.: ", "https://github.com/libffi/libffi/pull/561\n patch('powerpc-3.3.patch', when='@3.3')\n\n @property\n def headers(self):\n # The headers are probably in self.prefix.lib but we search everywhere\n return find_headers('ffi', self.prefix, recursive=True)\n\n def configure_args(self):\n args = []\n if self.spec.version >= Version('3.3'):\n # Spack adds its own target flags, so tell libffi not to\n # second-guess us\n args.append('--without-gcc-arch')\n return args\n" ]

{ "pile_set_name": "Github" }

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[ "Q:\n\nsysdate format not working in where clause with time\n\nI am trying to run following query on oracle at PL/SQL developer to select a list of time slots between current time and end of the day:\nSELECT T.VISIT_DATE\n FROM REGISTRATION.VU_SCHEDULE T\n WHERE T.VISIT_DATE BETWEEN TO_DATE(SYSDATE, 'DD-MON-YYYY HH24:MI:SS')\n AND TO_DATE('27-MARCH-2020 23:59:59', 'DD-MON-YYYY HH24:MI:SS')\n ORDER BY VISIT_DATE\n\nbut it gives me result of whole day instead of current time of day \n VISIT_DATE\n1 3/27/2020 9:00:00 AM\n2 3/27/2020 9:15:00 AM\n3 3/27/2020 9:30:00 AM\n4 3/27/2020 9:45:00 AM\n5 3/27/2020 10:00:00 AM\n6 3/27/2020 10:15:00 AM\n7 3/27/2020 10:30:00 AM\n8 3/27/2020 10:45:00 AM\n9 3/27/2020 11:00:00 AM\n10 3/27/2020 11:15:00 AM\n11 3/27/2020 11:30:00 AM\n12 3/27/2020 11:45:00 AM\n\ne.g if current time is 11:00 AM then it should give result from current time.", "\nI've tried trunc(sysdate) but it doesn't work\nNOTE:\nThe condition must have date and time from now to the end of the day with format.", "\n\nA:\n\nmust have date and time from now to the end of the day with format.", "\n\nYou could do:\nwhere t.visit_date >= sysdate and t.visit_date < trunc(sysdate) + 1\n\nRationale:\n\nsysdate gives you the current date/time, that represents the lower bound of the interval\ntrunc(sysdate) is the beginninig of the current day (today at midnight), to which you can add 1 to get the beginning of the next day; this is the (exclusive) upper bound of the range\n\nNote that there is no point applying to_date() to function sysdate, that produces a date alreay.", "\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "Alpha 2-macroglobulin and proliferative retinopathy in type 1 diabetes.", "\nSerum alpha 2-macroglobulin (alpha 2m) and total glycosylated haemoglobin (HbA1) concentrations were measured in 110 insulin dependent Type 1 diabetics with minimal or no fundoscopic retinopathy, referred to as non-retinopaths, and in 52 proliferative retinopaths. ", "Proteinuria was recorded in 8 (7%) non-retinopaths and 29 (56%) retinopaths and was accompanied by elevated alpha 2m concentrations in both groups of diabetics but only significantly so in the non-retinopaths. ", "Diabetics without proteinuria showed a significant correlation between alpha 2m concentration and duration of diabetes, HbA1 and age (being higher at extremes of age). ", "Alpha 2m concentrations were significantly higher in retinopaths than in non-retinopaths without proteinuria when allowance was made for the influence of age and duration of diabetes on alpha 2m. This difference may be attributed to the higher HbA, levels found in retinopaths than in non-retinopaths and was no longer evident when account was taken of the prevailing HbA1 concentration in individual patients." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Qaratoba\n\nQaratoba (also, Karatoba) is a village and municipality in the Qusar Rayon of Azerbaijan. ", " It has a population of 637.", "\n\nReferences \n\nCategory:Populated places in Qusar District" ]

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

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[ "FYI- Study by Paul Joskow and Alfred Kahn that concludes, among other things, \nthat market fundamentals in California do not fully account for price levels \nin Californis this past summer.", "\n---------------------- Forwarded by Richard Shapiro/NA/Enron on 11/28/2000 \n11:39 AM ---------------------------\n\n\nAleck Dadson@ECT\n11/27/2000 12:27 PM\nTo: Richard Shapiro/NA/Enron@enron, James D Steffes/NA/Enron@Enron\ncc: \n\nSubject: Power Prices in California\n\nFYI\n\n__________________\n\nFYI\n----- Forwarded by Aleck Dadson/TOR/ECT on 11/27/2000 01:23 PM -----\n\n\t\"Colin Schuch\" <SchuchCo@oeb.gov.on.ca>\n\t11/24/2000 03:43 PM\n\t\t \n\t\t To: <Adadson@ect.enron.com>, <conway@enerconnect.com>\n\t\t cc: \n\t\t Subject: Power Prices in California\n\n\n\nGuys:\n\nI thought you might be interested in this paper by Joskow on the\nCalifornia crisis.", "\n\nRegards . . . ", "Colin\n\n - CalifWithholdJoskow-Khan.pdf" ]

{ "pile_set_name": "Enron Emails" }

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[ "Snom HS-MM3\n\nHeadsets allow users a greater range of movement than possible with a telephone receiver. ", "The ergonomically designed, sturdy HS-MM3 Snom headset is compatible with the Snom 300 telephone. ", "For all other models in the Snom D300 desk phone series, the HS-MM2 Snom headset was developed. ", "The headset has one ear pad, which may be worn on either ear, that offers superior wearing comfort and its noise-cancelling microphone does not compromise audio quality." ]

{ "pile_set_name": "Pile-CC" }

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[ "Recombinant human leukemia inhibitory factor does not enhance in vitro human blastocyst formation.", "\nTo assess the effect of human recombinant leukemia inhibitory factor in different doses on human blastocyst formation. ", "A university-based tertiary referral center (The Toronto Hospital). ", "Nontransferable human embryos (n = 473) at the two- to six-cell stage were obtained from patients undergoing IVF and were split randomly into five groups. ", "Embryos in group A (n = 164) were cultured as the control group in Ham's F-10 (GIBCO-BRL, Grand Island, NY) + 10% human sera. ", "Embryos in groups B, C, D, and E (n = 54, 78, 87, and 80, respectively) were cultured in the same medium supplemented with human recombinant leukemia inhibitory factor in four different concentrations (5, 7.5, 10, and 20 ng/mL, respectively). ", "Morphological assessment of embryo development was recorded daily. ", "Human blastocyst formation. ", "No significant difference was detected in the rate of blastocyst formation of embryos in the study groups when compared with embryos in group A. This study shows that 5 to 20 ng/mL of recombinant leukemia inhibitory factor in standard medium does not enhance in vitro human blastocyst formation. ", "It is possible that recombinant leukemia inhibitory factor may play a role at later stages of human embryogenesis and during implantation." ]

{ "pile_set_name": "PubMed Abstracts" }

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