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"Q:\n\nPassing a value to a child component Angular2\n\nI'm trying to pass a value from a parent component to a child component I tried this:\nThis is my parent component:\nimport {Component, View, NgFor} from 'angular2/angular2';\n\nimport {DisplayCard} from '../display-card/display-card';\n\n@Component({\n selector: 'display'\n})\n@View({\n templateUrl: './components/display/display.html',\n directives: [DisplayCard, NgFor]\n})\nexport class Display {\n displays: Array<any>;\n\n constructor(){\n this.displays = [\n {name: \"Lobby\", appName: \"Animal App\", Source: 3},\n {name: \"Wall\", appName: \"Idk App\", Source: 3},\n {name: \"Other Wall\", appName: \"Monkey App\", Source: 3},\n {name: \"Lobby Kiosk\", appName: \"Car App\", Source: 3},\n {name: \"Another Brick in the Wall\", appName: \"Pink Floyd App\", Source: 3},\n ]\n }\n}\n\nParent component HTML:\n<div class=\"col-md-3\" *ng-for=\"#display of displays\">\n <display-card name=\"{{display.name}}\"></display-card>\n</div>\n\nChild component:\nimport {Component, View} from 'angular2/angular2';\n\n@Component({\n selector: 'display-card'\n})\n\n@View({\n templateUrl: './components/display-card/display-card.html'\n})\n\nexport class DisplayCard{\n name: string;\n}\n\nChild HTML:\n<div class=\"display-card\">\n <div class=\"display-card-header\">\n\n </div>\n <div class=\"display-card-body\">\n <h1 class=\"display-card-title\">{{name}}</h1>\n <h4 class=\"display-card-subtitle\"></h4>\n </div>\n</div>\n\nI added the name property to the child component since this is the error I'm getting when I try this out:\nEXCEPTION: Can't bind to 'name' since it isn't a known property of the '<display-card>' element and there are no matching directives with a corresponding property\n\nIs this even possible with components?",
"\n\nA:\n\nYou need to specify the properties on your Component declaration : \n@Component({\n selector: 'display-card',\n properties: ['name']\n})\n\n"
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"Barone, Giuseppe - Ruling February 3, 1994\n\nRuling, February 3, 1994\n\nthe Application of Giuseppe Barone for Extension of a Tidal Wetlands Permit\npursuant to Environmental Conservation Law Article 25\n\nISSUES RULING\n\nDEC Application No. ",
"2-6308-126/1-0\n\nFebruary 3, 1994\n\nOn January 25, 1994, I wrote to both parties regarding whether it would be necessary to have a hearing on the question of whether Mr. Barone's permit could be extended or if he would need to apply for a new permit. ",
"In response to my letter, Mr. Saragoussi, on behalf of Mr. Barone, sent me copies of three letters which had not been included with the hearing referral. ",
"He also inquired about the regulations which were in effect regarding renewals and extensions of tidal wetlands permits on September 1, 1987.",
"\n\nSeptember 1, 1987 is the date of one of the three letters which Mr. Saragoussi sent to me. ",
"On that date, and October 8, 1987 (the effective date of the permit), the section of 6 NYCRR Part 621 regarding renewals of permits did not state that the application for a renewal needed to be submitted any specified number of days prior to the permit's expiration date. ",
"Part 661, however, as it read on both September 1 and October 8, 1987, contained a provision identical to that in the current tidal wetlands regulation. ",
"Former 661.22(b) and the current 661.13(b) both state that, \"The expiration date of any permit issued pursuant to this Part may be extended by the chief permit administrator for good cause shown upon a written request to him filed prior to the expiration date. ",
"Any such extension may not exceed one year in duration.\"",
"\n\nIn addition, the permit itself contained a general condition which provided that the permittee is responsible for keeping the permit active by submitting a renewal application no later than 30 days prior to the expiration date.",
"\n\nThere does not appear to be any dispute that the permit has expired and that the permittee did not request an extension until over two years after the permit expired. ",
"Thus, the permit could not be extended at this time and Mr. Barone will need to submit a new application for the project.",
"\n\nThis conclusion is essentially a ruling that, with respect to the request for an extension of the permit, no issues exist which would require adjudication in a hearing. ",
"The request for an extension of the permit is denied, unless this ruling is reversed or modified by the Commissioner of Environmental Conservation. ",
"I would emphasize that this conclusion does not relate to the merits of the project itself and that I am not making any findings or conclusions at this time regarding whether the project complies with the tidal wetlands regulations nor whether a permit should be issued in response to a new application.",
"\n\nThis issues ruling may be appealed to the Commissioner of Environmental Conservation pursuant to 6 NYCRR 624.6(d). ",
"I am extending the deadline for any such appeals to February 11, 1994. ",
"Any appeals must be mailed by February 11, 1994 and are to be sent to the following address: Commissioner Thomas C. Jorling, c/o Robert H. Feller, Assistant Commissioner for Hearings, NYS Department of Environmental Conservation, 50 Wolf Road, Albany, New York 12233-1550."
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"DeepCompare training code\n==========\n\nThis is training code for CVPR2015 paper \"Learning to Compare Image Patches via Convolutional Neural Networks\". ",
"http://www.cv-foundation.org/openaccess/content_cvpr_2015/papers/Zagoruyko_Learning_to_Compare_2015_CVPR_paper.pdf\n\nThe original code was rewritten to support:\n* parallel data augmentation via torchnet\n* Multi-GPU\n* half precision (fp16) training\n* CPU training\n\n# Required rocks\n\n```\nluarocks install torchnet\nluarocks install cudnn\n```\n\nCudnn is optional.",
"\n\nPreprocessing code depends on OpenCV. ",
"To install it follow https://github.com/VisionLabs/torch-opencv\n\n# Data preprocessing\n\nFirst download Brown dataset http://www.cs.ubc.ca/~mbrown/patchdata/patchdata.html\nThen run preprocessing with this script https://gist.github.com/szagoruyko/569c2b713a2c40629ecbe75fb3c9d980\n\n```\nth create_dataset_file.lua notredame/\nth create_dataset_file.lua yosemite/\nth create_dataset_file.lua liberty/\n```\n\nThis will convert the data to torch format for faster loading and compute per-patch mean.",
"\n\n# Testing existing models\n\n```\ntestOnly=true train_set=liberty/data.t7 test_set=notredame/data.t7 model=2ch_liberty.t7 th train.lua\n```\n\nOnly FPR95 value will be printed, to access TPR and FPR values see `fpr95meter.tpr` and `fpr95meter.fpr` tensors.",
"\nIt is easy to save them in torch/numpy/matlab format to visualize or compare with other methods.",
"\n\nTo test on CPU additionally set `data_type=torch.",
"FloatTensor`\n\n# Training\n\n```\ntrain_set=liberty/data.t7 test_set=notredame/data.t7 model=siam th train.lua\n```\n\nI prefer to save logs in a separate folder, here is the script:\n\n```bash\nexport train_set=/opt/datasets/daisy/notredame/data.t7\nexport test_set=/opt/datasets/daisy/liberty/data.t7\n\nexport save_folder=logs/deepcompare_${model}_$RANDOM$RANDOM\nmkdir -p $save_folder\n\nth train.lua | tee $save_folder/log.txt\n```\n\nTo train on multuple GPUs set: `nGPU=4`\n\nTo train in half-presicion set: `data_type=torch.",
"CudaHalfTensor`\n"
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"Monday, May 05, 2014\n\nLe format image PNM / PNM easy graphic format\n\nPNM (Portable aNy Map) is a graphic file format by Jef Poskanzer (b. 1958) in the eighties.",
"\n\nSuch graphic files can have more specific extensions:\n\n.pbm (Portable BitMap) for black/white graphics files\n\n.pgm (Portable GrayMap) for grays graphics files (it can be more than 50)\n\n.ppm (Portable PixMap) for coloured graphic files\n\nIt's no compressed format, and even worse (a single pixel can be encoded '243 222 123 '!), ",
"but very easy to create. ",
"A PNM begins with a tag ('P1' to 'P6'), a width, a height and (for gray files and coloured maps) a hightest value; after comes the data.",
"\n\nThe P1, P2 and P3 data are ascii-coded and space-separated. ",
"A comment is possible between an # and an end-of-line before the dimensions; the P4, P5 and P6 data are binary-coded, with no separation.",
"\n\nP1: black&white ascii-coded image\n\nA PNM Black/White file begins with 'P1 width height ' (width and height are pixel values), followed by '0' (white) or '1' (black), and - if you want - a space between each pixel.",
"\n\nP1 6 4\n1 1 1 1 1 1\n1 0 0 0 0 1\n1 0 0 0 0 1\n1 1 1 1 1 1\n\n\"P1 6 4 111111100001100001111111 \" is an equivalent (a last dummy pixels seems to be necessary).",
"\n\nNote: this graphic is a 6x4 pixels images, you'll have to zoom it.",
"\n\nA 1000x1000 pixels will be 1 or 2MB large, but it's possible to shrink it by 8 (each pixel is a bit) with the P4 binary format (see below).",
"\n\nP2: gray ascii-coded image\n\nThese files begins with 'P2' tag,\na width and a height, followed by the highest value (until 255). ",
"The data are also ascii-typed and must have space-separations. ",
"In the following sample the values go from 0 (black) to 6\n(white)\n\nP2 4 4 6\n6 5 4 3\n5 4 3 2\n4 3 2 1\n3 2 1 0\n\n\"P2 4 4 6 6 5 4 3 5 4 3 2 4 3 2 1 3 2 1 0 \" is an equivalent.",
"\n\nP3: coloured ascii-coded image\n\nA coloured graphic ASCII begins with a 'P3' tag, follow by a width, a height and a maximal value. ",
"The datas are a sequence of three values which are the red, green and blue values:\n\nThe number of spaces betwen each value doesn't have any importance. ",
"Red, green and blue are only coded with 0 or 255: in this example, it's possible to code in an easier way, setting the maximal value to 1 (before the '#'):\n\nP4, P5 et P6: binary formats\n\nP4, P5 et P6 tags in the beginning of a PNM file are respectivily for black/white, gray scaled and coloured graphics where values are binary coded:\n\nP4: black & white binary-coded:\n\nP4 16 16\n...byte-coded data\n\n...without space nor carriage-return ('\\n','\\r')\n\nFor a P4-PNM file, the first eight pixels must be translated into a value between 0 ('00000000') and 255 ('11111111').",
"\n\nFor instance, WBBWWBBW is encoded through the binary number '01100110' = 102, (the 'f' character).",
"\n\nYou can translate the binary number with int(number,2), and transform it into a character with char():\n\nchar(int(\"01100110\",2))\n\nThe file will be:\n\n\"P4 8 4\nffff\"\n\nSome values cannot be written with ASCII-character. ",
"You can use chr(int('001100110',2) in a routine.",
"\n\nThe best should be adding a line in your script with a command which transforms a PNM-file into PNG-one with os.system(\"convert image.pnm image.png\") from the ImageMagick package (Unix only?).",
"\n\nP5 gray binary-coded image: each pixels is coded by a byte.",
"\n\nP6 colour binary-coded image: each pixel is coded by three bytes (red/green/blue)\n\nHow to generate a P1-file\n\nThis script generates a black circle on a white background (you give the radius). ",
"It tests the pixels one by one: are they at the good distance from the center (x°,y°)? ",
"Pythagore answers with r²=(x-x°)²+(y-y°)². ",
"A file 'circle'+diameter+'.pnm' is created.",
"\n\nAdd comment\n\nAdd comment\n\nYour name\n\nEnter single word term described on the image\n\nSearch\n\nAbout The Author\n\nSociologist specialized in credences, I like scriptings and I find python is a rather good replacement for Omikron BASIC (8:), which unfortunately doesn't exist on Linux (and Atari doesn't exist anymore, though FireBee does exist).",
"\n\nAll scripts are here written on GNU/Linux/Debian/Python 2.x, I'm not sure it's easy to adapt them in a Windows or Mac environment.",
"\n\nI write french pages about python: www.jchr.be/python, and some more on www.jchr.be (in french, since I'm a french-speaking Belgian)"
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"An attendee tries out a Samsung Electronics Co. Gear VR headset during a media event in Seoul, South Korea, on Thursday, Aug. 11, 2016. ",
"SeongJoon Cho | Bloomberg | Getty Images\n\nAmazon.com has been a rough place this holiday season for sellers of Samsung products. ",
"In mid-November, just ahead of the Black Friday and Cyber Monday rush, a number of online sellers of Samsung phones, chargers, cables and TVs were booted from the e-commerce site because of apparently mistaken claims of infringement. ",
"The suspensions were based on notices of inauthentic sales that were sent to Amazon from the e-mail address [email protected]. ",
"MarkMonitor is a digital brand protection agency. ",
"But Amazon got it wrong. ",
"The Seattle-based company told third-party sellers by e-mail as recently as last week that, \"upon further investigation, we have determined that [email protected] did not submit the report.\"",
"\n\nThe e-mail went on to say, \"Rather, Richard Nelson of Sideman & Bancroft LLP ([email protected]) submitted the Intellectual Property complaint on behalf of Samsung.\" ",
"Amazon is admitting that during the busiest shopping season of the year it incorrectly identified the source of an infringement complaint that led to multiple seller suspensions. ",
"The company is now saying that the claim was submitted by Nelson, a San Francisco-based attorney who specializes in IP and fraud enforcement.",
"\n\n\n\n\"How could sellers be so badly misdirected to the wrong agent?\" ",
"said Kelly Johnston, a former risk investigations manager at Amazon who now helps sellers with compliance issues on the site. \"",
"From an operational perspective, this is a massive failure.\"",
"\n\nAn Amazon spokesperson declined to comment, and a representative for MarkMonitor didn't respond to a request for comment. ",
"An e-mail to Nelson requesting comment was forwarded to Samsung. ",
"The company never provided an explanation. ",
"Johnston said her firm, Cascadia Seller Solutions, represents several clients who were suspended from Amazon because of the Samsung issue and not all of them have been reinstated. ",
"One merchant, who spoke on the condition of anonymity for fear of retribution from Amazon, said he was shut down until after Cyber Monday, and knows of other Samsung sellers who were just readmitted last week.",
"\n\nWhile this particular matter only affected a small number of sellers out of the millions on the platform, it further illustrates the chaos that merchants are experiencing trying to navigate Amazon's rapidly growing marketplace. ",
"In response to an influx of counterfeit products and the negative publicity that followed, Amazon has aggressively clamped down on infringers by responding to complaints and shutting down accounts. ",
"Another way Amazon has tried to clean up the site is by expanding its use of so-called brand gating — forcing third-party sellers to pay a fee to sell big brands after first proving the inventory was properly sourced. ",
"In August, sellers of brands including Nike, Adidas and Hasbro had to start providing invoices from manufacturers or distributors showing the purchase of 30 items within the last 90 days.",
"\n\nCertain categories like electronics and software are increasingly risky for third parties, as companies like Samsung, and try to weed out fakes and unauthorized sales. ",
"The crackdown isn't just on Amazon. ",
"Earlier this month, New York police raided a warehouse in Brooklyn and seized more than $7 million worth of inauthentic Samsung and Apple items. ",
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"Chris McCabe, a former Amazon employee who, like Johnston, is now independently helping sellers, said the Samsung case illustrates the shortcomings of Amazon's procedures. \"",
"There's no effective process for verifying that the party sending in the infringement form is accurate or legitimate,\" McCabe said.",
"\n\nMcCabe has been able to restore some of his clients' accounts, but only after they went weeks without any transactions.",
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"\n\nHistory\nUSBWA College Player of the Year was started in 1959, which makes it the oldest running trophy for the college player of the year. ",
"The USBWA annually selects a player of the year and All-America teams for both men and women in college basketball. ",
"The USBWA men's player of the year award is now called the Oscar Robertson Trophy.",
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"It was renamed after the college and professional legend Oscar Robertson in 1998. ",
"Five nominees are presented and the individual with the most votes receives the award during the NCAA Final Four. ",
"The Oscar Robertson Trophy, previously known as the Player of the Year Award, was renamed in 1998 because of Robertson's outstanding career (including winning the first two awards) and his continuing efforts to promote the game of basketball. ",
"He averaged 32.6 points per game in his sophomore year at Cincinnati.",
"\n\nKey\n\nWinners\n\nSee also\nList of U.S. men's college basketball national player of the year awards\n\nReferences\n\nCategory:College basketball player of the year awards in the United States\nCategory:Awards established in 1959"
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"Long Range Wireless Communication Broke Record Distance and Uses Almost No Power\n\nUsing super low power devices, researchers from the University of Washington just broke a long-held distance record by wirelessly transmitting data up to 1.74 miles (2.8 km)! ",
"Their latest version uses 1,000 times LESS power than other current technologies reaching this distance.",
"\n\nPerhaps the people happiest about this breakthrough are those invested in small sensor technologies used in the medical, agricultural, military, wearable consumer tech, and other industries. ",
"This basically means sensors can be made smaller and cheaper without batteries and people won’t have to carry a receiver so close to collect data but can instead monitor many more devices remotely.",
"\n\nThe UW team’s long-range backscatter system uses reflected radio signals to send data at extremely low power and low cost. ",
"They successfully transmitted signals throughout a 4,800-square-foot house, a 41-room office area, and a one-acre vegetable farm. ",
"The system is detailed in a paper to be presented Sept. 13 at UbiComp 2017.",
"\n\n“Until now, devices that can communicate over long distances have consumed a lot of power. ",
"The tradeoff in a low-power device that consumes microwatts of power is that its communication range is short,” said Shyam Gollakota, lead faculty and associate professor in the Paul G. Allen School of Computer Science & Engineering. “",
"Now we’ve shown that we can offer both, which will be pretty game-changing for a lot of different industries and applications.”",
"\n\nThe advantage of reflected (“backscattered”) radio signals is the sensors need almost no power and can get it through thin cheap, flexible printed batteries or ambient sources. ",
"The disadvantage is the receiver’s difficulty distinguishing the extremely weak reflections from the original signal and other noise.",
"\n\nThe system has three components:\n1. ",
"a source that emits a radio signal,\n2. ",
"sensors that encode information in reflections of that signal\n3. ",
"and an inexpensive off-the-shelf receiver that decodes the information.",
"\n\n“It’s like trying to listen to a conversation happening on the other side of a thick wall — you might hear some faint voices but you can’t quite make out the words,” said Mehrdad Hessar, an Allen School doctoral student. “",
"With our new technology, we can essentially decode those words even when the conversation itself is hard to hear.”",
"\n\nThese young electrical engineers exemplify the entrepreneurial spirit. ",
"Instead of trying to solve a problem from within its paradigm, they started from scratch and came up with a breakthrough solution. ",
"They created a business around their invention called Jeeva Wireless that will sell product next year.",
"\n\nThese high-tech transmitters provide the tools to embed micro monitors in countless everyday objects. ",
"As with all advancements of technology, we must be cautious of the effects to our innate rights. ",
"With smaller and smaller sensors communicating data across vaster distances in their own encrypted language, our privacy may be at risk."
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"Q:\n\nUsing AFNetworking to process multiple JSON responses for a single request\n\nI'm trying to find a way to open up a connection to a web service and have that service send down JSON objects on an as-needed basis.",
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"Arrow: Here's what Stephen Amell wants to see in season 5\n\nArrow type TV Show network The CW genre Superhero\n\nWarning: This story contains major spoilers from the season finale of Arrow. ",
"Read at your own risk!",
"\n\nIt was the end of the world as we knew it in the Arrow finale, that is, until Oliver once again saved the day.",
"\n\nDamien Darhk (Neal McDonough) nuked a nearby town, and those deaths made him immensely powerful, making it nearly impossible for Oliver (Stephen Amell) to counteract his magic. ",
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"Their collective hope helped Oliver combat Damien’s magic, buying Felicity (Emily Bett Rickards) enough time to stop the nukes before Oliver ultimately put the big bad down.",
"\n\nIn the end, the finale went the opposite route of last season, as Amell teased would happen. ",
"Lance (Paul Blackthorne) was officially fired, so he decided to skip town with Donna (Charlotte Ross); Thea (Willa Holland) quit the team to find herself; and Diggle (David Ramsey) reenlisted, leaving just Oliver and Felicity to pick up the pieces after he’s appointed the new mayor of Star City.",
"\n\nDespite the exodus, it sounds like there will be a team next season — at least based on the recently released logline: “Sinister players with a connection to Oliver’s past will push the team to its breaking point, threatening everything Oliver’s worked for and his legacy as the Green Arrow.”",
"\n\nNow to the flashbacks: In one of the show’s more obvious uses of foreshadowing, Oliver had promised Taiana (Elysia Rotaru) that if she didn’t get off the island, he would go to Russia to tell her parents what happened. ",
"Cue Oliver mercy-killing Taiana after her magical overload and heading to Russia to fulfill his promise. ",
"Hmm, maybe that’s where he’ll meet the recently mentioned Kovar.",
"\n\nIn the wake of Oliver saving the world, Amell hopes the series will get back to basics in its fifth season. “",
"When we started Arrow, we were the superpower-less superhero show,” Amell told EW while promoting his new film Teenage Mutant Ninja Turtles: Out of the Shadows. “",
"Because of our success and because of opportunities that The CW has had, we’ve had to break away from that original modus operandi a little bit, because we were introducing Barry Allen, and in subsequent seasons, we’ve shepherded some of the Legends of Tomorrow onto their own show.",
"\n\n“Even though Supergirl is joining the ranks, there’s no new person or new show to introduce this year, and I think as a result of that, we need to get back to focusing more on some of the core elements that used to define Arrow,” Amell continued. “",
"To me, that’s hand-to-hand combat, no superpowers, and dealing with the job of cleaning up Star City.”",
"\n\nArrow will return this fall on The CW. ",
"In the meantime, read our breakdown of The Flash finale’s nod to Black Flash, the potential for season 3 to explore Flashpoint, and that reveal of the man in the iron mask.",
"\n\nReporting by Nina Terrero."
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[
"#region License\n/*\n * TcpListenerWebSocketContext.cs\n *\n * The MIT License\n *\n * Copyright (c) 2012-2018 sta.blockhead\n *\n * Permission is hereby granted, free of charge, to any person obtaining a copy\n * of this software and associated documentation files (the \"Software\"), to deal\n * in the Software without restriction, including without limitation the rights\n * to use, copy, modify, merge, publish, distribute, sublicense, and/or sell\n * copies of the Software, and to permit persons to whom the Software is\n * furnished to do so, subject to the following conditions:\n *\n * The above copyright notice and this permission notice shall be included in\n * all copies or substantial portions of the Software.",
"\n *\n * THE SOFTWARE IS PROVIDED \"AS IS\", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR\n * IMPLIED, INCLUDING BUT NOT LIMITED TO THE WARRANTIES OF MERCHANTABILITY,\n * FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT. ",
"IN NO EVENT SHALL THE\n * AUTHORS OR COPYRIGHT HOLDERS BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER\n * LIABILITY, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM,\n * OUT OF OR IN CONNECTION WITH THE SOFTWARE OR THE USE OR OTHER DEALINGS IN\n * THE SOFTWARE.",
"\n */\n#endregion\n\n#region Contributors\n/*\n * Contributors:\n * - Liryna <[email protected]>\n */\n#endregion\n\nusing System;\nusing System.",
"Collections.",
"Generic;\nusing System.",
"Collections.",
"Specialized;\nusing System.",
"IO;\nusing System.",
"Net.",
"Security;\nusing System.",
"Net.",
"Sockets;\nusing System.",
"Security.",
"Principal;\nusing System.",
"Text;\n\nnamespace WebSocketSharp.",
"Net.",
"WebSockets\n{\n /// <summary>\n /// Provides the access to the information in a WebSocket handshake request to\n /// a <see cref=\"TcpListener\"/> instance.",
"\n /// </summary>\n internal class TcpListenerWebSocketContext : WebSocketContext\n {\n #region Private Fields\n\n private Logger _log;\n private NameValueCollection _queryString;\n private HttpRequest _request;\n private Uri _requestUri;\n private bool _secure;\n private System.",
"Net.",
"EndPoint _serverEndPoint;\n private Stream _stream;\n private TcpClient _tcpClient;\n private IPrincipal _user;\n private System.",
"Net.",
"EndPoint _userEndPoint;\n private WebSocket _websocket;\n\n #endregion\n\n #region Internal Constructors\n\n internal TcpListenerWebSocketContext (\n TcpClient tcpClient,\n string protocol,\n bool secure,\n ServerSslConfiguration sslConfig,\n Logger log\n )\n {\n _tcpClient = tcpClient;\n _secure = secure;\n _log = log;\n\n var netStream = tcpClient.",
"GetStream ();\n if (secure) {\n var sslStream = new SslStream (\n netStream,\n false,\n sslConfig.",
"ClientCertificateValidationCallback\n );\n\n sslStream.",
"AuthenticateAsServer (\n sslConfig.",
"ServerCertificate,\n sslConfig.",
"ClientCertificateRequired,\n sslConfig.",
"EnabledSslProtocols,\n sslConfig.",
"CheckCertificateRevocation\n );\n\n _stream = sslStream;\n }\n else {\n _stream = netStream;\n }\n\n var sock = tcpClient.",
"Client;\n _serverEndPoint = sock.",
"LocalEndPoint;\n _userEndPoint = sock.",
"RemoteEndPoint;\n\n _request = HttpRequest.",
"Read (_stream, 90000);\n _websocket = new WebSocket (this, protocol);\n }\n\n #endregion\n\n #region Internal Properties\n\n internal Logger Log {\n get {\n return _log;\n }\n }\n\n internal Stream Stream {\n get {\n return _stream;\n }\n }\n\n #endregion\n\n #region Public Properties\n\n /// <summary>\n /// Gets the HTTP cookies included in the handshake request.",
"\n /// </summary>\n /// <value>\n /// <para>\n /// A <see cref=\"WebSocketSharp.",
"Net.",
"CookieCollection\"/> that contains\n /// the cookies.",
"\n /// </para>\n /// <para>\n /// An empty collection if not included.",
"\n /// </para>\n /// </value>\n public override CookieCollection CookieCollection {\n get {\n return _request.",
"Cookies;\n }\n }\n\n /// <summary>\n /// Gets the HTTP headers included in the handshake request.",
"\n /// </summary>\n /// <value>\n /// A <see cref=\"NameValueCollection\"/> that contains the headers.",
"\n /// </value>\n public override NameValueCollection Headers {\n get {\n return _request.",
"Headers;\n }\n }\n\n /// <summary>\n /// Gets the value of the Host header included in the handshake request.",
"\n /// </summary>\n /// <value>\n /// <para>\n /// A <see cref=\"string\"/> that represents the server host name requested\n /// by the client.",
"\n /// </para>\n /// <para>\n /// It includes the port number if provided.",
"\n /// </para>\n /// </value>\n public override string Host {\n get {\n return _request.",
"Headers[\"Host\"];\n }\n }\n\n /// <summary>\n /// Gets a value indicating whether the client is authenticated.",
"\n /// </summary>\n /// <value>\n /// <c>true</c> if the client is authenticated; otherwise, <c>false</c>.",
"\n /// </value>\n public override bool IsAuthenticated {\n get {\n return _user !",
"= null;\n }\n }\n\n /// <summary>\n /// Gets a value indicating whether the handshake request is sent from\n /// the local computer.",
"\n /// </summary>\n /// <value>\n /// <c>true</c> if the handshake request is sent from the same computer\n /// as the server; otherwise, <c>false</c>.",
"\n /// </value>\n public override bool IsLocal {\n get {\n return UserEndPoint.",
"Address.",
"IsLocal ();\n }\n }\n\n /// <summary>\n /// Gets a value indicating whether a secure connection is used to send\n /// the handshake request.",
"\n /// </summary>\n /// <value>\n /// <c>true</c> if the connection is secure; otherwise, <c>false</c>.",
"\n /// </value>\n public override bool IsSecureConnection {\n get {\n return _secure;\n }\n }\n\n /// <summary>\n /// Gets a value indicating whether the request is a WebSocket handshake\n /// request.",
"\n /// </summary>\n /// <value>\n /// <c>true</c> if the request is a WebSocket handshake request; otherwise,\n /// <c>false</c>.",
"\n /// </value>\n public override bool IsWebSocketRequest {\n get {\n return _request.",
"IsWebSocketRequest;\n }\n }\n\n /// <summary>\n /// Gets the value of the Origin header included in the handshake request.",
"\n /// </summary>\n /// <value>\n /// <para>\n /// A <see cref=\"string\"/> that represents the value of the Origin header.",
"\n /// </para>\n /// <para>\n /// <see langword=\"null\"/> if the header is not present.",
"\n /// </para>\n /// </value>\n public override string Origin {\n get {\n return _request.",
"Headers[\"Origin\"];\n }\n }\n\n /// <summary>\n /// Gets the query string included in the handshake request.",
"\n /// </summary>\n /// <value>\n /// <para>\n /// A <see cref=\"NameValueCollection\"/> that contains the query\n /// parameters.",
"\n /// </para>\n /// <para>\n /// An empty collection if not included.",
"\n /// </para>\n /// </value>\n public override NameValueCollection QueryString {\n get {\n if (_queryString == null) {\n var uri = RequestUri;\n _queryString = QueryStringCollection.",
"Parse (\n uri !",
"= null ? ",
"uri.",
"Query : null,\n Encoding.",
"UTF8\n );\n }\n\n return _queryString;\n }\n }\n\n /// <summary>\n /// Gets the URI requested by the client.",
"\n /// </summary>\n /// <value>\n /// <para>\n /// A <see cref=\"Uri\"/> that represents the URI parsed from the request.",
"\n /// </para>\n /// <para>\n /// <see langword=\"null\"/> if the URI cannot be parsed.",
"\n /// </para>\n /// </value>\n public override Uri RequestUri {\n get {\n if (_requestUri == null) {\n _requestUri = HttpUtility.",
"CreateRequestUrl (\n _request.",
"RequestUri,\n _request.",
"Headers[\"Host\"],\n _request.",
"IsWebSocketRequest,\n _secure\n );\n }\n\n return _requestUri;\n }\n }\n\n /// <summary>\n /// Gets the value of the Sec-WebSocket-Key header included in\n /// the handshake request.",
"\n /// </summary>\n /// <value>\n /// <para>\n /// A <see cref=\"string\"/> that represents the value of\n /// the Sec-WebSocket-Key header.",
"\n /// </para>\n /// <para>\n /// The value is used to prove that the server received\n /// a valid WebSocket handshake request.",
"\n /// </para>\n /// <para>\n /// <see langword=\"null\"/> if the header is not present.",
"\n /// </para>\n /// </value>\n public override string SecWebSocketKey {\n get {\n return _request.",
"Headers[\"Sec-WebSocket-Key\"];\n }\n }\n\n /// <summary>\n /// Gets the names of the subprotocols from the Sec-WebSocket-Protocol\n /// header included in the handshake request.",
"\n /// </summary>\n /// <value>\n /// <para>\n /// An <see cref=\"T:System.",
"Collections.",
"Generic.",
"IEnumerable{string}\"/>\n /// instance.",
"\n /// </para>\n /// <para>\n /// It provides an enumerator which supports the iteration over\n /// the collection of the names of the subprotocols.",
"\n /// </para>\n /// </value>\n public override IEnumerable<string> SecWebSocketProtocols {\n get {\n var val = _request.",
"Headers[\"Sec-WebSocket-Protocol\"];\n if (val == null || val.",
"Length == 0)\n yield break;\n\n foreach (var elm in val.",
"Split (',')) {\n var protocol = elm.",
"Trim ();\n if (protocol.",
"Length == 0)\n continue;\n\n yield return protocol;\n }\n }\n }\n\n /// <summary>\n /// Gets the value of the Sec-WebSocket-Version header included in\n /// the handshake request.",
"\n /// </summary>\n /// <value>\n /// <para>\n /// A <see cref=\"string\"/> that represents the WebSocket protocol\n /// version specified by the client.",
"\n /// </para>\n /// <para>\n /// <see langword=\"null\"/> if the header is not present.",
"\n /// </para>\n /// </value>\n public override string SecWebSocketVersion {\n get {\n return _request.",
"Headers[\"Sec-WebSocket-Version\"];\n }\n }\n\n /// <summary>\n /// Gets the endpoint to which the handshake request is sent.",
"\n /// </summary>\n /// <value>\n /// A <see cref=\"System.",
"Net.",
"IPEndPoint\"/> that represents the server IP\n /// address and port number.",
"\n /// </value>\n public override System.",
"Net.",
"IPEndPoint ServerEndPoint {\n get {\n return (System.",
"Net.",
"IPEndPoint) _serverEndPoint;\n }\n }\n\n /// <summary>\n /// Gets the client information.",
"\n /// </summary>\n /// <value>\n /// <para>\n /// A <see cref=\"IPrincipal\"/> instance that represents identity,\n /// authentication, and security roles for the client.",
"\n /// </para>\n /// <para>\n /// <see langword=\"null\"/> if the client is not authenticated.",
"\n /// </para>\n /// </value>\n public override IPrincipal User {\n get {\n return _user;\n }\n }\n\n /// <summary>\n /// Gets the endpoint from which the handshake request is sent.",
"\n /// </summary>\n /// <value>\n /// A <see cref=\"System.",
"Net.",
"IPEndPoint\"/> that represents the client IP\n /// address and port number.",
"\n /// </value>\n public override System.",
"Net.",
"IPEndPoint UserEndPoint {\n get {\n return (System.",
"Net.",
"IPEndPoint) _userEndPoint;\n }\n }\n\n /// <summary>\n /// Gets the WebSocket instance used for two-way communication between\n /// the client and server.",
"\n /// </summary>\n /// <value>\n /// A <see cref=\"WebSocketSharp.",
"WebSocket\"/>.",
"\n /// </value>\n public override WebSocket WebSocket {\n get {\n return _websocket;\n }\n }\n\n #endregion\n\n #region Private Methods\n\n private HttpRequest sendAuthenticationChallenge (string challenge)\n {\n var res = HttpResponse.",
"CreateUnauthorizedResponse (challenge);\n var bytes = res.",
"ToByteArray ();\n _stream.",
"Write (bytes, 0, bytes.",
"Length);\n\n return HttpRequest.",
"Read (_stream, 15000);\n }\n\n #endregion\n\n #region Internal Methods\n\n internal bool Authenticate (\n AuthenticationSchemes scheme,\n string realm,\n Func<IIdentity, NetworkCredential> credentialsFinder\n )\n {\n var chal = new AuthenticationChallenge (scheme, realm).ToString ();\n\n var retry = -1;\n Func<bool> auth = null;\n auth =\n () => {\n retry++;\n if (retry > 99)\n return false;\n\n var user = HttpUtility.",
"CreateUser (\n _request.",
"Headers[\"Authorization\"],\n scheme,\n realm,\n _request.",
"HttpMethod,\n credentialsFinder\n );\n\n if (user !",
"= null && user.",
"Identity.",
"IsAuthenticated) {\n _user = user;\n return true;\n }\n\n _request = sendAuthenticationChallenge (chal);\n return auth ();\n };\n\n return auth ();\n }\n\n internal void Close ()\n {\n _stream.",
"Close ();\n _tcpClient.",
"Close ();\n }\n\n internal void Close (HttpStatusCode code)\n {\n var res = HttpResponse.",
"CreateCloseResponse (code);\n var bytes = res.",
"ToByteArray ();\n _stream.",
"Write (bytes, 0, bytes.",
"Length);\n\n _stream.",
"Close ();\n _tcpClient.",
"Close ();\n }\n\n #endregion\n\n #region Public Methods\n\n /// <summary>\n /// Returns a string that represents the current instance.",
"\n /// </summary>\n /// <returns>\n /// A <see cref=\"string\"/> that contains the request line and headers\n /// included in the handshake request.",
"\n /// </returns>\n public override string ToString ()\n {\n return _request.",
"ToString ();\n }\n\n #endregion\n }\n}\n"
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[
"Q:\n\nWhat is the typical convention for importing Java packages?",
"\n\nIn my programming classes in college, we would just import an entire package even if we just used one class from it. ",
"This may have been because we were supposed to use IDEs that did not offer autocompletion or anything fancy like that, so it would just make it easier to code in general.",
"\nHowever, now that I'm more of an experienced programmer, is it more conventional to import Java packages as a whole or just the classes from those packages that you would need?",
"\nFor example, instead of:\nimport java.util.*;",
"\n\nIs it conventional to say:\nimport java.util.",
"ArrayList;\nimport java.util.",
"List;\nimport java.util.",
"Random;\n\netc.?",
"\nDoes importing an entire package compared to select classes use more memory?",
"\n\nA:\n\nIt's not so much a memory issue, but rather that you run the risk of inadvertently importing the wrong class if you use the * notation. ",
" Generally it's not a problem, but if the * matches a class that you meant to pull in from another package it's a hard bug to find.",
"\nI've seen IDE's use the rule that specific class imports are replaced by a single '*' import statement if you're importing three or more classes from that package. ",
" I prefer to call out each imported class by name.",
"\n\nA:\n\nThis Wildcard type-import-on-demand declarations as you have given like import java.util.*; ",
"must NOT be used directly in code; use only required class name instead like import java.util.",
"ArrayList;\nThe following and many other reasons are there:\n\nThe important reason is that a new unexpected class file can be added to the same package. ",
" This new class can conflict with a type you are using from another package, thereby turning a previously correct program into an incorrect one without touching the program itself. ",
"\nExplicit class imports clearly convey to a reader the exact classes that are being used (and which classes are NOT being used). ",
"\nExplicit class imports provide better compile performance. ",
"While type-import-on-demand declarations are convenient for the programmer and save a little bit of time initially, this time is paid for increased compile time every time the file is compiled. ",
"\n\nFor more regarding coding conventions refer: http://geosoft.no/development/javastyle.html#\n\n"
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" factors of 2787.",
"\n3, 929\nList the prime factors of 1713.",
"\n3, 571\nList the prime factors of 1244.",
"\n2, 311\nWhat are the prime factors of 27639?",
"\n3, 37, 83\nList the prime factors of 19740.",
"\n2, 3, 5, 7, 47\nList the prime factors of 17592.",
"\n2, 3, 733\nWhat are the prime factors of 2001?",
"\n3, 23, 29\nWhat are the prime factors of 40413?",
"\n3, 19, 709\nList the prime factors of 4406.",
"\n2, 2203\nWhat are the prime factors of 25022?",
"\n2, 12511\nList the prime factors of 669.",
"\n3, 223\nWhat are the prime factors of 99032?",
"\n2, 12379\nList the prime factors of 2788.",
"\n2, 17, 41\nWhat are the prime factors of 2318?",
"\n2, 19, 61\nList the prime factors of 4707.",
"\n3, 523\nWhat are the prime factors of 111066?",
"\n2, 3, 107, 173\nWhat are the prime factors of 2845?",
"\n5, 569\nList the prime factors of 146.",
"\n2, 73\nWhat are the prime factors of 42656?",
"\n2, 31, 43\nWhat are the prime factors of 232?",
"\n2, 29\nList the prime factors of 2605.",
"\n5, 521\nWhat are the prime factors of 911?",
"\n911\nList the prime factors of 10250.",
"\n2, 5, 41\nList the prime factors of 17616.",
"\n2, 3, 367\nWhat are the prime factors of 6496?",
"\n2, 7, 29\nWhat are the prime factors of 1409?",
"\n1409\nWhat are the prime factors of 4936?",
"\n2, 617\nList the prime factors of 546.",
"\n2, 3, 7, 13\nList the prime factors of 11446.",
"\n2, 59, 97\nWhat are the prime factors of 2535?",
"\n3, 5, 13\nWhat are the prime factors of 47256?",
"\n2, 3, 11, 179\nWhat are the prime factors of 3889?",
"\n3889\nList the prime factors of 39700.",
"\n2, 5, 397\nList the prime factors of 7637.",
"\n7, 1091\nList the prime factors of 5339.",
"\n19, 281\nWhat are the prime factors of 65272?",
"\n2, 41, 199\nWhat are the prime factors of 28415?",
"\n5, 5683\nWhat are the prime factors of 1498?",
"\n2, 7, 107\nList the prime factors of 8355.",
"\n3, 5, 557\nList the prime factors of 727.",
"\n727\nList the prime factors of 993.",
"\n3, 331\nWhat are the prime factors of 777?",
"\n3, 7, 37\nWhat are the prime factors of 95126?",
"\n2, 47563\nWhat are the prime factors of 6834?",
"\n2, 3, 17, 67\nList the prime factors of 2124.",
"\n2, 3, 59\nList the prime factors of 13285.",
"\n5, 2657\nList the prime factors of 4887.",
"\n3, 181\nList the prime factors of 8068.",
"\n2, 2017\nWhat are the prime factors of 4429?",
"\n43, 103\nList the prime factors of 12752.",
"\n2, 797\nList the prime factors of 153.",
"\n3, 17\nList the prime factors of 1946.",
"\n2, 7, 139\nList the prime factors of 17915.",
"\n5, 3583\nList the prime factors of 1951.",
"\n1951\nList the prime factors of 45960.",
"\n2, 3, 5, 383\nWhat are the prime factors of 1008?",
"\n2, 3, 7\nWhat are the prime factors of 95?",
"\n5, 19\nWhat are the prime factors of 4335?",
"\n3, 5, 17\nList the prime factors of 30149.",
"\n7, 59, 73\nWhat are the prime factors of 6814?",
"\n2, 3407\nList the prime factors of 33496.",
"\n2, 53, 79\nList the prime factors of 138003.",
"\n3, 157, 293\nList the prime factors of 24703.",
"\n7, 3529\nWhat are the prime factors of 641?",
"\n641\nList the prime factors of 43304.",
"\n2, 5413\nList the prime factors of 4124.",
"\n2, 1031\nList the prime factors of 41722.",
"\n2, 23, 907\nList the prime factors of 2423.",
"\n2423\nWhat are the prime factors of 10189?",
"\n23, 443\nWhat are the prime factors of 2045?",
"\n5, 409\nList the prime factors of 24129.",
"\n3, 7, 383\nList the prime factors of 3673.",
"\n3673\nWhat are the prime factors of 3394?",
"\n2, 1697\nWhat are the prime factors of 2435?",
"\n5, 487\nList the prime factors of 20063.",
"\n20063\nList the prime factors of 6067.",
"\n6067\nWhat are the prime factors of 14092?",
"\n2, 13, 271\nWhat are the prime factors of 14762?",
"\n2, 11, 61\nList the prime factors of 5917.",
"\n61, 97\nList the prime factors of 20001.",
"\n3, 59, 113\nList the prime factors of 22652.",
"\n2, 7, 809\nWhat are the prime factors of 11917?",
"\n17, 701\nWhat are the prime factors of 11190?",
"\n2, 3, 5, 373\nList the prime factors of 85168.",
"\n2, 5323\nWhat are the prime factors of 10379?",
"\n97, 107\nList the prime factors of 678.",
"\n2, 3, 113\nWhat are the prime factors of 3038?",
"\n2, 7, 31\nWhat are the prime factors of 55780?",
"\n2, 5, 2789\nWhat are the prime factors of 38849?",
"\n53, 733\nList the prime factors of 1652.",
"\n2, 7, 59\nWhat are the prime factors of 5045?",
"\n5, 1009\nWhat are the prime factors of 45540?",
"\n2, 3, 5, 11, 23\nWhat are the prime factors of 708?",
"\n2, 3, 59\nWhat are the prime factors of 21445?",
"\n5, 4289\nList the prime factors of 873.",
"\n3, 97\nWhat are the prime factors of 371?",
"\n7, 53\nList the prime factors of 1247.",
"\n29, 43\nList the prime factors of 8403.",
"\n3, 2801\nWhat are the prime factors of 1315?",
"\n5, 263\nWhat are the prime factors of 5081?",
"\n5081\nList the prime factors of 41338.",
"\n2, 11, 1879\nWhat are the prime factors of 23780?",
"\n2, 5, 29, 41\nWhat are the prime factors of 12117?",
"\n3, 7, 577\nWhat are the prime factors of 159?",
"\n3, 53\nWhat are the prime factors of 23649?",
"\n3, 7883\nList the prime factors of 355.",
"\n5, 71\nWhat are the prime factors of 319?",
"\n11, 29\nList the prime factors of 4746.",
"\n2, 3, 7, 113\nWhat are the prime factors of 863?",
"\n863\nList the prime factors of 1364.",
"\n2, 11, 31\nWhat are the prime factors of 59261?",
"\n19, 3119\nWhat are the prime factors of 92395?",
"\n5, 17, 1087\nList the prime factors of 848.",
"\n2, 53\nWhat are the prime factors of 72?",
"\n2, 3\nList the prime factors of 809.",
"\n809\nList the prime factors of 3582.",
"\n2, 3, 199\nWhat are the prime factors of 112337?",
"\n112337\nWhat are the prime factors of 645?",
"\n3, 5, 43\nWhat are the prime factors of 3050?",
"\n2, 5, 61\nList the prime factors of 1724.",
"\n2, 431\nWhat are the prime factors of 6341?",
"\n17, 373\nWhat are the prime factors of 1774?",
"\n2, 887\nList the prime factors of 24398.",
"\n2, 11, 1109\nList the prime factors of 11554.",
"\n2, 53, 109\nWhat are the prime factors of 119276?",
"\n2, 29819\nWhat are the prime factors of 21076?",
"\n2, 11, 479\nWhat are the prime factors of 986?",
"\n2, 17, 29\nWhat are the prime factors of 3091?",
"\n11, 281\nList the prime factors of 33776.",
"\n2, 2111\nList the prime factors of 3703.",
"\n7, 23\nList the prime factors of 37993.",
"\n37993\nWhat are the prime factors of 2957?",
"\n2957\nList the prime factors of 37249.",
"\n193\nList the prime factors of 3981.",
"\n3, 1327\nWhat are the prime factors of 5037?",
"\n3, 23, 73\nWhat are the prime factors of 3333?",
"\n3, 11, 101\nList the prime factors of 623.",
"\n7, 89\nWhat are the prime factors of 2077?",
"\n31, 67\nList the prime factors of 31378.",
"\n2, 29, 541\nWhat are the prime factors of 58290?",
"\n2, 3, 5, 29, 67\nWhat are the prime factors of 2897?",
"\n2897\nList the prime factors of 1621.",
"\n1621\nList the prime factors of 56093.",
"\n56093\nWhat are the prime factors of 4625?",
"\n5, 37\nWhat are the prime factors of 594?",
"\n2, 3, 11\nList the prime factors of 156.",
"\n2, 3, 13\nList the prime factors of 1733.",
"\n1733\nList the prime factors of 7351.",
"\n7351\nList the prime factors of 5779.",
"\n5779\nList the prime factors of 42238.",
"\n2, 7, 431\nList the prime factors of 6751.",
"\n43, 157\nWhat are the prime factors of 38429?",
"\n83, 463\nList the prime factors of 855.",
"\n3, 5, 19\nList the prime factors of 156833.",
"\n156833\nWhat are the prime factors of 42135?",
"\n3, 5, 53\nList the prime factors of 17033.",
"\n17033\nWhat are the prime factors of 50821?",
"\n50821\nList the prime factors of 7725.",
"\n3, 5, 103\nList the prime factors of 19723.",
"\n11, 163\nWhat are the prime factors of 2982?",
"\n2, 3, 7, 71\nList the prime factors of 4056.",
"\n2, 3, 13\nList the prime factors of 1946.",
"\n2, 7, 139\nList the prime factors of 105312.",
"\n2, 3, 1097\nWhat are the prime factors of 5392?",
"\n2, 337\nWhat are the prime factors of 1030?",
"\n2, 5, 103\nList the prime factors of 10289.",
"\n10289\nWhat are the prime factors of 70784?",
"\n2, 7, 79\nList the prime factors of 12485.",
"\n5, 11, 227\nWhat are the prime factors of 53451?",
"\n3, 5939\nWhat are the prime factors of 48038?",
"\n2, 24019\nList the prime factors of 732.",
"\n2, 3, 61\nWhat are the prime factors of 23376?",
"\n2, 3, 487\nWhat are the prime factors of 15593?",
"\n31, 503\nList the prime factors of 30.",
"\n2, 3, 5\nList the prime factors of 3077.",
"\n17, 181\nWhat are the prime factors of 18087?",
"\n3, 6029\nWhat are the prime factors of 93867?",
"\n3, 67, 467\nWhat are the prime factors of 27264?",
"\n2, 3, 71\nWhat are the prime factors of 1298?",
"\n2, 11, 59\nWhat are the prime factors of 8363?",
"\n8363\nList the prime factors of 37875.",
"\n3, 5, 101\nWhat are the prime factors of 27879?",
"\n3, 9293\nWhat are the prime factors of 1153?",
"\n1153\nWhat are the prime factors of 62781?",
"\n3, 17, 1231\nList the prime factors of 2070.",
"\n2, 3, 5, 23\nList the prime factors of 22415.",
"\n5, 4483\nList the prime factors of 582.",
"\n2, 3, 97\nList the prime factors of 86339.",
"\n11, 47, 167\nWhat are the prime factors of 4055?",
"\n5, 811\nList the prime factors of 89791.",
"\n13, 6907\nWhat are the prime factors of 98851?",
"\n41, 2411\nList the prime factors of 4823.",
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"Bullous Pemphigoid: A 10-Year Study of Discordant Results on Direct Immunofluorescence.",
"\nBullous pemphigoid (BP) is the most common subepidermal autoimmune disorder characterized by tense bullae. ",
"It is associated with circulating autoantibodies against BP antigen-1 and BP antigen-2. ",
"Diagnosis is based upon clinical, histopathologic, and immunopathologic examination. ",
"Direct immunofluorescence (DIF) of perilesional skin highlights C3 with or without IgG in a linear pattern along the basement membrane. ",
"We hypothesized that repeat biopsies may be required for a definitive DIF diagnosis of BP, as initial DIF evaluation may result in a false-negative result. ",
"A retrospective chart review was conducted on 1143 specimens collected for evaluation for BP. ",
"Cases from 2 Vancouver Coastal Health Authority laboratories from 2006 to 2016 were reviewed. ",
"Results were interpreted as positive, negative, or indeterminate based on pathologic description and specimen quality. ",
"After meeting the inclusion criteria, 739 specimens were further evaluated. ",
"There were 289 cases of BP in the 10-year period. ",
"Five patients (1.73%; 95% confidence interval [CI], 1.50-1.96) required a second biopsy to support a BP diagnosis, and within this group, 1.04% of the 289 (95% CI, 0.811-1.27) were true successive negative-to-positive DIF results. ",
"DIF is the most reliable test used to diagnose BP; however, a small percentage of patients will initially have a negative result. ",
"False-negative or indeterminate results may be due to specimen sampling from lesional skin or due to a subthreshold quantity of immune complexes in the skin. ",
"Repeat biopsy is warranted despite an initial negative DIF if BP is clinically suspected."
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"Hunters (2020 TV series)\n\nHunters is an American drama web television series created by David Weil. ",
"It premiered on February 21, 2020 on Amazon Prime Video.",
"\n\nPremise\nThe series is inspired by a number of real Nazi hunters through the decades, but it is not meant to be a specific representation of any of them. ",
"It follows a diverse band of Nazi hunters living in 1977 New York City who discover that Nazi war criminals are conspiring to create a Fourth Reich in the U.S.\n\nCast and characters\n\nMain\nLogan Lerman as Jonah Heidelbaum, a teenage mathematics whiz who takes his grandmother's place on the Hunters\nJerrika Hinton as Millie Morris, an FBI agent who stumbles onto the Fourth Reich and the Hunters during a murder investigation\nLena Olin as The Colonel, leader of the Fourth Reich\nSaul Rubinek as Murray Markowitz, Mindy's husband and the Hunters' electronics expert\nCarol Kane as Mindy Markowitz, Murray's wife and the Hunters' signals expert\nJosh Radnor as Lonny Flash, actor and master of disguises for the Hunters\nGreg Austin as Travis Leich, a Nazi acolyte drawn into the Fourth Reich\nTiffany Boone as Roxy Jones, the Hunters' driver and first fighter\nLouis Ozawa as Joe Torrance, a Vietnam War veteran and the Hunters' combat expert\nKate Mulvany as Sister Harriet, a former MI6 operative who now works with the Hunters\nDylan Baker as Biff Simpson, an Undersecretary of State in the Carter administration and secretly a Nazi refugee\nAl Pacino as Meyer Offerman, a Jewish philanthropist and Holocaust survivor who recruited and leads the Hunters\nZack Schor as young Meyer\nChristian Oliver as Wilhelm Zuchs, \"The Wolf,\" a Nazi doctor at Auschwitz who tormented both Meyer and Jonah's grandmother Ruth\n\nRecurring\nJonno Davies as Tobias, the Colonel's body man\nJames LeGros as Hank Grimsby, former OSS operative and now Millie's boss at the FBI\nEbony Obsidian as Carol Lockhart\nCaleb Emery as Arthur “Bootyhole” McGuigan\nHenry Hunter Hall as Sherman “Cheeks” Johnson\nJeannie Berlin as Ruth Heidelbaum, Jonah's grandmother and a survivor of Auschwitz\nAnnie Hägg as young Ruth\nJulissa Bermudez as Maria\nPhoenix Noelle as Malika\nMegan Channell as Katarina Löw\n'Keena' Thort-Kourt Kyna Kynetruve as the Great Dane\nMiles G. Jackson as Danny Rohr\nBecky Ann Baker as Commerce Secretary Juanita M. Kreps\nCelia Weston as Dottie\nBen Livingston as President Jimmy Carter\n\nGuests\nJosh Mostel as Rabbi Steckler\nBarbara Sukowa as Tilda Sauer\nJune Ballinger as Woman with Cane\nJudd Hirsch as Simon Wiesenthal\nKeir Dullea as Klaus Rhinehart\nWilliam Sadler as Friedrich Mann\nJohn Noble as Fredric Hauser\n\nEpisodes\n\nProduction\n\nDevelopment\nOn May 17, 2018, it was announced that Amazon Video had given the production a straight-to-series order for a first season consisting of ten episodes. ",
"The series was created by David Weil who was set to executive produce alongside Jordan Peele, Tom Lesinski, Jenna Santoianni, and Win Rosenfeld. ",
"Weil was also expected to write for the series as well. ",
"Production companies involved with the series were slated to consist of Monkeypaw Productions and Sonar Entertainment. ",
"On August 7, 2018, it was announced that Nikki Toscano had joined the production as an executive producer and would also serve as co-showrunner alongside Weil.",
"\n\nCasting\nOn December 13, 2018, it was reported that Logan Lerman was in talks for a lead role in the series, Jonah Heidelbaum. ",
"On January 10, 2019, it was reported that Al Pacino was finalizing a deal for a starring role in the series. ",
"On February 7, 2019, it was reported that Jerrika Hinton, Dylan Baker, Lena Olin, Greg Austin, Catherine Tate, Tiffany Boone, Saul Rubinek, and Carol Kane were in various stages of negotiations to join the cast of the series. ",
"Four days later, it was announced that Boone had officially joined the cast. ",
"Josh Radnor was cast in March. ",
"In April 2019, Kate Mulvany, James LeGros, Ebony Obsidian, Caleb Emery, Henry Hunter Hall and Jeannie Berlin joined the cast of the series, with Mulvany joining as a series regular.",
"\n\nReception\nHunters received polarizing reviews, with criticism for its tone and pacing and praise for its performances. ",
"The series has a 65% approval rating with 92 reviews on Rotten Tomatoes, with an average rating of 6.21. ",
"Metacritic gave the series a score of 55 out of 100 based on 37 critics, indicating \"mixed or average reviews\".",
"\n\nThe series has received some criticism from the Auschwitz-Birkenau State Museum due to inaccurate use of the Auschwitz Concentration Camp. ",
"The scene depicting prisoners being forced to participate in a game of human chess was called out as \"dangerous foolishness and caricature\". ",
"The museum was also concerned that the show \"welcomes future deniers\".",
"\n\nReferences\n\nExternal links\n\nTrailer\n\nCategory:2020s American drama television series\nCategory:Amazon Video original programming\nCategory:English-language television programs\nCategory:Nazi hunters in popular culture\nCategory:Television series set in 1977\nCategory:Television series set in the 1970s\nCategory:2020 American television series debuts"
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"Neonatal diabetes mellitus.",
"\nNeonatal diabetes mellitus is an uncommon disorder of unknown cause that can be encountered in the first days to weeks of life. ",
"Two forms--transient and permanent--have been described. ",
"Signs and symptoms of both forms are identical with the ongoing need for insulin therapy past the neonatal period the only method to distinguish between them. ",
"This article describes the infant with transient neonatal diabetes and reviews the clinical characteristics of both the transient and permanent forms. ",
"The role of the nurse practitioner in the care and management of these infants is also addressed."
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"It is not what it was designed for (long poll), but as you can see, to run a single command and grab its output.",
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"Q:\n\nOkhttp3 - RequestBody.create(contentType, content) Deprecated\n\nI did not find any example of how to replace the deprecation method.",
"\nThe examples on the okhttp3 main page are old.",
"\nThis is one of them:\npublic static final MediaType JSON = MediaType.get(\"application/json; charset=utf-8\");\n\nOkHttpClient client = new OkHttpClient();\n\nString post(String url, String json) throws IOException {\n RequestBody body = RequestBody.create(JSON, json);\n Request request = new Request.",
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"\nUpdate:\n I'm using 'com.squareup.okhttp3:okhttp:4.0.1'\n\nA:\n\nJava Solution:\nUse create(String, MediaType) instead of create(MediaType, String) for example\nKotlin Solution:\nUse the extension function content.toRequestBody(contentType);\nfor the File type file.asRequestBody(contentType)\nNote:\nI'm using kotlin, but my IDE just doesn't automatically import the class or method like import okhttp3.RequestBody.",
"Companion.toRequestBody, so I import it manually...then use it as the example given by Saeed Younus and Pratyesh below\nFor more: The documentation\n(In Android Studio or any Jetbrain's IDE, the solution to the deprecated methods or class can be found by just holding the Ctrl and clicking on the create(...) of RequestBody.create)\n\nA:\n\nIn com.squareup.okhttp3:okhttp:4.1.0\nMediaType.get(\"application/json; charset=utf-8\") no more available.",
"\ninstead this we need to use \"application/json; charset=utf-8\".toMediaTypeOrNull().",
"\nFor example how we need to create request body now since okhttp:4.1.0\nimport okhttp3.MediaType.",
"Companion.toMediaTypeOrNull\nimport okhttp3.RequestBody.",
"Companion.toRequestBody\n\n val jsonObject = JSONObject()\n jsonObject.put(\"name\", \"Ancd test\")\n jsonObject.put(\"city\", \"delhi\")\n jsonObject.put(\"age\", \"23\")\n val body = jsonObject.toString().toRequestBody(\"application/json; charset=utf-8\".toMediaTypeOrNull())\n\nTo those wondering where the answers are coming from!",
"\nAll the alternatives/solutions(as described by the answer) are documented in the corresponding deprecated code! ",
"Just manoeuvre to it (the deprecated code) using whichever means your IDE supports. ",
"For example, to see the alternative/solution to the deprecated code RequestBody.create(...,...) when using AndroidStudio or any Jetbrain's IDE, just long-press Ctrl and hover over the RequestBody.create(...,...) then click on it when it's hovered over successfully\n\nA:\n\nYou need to import these files manually may be this is a bug in android studio. ",
"It is not suggested but this is work for Okhttp 4.2.2\nimport okhttp3.MediaType.",
"Companion.toMediaTypeOrNull\nimport okhttp3.RequestBody.",
"Companion.asRequestBody\n\nand use as\nval file = File(\"path\")\nfile.asRequestBody(\"image/jpeg\".toMediaTypeOrNull())\n\n"
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[
"\n496 F.Supp. ",
"880 (1980)\nMONTANA WILDERNESS ASSOCIATION, Nine Quarter Circle Ranch, and the Wilderness Society, Plaintiffs,\nv.\nUNITED STATES FOREST SERVICE: John McGuire, its chief; Lewis Hawkes, Gallatin National Forest Supervisor; United States Fish and Wildlife Service, Harry Willoughby, its regional director; Burlington Northern, Inc., a Delaware Corporation; Bob Bergland, Secretary of Agriculture, Defendants.",
"\nNo. ",
"79-29-Bu.",
"\nUnited States District Court, D. Montana, Butte Division.",
"\nSeptember 11, 1980.",
"\n*881 James H. Goetz, Bozeman, Mont., for plaintiffs.",
"\nJames G. Watt; Michael H. Hyer, Denver, Colo., and J. C. Garlington of Garlington, Lohn & Robinson, Missoula, Mont., for Mountain States Legal Foundation, appearing as amicus curiae.",
"\nKurt W. Kroschel and K. Kent Koolen, Billings, Mont., for Burlington Northern.",
"\nRick Anderson, Asst. ",
"U. S. Atty., ",
"Butte, Mont., and Dorothy Burakreis & Peter Coppleman, Dept. ",
"of Justice, Washington, D. C., Land & Natural Resources, Washington, D. C., for all United States defendants.",
"\n*882 John L. Peterson, Butte, Mont., and Shea & Gardner, Washington, and Richard S. Wasserstrom, Washington, D. C., Intervenor as a party defendant for Nat. ",
"Forest Products Ass'n.",
"\n\nMEMORANDUM OPINION\nWILLIAM D. MURRAY, Senior District Judge.",
"\n\nI. INTRODUCTION\nPlaintiffs bring this action against several federal defendants and Burlington Northern, Inc., seeking a preliminary injunction and moving for partial summary judgment. ",
"The court denied the motion for preliminary injunction and will issue findings of fact and conclusions of law in a separate order.",
"\nThis memorandum opinion is to address those legal issues raised by the various motions and cross-motions for partial summary judgment. ",
"Prior to addressing those issues, a brief explanation of the controversy will be undertaken, followed by a historical discussion and a synopsis of the instant litigation.",
"\n\nA. Factual Background\n\nDefendant Burlington Northern owns property in the Buck Creek and Yellow Mules drainages within the confines of the highly scenic Gallatin National Forest southwest of Bozeman, Montana, and plans to conduct logging activities on that property. ",
"In order to reach its property and carry out the proposed logging Burlington Northern must construct a road across National Forest lands.",
"\nThe Buck Creek and Yellow Mules drainages are within the Taylor-Hilgard Wilderness Study Area which has been set aside by Congress under the Montana Wilderness Study Act of 1977, P.L. 95-150, 91 Stat. ",
"1243, for further study and Congressional consideration regarding its potential for wilderness designation. ",
"Burlington Northern's plans to log portions of its property within the boundaries of the area would disqualify that area from possible wilderness designation. ",
"For that reason, among others, plaintiffs seek to prevent construction of the proposed logging road.",
"\nThe national forest sections over which the road is to be constructed are intermingled with Burlington Northern sections in what is generally known as a \"checkerboard\" fashion. ",
"This pattern of ownership resulted from the grant of alternate sections by the United States to Burlington Northern's corporate predecessor, Northern Pacific Railroad Co., under the Northern Pacific land grants of 1864. ",
"A brief discussion of the history of the Northern Pacific land grants and land grants to the railroads in general is undertaken below.[1]\n\nB. Historical Background\n\nOn July 2, 1864, an act creating the Northern Pacific Railroad Company and authorizing that company to construct a railroad from Lake Superior to Puget Sound was enacted. ",
"13 Stat. ",
"365. ",
"That Act was the outgrowth of a tremendous desire on behalf of the federal government that the West be settled. ",
"Railroads through the unsettled territories were the means to accomplish this goal. ",
"Yet private investors were unwilling to build the railroads without substantial governmental inducement. ",
"Inducement came in the form of an enormous grant of public land to the Northern Pacific Railroad Company, which was typical of other Congressional land-grant subsidies to railroads in that era. ",
"See, Leo Sheep Co. v. United States, 440 U.S. 668, 99 S.Ct. ",
"1403, 59 L.Ed.2d 677 (1979).",
"\nUnder the terms of the 1864 Act, Northern Pacific was granted every alternate section of public land, not mineral, to the amount of twenty sections per mile on each side of the line through territories and ten *883 sections per mile through the states. ",
"In case any of these sections had been occupied by homesteaders or otherwise disposed of at the time of definite location of the railroad, Northern Pacific was entitled to select, in lieu thereof, alternate odd-numbered sections not more than ten miles beyond the limits of the grant. ",
"In lieu of mineral lands, the company was given the right to select a like quantity of agricultural land \"nearest to the line of such road and within fifty miles thereof.\" ",
"13 Stat. ",
"365, Sec. ",
"3.[2]\nThe checkerboard ownership pattern came about as a result of opposition to the railroad land grants from strict constructionists who believed that the Constitution provided no authority for the direct use of government funds for internal improvements, such as railroads. ",
"Leo Sheep, supra, 671-674, 99 S.Ct. ",
"1405-1407. ",
"The opponents were ultimately persuaded, however, by the argument that construction of the railroads and the resulting development of the alternate sections granted to the railroads would lead to an appreciation in value of the retained federal lands. ",
"It was claimed, therefore, that the land grants were not a direct federal subsidy but rather were a means of increasing federal revenues from the sale of the retained lands. ",
"Thus, the checkerboard ownership pattern, now pervasive in the West, was created.",
"\n\nC. The Instant Litigation\n\nIn order to construct the proposed road across federal land Burlington Northern applied for and was granted a special use permit by the Forest Service. ",
"Following administrative appeal of the decision to issue the permit, plaintiffs filed the instant lawsuit on May 9, 1979, seeking a temporary restraining order and preliminary injunction against construction of the road by Burlington Northern. ",
"This court granted the temporary restraining order and scheduled a hearing on the motion for preliminary injunction for September 4, 1979.",
"\nIn the interim, however, the Forest Service, at the request of the Department of Justice, suspended the permit and the hearing was vacated. ",
"Thereafter, the Secretary of Agriculture requested a formal opinion from the Attorney General to resolve the many questions which had arisen regarding the access rights of landowners whose land, like Burlington Northern's, is completely surrounded by property owned by the United States.",
"\nOn June 23, 1980, the Attorney General issued his formal Opinion responding to the questions posed by the Secretary of Agriculture. ",
"In that Opinion, the Attorney General concluded that 16 U.S.C. § 478 upon which the Forest Service had previously relied to find a right of access did not provide such a right. ",
"He further stated that \"a right of access may be implied from the terms of the federal grant only if Congress intended to grant the right.\" ",
"Op. ",
"Atty. ",
"Gen. at 1-2 (June 23, 1980).",
"\nThe Department of Agriculture thereafter determined that Burlington Northern has a right of reasonable access implicit in the 1864 land grant and directed the Forest Service to reinstate Burlington Northern's permit, which was done July 30, 1980. ",
"Plaintiffs then filed motions for a temporary restraining order, preliminary injunction and motions for partial summary judgment. ",
"The court granted the temporary restraining order, but denied the motion for preliminary injunction. ",
"This opinion deals with plaintiffs' motion for partial summary judgment and the cross-motions of both federal defendants and Burlington Northern for partial summary judgment.",
"\n\nII. ",
"BURLINGTON NORTHERN HAS ACCESS TO ITS PROPERTY BY WAY OF NECESSITY\nDefendant Burlington Northern contends that it has an easement by necessity across the federal lands to reach its own, and has moved for summary judgment on that issue. ",
"The motion is resisted by federal defendants and plaintiff, both of whom rely to a great extent on Attorney General Civiletti's *884 Opinion of June 23, 1980. ",
"In that opinion the Attorney General addressed the precise issue here presented and concluded that\n\"the common law doctrine of easement by necessity does not apply to land owned by the federal government.\" ",
"Op. ",
"Atty. ",
"Gen. at 2 (June 23, 1980).",
"\nWhile it is true that opinions of the Attorney General are given great weight, an Attorney General's opinion is not the judgment of a court of law and is not binding on this court. ",
"Pueblo of Taos v. Andrus, 475 F.Supp. ",
"359, 365, n. 4 (D.D.C. 1979). ",
"In this instance his conclusion as to the doctrine of easements by necessity must be rejected and Burlington Northern's motion for summary judgment granted.",
"\nPlaintiffs contend that the recent United States Supreme Court decision in Leo Sheep Co. v. United States, 440 U.S. 668, 99 S.Ct. ",
"1403, 59 L.Ed.2d 677 (1979) controls this court's decision. ",
"The federal defendants and Burlington Northern, while conceding the applicability of Leo Sheep, persuasively argue that it is not controlling. ",
"A review of the decision is necessary.",
"\nPetitioners were livestock companies holding certain odd-numbered sections of land in Wyoming as successors in fee of the Union Pacific Railroad, which had received the land under the Union Pacific Act of 1862, 12 Stat. ",
"489. ",
"The government retained the even-numbered sections, creating a checkerboard ownership pattern. ",
"The issue presented was whether the United States held an implied easement to build a road across the private land to provide access to a public reservoir. ",
"The landowners refused to allow the construction.",
"\nPrior to reaching what it considered as the critical issue in the case-whether the government had an implied easement based on the original land grant-the Court considered the question of whether the government had an easement by necessity across the private land. ",
"The Court described easement by necessity as follows:\nWhere a private landowner conveys to another individual a portion of his lands in a certain area and retains the rest, it is presumed at common law that the grantor has reserved an easement to pass over the granted property if such passage is necessary to reach the retained property. ",
"These rights-of-way are referred to as \"easements by necessity.\" ",
"440 U.S. at 679, 99 S.Ct. ",
"at 1409.",
"\nThe Court proceeded to hold that the government could not avail itself of the doctrine. ",
"The major reason for that conclusion was that \"the easement is not actually a matter of necessity in this case because the Government has the power of eminent domain.\" ",
"Id. at 679-680, 99 S.Ct. ",
"at 1410. ",
"The Court stated that \"[t]he applicability of the doctrine of easement by necessity in this case is, therefore, somewhat strained, and ultimately of little significance.\" ",
"Id. at 680-681, 99 S.Ct. ",
"at 1410.",
"\nPlaintiffs argue that the Leo Sheep holding that the easement by necessity doctrine is not available to the United States is binding on this court's determination of whether the doctrine may be applied against the United States. ",
"Such is not the case for the Leo Sheep holding that the doctrine of easement by necessity does not apply to the sovereign was based on the fact that the government has the power of eminent domain if it requires access. ",
"Burlington Northern has no such power. ",
"It is apparent, then, that Leo Sheep does not settle the question of whether an easement by necessity can apply against the sovereign. ",
"It is therefore necessary to examine the few decisions which have dealt with the issue.",
"\nUnder common law it was assumed that a grantor of property intended to include in the conveyance whatever was necessary for the beneficial use and enjoyment of the property. ",
"Mackie v. United States, 194 F.Supp. ",
"306, 308 (D.Minn.1961). ",
"The preliminary issue this court must decide is whether that common law assumption applies to lands granted by the United States. ",
"In Mackie the court seems to have simply assumed that an easement by necessity accompanied the government's grant of a patent to the plaintiff's predecessor. ",
"The issue *885 was not directly dealt with, however, because the court found the element of necessity lacking due to the availability of an alternate access route.",
"\nTwo Ninth Circuit cases have recognized that easements by necessity could be derived from land grants by the federal government. ",
"Superior Oil Co. v. United States, 353 F.2d 34 (9th Cir. ",
"1965) recognized this impliedly while the issue was spoken to in a footnote in United States v. Dunn, 478 F.2d 443 (9th Cir. ",
"1973). ",
"In Dunn, the dissent argued that an easement by necessity could not be binding on the United States. ",
"In a footnote, Id. at 444, n. 2, the court stated that while in its judgment the point had not been raised, the court \"nevertheless did give it due consideration and concluded that it lacked merit.\" (",
"citing) 3 Powell, Real Property, 443-444, and Superior Oil Co. v. United States, supra. ",
"While neither of these cases are controlling they are, at a minimum, persuasive on the issue of whether a way of necessity can exist against the government.",
"\nNeither the case law on the issue nor the reasons set forth by plaintiffs convince this court that an easement by necessity cannot be asserted against the government. ",
"Whether or not the easement actually exists is the next inquiry.",
"\nThere are three prerequisites to the creation of an easement by necessity.[3] First, the titles to the two tracts in question must have been held by one person. ",
"Second, the unity of title must have been severed by a conveyance of one of the tracts. ",
"Third, the easement must be necessary in order for the owner of the dominant tenement to use his land. ",
"This necessity must exist both at the time of the severance of title and at the time of exercise of the easement.",
"\nIn this instance all three factors are established. ",
"Prior to the Northern Pacific Railroad land grant in 1864 the United States held title to all of the land. ",
"The land grant severed the unity of title. ",
"And, finally, due to the checkerboard ownership pattern, easement was and is necessary for access to the property.",
"\nWhile the prerequisites of the common law easement by necessity doctrine are satisfied in this case, that does not of itself establish the easement. ",
"This court must look to the intent of the parties to the conveyance and the purposes of the conveyance. ",
"Superior Oil Co. v. United States, 353 F.2d 34, 36 (9th Cir. ",
"1965).[4] In this case, that is ascertained by looking to the purposes of the 1864 land grant, 13 Stat. ",
"365. ",
"While a more detailed analysis of the granting statute appears in Section III below, several observations must be made here which compel the conclusion that Congress intended, or at least expected, that grantees of its land would enjoy a right of access by way of necessity.[5]\nAs was discussed in Section I B above, the overriding purpose of the railroad land grants was to induce private companies to undertake the task of building the transcontinental railroad. ",
"The Act granting lands to the Northern Pacific Railroad Company stated its purpose was one of \"aiding in the construction of said railroad and telegraph line to the Pacific Coast,\" 13 Stat. ",
"365, § 3. ",
"Without the land grants as inducement the railroads would not have been built, for as Horace Greeley stated: \"The amount is too vast; the enterprise too formidable; the returns too remote and uncertain.\" ",
"Cited in Leo Sheep v. United States, 440 U.S. 668, 671, n. 3, 99 S.Ct. ",
"1403, 1406, n. 3, 59 L.Ed.2d 677.",
"\nFor that reason Congress granted enormous amounts of land to the Northern Pacific Railroad Company. ",
"Without access to *886 those lands, they would be worthless-a barren gift. ",
"Thus, it can be assumed that Congress intended that the grantees of the land also be given a right of access to use that land.",
"\nThe court's decision does not rest on this logical assumption alone, for it was assumed at common law that a grantor intended to include in the conveyance whatever was necessary for the use and enjoyment of the land in question. ",
"Mackie v. United States, 194 F.Supp. ",
"306, 308 (D.Minn.1961). ",
"This general assumption was known to Congress at the time of the 1864 land grant, and the Act was passed with this assumption as background.",
"\nFurthermore, a railroad land grant is to \"receive at the hands of the court a more liberal construction in favor of the purposes for which it was enacted.\" ",
"Leo Sheep v. United States, 440 U.S. at 683, 99 S.Ct. ",
"at 1411, quoting United States v. Denver and Rio Grande Ry. ",
"Co., 150 U.S. 1, 14, 14 S.Ct. ",
"11, 15, 37 L.Ed. ",
"975 (1893). ",
"The overriding purpose of the land grants was to induce the railroad companies to build railroads, in order that the West be settled and developed. ",
"Absent a right of access, the entire congressional scheme would have been frustrated. ",
"The grantees could not have utilized the timber on the property, the land would have little value for sale, and settlement would thereby have been retarded.",
"\nIt is apparent, then, that Burlington Northern has an easement by necessity to cross federal land to reach its own. ",
"The common law doctrine of easement by necessity may be applied against the United States when, as here, doing so will effectuate the purposes of the original land grants to the railroad. ",
"A more detailed analysis of those purposes is undertaken below.",
"\n\nIII. ",
"BURLINGTON NORTHERN HAS AN IMPLIED RIGHT OF ACCESS\nThe Attorney General, in his opinion of June 23, 1980, stated that\n\"[a] right of access may be implied from the terms of a federal land grant only if Congress intended to grant the right. ",
"This intent may be shown from the circumstances surrounding the grant, including the purpose for which it was made.\" ",
"Op. ",
"Atty. ",
"Gen. at 2 (June 23, 1980).",
"\nAs explained in the introduction, the Forest Service reinstated Burlington Northern's special use permit on the grounds that \"Burlington Northern has a right of reasonable access to its lands implicit in the original statutory grant by Congress to the Northern Pacific Railroad in 1864.\" ",
"The federal defendants and Burlington Northern move for summary judgment as to this issue. ",
"The motions must be granted.",
"\nThroughout the following analysis it is important to keep in mind the canon of construction controlling this court's review. ",
"As stated in Section II, supra, a railroad land grant \"should receive at the hands of the court a more liberal construction in favor of the purposes for which it was enacted.\" ",
"Leo Sheep Co. v. United States, 440 U.S. 668, 683, 99 S.Ct. ",
"1403, 1411, 59 L.Ed.2d 677, quoting United States v. Denver & Rio Grande Ry. ",
"Co., 150 U.S. 1, 14, 14 S.Ct. ",
"11, 15, 37 L.Ed. ",
"975 (1893).",
"\nIn order to determine whether Congress intended to impliedly grant a right of access to those lands granted to the Northern Pacific in 1864, the court must look to the words of the granting statute and its legislative history. ",
"In this case, however, such an inquiry is fruitless, for neither the language of the statute, 13 Stat. ",
"365, nor the extensive Congressional debates mentions the question of access to the granted lands. ",
"It is necessary, then, to \"look at the condition of the country when the grant was made, as well as the declared purpose of the grant.\" ",
"Op. ",
"Atty. ",
"Gen. at 20, citing Leo Sheep, supra, 440 U.S. at 682, 99 S.Ct. ",
"at 1411; Winona & St. Peter R.R. v. Barney, 113 U.S. 618, 625, 5 S.Ct. ",
"606, 609, 28 L.Ed. ",
"1109 (1885); and Platt v. Union Pacific R.R., 99 U.S. 48, 64, 25 L.Ed. ",
"424 (1878).",
"\nThe historical background of the Northern Pacific land grant is set forth in Section I, supra. ",
"A review of that history indicates the importance that Congress attached to *887 the construction of the railroads. ",
"Settlement and development of the West was of paramount importance, and Congress felt a railroad necessary to accomplish the task. ",
"The benefits Congress expected to come of a transcontinental railroad were myriad, including general strengthening of the country through settlement and increased taxation, increased military defense capabilities, food, mineral resources, and development of foreign commerce. (",
"Remarks of Rep. Sweat in debate on the Northern Pacific's land grant bill, Cong.",
"Globe, 38th Cong., ",
"1st Sess. ",
"at 1701-1702 (1864).) ",
"As stated by Rep. Stevens: \"The value of our northwestern possessions depends upon their being populated, and their population depends wholly upon the construction of such a [rail] road.\" ",
"Id., at 2296.",
"\nCongress clearly expected that the land given to the railroad would be settled and developed. ",
"Indeed, Congress regarded the land it held as worthless without the railroad. ",
"Cong.",
"Globe, 38th Cong., ",
"1st Sess. ",
"2296 (1864) (remarks of Rep. Stevens). ",
"But with the railroad, it was expected that the land retained by the government would increase in value. ",
"One Congressman, Rep. Sloan, predicted a hundred-fold increase in value. ",
"Id., at 1699. ",
"Such high expectations would be senseless if Congress did not expect and intend that settlers and the railroads themselves have access to the granted lands. ",
"Without access, the settlement and development of the West would have been impossible. ",
"It is therefore reasonable and logical to conclude that Congress intended that the grantees have access to the land.",
"\nPlaintiffs attempt to escape this conclusion by arguing that Congressional intent on the issue of access is inconclusive. ",
"This argument the court must reject for all the reasons set forth above. ",
"Plaintiffs further argue that Congress intended to deal with rights of access by statute rather than by implication and point to two specific acts of Congress to support their conclusion; Section 8 of the Act of July 26, 1866, 14 Stat. ",
"253, and the Organic Act of June 4, 1897, now codified at 16 U.S.C. § 478. ",
"Neither of these statutes support plaintiffs' position.",
"\nThe 1866 statute, enacted two years after the 1864 Northern Pacific land grant, provided: \"The right of way for construction of highways over public lands, not reserved for public uses is hereby granted.",
"\"[6] Plaintiffs argue that this statute is \"clear evidence\" that Congress intended to deal with the question of access over federal lands \"by statute rather than via dubiously applicable common-law doctrines of implied easements or ways of necessity.\" ",
"As demonstrated by Section II of this court's opinion, the common-law doctrine of ways of necessity is directly applicable.",
"\nMore importantly, however, there are two reasons plaintiffs' argument must be rejected. ",
"First, in construing railroad land grants, the court \"must look to the condition of the country when the acts were passed, . . ..\" ",
"Winona & St. Peter R.R. Co. v. Barney, 113 U.S. 618, 625, 5 S.Ct. ",
"606, 609, 28 L.Ed. ",
"1109 (1885). ",
"The intent of the 1864 Congress cannot be definitively ascertained by examining congressional action taken in 1866. ",
"See, Platt v. Union Pacific R. Co., 99 U.S. 48, 63-64, 25 L.Ed. ",
"424 (1878); Leo Sheep Co. v. United States, 440 U.S. 668, 677, n. 13, 99 S.Ct. ",
"1403, 1408, 59 L.Ed.2d 677 (1979).",
"\nSecond, the legislative history of the 1866 statute is silent as to its intended meaning. ",
"In United States v. Dunn, 478 F.2d 443 (9th Cir. ",
"1973), however, the court, in discussing the statute, stated:\nSuffice to say that the statute was passed to protect persons who have already encroached upon the public domain without authorization but who have been allowed to remain there with the knowledge and acquiescence of the government and who should not in conscience be deemed trespassers. ",
"It was not intended to grant rights, but instead to give legitimacy to *888 an existing status otherwise indefensible. ",
"That such is its purpose is clear.",
"\nId., at 445, n. 2.",
"\nPlaintiffs also point to the Organic Act of 1897, supra, to support their argument. ",
"To the degree that plaintiffs ask this court to divine the intent of the 1864 Congress from Congressional action thirty-three years later, the plea must be rejected. ",
"Furthermore, the 1897 Act was enacted after Congress had soured on the idea of the railroad land grants. ",
"As the Supreme Court noted in Great Northern Ry. ",
"Co. v. United States, 315 U.S. 262, 275, 62 S.Ct. ",
"529, 534, 86 L.Ed. ",
"836 (1942), there was a \"sharp change in Congressional policy with respect to railroad grants after 1871, . . ..\" ",
"Thus, the 1897 Organic Act provides no support for the proposition forwarded by plaintiffs that Congress intended to provide access to the granted lands by statute.",
"\nThe conclusion that Congress intended a right of access to the granted lands is inescapable. ",
"Given the rule of liberal construction in interpreting railroad land grants, Leo Sheep, 440 U.S. at 683, 99 S.Ct. ",
"at 1411, and the clear Congressional intent that the granted lands be settled and developed, the court must conclude that Congress intended that Northern Pacific (or its successors) have access to the granted lands. ",
"The motions of the federal defendants and Burlington Northern as to this issue must be granted.",
"\n\nIV. ",
"BURLINGTON NORTHERN'S RIGHT OF ACCESS IS ONE OF THOSE RIGHTS PROTECTED UNDER 16 U.S.C. § 478\nBurlington Northern contends that its right of access was recognized and reaffirmed by the second sentence of 16 U.S.C. § 478. ",
"That statute states:\n\"Nothing . . . [",
"herein] . . . ",
"shall be construed as prohibiting the egress or ingress of actual settlers residing within the boundaries of national forests, or from crossing the same to and from their property or homes; and such wagon roads and other improvements may be constructed thereon as may be necessary to reach their homes and to utilize their property under such rules and regulations as may be prescribed by the Secretary of Agriculture. ",
"Nor shall anything herein prohibit any person from entering upon such national forests for all proper and lawful purposes, including that of prospecting, locating, and developing the mineral resources thereof. ",
"Such persons must comply with the rules and regulations covering such national forests.\"",
"\nThere is no question that Burlington Northern has no right of access pursuant to the first sentence of 16 U.S.C. § 478, for it is not an \"actual settler.\" ",
"Under the second sentence of that statute, however, Burlington Northern's pre-existing right of access is recognized. ",
"A review of the history of that Act shows that one reason Congress passed the Act was to make clear that pre-existing access rights of owners of lands surrounded by federal lands were not to be impaired by the establishment of the national forest system.",
"\nIn 1891, a law authorizing the President to reserve forest lands from the public domain was enacted. ",
"Act of March 3, 1891, ch. ",
"561, § 24, 26 Stat. ",
"1103. ",
"On February 22, 1897, President Cleveland, pursuant to the 1891 Act, issued proclamations placing some twenty million acres of public land in forest reserves. ",
"For a discussion of this action, see Op. ",
"Atty. ",
"Gen. at 6-7 (June 23, 1980).",
"\nIn response to President Cleveland's action, which outraged Congressmen from states affected by the proclamations, Congress passed what is now codified as 16 U.S.C. § 478. ",
"As stated by the Attorney General, Op. ",
"Atty. ",
"Gen. at 9 (June 23, 1980), a review of the legislative history \"demonstrates that the effect of the second sentence of § 478 is to protect whatever rights and licenses with regard to the public domain existed prior to the reservation.\" ",
"The Attorney General further stated that \"[t]he language grants no rights not already in existence.\" ",
"Id.\n*889 As established above, Burlington Northern, as successor to the Northern Pacific, enjoys a right of access dating back to the 1864 land grant. ",
"Thus, 16 U.S.C. § 478 merely protects what is a pre-existing right. ",
"If that right of access did not already exist by way of implication or as an easement by necessity, the statute would be of no effect.",
"\nTo the extent that 16 U.S.C. § 478 has been relied upon by the Forest Service and Burlington Northern as creating an absolute right of access, that reliance is misplaced. ",
"See, Op. ",
"Atty. ",
"Gen. at 2 (June 23, 1980). ",
"The mere fact that a person is an inholder does not entitle him to access under 16 U.S.C. § 478, and the Forest Service retains discretionary authority to deny such access, provided that a right of access does not otherwise exist. ",
"Id. In this case, however, such a right of access does exist.",
"\nTo the extent it is not inconsistent with the above discussion, Burlington Northern's motion for partial summary judgment as to access under 16 U.S.C. § 478 is granted.",
"\n\nV. CONCLUSION\nFor all of the reasons stated above the court holds that Burlington Northern does have a right of access to its property across federal lands. ",
"The exercise of that right is, of course, not absolute. ",
"Under the Constitution, Congress has the authority and responsibility to manage federal land. ",
"U.S.Const. ",
"Art. ",
"IV, § 3, cl. ",
"2. ",
"Congress has by statute delegated this authority to agencies such as the Forest Service, e. g., the Federal Land Policy and Management Act, 43 U.S.C. § 1701, et seq. ",
"The United States, as the holder of the servient tenement, has the right to limit the location and use of Burlington Northern's easement of access, to that which is necessary for Burlington Northern's reasonable enjoyment of that right. ",
"Thus, although Burlington Northern must be allowed access to its property, the United States may regulate that access under statutes such as the Federal Land Policy and Management Act. ",
"See, Utah v. Andrus, 486 F.Supp. ",
"995 (D.Utah 1979). ",
"In this case the United States, through the Forest Service, has so regulated Burlington Northern's access through conditions placed on the special use permit.",
"\nFor all of the above reasons,\nIT IS ORDERED that defendant Burlington Northern's cross-motions for partial summary judgment as to the issues of easement by necessity and implied easement are granted. ",
"Its motion as to its right of access pursuant to 16 U.S.C. § 478 is granted insofar as it is not inconsistent with the court's discussion in Section IV above.",
"\nIT IS FURTHER ORDERED that the federal defendants' cross-motion for partial summary judgment on the implied easement issue is granted. ",
"Its cross-motions for summary judgment as to the issues of easement by necessity and the issue of access under 16 U.S.C. § 478 are denied.",
"\nIT IS FURTHER ORDERED that plaintiffs' motions for summary judgment as to all three issues are denied.",
"\nNOTES\n[1] Decisions containing fuller historical discussions of the railroad land grants include, Leo Sheep Co. v. United States, 440 U.S. 668, 99 S.Ct. ",
"1403, 59 L.Ed.2d 677 (1979); Great Northern Ry. ",
"Co. v. United States, 315 U.S. 262, 62 S.Ct. ",
"529, 86 L.Ed. ",
"836 (1942); United States v. Northern Pacific Ry. ",
"Co., 311 U.S. 317, 61 S.Ct. ",
"264, 85 L.Ed. ",
"210 (1940); and Platt v. Union Pacific Ry., ",
"99 U.S. 48, 25 L.Ed. ",
"424 (1878).",
"\n[2] The provisions of the Act are well summarized in United States v. Northern Pacific Railway Co., 311 U.S. 317, 61 S.Ct. ",
"264, 85 L.Ed. ",
"210 (1940).",
"\n[3] See generally, 3 Powell on Real Property § 410 (1979); 2 Thompson on Real Property § 363, at 424-27 (1961 and 1978 Supp.); ",
"Comment, Easements By Way of Necessity Across Federal Lands, 35 Wash.L.Rev. ",
"105, 107 (1960).",
"\n[4] See also, Kinscherff v. United States, 586 F.2d 159, 161 (10th Cir. ",
"1978); Utah v. Andrus, 486 F.Supp. ",
"995, 1002 (D.Utah 1979).",
"\n[5] These observations are also relevant to the discussion of the implied easement issue in Section III below.",
"\n[6] The 1866 statute, 14 Stat. ",
"253, later codified as 43 U.S.C. § 932, was repealed in 1976 by the Federal Land Policy and Management Act, Pub.",
"L. 94-579, Title VII, § 706(a), Oct. 21, 1976, 90 Stat. ",
"2793.",
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"\n\n\n\nI know what you are thinking...did she cut her nails? ",
"Yes, I had to nubbinize. ",
"I had a really bad low break. ",
"I patched it with the tea bag method, but the length was too much and it couldn't hold it together. ",
"The nubs allow me to use the patch and as Frosso pointed out, if a broken nail is the only thing that goes wrong for the wedding, thats a good thing. ",
"Prospective people! ",
"I've got several pre-break posts prepared for you all, so don't be shocked when my nails veer from long to short and back again.",
"\n\n\n\n\n\nFor the next bit, on 3 of my fingers I topped LG with Cirque's XX. ",
"XX is confetti in a bottle. ",
"It's got so many different shapes, all in holographic colors that you are guaranteed to love it. ",
"On my middle and ring finger I stamped on a design from MoYou London Hipster 08 plate.",
"\n\n\n\n\n\n\n\n\n\nI love this design, purely because the boxes are an optical illusion. ",
"Stare at them long enough and they'll switch directions.",
"\n\n\n\n\n\nDon't forget, link up your stamped mani's below. ",
"My favorite part of Stamping Saturday is seeing what everyone else came up with!",
"\n\n\n\n\n\nEnjoy & until next time, Amy Lee\n\n*all products used in this look were purchased by me\n\n\n\n\n\nI know you all are excited about Stamping Saturday, but can you just take a moment to squeal in happiness with me. ",
"As you are reading this post, I'm probably getting married, or getting ready to get married or putting my dress on or.....ok, I think you get the point. ",
"The point is IMGETTINGMARRIEDTODAY!!!! ",
"Yay!!! ",
"It's finally here. ",
"Ok, on to the look.",
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"Swatches of this polish were my gateway drug to Cirque and I think you all know how out of control that obsession has gotten. ",
"This is an emerald green holographic polish, and wow, is it pretty."
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"20170119 FP Wittes\n\nIt’s not just Democrats that have embraced the idea that helping to improve women’s health and livelihood in developing countries also bolsters national security. ",
"George W. Bush’s White House enthusiastically endorsed the approach in the wake of the 9/11 attacks."
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"The year 2015 was quite the roller coaster for the Duggar family. ",
"They saw the ratings for their reality show 19 Kids and Counting soar at the beginning of the year, only to have the show cancelled later in the year after the whole “Our son Josh molested people” fiasco came to light. ",
"In December, however, the Duggars (sans Josh) made their way back to our TVs with three TLC specials entitled Jill & Jessa: Counting On.",
"\n\n\n\nIf the ratings for the specials indicate anything, it’s that America still cares about the Duggar family. ",
"In fact, all three special received relatively high ratings (especially the third installment, which showcased Jessa grunting out her first kid). ",
"While TLC has not confirmed that the Duggars will be back on the network in 2016, the ratings are pointing in that direction.",
"\n\nAccording to the Nielson Company, the premiere episode of ‘Jill & Jessa’ on Sunday, December 13 garnered a rating of 0.8. (",
"This indicates how many target viewers, aged 18-49, tuned in.) ",
"Over 2.2 million people watched the first episode of ‘Jill & Jessa.’",
"\n\nThe second episode also did well, with a rating of 0.7 and a viewership of nearly 1.9 million.",
"\n\nThe most successful episode was the the third, with over 2.5 million people tuning in to watch Jessa give birth to The Spurge. ",
"The episode, which received a rating of 0.8, ranked in the Top 5 cable shows for the night.",
"\n\n(To put this in perspective, ABC’s Shark Tank ranked a 0.5 that night, and had 1.91 million viewers.)",
"\n\nWhile it is very unlikely that TLC will bring back ’19 Kids and Counting,’ it seemed that the network was “testing the waters” by airing these specials, to determine if viewers were still interested in seeing the Duggars on their TVs. ",
"The answer is “yes!”",
"\n\nThe Ashley has reached out to TLC for more information on the fate of ‘Jill & Jessa’ and will update this post when new info becomes available.",
"\n\n(Photo: TLC)"
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"There are many acute and chronic diseases/disorders that are inflammatory in their nature including but not limited to rheumatoid diseases e.g. rheumatoid arthritis, osteoarthritis, diseases of the visceral system e.g. inflammatory bowel syndrome, autoimmune diseases, e.g. lupus erythematodes, lung diseases like asthma and COPD. ",
"Current treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX)-2 inhibitors are efficacious, but show a prevalence for gastrointestinal and cardiovascular side effects. ",
"There is a high need for new treatment options showing equivalent efficacy with an improved side effect profile.",
"\nmPGES inhibitors may show such an improved side effect profile because they block the generation of PGE2 in a more specific manner as described below.",
"\nNSAIDs and COX-2 inhibitors reduce inflammation and pain through inhibition of one or both isoformes of COX enzymes. ",
"The cyclooxygenase (COX) enzyme exists in two forms, one that is constitutively expressed in many cells and tissues (COX-1), and one that in most cells and tissues is induced by pro-inflammatory stimuli, such as cytokines, during an inflammatory response (COX-2). ",
"COXs metabolise arachidonic acid to the unstable intermediate prostaglandin H2 (PGH2). ",
"PGH2 is further metabolized to other prostaglandins including PGE2, PGF2a, PGD2, prostacyclin and thromboxane A2. ",
"These arachidonic acid metabolites are known to have pronounced physiological and pathophysiological activity including pro-inflammatory effects. ",
"PGE2 in particular is known to be a strong pro-inflammatory mediator, and is also known to induce fever, inflammation and pain. ",
"Consequently, numerous drugs were developed with a view to inhibiting the formation of PGE2, including “NSAIDs” (non-steroidal antiinflammatory drugs) and “coxibs” (selective COX-2 inhibitors). ",
"These drugs act predominantly by inhibition of COX-1 and/or COX-2, thereby reducing the formation of PGE2.",
"\nHowever, the inhibition of COXs has the disadvantage that it results in the reduction of the formation of all metabolites downstream of PGH2, some of which are known to have beneficial properties. ",
"In view of this, drugs which act by inhibition of COXs are therefore known/suspected to cause adverse biological effects.",
"\nFor example, the non-selective inhibition of COXs by NSAIDs may give rise to gastrointestinal side-effects and affect platelet and renal function. ",
"Even the selective inhibition of COX-2 by coxibs, whilst reducing such gastrointestinal side-effects, is believed to give rise to cardiovascular problems.",
"\nAn alternative treatment of inflammatory diseases that does not give rise to the above-mentioned side effects would thus be of real benefit in the clinic. ",
"In particular, a drug that preferably inhibits the transformation of PGH2 to the pro-inflammatory mediator PGE2 selectively might be expected to reduce the inflammatory response in the absence of a corresponding reduction of the formation of other, beneficial arachidonic acid metabolites. ",
"Such inhibition would accordingly be expected to alleviate the undesirable side-effects mentioned above.",
"\nPGH2 may be transformed to PGE2 by prostaglandin E synthases (PGES). ",
"Two microsomal prostaglandin E synthases (mPGES-1 and mPGES-2), and one cytosolic prostaglandin E synthase (cPGES) have been described. ",
"mPGES-1 is proposed to be closely linked to COX-2 and both enzymes are upregulated during e.g. inflammation. ",
"Thus agents that are capable of inhibiting the action of mPGES-1 and thereby reducing the formation of PGE2 are likely to be of benefit for the treatment of inflammation and more general acute and chronic pain conditions\nBenzimidazole and imidazopyridine derivatives with mPGES-1 inhibitory activity are disclosed in WO 2010/034796, WO 2010/034797, WO 2010/034798, WO 2010/034799. ",
"PCT/EP2010/052799 describes a broad class of different 2-arylamino benzimidazoles in which the aryl group bears a particular side chain."
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"Q:\n\nFilter rows based on field text in Google Sheets\n\nIn Google Sheets, I'm trying to get the sum of all values in column B for which column A equals to 'Lorem'. ",
"The result should be 15.",
"\n A B\n1. ",
"Lorem 5\n2. ",
"Lorem 5\n3. ",
"Ipsum 100\n4. ",
"Lorem 5\n\nTried the following formule, but get the error: Formula parse error.",
"\n=SUM(FILTER(B1:B4,A1:A4='Lorem'))\n\nHere is the Google Sheet for reference.",
"\n\nA:\n\nUse double quotes around the string.",
"\n=SUM(FILTER(B1:B4,A1:A4=\"Lorem\"))\n\nAlternative ways would be..\n=SUMIF(A1:A4, \"Lorem\", B1:B4)\n\nor\n=SUMPRODUCT(A1:A4=\"Lorem\", B1:B4)\n\n"
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"While competitors fell, First State survived\n\nConservative focus key for Macomb bank\n\n\"The focus here has not been about generating revenue, but in building value. ",
"There was never any point in time we were out chasing earnings,\" said Gene Lovell, First State Bank's president and CEO.",
"\n\nFrom 2000 to 2007, First State Bank of St. Clair Shores was the tortoise losing the race, and losing it badly.",
"\n\nDuring the community banking boom that preceded the Great Recession, if First State had been publicly traded, its shareholders might very well have complained that the bank wasn't making the return on equity that its competitors were.",
"\n\nBut by being conservative throughout the boom days, First State avoided the quick-return temptations of subprime mortgages. ",
"It didn't make risky commercial real estate loans on the premise that property owners would always appreciate, so creditworthiness was something to be worked around.",
"\n\n\"The focus here has not been about generating revenue, but in building value. ",
"There was never any point in time we were out chasing earnings,\" said Gene Lovell, the bank's president and CEO.",
"\n\nThe bank wasn't immune to the recession and loan defaults. ",
"It lost money — a lot of money for a small community bank. ",
"It went from net income of $1.6 million in 2006 to a loss of $8.7 million in 2007. ",
"It lost $5.5 million in 2008 and $5 million in 2009 before returning to profitability in 2010, as other local banks were locked into downward spirals.",
"\n\nAnd assets fell from a peak of $750 million in 2006 to about $575 million today.",
"\n\nLosses aside, Lovell said, First State's old-fashioned way of banking based on nearly 80 years of family ownership brought it through the recession relatively unscathed and poised for growth.",
"\n\nIf First State was the Macomb County tortoise, the hares it was competing with didn't just finish behind it. ",
"They collapsed and died along the way.",
"\n\nAs the recession began making itself felt in 2007, the competitive banking landscape in Macomb County was filled.",
"\n\nThere was Community Central Bank of Mt. Clemens; Warren Bank; Lakeside Bank of Sterling Heights; Peoples State Bank of Madison Heights; and Citizens State Bank of New Baltimore.",
"\n\nAnd community banks based in other counties had a strong presence in Macomb County — Paramount Bank of Farmington Hills, Fidelity Bank of Dearborn and Citizens First Bank of Port Huron.",
"\n\nNone of them remain. ",
"All were shut down by federal and state regulators after their loan portfolios had blown up and their losses had gone on for years. ",
"First State Bank is the only bank left based in Macomb County. ",
"And large regional banks such as LaSalle and National City that had large market shares in the county were bought in fire sales by other large banks.",
"\n\n\"I knew we'd survive, but I didn't know how much pain we would have to bear,\" said Lovell, who joined the bank as an auditor in 1991, became CFO in 2004 and was named president and CEO in 2008, just as the recession hit.",
"\n\nDealing with the downturn\n\nThe bank had seen warning signs of a downturn early in 2007 and began selling off a large chunk of what had been its bread and butter, its home-mortgage portfolio, to other banks still eager to buy those loans.",
"\n\nAt the end of 2007, the bank decided to aggressively take write-downs on troubled commercial loans by adding significantly to its provisions for loan losses on the balance sheet.",
"\n\n\"We wanted to deal with it and get it behind us,\" said Lovell.",
"\n\nThe loan-loss provisions went from $4.6 million in 2006 to $19.1 million in 2007, and the bottom line from net income of $1.6 million to a loss of $8.7 million.",
"\n\nThe bank has steadily grown the bottom line since then, with net income hitting $4.7 million in 2013.",
"\n\n\"I can't say we foresaw how bad it was going to be. ",
"The problems kept on coming, but we were a very solid bank to begin with, and when things kept on snowballing, we were prepared,\" said Lovell. \"",
"I knew we'd come through it.\"",
"\n\nThe key metric eyed by regulators is the Tier 1 ratio of equity capital to assets. ",
"Anything below a 2 percent ratio put a bank on death watch, a level hit by every other bank based in Macomb County. ",
"First State's never got below 8.1 percent. ",
"Today, it stands at 10.76.",
"\n\nLovell has beefed up his mortgage group in the last three years, from a team of three at the bottom of the recession to 15 now, and he wants to be more active in commercial lending.",
"\n\nFirst State's loan portfolio has climbed steadily, from $281 million in 2010 to $368 million now.",
"\n\n\"We never stopped lending. ",
"When other banks were getting out of Dodge, we kept lending. ",
"We were here to serve the community,\" said Lovell.",
"\n\nFirst State opened its 12th branch in Sterling Heights in December. ",
"In January, it consolidated a banking branch and a stand-alone loan office into a new location in Clinton Township, and in January it signed a lease doubling the space in a mortgage office it opened in Oakland County at Orchard Lake and 14 Mile roads in December 2012.",
"\n\nLovell would like to add to the bank's presence with a retail banking branch there, too. \"",
"I'd like to explore that as a possibility, if not later this year, then next year,\" he said.",
"\n\n\"Gene Lovell is a good, conservative banker with a good reputation. ",
"It's a very well-run bank. ",
"They've been around a long time, and they've gone through a lot of economic cycles. ",
"To weather them all is impressive. ",
"It really is,\" said J. Grant Smith, president and CEO of Clarkston State Bank, which barely weathered the last cycle itself but is thriving again.",
"\n\n\"They did a good job of navigating the recession, and they've done a great job as a community bank. ",
"They've built a good footprint in Macomb County,\" said Patrick McQueen, the former state banking commissioner who consults for his son Charles' firm, McQueen Financial Advisors of Royal Oak, and BBK Ltd. in Southfield.",
"\n\n\"First State has a long and rich history and has been a jewel on the east side,\" he said.",
"\n\nThe Halfway Bank\n\nFirst State opened its doors on Oct. 20, 1917, as the Halfway State Bank, in a building at the intersection of Nine Mile Road and Gratiot, launched with a capitalization of $25,000.",
"\n\nThe area was first settled by Irish and German immigrants in the 1830s, and in October 1897, a U.S. Post Office branch was opened with the name of Half-way, because it was about halfway on the long trip up Gratiot Avenue from downtown Detroit to the county seat in Mt. Clemens.",
"\n\nThe village of Halfway was incorporated in 1924 and reincorporated as the city of East Detroit, now Eastpointe, in 1929. ",
"That's when the bank changed its name to the First State Bank of East Detroit, just in time for the Great Depression.",
"\n\nStruggling to stay afloat, the bank was reorganized in 1935, taking on capital from new investors, which included Christian Nill, a butcher who was also the city's mayor, who joined the board of directors. ",
"His nephew, William Nill, is a former president of the bank and the retired chairman.",
"\n\nThe Nill family remains the bank's largest shareholder, with four members on the board of directors. ",
"The bank moved its headquarters to St. Clair Shores in 1989.",
"\n\nLovell said the family tradition kept the bank grounded during the go-go days that preceded the recession.",
"\n\n\"The family structure lends itself to caution,\" Lovell said. \"",
"To being conservative. ",
"This has never been an investment strictly to generate earnings. ",
"The focus has always been on building value.\"",
"\n\nIf you enjoy the content on the Crain's Detroit Business Web site and want to see more, try 8 issues of our print edition risk-free. ",
"If you wish to continue, you will receive 44 more issues (for a total of 52 in all), including the annual Book of Lists for just $59. ",
"That's over 55% off the cover price. ",
"If you decide Crain's is not for you, just write \"Cancel\" on the invoice, return it and owe nothing. ",
"The 8 issues are yours to keep with no further obligation to us. ",
"Sign up below.",
"\n\nIf you enjoy the content on the Crain's Detroit Business Web site and want to see more, try 8 issues of our print edition risk-free. ",
"If you wish to continue, you will receive 44 more issues (for a total of 52 in all), including the annual Book of Lists for just $59. ",
"That's over 55% off the cover price. ",
"If you decide Crain's is not for you, just write \"Cancel\" on the invoice, return it and owe nothing. ",
"The 8 issues are yours to keep with no further obligation to us. ",
"Sign up below."
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"Spray Foam Insulation and your HVAC System How properly insulating your house can make your HVAC last longer! ",
"As homeowner’s, one of the biggest concerns is our expensive HVAC systems going out. ",
"They can be very costly to replace or repair, and while you...\n\nSpray Foam Insulation for Cold Weather Welcome to 2017 and a new year! ",
"It is January, and is traditionally the coldest month of the year for most of the Northern Hemisphere. ",
"Our heating bills rise, and we start to get a little anxious about the quality of the..."
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"Ask HN: What are the technical and scientific achievements of this decade? - ",
"aryamaan\n======\nthrwaway69\nGANs? ",
"Deep[insert]? ",
"I like how they are developed through curiosity and\ntesting by randos online, instead of having researchers warm up in their labs.",
"\n3D printing? ",
"Self driving cars? ",
"CRISPR? ",
"Vocaloid?",
"\n\n------\neesmith\nGravitational astronomy.",
"\n\n"
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"Background {#Sec1}\n==========\n\nIdiopathic pulmonary fibrosis (IPF) is the most common form of the idiopathic interstitial lung diseases \\[[@CR1]\\]. ",
"The most common cause of death in IPF patients has been reported to be the disease itself followed by cardiac disorders and lung cancer \\[[@CR2]--[@CR5]\\]. ",
"A rapid deterioration of the disease may be caused by pulmonary embolism, pneumothorax, infections or heart failure \\[[@CR6]\\]. ",
"Nearly half of all patients (47%) dying primarily from IPF had experienced a deterioration of their lung disease prior to their death \\[[@CR7]\\]. ",
"A new definition and revised diagnostic criteria for acute exacerbation of IPF have been proposed recently; exclusion of infection or other potential triggers is no longer required, the only qualifier is that the clinician should determine that cardiac failure or fluid overload does not fully explain the radiological findings of new bilateral ground glass opacification or consolidation \\[[@CR8]\\].",
"\n\nGlobal mortality from IPF has been increasing, with males being reported to have higher mortality than females \\[[@CR9]--[@CR12]\\]. ",
"It seems that mortality varies between countries depending on the definition and diagnosis codes used \\[[@CR9]\\]. ",
"In the years 2011--2013 in the European Union (EU), the highest IPF mortality rates were reported in the United Kingdom while the lowest rates were in Lithuania \\[[@CR12]\\]. ",
"In Finland, the median mortality rate for males was 7.36 per 100,000 and 3.62 per 100,000 for females, these values being the second highest in the EU \\[[@CR12]\\].",
"\n\nThe aim of this study was to examine the mortality rates of patients with IPF in the Kuopio University Hospital (KUH) area located in eastern Finland. ",
"The underlying and immediate causes of death from the patients' death certificates were gathered. ",
"All data was explored in the whole study group as well as separately for females and males. ",
"Smoking history, disease progression categorized according to the life span into rapid (0--2 years), moderate (2--5 years) and slow (\\> 5 years) as well as gender-age-physiology (GAP) stage were taken into account. ",
"Furthermore, the total numbers of deaths due to pulmonary fibrosis (PF) according to the ICD-10 code J84 were investigated in Finland between the years 1998--2015 from the national registry database of Statistics Finland and this data was compared to that from the local area served by KUH.",
"\n\nMethods {#Sec2}\n=======\n\nPatients and data collection {#Sec3}\n----------------------------\n\nA total of 223 patients (91 female, 132 male) with PF treated in KUH between 1st January 2002 and 31st December 2012 were collected from the hospital's medical records by using ICD-10 codes J84.1, J84.8 and J84.9. ",
"Clinical, radiological and histological information of each patient was transferred from medical records to special forms designed for the present study. ",
"PF with a known etiology i.e. associated with rheumatoid arthritis or connective-tissue disease and asbestosis, were excluded. ",
"The data concerning causes of death and places of death was updated on 14th December 2016.",
"\n\nSmoking history was assessed such that the individual was defined as a non-smoker, ex-smoker or current smoker. ",
"Pulmonary function tests included results of forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), FEV1 / FVC ratio and diffusion capacity of carbon monoxide (DLco). ",
"Information was collated from histological samples from surgical lung biopsies or autopsy.",
"\n\nDeath causes were obtained from the death certificates using ICD-10 codes and registered as underlying and immediate causes of death. ",
"Places of death were also registered. ",
"The overall death rates due to PF according to ICD-10 code J84 and ischemic heart diseases (ICD-10 codes I21--25) were obtained from the open national database of Statistics Finland, in which the ICD-10 codes are available only at a 3-character level, and therefore data with more specific codes, such as J84.1, was not available \"<http://www.stat.fi/til/ksyyt/2015/ksyyt_2015_2016-12-30_tau_001_en.html>\". ",
"In Finland, the disease classification of the death certificates was altered in the years 2005--2006. ",
"Subsequently, pneumonia was no longer accepted as the underlying cause of death if some other chronic disease had weakened the patient prior to the development of pneumonia. ",
"In such cases, the weakening chronic illness is recorded as the underlying cause of death \"<http://www.stat.fi/til/ksyyt/2015/ksyyt_2015_2016-12-30_tau_001_en.html>\".",
"\n\nAcute exacerbation was defined using diagnostic criteria with 1) a previous diagnosis of IPF 2) acute worsening or development of dyspnea typically of less than 1 month duration 3) computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with UIP and 4) a deterioration not fully explained by cardiac failure or fluid overload \\[[@CR8]\\]. ",
"If computed tomography was not available, the designation of suspected acute exacerbation of IPF was used.",
"\n\nNo consents for the inclusion into this study were collected since it was retrospective, with the majority of the patients already deceased. ",
"The study protocol was approved by the Research Ethics Committee of the Northern Savo Hospital District (statement 17/2013) and from the National Institute for Health and Welfare (Dnro THL/1052/5.05.01/2013). ",
"Permission to use data from death certificates was given by Statistics Finland (Dnro: TK-53-911-13). ",
"This study was conducted in compliance with the Declaration of Helsinki.",
"\n\nAssessment of the data {#Sec4}\n----------------------\n\nThe findings of the first and last high resolution computed tomography (HRCT) of each patient were re-evaluated by an experienced radiologist according to the recent statement of the American Thoracic Society (ATS) and the European Respiratory Society (ERS) and re-classified as usual interstitial pneumonia (UIP), possible UIP and not UIP \\[[@CR1], [@CR13]\\]. ",
"All the patients whose re-analyses were categorized as not definite UIP in HRCT or histology were evaluated during a multidisciplinary discussion with a radiologist, a pathologist and a pulmonologist before inclusion into the present study.",
"\n\nThe patients were categorized into classes according to the observed time elapsing until their death: 1) rapid (0--2 years), 2) moderate (2--5 years) and 3) slow (\\> 5 years). ",
"Those patients that were still alive and with a follow-up time less than 5 years were not included into the categorization. ",
"The GAP stage was calculated using gender, age and results of FVC and DLco (physiology) at the time of IPF diagnosis to obtain a total points score, which was then used to classify patients into stages I (0--3 points), II (4--5 points), or III (6--8 points) \\[[@CR14]\\].",
"\n\nStatistical analysis {#Sec5}\n--------------------\n\nStatistical analysis was performed with IBM SPSS Statistics version 21. ",
"Group differences were tested by Chi-square testing or Fisher exact test with categorical variables. ",
"Data is presented as mean with standard deviation for continuous variables or frequencies with percentages when variables are categorical. ",
"The survival was estimated by the Kaplan-Meier method using the time of diagnosis as the starting-point and death or lung transplantation as the end-point. ",
"The median survival time is presented. ",
"Multivariate survival analyses were computed using Cox regression models and results are shown in the form of a hazard ratio (HR) with 95% confidence intervals. *",
"P*-value \\< 0.05 was considered as statistically significant.",
"\n\nResults {#Sec6}\n=======\n\nPatient characteristics {#Sec7}\n-----------------------\n\nAfter re-analyses of radiological, histological and clinical data from a total of 223 patients, 89 cases were excluded due to diagnoses other than IPF, i.e. 132 patients with IPF were included in this study. ",
"Four patients had missing data of their smoking histories. ",
"Out of 128 patients, 45 (35.2%) were non-smokers, 66 (51.6%) were ex-smokers and 17 (13.3%) were current smokers. ",
"A total of 117 deaths had occurred by 14th December 2016. ",
"Three male patients, two current smokers and one ex-smoker, had undergone lung transplantation; one of them was a current smoker and had subsequently died. ",
"We calculated the following mean ages; the time of diagnosis, 70.5 years (SD 9.78); at death, 74.8 years (SD 8.98) and at lung transplantation, 53.3 years (SD 8.08). ",
"At the time of diagnosis, mean FVC was 76.7% predicted (SD 18.51), mean FEV1 77.0% predicted (SD 16.99), mean FEV1/FVC 101.4% predicted (SD 9.68) and mean DLco 56.1% predicted (SD 17.51) (Table [1](#Tab1){ref-type=\"table\"}.)Table 1Demographic characteristics of the patientsTotalMaleFemale*p*-value^a^N (%)132 (100)97 (73.5)35 (26.5)Age years (SD)70.5 (9.78)70.2 (10.34)71.3 (8.17)0.562Median survival (Mo)42.036.060.00.045Non-smokers n (%)45 (35.2)21 (22.1)24 (72.7)\\< 0.001Former smokers n (%)66 (51.6)60 (63.2)6 (18.2)\\< 0.001Current smokers n (%)17 (13.3)14 (14.7)3 (9.1)\\< 0.001*Pulmonary function test results at the time of diagnosis* ^*b*^ FVC % predicted (SD)76.7 (18.51)75.7 (18.91)79.2 (17.39)0.354 FEV1% predicted (SD)77.0 (16.99)75.3 (17.22)81.6 (15.66)0.065 FEV1/FVC % predicted101.4 (9.68)100.3 (9.45)104.2 (9.88)0.049 DLCO % predicted (SD)56.1 (17.51)55.8 (18.02)56.7 (16.33)0.803*p*-values calculated using Fisher test, Chi-squared test or Kaplan-Meier log-rank test^a^Between genders^b^Spirometry results were missing from 6 patients and diffusion capacity results from 8 patients*N* number, *Mo* months, *FVC* forced vital capacity, *FEV1* forced expiratory volume in one second, *DLco* diffusion capacity of carbon monoxide\n\nThe median survival was 42.0 months. ",
"Fifty (43.5%) patients died in a tertiary hospital; 4 of them (8.0%) in an intensive care unit; 50 (43.5%) in a community hospital, 16 (13.9%) at home and 1 (0.9%) in a nursing home.",
"\n\nMortality {#Sec8}\n---------\n\nIn the KUH district, which was serving 248,000 citizens at the end of year 2012, the 5 year overall mortality rate between the years 2003--2007 was 2.5 per 100,000 whereas between the years 2008--2012, it was 4.7 per 100,000. ",
"When including only patients with IPF (ICD-10 code J84.1) as the underlying cause of death i.e. disease-specific mortality, the 5 year mortality rates were 1.7 per 100,000 and 3.1 per 100,000 in 2011 and 2012, respectively. ",
"The total numbers of PF deaths (ICD-10 code J84) in Finland from 1998 to 2015 are presented in Fig.",
" [1](#Fig1){ref-type=\"fig\"} \"<http://www.stat.fi/til/ksyyt/2015/ksyyt_2015_2016-12-30_tau_001_en.html>\". ",
"There were 280 PF deaths in the year 2015 in Finland; from these values, one can calculate a mortality rate of 5.1 per 100,000, when the official total population of Finland at the end of the year 2015 was 5,487,308 \"<http://www.stat.fi/til/ksyyt/2015/ksyyt_2015_2016-12-30_tau_001_en.html>; <http://www.stat.fi/til/vaerak/2015/vaerak_2015_2016-04-01_tie_001_en.html?ad=notify>\".Fig. ",
"1The number of pulmonary fibrosis deaths in Finland between the years 1998--2015 \"<http://www.stat.fi/til/ksyyt/2015/ksyyt_2015_2016-12-30_tau_001_en.html>\". ",
"Underlying cause of death according to J84 (ICD-10, 3-character level): The data of this time series is otherwise comparable, but the classification of pneumonia was altered in 2005 and 2006. ",
"From that time onwards, an international guideline was adopted. ",
"Accordingly, pneumonia is not accepted as the underlying cause of death if a chronic disease which has weakened the individual, is mentioned in the death certificate. ",
"In such cases, the disease in question is recorded as the person's underlying cause of death. ",
"The revision of the classification was gradually taken into use in 2005 and 2006 \"<http://www.stat.fi/til/ksyyt/2015/ksyyt_2015_2016-12-30_tau_001_en.html>\"\n\nThe 5 year mortality rates in KUH district between years 2003--2007 were 0.7 and 1.9 per 100,000 for females and males, respectively; between the years 2008--2012, the mortality rates were 1.85 per 100,000 for females and 3.3 per 100,000 for males.",
"\n\nExacerbations and causes of death {#Sec9}\n---------------------------------\n\nThe main underlying causes of death were IPF, ischemic heart disease and lung cancer. ",
"The most common immediate causes of death were IPF, pneumonia and ischemic heart disease (Table [2](#Tab2){ref-type=\"table\"}). ",
"An acute exacerbation was observed in 10 (12.7%) and a suspected acute exacerbation of IPF in 28 (35.4%) patients with IPF as the underlying cause of death. ",
"An acute exacerbation was observed in 7 (12.9%) and a suspected acute exacerbation in 18 (33.3%) patients with IPF as the immediate causes of death. ",
"Sixty (52.2%) patients had coronary artery disease (CAD) as a comorbidity from which 28.3% had ischemic heart disease as the underlying cause of death and 25.0% as the immediate causes of death. ",
"Compared to males, a higher percentage of females died from IPF. ",
"In contrast, more males than females had pneumonia as the immediate cause of death (Table [2](#Tab2){ref-type=\"table\"}).Table 2Causes of death in the patients with IPF in the Kuopio University Hospital areaTotal (*n* = 132)Female (*n* = 35)Male (*n* = 97)*p*-value^a^Deaths N (%)117 (88.6)31 (88.6)86 (90.7)0.774Underlying cause of death IPF79 (67.5)27 (87.1)52 (60.5)0.007 Pneumonia3 (2.3)3 (3.1)0.292 Ischemic heart disease17 (14.5)3 (9.7)14 (16.3)0.371 Lung cancer7 (6.0)7 (8.1)0.101 Pulmonary embolism2 (1.7)1 (3.2)1 (1.2)0.447 Colon cancer2 (1.7)2 (2.3)0.392 COPD1 (0.9)1 (1.2)0.547 Other^b^6 (5.2)6 (7.1)Immediate cause of death IPF54 (47.0)23 (74.2)31 (36.0)\\< 0.001 Pneumonia25 (21.4)1 (3.2)24 (27.9)0.004 Ischemic heart disease15 (12.8)2 (6.5)13 (15.1)0.216 Heart failure^c^8 (6.8)2 (6.5)6 (7.0)0.921 Lung cancer5 (4.3)5 (5.8)0.170 Pulmonary embolism2 (1.7)1 (3.2)1 (1.2)0.447 Colon cancer2 (1.7)2 (2.4)0.392 Other^d^6 (5.2)1 (3.2)5 (6.0)Exacerbations preceding death Acute exacerbation11 (9.4)3 (9.7)8 (9.3)0.932 Suspected acute exacerbation^e^31 (26.5)7 (22.6)24 (27.9)0.609p-values calculated using Fisher test*IPF* idiopathic pulmonary fibrosis, *COPD* chronic obstructive pulmonary disease;^a^Between genders^b^Sick sinus syndrome (*N* = 1), cerebral infarction (*N* = 1), aortic rupture (*N* = 1), ileum strangulation (*N* = 1), heart failure (*N* = 1), drowning (*N* = 1)^c^For any reason, including cor pulmonale^d^Cerebral infarction (*N* = 1), aortic arteriosclerosis (*N* = 1), ileum strangulation (*N* = 1), hypotension (*N* = 1), respiratory failure due to COPD (*N* = 1), drowning (*N* = 1)^e^No HRCT confirmation\n\nEx-smokers and current smokers had more often lung cancer as the underlying cause of death compared to non-smokers (*p* = 0.045 and 0.016, respectively). ",
"Non-smokers had more often IPF and less often pneumonia mentioned as the immediate cause of death compared to ex-smokers (*p* = 0.043 and *p* = 0.007, respectively). ",
"A trend towards a statistically significant difference was observed when comparing the underlying causes of death between non-smokers and current smokers (*p* = 0.062 for IPF and *p* = 0.091 for pneumonia). ",
"No statistically significant differences were observed in the causes of death between ex-smokers and current smokers (Table [3](#Tab3){ref-type=\"table\"}).Table 3Causes of death according to smoking historyNon-smokers (*n* = 45)Ex-smokers (*n* = 66)Current smoker (*n* = 17)*p*-value^a^Total N of deaths (%)43 (95.5)55 (83.3)15 (88.2)0.153Underlying cause of death IPF34 (79.1)35 (63.6)8 (53.3)0.111 Pneumonia2 (3.6)1 (6.7)0.315 Ischemic heart disease6 (14.0)6 (10.9)3 (20.0)0.646 Lung cancer5 (9.1)2 (13.3)0.084 Pulmonary embolism2 (4.7)0.191 Colon cancer2 (3.6)0.342 COPD1 (6.7)0.133 Other^b^1 (2.3)5 (9.1)Immediate cause of death IPF27 (60.5)21 (38.2)6 (40.0)0.076 Pneumonia4 (9.3)18 (32.7)3 (20.0)0.021 Ischemic heart disease5 (11.6)6 (10.9)3 (20.0)0.627 Heart failure^c^4 (9.3)2 (3.6)1 (6.7)0.512 Lung cancer4 (7.3)1 (6.7)0.200 Pulmonary embolism2 (4.8)0.191 Colon cancer2 (3.6)0.342 Other^d^1 (2.3)3 (5.5)1 (7.1)Exacerbations preceding death Acute exacerbation5 (11.6)6 (10.7)0.370 Suspected acute exacerbation^e^11 (25.6)16 (28.6)4 (25.0)0.929p-values calculated using Fisher test*IPF* idiopathic pulmonary fibrosis, *COPD* chronic obstructive pulmonary disease;^a^*p*-value between different smoking histories^b^Sick sinus syndrome (*N* = 1), cerebral infarction (*N* = 1), aortic rupture (*N* = 1), ileum strangulation (*N* = 1), heart failure (*N* = 1), drowning (*N* = 1)^c^For any reason, including cor pulmonale^d^Cerebral infarction (*N* = 1), aortic arteriosclerosis (*N* = 1), ileum strangulation (N = 1), hypotension (*N* = 1), respiratory failure due to COPD (*N* = 1), drowning (*N* = 1)^e^No HRCT confirmation\n\nA multivariate analysis was performed to investigate whether differences in deaths between genders could potentially be explained by smoking status or vice versa. ",
"It was found that both gender and smoking status were independent predictors of mortality; for males, the HR was 1.7 (1.05--2.90) compared to females (*p* = 0.033) and for ex-smokers, the HR was 2.0 (1.10--3.60) compared to current smokers (*p* = 0.024).",
"\n\nThere were significantly more deaths (100%) in the rapid disease progression group compared to slow disease progression (80%) (*p* = 0.006). ",
"More patients with a slow disease progression had IPF as the underlying cause of death compared to patients with a moderate disease progression (*p* = 0.033). ",
"More patients with a rapid disease progression died from an acute exacerbation compared to their counterparts with a moderate and slow disease progression (Table [4](#Tab4){ref-type=\"table\"}). ",
"No statistically significant differences were detected in the causes of death in the different GAP stages (Table [5](#Tab5){ref-type=\"table\"}).Table 4Causes of death in different types of disease progressionRapid (*n* = 40)Moderate (*n* = 42)Slow (*n* = 45)*p*-value^a^Total N of deaths (%)40 (100)41 (97.6)36 (80.0)\\< 0.001Underlying cause of death IPF29 (72.5)22 (53.7)28 (77.8)0.056 Pneumonia2 (5.0)1 (2.4)0.387 Ischemic heart disease5 (12.5)9 (22.0)3 (8.3)0.216 Lung cancer1 (2.5)4 (9.8)2 (5.6)0.384 Pulmonary embolism1 (2.5)1 (2.8)0.575 Colon cancer1 (2.4)1 (2.8)0.586 COPD1 (2.4)0.393 Other^b^1 (2.0)3 (4.9)1 (2.8)Immediate cause of death IPF20 (50.0)16 (39.0)18 (50.0)0.524 Pneumonia10 (25.0)9 (22.0)6 (16.7)0.672 Ischemic heart disease5 (12.5)7 (17.1)3 (8.3)0.518 Heart failure^c^1 (2.5)3 (7.3)4 (11.1)0.328 Lung cancer1 (2.5)2 (4.9)2 (5.6)0.783 Pulmonary embolism1 (2.5)1 (2.8)0.575 Colon cancer1 (2.4)1 (2.8)0.586 Other^d^2 (4.1)3 (7.3)1 (2.8)Exacerbations preceding death Acute exacerbation8 (20.0)1 (2.4)2 (5.4)0.014 Suspected acute exacerbation^e^15 (37.5)6 (14.3)10 (27.0)0.056p-values calculated using Fisher testRapid = survival ≤2 years, moderate = survival 2--5 years, slow = survival ≥5 years*IPF* idiopathic pulmonary fibrosis, *COPD* chronic obstructive pulmonary disease^a^*p*-value between the groups of different disease progression^b^Sick sinus syndrome (*N* = 1), cerebral infarction (*N* = 1), aortic rupture (*N* = 1), ileum strangulation (*N* = 1), heart failure (*N* = 1), drowning (*N* = 1)^c^For any reason, including cor pulmonale^d^Cerebral infarction (*N* = 1), aortic arteriosclerosis (*N* = 1), ileum strangulation (*N* = 1), hypotension (*N* = 1), respiratory failure due to COPD (*N* = 1), drowning (*N* = 1)^e^No HRCT confirmationTable 5Causes of death according to the GAP stageGAP I (*n* = 67)GAP II (*n* = 47)GAP III (*n* = 12)*p*-value^a^Deaths N (%)57 (85.1)42 (93.3)12 (100)0.455Underlying cause of death IPF41 (71.9)24 (57.1)10 (83.3)0.140 Pneumonia3 (7.1)0.079 Ischemic heart disease10 (17.5)6 (14.3)1 (8.3)0.703 Lung cancer3 (5.3)3 (7.1)1 (8.3)0.888 Pulmonary embolism1 (1.8)0.620 Colon cancer2 (3.5)0.381 COPD1 (2.4)0.437 Other^b^5 (11.9)Immediate cause of death IPF28 (49.1)17 (40.5)7 (58.3)0.487 Pneumonia10 (17.5)11 (26.2)3 (25.0)0.561 Ischemic heart disease3 (5.3)3 (7.1)0.440 Heart failure^c^4 (7.1)3 (7.1)0.636 Lung cancer2 (3.5)2 (4.8)1 (8.3)0.761 Pulmonary embolism1 (1.8)0.620 Colon cancer2 (3.5)0.381 Other^d^4 (9.5)Exacerbations preceding death Acute exacerbation6 (10.2)3 (7.1)2 (16.7)0.610 Suspected acute exacerbation^e^10 (16.9)14 (33.3)5 (41.7)0.072p-values calculated using Fisher test*GAP* Gender-Age-Physiology stage, *IPF* idiopathic pulmonary fibrosis, *COPD* chronic obstructive pulmonary disease^a^*p*-value between different GAP-stages^b^Sick sinus syndrome (*N* = 1), cerebral infarction (*N* = 1), aortic rupture (*N* = 1), ileum strangulation (*N* = 1), heart failure (*N* = 1), drowning (*N* = 1)^c^For any reason, including cor pulmonale; ^d^ Cerebral infarction (*N* = 1), aortic arteriosclerosis (*N* = 1), ileum strangulation (*N* = 1), hypotension (*N* = 1), respiratory failure due to COPD (*N* = 1), drowning (*N* = 1)^e^No HRCT confirmation\n\nDiscussion {#Sec10}\n==========\n\nAs far as we are aware, this is the first detailed clarification of the causes of death in patients with IPF taking into account differences between genders and smoking histories as well as disease progression. ",
"Even in this relatively small patient cohort, differences in the causes of death were detected between females and males. ",
"Moreover, by examining the smoking histories, we observed that more males and ex-smokers as well as more current smokers died of triggered exacerbations of IPF. ",
"Furthermore, more patients with a rapid disease progression died from an acute exacerbation compared to the other disease progression subtypes.",
"\n\nDepending on the methods and diagnostic codes used, the mortality rates have been shown to vary globally and in different countries in the EU \\[[@CR9], [@CR12]\\]. ",
"Data from death certificates using ICD-10 codes J84 mortality in 2012 have been reported to be 4.25 per 100,000 in Sweden, 8.88 per 100,000 in Scotland and 8.22 per 100,000 in England and Wales \\[[@CR15]\\]. ",
"In Finland, the mortality rate was 5.1 per 100,000 in 2012, being rather similar to the value from Sweden. ",
"When classified according to code J84.1, mortality in England and Wales was reported to be 6.90 per 100,000 in 2012 which is higher than our value i.e. 4.7 per 100,000 in the period from 2008 to 2012 \\[[@CR15]\\]. ",
"A recent publication based on World Health Organization (WHO) mortality data revealed that the median IPF mortality rate has been rising between the years 2001 and 2013 in 10 out of 17 EU countries, being highest in the United Kingdom (12.01 and 5.63 per 100,000 for males and females, respectively) \\[[@CR12]\\]. ",
"The mortality rates in Finland were the second highest i.e. 7.36 and 3.62 per 100,000 for males and females, respectively \\[[@CR12]\\]. ",
"Our results are in line with the above-mentioned study revealing that mortality of PF and IPF has risen during the twenty-first century in Finland \\[[@CR12]\\].",
"\n\nThe number of PF deaths in Finland has doubled in the last 15 years; in addition, a gender difference has become more apparent since currently more males than females die from PF \"<http://www.stat.fi/til/ksyyt/2015/ksyyt_2015_2016-12-30_tau_001_en.html>\". ",
"It could be argued that the changes in the death certificates' disease classification in the years 2005--2006 may have had some effect on the rising number of PF deaths in Finland \"<http://www.stat.fi/til/ksyyt/2015/ksyyt_2015_2016-12-30_tau_001_en.html>\". ",
"This argument, however, was not supported by the results of our study on KUH patient cohort, since the numbers of the patients with pneumonia as the underlying cause of death have not changed after the year 2006; in fact, only three patients had pneumonia as the underlying cause of death during the complete study period. ",
"However, the diagnostic methods have improved in the past 10--20 years after the appearance of ATS guidelines for IPF in 2000 \\[[@CR16]\\]. ",
"It is possible that more of the other types of interstitial lung diseases such as non-specific interstitial pneumonia were included with IPF at the beginning of the twenty-first century. ",
"Since IPF is the most common form of idiopathic PF, the numbers of deaths for PF coded as J84 are likely to reflect the actual number of IPF deaths. ",
"The rising trend was also seen in the mortality rate in the KUH cohort. ",
"This proposal is supported by the recent data from the WHO mortality database, from which it can be estimated that in the year 2001 the mortality rates in males were 4.7 and 5.0 per 100,000 for the narrow (ICD-10 code J84.1) and the broad (ICD-10 code J84) definitions, respectively, while in females, the rates were around 3.0 per 100,000 with both definitions \\[[@CR12]\\]. ",
"In the year 2013, the estimated mortality rates were 7.9 and 8.6 per 100,000 for males, and 3.5 and 3.9 per 100,000 for females, with the narrow and broad definitions, respectively \\[[@CR12]\\]. ",
"Thus, it can be concluded that most of the cases coded as J84 represented code J84.1. ",
"Moreover, since 30% of IPF patients in the KUH area died for reasons other than IPF, one can estimate from the statistics that approximately 350--400 IPF patients die every year in Finland.",
"\n\nA previous study reported that most IPF patients with CAD die from IPF and only 12% from CAD \\[[@CR17]\\]. ",
"Here, the number of ischemic heart disease deaths among IPF patients with CAD was higher (28.3%) probably due to the large disease burden of CAD and other cardiovascular diseases in Finland \"<http://urn.fi/URN:NBN:fi-fe2016111829194>\". ",
"However, the total proportion of ischemic heart disease deaths was in line with published reports \\[[@CR3], [@CR5]\\]. ",
"In our previous study, we determined that 72.7% of the patients had one or more cardiovascular diseases (hypertension, CAD, cerebral infarction) as a comorbidity and CAD was diagnosed in 49.2% of the patients \\[[@CR13]\\]. ",
"Lung cancer accounted for approximately 6% of the deaths in this study, which is somewhat less common than in the previous studies \\[[@CR4], [@CR18]\\].",
"\n\nOne can speculate on the reasons for the relatively high number of pneumonias and the low number of acute exacerbations. ",
"The data of the current study was collected from the IPF patients diagnosed in KUH between the years 2002--2012 i.e. during the period when the first international perspectives including diagnostic criteria for acute exacerbation of IPF were published (2007) \\[[@CR19]\\]. ",
"Since then, Finnish physicians specializing in respiratory medicine have gradually become aware of the exacerbation phenomenon. ",
"Since nearly 60% of the patients in our study died outside of tertiary centers, most of the death certificates had been prepared by primary health care physicians. ",
"Thus, it is possible that the acute exacerbations were not correctly identified due to the time point of the study and the places of death. ",
"Furthermore, HRCT, which would have been needed for diagnosing an acute exacerbation of IPF, is usually not available in the community hospitals in which most of the deaths occurred.",
"\n\nNever-smokers have been claimed to possess a higher risk for acute exacerbation of IPF, although this finding has not been confirmed in all studies \\[[@CR20]--[@CR22]\\]. ",
"A recent study revealed no gender difference in the numbers of acute exacerbations \\[[@CR22]\\]. ",
"We observed that few death certificates reported acute exacerbations whereas pneumonias were reported to be the second most common immediate cause of death. ",
"Pneumonias are likely to represent triggered acute exacerbations as defined in the recent statement \\[[@CR8]\\]. ",
"Since we found significantly less mentions of pneumonia as the immediate cause of death in females than in males and in non-smokers than ex-smokers, it seems that males and ex-smokers experienced more acute pneumonia-triggered exacerbation-linked deaths than females and non-smokers. ",
"If that is the case, the exacerbation may be associated with smoking since non-smokers were also less likely to suffer pneumonia than current smokers.",
"\n\nA recently published study, which investigated causes of death associated with GAP scoring (using GAP points), detected no differences between the groups with different scores \\[[@CR23]\\]. ",
"In our study, more patients in GAP stage III (GAP score 6) died from IPF (83.0% vs 46.2%) and fewer from infections (0 vs 30.8%). ",
"The other GAP stages are more difficult to compare due to their different study approach. ",
"However, our study confirms that acute exacerbation leading to death may develop at any stage of the disease. ",
"We also found that IPF patients living less than 2 years suffered from lethal acute exacerbations more often than patients with longer survival times.",
"\n\nThe limitations of the study mainly result from the relatively small number of patients and the retrospective study protocol. ",
"Our data is, however, comparable with those of other studies and moreover, it was very thoroughly collected and re-evaluated. ",
"Since histological data was available from only a minority of patients, the diagnoses are mostly based on clinical and radiological investigations which reflect diagnostic procedures of true clinical practice. ",
"The percentage of histological diagnoses in this study, however, was comparable with most of the previous studies. ",
"Nevertheless, the radiological data of all patients has been carefully re-evaluated and re-classified. ",
"The decision to utilize the national death registry base of Finland and its ICD-10 code at the 3 character level i.e. J84, may mean that it includes other fibrotic lung diseases in addition to IPF. ",
"We aimed to reduce this potential inaccuracy by investigating the same ICD-codes in our local KUH cohort.",
"\n\nConclusions {#Sec11}\n===========\n\nThe mortality determined in this study population reflects the demographics of IPF since there has been a year-on-year increase in the numbers of males and smokers with IPF dying from this disease. ",
"Even though the overall mortality was higher in males, the disease-specific mortality for IPF was higher in females, with males having more commonly comorbidities as the underlying cause of death. ",
"An acute exacerbation of IPF may be associated with smoking and gender since females and non-smokers were less likely to develop pneumonia, an illness that is known to trigger acute exacerbations. ",
"Thus, we conclude that disease progression at the end of life may vary depending on smoking habits and gender in IPF patients.",
"\n\nATS\n\n: American Thoracic Society\n\nCAD\n\n: Coronary artery disease\n\nDLco\n\n: Diffusion capacity of carbon monoxide\n\nERS\n\n: European Respiratory Society\n\nEU\n\n: European Union\n\nFEV1\n\n: Forced expiratory volume in one second\n\nFVC\n\n: Forced vital capacity\n\nGAP\n\n: Gender-age-physiology index\n\nHR\n\n: Hazard ratio\n\nHRCT\n\n: High resolution computed tomography\n\nICD-10\n\n: International Classification of Diseases version 10\n\nIPF\n\n: Idiopathic pulmonary fibrosis\n\nKUH\n\n: Kuopio University Hospital\n\nPF\n\n: Pulmonary fibrosis\n\nUIP\n\n: Usual interstitial pneumonia\n\nWHO\n\n: World Health Organization\n\nThe authors wish to thank Ewen MacDonald for providing assistance with the language.",
"\n\nFunding {#FPar1}\n=======\n\nM. K. Has received grants for scientific work from the Foundation of the Finnish Anti-Tuberculosis Association, the Organization for Respiratory Health in Finland, Väinö and Laina Kivi Foundation, the Kuopio region respiratory foundation and Jalmari and Rauha Ahokas foundation; H.N. Has received grants for scientific work from the Foundation of the Finnish Anti-Tuberculosis Association, the Organization for Respiratory Health in Finland, Väinö and Laina Kivi Foundation, the North Savo Regional Fund of the Finnish Cultural Foundation, the Kuopio region respiratory foundation, Jalmari and Rauha Ahokas foundation and the state subsidy of the Kuopio University Hospital; M.P. Received grants for scientific work from research director of Kuopio University Hospital, Foundation of the Finnish Anti-Tuberculosis Association, the Kuopio region respiratory foundation and the Jalmari and Rauha Ahokas foundation; R. K. Has received grants for scientific work and for the research team from the state subsidy of Kuopio University Hospital, the Foundation of the Finnish Anti-Tuberculosis Association and the Kuopio Region Respiratory Foundation.",
"\n\nAvailability of data and materials {#FPar2}\n==================================\n\nThe datasets generated and analyzed during the current study are not publicly available due to the relatively small population of eastern Finland i.e. we could not guarantee individuals' anonymity as the data was collected in a detailed manner, but it is available from the corresponding author on reasonable request.",
"\n\nMK collected the study material, analyzed the data and takes responsibility for the integrity of the data and accuracy of the data analysis and prepared the draft of the manuscript. ",
"HN participated in the interpretation of the data and the presentation of the results. ",
"H-PK planned the radiological data collection form and performed the radiological analyses. ",
"TS participated in the statistical analyses. ",
"MP contributed to the study design, planning of the data collection form and data interpretation. ",
"RK managed and designed the study, planned the data collection form and interpreted the data. ",
"All authors participated in the preparation of the manuscript, read and have approved the final manuscript.",
"\n\nEthics approval and consent to participate {#FPar3}\n==========================================\n\nThe study protocol was approved by the Research Ethics Committee of the Northern Savo Hospital District (statement 17/2013) and from the National Institute for Health and Welfare (Dnro THL/1052/5.05.01/2013). ",
"Permission to use data from death certificates was given by Statistics Finland (Dnro: TK-53-911-13). ",
"In this retrospective study, most of the patients were deceased and no consents to participate were gathered due to the register-based nature of research in accordance with Finnish legislation.",
"\n\nCompeting interests {#FPar4}\n===================\n\nM.K. has received congress travel grants from Intermune, Boehringer-Ingelheim, Orion Pharma and Roche; lecture fee from Boehringer-Ingelheim; H. N. has received congress travel grants from Boehringer-Ingelheim, Lilly Oncology, Novartis, Orion Pharma and GlaxoSmithKline; Consulting fees from Boehringer-Ingelheim and Roche Oy; H-P.K. received consulting fees from Roche Oy; M. P. has received travel grants from Boehringer-Ingelheim Finland Ltd., Takeda Leiras Ltd., Roche, personal fees from Boehringer-Ingelheim Finland Ltd., Chiesi, Intermune, Orion Pharma Ltd., Roche, Takeda Leiras Ltd.; T.S. has no conflicts of interest, R.K. has received congress and meeting travel costs from Orion Pharma, Roche and Boehringer-Ingelheim, consulting fees from GSK and lecture fees from Roche and Ratiopharm.",
"\n\nPublisher's Note {#FPar5}\n================\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.",
"\n"
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"A Maryland man was planning to commit a terrorist attack at National Harbor, just outside Washington, DC, using a stolen truck and tactics 'inspired' by Islamic State, according to the US Department of Justice\n\nRondell Henry, 28, allegedly planned to use a vehicle to kill pedestrians at the waterfront development just outside the US capital, according to the federal indictment announced by the DOJ on Monday. ",
"He was charged with “interstate transportation of a stolen vehicle.”",
"\n\n#BREAKING Maryland man accused of stealing a truck and plotting to drive it into a crowd full of people at #NationalHarbor. ",
"Rondell Henry was arrested last Wednesday. ",
"Federal prosecutors say he was inspired by ISIS @WMAR2Newspic.twitter.com/rIav0Xcy2x — Mallory Sofastaii WMAR (@mal_sofastaii) April 8, 2019\n\nHenry was arrested March 28 in Prince George’s County, Maryland, with a U-Haul truck stolen from a parking garage in nearby Alexandria, Virginia several days earlier.",
"\n\n“He had no escape plan, intending to die while killing others for his cause,” the DOJ said in a court filing.",
"\n\nBREAKING: Federal authorities have charged 28yo Rondell Henry of Germantown, Md., alleging he stole a UHaul van and planned to use it to run over a large group of people at National Harbor. “",
"He harbored hatred for those who do not practice the Muslim faith,” authorities say. ",
"pic.twitter.com/n9qScYnpqX — Kevin Lewis (@ABC7Kevin) April 8, 2019\n\nFederal authorities say that Henry harbored “hatred” for non-Muslims for two years, and that he was inspired by videos of foreign terrorists to replicate the Nice attack.",
"\n\nA truck ramming attack killed 86 and wounded 450 people in Nice, France during the Bastille Day celebrations in July 2016. ",
"The attacker was identified as 31-year-old French resident of Tunisian origin, Mohamed Lahouaiej-Bouhlel.",
"\n\nHenry’s first target was Dulles International Airport in Virginia, where he drove the stolen U-Haul on March 27, but he gave up after two hours of unsuccessfully trying to breach the airport’s security perimeter, the DOJ said. ",
"He then allegedly drove to National Harbor, where he spent the afternoon before breaking into a boat overnight. ",
"Henry was arrested by Prince George’s County police the following morning, after leaping over the security fence around the boat dock.",
"\n\nThe detention hearing is scheduled for Tuesday before a federal judge in Maryland. ",
"If convicted, Henry faces a maximum sentence of 10 years in prison.",
"\n\nIslamic State (IS, formerly ISIS/ISIL) once held large portions of Iraq and Syria and declared itself a “caliphate.” ",
"Starting in mid-2015, it was rolled back by Russian-backed Syrian army on one side, and the US-backed Iraqi army and Kurdish militias on the other. ",
"The last IS outpost on the Syrian-Iraqi border surrendered last month.",
"\n\nLike this story? ",
"Share it with a friend!"
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"\n\nBy ALEX LEARY and JENNIFER LIBERTO\nPublished September 21, 2006\n\nTALLAHASSEE - It took Janet Reno two days. ",
"Tom Gallagher, two days. ",
"Rod Smith - two weeks and counting.",
"\n\nLosers of hard-fought primary contests may want nothing to do with the victor but are typically quick to show up at unity events that, with broad smiles and firm handshakes, are designed to send a signal to voters and campaign contributors that from here on out, it's the party that matters.",
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"\n\n\"There's no way Democrats can be competitive without Rod Smith and Jim Davis standing together and offering an alternative to the Republican plan. ",
"It just won't happen,\" said Democratic strategist Bob Buckhorn. \"",
"I can guarantee you, on the other side they are united.\"",
"\n\nJust two days after their tough primary, Gallagher and Crist set off on a statewide tour with Gov. Jeb Bush and other top Republicans (except U.S. Rep. Katherine Harris) as a show of unity. ",
"Four years ago, in the intensely close Democratic primary for governor, Reno promptly showed up for an event with winner Bill McBride. \"",
"He is going to make us proud,\" she said moments before the two walked off the stage to the soul classic Love Train. ",
"Three days later, they did it again.",
"\n\nGenuine or not, such events generate widespread news coverage and a pep-rally atmosphere for rank-and-file party activists.",
"\n\nSmith on Wednesday denied he was avoiding Davis, saying he took time off and now is trying to restart his law practice. ",
"He will try to make a Democratic dinner tonight in Gainesville, where Davis' running mate Daryl Jones will speak, but noted there is a Tom Petty concert in town at the same time.",
"\n\nHe said he cannot make a stop with Davis and Jones on Saturday in Pensacola because he wants to join his wife, Dee Dee Smith, at their vacation home in North Carolina. (",
"There is a televised University of Florida football game that day, Smith added in jest.)",
"\n\n\"There's no avoidance; it's just the realities,\" he said. \"",
"I've now got to acclimate myself to the demands of private life, which I've explained to both Daryl and Jim.\" ",
"Smith put out two statements within days after the primary calling for Democrats to rally behind Davis.",
"\n\nThe last time the men were in the same room together was during the televised debate in Tampa on Aug. 23. ",
"The outcome of their primary was not known until after 11 p.m. primary election night, and each mentioned the other in their speeches.",
"\n\nAbout halfway though his 11-minute address, Davis called Smith \"magnanimous\" and a tough opponent, urging the crowd at a Hilton in Tampa to give him a round of applause.",
"\n\nSmith dedicated the first 30 seconds of a four-minute speech congratulating Davis. ",
"Three minutes after he finished, a news release from the Davis campaign boasted of victory over \"a $5 million smear campaign funded by special interests.\" ",
"The tone rattled Smith staffers and family. ",
"Many at the time compared it to pouring lemon juice over a wound.",
"\n\nDavis spokesman Josh Earnest said the e-mail was targeted not at Smith or his team, but the negative effects of special interests, a defining theme of Davis' campaign. ",
"Big Sugar had poured $5-million into pro-Smith political groups to attack Davis on his voting record.",
"\n\nThe news release credited, in the third and fourth paragraphs, Smith's \"passionate advocacy of Democratic values\" and said that the men planned to work together.",
"\n\nIn a way, they already have.",
"\n\nDavis and Smith have had several phone conversations since election day (Smith lauded Davis' selection of Jones as his running mate and has offered advice) and several top Smith supporters have turned their efforts toward Davis. ",
"They include Bob Butterworth, the former state attorney general, and Chris Korge, Smith's campaign chairman. ",
"Korge said Wednesday that he is raising national money for the Democratic Party to help Davis.",
"\n\nSome said any division between the two was overstated.",
"\n\nAppearing together is purely symbolic and can happen any time, preferably in front of lot of people, said Jim Krog, a Democratic lobbyist who backed Smith.",
"\n\n\"Are they ever going to be best buddies? ",
"No. ",
"They're just not the same kind of people,\" said Screven Watson, a Smith adviser. \"",
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"\n\nBut as the Los Angeles Times reports, \"a pocket-size drone dubbed the Nano Hummingbird for the way it flaps its tiny robotic wings has been developed for the Pentagon by a Monrovia [Calif.] company.\"",
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"\n\nAccording to the Times, the little flyer has \"a wingspan of 6.5 inches, the mini-drone weighs 19 grams, or less than a AA battery.\" ",
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"Hiiraan Online\n\nFriday March 2, 2018\n\n\n\nImage Courtesy: DP World\n\n\n\nMogadishu (HOL) - The Somali government blasted the tripartite agreement between Somaliland, Ethiopia and DP world to manage Berbera Port, calling the deal illegal and declaring it \"null and void\"\n\n\n\nThe agreement signed on Thursday gave DP World a 51% stake in the port and Ethiopia would acquire 19%. ",
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"\n\n\n\nIn a statement dated March 2nd, Somalia's Ministry for Ports and Marine Transport challenged the legality of the deal saying the agreement is a threat to the unity and sovereignty of Somalia.",
"\n\n\n\nAds By Google\n\nSomalia's Prime Minister Hassan Ali Khaire reiterated the government's position on his Twitter account on Friday morning.",
"\"As National leaders we do not take the responsibility of protecting Somalia’s unity, sovereignty and independence lightly. ",
"The FGS is committed and determined to protecting [sic] this responsibility in accordance with our constitution.",
"\"The three-way-deal was signed while Somali PM Hassan Ali Khaire was on a state visit to the UAE. ",
"It is unclear if he voiced his concerns with the Emirati's.",
"The Prime Minister's sentiment came barely a day after Ethiopia's Transport minister, Ahmed Shiden announced that the land-locked country secured 19% stake in the Berbera port in northern Somalia."
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"Bible translations into Tibetan\n\nThe first portion of the Bible, the Gospel of John, in a Tibetic language was translated by Moravian Church missionaries William Heyde, Edward Pagel, and Heinrich August Jäschke, and later Dr. August Francke. ",
"It was printed in 1862 at Kyelang capital of Lahul in Kashmir. ",
"The whole New Testament was printed in 1885 in Ladakh. ",
"Another version was translated in 1903. ",
"So as not to have the problem of various dialectal differences it was translated into classical Tibetan, but this was not understood by most people. ",
"Yoseb Gergen (aka Sonam Gergen), a Tibetan Christian translated the entire Bible, complete in 1935. ",
"This version was translated into a dialect of Tibetan Gergen had accidentally stumbled across, and which was understandable by all Tibetans. ",
"It was finally published in 1948. ",
"This is known in India as the Tibetan OV Bible. ",
"Eliya Tsetan Phuntshog published a New Testament in 1970. ",
"There is currently a project going on to translate the Bible into the East Tibetan dialect.",
"\n\nDialectal Variation and Register \n\nRecent research has shown there are approximately 50 Tibetan languages and over 200 varieties of Tibetan.",
"\n\nThe complex task of translating the Scriptures into the different varieties of Tibetan is made more difficult by the need to choose between different linguistic registers. ",
"These are: the high literary register (the language used for the Tibetan Buddhist scriptures, also known as ); the mid literary register (a mixture of high literary and some known common spoken and non-spoken words); and one of many varieties of the low register (the vernacular/spoken language), which are specific to particular regions. ",
"\n\nThere are advantages and disadvantages of translating into each different register. ",
"A translation into one of the varieties of the low register will be easily understood in one specific region but its geographical reach will be limited, and it will be seen as less prestigious than the high and mid registers. ",
"Mid Literary is more difficult to understand than the spoken language but has a wider geographical reach. ",
"The high literary register can reach even further geographically but it requires people first to learn a literary language in order to understand what is written in it.",
"\n\nHistory of translations into Mid and High Literary registers \nThe Moravian missionary H. A. Jäschke (1817–1883) spent three months in Ladakh in 1857, and subsequently worked in Keylong (Lahul) until 1868. ",
"He studied the spoken languages of the region. ",
"However, he decided to translate the New Testament into Classical Tibetan, drawing on the assistance and advice of speakers and scholars of different forms of Tibetan in both the Western Himalayan region and Darjeeling. ",
"He hoped that his choice of language would ensure that the written text would be widely understood across Tibet and the Himalayan border regions. ",
"\n\nJäschke’s successor F. A. Redslob (1838–1891) completed the translation of the New Testament in 1885. ",
"Between 1898 and 1902, a committee chaired by another Moravian missionary A. W. Heyde (1825–1907) prepared a revised version of the Tibetan New Testament under the sponsorship of the British and Foreign Bible Society. ",
"Later, Dr A. H. Francke (1870–1930) and his Ladakhi colleague Yoseb Gergan (1878–1946) translated the Old Testament into Classical Tibetan. ",
"The draft translation of the Old Testament was completed by 1935, but the full Tibetan Bible was not published until 1948.",
"\n\nIn 1959, Eliyah Tsetan Phuntsog (son-in-law of Yoseb Gergan) started to revise the New Testament with Pierre Vittoz (a Swiss missionary). ",
"They translated it into a Mid Literary register, hoping that this would be accessible to the various Tibetan-speaking peoples in both India and Tibet. ",
"This version was published in 1970. ",
"However, most of the Ladakhis who were not trained in the Literary register found all these versions difficult to understand.",
"\n\nIn 2011, a Tibetan Old Testament (TOT11) was completed, attributed to the Nepal Bible Society.",
"\n\nA translation of the New Testament into modern \"low literary\" Tibetan, often called the Central Tibetan Bible (CTB), and released in 2018 under the subheading (Wylie: ) \"Radiant Light to the Ends of the Earth\", and printed by Central Asia Publishing, as well as being available digitally. ",
"The rights to the Bible are held by the Wycliffe Bible Translators.",
"\n\nIn 2019, a translation of the New Testament was released as the New Tibetan Bible (NTB) in a form of literary Tibetan, available digitally. ",
" Rights to this are also held by the Wycliffe Bible Translators.",
"\n\nTranslations into Ladakhi\nLadakhi is a language spoken in India in regions bordering both China and Pakistan; its neighbouring languages are Purik, Balti, Zanskari, Nubra, and the more divergent Changthang (see map). ",
"All these languages are part of the Western Tibetan language grouping and quite distinct from the Central, Amdo and Khams Tibetan spoken varieties. ",
"\n\nAlongside his main Tibetan translation work, Jäschke translated the Harmony of the Gospels, a selection of texts used by the Moravian church in Easter Week, into vernacular Ladakhi. ",
"He noticed that the Ladakhi Christians were more attentive when listening to the Harmony, than they were when they heard texts written in the High Register of Classical Tibetan.",
"\n\nLike Jäschke, Francke put his main efforts into Bible translation into literary Tibetan. ",
"However, he also emphasised the need to translate at least some portions of the Bible into the spoken languages of the region. ",
"In 1907, he printed a revised version of Jäschke’s Harmony. ",
"He also prepared a Ladakhi Life of Christ, and in 1908, he published a Ladakhi version of Mark's Gospel. ",
"Yoseb Gergan produced a revised version of the Ladakhi St Mark, and this was published at Lahore in 1919.",
"\n\nThese early vernacular translations adapted the classical literary spelling system rather than using a phonetic transcription of spoken Ladakhi. ",
" In the early 1950s, E. T. Phuntsog experimented with a greatly simplified spelling system for writing Ladakhi. ",
"However, he ran into opposition from a segment of the Ladakhi community who wanted to preserve the classical spelling system of the Buddhist Scriptures. ",
"Phuntsog translated excerpts from the Gospels of St Mark and St Luke using this script. ",
"However, his proposals were never accepted outside the small Christian community, and he was forced to put them on one side.",
"\n\nToday there is an ongoing project to translate the complete Bible into the low register of spoken Ladakhi (Zhung/Leh dialect) using a more phonemic spelling structure. ",
"Currently the New Testament and Genesis 1-16 have been completed.",
"\n\nReferences\n\nCategory:Tibetan language\nCategory:Christianity in China\nTibetan\nCategory:Religion in Tibet"
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"He replaced the ball cock\nand sealed the overflow pipe that was weeping.",
"\n\nThe forecast for today was dull cloud, but by mid morning\nit was raining, and it continued on and off throughout the afternoon.",
"\n\nShortly\nbefore midday I had a dental appointment, but by making an early start on the\npatio I was able to lay three slaps before the appointment and one after. ",
"While\nit was raining in the afternoon I visited B&Q for more sand and a packet of\nmortar. ",
"By the time I arrived home the rain had stopped and I laid the shaped\nslab I cut yesterday."
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"Reviews\n\nDescription\n\nNuby's Splash N Catch Bathtime Fishing Set is a fun fishing game helps develop baby's motor skills. ",
"Each set includes four fun characters to catch in the net. ",
"These characters can also be linked together to help with hand to eye co-ordination and encourage counting. ",
"Brightly coloured for stimulation. ",
"Scoop up the toys at the end of bath time for a quick tidy up. ",
"Hours of fun and great value. ",
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"For anyone familiar with my previous breakdown of anti-trans “science” you’ll remember that I covered the American College of Pediatrics piece “Gender Identity Harms Children” in a video series over on YouTube (part 8 got taken down by a claim unfortunately) where I pointed out that children aren’t being given hormones, gender dysphoria for children requires several criteria to be met (including symptoms lasting over 6 months), and the treatment for those prior to puberty is observation and once they reach puberty it is a case by case basis based on the child whether or not to use things such as hormone blockers and other therapies. ",
"Almost all of the points made by the group of doctors who broke from the known hate group were not only easily debunked, but the points required intentional conflation of terms and outdated/debunked information.",
"\n\nSo this isn’t the first time anti-trans people have attempted to use “science” to push the narrative that allowing a child to figure out their gender in a safe and controlled manner is somehow abusive or harmful.",
"\n\nNow one of the main points in the DSM-V for gender dysphoria in children is that not only must the child meet six out of eight points on the list with the first point on the list being required to be met, but that the marked incongruence between the child’s gender and assigned gender must have lasted at least 6 months. ",
"Now I’m no expert, but when I think rapid I think under a month at the longest, and multiple articles have pointed this out including one of the articles I listed above.",
"\n\nThe website Transgender Trend is the provider of the information on the so-called new phenomenon, and does try its best to appear as a reputable source that wants to help trans youth and their parents, including providing materials for schools and parents. ",
"I went through the “resources” they provided, and could not find the source of the studies they claim prove their point, so if one of my readers can find it, please let me know in the comments below. ",
"For more technical aspects of why rapid onset is bullshit I will suggest reading the above articles and sources, what I’m going to discuss is what I dealt with personally as a child discovering their gender wasn’t matching up with their assigned gender.",
"\n\nOne of the main points I noticed was that they claim that the condition is affecting mostly teenage girls, which seems to go along with what I am finding on the hashtag #FtMSurge (which itself is anti-trans attacks on trans men and claims that need their own article to cover). ",
"Now, I was assigned the gender of female at birth due to the observation of my genitals as most kids are. ",
"Looking at pictures of me in my childhood you can see a baby in various cute feminine outfits, even a young girl wearing dresses and smiling at the camera. ",
"What isn’t shown though, is that around the age of eight I started noticing something was…off.",
"\n\nAww….look at that cute little baby!",
"\n\nMy parents were wonderful in that they didn’t try to force traditional gender norms on me as much as most, allowing me to be a “tom boy” and to play with toys generally associated with boys such as Ninja Turtles. ",
"Instead of an easy bake oven, I got a science kit (and turned part of my bedroom’s carpet blue), I got books on all sorts of subjects, I was allowed to explore who I was in a relatively safe manner. ",
"Looking back I can see that prior to puberty I saw myself as the same as my brother and many of my cousins, just I had an “innie” while they had an “outie” for their privates. ",
"I knew I was a boy, and my child mind gave a reasonable explanation for why I looked a little different.",
"\n\nBoys aren’t supposed to have periods! ",
"Only fat boys have breasts and they don’t look like what I have!",
"\n\nAround second grade is when I also started pushing for more masculine aspects of myself and being treated like I was a boy, though it was often met with pushback so over time I had to learn to be more subtle about it. ",
"We had to learn a dance for the Cinco de Mayo celebration every year in elementary school, and the class had more girls than boys, so some girls would have to be “boys” in the dance. ",
"In both second and third grade I jumped at the opportunity to be a boy, because that is what I was. ",
"I would get to dress, act, and learn the “boy” parts of the dance and this was a major validation for me even though people just assumed it was because I didn’t like dresses (yes, that had already started by this point).",
"\n\nThings went completely pear shaped for me when I started my period and my breasts began to grow. ",
"Boys aren’t supposed to have periods! ",
"Only fat boys have breasts and they don’t look like what I have! ",
"I remember being so angry about my body betraying me that I wanted to hurt myself to make it stop. ",
"While a child today could talk with their parents about what was going on and could get help with dealing with whether or not they were actually transgender or not, when I was a kid that just didn’t happen. ",
"We were still in the middle to tail end of the AIDS epidemic, so it was bad enough if you were LGB let alone T.\n\nThe DSM-IV wasn’t due out until 1994 (when I was 12) so if I tried to discuss my gender issues with someone medical professionals would have referred to the DSM-III which listed not only Transsexualism (302.5x) as the diagnosis but also included a category called “Transvestic Fetishism”. ",
"Gender Identity Disorder (which would later be renamed and reassessed as Gender Dysphoria) was listed under “Psychosexual Disorders” in the DSM-III and broken into multiple parts, included questions about one’s sexuality (the x portion of the part of the transsexualism diagnosis code), put both transvestism and transsexualism under the same umbrella (we no know this is incorrect), and the section on Gender Identity Disorder of Childhood used terms like, “boys who cross-dress” and lists under complications, “In a small number of cases, the disorder becomes continuous with Transsexualism.”",
"\n\nThese were the criteria for diagnoses (If you wish to read the entire section I posted the link to the DSM-III above):\n\nThis slideshow requires JavaScript.",
"\n\nI would have been labeled even more mentally ill than I already was (I was diagnosed with depression at the age of 6 and have been in and out of therapy and off and on medications since then), which would have led to more bullying at school from not just the girls, but also the boys. ",
"I was already being physically bullied by the time I hit puberty by various students, and had learned to keep quiet about a vast number of things. ",
"I would never have felt safe coming out back then, even if it had been an option.",
"\n\nSo instead, I repressed it. ",
"I told myself I was a girl even though I could feel myself screaming, “LIAR!” ",
"every time I did so. ",
"This was around the time when I was being expected to be more ladylike and feminine, with sitting with my legs crossed at the ankles, not sitting with my legs apart if they weren’t crossed, not acting in a non-ladylike manner (no belching, no acting like a man, all sorts of fun stuff). ",
"So my dysphoria only grew as I grew older and more expectations of being a woman were put on me. ",
"My dysphoria had symptoms that got associated with other illnesses ranging from depression to ADHD to defiance issues. ",
"I started becoming more violent in response to emotional and stressful triggers in my environment, which landed me in more therapy.",
"\n\nYou can practically hear the screams I’m holding inside.",
"\n\nI tried dressing as masculine as I could while still being feminine, my own way of trying to deal with the issue, but that tended to get me teased even more, being referred to as “Terminator” in the yearbook one year and being the punchline of all sorts of jokes and pranks that were highly inappropriate for any age.",
"\n\nI continued to repress who I was for over two decades, my dysphoria symptoms growing worse the more I repressed myself, until one day after a breast cancer scare I turned to look at my husband while I was driving home and it all just came rushing out.",
"\n\n“I should have been born a man, I’m not a woman.”",
"\n\nI came out publicly on July 20, 2014 to my parents, my viewers, everyone. ",
"While some people weren’t surprised by it, many felt it was “sudden” because they saw a woman who had three children, a loving husband, and who by most assumptions was a happy neurodivergent female. ",
"Even my therapist at the time questioned if I was actually trans or if I was just dealing with the cancer scare in an unhealthy way.",
"\n\nImagine what would have happened if I’d come out at eight or even ten and been asked if I was just “faking it” or if I actually had dysphoria.",
"\n\nNow I’m sure you’re all thinking, “What does any of that have to do with rapid onset?” ",
"Well I’m glad you asked. ",
"In the article Rapid Onset Gender Dysphoria and Other Myths there is a screenshot of part of the explanation of rapid onset, which includes this piece right here::\n\nSee, I didn’t “show signs” of dysphoria for much of my pre-puberty childhood, and my dysphoria from an outside view would have appeared rapid onset. ",
"One day I was fine, the next everything was wrong and I was highly dysphoric and distressed. ",
"My dysphoria technically started with the start of puberty because I’d found a way to rationalize my body to myself prior to that.",
"\n\nUnlike the youth today, who have access to the internet and to resources to do their own searching on what they’re feeling and experiencing, I would have been forced to go to my parents, and while they are supportive and loving of me regardless of my gender and sexuality (I’m asexual), at the time I felt that I would just wind up in more therapy and that I was broken.",
"\n\nI hid who I was because I didn’t want to be seen as even more broken than I already was.",
"\n\nToday we have youth being able to express their gender at an earlier age and thus catching things such as gender dysphoria at a much younger age than the start of puberty, we have youth who are able to do some research on their own to figure out what is going on before talking to their parents and working it out from there. ",
"We have resources for youths who don’t have a family that would be supportive of them, allowing them to get support for dealing with their dysphoria safely while not being punished or harmed by their parents. ",
"There are multiple communities online that help trans people work out who they are, where to get help, and many other things, even sometimes just needing people to send them pictures of cute animals because they’re feeling especially dysphoric that day and that helps them.",
"\n\nWhat we’re seeing isn’t a sudden rise in rapid onset gender dysphoria. ",
"We’re not seeing a sudden #FtMSurge of trans men popping up out of the woodwork due to sites like Tumblr and DeviantArt. ",
"What we’re seeing is trans youth feeling safe enough to come out early on instead of holding it in until they are past the point where things such as puberty blockers could have helped them while they dealt with coming to terms with their gender. ",
"We are seeing trans youth and non binary youth feeling able to come out due to having a pretty good feeling thanks to research as to what is going on with them so they can better explain it to their parents.",
"\n\nThis is not a “new phenomenom”, puberty tends to be a massive trigger for gender dysphoria and symptoms of dysphoria for trans individuals such as myself.",
"\n\nWe are not seeing a sudden surge in trans men because they’re learning about being trans from online groups or social media sites, what we’re seeing is trans men finally being listened to and properly treated and helped instead of just telling them they’re more masculine than other girls or that they’re just a “tom boy” and that they’ll grow out of it. ",
"The so-called surge is nothing more than people finally listening to trans men and their needs starting to be met with more frequency instead of sweeping them under the rug while focusing on trans women due to society’s obsession with women and the desire to either silence trans women or hold them under the same microscope cis women are held under, waiting for the tiniest of flaws to show up so that people have something to use to attack the trans woman in question.",
"\n\nBecause trans men were for so long viewed as just butch women or tom boys or essentially just masculine women, it is understandable that trans men finally being listened to and heard is going to look like some sort of surge. ",
"The thing is that we’ve always been here, we’ve just gone unnoticed by the vast majority of society and often ignored by medical professionals due to biases aimed towards women who don’t conform to expectations of gender.",
"\n\nPer the guidelines of rapid onset gender dysphoria, my dysphoria was rapid onset, yet it continued for over twenty years until it finally was treated when I started hormones on April 7, 2017 and when I had my top surgery on December 15, 2017. ",
"It took over 20 years to finally deal with and for the most part cure my dysphoria, yet per the guidelines set forth by the anti-trans group Transgender Trend, it was a rapid onset.",
"\n\nAnd wouldn’t you know, even with the dysphoria pretty much gone, I’m still trans!",
"\n\nPerhaps…perhaps the pseudoscientific lies being put forth are not some sort of new trend or happening, but something that is finally being examined in a way that others can see it? ",
"Or perhaps we’ve always been there, dealing with these issues, and this is just another way to attempt to silence trans and non-binary youth and force them to conform to outdated expectations of gender just like what was done to LGB youth back when the DSM-II listed homosexuality as a mental disorder?",
"\n\nPerhaps the same “science” being used to invalidate trans youth is the same sort of “science” that was used to justify conversion therapy.",
"\n\nWhat are your thoughts?",
"\n\nAdvertisements\n\nShare this:\n\nLike this:\n\nLikeLoading...\n\nRelated\n\nPublished by Michea B\n\nI am a trans man who hails from southern Oregon. ",
"I work as a freelance writer and photographer, as well as work as a volunteer activist. ",
"I create whimsical clay creations and make YouTube videos on social issues.",
"\nView all posts by Michea B\n\nHi Michea. ",
"I just wanted to say that I appreciate your writing style, your courage and I always feel like I’ve learned something when I’m done reading. ",
"Though I’m not a trans man, there’s a lot of things I can relate to in your description of your childhood.",
"\nI didn’t even know that non-binary was something you could be until the last couple of years. ",
"Had I known I would, probably, have come out in my early teens."
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"On 24 September, wrote the German tabloid Bild with reference to the founder of the “Cinema for peace” Yak of Bisila.",
"\n\nUpstairs\n\nAccording to the newspaper, Verzilov and other activists Pussy Riot “feel the danger” in Berlin. ",
"According to Bisile, which oversees the activists, two unknown men followed the Manager Verzilova to the hospital. ",
"After that the police decided to put security at the campus, where is the Russian.",
"\n\nAlso, according to Bild, police were sent to the house where relatives live Verzilova.",
"\n\nThe police of Berlin, the publication refused to comment on the security measures Verzilova and his family.",
"\n\nPussy Riot activist and publisher of “media zones” Pyotr Verzilov was in intensive care in Moscow on 11 September, shortly after the court session on the administrative case against his girlfriend Veronica Nikulinoj. ",
"He was reported in serious condition. ",
"According to Nikulinoj, Verzilov told her that “going blind”.",
"\n\nAccording to “Interfax”, the Russian doctors have ruled out poisoning of the animals. ",
"A source said that the activist entered in a “pre-stroke condition”. ",
"However, close Verzilova believe that he was poisoned. ",
"He was taken to the Berlin hospital, and on September 18 the German doctors declared that he had found in his body traces of toxins.",
"\n\nSeptember 24 it became known that the lawyer Dmitry Dinze asked the Investigative Committee in Moscow to check possible poisoning Verzilova. ",
"The reason for this was the article of “media zones” where journalists have gathered the basic facts and accounts of what happened to her publisher.",
"\n\nRead also: Khodorkovsky: poisoning Peter Verzilova due to the death of journalists in the Central African Republic"
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"Q:\n\nRemoving element from DOM via ng-if bound to attribute directive scope property\n\nI assumed this would be straightforward, but it's seemingly not!",
"\nI'm trying to create a generic attribute directive that will call a method in one of my services and conditionally cause the element in which it is placed to not be added to the DOM if the service method returns false. ",
"Basically, ng-if, but an ng-if that internally calls a service method and acts on that\nLink to Plunker\nI have an element containing an attribute directive: e.g\n<p ng-if=\"visible\" my-directive>Hi</p>\nI set visible to true in the myDirective directive. ",
"I was expecting the <p> element to be removed from the DOM when visible was falsy and added to the DOM when it's truthy. ",
"Instead, the ng-if never seems to spot that visible has been set to true in the directive's link function and, hence, the <p> element never displays.",
"\nI wasn't 100% sure it would work since the directive is removing the element on which it exists, bit of a catch 22 there. ",
"\nI've spent far too long on this and have so far tried (unsucessfully):\n\nAdding an ng-if attribute in the link function via these two methods\n\nattr.ngIf = true;\nelement.attr('ng-if', true);\n\nChanging the ng-if in the <p> to ng-show, thereby not removing the element (which I really want to do)\n\nI'm wondering if it's something as simple as scope? ",
"Since the ng-if is bound to a property of the <p> element, is setting visible in the directive scope setting it on the same scope?",
"\nOn the other hand, I may be drastically over-simplifying, I have a nasty feeling I may have to consider directive compilation and transclusion to get a solution for this.",
"\nDoes anyone have any feel for where I might be going wrong?",
"\n\nA:\n\ntldr: apparently you want your directive to be self-contained and it should be able to remove and add itself to the DOM. ",
"This is possible and makes the most sense via isolated scope or manual manipulation of the DOM (see below).",
"\nGeneral\nWhen you do <p ng-if=\"visible\" my-directive>Hi</p> angular looks for the visible on the current scope, which is the parent scope of the directive. ",
"When visible is defined, the directive is inserted in the DOM, e.g. taken from your plunker\n<body ng-controller=\"MainCtrl\">\n <p my-directive=\"showMe\" ng-if=\"visible\">I should be shown</p>\n</body>`<br>\n\napp.controller('MainCtrl', function($scope) {\n $scope.visible = 3;\n});\n\nwould make the directive being shown. ",
"As you defined an isolated scope on your directive\napp.directive('myDirective', function() {\n return {\n restrict: 'A',\n scope: {\n myDirective: '='\n },\n link: function(scope, element, attr, ctrl) {\n scope.visible = (scope.myDirective == 'showMe') ? ",
"true : false;\n }\n }\n});\n\nscope.visible in the directive does not affect the visible taken into account for ngIf.",
"\nChild Scope\nYou could define a child scope to get access to the parent scope. ",
"If you do that, you can actually affect the right visible property, but you have to put it on an object so that the directive can follow the scope prototype chain.",
"\n<body ng-controller=\"MainCtrl\">\n <p my-directive ng-if=\"visibleDirectives.directive1\">I should be shown</p>\n</body>\n\nThe $timeouts are there for demonstration purposes. ",
"Initially the ngIf has to evaluate to true else the directive is not being created at all.",
"\napp.controller('MainCtrl', function($scope) {\n $scope.visibleDirectives = { directive1 : true };\n});\n\napp.directive('myDirective', function($timeout) {\n return {\n restrict: 'A',\n scope : true,\n link: function(scope, element, attr, ctrl) {\n console.log(scope);\n $timeout(function() {\n scope.visibleDirectives.directive1 = !",
"scope.visibleDirectives.directive1;\n $timeout(function() {\n scope.visibleDirectives.directive1 = !",
"scope.visibleDirectives.directive1;\n }, 2000);\n }, 2000);\n }\n }\n});\n\nLike this the directive has to know about the property that defines it's visibility beforehand (in this case scope.visibleDirectives.visible1), which is not very practical and prohibits several directives.",
"\nIsolated Scope\nIn your example you used an isolated scope. ",
"This allows reusing the directive. ",
"In order for the directive to be able to modify the appropriate property for ngIf you have to again give it the right reference.",
"\n<body ng-controller=\"MainCtrl\">\n <p my-directive=\"directive1\" ng-if=\"directive1.visible\">I should be shown</p>\n</body>\n\nAgain you have to provide the property on an object so that the directive can follow the object reference to modify the right visible.",
"\napp.controller('MainCtrl', function($scope) {\n $scope.directive1 = {\n visible : true\n };\n});\n\napp.directive('myDirective', function($timeout) {\n return {\n restrict: 'A',\n scope : {\n myDirective : '='\n },\n link: function(scope, element, attr, ctrl) {\n $timeout(function() {\n scope.myDirective.visible = !",
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"\nManual manipulation of the DOM\nYou can also just manually remove and append the node of the directive without consulting angular.",
"\n<body ng-controller=\"MainCtrl\">\n <p my-directive>I should be shown</p>\n</body>\n\nIn this case you don't need the angular version of setTimeout and can even use a setInterval as the Interval is created only once, but you have to clear it.",
"\napp.controller('MainCtrl', function($scope) { });\n\napp.directive('myDirective', function() {\n return {\n restrict: 'A',\n scope : { },\n link: function(scope, element, attr, ctrl) {\n var el = element[0];\n var parent = el.parentNode;\n var shouldBeShown = false;\n var interval = setInterval(function() {\n var children = parent.children;\n var found = false;\n for(var i = 0; i < children.length; i++) {\n if(children[i] === el) {\n found = true;\n break;\n }\n }\n if(shouldBeShown) {\n if(!found)\n parent.appendChild(el);\n }\n else {\n if(found)\n parent.removeChild(el);\n }\n shouldBeShown = !",
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[
"Q:\n\nLogging on Spark\n\nI'm using Spark to distribute a job which is currently not distributed. ",
"Many classes generate useful logging (log4j), and these classes are not supposed to be Spark-specific (they implement filtering operations and stuff, so they should be used as is). ",
"\nHowever, their code is executed on the slaves, so I don't get this logging back to the master. ",
"Is there a clever way, with no Spark-related code in these classes, and changes as minor as possible, to do this ?",
"\nPS : as the tags show it, I'm working with the Java API.",
"\n\nA:\n\nIf you don't want to change your code you may consider configuring log4j to deliver the log messages to a central location.",
"\nYou can choose e.g. FlumeAppender, JMSAppender JDBCAppender...\nIf you don't like any of these you can implement your own appender.",
"\n\n"
] | {
"pile_set_name": "StackExchange"
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[
"package so_DJ\n\nimport (\n\t\"testing\"\n\t\"time\"\n\n\t\"github.com/go-playground/locales\"\n\t\"github.com/go-playground/locales/currency\"\n)\n\nfunc TestLocale(t *testing.",
"T) {\n\n\ttrans := New()\n\texpected := \"so_DJ\"\n\n\tif trans.",
"Locale() !",
"= expected {\n\t\tt.Errorf(\"Expected '%s' Got '%s'\", expected, trans.",
"Locale())\n\t}\n}\n\nfunc TestPluralsRange(t *testing.",
"T) {\n\n\ttrans := New()\n\n\ttests := []struct {\n\t\texpected locales.",
"PluralRule\n\t}{\n\t// {\n\t// \texpected: locales.",
"PluralRuleOther,\n\t// },\n\t}\n\n\trules := trans.",
"PluralsRange()\n\t// expected := 1\n\t// if len(rules) !",
"= expected {\n\t// \tt.Errorf(\"Expected '%d' Got '%d'\", expected, len(rules))\n\t// }\n\n\tfor _, tt := range tests {\n\n\t\tr := locales.",
"PluralRuleUnknown\n\n\t\tfor i := 0; i < len(rules); i++ {\n\t\t\tif rules[i] == tt.expected {\n\t\t\t\tr = rules[i]\n\t\t\t\tbreak\n\t\t\t}\n\t\t}\n\t\tif r == locales.",
"PluralRuleUnknown {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, r)\n\t\t}\n\t}\n}\n\nfunc TestPluralsOrdinal(t *testing.",
"T) {\n\n\ttrans := New()\n\n\ttests := []struct {\n\t\texpected locales.",
"PluralRule\n\t}{\n\t// {\n\t// \texpected: locales.",
"PluralRuleOne,\n\t// },\n\t// {\n\t// \texpected: locales.",
"PluralRuleTwo,\n\t// },\n\t// {\n\t// \texpected: locales.",
"PluralRuleFew,\n\t// },\n\t// {\n\t// \texpected: locales.",
"PluralRuleOther,\n\t// },\n\t}\n\n\trules := trans.",
"PluralsOrdinal()\n\t// expected := 4\n\t// if len(rules) !",
"= expected {\n\t// \tt.Errorf(\"Expected '%d' Got '%d'\", expected, len(rules))\n\t// }\n\n\tfor _, tt := range tests {\n\n\t\tr := locales.",
"PluralRuleUnknown\n\n\t\tfor i := 0; i < len(rules); i++ {\n\t\t\tif rules[i] == tt.expected {\n\t\t\t\tr = rules[i]\n\t\t\t\tbreak\n\t\t\t}\n\t\t}\n\t\tif r == locales.",
"PluralRuleUnknown {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, r)\n\t\t}\n\t}\n}\n\nfunc TestPluralsCardinal(t *testing.",
"T) {\n\n\ttrans := New()\n\n\ttests := []struct {\n\t\texpected locales.",
"PluralRule\n\t}{\n\t// {\n\t// \texpected: locales.",
"PluralRuleOne,\n\t// },\n\t// {\n\t// \texpected: locales.",
"PluralRuleOther,\n\t// },\n\t}\n\n\trules := trans.",
"PluralsCardinal()\n\t// expected := 2\n\t// if len(rules) !",
"= expected {\n\t// \tt.Errorf(\"Expected '%d' Got '%d'\", expected, len(rules))\n\t// }\n\n\tfor _, tt := range tests {\n\n\t\tr := locales.",
"PluralRuleUnknown\n\n\t\tfor i := 0; i < len(rules); i++ {\n\t\t\tif rules[i] == tt.expected {\n\t\t\t\tr = rules[i]\n\t\t\t\tbreak\n\t\t\t}\n\t\t}\n\t\tif r == locales.",
"PluralRuleUnknown {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, r)\n\t\t}\n\t}\n}\n\nfunc TestRangePlurals(t *testing.",
"T) {\n\n\ttrans := New()\n\n\ttests := []struct {\n\t\tnum1 float64\n\t\tv1 uint64\n\t\tnum2 float64\n\t\tv2 uint64\n\t\texpected locales.",
"PluralRule\n\t}{\n\t// {\n\t// \tnum1: 1,\n\t// \tv1: 1,\n\t// \tnum2: 2,\n\t// \tv2: 2,\n\t// \texpected: locales.",
"PluralRuleOther,\n\t// },\n\t}\n\n\tfor _, tt := range tests {\n\t\trule := trans.",
"RangePluralRule(tt.num1, tt.v1, tt.num2, tt.v2)\n\t\tif rule !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, rule)\n\t\t}\n\t}\n}\n\nfunc TestOrdinalPlurals(t *testing.",
"T) {\n\n\ttrans := New()\n\n\ttests := []struct {\n\t\tnum float64\n\t\tv uint64\n\t\texpected locales.",
"PluralRule\n\t}{\n\t// {\n\t// \tnum: 1,\n\t// \tv: 0,\n\t// \texpected: locales.",
"PluralRuleOne,\n\t// },\n\t// {\n\t// \tnum: 2,\n\t// \tv: 0,\n\t// \texpected: locales.",
"PluralRuleTwo,\n\t// },\n\t// {\n\t// \tnum: 3,\n\t// \tv: 0,\n\t// \texpected: locales.",
"PluralRuleFew,\n\t// },\n\t// {\n\t// \tnum: 4,\n\t// \tv: 0,\n\t// \texpected: locales.",
"PluralRuleOther,\n\t// },\n\t}\n\n\tfor _, tt := range tests {\n\t\trule := trans.",
"OrdinalPluralRule(tt.num, tt.v)\n\t\tif rule !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, rule)\n\t\t}\n\t}\n}\n\nfunc TestCardinalPlurals(t *testing.",
"T) {\n\n\ttrans := New()\n\n\ttests := []struct {\n\t\tnum float64\n\t\tv uint64\n\t\texpected locales.",
"PluralRule\n\t}{\n\t// {\n\t// \tnum: 1,\n\t// \tv: 0,\n\t// \texpected: locales.",
"PluralRuleOne,\n\t// },\n\t// {\n\t// \tnum: 4,\n\t// \tv: 0,\n\t// \texpected: locales.",
"PluralRuleOther,\n\t// },\n\t}\n\n\tfor _, tt := range tests {\n\t\trule := trans.",
"CardinalPluralRule(tt.num, tt.v)\n\t\tif rule !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, rule)\n\t\t}\n\t}\n}\n\nfunc TestDaysAbbreviated(t *testing.",
"T) {\n\n\ttrans := New()\n\tdays := trans.",
"WeekdaysAbbreviated()\n\n\tfor i, day := range days {\n\t\ts := trans.",
"WeekdayAbbreviated(time.",
"Weekday(i))\n\t\tif s !",
"= day {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", day, s)\n\t\t}\n\t}\n\n\ttests := []struct {\n\t\tidx int\n\t\texpected string\n\t}{\n\t// {\n\t// \tidx: 0,\n\t// \texpected: \"Sun\",\n\t// },\n\t// {\n\t// \tidx: 1,\n\t// \texpected: \"Mon\",\n\t// },\n\t// {\n\t// \tidx: 2,\n\t// \texpected: \"Tue\",\n\t// },\n\t// {\n\t// \tidx: 3,\n\t// \texpected: \"Wed\",\n\t// },\n\t// {\n\t// \tidx: 4,\n\t// \texpected: \"Thu\",\n\t// },\n\t// {\n\t// \tidx: 5,\n\t// \texpected: \"Fri\",\n\t// },\n\t// {\n\t// \tidx: 6,\n\t// \texpected: \"Sat\",\n\t// },\n\t}\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"WeekdayAbbreviated(time.",
"Weekday(tt.idx))\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestDaysNarrow(t *testing.",
"T) {\n\n\ttrans := New()\n\tdays := trans.",
"WeekdaysNarrow()\n\n\tfor i, day := range days {\n\t\ts := trans.",
"WeekdayNarrow(time.",
"Weekday(i))\n\t\tif s !",
"= day {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", string(day), s)\n\t\t}\n\t}\n\n\ttests := []struct {\n\t\tidx int\n\t\texpected string\n\t}{\n\t// {\n\t// \tidx: 0,\n\t// \texpected: \"S\",\n\t// },\n\t// {\n\t// \tidx: 1,\n\t// \texpected: \"M\",\n\t// },\n\t// {\n\t// \tidx: 2,\n\t// \texpected: \"T\",\n\t// },\n\t// {\n\t// \tidx: 3,\n\t// \texpected: \"W\",\n\t// },\n\t// {\n\t// \tidx: 4,\n\t// \texpected: \"T\",\n\t// },\n\t// {\n\t// \tidx: 5,\n\t// \texpected: \"F\",\n\t// },\n\t// {\n\t// \tidx: 6,\n\t// \texpected: \"S\",\n\t// },\n\t}\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"WeekdayNarrow(time.",
"Weekday(tt.idx))\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestDaysShort(t *testing.",
"T) {\n\n\ttrans := New()\n\tdays := trans.",
"WeekdaysShort()\n\n\tfor i, day := range days {\n\t\ts := trans.",
"WeekdayShort(time.",
"Weekday(i))\n\t\tif s !",
"= day {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", day, s)\n\t\t}\n\t}\n\n\ttests := []struct {\n\t\tidx int\n\t\texpected string\n\t}{\n\t// {\n\t// \tidx: 0,\n\t// \texpected: \"Su\",\n\t// },\n\t// {\n\t// \tidx: 1,\n\t// \texpected: \"Mo\",\n\t// },\n\t// {\n\t// \tidx: 2,\n\t// \texpected: \"Tu\",\n\t// },\n\t// {\n\t// \tidx: 3,\n\t// \texpected: \"We\",\n\t// },\n\t// {\n\t// \tidx: 4,\n\t// \texpected: \"Th\",\n\t// },\n\t// {\n\t// \tidx: 5,\n\t// \texpected: \"Fr\",\n\t// },\n\t// {\n\t// \tidx: 6,\n\t// \texpected: \"Sa\",\n\t// },\n\t}\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"WeekdayShort(time.",
"Weekday(tt.idx))\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestDaysWide(t *testing.",
"T) {\n\n\ttrans := New()\n\tdays := trans.",
"WeekdaysWide()\n\n\tfor i, day := range days {\n\t\ts := trans.",
"WeekdayWide(time.",
"Weekday(i))\n\t\tif s !",
"= day {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", day, s)\n\t\t}\n\t}\n\n\ttests := []struct {\n\t\tidx int\n\t\texpected string\n\t}{\n\t// {\n\t// \tidx: 0,\n\t// \texpected: \"Sunday\",\n\t// },\n\t// {\n\t// \tidx: 1,\n\t// \texpected: \"Monday\",\n\t// },\n\t// {\n\t// \tidx: 2,\n\t// \texpected: \"Tuesday\",\n\t// },\n\t// {\n\t// \tidx: 3,\n\t// \texpected: \"Wednesday\",\n\t// },\n\t// {\n\t// \tidx: 4,\n\t// \texpected: \"Thursday\",\n\t// },\n\t// {\n\t// \tidx: 5,\n\t// \texpected: \"Friday\",\n\t// },\n\t// {\n\t// \tidx: 6,\n\t// \texpected: \"Saturday\",\n\t// },\n\t}\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"WeekdayWide(time.",
"Weekday(tt.idx))\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestMonthsAbbreviated(t *testing.",
"T) {\n\n\ttrans := New()\n\tmonths := trans.",
"MonthsAbbreviated()\n\n\tfor i, month := range months {\n\t\ts := trans.",
"MonthAbbreviated(time.",
"Month(i + 1))\n\t\tif s !",
"= month {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", month, s)\n\t\t}\n\t}\n\n\ttests := []struct {\n\t\tidx int\n\t\texpected string\n\t}{\n\t// {\n\t// \tidx: 1,\n\t// \texpected: \"Jan\",\n\t// },\n\t// {\n\t// \tidx: 2,\n\t// \texpected: \"Feb\",\n\t// },\n\t// {\n\t// \tidx: 3,\n\t// \texpected: \"Mar\",\n\t// },\n\t// {\n\t// \tidx: 4,\n\t// \texpected: \"Apr\",\n\t// },\n\t// {\n\t// \tidx: 5,\n\t// \texpected: \"May\",\n\t// },\n\t// {\n\t// \tidx: 6,\n\t// \texpected: \"Jun\",\n\t// },\n\t// {\n\t// \tidx: 7,\n\t// \texpected: \"Jul\",\n\t// },\n\t// {\n\t// \tidx: 8,\n\t// \texpected: \"Aug\",\n\t// },\n\t// {\n\t// \tidx: 9,\n\t// \texpected: \"Sep\",\n\t// },\n\t// {\n\t// \tidx: 10,\n\t// \texpected: \"Oct\",\n\t// },\n\t// {\n\t// \tidx: 11,\n\t// \texpected: \"Nov\",\n\t// },\n\t// {\n\t// \tidx: 12,\n\t// \texpected: \"Dec\",\n\t// },\n\t}\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"MonthAbbreviated(time.",
"Month(tt.idx))\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestMonthsNarrow(t *testing.",
"T) {\n\n\ttrans := New()\n\tmonths := trans.",
"MonthsNarrow()\n\n\tfor i, month := range months {\n\t\ts := trans.",
"MonthNarrow(time.",
"Month(i + 1))\n\t\tif s !",
"= month {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", month, s)\n\t\t}\n\t}\n\n\ttests := []struct {\n\t\tidx int\n\t\texpected string\n\t}{\n\t// {\n\t// \tidx: 1,\n\t// \texpected: \"J\",\n\t// },\n\t// {\n\t// \tidx: 2,\n\t// \texpected: \"F\",\n\t// },\n\t// {\n\t// \tidx: 3,\n\t// \texpected: \"M\",\n\t// },\n\t// {\n\t// \tidx: 4,\n\t// \texpected: \"A\",\n\t// },\n\t// {\n\t// \tidx: 5,\n\t// \texpected: \"M\",\n\t// },\n\t// {\n\t// \tidx: 6,\n\t// \texpected: \"J\",\n\t// },\n\t// {\n\t// \tidx: 7,\n\t// \texpected: \"J\",\n\t// },\n\t// {\n\t// \tidx: 8,\n\t// \texpected: \"A\",\n\t// },\n\t// {\n\t// \tidx: 9,\n\t// \texpected: \"S\",\n\t// },\n\t// {\n\t// \tidx: 10,\n\t// \texpected: \"O\",\n\t// },\n\t// {\n\t// \tidx: 11,\n\t// \texpected: \"N\",\n\t// },\n\t// {\n\t// \tidx: 12,\n\t// \texpected: \"D\",\n\t// },\n\t}\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"MonthNarrow(time.",
"Month(tt.idx))\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestMonthsWide(t *testing.",
"T) {\n\n\ttrans := New()\n\tmonths := trans.",
"MonthsWide()\n\n\tfor i, month := range months {\n\t\ts := trans.",
"MonthWide(time.",
"Month(i + 1))\n\t\tif s !",
"= month {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", month, s)\n\t\t}\n\t}\n\n\ttests := []struct {\n\t\tidx int\n\t\texpected string\n\t}{\n\t// {\n\t// \tidx: 1,\n\t// \texpected: \"January\",\n\t// },\n\t// {\n\t// \tidx: 2,\n\t// \texpected: \"February\",\n\t// },\n\t// {\n\t// \tidx: 3,\n\t// \texpected: \"March\",\n\t// },\n\t// {\n\t// \tidx: 4,\n\t// \texpected: \"April\",\n\t// },\n\t// {\n\t// \tidx: 5,\n\t// \texpected: \"May\",\n\t// },\n\t// {\n\t// \tidx: 6,\n\t// \texpected: \"June\",\n\t// },\n\t// {\n\t// \tidx: 7,\n\t// \texpected: \"July\",\n\t// },\n\t// {\n\t// \tidx: 8,\n\t// \texpected: \"August\",\n\t// },\n\t// {\n\t// \tidx: 9,\n\t// \texpected: \"September\",\n\t// },\n\t// {\n\t// \tidx: 10,\n\t// \texpected: \"October\",\n\t// },\n\t// {\n\t// \tidx: 11,\n\t// \texpected: \"November\",\n\t// },\n\t// {\n\t// \tidx: 12,\n\t// \texpected: \"December\",\n\t// },\n\t}\n\n\tfor _, tt := range tests {\n\t\ts := string(trans.",
"MonthWide(time.",
"Month(tt.idx)))\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestFmtTimeFull(t *testing.",
"T) {\n\n\t// loc, err := time.",
"LoadLocation(\"America/Toronto\")\n\t// if err !",
"= nil {\n\t// \tt.Errorf(\"Expected '<nil>' Got '%s'\", err)\n\t// }\n\n\t// fixed := time.",
"FixedZone(\"OTHER\", -4)\n\n\ttests := []struct {\n\t\tt time.",
"Time\n\t\texpected string\n\t}{\n\t// {\n\t// \tt: time.",
"Date(2016, 02, 03, 9, 5, 1, 0, loc),\n\t// \texpected: \"9:05:01 am Eastern Standard Time\",\n\t// },\n\t// {\n\t// \tt: time.",
"Date(2016, 02, 03, 20, 5, 1, 0, fixed),\n\t// \texpected: \"8:05:01 pm OTHER\",\n\t// },\n\t}\n\n\ttrans := New()\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"FmtTimeFull(tt.t)\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestFmtTimeLong(t *testing.",
"T) {\n\n\t// loc, err := time.",
"LoadLocation(\"America/Toronto\")\n\t// if err !",
"= nil {\n\t// \tt.Errorf(\"Expected '<nil>' Got '%s'\", err)\n\t// }\n\n\ttests := []struct {\n\t\tt time.",
"Time\n\t\texpected string\n\t}{\n\t// {\n\t// \tt: time.",
"Date(2016, 02, 03, 9, 5, 1, 0, loc),\n\t// \texpected: \"9:05:01 am EST\",\n\t// },\n\t// {\n\t// \tt: time.",
"Date(2016, 02, 03, 20, 5, 1, 0, loc),\n\t// \texpected: \"8:05:01 pm EST\",\n\t// },\n\t}\n\n\ttrans := New()\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"FmtTimeLong(tt.t)\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestFmtTimeMedium(t *testing.",
"T) {\n\n\ttests := []struct {\n\t\tt time.",
"Time\n\t\texpected string\n\t}{\n\t// {\n\t// \tt: time.",
"Date(2016, 02, 03, 9, 5, 1, 0, time.",
"UTC),\n\t// \texpected: \"9:05:01 am\",\n\t// },\n\t// {\n\t// \tt: time.",
"Date(2016, 02, 03, 20, 5, 1, 0, time.",
"UTC),\n\t// \texpected: \"8:05:01 pm\",\n\t// },\n\t}\n\n\ttrans := New()\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"FmtTimeMedium(tt.t)\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestFmtTimeShort(t *testing.",
"T) {\n\n\ttests := []struct {\n\t\tt time.",
"Time\n\t\texpected string\n\t}{\n\t// {\n\t// \tt: time.",
"Date(2016, 02, 03, 9, 5, 1, 0, time.",
"UTC),\n\t// \texpected: \"9:05 am\",\n\t// },\n\t// {\n\t// \tt: time.",
"Date(2016, 02, 03, 20, 5, 1, 0, time.",
"UTC),\n\t// \texpected: \"8:05 pm\",\n\t// },\n\t}\n\n\ttrans := New()\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"FmtTimeShort(tt.t)\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestFmtDateFull(t *testing.",
"T) {\n\n\ttests := []struct {\n\t\tt time.",
"Time\n\t\texpected string\n\t}{\n\t// {\n\t// \tt: time.",
"Date(2016, 02, 03, 9, 0, 1, 0, time.",
"UTC),\n\t// \texpected: \"Wednesday, February 3, 2016\",\n\t// },\n\t}\n\n\ttrans := New()\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"FmtDateFull(tt.t)\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestFmtDateLong(t *testing.",
"T) {\n\n\ttests := []struct {\n\t\tt time.",
"Time\n\t\texpected string\n\t}{\n\t// {\n\t// \tt: time.",
"Date(2016, 02, 03, 9, 0, 1, 0, time.",
"UTC),\n\t// \texpected: \"February 3, 2016\",\n\t// },\n\t}\n\n\ttrans := New()\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"FmtDateLong(tt.t)\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestFmtDateMedium(t *testing.",
"T) {\n\n\ttests := []struct {\n\t\tt time.",
"Time\n\t\texpected string\n\t}{\n\t// {\n\t// \tt: time.",
"Date(2016, 02, 03, 9, 0, 1, 0, time.",
"UTC),\n\t// \texpected: \"Feb 3, 2016\",\n\t// },\n\t}\n\n\ttrans := New()\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"FmtDateMedium(tt.t)\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestFmtDateShort(t *testing.",
"T) {\n\n\ttests := []struct {\n\t\tt time.",
"Time\n\t\texpected string\n\t}{\n\t// {\n\t// \tt: time.",
"Date(2016, 02, 03, 9, 0, 1, 0, time.",
"UTC),\n\t// \texpected: \"2/3/16\",\n\t// },\n\t// {\n\t// \tt: time.",
"Date(-500, 02, 03, 9, 0, 1, 0, time.",
"UTC),\n\t// \texpected: \"2/3/500\",\n\t// },\n\t}\n\n\ttrans := New()\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"FmtDateShort(tt.t)\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestFmtNumber(t *testing.",
"T) {\n\n\ttests := []struct {\n\t\tnum float64\n\t\tv uint64\n\t\texpected string\n\t}{\n\t// {\n\t// \tnum: 1123456.5643,\n\t// \tv: 2,\n\t// \texpected: \"1,123,456.56\",\n\t// },\n\t// {\n\t// \tnum: 1123456.5643,\n\t// \tv: 1,\n\t// \texpected: \"1,123,456.6\",\n\t// },\n\t// {\n\t// \tnum: 221123456.5643,\n\t// \tv: 3,\n\t// \texpected: \"221,123,456.564\",\n\t// },\n\t// {\n\t// \tnum: -221123456.5643,\n\t// \tv: 3,\n\t// \texpected: \"-221,123,456.564\",\n\t// },\n\t// {\n\t// \tnum: -221123456.5643,\n\t// \tv: 3,\n\t// \texpected: \"-221,123,456.564\",\n\t// },\n\t// {\n\t// \tnum: 0,\n\t// \tv: 2,\n\t// \texpected: \"0.00\",\n\t// },\n\t// {\n\t// \tnum: -0,\n\t// \tv: 2,\n\t// \texpected: \"0.00\",\n\t// },\n\t// {\n\t// \tnum: -0,\n\t// \tv: 2,\n\t// \texpected: \"0.00\",\n\t// },\n\t}\n\n\ttrans := New()\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"FmtNumber(tt.num, tt.v)\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestFmtCurrency(t *testing.",
"T) {\n\n\ttests := []struct {\n\t\tnum float64\n\t\tv uint64\n\t\tcurrency currency.",
"Type\n\t\texpected string\n\t}{\n\t// {\n\t// \tnum: 1123456.5643,\n\t// \tv: 2,\n\t// \tcurrency: currency.",
"USD,\n\t// \texpected: \"$1,123,456.56\",\n\t// },\n\t// {\n\t// \tnum: 1123456.5643,\n\t// \tv: 1,\n\t// \tcurrency: currency.",
"USD,\n\t// \texpected: \"$1,123,456.60\",\n\t// },\n\t// {\n\t// \tnum: 221123456.5643,\n\t// \tv: 3,\n\t// \tcurrency: currency.",
"USD,\n\t// \texpected: \"$221,123,456.564\",\n\t// },\n\t// {\n\t// \tnum: -221123456.5643,\n\t// \tv: 3,\n\t// \tcurrency: currency.",
"USD,\n\t// \texpected: \"-$221,123,456.564\",\n\t// },\n\t// {\n\t// \tnum: -221123456.5643,\n\t// \tv: 3,\n\t// \tcurrency: currency.",
"CAD,\n\t// \texpected: \"-CAD 221,123,456.564\",\n\t// },\n\t// {\n\t// \tnum: 0,\n\t// \tv: 2,\n\t// \tcurrency: currency.",
"USD,\n\t// \texpected: \"$0.00\",\n\t// },\n\t// {\n\t// \tnum: -0,\n\t// \tv: 2,\n\t// \tcurrency: currency.",
"USD,\n\t// \texpected: \"$0.00\",\n\t// },\n\t// {\n\t// \tnum: -0,\n\t// \tv: 2,\n\t// \tcurrency: currency.",
"CAD,\n\t// \texpected: \"CAD 0.00\",\n\t// },\n\t// {\n\t// \tnum: 1.23,\n\t// \tv: 0,\n\t// \tcurrency: currency.",
"USD,\n\t// \texpected: \"$1.00\",\n\t// },\n\t}\n\n\ttrans := New()\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"FmtCurrency(tt.num, tt.v, tt.currency)\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestFmtAccounting(t *testing.",
"T) {\n\n\ttests := []struct {\n\t\tnum float64\n\t\tv uint64\n\t\tcurrency currency.",
"Type\n\t\texpected string\n\t}{\n\t// {\n\t// \tnum: 1123456.5643,\n\t// \tv: 2,\n\t// \tcurrency: currency.",
"USD,\n\t// \texpected: \"$1,123,456.56\",\n\t// },\n\t// {\n\t// \tnum: 1123456.5643,\n\t// \tv: 1,\n\t// \tcurrency: currency.",
"USD,\n\t// \texpected: \"$1,123,456.60\",\n\t// },\n\t// {\n\t// \tnum: 221123456.5643,\n\t// \tv: 3,\n\t// \tcurrency: currency.",
"USD,\n\t// \texpected: \"$221,123,456.564\",\n\t// },\n\t// {\n\t// \tnum: -221123456.5643,\n\t// \tv: 3,\n\t// \tcurrency: currency.",
"USD,\n\t// \texpected: \"($221,123,456.564)\",\n\t// },\n\t// {\n\t// \tnum: -221123456.5643,\n\t// \tv: 3,\n\t// \tcurrency: currency.",
"CAD,\n\t// \texpected: \"(CAD 221,123,456.564)\",\n\t// },\n\t// {\n\t// \tnum: -0,\n\t// \tv: 2,\n\t// \tcurrency: currency.",
"USD,\n\t// \texpected: \"$0.00\",\n\t// },\n\t// {\n\t// \tnum: -0,\n\t// \tv: 2,\n\t// \tcurrency: currency.",
"CAD,\n\t// \texpected: \"CAD 0.00\",\n\t// },\n\t// {\n\t// \tnum: 1.23,\n\t// \tv: 0,\n\t// \tcurrency: currency.",
"USD,\n\t// \texpected: \"$1.00\",\n\t// },\n\t}\n\n\ttrans := New()\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"FmtAccounting(tt.num, tt.v, tt.currency)\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n\nfunc TestFmtPercent(t *testing.",
"T) {\n\n\ttests := []struct {\n\t\tnum float64\n\t\tv uint64\n\t\texpected string\n\t}{\n\t// {\n\t// \tnum: 15,\n\t// \tv: 0,\n\t// \texpected: \"15%\",\n\t// },\n\t// {\n\t// \tnum: 15,\n\t// \tv: 2,\n\t// \texpected: \"15.00%\",\n\t// },\n\t// {\n\t// \tnum: 434.45,\n\t// \tv: 0,\n\t// \texpected: \"434%\",\n\t// },\n\t// {\n\t// \tnum: 34.4,\n\t// \tv: 2,\n\t// \texpected: \"34.40%\",\n\t// },\n\t// {\n\t// \tnum: -34,\n\t// \tv: 0,\n\t// \texpected: \"-34%\",\n\t// },\n\t}\n\n\ttrans := New()\n\n\tfor _, tt := range tests {\n\t\ts := trans.",
"FmtPercent(tt.num, tt.v)\n\t\tif s !",
"= tt.expected {\n\t\t\tt.Errorf(\"Expected '%s' Got '%s'\", tt.expected, s)\n\t\t}\n\t}\n}\n"
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[
"INTRODUCTION\n============\n\nGlioblastoma is a devastating and universally fatal cancer that evades therapy because of its complex and adaptive cellular composition and its ability to rapidly develop resistance to conventional and targeted therapeutics ([@R1]). ",
"Novel strategies that aim to prime the patient's immune system against cancerous tissue have recently gained momentum in the clinic ([@R2]--[@R4]). ",
"In this context, glioblastoma has long been recognized as a local and systemic immunosuppressive neoplasm by releasing anti-inflammatory cytokines, reducing levels of antigen-presenting molecules, and engaging immune checkpoint--activating regulatory receptors on T cells ([@R2], [@R5]). ",
"There are increasing efforts to target glioblastoma clinically using immune therapies including immune checkpoint blockade, which has shown unprecedented activity in some tumors ([@R6]--[@R8]). ",
"Immune checkpoints refer to a broad spectrum of immune inhibitory pathways hardwired in the immune system that are pivotal in the balanced regulation of physiological T cell responses ([@R3]). ",
"One of the most prominent molecules used by tumor cells to engage T cell immune checkpoints is programmed death ligand 1 (PD-L1) ([@R9], [@R10]). ",
"PD-L1 expressed on the surface of tumor and antigen-presenting cells binds to programmed cell death protein 1 (PD1), which is expressed by activated T cells. ",
"In normal biology, this machinery is used to control T cell activation. ",
"However, in tumors, this leads to blockade of T cell activation and protects tumor cells from T cell--mediated killing. ",
"It is now clear that tumors use various mechanisms to hijack immune checkpoints to evade immune recognition, primarily against tumor neoantigen-specific T cells ([@R3], [@R4]).",
"\n\nGlioblastoma is a heterogeneous brain tumor, with three major transcriptionally defined subtypes \\[proneural (P), classical, and mesenchymal (M)\\] ([@R11]). ",
"Gene expression analysis suggests that these subtypes may use distinct immunosuppressive mechanisms, with M glioblastoma showing elevated expression of genes with immune functions, including significant elevation of PD-L1 when compared with P glioblastoma, suggesting that specific transcriptional subtypes may respond differentially to immune-based therapies ([@R12]). ",
"We now recognize that glioblastoma heterogeneity can be maintained by extracellular vesicles (EVs) shed by tumor cells ([@R13]). ",
"EVs, including exosomes and microvesicles, resemble small cellular surrogates that act as major conduits in cell-cell communication. ",
"When released from tumors, EVs locally and systemically transfer host cell biological materials (including proteins, RNA, and DNA) that facilitate tumor progression, angiogenesis, and immune tolerance ([@R14]--[@R16]). ",
"However, tumor EVs carry multiple layers of immune modulatory capacities, and the knowledge of how these influence infiltrating lymphocytes within the tumor microenvironment is still rudimental. ",
"Here, we show that glioblastoma-derived EVs block T cell receptor (TCR)--mediated T cell activation. ",
"Mechanistically, we show that, for some glioblastomas, this is partially rescued by treatment with an anti-PD1 antibody that blocks ligand binding and that PD-L1 on EVs can directly ligate PD1. ",
"We also show that glioblastoma EVs bind to the surface of T cells. ",
"PD-L1 expression correlates with the mesenchymal gene expression subtype and is enriched in cells located in the perinecrotic and pseudopalisading niches of glioblastomas. ",
"Furthermore, PD-L1 DNA is present in circulating EVs from glioblastoma patients, where it correlates with glioblastoma volumes of up to 60 cm^3^. These findings highlight novel roles of glioblastoma-derived EVs with the potential for both local and systemic suppression of antitumor immunity.",
"\n\nRESULTS\n=======\n\nWe sought to determine whether EVs derived from glioblastoma stem-like cells (GSCs) can mediate T cell immunosuppression. ",
"We asked whether EVs isolated from human GSCs could inhibit CD4^+^ or CD8^+^ T cells when activated through the TCR. [",
"Figure 1A](#F1){ref-type=\"fig\"} shows that EVs from human GSCs suppressed the activation of both CD4^+^ and CD8^+^ T cells by anti-CD3 to mimic antigen recognition through the TCR. ",
"This was initially performed in peripheral blood mononuclear cells (PBMCs) from healthy human donors; thus, anti-CD3 alone can be used for T cell stimulation because costimulation is provided by other cells within the assay. ",
"Data are shown as percent change in activation/proliferation for clarity to correct for patient-to-patient variability. ",
"In addition, to ensure that the observed EV-mediated suppression of T cell activation occurred in the context of TCR recognition of an antigen bound to the major histocompatibility complex, we used mouse CD8^+^ T cells that react to the gp33 epitope, isolated from transgenic P14 mice. ",
"To present the gp33 antigen, mouse dendritic cells (DCs) were pulsed with gp33 peptide and then co-incubated with gp33^+^ CD8^+^ T cells in the presence or absence of mouse glioma EVs. [",
"Figure 1B](#F1){ref-type=\"fig\"} shows that CD8^+^ T cell activation mediated by DC presentation of an antigen was also inhibited by EVs. ",
"Therefore, these findings demonstrate that glioma EVs suppressed T cell activation mediated by TCR reaction with anti-CD3 or mediated by DC presentation of antigen.",
"\n\n{#F1}\n\nGlioblastoma is known to express PD-L1 and is infiltrated by PD1--expressing tumor-infiltrating lymphocytes ([@R17]). ",
"PD-L1 functions by binding to PD1 and inhibiting TCR-related pathways ([@R3]). ",
"We thus wanted to know whether the observed mechanism of EV-mediated suppression of T cell activation involved PD-L1. ",
"First, we examined PD-L1 expression on GSC EVs by Western blotting. ",
"This showed that there was variability in the expression of PD-L1, which was readily detectable in some GSCs and their EVs (PD-L1^high^) ([Fig. ",
"2A](#F2){ref-type=\"fig\"}), in cells freshly explanted from glioblastoma patients \\[primary cell cultures (PCCs)\\] ([Fig. ",
"2B](#F2){ref-type=\"fig\"}), and in murine glioblastoma CT2A cells and their EVs (fig. ",
"S1A). ",
"However, PD-L1 was also expressed at low or nondetectable levels in some GSCs, PCCs, and their EVs (PD-L1^low^). ",
"This was confirmed by electron microscopy, which also showed that PD-L1 was present on the surface of PD-L1^high^ EVs but was barely detectable on the surface of PD-L1^low^ EVs (fig. ",
"S1, B and C). ",
"The overall EV size distribution did not reveal significant differences between PD-L1^high^ and PD-L1^low^ vesicles with an average diameter of 120 to 130 nm and a range of 50 to 170 nm (fig. ",
"S1D).",
"\n\n{#F2}\n\nNext, we tried to determine whether PD-L1 on EVs played a role in the observed T cell immunosuppression. ",
"T cell activation in PBMCs was then performed in the presence or absence of EVs derived from PD-L1^high^ GSCs, PD-L1^low^ GSCs, and neural stem cells (NSCs). ",
"There was significant down-regulation of CD69, CD25, and double-positive CD69^+^CD25^+^ activation markers on anti-CD3--activated CD4^+^ ([Fig. ",
"2C](#F2){ref-type=\"fig\"}) and CD8^+^ ([Fig. ",
"2D](#F2){ref-type=\"fig\"}) T cells exposed to either PD-L1^high^ or PD-L1^low^ GSC EVs when compared to NSC EVs. ",
"In addition, there was significant down-regulation of PD1, a chronic activation/exhaustion marker (fig. ",
"S1E). ",
"These observed changes in activation markers also correlated with functional changes because there was a significant down-regulation of anti-CD3--stimulated CD4^+^ and CD8^+^ T cell proliferation when exposed to either PD-L1^high^ or PD-L1^low^ GSC EVs versus NSC EVs ([Fig. ",
"2E](#F2){ref-type=\"fig\"}). ",
"NSCs were PD-L1^low^, as shown by Western blot (fig. ",
"S1F). ",
"To ensure that the observations were specific to T cells and not due to effects on other cells within the PBMC population in the assay, we then performed similar experiments in isolated CD3^+^ cells. ",
"T cell activation was inhibited by GSC-derived EVs in this assay, confirming a direct effect of EVs on T cells ([Fig. ",
"2](#F2){ref-type=\"fig\"}, F and G).",
"\n\nAs an additional control, we showed that glioblastoma-derived EVs did not alter activation marker expression in unstimulated T cells (data seen in downloadable figure, <http://harveycushing.bwh.harvard.edu/chiocca-lab/>) or change the overall CD3^+^ population. ",
"In a time-course assay, CD69 expression did not change significantly at the 24-, 48-, and 72-hour time points, whereas CD25 expression increased at 48 and 72 hours compared to 24 hours (fig. ",
"S1G). ",
"We conclude that the observed effects at the selected time point for the assay (48 hours) were not an artifact of the natural evolution of the temporal expression of marker activation, in agreement with published studies ([@R18], [@R19]). ",
"Furthermore, the effects of EVs were dose-dependent with an IC~50~ (median inhibitory concentration) of approximately 25 μg of EVs (fig. ",
"S1H). ",
"To determine whether this was physiologically relevant, we determined the amount of circulating EVs in 24 glioblastoma patients and found that they contained an average of 2 × 10^12^ EVs/ml of blood (fig. ",
"S1I). ",
"Because 5 × 10^7^ EVs is equal to approximately 5 μg of protein, these results indicate that the dose-response curve was well within the physiological range.",
"\n\nEVs fluorescently labeled with palmitoylated tdTomato (palmtdT) and palmitoylated green fluorescent protein (GFP) (palmGFP) ([@R20]) could be visualized to localize to the surface of PBMCs and CD3^+^-sorted cells (fig. ",
"S2A and movie S1). ",
"To investigate whether there was in vivo colocalization of labeled EVs to infiltrating lymphocytes in mouse glioblastomas, we intracranially injected palmGFP-labeled murine CT2A glioma cells that constantly produce palmGFP-EVs in mice. ",
"Figure S2C shows visual evidence of colocalization of these EVs to CD3^+^ cells in vivo in mouse glioblastomas. ",
"In summary, our observations suggest that GSC EVs can directly inhibit TCR-mediated T cell activation and that these effects were mediated by both PD-L1^high^ and PD-L1^low^ EVs.",
"\n\nBecause both PD-L1^high^ and PD-L1^low^ EVs inhibited T cell activation, we wanted to explore whether PD-L1 expression was superfluous to the observed EV inhibition. ",
"We thus proceeded to add a PD1 blocking antibody to the inhibition assays. ",
"PD1 blockade did partially restore the anti-CD3--mediated activation of CD4^+^ and CD8^+^ T cells exposed to the PD-L1^high^ GSC EVs, as measured by CD69 ([Fig. ",
"3](#F3){ref-type=\"fig\"}, A and B) and CD25 (fig. ",
"S3, A and B). ",
"Similar data were observed in isolated CD3 cells ([Fig. ",
"3](#F3){ref-type=\"fig\"}, C and D). ",
"However, this did not occur in cells exposed to the PD-L1^low^ GSC EVs, whereas PD1 levels increased through TCR activation (fig. ",
"S3C). ",
"Neither did we observe an activation of T cells by the PD1 blocking antibody itself (fig. ",
"S3D). ",
"EVs from PD-L1^high^ GSCs fluorescently labeled with palmtdT ([@R21]) bound specifically to plates coated with recombinant PD1, and this binding could be reversed by adding soluble anti-PD1 ([Fig. ",
"3E](#F3){ref-type=\"fig\"}). ",
"Furthermore, binding of fluorescently labeled PD-L1^high^ EVs to PD1 was dose-dependent (fig. ",
"S3E). ",
"We then asked whether PD-L1 on PD-L1^high^ GSC EVs could directly bind to PD1 on lymphocytes. ",
"GSCs were transduced with a vector encoding a PD-L1/red fluorescent protein (RFP) fusion protein to visualize PD-L1 expression. ",
"Purified PD-L1/RFP EVs from GSCs could be observed bound to the outer surface of PBMCs (fig. ",
"S3F). ",
"Addition of anti-PD1 reduced binding of PD-L1/RFP EVs to the surface of PBMCs (fig. ",
"S3G). ",
"The EVs shown to bind the surface of lymphocytes (presumably to PD1) and displaced by the PD1 antibody were seen to localize both to the surface and inside the cell. ",
"Quantification of high-power photomicrographs, where there were only a few lymphocytes per field, showed that there were 30 EVs internalized versus 18 EVs surface-bound on 18 randomly selected cells (table S1). ",
"Together, these results thus showed that PD-L1 in the PD-L1^high^ GSC EVs interacted with PD1 on PBMCs, and this interaction partially blocks suppression of T cell activation in PD-L1^high^ EVs.",
"\n\n{#F3}\n\nAs shown in [Fig. ",
"1](#F1){ref-type=\"fig\"}, there was detectable PD-L1 expression in PD-L1^high^ GSCs in contrast to PD-L1^low^ GSCs. ",
"Because up-regulation of PD-L1 is linked to infiltrating lymphocytes in some solid tumors, we investigated whether activated lymphocytes induce PD-L1 expression on GSCs. ",
"Supernatants of activated PBMCs significantly up-regulated PD-L1 on GSCs that were initially PD-L1^low^, and this up-regulation was inhibited when an anti--IFN-γ neutralizing antibody was added to the supernatants, confirming a likely role for IFN-γ in mediating the observed effect ([Fig. ",
"4A](#F4){ref-type=\"fig\"}). ",
"IFN-γ treatment itself, which has previously been shown to increase PD-L1 expression in some glioblastoma cells ([@R22]), resulted in a profound induction in PD-L1 levels in PD-L1^low^ GSCs but minimally increased PD-L1 in the PD-L1^high^ GSCs ([Fig. ",
"4B](#F4){ref-type=\"fig\"}). ",
"IFN-γ also increased PD-L1 levels in GSCs differentiated in serum (fig. ",
"S4A). ",
"Significantly, this up-regulation was also observed in EVs released by the PD-L1^low^ GSCs ([Fig. ",
"4B](#F4){ref-type=\"fig\"} and fig. ",
"S4B). ",
"The observation of IFN-γ--mediated induction of PD-L1 in PD-L1^low^ cells allowed us to further investigate its role in inhibition of T cell activation, and thus, we sought to determine whether EVs from IFN-γ--treated PD-L1^low^ GSCs also inhibited T cells. ",
"These EVs inhibited T cell activation ([Fig. ",
"4C](#F4){ref-type=\"fig\"} and fig. ",
"S4C), and blockade of PD1/PD-L1 interaction did significantly reverse the inhibition of T cell activation ([Fig. ",
"4C](#F4){ref-type=\"fig\"} and fig. ",
"S4C). ",
"As expected from the Western blot analysis in [Fig. ",
"4B](#F4){ref-type=\"fig\"}, there was no effect of IFN-γ treatment of PD-L1^high^ EVs on further inhibition of T cell activation or reversal by PD1 blockade (fig. ",
"S4D). ",
"These results thus showed that even PD-L1^low^ EVs had the potential to inhibit T cell activation if PD-L1 was up-regulated by IFN-γ. ",
"We also show that PD-L1^low^ EVs increase the levels of immunosuppressive molecules IDO and IL-10, which primarily derive from the CD3-negative cell population ([Fig. ",
"4](#F4){ref-type=\"fig\"}, E to H). ",
"This demonstrates the presence of multiple layers of immunosuppression that can be mediated by GSC EVs.",
"\n\n{#F4}\n\nWe next asked whether GSCs that were PD-L1^high^ versus PD-L1^low^ correlated with any glioblastoma transcriptome classes. ",
"We analyzed RNA sequencing (RNA-seq) data sets from The Cancer Genome Atlas (TCGA) ([@R23]) and Ivy Glioblastoma Atlas Project (Ivy GAP) ([@R24]) and found that M glioblastoma showed elevated PD-L1 expression compared with other subtypes ([Fig. ",
"5A](#F5){ref-type=\"fig\"}). ",
"The higher levels of PD-L1 in M glioblastoma were very pronounced in a subset of the samples. ",
"In the whole glioblastoma data set, the expression of IFN-γ response genes ([@R25]), such as interferon regulatory factor 1 (IRF1), HLA-A, and ICAM1, positively correlated with levels of PD-L1 ([Fig. ",
"5B](#F5){ref-type=\"fig\"}), in agreement with a model where glioblastoma evades immune recognition by expression of PD-L1 and engagement of PD1 ([@R26]). ",
"Similar results were obtained from two independent glioblastoma RNA-seq data sets (fig. ",
"S5). ",
"Additional RNA-seq analysis of laser-captured glioblastomas showed anatomical clustering of PD-L1 with known IFN-γ--responsive genes in different glioblastoma regions (infiltrating edge versus cellular tumor versus perinecrotic areas) ([Fig. ",
"5C](#F5){ref-type=\"fig\"}). ",
"PD-L1 gene expression anatomically localized within glioblastoma niches with high expression of other known mesenchymal genes, such as perinecrotic zones and pseudopalisading cells ([Fig. ",
"5D](#F5){ref-type=\"fig\"}). ",
"The expression of PD-L1 in these areas did not correlate with the expression of known T cell markers, such as CD25, CD69, CD3, CD4, and CD8 ([Fig. ",
"5E](#F5){ref-type=\"fig\"}). ",
"However, it did correlate with tumor cell markers, such as CD44, but not with astrocytic or neuronal markers, such as GFAP (glial fibrillary acidic protein), MAP2 (microtubule-associated protein 2), NCAM1 (neural cell adhesion molecule 1), or PECAM1 (platelet endothelial cell adhesion molecule 1) ([Fig. ",
"5F](#F5){ref-type=\"fig\"}). ",
"This in vivo association of PD-L1 expression predominantly with M glioblastoma genes was valid for the cells that were studied in [Figs. ",
"1](#F1){ref-type=\"fig\"} to [3](#F3){ref-type=\"fig\"}, where PD-L1^high^ cells turned out to be mesenchymal, whereas the PD-L1^low^ cells were proneural ([@R13], [@R27]). ",
"These data thus showed that PD-L1 gene expression was localized to glioblastoma niches characterized by relatively high expression of mesenchymal and IFN-γ--responsive genes and relatively low expression of activated T cell, astrocytic, and neural genes.",
"\n\n{#F5}\n\nTumor EVs may have systemic effects, are important potential biomarkers of disease, and may represent a useful tool to analyze tumor progression and responses. ",
"Therefore, we analyzed circulating patient EVs in serum and plasma from glioblastoma patients before surgery for their PD-L1 protein expression and compared it to healthy donor controls (fig. ",
"S6, A and B). ",
"There was no significant difference measured by Western blotting and enzyme-linked immunosorbent assay (ELISA)--type sandwich analysis. ",
"Because EVs contain DNA and RNA, we measured the amount of PD-L1 DNA by droplet PCR and found that 14 of 21 glioblastoma patient--derived samples showed enrichment of PD-L1 DNA in isolated EVs ([Fig. ",
"6A](#F6){ref-type=\"fig\"}). ",
"Next, we correlated EV PD-L1 DNA abundance with glioblastoma tumor volume, as measured by magnetic resonance (MR) imaging and specifically by contrast-enhancing tumor volume (CET) (fig. ",
"S6, C and D). ",
"The full patient cohort showed no significant correlation between PD-L1 DNA abundance and tumor volume. ",
"However, this was due to two patients with CET \\> 60 cm^3^, whose PD-L1 DNA levels were very low (fig. ",
"S6E). ",
"When we set the cutoff at 60 cm^3^ to remove these outliers, there was a highly significant correlation between PD-L1 DNA abundance in circulating EVs and CET ([Fig. ",
"6B](#F6){ref-type=\"fig\"}). ",
"There was also a positive correlation between PD-L1 expression in glioblastomas and PD-L1 DNA in patient EVs ([Fig. ",
"6C](#F6){ref-type=\"fig\"}), whereas the PD-L1 DNA did not correlate with the necrotic volume of the tumor (fig. ",
"S6F). ",
"The sum of these findings suggests that EV PD-L1 DNA may serve as a biomarker of glioblastoma in humans.",
"\n\n{#F6}\n\nDISCUSSION\n==========\n\nHere, we hypothesized that PD-L1 found on glioblastoma EVs could mediate inhibition of T cell activation, thus providing a novel mechanism for the capacity of glioblastoma to evade the immune system. ",
"We could show that (i) EVs from glioblastomas that are PD-L1^high^ significantly inhibit the magnitude of T cell activation and that this is partially reversed by PD1 blockade; (ii) EVs from glioblastomas that are PD-L1^low^ also inhibit T cell activation but not through PD-L1, unless they are stimulated by IFN-γ (IFN-γ up-regulates PD-L1 in EVs from PD-L1^low^ glioblastomas, and now, T cell inhibition can be partially reversed by PD1 blockade); (iii) PD-L1 on EVs binds to purified PD1 and to lymphocytes in vitro and localizes to lymphocytes in mice in vivo; (iv) PD-L1 gene expression clusters with mesenchymal and IFN-γ--responsive genes in glioblastoma niches that are anatomically localized to the perinecrotic and pseudopalisading cells but does not cluster with activated T cell markers and astrocytic or neural genes; and (v) circulating EV PD-L1 DNA correlates with glioblastoma tumor volumes of up to 60 cm^3^ in patients. ",
"Together, these findings suggest that PD-L1 on EVs may be another possible mechanism used by glioblastomas, particularly of the mesenchymal subtype, to evade T cell surveillance.",
"\n\nTo measure the effects of EVs on T cells, we used activation markers, such as CD69, CD25, and PD1 (an activation/\"exhaustion\" marker), and the functional assay of T cell proliferation. ",
"Although CD69 is classically described as an \"early\" activation marker and CD25 as a \"late\" activation marker, in our hands, we found that both were significantly elevated at the 48-hour time point when our assay was performed. ",
"This is in agreement with other studies ([@R18], [@R19]). ",
"The regulation of additional T cell functional changes in these assays is currently under detailed investigation over a series of time points. ",
"Although the observed inhibition of T cell activation by EVs was dose-dependent, it was not complete, suggesting that additional mechanisms of T cell inhibition are operative. ",
"PD-L1^low^ EVs caused an increase in mRNA levels of the immunosuppressive molecules IDO1 and IL-10 ([Fig. ",
"4](#F4){ref-type=\"fig\"}), which primarily derive from the non--T cell fraction of the PBMCs used in the assay. ",
"Our novel findings should be placed in the context of other published papers. ",
"In a series of elegant papers, the Whiteside laboratory has shown that tumor microvesicles expanded T regulatory cells and caused apoptosis of effector cytotoxic T cells through FasL (Fas ligand) and other immunosuppressive molecules ([@R28]--[@R31]). ",
"In addition, others have shown that tumor exosomes inhibited natural killer (NK) cells ([@R16]). ",
"Novel findings in our publication relate to the immunosuppressive role of PD-L1 in EVs, showing that it directly binds to PD1, that only EVs from PD-L1^high^ glioblastoma cells have such a function constitutively, and that PD-L1^low^ glioblastoma cells must be stimulated with IFN-γ to observe some level of PD-L1--dependent T cell inhibition.",
"\n\nAlthough our experiments were performed with activated and presumably immunologically functional T cells from healthy human volunteers, it is not known whether this can also be reproduced with dysfunctional and immunologically \"exhausted\" T cells from human glioblastoma patients. ",
"Although these experiments are in progress, we argue that these T cells may not activate well to begin with, thus rendering it difficult to measure inhibition by EVs. ",
"Physiologically, we did find that EVs injected in mice colocalized with lymphocytes in mouse brain glioblastomas. ",
"In addition, by immunoelectron microscopy, we estimate that 16% of EVs from PD-L1^high^ GSCs expressed PD-L1. ",
"Because an IC~50~ of T cell activation was provided by 25 μg of EV, this would translate to a concentration of 4 μg of PD-L1--containing EVs. ",
"These EV amounts in blood are within physiological ranges of what we measured in glioblastoma patients, thus suggesting validation of the inhibitory action of PD-L1 EVs.",
"\n\nWe found that in vitro EV PD-L1 bound to immobilized purified PD1 and that this can be displaced by anti-PD1 in a dose-dependent manner. ",
"We also visualized EVs that contain PD-L1 binding to the surface of lymphocytes and localizing in vivo to mouse tumor-infiltrating lymphocytes. ",
"However, it is evident that the EV PD-L1/PD1 interaction is only one of many possible immunosuppressive mechanisms mediated by EVs, as shown not only in this paper but also by others ([@R16], [@R28]--[@R31]). ",
"In this context, we showed that PD-L1^low^ EVs inhibited T cell activation in a PD-L1--independent manner. ",
"However, when PD-L1^low^ GSCs were exposed to IFN-γ, there was an up-regulation of PD-L1 in cells and their EVs. ",
"PD1 blockade experiments now suggested that this PD-L1 also led to a significant inhibition of T cell activation. ",
"Our data do not rule out a potential role for the other PD-L1 ligand, PD-L2, which may also be functional in our system, and is the subject of ongoing studies.",
"\n\nAlthough our experiments were conducted with GSCs, our data show that PD-L1 expression in cells and EVs is also found in glioblastoma cells from patients ([Fig. ",
"2B](#F2){ref-type=\"fig\"}), in differentiated GSCs (fig. ",
"S4A), and in vivo in tumor niches that colocalize with IFN-γ response genes ([Fig. ",
"5C](#F5){ref-type=\"fig\"}). ",
"These findings suggest that expression is independent of GSC differentiation status. ",
"In the tumor microenvironment, PD-L1 is expressed by other cell types including microglia, macrophages, and myeloid-derived suppressor cells, and these may also be sources of PD-L1 EVs in glioblastoma ([@R32]). ",
"PD-L1 expression from these other cells has also been shown to be important for glioblastoma immunosuppression ([@R32]).",
"\n\nThe TCGA and Ivy data would seem to show a correlation in humans with glioblastomas between PD-L1 expression, CET, and colocalization with IFN-γ response genes. ",
"However, the elevated PD-L1 levels in M glioblastoma were observed in a subset of M samples. ",
"At present, it is not clear what features of these specific samples were involved in PD-L1 elevation. ",
"However, our data suggest that the expression of PD-L1 is dependent on glioblastoma subtype. ",
"Here, we used four independent GSC lines: Two were PD-L1^high^ and were in the M subclass, and the two PD-L1^low^ were in the P subclass. ",
"Together with gene expression data, this suggests that M glioblastoma has elevated PD-L1 compared with P. However, there are P and M regions within the same tumor; thus, PD-L1 expression (along with subtype) may be dependent on the local microenvironment.",
"\n\nThe in vitro dose-response analysis of PD-L1 EVs shows that the amount needed to achieve 50% inhibition of T cell activation would be achievable in humans. ",
"We thus argue that this is strong suggestive evidence of an important physiological role for EV PD-L1 in glioblastoma. ",
"EVs have been reported not only to express tumor-associated antigens that can prime antitumor immune responses ([@R33]) but also to have inhibitory functions ([@R34]). ",
"Our data provide evidence that EVs hinder immune activation against glioblastoma by multiple mechanisms including the EV PD-L1/PD1 interaction described here. ",
"Together, we show that glioblastoma EVs hinder T cell activation in a subtype-specific manner and support studies of others who have shown immunosuppressive effects of glioblastoma EVs on other arms of the immune system ([@R35]), including microglia ([@R26]). ",
"Our findings represent one of the likely many mechanisms involved in EV-mediated immunosuppression. ",
"Emerging data from other tumor types reveal effects on macrophages, T cells, and NK cells and show that effects may vary depending on the tumor type ([@R36], [@R37]).",
"\n\nCirculating patient EVs also exhibited significantly elevated levels of PD-L1 DNA when compared to serum from five control subjects, and this correlated with tumor volumes of up to approximately 60 cm^3^. At this juncture, we do not have an explanation for the lack of correlation of serum PD-L1 DNA with tumor volumes above 60 cm^3^. If these findings can be further validated, they would imply that serum EV PD-L1 DNA could provide a surrogate marker of tumor volume and possibly help in real-time monitoring of disease progression. ",
"This should be validated in a prospective fashion.",
"\n\nMATERIALS AND METHODS\n=====================\n\nHuman specimens\n---------------\n\nTumor samples were obtained as approved by the Dana-Farber Cancer Institute (DFCI) Institutional Review Board (IRB). ",
"GSCs were obtained by dissociation of tumor samples and cultivated under stem cell--enriching conditions using glutamine-, B27-, fibroblast growth factor--, and epidermal growth factor--supplemented Neurobasal medium. ",
"Serum-free conditions were used to isolate and culture cells from patient specimens with no stem cell enrichment because this allows selection of cells with diverse transcriptomic characteristics. ",
"The unique identity of cultured patient-derived cells was confirmed by short tandem repeat analysis (table S2). ",
"Mycoplasma testing was routinely carried out by PCR. ",
"Glioblastoma subtype classification was carried out by gene expression profiling, as previously described ([@R13]). ",
"PBMCs were obtained from healthy donors approved by the IRB at Brigham and Women's Hospital and by the Medical Ethics Committee of the Chamber of Physicians of Hamburg. ",
"Informed consent was obtained from all patients. ",
"All experiments were performed in accordance with local guidelines and regulations. ",
"PBMCs were isolated from heparin-anticoagulated venous blood using Ficoll Paque Plus. ",
"Isolation was performed according to the manufacturer's recommendations.",
"\n\nCell culture\n------------\n\nPrimary human GSCs (G34, G35, G44, and G157) were obtained by dissociation of gross tumor samples and cultivated in neurosphere-specific medium, as previously described ([@R13]). ",
"Cells were grown in neurosphere stem cell medium, consisting of Neurobasal (Invitrogen) supplemented with 1% glutamine (Invitrogen), 2% B27 (Invitrogen), epidermal growth factor (20 ng/ml; PeproTech), and fibroblast growth factor--2 (20 ng/ml; PeproTech). ",
"Human NSCs were purchased from EMD Millipore. ",
"For IFN-γ stimulation, cells were treated with increasing doses of IFN-γ (10, 100, and 1000 IU/ml) for 48 hours. ",
"GSCs stably transduced with PALM-Tomato (M GSC) and PALM-GFP (P GSC) were sorted using fluorescence-activated cell sorting by the Harvard Medical School Flow Cytometry Core Facility. ",
"GSCs stably transfected with PDL1/RFP were cultured in neurosphere stem cell medium containing hygromycin (250 μg/ml; Thermo Fisher Scientific). ",
"Lymphocytes were cultured in RPMI (Invitrogen) containing 10% exosome-depleted fetal bovine serum (FBS; Invitrogen), 1% glutamine (Invitrogen), and 1% penicillin/streptomycin (Invitrogen). ",
"Exosome depletion was achieved by ultracentrifugation.",
"\n\nIsolation of EVs\n----------------\n\nConditioned medium, serum, and plasma were collected, and EVs were isolated by differential centrifugation and analyzed using NanoSight, as previously described ([@R13]). ",
"Briefly, conditioned media were centrifuged at 200*g* for 5 min to eliminate cells, followed by filtration through a 0.22-μm filter (Millipore), and, in the case of human serum and plasma, were centrifuged at 15,000*g* for 10 min. ",
"EVs were pelleted by ultracentrifugation (Thermo Fisher Scientific) at 100,000*g* for 70 min and subsequently washed with phosphate-buffered saline (PBS). ",
"The number and size of EVs were determined as previously described using NanoSight analysis ([@R13]). ",
"Briefly, EVs were analyzed using a NanoSight LM10 Nanoparticle Characterization system. ",
"All nanoparticle tracking analyses were carried out with identical experiment settings. ",
"Particles were measured for 60 s, and for optimal results, microvesicle concentrations were adjusted to obtain \\~50 microvesicles per field of view.",
"\n\nPlasmid constructs\n------------------\n\nPalmitoylation sequences of growth cone--associated protein (GAP43) were genetically fused to the NH~2~ terminus of GFP (palmGFP) and tdTomato (palmtdT) and cloned into lentiviral constructs, and in combination with lentiviral packaging, constructs were used to establish stable lines ([@R13]). ",
"The PD-L1/RFP fusion protein vector was purchased from Sino Biological Inc. Lipofectamine-transfected cell clones were positively selected by hygromycin resistance.",
"\n\nFlow cytometry\n--------------\n\nFlow cytometry was performed on a FACS LSR II or Fortessa (BD Biosciences). ",
"For lymphocyte activation studies, soluble anti-CD3 (500 ng/ml; clone OKT3, Bio X Cell) ± anti-CD28 (1 μg/ml; clone CD28.2, BD Biosciences) or IL-2 (PeproTech) was added to media for 2 days. ",
"Proliferation was measured by CFSE (eFluor 670, BD Biosciences) after 3 days. ",
"EVs were added every 24 hours (5 μg/ml). ",
"PD1 blockade was achieved by adding anti-PD1 (10 μg/ml; EH12) or immunoglobulin G control (clone MOPC-21, Bio X Cell). ",
"Cells were gated by FSC (forward scatter)/SCC (side scatter) while excluding duplets by FSC-A/FSC-H. Subsequently, CD3^+^CD56^−^ T cells were gated with further classification of CD4^+^ and CD8^+^ T cells. ",
"Finally, CD4^+^ and CD8^+^ T cells were measured for their CD69, CD25, PD1, and TIM3 expression (seen as a downloadable figure). ",
"Cells were stained with the following antibodies: CD3/PE-Cy5.5 (1:100; clone SK7, eBioscience), CD4/FITC (1:100; clone RPA-T4, BD Biosciences), CD8/AmCyan (1:10; clone SK1, BD Biosciences), CD16/APC-Cy7 (1:100, BD Biosciences), CD25/PE-Cy7 (1:10; clone BC96, eBioscience), CD56/V450 (1:30; clone B159, BD Biosciences), CD69/APC (1:10; clone FN50, BD Biosciences), TIM3/APC-Cy7 (1:100, clone F38-2E2, BD Biosciences), and PD1/PE (1:100; clone J105, eBioscience).",
"\n\nCell sorting\n------------\n\nCD3^+^ magnetic-activated cell sorting was performed using CD3 MicroBeads (\\#130-050-101, Miltenyi Biotec), as described by the manufacturer's protocol. ",
"CD3^+^ purified cells were stimulated with soluble anti-CD3 and anti-CD28 for sufficient TCR cross-linking.",
"\n\nEV suppression assay in mice\n----------------------------\n\nBone marrow DCs (BMDCs) were collected from femora and tibiae of naïve 6- to 8-week-old C57BL/6J mice and cultured in RPMI (Gibco), supplemented with 10% FBS, [l]{.smallcaps}-glutamine, penicillin/streptomycin, 50 μM β-mercaptoethanol, granulocyte-macrophage colony-stimulating factor (20 ng/ml; PeproTech), and IL-4 (10 ng/ml; PeproTech) for 7 days. ",
"Loosely adherent BMDCs were harvested thereafter and pulsed with LCMV gp33-41 peptide (10 μg/ml; GeneScript) for 2 hours at 37°C, followed by lipopolysaccharide (LPS) (10 μg/ml; *Escherichia coli* serotype 026:B6, Sigma-Aldrich) activation for 24 hours at 37°C. ",
"Gp33-41 antigen--specific P14 cells were isolated from the spleens of naïve 6- to 8-week-old P14 mice (bred in-house; a gift from P. Penaloza, Northwestern University) by CD8-negative selection (Miltenyi Biotec). ",
"For EV suppression assay, LPS-activated, gp33-41 peptide--pulsed BMDCs were cocultured with CellTrace Violet--labeled P14 cells at a ratio of 1:10 in a 96-well flat-bottom plate for 72 hours at 37°C, in the presence or absence of CT2A-derived EVs at a dose of 1 μg per well, supplemented every 24 hours. ",
"Fluorochrome-conjugated anti-mouse antibodies \\[anti-CD3 (17A2), anti-CD8α (53-6.7), anti-CD69 (H1.2F3), and anti-CD44 (IM7)\\] and the LIVE/DEAD Fixable Aqua Dead Cell Stain Kit (Invitrogen) for live cells were used for FACS (fluorescence-activated cell sorting) analysis (BD LSR II flow cytometer).",
"\n\nElectron microscopy\n-------------------\n\nEVs or cryo-sections were labeled with anti--PD-L1 (1:20; 9A11) and 5-nm gold particles. ",
"Grids were examined in a JEOL 1200EX transmission electron microscope or a Tecnai G^2^ Spirit BioTWIN, and images were recorded with an AMT 2k charge-coupled device (CCD) camera.",
"\n\nPD-L1/PD1 binding assay\n-----------------------\n\nHuman PD1 Fc fusion protein (2 μg/ml; BPS Bioscience) was coated on high protein-binding 96-well plates (\\#3590, Costar). ",
"After 1-hour incubation with blocking buffer (BPS Bioscience), PD-L1--carrying, palmtdT-labeled EVs were incubated for 2 hours at room temperature (RT). ",
"Finally, plates were washed and analyzed by confocal microscopy.",
"\n\nImmunohistochemistry\n--------------------\n\nHuman brain tumor tissue specimens were obtained following the guidelines approved by the IRB at DFCI. ",
"Immunohistochemistry (IHC) staining was performed as previously described ([@R21]). ",
"Briefly, tissue specimens were incubated with antibodies against PD-L1 (E1L3N, Cell Signaling Technology) and CD3 (Dako), followed by hematoxylin and eosin counterstaining.",
"\n\nELISA-type sandwich fluorescent measurement\n-------------------------------------------\n\nPurified exosomes were captured on a glass slide precoated with CD81 antibodies (JS-81, BD Biosciences). ",
"Subsequently, exosomes were labeled with fluorescent antibodies, and the fluorescence signal was measured. ",
"A commercially available kit (A20186, Thermo Fisher Scientific) was used for antibody-fluorophore conjugation, as recommended by the manufacturer's protocol.",
"\n\nIn vivo studies\n---------------\n\nAll animal work was approved by the authorities for health and consumer protection in Hamburg, Germany (protocol number 41/17). ",
"Six-week-old female C57BL/6 mice were purchased from the Jackson Laboratory. ",
"GL261-palmGFP (100,000 cells) or CT2A-palmGFP (100,000 cells) in 2 μl of PBS was injected intracranially to establish mouse brain tumors (2 mm right lateral, 1 mm frontal to the bregma, and 3 mm deep). ",
"For fluorescence microscopy, brains were perfused, fixed, and paraffin-embedded before making 10-μm sections.",
"\n\nHuman EVs and droplet PCR\n-------------------------\n\nTwo milliliters of serum or plasma from each patient was centrifuged at 300*g* for 5 min to remove cell debris. ",
"Supernatants were centrifuged at 15,000*g* for 15 min, and EVs were pelleted subsequently at 100,000*g* for 90 min. ",
"The pellet was resuspended in 30 μl of PBS. ",
"One microliter was used as template for Evergreen Droplet PCR (Bio-Rad). ",
"Primers can be found in table S3. ",
"RNA from human tumor samples was isolated, and the expression of PD-L1 was measured by qPCR.",
"\n\nImaging methods\n---------------\n\nMR images were corrected for gradient nonlinearity, and intensity was corrected using N4 bias field correction. ",
"Images were subsequently registered to the Montreal Neurological Institute 152 1-mm^3^ template using methods from ANTS (Advanced Normalization Tools) ([@R22]). ",
"Four subjects were excluded because of the lack of reliable images. ",
"A total of 19 subjects with MR imaging were segmented for CET using the iterative probabilistic voxel labeling (IPVL) algorithm ([@R38]). ",
"Visual inspections were performed by two independent reviewers (T.S. and J.T.) to ensure accurate preprocessing and segmentation. ",
"Necrosis volumes were segmented using custom software. ",
"Briefly, voxels within tumor-associated volumes determined from IPVL automatic segmentation were further segmented using T1 intrinsic signal intensity. ",
"Necrosis, on T1, is generally hyperintense to cerebrospinal fluid and hypointense to edematous brain. ",
"The resulting segmentations were reviewed manually to ensure accuracy.",
"\n\nImmunoblotting\n--------------\n\nCells were lysed using radioimmunoprecipitation assay buffer containing 50 mM tris-HCl (pH 7.5), 150 mM NaCl, aprotinin (10 μg/ml), 1 mM phenylmethylsulfonyl fluoride, leupeptin (10 μg/ml), 2 mM Na~3~VO~4~, 4 mM EDTA, 10 mM NaF, 10 mM sodium pyrophosphate, 1% NP-40, 0.1% sodium deoxycholate, 1% protease inhibitor (Calbiochem), and 5% phosphatase inhibitor cocktail (Roche). ",
"Total protein concentration was measured using the Bradford protein assay. ",
"The PD-L1 antibody 9A11 (1:1000) was obtained from Gordon Freeman (DFCI). ",
"CD81 (1:1000; sc-7635), and GAPDH (glyceraldehyde phosphate dehydrogenase; 1:10,000; Abcam \\#105430) were used according to the manufacturer's protocols.",
"\n\nImmunohistochemistry\n--------------------\n\nAll slides were baked for 60 min in an oven set to 60°C. ",
"They were then loaded into the Bond III staining platform with appropriate labels. ",
"Antigen retrieval was performed using Bond Epitope Retrieval 2 (Leica Biosystems) for 30 min. ",
"They were then incubated with PD-L1 (1:200; E1L3N, Cell Signaling Technology) for two applications of 60 min at RT. ",
"Primary antibody was detected using the Bond Polymer Refine Detection Kit (Leica Biosystems) and detected using DAB (3,3′-diaminobenzidine). ",
"Slides were then incubated in the second primary antibody CD3 (polyclonal) (Dako) at 1:250 for 30 min. ",
"Secondary antibody was detected using the Bond Polymer Refine Red Detection Kit (Leica Biosystems). ",
"Secondary antibody was developed using Fast Red, part of the detection kit. ",
"Slides were then dehydrated and coverslipped.",
"\n\nMicroscopy\n----------\n\nAll fluorescent and bright-field microscopy--based assays were observed using a Nikon Eclipse Ti microscope. ",
"High-resolution confocal fluorescent microscopy was performed using a Zeiss LSM 710 confocal microscope system (Carl Zeiss Inc.) and visualized using the ZEN Zeiss Imaging software. ",
"Electron microscopy was carried out as previously described (24310399) using transmission electron microscopy Tecnai G^2^ Spirit BioTWIN with an AMT 2k CCD camera.",
"\n\nElectron microscopy\n-------------------\n\nFor negative staining, 5 μl of the sample was adsorbed for 1 min to a formvar/carbon-coated grid. ",
"The grids were floated on a drop of water and then stained with 0.75% uranyl formate for 30 s. PBMCs were incubated with EVs for 3 to 4 hours before fixation (4% paraformaldehyde in 0.1 M sodium phosphate buffer for 2 hours at RT). ",
"Pellets were infiltrated with 2.3 M sucrose in PBS containing 0.2 M glycine for 15 min. ",
"Samples were snap-frozen in liquid nitrogen and sectioned at −120°C to 60- to 80-nm sections. ",
"Sections were transferred to formvar/carbon-coated copper grids. ",
"Grids were labeled with anti--PD-L1 (1:20; 9A11) in PBS containing 1% bovine serum albumin for 30 min, followed by rabbit anti-mouse bridging for 20 min. ",
"Protein A--gold (5 nm) was added for 20 min. ",
"Grids were examined in a JEOL 1200 EX transmission electron microscope or a Tecnai G^2^ Spirit BioTWIN, and images were recorded with an AMT 2k CCD camera.",
"\n\nQuantitative PCR\n----------------\n\nqPCR was carried out as previously described ([@R1]). ",
"Total RNA was extracted using TRIzol (Invitrogen) and treated with ribonuclease-free deoxyribonuclease (Qiagen). ",
"mRNA expression analysis was carried out using Power SYBR Green (Applied Biosystems). ",
"RNA concentration was quantified using NanoDrop RNA 6000 nano-assays and analyzed using the StepOnePlus Applied Biosystems PCR machine. ",
"See table S3 for the primer sequences.",
"\n\nBioinformatic analysis\n----------------------\n\nFunctional bioinformatic analyses were performed using Qiagen Ingenuity Pathway Analysis (IPA; Qiagen, [www.qiagenbioinformatics.com/products/ingenuity-pathway-analysis/](http://www.qiagenbioinformatics.com/products/ingenuity-pathway-analysis/)). ",
"The IPA analysis was used to select immune response module in GSC EV. ",
"The collection of the data from TCGA ([@R23]) was compliant with all applicable laws, regulations, and policies for the protection of human subjects, and necessary ethical approvals were obtained. ",
"Experimental and clinical data were analyzed using the Glioblastoma Bio Discovery Portal (<https://gbm-biodp.nci.nih.gov/>) ([@R24]), as previously described ([@R13]). ",
"Clinical data were downloaded from the TCGA data portal (<https://tcga-data.nci.nih.gov/docs/publications/tcga/>), as described in the TCGA research network. ",
"The two individual RNA-seq data sets (Bao and Ivy GAP) were obtained from the GlioVis portal (<http://gliovis.bioinfo.cnio.es>). ",
"Gene expression in the various anatomical regions of glioblastoma was analyzed using data from the Ivy GAP (<http://glioblastoma.alleninstitute.org/>).",
"\n\nGlioblastoma samples with RNA-seq data were downloaded from TCGA (December 2015), and samples with a 1p19q codeletion were removed in accordance with the classification of glioblastoma in the World Health Organization 2016 guidelines. ",
"These data were merged with the supplementary data from Ceccarelli *et al.* ([",
"@R39]) and those samples without a purity score obtained from ABSOLUTE (determined on the basis of mutant allele frequencies from exome data and therefore takes into account normal brain cells as well as immune infiltrates) were filtered out. ",
"Of the remaining samples (*n* = 134), the expression values were normalized to ABSOLUTE purity score, and each gene was correlated with the normalized expression score of PD-L1. ",
"Bonferroni's correction was used for statistical analysis of multiple testing.",
"\n\nIn silico analysis of immune response modules in GSC EVs\n--------------------------------------------------------\n\nFunctional bioinformatics analyses were performed using Qiagen IPA using casual network ([@R25]). ",
"Analysis was performed using EV proteome analysis from subtype-determined GSCs ([@R13], [@R27]). ",
"Lists of proteins differentially secreted between GSCs were analyzed on the basis of the IPA library of canonical pathways (content date, 8 May 2012). ",
"This approach did not take into account individual expression levels but instead assumed that transcriptionally altered genes were determined using a suitable cutoff applied to the measured expression change, which allowed list curation where each gene in the data set could be either up- or down-regulated. ",
"The significance of the association between each list and a canonical pathway was measured by Fisher's exact test. ",
"As a result, a *P* value was obtained, determining whether the probability that the association between the genes in experimental data set and a canonical pathway could be explained by chance alone.",
"\n\nGene expression in the various anatomical regions of glioblastoma tumors was analyzed using the Ivy GAP (<http://glioblastoma.alleninstitute.org/>). ",
"Gene expression in five major anatomic structures of glioblastoma \\[leading edge (LE), infiltrating tumor (IT), cellular tumor (CT), microvascular proliferation (MVP), and pseudopalisading cells around necrosis (PAN)\\] was quantified by RNA-seq in the anatomic structure RNA-seq study. ",
"The Ivy GAP cohort was composed of 42 tumors. ",
"Samples from the anatomic structures were collected by laser microdissection and validated by in situ hybridization. ",
"A curated list of genes expressed in GSC based on IPA analysis was queried with the Ivy GAP data set, and expression was visualized as a *z*-score heat map.",
"\n\nData and statistical analysis\n-----------------------------\n\nAll microscopy-based assays were edited/quantified using ImageJ (<https://imagej.nih.gov/ij/index.html>), including the Analyze Particles function of binary images with automatic threshold. ",
"RNA-seq data from TCGA and the Ivy GAP were downloaded from <https://tcga-data.nci.nih.gov/docs/publications/tcga/> and <http://glioblastoma.alleninstitute.org>, respectively ([@R40]). ",
"Data are means ± SD. ",
"The unpaired two-tailed Student's *t* test was used for comparison between two groups. ",
"Each group was tested for Gaussian distribution, if one-way ANOVA was passed, followed by Bonferroni's test. ",
"If this failed, the Kruskal-Wallis test, followed by Dunn's correction, was conducted to test for significance among multiple groups. ",
"Pearson's correlation with nonlinear regression analysis was performed to compute Pearson *r*, *R*^2^, and *P* values. ",
"Statistical analyses were performed using Microsoft Office Excel 2011 or GraphPad Prism 6 software. *",
"P* \\< 0.05 was considered statistically significant.",
"\n\nSupplementary Material\n======================\n\n###### http://advances.sciencemag.org/cgi/content/full/4/3/eaar2766/DC1\n\nWe thank M. Ericsson from the Harvard Electron Microscopy Core Facility for technical support. **",
"Funding:** This work was funded, in part, by the following: NIH \\[National Cancer Institute (NCI) P01 CA69246 (to E.A.C. and B.S.C.), NCI 1R01 CA176203-01A1 (to J.G.), and NIH UH3 TR000931 (to B.S.C.)\\], Deutsche Forschungsgemeinschaft (scholarship to F.L.R.; RI 2616/1-1 and RI 2616/2-1), 1RO1NS097649-01, the Doris Duke Charitable Foundation Clinical Scientist Development Award, the Sontag Foundation Distinguished Scientist Award, the Kimmel Scholar Award, and BWF 1006774.01 (to C.C.C.). ",
"U19 CA179563 was supported by the NIH Common Fund through the Office of Strategic Coordination/Office of the NIH Director (to X.O.B.) and NIH/NCI P01 CA069246 (to X.O.B.) and by an American-Italian Cancer Foundation Postdoctoral Research Fellowship (to C.P.). ",
"S.R. acknowledges support from the Center for Immuno-Oncology, Dana-Farber Cancer Institute. **",
"Author contributions:** F.L.R. designed, acquired, and analyzed overall assays; designed the study; and wrote the paper. ",
"Q.A. performed in vivo assays. ",
"H.K. acquired data and designed the study. ",
"A.B.M. acquired data and interpreted the results. ",
"M.C.S. acquired data and designed the study. ",
"J.L.H. performed bioinformatic analysis. ",
"K.L. and K.Y. performed ELISA-type sandwich fluorescent measurements. ",
"L.B. performed and analyzed droplet PCR. ",
"C.P. designed and performed the PD-L1/PD1 binding assay. ",
"A.K.R. performed short tandem repeat analysis and interpreted the data. ",
"S.K. performed confocal microscopy and interpreted the results. ",
"C.C.C. and I.N. obtained and controlled patient specimens. ",
"T.S. and J.T. analyzed MR data. ",
"S.R. performed and interpreted IHC staining. ",
"S.C., H.L., X.O.B., R.W., J.G., M.W., K.L., A.B., and G.J.F. assisted with the writing of the manuscript and with analysis and interpretation of the data. ",
"S.E.L. designed the study, analyzed the data, and wrote the manuscript. ",
"E.A.C. acquired patient specimens, designed the study, analyzed the data, and wrote the manuscript. ",
"All authors discussed the results and commented on the manuscript. **",
"Competing interest:** G.J.F. has patents/pending royalties on the PD1 pathway from Roche, Merck, Bristol-Myers Squibb, EMD Serono, Boehringer Ingelheim, AstraZeneca, Dako, and Novartis. ",
"All other authors declare that they have no competing interests. **",
"Data and materials availability:** All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. ",
"Additional data related to this paper may be requested from the authors. ",
"Correspondence and requests for materials should be addressed to S.E.L. and E.A.C.\n\nSupplementary material for this article is available at <http://advances.sciencemag.org/cgi/content/full/4/3/eaar2766/DC1>\n\nfig. ",
"S1. ",
"Glioblastoma EVs contain PD-L1.",
"\n\nfig. ",
"S2. ",
"Glioblastoma EVs are bound to the plasma membrane.",
"\n\nfig. ",
"S3. ",
"Glioblastoma EVs that contain PD-L1 bind to PD1.",
"\n\nfig. ",
"S4. ",
"IFN-γ increases PD-L1--positive EVs in PD-L1^low^ GSCs.",
"\n\nfig. ",
"S5. ",
"PD-L1 expression correlates with IFN-γ response genes.",
"\n\nfig. ",
"S6. ",
"EV PD-L1 is found in serum from both glioblastoma patients and healthy controls.",
"\n\ntable S1. ",
"EV number and their localization: Fluorescently labeled EVs were added to lymphocytes (5 μg/ml) for 3 hours.",
"\n\ntable S2. ",
"Short tandem repeat profile of cell lines used in the study.",
"\n\ntable S3. ",
"Primers used in the study.",
"\n\nmovie S1. ",
"PalmtdT EV bound to CD3^+^ T cell.",
"\n\n[^1]: Present address: Department of Neurosurgery, Emory University, 1365 Clifton Road Northeast, Atlanta, GA 30322, USA.",
"\n\n[^2]: Present address: Department of Neurosurgery, Baylor College of Medicine Medical Center---McNair Campus, 7200 Cambridge, Houston, TX 77030, USA.",
"\n"
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"A variety of chemical transformations have been developed relying on the high reactivity of arynes, which is generally manifested through a strained alkyne, 1,2-diradical, or 1,2-zwitterionic character depending on the reacting counterpart.[@cit1] In the presence of silver salt as a catalyst,[@cit2] yet another mode of reactivity was revealed, which is best formulated as a 1,2-dicarbene/carbenoid. ",
"Among many reactions involving arynes, the Alder-ene reaction has been shown to be one of the most efficient processes wherein arynes behave as a powerful ene-acceptor.[@cit3] Our interest in aryne-mediated Alder-ene reactions prompted us to explore both intramolecular and intermolecular Alder-ene reactions of arynes[@cit4] generated *via* the hexadehydro Diels--Alder reaction.[@cit5]\n\nIn our endeavor to further expand the scope of aryne-based Alder-ene reactions, we were intrigued by the possibility of an intramolecular Alder-ene reaction to form a four-membered ring, which is expected to be extremely difficult, and thus has not been reported to the best of our knowledge ([Scheme 1](#sch1){ref-type=\"fig\"}). ",
"The paucity of four-membered ring formation *via* a thermal Alder-ene reaction is due to not only the ring-strain of the incipient ring but also the geometrical constraints for the cyclic transition state. ",
"In the case of an aryne as an ene-acceptor, however, the relief of its high strain energy may provide a sufficient driving force for the reaction to proceed to form benzocyclobutenes.[@cit6] This reagent-free access to compounds containing a benzocyclobutene substructure would be meritorious since they are known as important building blocks for natural products,[@cit7] pharmaceutical ingredients[@cit8] and advanced materials.[@cit9]\n\n{#sch1}\n\nThe calculated Gibbs free energy for the Alder-ene reaction suggests that the product formation has a sufficient thermodynamic driving force (*ca.* ",
"50--63 kcal mol^--1^). ",
"To overcome the expected kinetic barrier, installation of a structural element (**I**) is expected to be crucial, whereby the steric bulk of the substituent will gear the ene-donor alkene *via* angle distortion to attain an appropriate transition state.[@cit10] In the actual substrate (**II**) the *ortho*-isopropanol moiety is expected to serve as an effective gearing element through internal hydrogen bonding. ",
"In this hydrogen-bonded conformation, the steric pressure exerted by the *gem*-dimethyl group against the ene-donor moiety would promote its interaction with the aryne moiety more effectively, which would facilitate the formation of benzocyclobutene (**III**).",
"\n\nHaving these concerns in mind, we designed propiolate-based triyne substrates **1a--h** and ynamide-based tetrayne **1i** and triyne **1j** ([Table 1](#tab1){ref-type=\"table\"}). ",
"These substrates contain a substituent that will impose a variable degree of steric interactions with the prenyl group at the transition state of the Alder-ene reaction. ",
"A prenyl group was chosen as the ene-donor based on its most favorable capacity for Alder-ene reactions.[@cit11] When triyne **1a** bearing a trimethylsilyl group (SiMe~3~, TMS) was heated at 130 °C (toluene), complete conversion was reached after 30 h and the isolated product was identified as the Alder-ene product **2a** in 45% yield (entry 1). ",
"Unexpectedly, the predominant diastereomer of **2a** (10 : 1 dr) was confirmed to have a *cis*-relationship between the silyloxy and isopropenyl groups. ",
"Under the same conditions, triyne **1b** containing a triethylsilyl group (SiEt~3~, TES) showed similar reactivity, affording product **2b** in 48% yield (entry 2). ",
"The reaction of **1c** containing a *tert*-butyldimethylsilyl group (SiMe~2~^*t*^Bu, TBS) was much slower, resulting in 25% conversion after 30 h to produce **2c** in 19% yield (entry 3). ",
"Triyne **1d** containing a triisipropylsilyl group (Si^i^Pr~3~, TIPS) remained intact even after 48 h (entry 4), which seems to be the consequence of extreme steric bulk of the TIPS group that prohibits the formation of an aryne intermediate. ",
"Gratifyingly, triyne **1e** containing an isopropanol moiety (CMe~2~OH) afforded Alder-ene product **2e** as a single diastereomer (for nOe data showing the *cis*-relationship see s32 and s33 of the ESI[†](#fn1){ref-type=\"fn\"}) in 65% yield with full conversion within 14 h (entry 5). ",
"The ^1^H NMR of product **2e** shows a characteristic sharp singlet at 6.2 ppm suggesting a hydrogen-bonded hydroxyl group. ",
"To compare the role of hydrogen bonding, similar substrates without a free hydroxyl group such as **1f** and **1g** were tested. ",
"While the TBS ether **1f** showed little conversion (\\<5%) (entry 7), ^*t*^butyl-containing substrate **1g** afforded **2g** (5 : 1 dr) in 45% yield at 75% conversion after 40 h (entry 6 and 7). ",
"Triyne **1h** containing an unsubstituted propiolate moiety did not provide an Alder-ene product although full conversion was achieved within 12 h (entry 8). ",
"As expected this is the consequence of relatively facile formation of an aryne intermediate but the Alder-ene reaction did not occur due to the lack of the necessary gearing effect. ",
"By the same token, the failure of a tetrayne **1i** in producing **2i** is the consequence of a small steric bulk of the 1-hexynyl substituent (entry 9). ",
"The important role of the hydrogen bonding was further demonstrated by a carbonyl-free triyne **1j** containing a CMe~2~OH substituent, which provided **2j** in only 28% yield although full conversion was achieved within 14 h (entry 10).",
"\n\n###### Effect of steric bulk and hydrogen bonding on the aryne Alder-ene reaction\n\n -------------------------------\n ![](",
"c8sc04277b-u1.jpg){#ugr1}\n -------------------------------\n\n^*a*^20--25 mg scale of **1**.",
"\n\n^*b*^Determined by ^1^H NMR of crude mixtures.",
"\n\n^*c*^Isolated yield.",
"\n\n^*d*^Diastereomeric ratios.",
"\n\n^*e*^52% yield with 75% conversion at 150 °C, 40 h.\n\n^*f*^Determined by ^1^H NMR with an internal standard.",
"\n\n^*g*^Starting material intact at 130 °C but decomposed at 170 °C.",
"\n\n^*h*^No product observed with decomposition of the starting materials.",
"\n\n^*i*^Heating at 90 °C.",
"\n\nHaving identified the crucial elements for the 4-membered-ring forming Alder-ene reaction of aryne species, we next examined the structural requirement of the ene-donor moiety ([Table 2](#tab2){ref-type=\"table\"}). ",
"Triyne **1k**, identical to **1e** but devoid of a silyloxy group, afforded **2k** in 72% yield (entry 1). ",
"In contrast, a free hydroxyl-containing substrate **1l** afforded product **2l** in significantly lower yield (30%) (entry 2). ",
"We surmise that an alternative hydrogen bonding by the secondary hydroxyl group may perturb the hydrogen bonding of the 3° hydroxyl group at the stage of the ene reaction. ",
"This hypothesis is supported by a new broad singlet at 5.6 ppm, which is significantly different from the characteristic signal in other products including **2e**. ",
"This clearly suggests the beneficial effect of the hydrogen bonding between 3° hydroxyl groups and the lactone carbonyl for the Alder-ene reaction. ",
"A structural limitation was recognized from the failure of triyne **1m** in generating Alder-ene product **2m** (entry 3). ",
"We assume that this failure is caused by the severe steric interaction between the aryne moiety and the incipient quaternary carbon center at the transition state of the ene reaction. ",
"Unexpectedly, triyne **1n** containing a *trans*-disubstituted ene-donor did not generate **2n** instead the starting material was decomposed (entry 4). ",
"Triyne **1o** containing a geraniol moiety afforded **2o** in 67% yield (*E*/*Z*, 2.5 : 1) (entry 5). ",
"On the other hand, triyne **1p** containing a nerol moiety afforded a single isomer **2p** in 62% yield, where only the methyl group reacted to become a methylidene moiety (entry 6). ",
"This is consistent with the previous observations that only the distal allylic C--H bonds on the *trans*-position of ene-donor alkenes can participate in the intramolecular Alder-ene reaction.[@cit3a] Despite the possibility of forming an 8-membered ring, the exclusive formation of 4-membered ene product **2p** from a nerol-derived substrate **1p** suggests that a kinetic preference to form a 4-membered ring may override the thermodynamic preference to form an 8-membered ring. ",
"Triyne **1q** tethered with a 3-methylcyclohexen-1-ol moiety afforded cyclohexane-fused benzocyclobutene **2q** in 56% yield (entry 7). ",
"The reaction of triyne **1r** provided **2r** where the *gem*-dimethyl bridge should control the *cis*-ring junction stereochemistry, which was confirmed by nOe experiments and X-ray diffraction analysis[@cit12] (entry 8). ",
"As expected, **2r′** containing a triethylsilyl group was obtained in 46% yield at higher temperature with a longer reaction time (150 °C, 40 h) compared to **2r** which was obtained in 68% at 130 °C within 14 h. A cholesterol-derived triyne **1s** afforded **2s** in 42% yield (entry 9). ",
"The relatively low yield of **2s** is assumed to be the consequence of a conformationally restricted ene-donor methylene unit within the decaline system. ",
"On the other hand, triyne **1t** tethered with a cyclooctylidene moiety afforded benzocyclobutene **2t** in 69% yield, where the ene-donor methylene conformation should be more flexible to achieve an appropriate transition state for the ene reaction (entry 10). ",
"Under the same conditions, triyne **1u** bearing an alkyne ene-donor was consumed but the Alder-ene product **2u** was not obtained (entry 11). ",
"In the presence of β-pinene (5 equiv.) ",
"however, **1u** afforded product **2u′** in 76% yield *via* an intermolecular reaction.[@cit13] This suggests that the putative aryne intermediate was formed properly from **1r** but the Alder-ene reaction between the aryne and the tethered propyne moiety failed. ",
"This is presumably because of the difficulty in accessing the required transition state with the alkyne moiety of linear geometry.",
"\n\n###### Effect of the substituents on the ene-donor\n\n -------------------------------\n ![](",
"c8sc04277b-u2.jpg){#ugr2}\n -------------------------------\n\n^*a*^Conditions: toluene, 130 °C, 14 h.\n\n^*b*^Isolated yield.",
"\n\n^*c*^ *cis*-Diastereomer only.",
"\n\n^*d*^Decomposition or polymerization of the aryne intermediates.",
"\n\n^*e*^ *E*/*Z*-mixture (2.5 : 1).",
"\n\n^*f*^With R = SiEt~3~, **2r′** was obtained in 46% yield at 150 °C at 40 h.\n\n^*g*^Intermolecular Alder-ene reaction with β-pinene (5 equiv.) ",
"of **1u** provided **2u′** (see [@cit13]).",
"\n\nNext, we investigated the effect of the tether of triynes on the efficiency of the Alder-ene reaction ([Table 3](#tab3){ref-type=\"table\"}). ",
"Triyne **3a** with a benzylic substituent afforded **4a** as a 1 : 1 mixture of diastereomers in 62% yield (entry 1). ",
"Imide-tethered triynes **3b** and **3c** containing a *gem*-dimethyl or a cyclohexylidene moiety provided **4b** and **4c** in 72 and 56% yield (entries 2 and 3). ",
"Triyne **3d** with a 3-methyl cyclohexen-1-ol moiety afforded **4d** in relatively low yield (42%). ",
"In the same vein, arene-tethered triynes **3e** and **3f** afforded **4e** and **4f** in 87 and 76% yield (entries 5 and 6). ",
"Triyne **3g** with an enone tether generate indenone **4g** in 56% yield (entry 7). ",
"A racemic chiral alcohol **3h** with sterically differentiated methyl and *tert*-butyl groups did not lead to the relative stereochemical induction, thus affording **4h** as a 1 : 1 diastereomer in 87% yield (entry 8).",
"\n\n###### Reactivity of triynes of different tethers[^*a*^](#tab3fna){ref-type=\"fn\"}\n\n -------------------------------\n ![](",
"c8sc04277b-u3.jpg){#ugr3}\n -------------------------------\n\n^*a*^Conditions: toluene, 90 °C, 14 h.\n\n^*b*^Isolated yield.",
"\n\n^*c*^Diastereomeric ratio as determined by ^1^H NMR of crude.",
"\n\n^*d*^At 130 °C, 14 h.\n\nThe competition for intramolecular Alder-ene reactions to form a strained benzocyclobutene *versus* an intermolecular reaction was examined with triyne **1e** ([Scheme 2](#sch2){ref-type=\"fig\"}). ",
"With 5 equivalents of β-pinene, a 4 : 1 mixture of **2e** and **2e′** was obtained but the ratio changed to 5 : 95 in neat β-pinene. ",
"An internal competition with triyne **3i** provided 6-membered ring product **4i** along with its derivative **4i′**.[@cit14] This indicates that the formation of a 6-membered ring is much more favorable than that of a 4-membered ring *via* the ene reaction.",
"\n\n{#sch2}\n\nTo gain insight into the role of the hydrogen bonding and the unexpected *cis*-stereoselectivity, the Alder-ene reactions of aryne intermediates **IN-1e** and **IN-1h** were compared by DFT calculations ([Scheme 3](#sch3){ref-type=\"fig\"}).[@cit15] The more facile Alder-ene reaction of **IN-1e** is due to a smaller angle distortion by *ca.* ",
"10° for reaching the transition states **TS-2~1e~** and **TS-2~1e′~**, compared to *ca.* ",
"18° for **IN-1h** to reach **TS-2~1h~**. ",
"This difference then translates to an activation energy difference of more than 11 kcal mol^--1^ between these two systems. ",
"Although *trans*-isomer **2e′** is more stable than *cis*-isomer **2e** by 1.3 kcal mol^--1^, the energy of **TS-2~1e~** is lower than that of **TS-2~1e′~** by 1.2 kcal mol^--1^, which can be attributed to the slightly lower angle distortion in **TS-2~1e~**, leading to the formation of *cis*-diastereomer **2e**.[@cit16]\n\n{#sch3}\n\nFinally, the benzocyclobutenes generated by Alder-ene reactions could be converted to various other molecular structures *via* ring expansion or cleavage of the 4-membered ring ([Scheme 4](#sch4){ref-type=\"fig\"}). ",
"Oxidation of benzocyclobutenol **2l** with MnO~2~ resulted in ring opening followed by two independent subsequent allylic oxidations, generating enal **5a** in good yield. ",
"However, efficient oxidation of **2l** to the corresponding ketone **5b** could be achieved with Dess--Martin periodinane. ",
"One-carbon insertion into **5b** afforded **5c**.[@cit17] Treating silyl ether **2e** with TBAF resulted in the ring-opened product **5d** as a mixture (1.5 : 1) of a terminal and an internal alkene. ",
"Also, direct ring expansion of the cyclobutanol moiety of **2o** cleanly afforded cyclooctenone **5e** under basic conditions.",
"\n\n{#sch4}\n\nIn summary, we have explored the Alder-ene reaction of arynes to form benzocyclobutenes, which was affected by installing a bulky substituent next to the ene-donor alkene moiety. ",
"It was found that internal hydrogen bonding is crucial not only to facilitate the hexadehydro Diels--Alder reaction to form an aryne intermediate but also to promote its Alder-ene reaction. ",
"DFT calculations revealed that the major role of the bulky hydrogen bonding element is to lower the activation barrier by destabilizing the intermediate, which is due to severe bond angle distortion. ",
"The transition state leading to the *cis*-isomer is more stable than the *trans*-isomer by 1.2 kcal mol^--1^, which is the consequence of slightly lower bond angle distortion than the transition state leading to the *trans*-isomer. ",
"This reagent-free method to form substituted benzocyclobutene scaffolds would be useful for natural product synthesis and transition metal-catalyzed transformations.[@cit18]\n\nConflicts of interest\n=====================\n\nThere are no conflicts to declare.",
"\n\nSupplementary Material\n======================\n\nSupplementary information\n\n###### \n\nClick here for additional data file.",
"\n\nCrystal structure data\n\n###### \n\nClick here for additional data file.",
"\n\nWe are grateful to NSF (CHE-1764141, D. L.) and NSFC (21873074 and 21572163, Y. X.) for financial support. ",
"The Mass Spectrometry Laboratory at UIUC is acknowledged.",
"\n\n[^1]: †Electronic supplementary information (ESI) available: Detailed experimental procedure and ^1^H and ^13^C spectra. ",
"CCDC [1843923](1843923). ",
"For ESI and crystallographic data in CIF or other electronic format see DOI: [10.1039/c8sc04277b](10.1039/c8sc04277b)\n"
] | {
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"Human biliary tree stem/progenitor cells immunomodulation: Role of hepatocyte growth factor.",
"\nHuman biliary tree stem/progenitor cells (hBTSC) are multipotent epithelial stem cells with the potential for allogenic transplant in liver, biliary tree, and pancreatic diseases. ",
"Human mesenchymal stem cells, but also epithelial stem cells, are able to modulate immune responses with different types of secretion molecules. ",
"The initial aim of the present study was to develop for the first time a culture protocol in order to expand hBTSC in vitro through passages, allowing to maintain a similar stem cell and secretome profile. ",
"Furthermore, we investigated the secretome profile of the hBTSC to assess the production of molecules capable of affecting immune feedback. ",
"We found that hepatocyte growth factor produced by hBTSC exerts its cytoprotective role inducing apoptosis in human immune cells, such as lymphocytes. ",
"The present study, therefore, supports the hypothesis that hBTSC can be useful for the purpose of regenerative medicine, as they can be banked and expanded, and they can secrete immunoregulatory factors."
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"Client side certificates allow the server to authenticate the source of the request. ",
"The client sends along it’s certificate with a request for the connection to be established. ",
"If everything checks out the server allows further communication. ",
"If it does not the requests from the client are not entertained.",
"\n\nOne of the most important use cases of client side certificates is in creation of mutual authentication systems. ",
"Where both client and the server authenticate each other. ",
"As opposed to the server side certificates, in which the client determines the identity of the server, certain applications, especially the ones where the load of distribution of certificates is low and security is of prime importance, this method provides a very natural way of establishing trust between a client and server.",
"\n\nTo use the client side certificate it becomes the responsibility of the client (while establishing a connection) to read the certificate file and send it to the server with the connection request. ",
"And while it’s fairly easy to do, you can delegate this responsibility of handling the certificate to a proxy so that the client talks to a proxy and the proxy talks to the server.",
"\n\nThis allows you to build applications where you are managing multiple client connections to a mutual authentication system with just one client certificate. ",
"The proxy authenticates a client and the server authenticates a proxy. ",
"Once you introduce a proxy you can also distribute the certificate level client authentication. ",
"That is, there can be multiple proxys just for managing the client connecting to a server.",
"\n\nIn business terms this translates into a scenario where you are a trusted associate with the ability to use services and resources of an organization and you want to be able to distribute these services to your own clients. ",
"Now the source organization will only be dealing with you and you’ll be dealing with your clients.",
"\n\nNginx can not only serve requests of the client but also act as a proxy to other servers (hence the name reverse proxy server) Nginx’s directives allow you to configure both server side and client side certificates. ",
"In this post we’ll see how to use nginx for proxy ssl certificates as well as for client side certificates. ",
"But first let’s define the upsteam and downstream terminology as used in nginx so that there’s no confusion when we use these terms.",
"\n\n“Upstream and downstream describe the flow of a message: all messages flow from upstream to downstream.”",
"\n\nThis means that when nginx is used as a normal server (serving the requests of a client) the request is downstream and response is upstream. ",
"Similarly when nginx acts as a proxy it acts as a client and it’s request becomes downstream where as the response from the proxied server becomes upstream.",
"\n\nIt becomes important to understand this message flow becomes when we talk about server side and client side certificates:-\n\nServer side certificate: By server side certificate we mean that the downstream , that is the requests coming in to nginx from the client is to an authenticated source. ",
"In other words the client establishes the authenticity of the server.",
"\n\nClient side certificate: By client side certificate, we mean that the upstream , that is the response going out of nginx is to an authenticated source. ",
"In other words the server establishes the authenticity of the client.",
"\n\nProxy certificates are used when the client’s request, instead of hitting the server directly, goes via nginx. ",
"In that case the client does not need to provide any certificate to the server directly. ",
"The proxy handles the responsibility of establishing the identity of the client to the server. ",
"The server for all intents and purposes treats the proxy as a known client, where as the proxy takes care of the responsibility of handling the identity verification of the clients conneting to it upon itself.",
"The proxy certificates are handled by the directives in the ngx_http_proxy module. ",
"In configuration files this translates into a couple of lines of code.",
"\n\n#edit this with your own cert proxy_ssl_certificate ./certs/cert.pem; ## edit this with your own key proxy_ssl_certificate_key ./keys/key_wrinq.pem;\n\nSimillarly the client side certificates are configured by the ssl_client_certificate in the ngx_http_module\n\n#edit this with your own ca cert ssl_client_certificate ./keys/ca.crt;\n\nTo verify a client certificate all you need to do is point the ssl_client_certificate directive to the location of your CA (Certificate authority) certificate that you used to sign the certificates for your clients. ",
"You can create a CA on your own server using openssl . ",
"With a CA cert and a certificate signing request (CSR) you can sign the certificates for your clients. ",
"A couple of lines of openssl can create signed certificates for your clients. ",
"Here’s the code for reference:-\n\n## Create a CA certificate openssl genrsa -des3 -out ca.key 4096 openssl req -new -x509 -days 365 -key ca.key -out ca.crt ## Create a CSR (certificate signing request) openssl genrsa -des3 -out client.key 1024 openssl req -new -key client.key -out client.csr # Sign the client certificate with our CA cert. ",
"openssl x509 -req -days 365 -in client.csr -CA ca.crt -CAkey ca.key -set_serial 01 -out client.crt\n\nOnce a certificate has been created you can distribute these to the client. ",
"It then becomes the responsibility of the client to send this certificate while establishing a connection. ",
"Our server which is also the CA in this case verifies the genuineness of the certificate by ensuring the validity of the digital signature. ",
"Once that is done a connection is established.",
"\n\nAny Questions?",
"\n\n…. ",
"wait a minute let me put on my glasses\n\nYes,Questions?",
"\n\n“What is a CA?",
"\n\nCA stands for certificate authority. ",
"A CA is responsible for issuing digital certificates. ",
"A client trusts the CA implicitly and relies upon the fact the CA’s signature on the certificate proves the authenticity of the certificate holder. ",
"If a client goes on the website www.bank.com and the certificate sent by the server contains the signature of a trusted CA (this trust is verified by the public key of the CA) then the client can be certain of the fact the certificate is valid and that he is indeed talking to the server of wwww.bank.com .",
"\n\n“So how do the client side certificates work?”",
"\n\nEssentially the purpose of client side certificates is authentication of the client by the server. ",
"The client sends it’s certificate to the server. ",
"The server checks whether the client certificate is valid. ",
"If it is, the connection is established for future requests and if not the request for connection is denied. ",
"As the use case of client side certificates is limited to scenarios where we can control the distribution of certificates, eg restful services to be used primarily by non browser clients,we can make our server the CA and create our own digitally signed certificate.",
"\n\nIn plain english:-\n\nClient obtains a digitally signed certificate from the server Client sends it’s certificate at the time of establishing a request. ",
"The server verifies the signature and hence the validity of the certificate and proceeds further\n\nNow all of this may just be a couple of lines of openssl magic but it does fulfill our long time fantasy of owning a Certificate Authority one day,does it not? ",
"The fruit of patience is sweet 🙂\n\n“Is there any benefit in letting nginx handle the certificates?”",
"\n\nYes. ",
"For one ssl handling in nginx is extremely optimized. ",
"It’s fast and light. ",
"And second it’s easy. ",
"All you got to do is add few directives and you are set. ",
"Furthermore the proxy_ssl_certificate directive allows you to play with concept of client side certificate in novel ways. ",
"You are able to design architectures that can reuse a single client certificate across a variety of clients allowing you to combine traditional authentication methods with certificate based identity management.",
"\n\n“What is your favorite animal?”",
"\n\nAhh.. hard to pick. ",
"I really like cows. ",
"They are so milky… and they can chew all day long. ",
"I’ve tried chewing gums a couple of times but strain in my jaw becomes unbearable after about 3 hours. ",
"I have to rely on a liquid diet for the rest of the day to restore myself. ",
"A man’s got to know his limitations, I suppose?",
"\n\n[ Digital ocean has a great guide on what it takes to create SSL certificates along with an explanation of some of the technical terms used.]"
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"Identification of potential Aurora kinase-C protein inhibitors: an amalgamation of energy minimization, virtual screening, prime MMGBSA and AutoDock.",
"\nGenomic instability is a trademark of cancer evolution, there is still a wide necessity to discover safe and effective anti-cancer drugs. ",
"Aurora kinase-C protein is a member of the Aurora kinase family involved in regulating mitosis phases of the cell cycle. ",
"Aurora kinase-C protein has an aberrant expression at spindle assembly checkpoint leading to human cervical cancer and colorectal cancer. ",
"Knowledge of 3D structure of the protein is vital for identify possible inhibitors. ",
"In the present study, 3D structure prediction of Aurora kinase-C protein is taken up by using comparative homology modeling techniques and minimized by NAMD-VMD Software. ",
"The quality of modeled protein was validated using ProSA and Ramachandran plot. ",
"Probable binding site in protein was identified from SiteMap and molecular docking based virtual screening was carried out using Asinex database to identify lead molecules. ",
"The obtained lead molecules were further optimized using PrimeMM-GBSA and AutoDock. ",
"ADME properties of the leads were calculated to ascertain the drug-like properties at lead molecules. ",
"Communicated by Ramaswamy H. Sarma."
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"In the fourth season of House of Cards, President Frank Underwood chose his wife as vice-presidential running mate while stretching the US constitution to breaking point by trying to derail an investigation into what newspapers called his “crooked path to the White House.”",
"\n\n\n\nSome viewers felt that, while enjoyable as TV drama, the scale of nepotism and corruption in the presidency of Kevin Spacey’s character was becoming politically unrealistic.",
"\n\nBut that was last March, when the consensus, after the Super Tuesday primaries, was that Senator Ted Cruz would easily see off the maverick insurgency of Donald Trump to gain the Republican nomination and then, in all probability, lose the White House race to Hillary Clinton.",
"\n\nNow, the risk – when the fifth season is released on Netflix on Tuesday – is that the deranged chaos of the Underwood White House will seem tame in comparison to the Trump administration.",
"\n\nSpeaking this week on the NBC show Late Night with Seth Meyers, Spacey acknowledged that the context of the show had changed. ",
"Referring to the way Underwood reached the Oval Office, the actor said: “What’s interesting is that there are people who watch the show ... and thought, ‘Oh that’s crazy. ",
"That could never happen.’ ",
"And then suddenly 18 months later it’s like, ‘Oh, wait a second. ",
"That actually could happen.’ ",
"Or it is happening.”",
"\n\nImpressively prophetic? … ",
"the trailer for the forthcoming series seems to show the president cracking down on dissent and possibly democracy itself. ",
"Photograph: David Giesbrecht/Netflix\n\nNetflix is protecting the content of the fifth season with a successful non-leak strategy that would be the envy of politicians everywhere. ",
"But the trailer for the forthcoming series seems to show the Underwoods winning the 2016 election on their joint ticket, as well as the president using physical violence against senators and other opponents in what appears to be a crackdown on dissent and possibly democracy itself.",
"\n\nSome of the hinted at storylines look impressively prophetic. ",
"Seeing protestors outside the White House holding signs that declare him unfit for office, Underwood has a Trumpian tantrum, raging: “The American people don’t know what’s good for them.” ",
"The trailer suggests a leader who will use any means to gain and maintain power.",
"\n\nThis isn’t the first time the House of Cards franchise has got unnervingly close to real politics. ",
"The Netflix show is an Americanised expansion of a BBC series of the same name – adapted by Andrew Davies from the novel by Michael Dobbs – which began with Margaret Thatcher being forced out of power and replaced by Francis Urquhart, played by Ian Richardson. (",
"The protagonists of both versions have the deliberately antagonistic initials FU.) ",
"The series first aired on 18 November 1990, four days after Thatcher resigned the premiership under pressure from cabinet colleagues.",
"\n\nBut, though the Underwood-Trump blurring may prove an advantage to House of Cards, in another sense the new series has been overtaken by American political history before it begins. ",
"Last year’s increasing emphasis on the ambition of Claire Underwood (Robin Wright) to become president in succession to her husband seemed to be a clear preparation for season five to shadow and satirise the presumed Clinton presidency. (",
"This year’s season of Homeland also lost a gamble on mirroring a female commander-in-chief.)",
"\n\nWill the new season of House of Cards work as a comically cathartic commentary on Trump – or seem dull next to the news? ",
"Photograph: David Giesbrecht/Netflix\n\nFictional and factual presidential cycles have not generally synchronised on US TV, though. ",
"Martin Sheen’s President Jed Bartlet in The West Wing (1999-2006) was a super-liberal super-intellectual, but the show’s last five seasons coincided with the incumbency of a commander-in-chief widely seen as an illiberal ignoramus, George W Bush. ",
"And the first four years of Netflix’s House of Cards ran the completely amoral Underwood – a liar and murderer with a multiply dysfunctional marriage – against the fiercely moral Barack Obama and Michelle Obama, one of the most admired first ladies in history.",
"\n\nThe challenge for House of Cards now is whether its depiction of a preposterously exaggerated president will work as a comically cathartic commentary on Trump or may seem dull and understated in comparison to the nightly news bulletins. ",
"Perhaps the best thing that could happen to the show is for President Trump to watch it and tweet about how unrealistic the whole thing is.",
"\n\nHouse of Cards season five is on Netflix from 30 May."
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"Q:\n\nFileSystemWatcher.",
"Created is not working properly\n\nI want to monitor some directory using FileSystemWatcher but FileSystemWatcher.created is not working at all . ",
"\nCODE\n using System;\n using System.",
"Collections.",
"Generic;\n using System.",
"Linq;\n using System.",
"Text;\n using System.",
"Threading.",
"Tasks;\n\n using System.",
"ComponentModel;\n using System.",
"Data;\n using System.",
"Diagnostics;\n using System.",
"IO;\n using System.",
"Configuration;\n using System.",
"Threading;\n using System.",
"Xml;\n\n namespace ConsoleApplication1\n {\n class Program\n {\n static string fileName;\n static string dirFileName;\n\n static void Main(string[] args)\n {\n\n string _Dir = ConfigurationManager.",
"AppSettings[\"Dir\"];\n\n Console.",
"WriteLine(\"MAIDProcessFileTest processing started\");\n FileSystemWatcher _watch = new FileSystemWatcher();\n _watch.",
"Path = _Dir;\n _watch.",
"Created += FileCreated;\n\n Console.",
"ReadLine();\n }\n\n private static void FileCreated(object sender, FileSystemEventArgs e)\n {\n\n Console.",
"WriteLine(\"Before is treat\");\n fileName = Path.",
"GetFileName(e.",
"FullPath);\n dirFileName = Path.",
"GetDirectoryName(e.",
"FullPath) + @\"\\\" + Path.",
"GetFileName(e.",
"FullPath);\n\n }\n }\n }\n\nCan anybody tell me that why this code is not working ... whenever I debug _watch.",
"Created += FileCreated; is not working at all. ",
"where is the error can anybody tell me . ",
"Please Help\n\nA:\n\nYou need to start it\n_watch.",
"EnableRaisingEvents = true;\n\nFileSystemWatcher.",
"EnableRaisingEvents Property\nYou should probably start here though\nFileSystemWatcher Class \nIt has a great example, and everything you need to know to use it\n\n"
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[
"\n313 S.E.2d 825 (1984)\nLinda BERGER\nv.\nMartin BERGER.",
"\nNos. ",
"831DC212, 831DC801.",
"\nCourt of Appeals of North Carolina.",
"\nApril 3, 1984.",
"\n*828 LeRoy, Wells, Shaw, Hornthal & Riley by Terrence W. Boyle, Elizabeth City, for plaintiff-appellee.",
"\nBattle, Winslow, Scott & Wiley by Jasper L. Cummings, Jr., Rocky Mount, for defendant-appellant.",
"\nVAUGHN, Chief Judge.",
"\n\nI.\nThe first order from which defendant appeals is the 11 October order denying his Rule 12(b) motions to dismiss.",
"\nWe first consider defendant's contention that the trial court erred in denying both his motion to dismiss for failure to state a claim upon which relief could be granted and his motion to dismiss for lack of subject matter jurisdiction. ",
"G.S. 1A-1, Rules 12(b)(1) and 12(b)(6). ",
"Generally, orders denying motions to dismiss are interlocutory and nonappealable, the reason being to prevent delay and expense from fragmentary appeals and to expedite the administration of justice. ",
"Shaver v. Construction Co., 54 N.C.App. ",
"486, 283 S.E.2d 526 (1981), later appeal, 63 N.C.App. ",
"605, 306 S.E.2d 519 (1983). ",
"Immediate appeal is generally allowed only from those orders affecting a substantial right and likely to result in injury to the appellant if not corrected before appeal from the final judgment. ",
"Love v. Moore, 305 N.C. 575, 291 S.E.2d 141, rehearing denied, 306 N.C. 393 (1982); see G.S. 1.277; G.S. 7A-27. ",
"Any error in the order not affecting a substantial right is correctable upon appeal from the final judgment. ",
"Id.\nThe trial court order denying defendant's Rule 12(b)(6) motion to dismiss for failure to state a claim was clearly interlocutory and not immediately appealable. ",
"O'Neill v. Bank, 40 N.C.App. ",
"227, 252 S.E.2d 231 (1979). ",
"The Supreme Court, furthermore, has recently clarified any doubt regarding the appealability of orders denying 12(b)(1) motions to dismiss for lack of subject matter jurisdiction. ",
"Pursuant to Teachy v. Coble Dairies, Inc., 306 N.C. 324, 293 S.E.2d 182 (1982), the denial of defendant's 12(b)(1) motion was also interlocutory and not immediately appealable. ",
"Defendant's appeal on these two grounds is, therefore, dismissed.",
"\nWe next consider defendant's right to appeal from the denial of his motion to dismiss on grounds of lack of personal jurisdiction. ",
"Defendant asserts that he is vested with an immediate right to appeal pursuant to G.S. 1-277(b). ",
"While G.S. 1-277(b) appears to authorize such right, it is our duty on appeal to examine the underlying nature of defendant's motion: If defendant's *829 motion raises a due process question of whether his contacts within the forum state were sufficient to justify the court's jurisdictional power over him, then the order denying such motion is immediately appealable under G.S. 1-277(b). ",
"If, on the other hand, defendant's motion, though couched in terms of lack of jurisdiction under Rule 12(b)(2), actually raises a question of sufficiency of service or process, then the order denying such motion is interlocutory and does not fall within the ambit of G.S. 1-277(b). ",
"Love v. Moore, supra; see Kaplan School Supply v. Henry Wurst, Inc., 56 N.C.App. ",
"567, 289 S.E.2d 607, review denied, 306 N.C. 385, 294 S.E.2d 209 (1982).",
"\nThe basis for defendant's appeal here concerns plaintiff's failure to strictly comply with Rule 3 of the Rules of Civil Procedure in commencing action by the issuance of a summons. ",
"Under Rule 3, a civil action may be commenced by the issuance of a summons when a person makes application to the court and requests permission to file a complaint within twenty days. ",
"Plaintiff in this case requested permission to file her complaint \"in due time.\" ",
"Later, pursuant to plaintiff's motion, the trial court amended the order for the summons so that it complied with the twenty-day time limit under Rule 3. ",
"See Rule 4(i) (authorizing the court to amend process or proof of service). ",
"The actual filing date of plaintiff's complaint, which occurred three days after the summons was issued, was well within the statutory time limit. ",
"After reviewing the facts in the instant case, we conclude that the substance of defendant's appeal concerns a question of process under Rule 12(b)(4), not a question of jurisdiction, contemplated by appeals brought under Rule 12(b)(2). ",
"Defendant's appeal, therefore, is not authorized by G.S. 1-277(b) and is premature.",
"\nThough not denominated such, defendant, in a final, separate argument again raises a question of in personam jurisdiction. ",
"Defendant asserts that the trial court lacked jurisdiction since neither party was a resident of North Carolina. ",
"Residency notwithstanding, defendant's contention lacks merit, since the trial court had clear grounds for jurisdiction under our \"long-arm\" statute, G.S. 1-75.4. ",
"Pursuant to G.S. 1-75.4(1)(a), defendant was a natural person present within North Carolina when he was served with process on 23 August 1982. ",
"Defendant, who lived and worked in Dare County from 1977 until 1982 when this action was instituted, and who, by claiming to be a North Carolina resident, caused a similar suit previously filed by plaintiff in a Virginia court to be dismissed based on a lack of jurisdiction, does not even raise for our consideration the question of minimum contacts contemplated by appeals brought pursuant to G.S. 1-277(b).",
"\nDefendant's first appeal from an interlocutory order must be and is dismissed.",
"\n\nII.",
"\nWe next consider defendant's appeal from the 1 December order, in which the trial court, after considering evidence and testimony from both parties, awarded plaintiff alimony and counsel fees pendente lite and child support.",
"\nDefendant, citing the general rule that an appeal removes the case from the jurisdiction of the trial court, contends that the trial court erred in proceeding to hear plaintiff's claim on the merits, since the previous order denying defendant's motions to dismiss was on appeal. ",
"See Utilities Comm. ",
"v. Edmisten, Attorney General, 291 N.C. 361, 230 S.E.2d 671 (1976). ",
"The general rule, however, is subject to the exception, applicable to the case at bar, that an appeal from an interlocutory order not affecting a substantial right is a nullity and does not divest the trial court of jurisdiction. ",
"Id. The trial court was correct, therefore, in proceeding in the action and rendering judgment on the merits.",
"\nDefendant also contends that the award of a total of $6,000 per month in alimony pendente lite and child support was not based upon proper findings of fact and contrary to the evidence. ",
"In recognition *830 of the rule espoused by this court in Stephenson v. Stephenson, 55 N.C.App. ",
"250, 285 S.E.2d 281 (1981), overruling Peeler v. Peeler, 7 N.C.App. ",
"456, 172 S.E.2d 915 (1970), we dismiss defendant's appeal as being premature.",
"\nIn Stephenson, this court recognized that appeals from pendente lite awards are often \"pursued for the purpose of delay rather than to accelerate determination of the parties' rights,\" and, in the interests of fairness and public policy, we held that awards pendente lite are interlocutory decrees not affecting a substantial right and not warranting an immediate right of appeal. ",
"Id. 55 N.C.App. ",
"at 251-52; 285 S.E.2d at 282. ",
"The Stephenson case has become precedent in a host of recent decisions dismissing appeals from pendente lite awards. ",
"In Fliehr v. Fliehr, 56 N.C. App. ",
"465, 289 S.E.2d 105 (1982), we expanded the Stephenson rule to prohibit an appeal from an order for child support, not designated pendente lite, but entered in conjunction with an order for alimony pendente lite. ",
"In Dixon v. Dixon, 62 N.C. App. ",
"744, 303 S.E.2d 606 (1983), wherein plaintiff had brought suit for divorce and equitable distribution, we held that defendant had no right to appeal a mandatory injunction ordering her to return property to plaintiff's residence pending final disposition of plaintiff's action for divorce and equitable distribution. ",
"See also Smart v. Smart, 59 N.C.App. ",
"533, 297 S.E.2d 135 (1982); Rokes v. Rokes, 55 N.C.App. ",
"397, 285 S.E.2d 306 (1982) (citing Stephenson, supra).",
"\nThe policy guiding the panel in Stephenson, to avoid unnecessary delay and to accelerate a just determination of the parties' rights, is especially pertinent in this case, where plaintiff's initial suit in a Virginia court was dismissed on defendant's motion for lack of jurisdiction, defendant contending to be a North Carolina resident. ",
"Plaintiff then commenced the present suit by serving defendant with a summons pursuant to G.S. 1A-1, Rule 3 because, plaintiff alleged, defendant was \"in the process of removing property and assets from the State of North Carolina in an attempt to evade process and secrete himself in another state or country.\"",
"\nPursuant to Stephenson, Fliehr, and other recent authority, defendant's second appeal from a pendente lite award is interlocutory and is therefore dismissed.",
"\n\nIII.",
"\nDefendant's third and final appeal concerns the order finding him in contempt for failure to pay the previous award of alimony and counsel fees pendente lite and child support.",
"\nWe note at the outset a dispute as to when the order of contempt was entered. ",
"Since entry of the judgment is a critical moment in determining the timeliness of defendant's appeal, we will treat plaintiff as having made a motion to dismiss and rule accordingly on such motion. ",
"See Rules 25 and 37, Rules of Appellate Procedure.",
"\nOrdinarily, an appellant has thirty days from the time appeal is taken to file and serve upon all other parties a proposed record. ",
"Rule 11(b), Rules of Appellate Procedure. ",
"In this case, pursuant to defendant's motion, the trial court granted defendant sixty days in which to file the proposed record. ",
"The parties here agree that defendant served the proposed record on 10 May 1983. ",
"Plaintiff contends, however, that the contempt order was entered on 14 February and that defendant's appeal is therefore subject to dismissal, the record having been served more than sixty days after entry of the judgment. ",
"See Rule 25, Rules of Appellate Procedure. ",
"Defendant contends that the contempt order was not entered until 5 April and that having served the record in due time, he is entitled to appellate review. ",
"For reasons set forth below, we conclude that the critical date of entry was 14 March, and we therefore deny plaintiff's motion to dismiss the appeal.",
"\nA review of the record shows that on 14 February, the court found defendant in contempt and asked plaintiff's attorney to prepare the formal written order. ",
"The *831 clerk's notation in the record reflects a judgment purportedly entered on 14 February. ",
"Ordinarily, the clerk's notation in the record marks the date from which the time for notice of appeal runs. ",
"Kahan v. Longiotti, 45 N.C.App. ",
"367, 263 S.E.2d 345, review denied, 300 N.C. 374, 267 S.E.2d 675 (1980), overruled on other grounds, Love v. Moore, supra. ",
"An exception to this rule occurs, however, when, as here, the trial judge instructs one of the attorneys to prepare the final order, thus indicating a later date for final entry of the judgment. ",
"Id.; see also Stanback v. Stanback, 287 N.C. 448, 215 S.E.2d 30 (1975). ",
"Another exception to the rule regarding date of entry occurs when, as did defendant in this case, a party makes a motion to alter or amend the judgment. ",
"Rule 3(c), Rules of Appellate Procedure. ",
"Since both exceptions apply to the case at bar, the time for serving the proposed record was extended.",
"\nA motion to alter or amend the judgment tolls the running of time for filing and serving notice of appeal until the motion is decided. ",
"Rule 3(c), Rules of Appellate Procedure. ",
"A hearing on defendant's motion in this case was held on 14 March. ",
"The record reflects that a final judgment was entered on 14 March, finding defendant in contempt. ",
"It appears from the record that the 14 February order of contempt was merged into this final order. ",
"Although the order was not signed by the trial judge until 30 March and not filed until 5 April, the critical moment of entry occurred on 14 March, as noted in the record. ",
"G.S. 1A-1, Rule 58; Rule 3(c), Rules of Appellate Procedure. ",
"We conclude, therefore, that the record was timely served. ",
"Since a contempt order affects a substantial right, defendant's third appeal warrants our immediate consideration. ",
"See Clark v. Clark, 294 N.C. 554, 243 S.E.2d 129 (1978).",
"\nThe first issue raised by defendant concerns the effect of a bond posted pursuant to G.S. 1-289 in order to stay execution of the order awarding plaintiff alimony and counsel fees pendente lite and child support. ",
"G.S. 1-289 authorizes an appellant to stay execution of a money judgment by assuring payment of any amount due upon appeal from said judgment. ",
"Our courts have construed orders for the payment of alimony, alimony pendente lite, child support, and counsel fees to be money judgments under G.S. 1-289. ",
"Quick v. Quick, 305 N.C. 446, 290 S.E.2d 653 (1982); Joyner v. Joyner, 256 N.C. 588, 124 S.E.2d 724 (1962); Faught v. Faught, 50 N.C.App. ",
"635, 274 S.E.2d 883 (1981). ",
"Defendant contends that the trial court erred in holding him in contempt since he had posted a bond for the amount due plaintiff.",
"\nIf we hold, however, as defendant urges, that posting a bond under G.S. 1-289 effectively stayed execution of the judgment, then we will have granted defendant the right to stay execution of a nonappealable pendente lite award. (",
"See discussion, supra, part II). ",
"This result would contravene the policy underlying Stephenson and its progeny wherein this court recognized the need to forestall appeals brought for purposes of delay. ",
"See Stephenson, supra; Fliehr, supra. ",
"We conclude, therefore, that while execution of a final judgment may be stayed pursuant to G.S. 1-289, execution of an interlocutory order like the one here is not subject to the stay provisions of G.S. 1-289.",
"\nThe contempt proceeding here was governed by G.S. 5A-21, which provides in pertinent part: \"Failure to comply with an order of a court is a continuing civil contempt as long as ... [the defendant] is able to comply with the order or is able to take reasonable measures that would enable him to comply with the order.\" ",
"To hold defendant in contempt, the trial court must find as a fact that defendant had the ability to comply with the award. ",
"Frank v. Glanville, 45 N.C.App. ",
"313, 262 S.E.2d 677 (1980).",
"\nThe trial court order included the following factual findings:\n9. ",
"The Defendant's financial affidavits and federal income tax returns for 1980 and 1981 filed in the record on *832 this action state that the Defendant has a net worth in the amount of two million dollars and receives substantial annual income ...\n10. ",
"According to the Defendant's 1980 federal income tax return, he reported income of approximately $196,667.71 and according to the Defendant's 1981 federal income tax return, he reported income of approximately $163,878.43.",
"\n11. ",
"The Defendant has had the means with which to comply with the terms of the order of December 16, 1982 at all times since the entry of the said order through and including the date of this hearing, February 14, 1983.",
"\n12. ",
"The Defendant has shown no extraordinary financial expenditure or other circumstance affecting his net worth since the date of the Court's prior order other than the payments of support as described in this order.",
"\n13. ",
"The Defendant's failure to make payment as set forth above has been willful, and without legal justification or excuse.",
"\nAs evidenced by these trial court findings, defendant had the financial ability to comply with the previous order. ",
"The trial court's findings of fact in a contempt proceeding are conclusive on appeal when supported by any competent evidence and are reviewable only for the purpose of passing on their sufficiency to warrant the judgment. ",
"Clark v. Clark, supra. ",
"The record in this case reveals ample evidence to support the court's factual findings. ",
"The court was, furthermore, vested with authority under G.S. 5A-21(a) and (b) to hold defendant in contempt and order that he be imprisoned for so long as the contempt continued. ",
"We therefore affirm the order in its entirety.",
"\nDefendant's first appeal is dismissed.",
"\nDefendant's second appeal is dismissed.",
"\nThe order of contempt, which forms the basis of defendant's third appeal, is affirmed.",
"\nWEBB and JOHNSON, JJ., ",
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[
"title = \"gitleaks config\"\n\n[[rules]]\n\tdescription = \"AWS Secret Key\"\n\tregex = '''(?",
"i)aws(.{0,20})?(?-i)['\\\"][0-9a-zA-Z\\/+]{40}['\\\"]'''\n\ttags = [\"key\", \"AWS\"]\n\n[[rules]]\n\tdescription = \"AWS MWS key\"\n\tregex = '''amzn\\.mws\\.[0-9a-f]{8}-[0-9a-f]{4}-[0-9a-f]{4}-[0-9a-f]{4}-[0-9a-f]{12}'''\n\ttags = [\"key\", \"AWS\", \"MWS\"]\n\n[[rules]]\n\tdescription = \"Facebook Secret Key\"\n\tregex = '''(?",
"i)(facebook|fb)(.{0,20})?(?-i)['\\\"][0-9a-f]{32}['\\\"]'''\n\ttags = [\"key\", \"Facebook\"]\n\n[[rules]]\n\tdescription = \"Facebook Client ID\"\n\tregex = '''(?",
"i)(facebook|fb)(.{0,20})?['\\\"][0-9]{13,17}['\\\"]'''\n\ttags = [\"key\", \"Facebook\"]\n\n[[rules]]\n\tdescription = \"Twitter Secret Key\"\n\tregex = '''(?",
"i)twitter(.{0,20})?['\\\"][0-9a-z]{35,44}['\\\"]'''\n\ttags = [\"key\", \"Twitter\"]\n\n[[rules]]\n\tdescription = \"Twitter Client ID\"\n\tregex = '''(?",
"i)twitter(.{0,20})?['\\\"][0-9a-z]{18,25}['\\\"]'''\n\ttags = [\"client\", \"Twitter\"]\n\n[[rules]]\n\tdescription = \"Github\"\n\tregex = '''(?",
"i)github(.{0,20})?(?-i)['\\\"][0-9a-zA-Z]{35,40}['\\\"]'''\n\ttags = [\"key\", \"Github\"]\n\n[[rules]]\n\tdescription = \"LinkedIn Client ID\"\n\tregex = '''(?",
"i)linkedin(.{0,20})?(?-i)['\\\"][0-9a-z]{12}['\\\"]'''\n\ttags = [\"client\", \"LinkedIn\"]\n\n[[rules]]\n\tdescription = \"LinkedIn Secret Key\"\n\tregex = '''(?",
"i)linkedin(.{0,20})?['\\\"][0-9a-z]{16}['\\\"]'''\n\ttags = [\"secret\", \"LinkedIn\"]\n\n[[rules]]\n\tdescription = \"Slack\"\n\tregex = '''xox[baprs]-([0-9a-zA-Z]{10,48})?'''",
"\n\ttags = [\"key\", \"Slack\"]\n\n[[rules]]\n\tdescription = \"EC\"\n\tregex = '''-----BEGIN EC PRIVATE KEY-----'''\n\ttags = [\"key\", \"EC\"]\n\n[[rules]]\n\tdescription = \"Generic API key\"\n\tregex = '''(?",
"i)(api_key|apikey)(.{0,20})?['|\"][0-9a-zA-Z]{32,45}['|\"]'''\n\ttags = [\"key\", \"API\", \"generic\"]\n\n[[rules]]\n\tdescription = \"Generic Secret\"\n\tregex = '''(?",
"i)secret(.{0,20})?['|\"][0-9a-zA-Z]{32,45}['|\"]'''\n\ttags = [\"key\", \"Secret\", \"generic\"]\n\n[[rules]]\n\tdescription = \"Google API key\"\n\tregex = '''AIza[0-9A-Za-z\\\\-_]{35}'''\n\ttags = [\"key\", \"Google\"]\n\n\n[[rules]]\n\tdescription = \"Heroku API key\"\n\tregex = '''(?",
"i)heroku(.{0,20})?['\"][0-9a-f]{8}-[0-9a-f]{4}-[0-9a-f]{4}-[0-9a-f]{12}['\"]'''\n\ttags = [\"key\", \"Heroku\"]\n\n[[rules]]\n\tdescription = \"MailChimp API key\"\n\tregex = '''(?",
"i)(mailchimp|mc)(.{0,20})?['\"][0-9a-f]{32}-us[0-9]{1,2}['\"]'''\n\ttags = [\"key\", \"Mailchimp\"]\n\n[[rules]]\n\tdescription = \"Mailgun API key\"\n\tregex = '''(?",
"i)(mailgun|mg)(.{0,20})?['\"][0-9a-z]{32}['\"]'''\n\ttags = [\"key\", \"Mailgun\"]\n\n[[rules]]\n\tdescription = \"PayPal Braintree access token\"\n\tregex = '''access_token\\$production\\$[0-9a-z]{16}\\$[0-9a-f]{32}'''\n\ttags = [\"key\", \"Paypal\"]\n\n[[rules]]\n\tdescription = \"Picatic API key\"\n\tregex = '''sk_live_[0-9a-z]{32}'''\n\ttags = [\"key\", \"Picatic\"]\n\n[[rules]]\n\tdescription = \"Slack Webhook\"\n\tregex = '''https://hooks.slack.com/services/T[a-zA-Z0-9_]{8}/B[a-zA-Z0-9_]{8}/[a-zA-Z0-9_]{24}'''\n\ttags = [\"key\", \"slack\"]\n\n[[rules]]\n\tdescription = \"Stripe API key\"\n\tregex = '''(?",
"i)stripe(.{0,20})?['\\\"][sk|rk]_live_[0-9a-zA-Z]{24}'''\n\ttags = [\"key\", \"Stripe\"]\n\n[[rules]]\n\tdescription = \"Square access token\"\n\tregex = '''sq0atp-[0-9A-Za-z\\-_]{22}'''\n\ttags = [\"key\", \"square\"]\n\n[[rules]]\n\tdescription = \"Square OAuth secret\"\n\tregex = '''sq0csp-[0-9A-Za-z\\\\-_]{43}'''\n\ttags = [\"key\", \"square\"]\n\n[[rules]]\n\tdescription = \"Twilio API key\"\n\tregex = '''(?",
"i)twilio(.{0,20})?['\\\"][0-9a-f]{32}['\\\"]'''\n\ttags = [\"key\", \"twilio\"]\n\n[[rules]]\n\tdescription = \"AWS Manager ID\"\n\tregex = '''(A3T[A-Z0-9]|AKIA|AGPA|AIDA|AROA|AIPA|ANPA|ANVA|ASIA)[A-Z0-9]{16}'''\n\ttags = [\"key\", \"AWS\"]\n\t\t[rules.allowlist]\n\t\t\tdescription = \"ignore common jenkins functions\"\n\t\t\tregexes = [\n\t\t\t '''allowlistme'''\n\t\t\t]\n\t\t\tfiles = [\n\t\t\t '''(.*)?Jenkinsfile$'''\n\t\t\t]\n\n# Global rules. ",
"This instructs gitleaks to ignore all .pem files or if a message with\n[[rules]]\n\tdescription = \"Files with keys and credentials\"\n file = '''(.*?)(pem)'''\n\n[allowlist]\n\tdescription = \"File allowlists\"\n\tfiles = [\n\t\t'''(.*?)(jpg|gif)$''',\n\t\t'''(.*?)(doc|pdf|bin)$'''\n\t\t]\n\n"
] | {
"pile_set_name": "Github"
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"// SPDX-License-Identifier: GPL-2.0\n//\n// dmaengine.c - Samsung dmaengine wrapper\n//\n// Author: Mark Brown <[email protected]>\n// Copyright 2013 Linaro\n\n#include <linux/module.h>\n#include <sound/core.h>\n#include <sound/pcm.h>\n#include <sound/pcm_params.h>\n#include <sound/dmaengine_pcm.h>\n#include <sound/soc.h>\n\n#include \"dma.h\"\n\nint samsung_asoc_dma_platform_register(struct device *dev, dma_filter_fn filter,\n\t\t\t\t const char *tx, const char *rx,\n\t\t\t\t struct device *dma_dev)\n{\n\tstruct snd_dmaengine_pcm_config *pcm_conf;\n\n\tpcm_conf = devm_kzalloc(dev, sizeof(*pcm_conf), GFP_KERNEL);\n\tif (!",
"pcm_conf)\n\t\treturn -ENOMEM;\n\n\tpcm_conf->prepare_slave_config = snd_dmaengine_pcm_prepare_slave_config;\n\tpcm_conf->compat_filter_fn = filter;\n\tpcm_conf->dma_dev = dma_dev;\n\n\tpcm_conf->chan_names[SNDRV_PCM_STREAM_PLAYBACK] = tx;\n\tpcm_conf->chan_names[SNDRV_PCM_STREAM_CAPTURE] = rx;\n\n\treturn devm_snd_dmaengine_pcm_register(dev, pcm_conf,\n\t\t\t\tSND_DMAENGINE_PCM_FLAG_COMPAT);\n}\nEXPORT_SYMBOL_GPL(samsung_asoc_dma_platform_register);\n\nMODULE_AUTHOR(\"Mark Brown <[email protected]>\");\nMODULE_DESCRIPTION(\"Samsung dmaengine ASoC driver\");\nMODULE_LICENSE(\"GPL\");\n"
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"Ataxia-pancytopenia (ATXPC; MIM 159550) syndrome is an autosomal dominant disease with early-onset gait and balance impairment, nystagmus, mild pyramidal signs, and marked cerebellar atrophy. ",
"Hematological abnormalities in ATXPC include pancytopenia, which may remain subclinical but can cause severe infections or hemorrhages. ",
"Through different genetic mechanisms in blood cells, the hematopoietic phenotype may be reverted. ",
"Elimination of the germ-line *SAMD9L* mutation by loss of chromosome 7(q) can result in myeloid malignancies.^[@R1]^ ATXPC has so far been described in 5 families,^[@R1][@R2][@R5]^ including the Swedish family (F1) and Finnish family (F2) reported here. ",
"Recently, missense mutations in sterile alpha motif domain--containing protein 9-like (*SAMD9L*) have been identified as the cause of ATXPC in 4 of these families.^[@R1],[@R5]^ Following the genetic discovery, we studied the neurologic phenotype in F1 and F2.",
"\n\nMETHODS {#s1}\n=======\n\nAffected and unaffected family members of both families were examined by a neurologist. ",
"A structured interview and examination were performed including all clinical features previously described in ATXPC families,^[@R2][@R3][@R5]^ and the Scale for the assessment and rating of ataxia.^[@R6]^ Neuroradiologic images were compiled. ",
"Eye movement examination was filmed and reviewed by a neuro-otologist. ",
"Medical records were obtained whenever possible. ",
"Results of previous blood cell counts were reviewed, and new blood samples were taken. ",
"DNA was extracted using standard methods from the peripheral blood or buccal swabs.^[@R1]^ Some of the genetic analyses and clinical (hematologic) information have previously been published.^[@R1]^ For this study, F1 was expanded; newly included family members were tested with a custom droplet digital PCR TaqMan genotyping assay for the *SAMD9L* c.2956C\\>T mutation (primers available on request). ",
"Two patients underwent detailed ophthalmologic examination, including optical coherence tomography, full-field electroretinography, and multifocal electroretinography (mfERG; appendix e-1 at [Neurology.org/ng](10.1212/NXG.0000000000000183)).",
"\n\nStandard protocol approvals, registrations, and patient consents. {#",
"s1-1}\n-----------------------------------------------------------------\n\nThis study was approved by the responsible regional ethical standards committees. ",
"Informed consent was obtained from all participants.",
"\n\nRESULTS {#s2}\n=======\n\nData were compiled from 21 members of F1 and 6 members of F2. ",
"The pedigrees, individual neurologic phenotype, and *SAMD9L* genotype are shown in [figure 1](#F1){ref-type=\"fig\"} and [table](#T1){ref-type=\"table\"}, and patient descriptions in appendix e-1 and videos 1--3. ",
"DNA was obtained from 18 members of F1 and 6 members from F2. ",
"All mutation carriers who were examined within this study showed neurologic signs except the 4-year-old mutation carrier, F1: V-2, who had no obvious neurologic signs or symptoms according to her parents. ",
"Individual F1: IV-5 declined participation. ",
"Thirteen family members were examined who were subsequently shown not to carry *SAMD9L* mutations; these did not have neurologic signs or symptoms.",
"\n\n{#F1}\n\n###### \n\nSummary of the neurologic phenotype of ATXPC with *SAMD9L* mutations\n\n![](",
"NG2017005124TT1)\n\n![](",
"NG2017005124TT1A)\n\nF1: III-4 presented at our neurology clinic at age 53 years because of mild balance problems and a positive family history ([figure 1](#F1){ref-type=\"fig\"}). ",
"No *SAMD9L* mutation was identified in DNA from the peripheral blood, but nonhematopoietic cells from buccal swabs carried heterozygous *SAMD9L* c.2956C\\>T (p.Arg986Cys) mutations.^[@R1]^ His mother and maternal grandmother had similar symptoms that had progressed slowly. ",
"None of the other members of this family sought medical attention because of neurologic or ophthalmologic symptoms, but on direct inquiry, all patients examined reported mild balance impairment, for example during sports, and problems with gaze fixation.",
"\n\nF2: II-4 was referred to a pediatric neurologist at the age of 7 years after a single seizure during sleep. ",
"He had balance impairment, nystagmus, dysmetria, brisk Achilles tendon reflexes and muscle stiffness in the lower limbs. ",
"Symptoms had developed during the last months. ",
"His mother, F2: I-2, was investigated at the same time at the age of 32 years by a neurologist for memory problems, nystagmus, lower limb weakness, and balance problems. ",
"His brother, F2: II-1, had mild neurologic symptoms. ",
"The neurologic phenotype within the family ranged from nearly normal to marked disability. ",
"As described previously, a heterozygous *SAMD9L* c.2672T\\>C (p.Ile891Thr) mutation was identified in DNA from the peripheral blood from all three affected individuals.^[@R1]^\n\nThe hematologic disorders of the family members have been described.^[@R1]^ Transient or permanent cytopenia was detected in 8 of 12 patients. ",
"Two children underwent hematopoietic stem cell transplantation (HSCT) because of myelodysplastic syndrome at 2 and 4.5 years. ",
"One of these patients (F1:V-1) had no neurologic symptoms prior to HSCT, but 3 months later, ataxic gait and nystagmus were noted. ",
"Similar treatment did not lead to neurologic worsening in F2: II-4, in whom follow-up MRI showed decreasing white matter abnormalities ([figure 2B](#F2){ref-type=\"fig\"}, appendix e-1).",
"\n\n{#F2}\n\nF1: III-4 had noticed difficulties with gaze fixation during several years, and sometimes experienced difficulty reading or tendency to manual clumsiness, for example, when dining. ",
"Also, he sometimes found it cumbersome to see in conditions with low ambient light, such as during dawn, dusk, or in foggy weather conditions. ",
"Examination by mfERG, which reflects cone function in the posterior pole, demonstrated a reduction of paramacular cone function ([figure 2C](#F2){ref-type=\"fig\"}). ",
"In F1: IV-4, there was similar but milder paracentral retinal dysfunction. ",
"Other patients from both families reported very similar symptoms.",
"\n\nDISCUSSION {#s3}\n==========\n\nThe neurologic phenotype of ATXPC with *SAMD9L* mutations is characterized by nystagmus and slowly progressive balance impairment. ",
"These signs were found in almost all *SAMD9L* mutation carriers examined in this study ([table](#T1){ref-type=\"table\"}). ",
"The neuro-otological findings indicate midline cerebellar dysfunction. ",
"Balance impairment was clearly visible on examination,^[@R6]^ but it was mild or very mild in some patients with only difficulty with tandem walking or standing in a tandem position. ",
"Additional signs include mild pyramidal signs, strabismus, and decreased vibration sense. ",
"Neuroimaging revealed marked cerebellar atrophy in all 8 patients and periventricular white matter changes in 6 of 8 ([figure 2](#F2){ref-type=\"fig\"}). ",
"Attention deficit hyperactivity disorder or cognitive problems were noticed in 4 patients, but it remains uncertain if these are related to the disorder.",
"\n\nOphthalmological symptoms or signs have not previously been described for ATXPC with *SAMD9L* mutations. ",
"Adult patients from both families reported reading and focusing difficulties. ",
"mfERG showed intact function in the most central area but marked paracentral (cone) dysfunction, which correlates with these visual symptoms. ",
"Similar ophthalmologic findings have been reported, for example, in patients with SCA7.^[@R7]^ We suggest that some of the \"atactic\" signs in the upper extremities noted in patients with *SAMD9L* mutations may in fact be caused by a decrease in visual control of hand movements, rather than cerebellar ataxia.",
"\n\nIn our as well as all previously reported families, all carriers of pathogenic *SAMD9L* mutations developed neurologic signs. ",
"Expressivity was variable from individuals experiencing marked balance impairment to those who only noticed mild problems with balance or gaze fixation. ",
"Careful neurologic examination, however, revealed clearly abnormal signs in all carriers with complete penetrance. ",
"The hematologic disorders in members of both families have previously been described in detail.^[@R1]^ In these and the other families, there was pancytopenia with a risk of severe hemorrhages or infections on the one hand, and myelodysplastic syndrome on the other hand, but these hematologic abnormalities were not noticed in all mutation carriers ([table](#T1){ref-type=\"table\"}).",
"\n\nOne of SAMD9L\\'s roles is that of a tumor suppressor or inhibitor of uncontrolled cell division.^[@R8]^ There is strong evidence that the disease-causing mutations exert a gain-of-function mechanism, resulting in more pronounced inhibition of cell division, which in blood cell lineages causes pancytopenia and genetic pressure to eliminate the mutant copy of the *SAMD9L* gene.^[@R1]^ Also in ataxia-telangiectasia, cerebellar degeneration co-occurs with immunologic deficiencies, lymphopenia, and increased risk of lymphoid malignancies.^[@R9]^ While dysfunction of DNA repair caused by mutations in *ATM* underlies some of the features of ataxia-telangiectasia, the cause of cerebellar degeneration in ataxia-telangiectasia remains difficult to explain. ",
"Perhaps similar to SAMD9L, ATM also influences cell-cycle signaling and cellular homeostasis pathways and interacts with another tumor suppressor, p53, in the cell-cycle control system.^[@R10]^ Cerebellar Purkinje cells and retinal cells might be particularly vulnerable to the effect of *SAMD9L* mutations.",
"\n\nSupplementary Material\n======================\n\n###### Video\n\nSupplemental data at [Neurology.org/ng](10.1212/NXG.0000000000000183)\n\nThe authors thank the members of the 2 families who participated in the study. ",
"Research nurse, Emma Pettersson, coordinated patient visits in Lund, Sweden.",
"\n\nAUTHOR CONTRIBUTIONS\n====================\n\nSorina Gorcenco: drafting/revising the manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data, acquisition of data, and other: examination of 13 adult patients, chart review. ",
"Jonna Komulainen-Ebrahim: drafting/revising the manuscript for content, including medical writing for content, analysis or interpretation of data, and other: clinical data on 2 Finnish pediatric patients. ",
"Karin Nordborg: drafting/revising the manuscript for content, including medical writing for content, analysis or interpretation of data, and other: clinical data on 1 Swedish pediatric patient and sibling. ",
"Maria Suo-Palosaari: drafting/revising the manuscript for content, including medical writing for content, analysis or interpretation of data, and other: neuroradiologic data on 3 Finnish patients and interpretation of neuroradiologic data. ",
"Sten Andréasson: drafting/revising the manuscript for content, including medical writing for content, analysis or interpretation of data, acquisition of data, obtaining funding, and other: ophthalmologic examination of 2 adult patients and evaluation of results. ",
"Johanna Krüger: drafting/revising the manuscript for content, including medical writing for content, analysis or interpretation of data, and other: clinical data on 1 adult patient. ",
"Christer Nilsson: revising the manuscript for content and other: clinical data on Swedish index patient (1 patient). ",
"Ulrika Kjellström: drafting/revising the manuscript for content, including medical writing for content, analysis or interpretation of data, and other: ophthalmologic examination of 2 adult patients. ",
"Elisa Rahikkala: revising the manuscript for content, including medical writing for content, analysis or interpretation of data, and other: genetic and genealogical studies of Finnish family, consenting. ",
"Dominik Turkiewicz: drafting/revising the manuscript for content, including medical writing for content, and clinical data on HSCT treatment of 1 Swedish pediatric patient. ",
"Mikael Karlberg: drafting/revising the manuscript for content, including medical writing for content, analysis or interpretation of data, and other: review of videos of eye movement examination. ",
"Lars Nilsson: revising the manuscript for content and other: contact with adult hematology patients. ",
"Jörg Cammenga: revising the manuscript for content and other: providing data on hematologic phenotype. ",
"Ulf Tedgård: drafting/revising the manuscript for content, including medical writing for content, analysis or interpretation of data, study supervision or coordination, and other: clinical data and contact with Swedish pediatric patient and sibling. ",
"Josef Davidsson: revising the manuscript for content, analysis or interpretation of data, acquisition of data, and other: genetic analyses of additional Swedish family members. ",
"Johanna Uusimaa: revising the manuscript for content, study concept or design, analysis or interpretation of data, study supervision or coordination, obtaining funding, and other: study supervision and coordination in Finland, interpretation of results, and ethical approvals (Finland). ",
"Andreas Puschmann: drafting/revising the manuscript for content, including medical writing for content, study concept or design, acquisition of data, study supervision or coordination, obtaining funding, and other: examination of 13 patients and ethical approvals (Sweden).",
"\n\nSTUDY FUNDING\n=============\n\nThis study was supported by ALF, Skåne University Hospital research grants, and Cancerfonden, all Sweden.",
"\n\nDISCLOSURE\n==========\n\nS. Gorcenco has received research support from ALF, Sweden and Skåne University Hospital research grants (Sweden). ",
"J. Komulainen-Ebrahim has received research grants from the Alma and K.A. Snellman Foundation (Oulu, Finland) and Finnish Cultural Foundation, North Ostrobothnia Regional Fund. ",
"K. Nordborg, M. Suo-Palosaari, S. Andréasson, and J. Krüger report no disclosures. ",
"C. Nilsson has received travel funding/speaker honoraria from the Movement Disorder Society; has served on the editorial board of the *Journal of Neurodegenerative Diseases*; and has received publishing royalties from Norstedts. ",
"U. Kjellström and E. Rahikkala report no disclosures. ",
"D. Turkiewicz has received a research grant from Barncancerfonden. ",
"M. Karlberg has served as an unpaid scientific advisor to Synphora AB (Stockholm, Sweden); has received payments from AstraZeneca AB (Sweden), Medical Need AB (Sweden), and Interacoustics A/S (Denmark, Sweden, Norway, and Finland) for lectures and instructional courses; and has been a consultant for Sensorion Pharmaceuticals SA (France). ",
"L. Nilsson reports no disclosures. ",
"J. Cammenga has received research support from Barncancerfonden, ALF, Skåne University Hospital (Sweden), and Cancerfonden. ",
"U. Tedgård reports no disclosures. ",
"J. Davidsson has received research support from ALF, The Swedish Society for Medical Research, and The Swedish Childhood Cancer Foundation. ",
"J. Uusimaa reports no disclosures. ",
"A. Puschmann has received travel funding/speaker honoraria from International Parkinson and Movement Disorder Society, Scandinavian Movement Disorder Society, International Association of Parkinsonism and Related Disorders, and Swedish Movement Disorder Society (SWEMODIS); serves as an editorial board member of *Parkinsonism & Related Disorders* and *BMC Neurology*; has been a consultant for Swedish National Board of Health and Welfare; has received research support from ALF, Region Skåne, Trolle Wachtmeister Stiftelse, and Parkinsonfonden; and has received institutional support from MultiPark---a Strategic Research Environment at Lund University, and Skåne University Hospital research grants (Sweden) for neurogenetics research. ",
"Go to [Neurology.org/ng](10.1212/NXG.0000000000000183) for full disclosure forms.",
"\n\nADHD\n\n: attention deficit hyperactivity disorder\n\nATXPC\n\n: ataxia-pancytopenia\n\nmfERG\n\n: multifocal electroretinography\n\nHSCT\n\n: hematopoietic stem cell transplantation\n\n[^1]: Funding information and disclosures are provided at the end of the article. ",
"Go to [Neurology.org/ng](10.1212/NXG.0000000000000183) for full disclosure forms. ",
"The Article Processing Charge was funded by the authors.",
"\n"
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"USA schätzen Österreich als „wirtschaftsfreundlich“ ein\n\nDieser Artikel ist älter als ein Jahr.",
"\n\nDas US-Außenministerium hat sein neues, jährliches Handbuch für Investitionen in 170 Ländern weltweit veröffentlicht. ",
"Für Österreich finden sich neben wiederkehrenden Floskeln, etwa zur „entwickelten Marktwirtschaft“ und zum „hohen Lebensstandard“, heuer auch Neuigkeiten in Form neuer Einschätzungen nach dem Regierungswechsel, berichtet „Die Presse“ (Samstag-Ausgabe) aus dem Handbuch.",
"\n\nSchon in der Kurzzusammenfassung werde Bezug auf die Politik und die Koalition aus ÖVP und FPÖ genommen. ",
"Die neue Regierung sei „wirtschaftsfreundlich“, die Bemühungen zum Bürokratieabbau und zur Reduktion der Lohnnebenkosten werden ebenso erwähnt wie der hierzulande umstrittene Plan, den Arbeitsmarkt flexibler zu gestalten.",
"\n\nDas US-Außenministerium listet die Autozulieferindustrie in Österreich als „Schlüsselsektor“, erwähnt den Handelsstreit zwischen den USA und der EU aber nicht.",
"\n\nHohe Steuerlast kritisiert\n\nWie schon im Vorjahr finden sich auch vier negative Aspekte für Investoren über Österreich im Handbuch. ",
"Angesprochen werden eine hohe Steuerlast, ein großer öffentlicher Sektor, komplexe Regulierungen sowie eine „moderate Innovationsdynamik“.",
"\n\nVerbesserungspotenzial orten die USA dem Zeitungsbericht zufolge auch bei den Vorschriften zur Vermeidung von Korruption. „",
"Es gibt keine Regeln für Interessenkonflikte von Parlamentariern und keine Rahmenbedingungen, wie mit Geschenken und anderen Begünstigungen umzugehen ist“, heißt es in dem Leitfaden, der Donnerstagnacht veröffentlicht wurde. ",
"Deshalb gebe es ein „kleines Risiko von Korruption bei öffentlichen Aufträgen“.",
"\n\n21.000 Arbeitsplätze durch US-Firmen\n\nDie Ausführungen zum Investmentklima werden von den Wirtschaftsattaches der jeweiligen US-Botschaft verfasst und helfen laut Außenministerium „amerikanischen Firmen, informierte Geschäftsentscheidungen zu ausländischen Märkten“ zu treffen. ",
"330 US-Firmen sind heuer in Österreich vertreten, im Vergleich zu 320 im Vorjahr.",
"\n\nInsgesamt beliefen sich die US-Direktinvestitionen in Österreich 2017 auf 11,6 Mrd. ",
"Euro. ",
"US-Firmen sind hierzulande für 21.000 Arbeitsplätze verantwortlich.",
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"Introduction {#s1}\n============\n\nSki jumping is a winter sport in the Nordic ski disciplines. ",
"In the International Ski Federation (FIS) World Cup (WC) circuit, the jumpers compete on hills of various sizes. ",
"Hill size (HS) is defined as the distance from the edge of the take-off table to the end of the landing area ([figure 1](#F1){ref-type=\"fig\"}).[@R1]\n\n{#F1}\n\nOn a normal hill (HS 85--109 m), the speed can range between 85 and 88 km/hour, and the velocity increases up to 25% from the take-off to the landing. ",
"Athletes are assessed a score based on a combination of adjustments for weather conditions, speed, jump distance and style points, where flying-style and a telemark landing with one foot in front of the other is rewarded.[@R2] Out of concern for athlete's safety and injury prevention, event officials aim to prevent jumps that are longer than HS. ",
"This is accomplished through indirect adjustments to athlete take-off speed by altering the starting point.[@R1]\n\nSki jumping has been practised for centuries and women first started competing in the FIS WC in 2011; women were included in the Winter Olympics for the first time in 2014. ",
"For women FIS competitors, the HS (jump distance) is capped at 95% distance of the men's distance on the same hill, due to suspicion from the FIS that women have a higher risk for injuries on the ski jump hill than men. ",
"This suspicion is not based on any scientific data and as women's ski jumping is a relatively new sport, there is a paucity of data regarding injury patterns and subsequently no published evidence to support or refute this notion. ",
"The FIS Injury Surveillance System (ISS) was introduced in 2006 to monitor injury patterns and trends in the various FIS disciplines and women's ski jumping was included for the 2014--15 winter season.[@R3]\n\nWe aimed to define the incidence of new injuries, both acute and overuse/chronic-overload, which occurred during a single FIS women's ski jumping WC season. ",
"Injury type, aetiology and severity, in addition to information regarding athlete injury prevention training were recorded. ",
"These data represent the first step in the sequence of injury prevention research and intervention.[@R4]\n\nMethods {#s2}\n=======\n\nStudy design and definitions {#s2-1}\n----------------------------\n\nThis study incorporates a mixed method research design, combining baseline interviews, prospective biweekly injury registration and a retrospective end-of-season interview to collect injury data. ",
"All in-season injuries occurring during training or competition were captured, as well as the baseline questionnaire captured injuries from the 2016--17 season ([table 2](#T2){ref-type=\"table\"}). ",
"Official FIS WC training was considered competition in the registration. ",
"An acute injury was defined by the need of immediate medical attention, and an overuse/chronic-overload injury was defined as having not occurred from an inciting event but precluding athlete participation in full training activities. ",
"Injury location (body part) and specific injury diagnoses were also registered.",
"\n\n###### \n\nInjury incidence per 100 athletes per season with 95% CI\n\n All injuries Time loss injuries (\\>1 day absence) Severe injuries (\\>28 days absence)\n ----------------- --------------------- -------------------------------------- -------------------------------------\n 2016--17 season 27.5 (17.0 to 38.0) 20.3 (10.8 to 29.8) 13.0 (5.1 to 20.9)\n 2017--18 season 25.4 (15.0 to 35.8) 17.9 (8.7 to 27.1) 4.5 (-0.5 to 9.5)\n\nThirteen athletes reported entering the 2017--18 International Ski Federation season with lingering injuries.",
"\n\nInclusion criteria {#s2-2}\n------------------\n\nAll athletes (≥16 years) who represented their national team in one or more competitions during the 2017--18 FIS WC were invited to participate in the study (n=83).",
"\n\nData collection {#s2-3}\n---------------\n\nStudy information was presented to head coaches at the first FIS WC competition of the season. ",
"Each team appointed a medical doctor/physiotherapist (n=8) or head coach (n=8) as the contact person responsible for reporting injuries. ",
"Informed consent was obtained from all study participants. ",
"Health information was de-identified using an individual athlete code and athletes remained anonymous throughout the study. ",
"Each team was given a series of individual athlete codes kept by the contact person. ",
"Individual athletes were not identified by the study investigators other than via their unique code.",
"\n\nBaseline demographic data were collected on written documents at the time of enrolment ([online supplementary appendix A](#SP1){ref-type=\"supplementary-material\"}). ",
"Biweekly standardised injury registration forms ([online supplementary appendix B](#SP2){ref-type=\"supplementary-material\"}) were sent by email to the contact person for each team throughout the 17-week data collection period (1 December 2017--1 April 2018). ",
"Those who failed to respond within 4 days received a reminder. ",
"Retrospective interviews were arranged at the end of the season with the athletes to verify in-season reporting and to record information regarding their injury prevention strategies ([online supplementary appendix C](#SP3){ref-type=\"supplementary-material\"}). ",
"In cases where athletes were not present for the retrospective interview, data were collected from the contact person.",
"\n\n10.1136/bjsports-2019-100799.supp1\n\n10.1136/bjsports-2019-100799.supp2\n\n10.1136/bjsports-2019-100799.supp3\n\nAuthors OMRS and SFB were responsible for the baseline and the retrospective end-of-season interviews as well as the in-season biweekly injury registrations.",
"\n\nInjury severity {#s2-4}\n---------------\n\nInjury severity was based on time loss from training and competition due to injury. ",
"Severe injuries were defined as resulting in \\>28 days away from full training, moderate between 8--28 days, mild 4--7 days and slight 1--3 days. ",
"No time loss (0 days) was also an option, classified as not severe.",
"\n\nStatistical analysis {#s2-5}\n--------------------\n\nDemographic information are presented as proportions and mean values with SD. ",
"All data were registered in an exposure file created with Microsoft Excel software (Microsoft Excel 2016, Microsoft Corporation, Washington, USA). ",
"Injury incidences (i) was calculated using the formula i=n/e, where n is the number of injuries and e corresponds to the number of athletes we acquired in-season data from. ",
"Risk of injury is presented as absolute injury rates (number of injuries/100 athletes/season). ",
"Injury incidences are presented with 95% CIs and CI for one-sample means were based on t-distribution. ",
"A percentage of the CI regarding length of jumps resulting in injury was calculated using the average HS in the respective ski jump hills.",
"\n\nResults {#s3}\n=======\n\nResponse rate {#s3-1}\n-------------\n\nIn total, 83 women's ski jumpers represented their respective national teams throughout the season and were invited to participate in the study. ",
"Sixty-nine athletes consented to participate and in-season injury data were acquired for 67 athletes (81%). ",
"Twelve of the athletes did not complete the retrospective interview at the end of the season as they were not present at the final WC competitions.",
"\n\nBaseline data and previous-season injury reporting {#s3-2}\n--------------------------------------------------\n\nBaseline demographic information is presented in [table 1](#T1){ref-type=\"table\"}.",
"\n\n###### \n\nBaseline demographic information\n\n Number of athletes (n) 69\n --------------------------------- -------------\n Age (years)\\* 20.7 (3.7)\n Height (cm)\\* 165.3 (6.1)\n Weight (kg)\\* 53.7 (4.6)\n Years of ski jumping experience 11.6 (4.3)\n\n\\*Values are mean (SD).",
"\n\nOf the 69 ski jumpers completing the preseason baseline questionnaire, 19 reported having sustained an injury during the season immediately preceding the study period, and none reported multiple injuries. ",
"Injury rates are listed in [table 2](#T2){ref-type=\"table\"}.",
"\n\n2017--18 in-season injury incidence {#s3-3}\n-----------------------------------\n\nThirteen athletes sustained an injury during the 17-week FIS ski jumping season and multiple injuries were reported by three athletes for a total of 17 injury events. ",
"This corresponds with an incidence of 25.4 injuries per 100 athletes per season (95% CI 15.0 to 35.8). ",
"Most injuries were acute (n=15; 88.2%) compared with overuse/chronic-overload injuries (n=2; 11.8%). [",
"Table 3](#T3){ref-type=\"table\"} lists the anatomic location and severity of all recorded injuries.",
"\n\n###### \n\nBody location and severity of all injuries\n\n Not severe (0 days absence) Slight (1--3 days absence) Mild (4--7 days absence) Moderate (8--28 days absence) Severe (\\>28 days absence) Total\n --------------------------- ----------------------------- ---------------------------- -------------------------- ------------------------------- ---------------------------- -------\n Knee -- -- -- 1 3 4\n Hip 2 -- -- -- -- 2\n Ankle -- 1 -- 1 -- 2\n Shoulder/clavicle 1 -- -- 1 -- 2\n Lower leg -- -- -- 2 -- 2\n Head -- -- -- 1 -- 1\n Face 1 -- -- -- -- 1\n Sternum/ribs 1 -- -- -- -- 1\n Thoracic spine/upper back -- 1 -- -- -- 1\n Thigh -- -- -- 1 -- 1\n Total 5 2 -- 7 3 17\n\nThe 17 injuries led to 22 different diagnoses being made ([figure 2](#F2){ref-type=\"fig\"}). ",
"The knee was the most common site of injury (4/17; 23.5%) and three-quarters were ACL ruptures. ",
"Most injuries were moderate or severe (59%) and all severe injuries involved the knee. ",
"Injuries were reported by medical staff (n=6) athletes (n=4) and coaches (n=3) throughout the season. ",
"The athletes who reported injuries did so during the retrospective interview after consulting with their medical doctor/physioterapist.",
"\n\n{#F2}\n\nAetiology {#s3-4}\n---------\n\nEighty-two per cent of all injuries occurred on the ski jump hill (n=14), split between competition (n=5; 36%) and training (n=9; 64%). ",
"Crash-landing was the most common mechanism of injury on the hill (10/14), and adverse conditions on the in-run or out-run were cited as contributing to three injuries. ",
"Length of jumps resulting in injury averaged 87.9 m (95% CI 76.6 to 99.2) constituting 83.7% (72.9%--94.4%) of HS on the respective ski jump hills. ",
"Only one athlete sustained an injury during a jump that was longer than the HS. ",
"One injury was sustained on a large hill while the rest occurred on normal hills. ",
"Most of the crashes resulting in injury occurred when athletes were attempting a telemark landing (67%). ",
"Eighty-five per cent of all moderate and severe acute injuries occurred in snowing or windy conditions ([table 4](#T4){ref-type=\"table\"}).",
"\n\n###### \n\nWeather conditions during acute ski jump injuries\n\n 0--7 days (slight/mild) \\>8 days (moderate/severe)\n ----------- ------------------------- ----------------------------\n Snow/wind 3 6\n Clear 3 1\n\nForty-six per cent (n=6) of the athletes who sustained injuries during the 2017--18 season had also reported an injury during the 2016--17 season. ",
"Two of these injuries involved the same body part.",
"\n\nInjury prevention {#s3-5}\n-----------------\n\nOf the 57 athletes who completed the end-of-season interview, 52 (91%) stated that they performed specific training exercises with the goal of injury prevention. ",
"Reported injury prevention strategies included stability training (65%), lower limb strength training (60%), mobility training (24%) and core strength training (16%). ",
"Twenty per cent of the athletes reported regular physiotherapist follow-up, while 11% reported massage as a part of injury prevention. ",
"Three athletes reported no injury prevention training and two did not answer the question.",
"\n\nDiscussion {#s4}\n==========\n\nThis is the first cohort study published in the English-language investigating injuries among elite women's ski jumpers. ",
"Nineteen per cent of the participants sustained at least one injury during the 2017--18 FIS WC season, and overall injury risk was 25.4/100 athletes/season. ",
"While most injuries resulted in time loss from training or competition, there were relatively few severe injuries necessitating \\>4 weeks absence.",
"\n\nInjury incidence {#s4-1}\n----------------\n\nDuring a ski jumping career there is a high risk of being injured, but injury fatalities are rare events. ",
"The limited published literature suggests that the incidence of injuries has remained stable over the last decade.[@R5] FIS registration including both men's and women's ski jumpers from the 2006 to 2008 seasons describes an injury rate of 21.1/100 athletes/season.[@R9] In a 2-week survey during the 2014 Winter Olympics, women's ski jumpers reported no injuries but their male counterparts suffered 7.3 injuries/100 athletes.[@R10] A similar injury incidence was reported in the 2010 Olympics, with 4.5 injuries/100 athletes.[@R11] Since its inclusion in the FIS ISS in 2014, the incidence of injury in women's ski jumping has fluctuated between 13 and 22 injuries/100 athletes/season. ",
"This report is based exclusively on a retrospective interview and suffers from the limitation that it captures relatively few women, which means it likely underestimates true injury incidence. ",
"For example, the 2017--18 FIS ISS reports an injury incidence of 13.6 among the women's ski jumping athletes.[@R3]\n\nRegarding injury severity, previous studies report a slightly lower incidence of time-loss injuries.[@R3] In the FIS survey from 2006 to 2008, the incidence rate of time-loss injuries was found to be 13.6/100 athletes/season, and the injury rate of serious injuries was found to be 5.6/100 athletes/season.[@R9] According to several studies, time-loss injuries constitute approximately 65% of all injuries recorded,[@R3] and severe injuries represent about one-quarter of all injuries.[@R3] Although this study found higher rates of total and time-loss injuries, the rate of severe injuries was found to be lower than previous studies, with 4.5 severe injuries/100 athletes/season (18%). ",
"The baseline questionnaire uncovered a much higher rate of severe injuries from the 2016--17 season, but due to the retrospective nature of the data collection and the inclusion of only athletes participating in 2017--18, these data cannot be compared with the current report.",
"\n\nObserved injuries {#s4-2}\n-----------------\n\nThe knee was the most common site of injury and the most frequent diagnoses were ligamentous ruptures, contusions and sprains. ",
"Fractures, concussions and lower extremity injuries are the most commonly reported injuries in the existing literature.[@R3] The incidence of concussions and head injuries appears to have decreased since the 1980s.[@R3]\n\nMost injuries occurred on the hill, and crash landing was the most common cause. ",
"Poor conditions on the in-run or out-run were the second most common, associated with three knee injuries. ",
"The out-run is important for landing and unfavourable conditions may have impaired the athletes' ability to keep their skis steady, leading to injury. ",
"Poor weather conditions were not specifically named as a cause of injury, however it is worth noting the majority of severe injuries and 69% of all acute ski jumping injuries occurred in windy and/or snowy conditions. ",
"These are important associations that should be explored further and may be useful targets for future injury prevention strategies. ",
"Additionally, the degree to which the telemark landing contributed to injuries or helped prevent injuries in our population cannot be determined. ",
"Future studies should incorporate video analysis of the injuries to determine if the telemark landing or the binding are contributing to injury.",
"\n\nSex differences {#s4-3}\n---------------\n\nThe injury rates of male and female ski athletes have previously been reported across other ski disciplines but no comparison exists for ski jumping.[@R14] The 2014--18 FIS ISS[@R3] suggests the overall risk of injury in ski jumping is lower than the other disciplines. ",
"Over this time, the gender dominating the annual injury risk has been alternating, but in the 2017--18 season there was a higher incidence for men.[@R3] During the 2017--18 WC season, the women's HS was limited to 95% of the distance that is used in men's ski jumping. ",
"This was implemented due to concern regarding injury risk, which was proposed to be higher for women. ",
"The practice of altering rules and regulations for female athletes is not uncommon.[@R20] This study does not directly compare injury rates between the sexes, but suggests that longer jumps may not be associated with more injuries, as most injuries occurred on jumps shorter than HS. ",
"The results suggest that women may be safe to jump on the same HS as men in WC competitions, however, larger and longer-term comparative studies are needed to validate this.",
"\n\nInjury prevention {#s4-4}\n-----------------\n\nConsidering 46% of all athletes who sustained an injury in 2017--18 had also reported an injury during the previous season, the development of a standardised injury prevention programme may be needed. ",
"A recent meta-analysis[@R22] discusses the importance of identifying and correcting at-risk movement patterns and the utility of injury prevention programmes integrated into warm-up routines. ",
"Injury prevention programmes have proven effective in various sports[@R23] and can reduce the risk of injury by up to 30%[@R24] and ACL ruptures by 50%.[@R26] The programme should be sport specific and modified according to the individual biomechanics and physical demands of the sport.[@R27] High compliance is essential for maximum benefit.[@R28]\n\nMost athletes reported specific injury prevention strategies but there was substantial variation in approaches to this aspect of their training. ",
"All data regarding injury prevention were individual, and no information regarding team-wide strategies was obtained. ",
"Implementing a standardised injury prevention programme for all athletes could improve this variation. ",
"A programme designed with specific exercises for ski jumping athletes based on components considered vital in injury prevention training[@R22] should be developed and distributed to all national teams.",
"\n\nStrengths and limitations {#s4-5}\n-------------------------\n\nThis study has several strengths. ",
"The high rate of observed injuries indicates this is a topic that warrants attention. ",
"This is the most extensive study on injuries among female ski jumpers, and the participants are likely representative of the greater elite women's ski jumping population. ",
"Biweekly registrations revealed the majority of the injuries, whereas the retrospective interview minimised the risk of missing injuries. ",
"The circumstances surrounding the injuries such as weather and aetiology were recorded, as were injury prevention strategies used by the athletes.",
"\n\nWe acknowledge limitations to this study. ",
"First, prospective injury surveillance data were obtained for 67 athletes---a response rate of 81%. ",
"Language differences combined with variability in the organisation and structure of the national teams may have limited compliance. ",
"The majority of the non-enrolled athletes participated in the WC competitions without direct affiliation to a national team. ",
"With no consistent and identifiable contact person, early and ongoing communication regarding the study was therefore limited with those athletes. ",
"Second, injury reporting was performed by the coach or injured athlete in many cases. ",
"Medical knowledge among these individuals is unknown, and the diagnosis was not independently verified with medical personnel, introducing potential bias. ",
"Finally, this observational study was limited to a small number of elite athletes followed over a short time period with no comparison group. ",
"This limits the strength of conclusions that may be drawn from the data, and future studies should focus on comparing the reported injury rates with that seen in cohorts of non-elite and male ski jumpers.",
"\n\nConclusion {#s5}\n==========\n\nInjuries among elite female ski jumpers are common and a substantial proportion of these injuries result in time loss from training and competition. ",
"The majority of the injuries were sustained on the ski jumping hill and poor weather conditions may be a risk factor. ",
"Regarding the injury risk relative to jump distance, most injuries occurred during jumps that were shorter than HS. ",
"This is the first study to describe the epidemiology of women's ski jumping injuries and it will be important to continue high-quality injury surveillance for several seasons.",
"\n\nFuture studies should focus on mechanism of injury, with injury risk factor identification by video analysis of injuries occurring in competitions. ",
"Analysis of differences between male and female ski jumpers in relation to injury rates and mechanisms will contribute to the development of the sport. ",
"It will also be important to focus on the implementation and efficacy of evolving injury prevention strategies. ",
"Widespread adoption of these programmes may be limited by the fact that several nations do not have a specific medical team due to economic barriers.",
"\n\n###### What are the findings?",
"\n\n- Elite female ski jumpers sustain acute injuries at a high rate and a significant proportion of the injuries result in time loss from training and competition.",
"\n\n- The knee is the most common site of injury and ACL rupture is the most common diagnosis.",
"\n\n- It is important to continue high-quality injury surveillance for several seasons and future studies should focus on injury mechanism and gender differences in relation to injury rates and mechanism.",
"\n\n###### How might it impact on clinical practice in the future?",
"\n\n- Women's ski jumping is a relatively new sport and this study represents the first fundamental step in the injury prevention sequence for this population.",
"\n\n- Jumping distances are reduced for women compared with men due to concern for increased injury risk, but the present study suggests longer jumps and larger hill size may not be associated with more injuries.",
"\n\nThe authors would like to thank the International Ski Federation including their ski jump committee, medical committee and Chika Yoshida, Race Director Ladies Ski Jumping, for all practical support. ",
"The authors would like to thank the World Cup athletes, coaches and medical team personnel who participated. ",
"The Oslo Sports Trauma Research Center has been established at the Norwegian School of Sport Sciences through generous grants from the Royal Norwegian Ministry of Culture, the South-Eastern Norway Regional Health Authority, the IOC and the Norwegian Olympic Committee and Confederation of Sport. ",
"The Injury Registration Form was based on the form 'Daily Report on Injuries and Illnesses' created by the IOC.",
"\n\n**Contributors:** OMRS, SFB and LE contributed to project planning. ",
"SFB and OMRS contributed to data collection. ",
"OMRS, SFB, RKM and LE contributed to manuscript preparations and data analysis. ",
"LE is responsible for the overall content as the guarantor.",
"\n\n**Funding:** This study was funded internally by the Oslo Sport Trauma Research Center.",
"\n\n**Competing interests:** None declared.",
"\n\n**Patient and public involvement statement:** Patients were not involved in designing the study.",
"\n\n**Patient consent for publication:** Not required.",
"\n\n**Ethics approval:** The study was approved by the FIS medical committee and reviewed by the South-Eastern Norway Regional Committee for Research Ethics and Norwegian Center for Research Data.",
"\n\n**Provenance and peer review:** Not commissioned; externally peer reviewed.",
"\n\n**Data availability statement:** All data relevant to the study are included in the article or uploaded as supplementary information.",
"\n"
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"\n\nForwards Gabriel Agbonlahor – who scored in Villa’s 1-0 win at Anfield in September – and Scott Sinclair are both expected to miss the game, along with long-term absentee Libor Kozak.",
"\n\nIn midfield, they’re expected to be without Carlos Sanchez, Ashley Westwood and new signing Carles Gil.",
"\n\nIn defence, Alan Hutton, Philippe Senderos, Cieran Clark and Aly Cissoko are all either doubts or definitely ruled out.",
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"A strategy for predicting prognosis from biopsy-based pathological evaluation has not been well established because of lack of reproducibility and inappropriate categorization. ",
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"1. ",
"Technical Field\nThe invention relates to apparatus and method for measuring cavitation energy profiles on devices placed in ultrasonic and megasonic cleaning systems.",
"\n2. ",
"Field of the Invention\nUltrasonic and megasonic cleaning systems are well known and are used in a wide variety of applications to clean various types of devices. ",
"Typically, a cleaning system has a tank with a cleaning bath that may consist of water with a cleaning material such as a detergent recommended and selected for use in cleaning particular types of devices. ",
"Ultrasonic and megasonic systems, sometimes referred to as agitation systems, have a transducer designed to generate high frequency vibrations in the cleaning tank in response to an electric input top the transducer. ",
"An ultrasonic cleaning system may operate in a range of 20 kHz to 400 kHz while a megasonic system may operate in a range of 500 kHz to 3 MHz.",
"\nIn operation, the transducer vibrations are introduced into the cleaning tank containing the bath and the device or devices to be cleaned. ",
"The introduced vibrations generate pressure gradients within the bath, which form cavitation bubbles in low-pressure areas. ",
"The bubbles begin to grow until entering a high-pressure region and then collapse against a surface of the device to be cleaned thereby dislodging contaminants. ",
"The implosion of the bubbles creates a strong force over a period of time to clean devices such as memory disks, semiconductor wafers, LCD and other like devices.",
"\nUltrasonic energy is a series of pressure points, or rather a series of compression and rarefaction. ",
"If the energy is of sufficient intensity, the cleaning liquid of the bath will actually be pulled apart and small bubbles or cavities will be formed. ",
"The bubbles collapse or implode throughout the cleaning fluid creating an effective force, which is uniquely suited to cleaning. ",
"This process is known as cavitation. ",
"Although the energy released from a single cavitation bubble is extremely small, the collapse of millions of bubbles produces an intense scrubbing action of the surface of the device to be cleaned. ",
"In many cleaning processes the control of cavitation energy is one of the most critical parameters affecting product yield. ",
"A problem arises in that if not enough energy is present on a surface location, the device will not be cleaned. ",
"Another problem arises in that if too much energy is present in one location the excessive force may damage the device being cleaned. ",
"One method of measuring cavitation is an indirect method that consists of exposing aluminum foil to the cavitation process and then examining the foil for dents and holes caused by the cavitation process. ",
"The current technology is limited to the measurement of the ultrasonic sound waves energy by the use of instructions called hydrophones. ",
"A problem with hydrophones systems arises in that they are limited to detecting only very low frequencies typically in the range of 40 kHz to 68 kHz. ",
"Thus, hydrophone systems act as a low-pass filter, which automatically filters out and removes the higher frequency cavitation energy. ",
"Neither of these methods measure the cavitation process at various locations within the cleaning bath. ",
"Accordingly, a need exists in the art for apparatus and a method for actively measuring the cavitation process at various locations in the cleaning bath during operation of removing contaminants from devices placed in the bath.",
"\nApparatus solves the foregoing problem by measuring the cavitation process at various locations in a cleaning bath during ultrasonic and megasonic sonic cleaning of devices placed in the cleaning bath.",
"\nIt is an object of this invention to provide apparatus for measuring the cavitation activity occurring in various locations in an ultrasonic and megasonic cleaning bath and for generating a profile of the cavitation process occurring at various locations on the surface of a device resident in the cleaning bath.",
"\nIt is also an additional object of this invention to provide probe apparatus having a plurality of probe sensors for measuring cavitation energy appearing at various locations in an ultrasonic and megasonic cleaning bath.",
"\nIt is also an additional object of this invention to provide apparatus coupled to each probe of the probe array immersed in an ultrasonic and megasonic cleaning bath for analyzing the voltage waveform generated by each probe and determining a cavitation energy profile occurring on surfaces of a device located in the bath.",
"\nIn the preferred embodiment of the invention apparatus for measuring cavitation energy of a bath resident in a tank of ultrasonic and megasonic cleaning systems has probe apparatus having an array of probes positioned within the bath for detecting the pressure formed by the collapse of bubbles at various locations within the bath that are generated by ultrasonic and megasonic vibrations applied to the bath and with each probe of the array generating an electrical waveform in response to the detection of the bubbles. ",
"Apparatus coupled to each probe of the probe array analyzes the voltage generated each probe and determines a cavitation energy profile occurring on surfaces of a device located in the bath."
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"\nThanks!",
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"Community managers: Ce qu’ils font & comment être un bon CM\n\nLes médias sociaux ont transformé les relations entre les individus et les organisations. ",
"C’est pourquoi le rôle des community managers est désormais si vital.",
"\n\nTwitter, avec ses 126 millions d’utilisateurs actifs quotidiens, est une plate-forme avec une tonne de potentiel pour les entreprises qui veulent accroître la notoriété et renforcer la personnalité de leur marque. ",
"Ces dernières années, de grands noms comme Netflix, Wendy’s et Taco Bell sont devenus célèbres sur Twitter pour leurs commentaires pleins d’esprit et leurs interactions agréables avec leurs abonnés.",
"\n\nTwitter n’est pas non plus la seule plateforme qui récompense l’engagement du public. ",
"En fait, 83% des consommateurs sur Facebook préfèrent la personnalité de la marque. ",
"Mais comment les entreprises peuvent-elles se forger une réputation originale, pertinente et fiable tout en conservant leur voix unique?",
"\n\nEn termes simples, les community managers doivent négocier le lien entre une entreprise et son public.",
"\n\nQu’est-ce qu’un Community Manager?",
"\n\nUn community manager sert de liaison entre une organisation et son public. ",
"Il agit en tant que voix, ton et modérateur de la marque grâce au soutien de la communauté, à la distribution de contenu et à l’engagement numérique pour renforcer la présence et la confiance de la marque, en ligne et en personne.",
"\n\n21% des consommateurs sont plus susceptibles d’acheter auprès de marques accessibles via les médias sociaux. ",
"Ce qui signifie que c’est un élément essentiel de votre stratégie marketing. ",
"Le poste de community manager renforce la personnalité de la marque et la confiance des consommateurs, ce qui peut finalement conduire à une sensibilisation accrue et une amélioration des performances de l’entreprise.",
"\n\nMais qu’est-ce qu’un community manager, de toute façon? ",
"Ici, nous allons explorer ce qu’est un community manager et – si vous postulez ou commencez dans ce rôle – comment être un excellent gestionnaire de communauté.",
"\n\nComment devenir community managers\n\nLes profils de community management viennent d’horizons divers – allant du recrutement au journalisme en passant par l’ingénierie – car réussir dans ce rôle repose davantage sur un ensemble de compétences que sur un diplôme.",
"\n\nTout d’abord, il est important pour les community managers de connaitre l’entreprise à fond l’entreprise pour laquelle ils travaillent. ",
"Les community managers doivent pouvoir s’appuyer sur leur expérience avec leur organisation pour s’adresser en toute confiance à leur public ou puiser dans les ressources internes pour gérer de manière appropriée les problèmes qui peuvent survenir. ",
"Au-delà d’une compréhension pratique de l’entreprise, les community managers doivent établir des relations productives et professionnelles à la fois en interne et en externe afin d’être un ambassadeur de marque plus authentique et fiable.",
"\n\nDescription du poste des community managers\n\nAfin de défendre et de préserver la marque d’une organisation, les community managers doivent avoir des compétences générales incroyablement solides. ",
"Surtout, l’empathie, de bonnes capacités d’écoute et l’adaptabilité sont cruciales pour promouvoir des impressions favorables d’une organisation.",
"\n\nAu-delà des compétences interpersonnelles, les meilleurs community managers recherchent activement les tendances et les sujets d’actualité. ",
"En s’engageant avec les derniers développements de l’industrie, les community managers sont mieux en mesure de se connecter avec les publics concernés et de leur fournir les ressources et les meilleures pratiques les plus à jour.",
"\n\nL’adaptabilité était une caractéristique importante pour la réussite dans le rôle. ",
"Puisque le poste est toujours en développement et que les community managers élaborent souvent leurs propres descriptions de travail. ",
"Etre flexible afin de s’adapter aux nouvelles tendances et attentes vous serviront à long terme.",
"\n\nEn fin de compte, les grands community managers comprennent que leur rôle est basé sur le service à la clientèle. ",
"Ils doivent écouter donc activement les clients, répondre aux préoccupations, démontrer une présence sociale authentique et entretenir des partenariats productifs avec les consommateurs. (",
"soyez un bon être humain pour votre public au nom de votre marque).",
"\n\nQue font les community Managers?",
"\n\nLes community managers sont responsables de la création et du maintien de la communauté d’une marque – en ligne et hors ligne – et de la perception du public. ",
"Le travail nécessite d’engager le public sur une variété de points de vente, y compris les forums en ligne, les plateformes de médias sociaux, Slack, les groupes et plus encore pour atteindre tous les publics la où ils se trouvent. ",
"Étant donné que les différents espaces numériques ont des cultures et des meilleures pratiques uniques, les community managers doivent être le ton et la voix cohérents de la marque.",
"\n\nEn tant que gestionnaire de communauté, toute la messagerie, le contenu et la gestion des crises sur les réseaux doivent être rapides, cohérents avec votre marque et empathiques pour créer une communauté fidèle et ravie.",
"\n\nLes relations publiques sont un autre principe de base de la gestion et de l’extension de l’audience d’une marque, car les community managers s’engagent avec toutes sortes de presse – à la fois positive et négative – générée au sujet de leur entreprise. ",
"La façon dont les gestionnaires gèrent les problèmes juridiques ou la presse négative peut séparer les bons community managers des grands. ",
"Les faux pas dans ce rôle peuvent nuire réellement à une marque, donc la connexion avec les équipes juridiques, relations presse ou liées de votre organisation peut aider à atténuer les problèmes et à vous assurer que les réponses sortent de manière appropriée.",
"\n\nDe plus, les grands community managers réfléchissent constamment à la manière dont ils pourraient expérimenter. ",
"Une tactique ou un test ne fonctionnera pas la première fois, mais ne vous découragez pas. ",
"Les progrès prennent du temps, les community managers doivent penser à long terme. ",
"Plus vous investissez dans une stratégie améliorée, une nouvelle orientation ou le poste lui-même, plus vous en tirerez profit.",
"\n\nDe plus, une ressource facilement oubliée est un réseau externe d’autres community managers! ",
"Trouver d’autres personnes dans des postes similaires peut être très utile pour externaliser des solutions éclairées ou s’appuyer sur d’autres personnes expérimentées qui ont géré des situations similaires dans le passé.",
"\n\nL’expérience de s’engager avec une communauté numérique peut être volatile. ",
"Un jour pourrait être plein de discussions positives et enrichissantes, tandis que le lendemain pourrait être traqué par des plaintes et des utilisateurs mécontents. ",
"Il est important que les community managers maintiennent et contrôlent les émotions afin de gérer les différents problèmes qui surviennent.",
"\n\nS’appuyant sur l’utilité d’un ensemble de compétences en relations publiques, les community managers doivent être vigilants quant à la présence de la marque de leur organisation et évaluer les conséquences potentielles de leurs communications d’entreprise. ",
"La présence de la marque inclut la cohérence de la voix sur toutes les plateformes pour garder l’entreprise sur la bonne voie en termes de sensibilisation et d’engagement du public cible. ",
"Les consommateurs devraient être en mesure de reconnaître la voix de la marque sur tous les piliers, qu’ils voient une publication sur Instagram ou une question sur Quora.",
"\n\nAu-delà de l’interaction directe entre la marque et son public, les community managers enregistrent et rapportent également l’engagement qu’ils voient au moins une fois par mois. ",
"Les autres équipes qui créent du contenu opèrent principalement sur le backend. ",
"C’est donc les community managers qui voient la réponse des consommateurs. ",
"Ils peuvent aider à savoir si les abonnés sont confus ou quels types de changements ils observent au sein des communautés numériques. ",
"Il faut développer une intuition sur la psychologie du public de l’entreprise, et pouvoir donc évoluer et modifier sa stratégie de sensibilisation afin de s’engager le plus efficacement possible auprès des publiques cibles.",
"\n\nEn outre, les community managers gardent à l’esprit leur public idéal, façonnant le contenu et les communications pour cibler le bon public plutôt que d’en construire simplement un plus large.",
"\n\nEnfin, les grands community managers ravissent leur communauté! ",
"En établissant des relations positives avec les membres de votre communauté – qu’ils aient une impression positive de la marque ou une image négative – vous construisez une perception de marque fiable et digne de confiance."
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[
"# Translation of Odoo Server.",
"\n# This file contains the translation of the following modules:\n# \t* social_media\n# \n# Translators:\n# Martin Trigaux, 2019\n# Yihya Hugirat <[email protected]>, 2019\n# ZVI BLONDER <[email protected]>, 2020\n# \nmsgid \"\"\nmsgstr \"\"\n\"Project-Id-Version: Odoo Server 13.0\\n\"\n\"Report-Msgid-Bugs-To: \\n\"\n\"POT-Creation-Date: 2020-04-27 09:22+0000\\n\"\n\"PO-Revision-Date: 2019-08-26 09:14+0000\\n\"\n\"Last-Translator: ZVI BLONDER <[email protected]>, 2020\\n\"\n\"Language-Team: Hebrew (https://www.transifex.com/odoo/teams/41243/he/)\\n\"\n\"MIME-Version: 1.0\\n\"\n\"Content-Type: text/plain; charset=UTF-8\\n\"\n\"Content-Transfer-Encoding: \\n\"\n\"Language: he\\n\"\n\"Plural-Forms: nplurals=4; plural=(n == 1 && n % 1 == 0) ? ",
"0 : (n == 2 && n % 1 == 0) ? ",
"1: (n % 10 == 0 && n % 1 == 0 && n > 10) ? ",
"2 : 3;\\n\"\n\n#. ",
"module: social_media\n#: model:ir.model,name:social_media.model_res_company\nmsgid \"Companies\"\nmsgstr \"חברות\"\n\n#. ",
"module: social_media\n#: model:ir.model.fields,field_description:social_media.field_res_company__social_facebook\nmsgid \"Facebook Account\"\nmsgstr \"חשבון פייסבוק\"\n\n#. ",
"module: social_media\n#: model:ir.model.fields,field_description:social_media.field_res_company__social_github\nmsgid \"GitHub Account\"\nmsgstr \"חשבון GitHub \"\n\n#. ",
"module: social_media\n#: model:ir.model.fields,field_description:social_media.field_res_company__social_instagram\nmsgid \"Instagram Account\"\nmsgstr \"חשבון אינסטגרם\"\n\n#. ",
"module: social_media\n#: model:ir.model.fields,field_description:social_media.field_res_company__social_linkedin\nmsgid \"LinkedIn Account\"\nmsgstr \"חשבון לינקדאין\"\n\n#. ",
"module: social_media\n#: model_terms:ir.ui.view,arch_db:social_media.view_company_form_inherit_social_media\nmsgid \"Social Media\"\nmsgstr \"רשת חברתית\"\n\n#. ",
"module: social_media\n#: model:ir.model.fields,field_description:social_media.field_res_company__social_twitter\nmsgid \"Twitter Account\"\nmsgstr \"חשבון טוויטר\"\n\n#. ",
"module: social_media\n#: model:ir.model.fields,field_description:social_media.field_res_company__social_youtube\nmsgid \"Youtube Account\"\nmsgstr \"חשבון יוטיוב\"\n"
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[
"[alert color=”yellow”]Issue #1 of my Newsletter comes out at the end of this month! ",
"It’ll be a monthly publication, include the top articles worth reading, and will have a few extra tips to help you. ",
"Be sure to subscribe to get it (and other cool perks, like free guides!)![/alert]\n\nEvery iOS developer inevitably runs into two common issues during development:\n\nThings begin slowing down, bringing with it noticeable stuttering and delays.",
"\n\nCrashes emerge from ballooning memory usage.",
"\n\nWe want our apps to be amazing, right? ",
"While there are other issues that can haunt development, those two can turn the tide against us quickly. ",
"Apple provides a great monitoring tool called instruments. ",
"Instruments give us the ability to watch a wide array of areas within our app. ",
"This helps to pinpoint what exactly could be causing a particular problem.",
"\n\nIf you’re new to the iOS landscape I encourage you to experiment with instruments. ",
"In this post we’re going to cover the 3 instruments I routinely use with every app I lay my hands on. ",
"By the time you’ve finished this article you’ll know how to tackle the performance side of iOS development.",
"\n\nYou’ll learn how to use the Time Profiler to measure the time it takes to execute code.",
"\n\nYou’ll see how quickly memory can add up, potentially crashing your app, by using the Allocation instrument.",
"\n\nYou’ll discover that ARC (automatic reference counting) isn’t so automatic when we dive into the Leaks instrument.",
"\n\nThe Example App\n\nI built this example app with the purpose of highlighting the areas these instruments target. ",
"My hope is that you can get a sense of how the instruments behave. ",
"One of the things that confused me early was just figuring out what I was looking at.",
"\n\nGrab the same project & follow along!",
"\n\n[alert color=”yellow”]Grab the same project from github.com & follow along![/alert]\n\nIntroducing the Time Profiler\n\nI touched on measuring speed in my article 10 Actionable Performance Tips To Speed Up Your Table View. ",
"The Time Profile instrument captures stack trace information depending on interval (default is 1ms). ",
"It provide a decent approximation for how much time a given method took by comparing the state of the stack trace against the interval.",
"\n\nSorting\n\nIn the following example we’re exploring two sorting algorithms; insertion sort, and bubble sort.",
"\n\n/* Reference: http://waynewbishop.com/swift/sorting-algorithms/ */ func insertionSort() { var x, y, key: Int for (x = 0; x < numberList.count; x++) { key = numberList[x] for (y = x; y > -1; y--) { if key < numberList[y] { numberList.removeAtIndex(y + 1) numberList.insert(key, atIndex: y) } } } } func bubbleSort() { var x, y, z, passes, key : Int for (x = 0; x < numberList.count; ++x) { passes = (numberList.count - 1) - x; for (y = 0; y < passes; y++) { key = numberList[y] if (key > numberList[y + 1]) { z = numberList[y + 1] numberList[y + 1] = key numberList[y] = z } } } } 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 /* Reference: http://waynewbishop.com/swift/sorting-algorithms/ */ func insertionSort ( ) { var x , y , key : Int for ( x = 0 ; x < numberList . ",
"count ; x ++ ) { key = numberList [ x ] for ( y = x ; y > - 1 ; y -- ) { if key < numberList [ y ] { numberList . ",
"removeAtIndex ( y + 1 ) numberList . ",
"insert ( key , atIndex : y ) } } } } func bubbleSort ( ) { var x , y , z , passes , key : Int for ( x = 0 ; x < numberList . ",
"count ; ++ x ) { passes = ( numberList . ",
"count - 1 ) - x ; for ( y = 0 ; y < passes ; y ++ ) { key = numberList [ y ] if ( key > numberList [ y + 1 ] ) { z = numberList [ y + 1 ] numberList [ y + 1 ] = key numberList [ y ] = z } } } }\n\nThe example will give you a general awareness of the impact adding and removing items with an array can have. ",
"The methods themselves may not take a lot of time, but behind the scenes there is a lot going on.",
"\n\n\n\nSo what in the world is going on here? ",
"In this case we have a situation where what we are doing is causing the system to perform a lot of tasks behind the scenes. ",
"We are seeing a lot of indirect dependencies that our code needs. ",
"Everything in the list above is a system library that our code relies upon. ",
"Dealing with large data sets can be expensive, so offload heavy operations into the background. ",
"If you haven’t noticed yet, this code is on a background thread. ",
"In the above call stack you’ll see dispatch_worker_thread3. ",
"If you were to execute this code on the main thread your app would come to a standstill.",
"\n\nIn fact. ",
"Try it.",
"\n\nGrab the sample app and remove the dispatch_async calls. ",
"This will keep everything on the same thread. ",
"You’ll notice is that the status label doesn’t update until a few seconds after you launch the screen.",
"\n\nImage Loading\n\nOur second example now focuses on image loading.",
"\n\n\n\nHere we have 3 image loading methods.",
"\n\nloadSlowImage1 : Downloads an image from a given URL path\n\nloadImage2 : Loads an image from the local bundle (important: this is not cached by the system)\n\nloadFastImage3 : Loads an image that is cached by the system\n\nTo verify we get the speed we expected we can run the time profiler to look at a few things. ",
"In this example I load up the second example in the list (image loading) and reload it 10 times. ",
"This’ll give us a good amount of data to look at. ",
"I then zone in on the area that I care about (as you can see from the selection area). ",
"If we double click on the reload method (the line I have highlighted above), we’ll move to our code to check time spent there.",
"\n\n\n\nWith the image above you can see where the app spent the most time. ",
"There isn’t much you can do with optimization here, but you can recognize the value of caching. ",
"If you’re needing to call loadSlowImage: many times it pays to cache that image away so you’re not doing so much.",
"\n\nAdditional Notes\n\nA few things to point out with this instrument.",
"\n\n\n\nThese options are not selected by default. ",
"When you launch this instrument you’ll want to make sure to select them. ",
"This will help you find your methods (which will likely the main issue).",
"\n\nSeparate by Thread : You really want to isolate operations per thread so you know which thread is the issue. ",
"This is especially important for the main thread (where all of the interface drawing happens). ",
"Blocking the main thread is the #1 reason for stuttering and freezing.",
"\n\n: You really want to isolate operations per thread so you know which thread is the issue. ",
"This is especially important for the main thread (where all of the interface drawing happens). ",
"Blocking the main thread is the #1 reason for stuttering and freezing. ",
"Invert Call Tree : You want to see the most expensive operations. ",
"This flips the call tree to show you the methods that were originally started with.",
"\n\n: You want to see the most expensive operations. ",
"This flips the call tree to show you the methods that were originally started with. ",
"Hide Missing Symbols : This will help declutter your view. ",
"Basically, if the dSYM file cannot be found (or system framework), you’ll see strange hex values that are useless. ",
"This option will hide those.",
"\n\n: This will help declutter your view. ",
"Basically, if the dSYM file cannot be found (or system framework), you’ll see strange hex values that are useless. ",
"This option will hide those. ",
"Hide System Libraries : This option will let you focus on the symbols that are directly relevant to your code.",
"\n\n: This option will let you focus on the symbols that are directly relevant to your code. ",
"Flatten Recursion : Instead of seeing a recursive function as multiple entries (since a recursive function calls itself), you’ll see a single entry.",
"\n\n: Instead of seeing a recursive function as multiple entries (since a recursive function calls itself), you’ll see a single entry. ",
"Top Functions: This will let you focus on your most time consuming methods.",
"\n\nAdditionally. ",
"The first image produce results for the entire time we tested. ",
"Often times you need to focus in on an area. ",
"To do that hold Option and Click > Drag on the timeline (showed above). ",
"This is a much easier way to focus in on what matters.",
"\n\nForget an instrument?",
"\n\n\n\n\n\nYou can click the plus icon anytime to add an instrument.",
"\n\nHello Allocations\n\nOften times, especially with photo apps, you’ll run into scenarios where you must download a lot of images from a server. ",
"If you’re not careful memory usage can balloon dramatically. ",
"You must make sure that you are caching images to the side that you expect to reuse. ",
"Let’s look at the memory usage of our image example above.",
"\n\n\n\n\n\nHere you can see spikes of memory usage each time we press reload. ",
"We allocate a bunch of memory, replacing existing images, which then deallocate the memory we were using. ",
"As you can imagine this is highly inefficient. ",
"Imagine if we were downloading much bigger files.",
"\n\nIf you look at the line ImageIO_PNG_Data you can see that we have 9 active image objects consuming 12.38 MB of memory. ",
"This is ballooning our heap memory allocation, which is memory that is not being released/cached by the system. ",
"If you look at how a caching library works you’ll see this in action.",
"\n\n\n\nIn this example I’m using a caching library. ",
"I still pressed reload 5 times, but you’ll notice that we’re not holding onto any image data objects (ImageIO_PNG_Data). ",
"Our heap size is only 2.51 MB compared to 14.61 MB in the previous example. ",
"Anonymous virtual memory is the system trying to be smart by keeping a chunk of memory available in anticipation that we’ll immediately use it again. ",
"To prevent crashes you want to avoid your heap from ballooning at a rapid pace.",
"\n\nYou’ll also notice by loading our images asynchronously we’re not waiting for all the images to download to reveal them (like first allocation example). ",
"Most image caching libraries kicks this work to the background so you’re not spending precious main thread cycles. ",
"I’m using a Swift library Haneke for this example.",
"\n\nLeaking Memory\n\nEven though Apple introduced Automatic Reference Counting (ARC), you need to be aware that the potential for leaks do remain. ",
"It’s not a bullet proof system! ",
"Even if you’re using Swift.",
"\n\nExplaining how memory works is beyond the scope of this article so please make the jump to Apple’s documentation to review more about ARC and memory. ",
"Visit the article and type the examples so that you have deep understanding of how this works.",
"\n\nI do want to share one basic example so that you can see a leak in action. ",
"First, on the most fundamental level a leak happens when you create objects that have a strong reference to each other. ",
"When one object is released, the other object is not allowed to be released since it’s also classified strong.",
"\n\nIn the given example we have 2 objects. ",
"They both have a variable that own a strong reference to each other. ",
"When we release one of them we fail to remove the reference from the other. ",
"This leads to a memory leak since ARC can’t determine if we were officially done with the remaining object.",
"\n\n\n\nWe fix this by assigning weak to one of the variables so that it doesn’t add a retain cycle.",
"\n\nI often see leaks bite developers when it comes to view controller management. ",
"They may think they moved to a new controller, releasing the old controller, but it was never deallocated. ",
"This can leave a ton of objects behind. ",
"It pays to just run through your app with the leaks tool to clean up any inadvertent strong reference cycles.",
"\n\nOther Instruments\n\nBy no means are these the only instruments you should spend time with. ",
"Apple has provided several worthwhile instruments that can help you with your development. ",
"It really depends on what you’re doing and where you need insight.",
"\n\nCore Data : Examines fetches, cache misses, and saves. ",
"This is a great way to visually see if you’re saving far more frequently than needed.",
"\n\n: Examines fetches, cache misses, and saves. ",
"This is a great way to visually see if you’re saving far more frequently than needed. ",
"Cocoa Layout : Observes constraint changes to help you determine where layout code broke.",
"\n\n: Observes constraint changes to help you determine where layout code broke. ",
"Network : Observes TCP/IP and UDP/IP connections\n\n: Observes TCP/IP and UDP/IP connections Automation : Lets you create and edit test scripts to automate user interface tests in your iOS app And many more. ",
"I assume you will primarily use the above instruments, but feel free to spend time getting to know the others I didn’t list.",
"\n\nWrapping up\n\nTo be very clear, I don’t want to advocate pre-mature optimization. ",
"Don’t worry about using these tools if you are not experiencing slowness with your app. ",
"Unless you have some time to do sanity checks. ",
"When you start to notice choppy behavior then dive into a few instruments to determine where things are going awry.",
"\n\nTakeaway\n\nIf you’re a beginner it pays to spend time with instruments to get a feel for how it all works. ",
"This will set you up for a much smoother experience in the future when things really matter! ",
"These are invaluable tools that will help you create an even better user experience. ",
"Given the high bar that exists on the app store it pays to focus your attention on making a smooth experience.",
"\n\nYour Turn\n\nWhat are your top 3 instruments? ",
"Any helpful tips?",
"\n\n[alert color=”yellow”]Reminder: Issue #1 of my Newsletter comes out at the end of this month! ",
"It’ll be a monthly publication, include the top articles worth reading, and will have a few extra tips to help you. ",
"Be sure to subscribe to get it (and other cool perks, like free guides!)![/alert]"
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" UNPUBLISHED\n\n UNITED STATES COURT OF APPEALS\n FOR THE FOURTH CIRCUIT\n\n\n\n No. ",
"97-4859\n\n\n\nUNITED STATES OF AMERICA,\n\n Plaintiff - Appellee,\n\n versus\n\n\nDMITRY BRON,\n\n Defendant - Appellant.",
"\n\n\n\nAppeal from the United States District Court for the Eastern Dis-\ntrict of Virginia, at Norfolk. ",
"Raymond A. Jackson, District Judge.",
"\n(CR-96-176)\n\n\nSubmitted: February 26, 1998 Decided: June 2, 1998\n\n\nBefore WILKINS, NIEMEYER, and HAMILTON, Circuit Judges.",
"\n\n\nDismissed by unpublished per curiam opinion.",
"\n\n\nAndrew Michael Sacks, SACKS & SACKS, Norfolk, Virginia, for Appel-\nlant. ",
" Janet S. Reincke, OFFICE OF THE UNITED STATES ATTORNEY,\nNorfolk, Virginia, for Appellee.",
"\n\n\nUnpublished opinions are not binding precedent in this circuit.",
"\nSee Local Rule 36(c).",
"\n\fPER CURIAM:\n\n Appellant filed an untimely notice of appeal. ",
"We dismiss the\n\nappeal for lack of jurisdiction. ",
"The time periods for filing\n\nnotices of appeal are governed by Fed. ",
"R. App. ",
"P. 4. ",
"These periods\n\nare \"mandatory and jurisdictional.\" ",
"Browder v. Director, Dep't of\n\nCorrections, 434 U.S. 257, 264 (1978) (quoting United States v.\n\nRobinson, 361 U.S. 220, 229 (1960)). ",
"A defendant appealing his\n\ncriminal conviction must file his notice of appeal in the district\n\ncourt within ten days after the entry of the judgment. ",
"Fed. ",
"R. App.",
"\n\nP. 4(b).",
"\n\n The district court entered its order on October 8, 1997.",
"\n\nAppellant's notice of appeal was filed on October 30, 1997. ",
"Appel-\n\nlant's failure to file a timely notice of appeal or to obtain\n\neither an extension or a reopening of the appeal period leaves this\n\ncourt without jurisdiction to consider the merits of Appellant's\n\nappeal. ",
"We therefore dismiss the appeal. ",
"We grant Appellant's mo-\n\ntion to extend time to file his response to the Government's motion\n\nto dismiss. ",
"We deny counsel's motion to withdraw, Appellant's\n\nmotions to relieve counsel and to obtain copies of his presentence\n\nreport and transcripts, and the Government's motion to dismiss the\n\nappeal. ",
"We dispense with oral argument because the facts and legal\n\ncontentions are adequately presented in the materials before the\n\ncourt and argument would not aid the decisional process.",
"\n\n\n\n\n 2\n\f DISMISSED\n\n\n\n\n3\n\f"
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"\n\nThe company, the largest Canadian railroad operator, offered the Teamsters Canadian Rail Conference a binding arbitration, which the union declined, CN’s Chief Operating Officer Rob Reilly said in a statement.",
"\n\n“If a settlement cannot be reached this weekend, we will once again encourage the union leadership to accept binding arbitration as an alternative to disrupting the Canadian economy,” Reilly said.",
"\n\n“We remain committed to constructive talks to reach an agreement without a work stoppage,” he added.",
"\n\nThe union did not immediately respond to a request for comment.",
"\n\nCanada, one of the world’s biggest exporters of farm products, relies on its two main railways to move canola and wheat over the vast distances from western farms to ports. ",
"Crude oil shippers in Alberta have also increasingly used trains in the past year to reach U.S. refineries as an alternative to congested pipelines.",
"\n\nCN’s estimated 3,000 conductors, trainpersons and yardpersons voted in favour of strike action in September, after negotiations failed to produce a contract. ",
"The previous collective agreement expired on July 23, 2019.",
"\n\nCN said on Friday it would cut management and union jobs, as it grapples with an economic slowdown. ",
"The company will lay off 1,600 employees in the United States and Canada, according to a report by the Globe and Mail. (",
"Reporting by Akshay Balan in Bengaluru, Allison Lampert in Montreal Additional reporting by Rod Nickel in Winnipeg Editing by Frances Kerry)"
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"Clinical trials of oral type II collagen (CII) in patients with rheumatoid arthritis (RA) have yielded somewhat conflicting and controversial results. ",
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"Basic studies in murine models have clearly shown that NSAIDs markedly inhibit immune tolerance induction to certain orally administered antigens. ",
"Our preliminary studies in the DBA/1 mouse CII-induced arthritis (CIA) models show that oral tolerance to bovine VII is markedly impaired in mice concomitantly fed oral NSAID. ",
"To adequately evaluate the effect of oral CII tolerance induction on clinical and immune parameters in RA patients, we propose that patients will have to be withdrawn from daily NSAIDs, which our animal data suggest interfere with the ability of the gut associated lymphoid tissue (GALT) to mount a tolerogenic response to orally administered CII. ",
"We, therefore, hypothesize that daily oral CII will induce tolerance to CII in RA patients off NSAIDs and other disease modifying anti-rheumatic drugs (DMARDs). ",
"The four Specific Aims of this application will 1) determine by use of a \"balanced incomplete block design\" which, if any, of 3 different doses of bovine CII (20 microgram/day) are superior in efficacy to a standard NSAID in RA patient with early disease; 2) determine in RA patients with demonstratable immunity to CII whether clinical improvement as a result of oral CII therapy is accompanied by a reduction in CII immunity; 3) determine in RA patients exhibiting a clinical response to oral CII treatment whether the peripheral blood T cell cytokine response to CII is altered; and 4) determine whether specific HLA-DR or-DQ genotypes are associated with a clinical response to oral CII treatment or with the presence of immunity to CII at entry into the study. ",
"In summary, by withdrawing NSAIDs, which interfere with oral tolerance induction, from RA patients we believe this study will fully explore the therapeutic potential of oral CII tolerance induction in RA."
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"1. ",
"Technical Field\nThe present invention generally relates to reliable distributed computing, and more particularly to transaction processing. ",
"Specifically, the present invention relates to a method of insuring that a desired transaction either happens exactly once in entirety or not at all, even when there is a partial system failure while the transaction is processed.",
"\n2. ",
"Description of Related Art\nA desirable feature of a computing system is the ability to recover from partial system failures A partial system failure occurs, for example, when the system \"crashes\" due to an infrequent software error in the operating system, and the operating system can be restarted. ",
"If an application program has a memory write operation in progress at the time of the system failure, it is most likely that the memory record will become erroneous. ",
"To enable the recovery of memory records after a partial system failure, it is necessary for the application program to keep backup copies of the records in nonvolatile memory. ",
"When the operating system is restarted, the memory records to be recovered are replaced with the backup copies. ",
"Then the application program must be restarted to repeat the operations having occurred after the backup copies were made.",
"\nTo facilitate the making of backup copies and the recovery of memory records, the operating system typically provides an established set of memory management procedures that can be invoked or called from an application program. ",
"A typical example is a \"recovery unit journaling\" feature of Records Management Services (RMS) software sold by Digital Equipment, Corporation, Maynard, MA 01754, for use with the VAX/VMS operating system. ",
"To provide for recovery of a memory record, an initial portion of an application program allocates nonvolatile memory for backup copies by invoking an RMS procedure called by the program statement \"$SET FILE [FILENAME]/RU.sub.-- JOURNAL\" where FILENAME is the name of the file including the memory record to be recovered. ",
"To actually make a backup copy and to define the beginning of a \"recovery unit,\" the application program invokes an RMS procedure called by the statement \"$START.sub.-- RU\". ",
"To define the end of a \"recovery unit,\" the application program invokes an RMS procedure called by the statement \"$COMMIT.sub.-- RU\". ",
"If a partial system failure occurs during execution of the \"recovery unit,\" then the memory record is recovered from the backup copy.",
"\nA \"recovery unit\" is comprised of a set of program\nstatements between the \"$START.sub.-- RU\" statement and the \"$COMMIT.sub.-- RU\" statement. ",
"All of the statements in the \"recovery unit\" must be completed before the memory records modified by the statements in the recovery unit are made available for subsequent processing. ",
"In other words, the statements in the \"recovery unit\" specify operations in a single \"transaction.\" ",
"The operations in a \"transaction\" are either all completed at once, or none of them is completed.",
"\nThe operations in a transaction may modify multiple files in different data bases which could be accessed by multiple processors or nodes in a distributed computing system. ",
"In this case, when one processor or node is performing a transaction which modifies a respective set of files, none of the other processors may modify that set of files. ",
"Therefore, the application program can ensure internal consistency of the data stored in the files. ",
"By defining a group of related operations as a recovery unit, for example, a transfer of funds involving the debiting of a first account and the crediting of a second account, the programmer can ensure that all of the operations in the transaction will be complete before the updated records are made available for further use.",
"\nIn the event of a partial system failure or other abnormal termination (such as a system \"reset\") of an application program, the files defined as recoverable will be recovered or updated only to the most recently completed recovery unit, and the data in the files will be consistent. ",
"For example, in a transfer of funds application, a system failure will not cause the first account to be debited without the crediting of the second account.",
"\nIn a typical \"transaction processing\" system the states of the \"objects\" manipulated by the transaction are deemed to be whatever is recorded in permanent memory. ",
"In a multiprocessor system, for example, a typical method of communication is by shared access to a common permanent memory holding the states of the objects. ",
"To restore the state of the system after \"crash\" of any one of the processors, the memory management procedure for recovery unit journaling performs a well-known \"state restoration method.\"",
"\nIn the state restoration method, the \"START\" operation causes \"write locks\" to be put on the permanent memory records for all of the objects manipulated by the respective transaction. ",
"The \"START\" operation then causes the states of the objects to be saved in the permanent memory records which hold the states of the objects, and the records are copied so that a copy is kept for modification during execution of the recovery unit. ",
"Then the transaction defined by the recovery unit is performed upon the copy kept for modification. ",
"When the transaction is finished, the \"COMMIT\" operation causes the states in permanent memory of all of the objects manipulated by the recovery unit to be updated, in one \"atomic\" step, with the modifications having been made during the transaction. ",
"Finally, the write locks on the permanent memory records having been updated are released.",
"\nIt should be apparent that the implementation of the state restoration method involves only one difficult step, which is the \"atomic\" step of updating the permanent memory states of all objects manipulated by the recovery unit. ",
"By definition, an \"atomic\" step is a step that is performed in its entirety, or not at all, regardless of a partial system failure or abnormal termination of the application program. ",
"Although such an \"atomic step\" could be performed directly by a specially designed memory unit, it can also be performed indirectly in any conventional computing system by allocating two permanent memory records for every object manipulated during a transaction, and allocating an additional permanent memory location as a flag or switch indicating which permanent memory record holds the permanent state of the object; the other permanent memory record is used whenever the volatile state of the object is written to permanent memory. ",
"Therefore, the updating of the permanent memory state of all objects manipulated by the recovery unit can be performed in one atomic step by execution of a single machine instruction that changes the flag or switch for the permanent memory records of the objects modified by the transaction.",
"\nIn the above implementation, a \"partial system failure\" is any failure which insures that the single machine instruction is either completed in its entirety or not at all. ",
"The \"START\" operation write locks the respective permanent memory files defined for a respective processor against access by other processors, and saves the respective files by causing any write operations to be performed upon copies in respective permanent memory flagged for use whenever writing to permanent memory. ",
"The \"COMMIT\" operation switches the flag for the respective files, and finally removes the write locks.",
"\nAs described above, the state restoration method insures that the updates made by any given processor are made consistently, even when a crash may prevent all of the updates from being made at any given node. ",
"A more difficult problem is ensuring that after a crash, the state of the system can be automatically restored and processing may continue until completion with the assurance that the transactions interrupted by the crash are completed exactly once. ",
"For some transactions, at-least-once semantics is acceptable. ",
"For example, a transaction that updates the mailing addresses of newspaper subscribers could be performed more than once without any adverse consequences. ",
"In other transactions, however, exactly-once semantics is crucial. ",
"In a financial accounting system, for example, a transaction that debits one account and credits another must be performed exactly once for each real-world financial transaction.",
"\nExactly-once semantics has been assured by using procedures such as the \"two-phase commit protocol\" and its derivations. ",
"These procedures are described in J. Eliot B. Moss, Nested Trasactions--An Approach to Reliable Distributed Computing, The MIT Press, Cambridge, Mass., 1985. ",
"The \"two-phase commit protocol\" permits a recovery with exactly-once semantics even though updates to files are performed by a number of different processors in a system. ",
"Typically in such a system each transaction is assigned a unique \"transaction identification number\" and each object is assigned a unique \"object identification number\" so that the respective operation to be performed or acknowledged for a transaction by any given processor can be signalled by the receipt or transmission of the transaction identification number, and the changes to the state of an object can be communicated along with the object identification number. ",
"One processor in the system is assigned the role of a coordinator which initiates a transaction. ",
"To begin a transaction, the coordinator sends a prepare command to all of the processors participating in the transaction.",
"\nUpon receipt of the \"prepare\" command, each processor participating in the transaction performs the \"START\" operation described above, writes the transaction ID into permanent memory to remember that it is prepared for the transaction, and then sends an acknowledgment back to the coordinator processor, but does not yet perform its part of the transaction. ",
"The coordinator waits for acknowledgments from all of the participants. ",
"When the coordinator receives acknowledgments from all of the participants, the coordinator records in permanent memory a list of the participants and a notation that the transaction is now being completed.",
"\nThe coordinator then sends \"commit\" commands to all of the participants. ",
"Upon receipt of the \"commit\" commands, each participant checks its permanent memory for the transaction ID to determined whether it has been prepared for the transaction, and if it has, it performs its part of the transaction, and then performs the \"COMMIT\" operation described above (which in the process clears the transaction ID from permanent memory when permanent memory is updated), and finally sends an acknowledgment back to the coordinator; if the transaction ID cannot be found in permanent memory, the participant just sends an acknowledgment back to the coordinator. ",
"When the coordinator receives acknowledgments from all of the participants, it erases the list of participants from permanent memory, and the transaction is finished.",
"\nIf a crash occurs during the transaction, then the coordinator may use its list of participants to ensure completion of any transaction that was being completed but which did not finish. \"",
"Commit\" commands are retransmitted to each of the participants included in the list. ",
"Any participant that did not complete its portion of the transaction because of the crash (as indicated by its permanent memory having a record of preparation for the transaction ID) will complete its portion for the first time. ",
"Any participant that had already completed its portion of the transaction (as indicated by its permanent memory having no record of preparation for the transaction ID) will not repeat its portion of the transaction. ",
"Therefore, the two-phase commit protocol ensures that all portions of an interrupted transaction are performed exactly once when the recovery is finished."
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"Q:\n\nProblems scraping web page in R\n\nI'm tryig to scrape an specific location of a web page using XPath to find it. ",
"\nThe path seems to be \"hidden\" as other parts of the web page are easily reachable, but this section returns a NULL value.",
"\nI've tried using several packages, but i'm really not an expert in the subject so i can't really assess what's going on and if the is a way to solve it.",
"\nThis is what i've tried.",
"\nrequire(\"XML\")\nrequire(\"scrapeR\")\nrequire(\"httr\")\n\nurl <- \"http://www.claro.com.ar/portal/ar/pc/personas/movil/eq-new/?eq=537\"\nxp <- '//*[@id=\"dv_MainContainerEquiposResumen\"]/div[1]/h1'\n\npage <- scrape(url)\nxpathApply(page[[1]], xp, xmlValue)\n# NULL\n\nurl.get = GET(url)\nxpathSApply(content(url.get), xp)\n# NULL\n\nwebpage = getURL(url)\ndoc = htmlTreeParse(webpage, error=function(...){}, useInternalNodes = TRUE)\nxpathSApply(doc, xp)\n# NULL\n\nA:\n\nYou can scrape the page using Selenium and the RSelenium package:\nurl <- \"http://www.claro.com.ar/portal/ar/pc/personas/movil/eq-new/?eq=537\"\nxp <- '//*[@id=\"dv_MainContainerEquiposResumen\"]/div[1]/h1'\nrequire(RSelenium)\nRSelenium::startServer()\nremDr <- remoteDriver()\nremDr$open()\nremDr$navigate(url)\nwebElem <- remDr$findElement(value = xp)\n> webElem$getElementAttribute(\"outerHTML\")[[1]]\n[1] \"<h1>Samsung Galaxy Core</h1>\"\n> webElem$getElementAttribute(\"innerHTML\")[[1]]\n[1] \"Samsung Galaxy Core\"\nremDr$close()\nremDr$closeServer()\n\n"
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"/*\n** fscheck\n** The Sleuth Kit \n**\n** Brian Carrier [carrier <at> sleuthkit [dot] org]\n** Copyright (c) 2004-2005 Brian Carrier. ",
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"\n10 B.R. 76 (1981)\nIn re Elizabeth M. BRASINGTON, Robert W. Brasington, III, Debtors.",
"\nVon G. MEMORY, Trustee, Plaintiff,\nv.\nElizabeth M. BRASINGTON, Robert W. Brasington, III, Defendants.",
"\nBankruptcy No. ",
"80-01740.",
"\nUnited States Bankruptcy Court, M.D. Alabama.",
"\nMarch 6, 1981.",
"\n*77 Von G. Memory, Trustee, Montgomery, Ala., for plaintiff.",
"\nBob E. Allen, Montgomery, Ala., for defendants.",
"\n\nOPINION AND ORDER ON TRUSTEE'S MOTION OBJECTING TO HOMESTEAD EXEMPTION\nRODNEY R. STEELE, Bankruptcy Judge.",
"\nOn January 28, 1981, Von G. Memory, Trustee in bankruptcy, filed a Motion objecting to the Debtors' claim for a homestead exemption.",
"\nAn Order setting the Motion for hearing was issued on February 2, 1981, and set the date for hearing at 2:00 p.m., February 23, 1981, at Montgomery, Alabama. ",
"Notice was supplied to the Trustee and to the Debtors and their attorney.",
"\nThe Motion was called at the appointed time and place. ",
"Present were the Trustee, the Debtors and their attorney. ",
"Testimony was taken from Jan Wilson, Jill Wilson and Elizabeth Brasington.",
"\nThe issue before the Court is whether the Debtor's claim to homestead exemption in property located at 3103 LeBron Road in Montgomery, Alabama should be allowed under applicable law.",
"\n\nFINDINGS OF FACT\nThe Brasingtons listed their home at 3103 LeBron Road for sale in May of 1980. ",
"They hired Jill Wilson, a realtor with Sawyer Group as their agent. ",
"They were attempting to sell the house to pay some debts, including debts for improvement of the home at 3103 LeBron which improvement debts ultimately amounted to over $100,000.00.",
"\nThen on June 20, 1980, the Brasingtons filed bankruptcy under Chapter 13 in hopes of working out something with their creditors and thus avoiding a sale of their home. ",
"But their plan was not approved. ",
"The Court in Chapter 13 suggested that the house would have to be sold and certain debts paid therefrom before a plan would be feasible. ",
"The case was dismissed on September 5, 1980.",
"\nIn the meantime there had been two contracts to purchase the house in August of 1980. ",
"The Brasingtons thought they had sold the house for $89,000.00 in that month. ",
"The last contract closing was to have been September 5, 1980; however, both proposed sales fell through.",
"\nBelieving however that they had sold the house, the Brasingtons moved out and *78 moved to 315 South Capitol Parkway on or about September 12, 1980. ",
"They left some household goods at 3103 LeBron Road but most of their belongings were moved.",
"\nJan Wilson was the owner of the house at 315 South Capitol Parkway and had her house for sale with Justice Realty Company at the beginning of September 1980. ",
"She was told by her realtor that her house had been sold to the Brasingtons and that she would have to move out by September 5, 1980. ",
"She testified that the Brasingtons had moved into the house by September 12, 1980. ",
"Then the sale of the house to the Brasingtons fell through; they entered into an oral contract with David Justice, Ms. Wilson's realtor; he bought the house from Jan Wilson, and rented it to the Brasingtons with an option to purchase. ",
"The first payment on the house at 315 South Capitol Parkway was made by the Brasingtons on September 15, 1980. ",
"The Brasingtons have been living in that house continuously since September.",
"\nAfter the Chapter 13 dismissal the Brasingtons filed a petition in bankruptcy under Chapter 7 on October 15, 1980. ",
"They claimed a homestead exemption in the property at 3103 LeBron Road in the bankruptcy petition. ",
"The Trustee objects to the claim of homestead exemption on the grounds that the Debtors were not in physical possession of the property on the date of the filing of the petition in bankruptcy.",
"\nThe Code of Alabama 1978 at Section 6-10-11 provides for exemptions Alabama residents may claim in Federal bankruptcy.",
"\n. . . [",
"T]here shall be exempt from the property of the estate of an individual debtor only that property and income which is exempt under the laws of the State of Alabama and under Federal laws other than Subsection (d) of Section 522 of said Title 11 of the United States Code.",
"\nThis Alabama statute on homestead preempts 11 U.S.C. § 522(d). ",
"See 11 U.S.C. § 522(b)(1). ",
"The effective date of the preemptive Alabama amendment to the exemption statute of Alabama was May 19, 1980, which preceded the Brasington's date of filing in bankruptcy.",
"\nCode of Alabama 1975, Section 6-10-2 defines the homestead exemption in Alabama, applicable, then in bankruptcy, and gives debtors a $5,000.00 homestead exemption.",
"\n\nCONCLUSIONS\nAn essential element of the right of homestead is actual occupancy at the time the property is claimed as exempt. ",
"At the date of bankruptcy there must be occupancy in fact and a clearly defined intention of present residence and occupancy. ",
"Blum v. Carter, 63 Ala. 235 (1879). ",
"Intention without occupancy does not create the homestead right. ",
"40 Am.",
"Jur.2d, Homestead § 75. ",
"It is the home where the family dwells that is subject to a claim for homestead. ",
"It does not extend to a house in which the family does not dwell. ",
"Jaffrey v. McGough, 88 Ala. 648, 7 So. ",
"333 (1890).",
"\nA family cannot have two homesteads. ",
"When the evidence shows that a debtor occupies premises in the manner contemplated by the homestead statute, he may not claim homestead in respect of another residence. ",
"Where it is shown that he no longer occupies the disputed property and has established a residence elsewhere, he may not successfully assert the homestead right. ",
"40 Am.",
"Jur.2d, Homestead § 74. ",
"Ownership and occupation are the essential conditions. ",
"McConnaughy v. Baxter, 55 Ala. 379. \"",
"Unless devoted to use and occupancy as a home, a dwelling place, protection is not extended to it. ",
"It is because of its use and occupancy as a home to secure and preserve it as such that exemption from sale under judicial process is granted.\" ",
"Dexter v. Strobach, 56 Ala. 233.",
"\nAt the date of filing in bankruptcy, October 15, 1980, the Brasingtons were no longer living in the house at 3103 LeBron. ",
"They had established a residence at 315 South Capitol Parkway one month before bankruptcy. ",
"They had no intention of returning to the house at 3103 LeBron to permanently reside. ",
"They moved out, because they knew they must sell the house to pay debts. ",
"They could not continue to live there whether in bankruptcy or not, and they knew it. ",
"They did not occupy the house as their principal residence at the *79 date of bankruptcy. ",
"They had, at most, a hope that by some fortuitous circumstance they might one day return to the house on LeBron.",
"\nTaking all the evidence presented into account, the Brasingtons are not entitled to a homestead exemption in the house located at 3103 LeBron Road because it was not their residence at the date of bankruptcy.",
"\nIt is therefore ORDERED\nThat the homestead exemption claimed by Robert W. Brasington and Elizabeth M. Brasington in the house at 3103 LeBron Road, Montgomery, Alabama should be and is hereby DISALLOWED.",
"\n"
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"Q:\n\nWhat's the relationship between classical gravitational waves and gravitons?",
"\n\nLIGO have detected gravitational waves, why we are still far away from detecting gravitations?",
"\nhow to understand the statement below?",
"\n\nA classical wave may be considered to be a coherent\n superposition of a large number of gravitons.",
"\n\nA:\n\nTo shift your question to QED: Detecting the particle nature of light is a complete different task from detecting light in general.",
"\nWhen people say Graviton they usually mean the particle structure of the theory (quantized theory). ",
"Like in Electromagnetism where it was discovered that light in fact behaves like particles and that EM is the classical limit of QED.",
"\nWe dont know yet if gravity is quantized, but many people believe it for many good reasons.",
"\n\n"
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"Critical Mass - Body Language - Catholic CD Review\n\nHow’s this for counter-cultural? ",
"Critical Mass, a Catholic rock group based out of Toronto, has crafted their latest CD, Body Languageusing rock music–a musical genre notorious for reveling in salacious and lewd imagery–to demonstrate and instruct about the Theology of the Body.",
"\n\nFor those unfamiliar with the Theology of the Body, it was a series of lectures given by Pope John Paul II, upon arrival to his pontificate, about understanding sex–in all its fullness–in light of the Catholic Gospel. ",
"George Weigel, the biographer of Pope John Paul II, called this series a “theological time-bomb” which would soon “reshap[e]the way Catholics think about our embodiedness as male and female, our sexuality, our relationships with each other, our relationships with God–even God himself.” (",
"Forward, Theology of the Body Explained, Christopher West).",
"\n\nDisseminating such knowledge to the level that a non-theologian can grasp its truths is hard enough for an author or a public speaker… but a rock group? ",
"Music has a language all its own, and popular music disseminates thoughts with a series of sentence fragments—oftentimes speaking to the lowest-common denominator, building to a repetitive and hook-y chorus, with the option to incorporate a bridge—an alternate melodic and lyrical detour—if need be. ",
"Popular music today can be used as an effective teaching tool, especially when the music gives the lyrics a voicing that provides emotional depth to the cut-and-dry images contained in the lyrics.",
"\n\nMusically, Critical Mass is up to the challenge. ",
"After following this band for many years, I believe this is the best they’ve ever sounded. ",
"There is clarity and musicality in its guitar riffs, accompanied by solid production chops that are equal to what I hear on secular radio. ",
"The style veers from hard-rock (“Body is a Language,” “No Consequence”), to joyous pop-rock (“Alone,” “Walk You Home”) to rock balladry (“Devotion”) to praise and worship (“Body and Blood (Adoremus version)”). ",
"Regarding this last song, a reworking of an earlier song, it stands head and shoulders above the praise and worship musical landscape, improving upon the original with a wonderfully ethereal tone, and incorporating traditional Latin lyrics to the final product. ",
"I really appreciate it when Critical Mass lets it all out, taking musical chances and coming up golden.",
"\n\nLyrically, David Wang and company have stretched their craft and raised the bar; there are stories here that speak to teenagers about the sexual permissiveness in society (“No Consequence”), the Steve Taylor-esque slam on artificial contraception (“Contraception Interception”), and the joys of committed celibacy (“Alone”). ",
"You may be hard-pressed to find a musical project that works this hard to shine the light of God’s grace with this much minute detail in the darkened corners of our sexually saturated society.",
"\n\nTaking into account that this is Critical Mass’s finest musical testament to date, with deep, detailed lyrics that are this faithful to a pertinent and applicable aspect of Catholic teaching today, I am hesitant to say that, to my ears, the marriage between lyrics and music do not entirely work.",
"\n\nOne of the problems is that the melodies sometimes project an anger, a roughness, that runs contrary to the tone of some songs. ",
"Granted, this isn’t a problem when singing about the corruption of today’s media, or the problems within artificial contraception, but hearing the angry guitar riffs for “Friend” (a plea for compassion) and “Body is a Language”, which lays the foundation for the glorious teaching of the Theology of the Body, is disconcerting. ",
"Not to mention that most of the lyrics are barely audible underneath the band’s wall of sound (admittedly not a problem for those who have the liner notes on hand).",
"\n\nBut even reading the lyrics and the liner notes, you read words that are more likely associated with PhD dissertations than in popular rock songs. ",
"Phenomenology. ",
"Phylogeny. ",
"Manichaeism. ",
"Pyres. ",
"There is a certain novelty in hearing such words used in a popular song format (in which the first of these words was vocally truncated into four syllables). ",
"In fairness, the band tries very hard to explain these concepts to the average listener in the liner notes; but it’s still got a ways to go.",
"\n\nEven though I have reservations about the final product, I wish all bands choose to not play it safe, and take the educated risks that Critical Mass has done. ",
"They ought to be commended for helping advance Catholic music and raise the listener up with knowledge and wisdom of our faith. ",
"This is most especially true for the sonic blast that accompanied this theological time bomb of the Theology of the Body."
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"Big Cocks like Yours make me want to submit. ",
"Especially when i am chasted. ",
"A very long time ago i have been trying some ballstretching, it looked nice but i didn't like the feeling. ",
"Now i am more into chastity and stretching my ass with different toys :P ."
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"I cannot find any suitable explanation for my question in the internet. ",
"Maybe i am just to stupid to find the right question..\nThis is how a linked list should look when it is initialized:\n\n[Head][Tail]\n\nBut will the actual Head and Tail Nodes still exist when i add Values to the List or will they be overwritten when i add values?",
"\nShould it look like this:\n[Head][Value1][Value2][Value3][Value4][Tail]\n\nor like this: \n[Value1][Value2][Value3][Value4][Value5]\n\nA:\n\nWhen a list is initialized it's like:\n[]\nHead=null, Tail=null\n\nAfter inserting Value1 it becomes\n[Value1]\nHead = Value1, Tail = Value1\n\nAfter inserting Value2 it becomes\n[Value1][Value2]\nHead = Value1, Tail = Value2\n\nYou don't have seperate node for Head and Tail. ",
"Head and Tail are just references to existing Nodes. ",
"Hence real nodes are only the Value* nodes while Head and Tail are just references.",
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"Iran's Revolutionary Guard Corps says the country is now able to \"monitor the world from space\", after successfully launching its first military satellite into orbit.",
"\n\nThe US has accused Tehran in the past of using its space programme as a cover for missile development.",
"\n\nAnd President Donald Trump, without addressing the launch directly, has threatened to destroy Iranian gunboats which he says, have been harassing US ships at sea.",
"\n\nAl Jazeera’s Zein Basravi reports."
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"T. R. R. Cobb House\n\nThe T. R. R. Cobb House built in 1842 is an historic octagon house originally located at 194 Prince Avenue in Athens, Georgia. ",
"On June 30, 1975, it was added to the National Register of Historic Places.",
"\n\nThe original part of the home of Thomas Reade Rootes Cobb is a Greek Revival four-over-four \"Plantation Plain\" built about 1834. ",
"The house given in 1844 to Cobb and his new wife, Marion Lumpkin, as a gift from his father-in-law, Joseph Henry Lumpkin, the first Chief Justice of the Georgia Supreme Court. ",
"Cobb made additions to the house of new rooms, and by 1852, it had acquired its octagon shape and two-story portico. ",
"Cobb died in 1862, and his widow remained in the house until 1873 when she sold it. ",
"The house was maintained and the Cobb family was served by the two dozen enslaved people Cobb owned, who lived behind the main house.",
"\n\nUntil 1962, the house was used for a variety of purposes including rental property, a fraternity house, and a boarding house. ",
"In 1962, the Archdiocese of Atlanta bought the house to use as the rectory and offices for St. Joseph Catholic Church. ",
"In the 1980s, the parish was planning to demolish the house, and the Stone Mountain Memorial Association stepped forward in 1984, bought it, and relocated it to Stone Mountain Park in 1985.",
"\n\nThe restoration of the house never took place because of lack of funding, and the house sat for nearly twenty years. ",
"In 2004 the Watson-Brown Foundation bought the house and returned it to Athens in the spring of 2005. ",
"The Watson-Brown Foundation restored the house to its appearance of 1850; in 2008, the Georgia Trust gave their work its Preservation Award for excellence in restoration.",
"\n\nThe house was delisted from the National Register in 1985, but was re-listed on July 23, 2013.",
"\n\nThe house is now open as a house museum located at 175 Hill Street in Cobbham Historic District.",
"\n\nReferences\n\nExternal links\n T. R. R. Cobb House - official site\n\nCategory:Houses on the National Register of Historic Places in Georgia (U.S. state)\nCategory:Houses in Athens, Georgia\nCategory:Octagon houses in the United States\nCategory:Houses completed in 1842\nCategory:Museums in Clarke County, Georgia\nCategory:Historic house museums in Georgia (U.S. state)\nCategory:1842 establishments in Georgia (U.S. state)\nCategory:Relocated buildings and structures in Georgia (U.S. state)\nCategory:National Register of Historic Places in Clarke County, Georgia\nCategory:Greek Revival houses in Georgia (U.S. state)"
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"Q:\n\nHow to catch new thread in gdb console mode?",
"\n\nI am running my Qt app from gdb, and i want to stop when new threads creates.",
"\n(when gdb prints message [New Thread address (LPW number)].",
"\nI have set breakpoint b __pthread_create_2_1.",
"\nThat allows me to catch most of new threads prints. ",
"but i still got few new threads that are not catched.",
"\nWhat else can i do to catch their creation?",
"\n\nA:\n\nProbably what you want is\ncatch syscall clone (see here https://sourceware.org/gdb/onlinedocs/gdb/Set-Catchpoints.html)\nAlso by default gdb let other threads continue their execution if a breakpoint or catchpoint event occurs.",
"\nSo maybe you want to take a look at the All-Stop mode (https://sourceware.org/gdb/onlinedocs/gdb/Thread-Stops.html)\n\n"
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"Because, let’s face it, you’ll do anything to win."
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"Q:\n\nGWT (Graph) Diagram Frameworks?",
"\n\nI'm looking for a framework for GWT to visualize graphs such as workflow/process diagrams (ideally BPMN capabilites) with a useable auto-layouter and nice shapes. ",
"GraphViz has a good layouter but the shapes are not very nice (except you implement your owns).",
"\nUnfortunatelly GWT-Diagram seems to be abandoned. ",
"\nCheers!",
"\nJack\n\nA:\n\nAt jgraph you can find a mxGraph library which is a JavaScript based diagramming framework. ",
"A GWT version of it is in development. ",
"For a hint about it's capabilities you can go to Diagram.ly. ",
"The GWT version will be just as powerful.",
"\nDisclaimer :\nI am a developer associated with JGraph and I'm currently working on creating a GWT versions of Diagram.ly and mxGraph.",
"\nUpdate\nWe have setup a github repo. ",
"You can checkout our latest source from here.",
"\n\nA:\n\nI hope I'm wrong, but I suspect you're out of luck. ",
"Decent diagramming frameworks are rare as hens' teeth. ",
"You might have some luck with mxgraph (from jgraph), but according to this question over here I suspect that's the best available. ",
"GWT-Links looks alive, but very young.",
"\n\n"
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[
"Introduction {#s1}\n============\n\nCry proteins isolated from *Bacillus thuringiensis* (Bt) are the most widely used insecticidal proteins worldwide. *",
"Cry* genes have been transferred to many crops to improve their insect resistance, such as cotton, maize, potato, tobacco, rice, soybean, tomato, and eggplant, although some of these crops have not yet been commercialized (Romeis et al., [",
"@B62]; Saker et al., [",
"@B64]; James, [@B36]). ",
"The first transgenic rice line harboring a Bt delta-endotoxin gene (under control of the CaMV 35S promoter) was generated in 1989 (Yang et al., [",
"@B89]). ",
"Since then, Bt rice lines expressing *cry* genes, including *cry1Aa, cry1Ab, cry1Ac, cry1Ab/Ac, cry1C*, and *cry2A*, have been developed and have undergone various stages of testing (Chen et al., [",
"@B13]). ",
"Bt rice lines, such as KMD, T1c-9, T2A-1, were reported to effectively control target Lepidoptera insects such as stem borer and leaf folder (Ye et al., [",
"@B90], [@B91]; Chen et al., [",
"@B11]; Zheng et al., [",
"@B97]; Wang et al., [",
"@B81]). ",
"As Bt protein is toxic to target pests, its potential effects on the environment have attracted widespread attention, especially its influence on the food safety and ecological security of non-target organisms (O\\'Callaghan et al., [",
"@B55]; Chen et al., [",
"@B15]; Wang et al., [",
"@B77]; Yu et al., [",
"@B92]). ",
"The potential risks of Bt rice to arthropod communities, non-target herbivores, predators and parasitoids have been widely assessed. ",
"No detrimental effects of Bt rice have been found on most of the assessed arthropods, such as predator spiders *Pardosa pseudoannulata, Ummeliata insecticeps* and *Pirata subpiraticus*, green lacewing *Chrysoperla sinica*, mirid bug *Cyrtorhinus lividipennis* and parasitoid of brown planthopper (BPH) *Anagrus nilaparvatae* (Chen et al., [",
"@B14]; Gao et al., [",
"@B25]; Tian et al., [",
"@B73], [@B72]; Han et al., [",
"@B30]; Li et al., [",
"@B44], [@B45]). ",
"However, significantly longer nymph duration and lower fecundity was found in the non-target herbivores BPH *Nilaparvata lugens* Stål, thrip *Stenchaetothrip biformis* (Bagnall), leafhopper *Nephotettix cincticeps* and ladybird beetle *Propylea japonica* (Thunberg) feeding on Bt rice in laboratory experiments (Akhtar et al., [",
"@B2]; Chen et al., [",
"@B16]; Lu et al., [",
"@B50]; Li et al., [",
"@B45]), although no significant reduction in population density was found under field conditions. ",
"Li et al. ([",
"@B45]) attributed the effect of Bt rice on *P. japonica* to unknown differences in the nutritional composition of Bt rice pollen, as it was confirmed that these insects are not sensitive to pure Cry protein. ",
"Therefore, Bt-independent variation is thought to exist, which might render rice plants more defensive and/or less nutritious to these insects.",
"\n\nBPH has become the most destructive insect pests of rice in the main Asia-Pacific rice-producing region since the 1970s. ",
"To date, 28 BPH resistance loci, including 20 dominant and 8 recessive genes, have been identified from cultivated or wild species of rice; 23 of these genes were mapped to rice chromosome 2, 3, 4, 6, 7, and 12, and only three have been cloned (Du et al., [",
"@B22]; Cheng et al., [",
"@B17]; Fujita et al., [",
"@B24]; He et al., [",
"@B32]; Tamura et al., [",
"@B70]; Wu et al., [",
"@B84]; Liu et al., [",
"@B48]). ",
"However, little is known about the molecular interactions between plants and sucking pests due to the sophisticated behavior of these insects. ",
"The response of plants to piercing-sucking pests such as whitefly, aphid and BPH is thought to be similar to the pathogen defense response (Zhang et al., [",
"@B96]; Yuan et al., [",
"@B93]; Li et al., [",
"@B42]; Zarate et al., [",
"@B94]). ",
"Once the pathogen invades the plant, Ca^2+^ influx triggers reactive oxygen species (ROS) production *in situ*, which in turn activates the hypersensitive response in infected cells (Tenhaken et al., [",
"@B71]). ",
"The molecular mechanism of the plant immune response to BPH is not quite clear but is thought to be somewhat similar to the pathogen defense response. ",
"Pattern recognition receptors (PRRs) on the cell membrane recognize herbivore- and damage-associated molecular patterns (HAMPs and DAMPs) and thus induce PRR-triggered immunity (PTI, Boller and Felix, [@B6]; Schulze-Lefert and Panstruga, [@B65]). ",
"PTI, together with the effectors secreted in watery saliva, promotes the basal resistance response, including the activation of salicylic acid (SA), ethylene (ET) and MAPK cascade signaling pathways (Du et al., [",
"@B22]; Hu et al., [",
"@B34]; Lu et al., [",
"@B51]; Cheng et al., [",
"@B17]). ",
"It was hypothesized that jasmonic acid (JA) negatively regulates resistance to the phloem-feeding insect BPH in rice, while the SA and ET pathways positively affect plant resistance to sucking pests (Li et al., [",
"@B42]; Hao et al., [",
"@B31]; Zhou et al., [",
"@B98]; Lu et al., [",
"@B51]; Tong et al., [",
"@B74]). ",
"Secondary metabolites that deter feeding and inhibit digestion, and plant volatiles that repel herbivores or attract natural enemies, are important components in the interaction between plants and insects. ",
"In response to BPH infestation, Ca^2+^ influx can also lead to protein plugging and callose deposition on the sieve (Hao et al., [",
"@B31]; Hogenhout and Bos, [@B33]; Bonaventure, [@B7]), especially in rice carrying *Bph* resistance genes. ",
"Volatile organic compounds (VOCs) are useful signals in hosts searching for herbivore insects (Halitschke et al., [",
"@B29]; Cheng et al., [",
"@B17]). ",
"Meanwhile, the herbivore-induced VOCs also serve as indirect defense signals (Beale et al., [",
"@B5]).",
"\n\nWe previously showed that the Bt insecticidal protein Cry1Ab could be concentrated in *S. bioformis* adults but not in BPH. ",
"Although the concentration of Bt insecticidal protein was quite low in BPH, the developmental duration of BPH feeding on Bt rice line Kemingdao 2 (KMD2) was significantly delayed for the first and second generation. ",
"Moreover, the fecundity of BPH was significantly lower when fed on Bt rice than on the non-Bt parental plants (Chen et al., [",
"@B16]). ",
"The exact cause of the delayed development and reduced fecundity of non-target herbivores fed on Bt rice remains unknown. ",
"In the current study, to investigate the variation in Bt rice that causes changes in BPH performance, we performed microarray (GeneChip) analysis to compare the gene expression profiles between Bt rice and non-transgenic parental plants in response to BPH infestation. ",
"The goal of microarray analysis was to detect unintended changes that may have occurred during transformation or tissue culture that have made Bt rice less suitable for feeding and oviposition of the non-target insect pest BPH.",
"\n\nMaterials and methods {#s2}\n=====================\n\nPlant materials\n---------------\n\nBt rice line KMD2, which is highly resistant to stem borer and was developed using *Agrobacterium*-mediated methods, was used in this experiment, along with its untransformed parental *japonica* cultivar Xiushui 11. ",
"The Bt rice line expresses the insecticidal protein gene *Cry1Ab* under the control of the maize *ubiquitin* promoter, which is linked in tandem with *gus* (encoding β-glucuronidase), *hpt* (encoding hygromycin phosphotransferase) and *npt* (encoding neomycin phosphotransferase) (Ye et al., [",
"@B90]). ",
"A total of 200 uniform seeds per line were soaked in deionized water at 25°C for 2 days, germinated on a plastic board covered with plastic film at 35°C for 1 day and grown in a controlled chamber at 30°C in the light and 25°C in the dark under a 16:8 h light: dark regime. ",
"The relative humidity was maintained at 85%. ",
"Three weeks later, rice seedlings of similar sizes were transplanted into glass tubes (38 × 250 mm) covered with nylon mesh, with one tube per seedling. ",
"The glass tube was filled with 5 ml nutrient solution, which was renewed every 3 days (Akhtar et al., [",
"@B2]).",
"\n\nFor BPH treatment, 10 s-instar nymphs were infested onto each 30-day-old seedling. ",
"More than 30 replicates were prepared for each treatment. ",
"After 72 h, the BPH nymphs were carefully removed and rice shoots of both BPH-infested and non-infested plants were sampled for analysis. ",
"The BPH colony was originally collected from paddy fields at the Zhejiang University farm in 2008 in Hangzhou, China and was reared on \"Taichung Native 1\" (TN1) rice (*Oryza sativa* L.) seedlings at 28°C under a photoperiod of 14:10 h (light: dark), as described in Chen et al. ([",
"@B16]).",
"\n\nRNA extraction and microarray analysis\n--------------------------------------\n\nFrozen rice shoots were homogenized in liquid nitrogen using a mortar and pestle. ",
"Three biological replicates were collected for each treatment. ",
"Total RNA was extracted using Trizol regent according to the supplier\\'s recommendation (Invitrogen, Karlsruhe, Germany). ",
"Residual DNA was removed using an RNeasy MinElute Cleanup Kit (Qiagen). ",
"After mixing with poly-A RNA controls, the total RNA was first reverse transcribed using T7-Oligo^(dT)^ Promoter Primer for the first-strand cDNA synthesis reaction. ",
"Following RNase H-mediated second-strand cDNA synthesis, the double-stranded cDNA was purified and served as a template in the subsequent *in vitro* transcription reaction, which was carried out in the presence of T7 RNA polymerase and a biotinylated nucleotide analog/ribonucleotide mix for complementary RNA (cRNA) amplification and biotin labeling. ",
"The biotin-labeled cRNA targets were then cleaned up, fragmented and hybridized to the Affymetrix GeneChip 57 K Rice Genome Array according to the manufacturer\\'s protocol. ",
"This expression array contains probe-sets to query 51,279 transcripts representing two rice cultivars, with approximately 48,564 *japonica* transcripts and 1260 transcripts representing the *indica* cultivar (Sharma et al., [",
"@B68]). ",
"Expression profiling analysis was carried out in three replications by CapitalBio Corp. (Beijing, China).",
"\n\nqRT-PCR analysis\n----------------\n\nAn aliquot of purified RNA was reverse transcribed using a first-strand cDNA synthesis kit (Toyobo, Japan), and quantitative real-time PCR was performed using the ABI7500 Real-time PCR Detection System (ABI, Hercules, CA, USA). ",
"PCR was performed using SYBR® premix Ex Taq™ with ROX reference dye (Takara, Dalian, China). ",
"The PCR conditions consisted of denaturation at 95°C for 30 s, followed by 40 cycles of denaturation at 95°C for 3 s, annealing at 60°C for 34 s. A dissociation curve was generated at the end of each PCR cycle to verify that a single product was amplified. ",
"Expression of the target gene was normalized relative to the expression of the housekeeping gene *actin*. ",
"The quantification of mRNA levels was based on the method of Livak and Schmittgen ([@B49]). ",
"Primers used for qRT-PCR are listed in Supplementary Table [S1](#SM1){ref-type=\"supplementary-material\"}.",
"\n\nQuantification of plant hormones by LC-ESI-MS/MS\n------------------------------------------------\n\nSamples were prepared according to Pan et al. ([",
"@B57]) and Liu et al. ([",
"@B46]) with minor modifications. ",
"Approximately 0.5 g fresh rice shoots for each replicate was ground to a powder in liquid nitrogen, and 4 ml 80% methanol (methanol: water, 80:20, v/v) was added as extraction buffer. ",
"Three biological replications were prepared for each treatment. ",
"The homogenate was transferred to a 10-ml tube and incubated in a shaker at 100 rpm for 16 h at 4°C. ",
"After centrifugation at 10,000 g for 10 min at 4°C, the supernatant was transferred to a fresh tube and concentrated using a nitrogen evaporator with nitrogen flow. ",
"Samples were redissolved in 200 μl methanol. ",
"Then, 20 μl of sample was injected and analyzed on an Agilent 6460 triple quadrupole LC/MS system (Agilent Technologies, Heilbronn, Germany) outfitted with an electrospray (ESI) source. ",
"The hormones were separated by reversed-phase HPLC on a Zorbax XDB C18 column (2.1 × 150 mm, 3.5 μm, Agilent). ",
"Separations were performed using a binary solvent system composed of MeOH (solvent A) and 0.1% formic acid in water (solvent B) as a mobile phase at a flow rate of 0.3 ml min^−1^. The elution gradient profile was set as follows: 0--1 min, 40% A + 60% B; 1--6.5 min, 100% A+ 0% B; 6.5--10 min, 100% A+ 0% B. Tandem mass spectrometric analysis was performed in multiple reaction monitoring (MRM) mode. ",
"The MRM parameters of each compound are listed in Table [1](#T1){ref-type=\"table\"}. ",
"Standard chemical regents including IAA (indole-3-acetic acid), GA~1~ (gibberellin A~1~), JA, SA, and ABA (abscisic acid) were purchased from Sigma-Aldrich Chemical Co. (Shanghai, China). ",
"The concentration of each plant hormone was calculated using the following formula:\n\nPlant hormone\n\n(\n\nng/gFW\n\n)\n\n=\n\nC\n\nstandard\n\n×\n\nA\n\nsample\n\n×\n\nV\n\nsample\n\n/\n\n(\n\nA\n\nstandard\n\n×\n\nFW\n\nsample\n\n)\n\n(\n\nC\n\n,\n\n concentration \n\n(\n\nng/ml\n\n)\n\n;\n\n A\n\n,\n\n peak area\n\n;\n\n V\n\n,\n\n volume \n\n(\n\nml\n\n)\n\n;\n\nFW\n\n,\n\n fresh weight \n\n(\n\ng\n\n)\n\n)\n\n###### \n\n**Optimized MRM parameters for the quantification of phytohormones**.",
"\n\n **Analytes** **Scan mode** **Transition (m/z)** **Cone voltage (V)** **Collision energy (V)**\n -------------- --------------- ---------------------- ---------------------- --------------------------\n IAA \\+ 176.1 → 130.1 75 10\n JA − 209.1 → 59.1 70 2\n SA − 137 → 93 75 10\n GA~1~ − 345.2 → 143.1 220 15\n ABA − 263.1 → 153 75 0\n\nScan mode: + positive, − negative.",
"\n\nStatistical analysis\n--------------------\n\nThe relative expression levels of genes and concentrations of phytohormones were analyzed using Two-way analysis of variance (ANOVA), followed by a Duncan\\' multiple range significant test. ",
"All statistical analysis was performed by the Data Processing System (DPS) package (Version 9.5).",
"\n\nResults {#s3}\n=======\n\nOverview of gene expression profiles in response to BPH infestation\n-------------------------------------------------------------------\n\nUsing Affymetrix GeneChip analysis, we found that 21,917 and 21,782 probe-sets were expressed (*P* \\< 0.05) in non-Bt parental and Bt rice, respectively. ",
"The numbers of probe-sets responsive to BPH infestation with different fold-change thresholds, identified using significance analysis of microarray (SAM) methodology, are listed in Table [2](#T2){ref-type=\"table\"}. ",
"More genes were affected by BPH infestation in non-Bt than in Bt rice. ",
"Genes were considered to be differentially expressed at a threshold of 2.0 fold change (FC) up or down (FC ≥ 2.0, upregulated; or FC ≤ 0.5, downregulated; *q*-value \\< 0.05). ",
"When we compared rice shoots infested by BPH for 72 h with non-infested shoots, 3834 and 3273 differentially expressed probe-sets were identified in non-Bt parent and Bt rice line, respectively. ",
"Of these, 2589 probe-sets representing 2371 different expressed genes (DEGs) showed similar responses to BPH infestation in the two rice lines, as more than one probe-set corresponds to one gene in some instances (Deveshwar et al., [",
"@B20]; Supplementary Table [S2](#SM2){ref-type=\"supplementary-material\"}); the number of downregulated probe-sets was nearly two-fold that of upregulated (907 up/1682 down). ",
"There were 1490 probe-sets that only exhibited significant changes in expression in one rice line, but no significant difference were found between two lines as the ratio of FC~Bt\\ rice~ to FC~non−Bt\\ rice~ (data not shown). ",
"The impact of BPH attack on the expression of 439 probe-sets (representing 400 DEGs) differed markedly between rice lines (Figure [1A](#F1){ref-type=\"fig\"}; Supplementary Table [S3](#SM3){ref-type=\"supplementary-material\"}). ",
"Of these, 117 (26.6%) and 164 (37.4%) probe-sets were up- and down-regulated in Bt rice, while there were 197 (44.9%) and 135 (30.8%) probe-sets upregulated and downregulated in non-Bt parent plants, respectively. ",
"In addition, there were 107 showed no change in non-Bt parent plants and were up-/down-regulated in Bt rice (Figure [1A](#F1){ref-type=\"fig\"}).",
"\n\n###### \n\n**Number of probe-sets responsive to BPH infestation with different fold change thresholds (***q***-value \\< 0.05) identified using significance analysis of microarray (SAM) methodology**.",
"\n\n **Fold change** **Up-regulated** **Down-regulated** **Total** \n ----------------- ------------------ -------------------- ----------- ------ ------ ------\n ≥2.0 1534 1269 2300 2004 3834 3273\n ≥3.0 578 429 1137 967 1715 1396\n ≥4.0 318 205 744 633 1062 838\n ≥5.0 200 120 533 452 733 572\n ≥6.0 131 96 429 350 560 446\n ≥7.0 102 64 347 290 449 354\n ≥8.0 84 41 286 241 370 282\n\n{#F1}\n\nPathway analysis of genes showing the same response to BPH infestation in Bt and non-Bt rice\n--------------------------------------------------------------------------------------------\n\nPathway analysis of the 2371 DEGs revealed similar responses to BPH infestation in both rice lines, which was carried out with the Plant MetGenMAP system using the FDR correction method at a threshold of 0.05 (Joung et al., [",
"@B38]). ",
"Altogether, 154 significantly altered pathways were detected, including 43 that were upregulated and 52 that were downregulated. ",
"There were also 59 pathways that were either upregulated or downregulated by BPH infestation in both rice lines (Table [3](#T3){ref-type=\"table\"}). ",
"Plant nitrogen assimilation, chlorophyll biosynthesis, fatty acid biosynthesis and elongation pathways were significantly downregulated in response to BPH feeding. ",
"Superoxide radical removal and cell wall modification-related pathways (such as epicuticular wax biosynthesis) were also suppressed. ",
"On the other hand, biosynthesis of plant hormones such as IAA and JA was activated by BPH attacking, while salicylate biosynthesis was suppressed. ",
"The GA inactivation pathway was upregulated, while ET and brassinosteroid (BRs) biosynthesis pathways were either up- or downregulated. ",
"Biosynthesis of amino acids such as asparagine, glutamine and lysine was significantly downregulated, while degradation of arginine, leucine and lysine was upregulated.",
"\n\n###### \n\n**Pathway analysis of genes showing similar responses to BPH infestation in Bt and non-Bt rice**.",
"\n\n **Categories** **Pathway name** ***p*****-value** \n --------------------------------------------- ------------------------------------------------------------------------------- ------------------- ----------\n Amino acid and derivative metabolism Arginine degradation II 0.02291 \n Arginine degradation X (arginine monooxygenase pathway) 0.02291 \n β-alanine biosynthesis II 1.35E-06 \n Citrulline biosynthesis 0.02291 \n Homocysteine and cysteine interconversion 0.02291 \n Isoleucine degradation I 0.02291 \n Leucine biosynthesis 0.02291 \n Leucine degradation I 0.02291 \n Lysine degradation II 0.00105 \n Methionine biosynthesis I 0.02291 \n Methionine degradation III 3.33E-05 \n Phenylalanine biosynthesis I 0.02291 \n Proline biosynthesis I 0.02291 \n Proline biosynthesis II 0.02291 \n Superpathway of citrulline metabolism 0.02291 \n Superpathway of sulfur amino acid biosynthesis (*Saccharomyces cerevisiae*) 0.02291 \n Tryptophan biosynthesis 0.00105 \n Carbohydrates metabolism Acrylonitrile degradation 0.02291 \n Acetyl CoA fermentation to butyrate 0.02291 \n Aldoxime degradation 0.02291 \n D-lactate fermentation to propionate and acetate 1.35E-06 \n Ethanol fermentation to acetate 1.35E-06 \n Ethylene glycol degradation 0.02291 \n Glutamate degradation VII (to butyrate) 0.00105 \n Glutaryl-CoA degradation 0.02291 \n Glycolipid biosynthesis 0.02291 \n Xylulose-monophosphate cycle 3.33E-05 \n Pentose phosphate pathway (oxidative branch) 0.02291 \n GDP-D-rhamnose biosynthesis 0.02291 \n GDP-L-fucose biosynthesis I (from GDP-D-mannose) 0.02291 \n Oxidative ethanol degradation I 3.30E-05 \n Plant hormone and secondary metabolites 13-LOX and 13-HPL pathway 0.00105 \n Divinyl ether biosynthesis II (13-LOX) 0.00105 \n Anandamide degradation 0.02291 \n Gibberellin inactivation 0.02291 \n IAA biosynthesis IV 0.02291 \n IAA biosynthesis VI (via indole-3-acetamide) 0.02291 \n Jasmonic acid biosynthesis 1.35E-06 \n Leucopelargonidin and leucocyanidin biosynthesis 0.00105 \n Nicotine degradation II 0.02291 \n Tetrapyrrole biosynthesis I 0.02291 \n Nucleosides and nucleotide ppGpp biosynthesis 0.02291 \n Salvage pathways of pyrimidine ribonucleotides 0.02291 \n Amino acid and derivative metabolism Asparagine biosynthesis I 0.00786\n Asparagine degradation I 0.00786\n Aspartate biosynthesis I 0.00786\n Aspartate degradation II 0.0095\n Cysteine biosynthesis I 0.00786\n formylTHF biosynthesis I 0.00095\n formylTHF biosynthesis II 0.00786\n Glutamine biosynthesis I 0.00786\n Glutamine degradation III 0.00786\n Glycine cleavage complex 0.00095\n Lysine biosynthesis I 0.00786\n Lysine biosynthesis II 0.00786\n Lysine biosynthesis VI 0.00786\n Threonine degradation II 0.00786\n Threonine degradation III (to methylglyoxal) 7.86E-03\n Carbohydrates metabolism Aminopropanol biosynthesis 0.00786\n Glycerol degradation I 0.00095\n Glycerol degradation IV 0.00786\n Glycolipid desaturation 0.00786\n Reductive TCA cycle I 7.86E-03\n Starch biosynthesis 0.00786\n Respiration (anaerobic) 0.00095\n Cell Wall Epicuticular wax biosynthesis 0.00786\n Homogalacturonan degradation 6.91E-08\n Suberin biosynthesis 0.00095\n Lipid metabolism Cyclopropane and cyclopropene fatty acid biosynthesis 0.00012\n Cyclopropane fatty acid (CFA) biosynthesis 0.00012\n Fatty acid biosynthesis---initial steps 7.40E-07\n Fatty acid elongation---saturated 6.91E-08\n Fatty acid elongation---unsaturated II 7.40E-07\n Phospholipid desaturation 0.00786\n Phospholipid biosynthesis I 0.00786\n Superpathway of fatty acid biosynthesis 6.91E-08\n Nitrogen metabolism Ammonia assimilation cycle II 0.00786\n Nitrate reduction II (assimilatory) 0.00786\n Nucleosides and nucleotide *De novo* biosynthesis of pyrimidine deoxyribonucleotides 0.00095\n Purine nucleotides de novo biosynthesis I 1.20E-04\n Purine nucleotides de novo biosynthesis II 0.00786\n Ribose degradation 0.00786\n Salvage pathways of purine nucleosides 0.00095\n Superpathway of ribose and deoxyribose phosphate degradation 0.00786\n tRNA charging pathway 5.06E-10\n Photosynthesis Chlorophyllide a biosynthesis 0.00095\n Secondry metabolism Chorismate biosynthesis 0.00095\n DIMBOA-glucoside degradation 0.00786\n Folate polyglutamylation I 0.00786\n Folate transformations 0.00095\n Phenylpropanoid biosynthesis 0.00786\n Phenylpropanoid biosynthesis, initial reactions 0.00786\n Salicylate biosynthesis 0.00786\n Secologanin and strictosidine biosynthesis 0.00012\n Stress response Removal of superoxide radicals 0.00786\n Amino acid and derivatives metabolism Arginine degradation I (arginase pathway) 0.02291 0.00095\n Glutamate degradation III 0.02291 0.00786\n Histidine biosynthesis I 0.02291 0.00095\n 4-hydroxyproline degradation I 0.02291 0.00095\n Isoleucine biosynthesis from threonine 0.00105 0.00095\n Isoleucine degradation II 1.35E-06 0.00786\n Leucine degradation III 1.35E-06 0.00786\n Methionine biosynthesis II 0.02291 0.00095\n Methionine salvage pathway 0.02291 0.00786\n Phenylalanine degradation III 1.35E-06 0.00786\n Proline degradation I 0.02291 0.00095\n Proline degradation II 0.02291 0.00095\n Superpathway of leucine, valine, and isoleucine biosynthesis 0.00105 0.00095\n Superpathway of lysine, threonine and methionine biosynthesis II 0.02291 7.40E-07\n Threonine degradation III (to methylglyoxal) 0.02291 7.86E-03\n Tyrosine degradation I 0.02291 0.00786\n Valine biosynthesis 0.00105 0.00095\n Valine degradation I 0.00105 0.00786\n Valine degradation II 1.35E-06 0.00786\n Carbohydrates metabolism CALVIN cycle 2.97E-09 4.41E-09\n Cytokinins 7-N-glucoside biosynthesis 3.33E-05 6.41E-09\n Cytokinins 9-N-glucoside biosynthesis 3.33E-05 5.06E-10\n Cytokinins-O-glucoside biosynthesis 3.33E-05 5.06E-10\n Fructose degradation to pyruvate and lactate (anaerobic) 3.33E-05 4.88E-12\n Galactose degradation II 3.33E-05 6.91E-08\n Gluconeogenesis 1.35E-06 7.40E-07\n Glucose fermentation to lactate II 0.00105 6.91E-08\n Glycolysis I 1.35E-06 5.28E-11\n Glycolysis IV (plant cytosol) 3.33E-05 5.28E-11\n Mixed acid fermentation 0.000333 0.00095\n Pentose phosphate pathway (non-oxidative branch) 0.02291 0.00786\n Starch degradation 1.35E-06 0.00095\n Sucrose biosynthesis 0.002291 0.00786\n Sucrose degradation III 0.00105 0.00786\n Sucrose degradation to ethanol and lactate (anaerobic) 1.25E-10 3.43E-15\n UDP-galactose biosynthesis (salvage pathway from galactose using UDP-glucose) 0.00105 9.77E-06\n UDP-glucose conversion 0.02291 6.41E-09\n UDP-N-acetylgalactosamine biosynthesis 0.02291 9.77E-06\n Cell wall Cellulose biosynthesis 1.25E-10 4.02E-13\n Co factors Pantothenate and coenzymeA biosynthesis II 0.02291 0.00095\n Pantothenate biosynthesis I 0.02291 0.00095\n Pantothenate biosynthesis II 0.02291 0.00095\n Energy metabolism and electron transmission Aerobic respiration---electron donor II 1.35E-06 0.00095\n Aerobic respiration---electron donor III 3.33E-05 0.00095\n Aerobic respiration---electron donors reaction list 3.33E-05 7.40E-07\n NAD salvage pathway II 0.00105 7.40E-07\n NAD/NADH phosphorylation and dephosphorylation 3.33E-05 0.00012\n photorespiration 0.02291 0.00012\n Respiration (anaerobic)---electron donors reaction list 3.33E-05 7.40E-07\n Lipid metabolism Fatty acid β-oxidation I 1.35E-06 0.00786\n Fatty acid β-oxidation II (plant, saturated) 0.02291 0.00786\n Phospholipases 0.00105 0.00786\n Triacylglycerol degradation 3.33E-05 9.77E-06\n Nucleosides and Nucleotides Salvage pathways of purine and pyrimidine nucleotides 0.02291 0.00786\n Plant hormone and Secondary metabolism Ethylene biosynthesis from methionine 0.02291 0.00786\n Enterobactin biosynthesis 1.35E-06 0.00786\n Betanidin degradation 1.35E-06 1.06E-31\n Brassinosteroid biosynthesis II 3.33E-05 3.51E-14\n Stress response Glutathione-mediated detoxification 2.97E-09 0.00095\n\nPathway analysis of the 2371 DEGs showing similar responses to BPH in Bt and non-Bt rice plants using the Plant MetGenMAP system identified 145 significantly changed pathways with FDR correction at a threshold of 0.05: 43 pathways were significantly upregulated (raw values in yellow), while 52 pathways were significantly downregulated (raw values in light green). ",
"The remaining 59 pathways were either upregulated or downregulated.",
"\n\nProfiles of DEGs in response to BPH infestation between Bt and non-Bt rice\n--------------------------------------------------------------------------\n\nA total of 439 probe-sets (representing 400 DEGs) showing differential responses to BPH infestation between the Bt and non-Bt rice were identified and classified into eight categories (Supplementary Table [S3](#SM3){ref-type=\"supplementary-material\"}; Figure [1](#F1){ref-type=\"fig\"}). ",
"There were 68.4% more upregulated genes in non-Bt parent than in Bt rice line, particularly genes involved in stress response, signal transduction, transcriptional regulation, transport, and unknown function (Figure [1B](#F1){ref-type=\"fig\"}). ",
"Moreover, for most genes upregulated after BPH attack in both lines, FC values were more significant in non-Bt parent than in Bt rice. ",
"A high percentage of DEGs were in the categories genes of unknown function and stress response-related; 40.1% of DEGs (111, 121 probe-sets) were stress-related and were therefore further classified. ",
"As shown in Figure [1C](#F1){ref-type=\"fig\"}, genes involved in oxidative stress response, pathogenesis-related proteins and protein inhibitors were significantly induced by BPH feeding, especially in non-Bt parent. ",
"In Bt rice, the expression of four of the 8 oxidative stress response genes remained unchanged, and two were even suppressed. ",
"Signal transduction-related genes and transcription factor (TF) genes were also more affected in non Bt parent than in Bt rice. ",
"The expression of 17 of the 20 TF genes was more significantly altered in non-Bt parent in response to BPH feeding, whereas that of three TF genes was only significantly altered in Bt rice, including the MYB (v-myb avian myeloblastosis viral oncogene homolog), TCP (Teosinte branched1/Cycloidea/ Proliferating cell factor 1) and bHLH (basic Helix-Loop-Helix) family TF genes (Figure [1](#F1){ref-type=\"fig\"}; Supplementary Table [S3](#SM3){ref-type=\"supplementary-material\"}). ",
"On the other hand, phytohormone biosynthesis and signaling genes were more affected by BPH feeding in Bt rice. ",
"GA biosynthesis and signaling-related genes were downregulated in Bt rice line but their expression remained unchanged in non-Bt parent; ET biosynthesis gene *ACS* (1-aminocyclopropane-1-carboxylate synthase) was more strongly suppressed while JA signaling-related genes were more strongly induced in Bt rice.",
"\n\nGenes likely related to the altered performance of BPH fed on Bt rice\n---------------------------------------------------------------------\n\nGenes specifically induced or repressed in Bt rice, and those that are more strongly induced or less repressed in Bt rice vs. the non-transgenic parent, are thought to be closely related to the altered performance of BPH. ",
"Of the 439 probe-sets showing differential expression in response to BPH between lines, 38 and 69 (representing 36 and 62 DEGs) were upregulated or downregulated, respectively, only in Bt rice (Figure [1A](#F1){ref-type=\"fig\"}; Supplementary Table [S4](#SM4){ref-type=\"supplementary-material\"}). ",
"Excluding two genes that showed similar expression patterns between rice lines in the absence of BPH treatment, 46 DEGs (47 probe-sets, 9 up/38 downregulated) with FC \\> 3.0 were considered most likely to contribute to the impact of Bt rice on BPH performance (Table [4](#T4){ref-type=\"table\"}). ",
"These DEGs included early nodulin genes, lipid metabolism genes, stress response genes and TF genes. *",
"Early nodulin 93* (Os06g04990) and a retrotransposon gene (Os01g37350) were upregulated in non-transgenic parent but downregulated in Bt rice upon BPH feeding, whereas two lipid metabolism-related genes, *LTPL65* and *phosphotransferase*, were induced in Bt rice but repressed in the non-Bt rice plants. ",
"These four genes are also likely related to the variation in Bt rice (Table [4](#T4){ref-type=\"table\"}). ",
"Of the remaining 170 probe-sets showing significant changes in expression in both rice lines upon BPH attack, 14 (14 DEGs) were more significantly induced by BPH, while 50 (47 DEGs) were less suppressed in Bt rice. ",
"Excluding one showing similar expression patterns before BPH infestation, the remaining 60 DEGs (13 up/47 downregulated) probably participate in BPH-induced defense, including signal transduction-related genes, phytohormone biosynthesis and signaling genes and other stress response genes (Supplementary Table [S4](#SM4){ref-type=\"supplementary-material\"}). ",
"Finally, 118 probe-sets were significantly upregulated and 40 were significantly downregulated only in non-transgenic parent; these might represent stress-sensitive genes.",
"\n\n###### \n\n**Genes most likely contributing to the variation in BPH performance on Bt rice**.",
"\n\n **Probe set ID** **BPH-infested/non-infested** **Gene ID and annotation** **Classification** \n ------------------------- ------------------------------- ---------------------------- -------------------- ---- ------------------------------------------------------------------------------------------------------- ------------------------------------\n Os.50961.1.S1_at 4.125 D 1.046 -- LOC_Os03g58890//oxidoreductase, 2OG-Fe oxygenase family protein Carbohydrates metabolism\n Os.11244.3.S1_x\\_at 3.643 D 0.884 -- LOC_Os06g04200//Granule-bound starch synthase 1, chloroplast precursor \n Os.10546.1.S1_s\\_at 3.458 D 0.901 -- LOC_Os09g34230//UDP-glucoronosyl and UDP-glucosyltransferase family protein \n Os.21369.1.S1_at 3.383 D 1.740 -- LOC_Os08g32780//bifunctionalmonodehydroascorbate reductase and carbonic anhydrasenectarin-3 precursor \n Os.27281.1.S1_at 3.147 D 0.880 -- LOC_Os04g02620//oxidoreductase, short chain dehydrogenase/reductase family protein \n Os.49281.1.S1_at 3.025 D 0.926 -- LOC_Os06g21240//Glycine rich protein family protein \n OsAffx.27459.2.S1_s\\_at 9.600 D 0.685 -- LOC_Os06g05000//Early nodulin 93 ENOD93 protein Growth regulation\n Os.38638.3.S1_x\\_at 7.855 D 0.958 -- LOC_Os06g05010//Early nodulin 93, putative \n Os.38638.1.S1_at 5.593 D 2.311 U LOC_Os06g04990//Early nodulin 93, putative \n Os.11212.1.S1_at 4.388 D 1.132 -- LOC_Os07g18750//LTPL42---Protease inhibitor/seed storage/LTP family protein precursor, Lipids metabolm\n Os.27520.1.S1_at 3.508 D 0.632 -- LOC_Os12g02320//LTPL12---Protease inhibitor/seed storage/LTP family protein precursor, \n Os.13246.1.S1_at 2.174 U 16.584 D LOC_Os01g59870//LTPL65---Protease inhibitor/seed storage/LTP family protein precursor, \n Os.13835.2.S3_a\\_at 2.147 U 2.028 D LOC_Os01g51920//phosphotransferase \n Os.9538.1.S1_s\\_at 3.415 U 1.344 -- LOC_Os06g39870//26S protease regulatory subunit 8 Nucleotides and protein metabolism\n Os.27804.1.S1_at 4.783 D 0.629 -- LOC_Os08g10310//SHR5-receptor-like kinase \n Os.10246.4.S1_x\\_at 4.709 D 0.572 -- LOC_Os06g06510//Histone H3 \n Os.16899.1.S1_at 3.617 D 0.718 -- LOC_Os07g30150//phosphoribosyl transferase \n Os.8570.3.S1_s\\_at 3.416 D 0.845 -- LOC_Os03g19600//retrotransposon protein, putative, Ty3-gypsy subclass Others\n Os.10255.1.S1_s\\_at 2.254 D 3.048 U LOC_Os01g37350//retrotransposon protein, putative, Ty3-gypsy subclass \n Os.5044.1.S1_at 4.864 U 1.966 -- LOC_Os01g50410//STE_MEKK_ste11_MAP3K.6 Signal transduction\n OsAffx.26237.1.S1_at 4.28 D 0.998 -- LOC_Os04g29770//wall--associated receptor kinase-like 3 precursor \n Os.12535.1.S1_at 6.262 U 1.769 -- LOC_Os01g52230//phosphoethanolamine/phosphocholine phosphatase Stress response\n Os.53670.1.S1_at 4.675 U 1.710 -- LOC_Os05g15880//glycosyl hydrolase \n Os.25329.1.A1_at 3.827 U 1.087 -- LOC_Os12g43440//Thaumatin-like protein precursor \n Os.20260.1.S1_at 6.624 D 1.475 -- LOC_Os01g22352//peroxidase 2 precursor \n Os.49627.1.S1_at 5.695 D 0.552 -- LOC_Os06g37150//L-ascorbate oxidase \n OsAffx.14201.1.S1_at 5.063 D 1.017 -- LOC_Os04g39360//heavy metal transport/detoxification protein \n OsAffx.32039.1.S1_x\\_at 5.013 D 0.518 -- LOC_Os12g35610//respiratory burst oxidase homolog \n Os.7611.1.S1_at 4.413 D 0.737 -- LOC_Os03g06670//Core histone H2A/H2B/H3/H4 domain containing protein \n Os.35510.1.S1_at 4.211 D 0.517 -- LOC_Os02g01220//Rhodanese-like domain containing protein \n Os.5338.1.S1_at 3.597 D 0.644 -- LOC_Os10g30150//universal stress protein family protein \n Os.5583.1.S1_at 3.328 D 1.242 -- LOC_Os03g19270//universal stress protein family protein \n OsAffx.11838.1.S1_x\\_at 3.154 D 1.0783 -- LOC_Os01g73250//abscisic stress-ripening \n Os.22580.1.S1_s\\_at 3.033 D 0.902 -- LOC_Os01g73250//abscisic stress-ripening \n Os.1479.1.S1_at 6.91 D 0.871 -- LOC_Os07g48980//Nicotianamine synthase 3 \n Os.54454.1.S1_at 5.698 D 0.516 -- LOC_Os11g32650//chalcone synthase \n OsAffx.27442.1.S1_at 3.035 U 0.683 -- LOC_Os06g03670//dehydration-responsive element-binding protein 1A Transcription factors\n Os.21231.1.S1_at 6.147 D 0.600 -- LOC_Os01g38610//Helix-loop-helix DNA-binding domain containing protein \n Os.7512.1.S1_at 3.464 U 1.698 -- LOC_Os04g56990//myb-like DNA-binding domain, SHAQKYF class family protein \n Os.9303.1.S1_at 4.955 D 0.559 -- LOC_Os02g46460//peptide transporter PTR3-A Transport\n Os.57361.1.S1_at 7.482 U 1.948 -- LOC_Os08g13400//hypothetical protein Unknown\n Os.9886.1.S1_at 3.544 U 1.227 -- LOC_Os04g02530//Conserved hypothetical protein \n Os.56964.1.S1_at 6.937 D 0.912 -- LOC_Os06g46980//expressed protein \n Os.5390.1.S1_at 6.669 D 0.582 -- LOC_Os12g33130//expressed protein \n Os.8558.1.S1_at 4.388 D 0.629 -- LOC_Os02g11770//hypothetical protein \n OsAffx.23641.1.S1_at 3.635 D 0.595 -- LOC_Os01g43230//expressed protein \n OsAffx.31409.1.S1_s\\_at 3.558 D 1.314 -- LOC_Os11g40660//hypothetical protein \n Os.50018.1.S1_at 3.475 D 0.623 -- LOC_Os07g47750//expressed protein \n Os.53428.1.S1_at 3.391 D 0.600 -- LOC_Os09g26370//expressed protein Unknown\n Os.7382.1.S1_at 3.274 D 0.939 -- LOC_Os05g46950//expressed protein \n OsAffx.16877.1.S1_at 3.117 D 0.795 -- LOC_Os08g07490//expressed protein \n\nNine Bt rice-specific upregulated and 37 (38 probe-sets) Bt rice-specific downregulated genes, as well as four genes showing opposite responses to BPH between Bt and non Bt rice plants were identified. ",
"These genes are involved in carbohydrate, lipid, nucleotide and protein metabolism, growth regulation, signal transduction, stress responses, or they encode transcription factors and transporters. ",
"FC, fold change value; RP, regulation pattern; D, down regulated; U, up regulated; --, no significant change.",
"\n\nQuantitative RT-PCR verification of genes contributing to the effect of Bt rice on BPH performance\n--------------------------------------------------------------------------------------------------\n\nWe selected seven genes for qRT-PCR verification out of the 50 DEGs (51 probe-sets) that most likely contribute to the effect of Bt rice on BPH performance, including two TF genes, lipid metabolism gene *LTPL65*, early nodulin gene *ENOD93* (Os06g04990), ABA-responsive gene *Asr* and two other stress response genes. ",
"As shown in Figure [2](#F2){ref-type=\"fig\"}, the expression patterns of these seven genes were almost entirely consistent with the data obtained from microarray analysis, except for *ENOD93*. ",
"TF gene *bHLH* (Os01g38610) was specifically repressed, while *MYB* (Os04g56990) was specifically induced in Bt rice line. ",
"ABA responsive gene *Asr* (Os01g73250) and L-ascorbate oxidase *APx* (Os06g37150) were specifically downregulated upon BPH attack, while a pathogenesis-related thaumatin-like protein gene (Os12g43440) was specifically induced in Bt rice. ",
"The qRT-PCR analysis also confirmed the opposite expression patterns of *LTPL65* between Bt rice and non-Bt parent. ",
"However, the expression of *ENOD93* was dramatically increased in Bt rice upon BPH feeding, as revealed by qRT-PCR analysis, which contrasts with the results of microarray analysis.",
"\n\n{#F2}\n\nVerification of the involvement of phytohormones in induced BPH defense\n-----------------------------------------------------------------------\n\nPathway analysis of genes with similar expression patterns revealed that IAA and JA biosynthesis, and GA deactivation pathways were induced upon BPH feeding, while SA biosynthesis was suppressed. ",
"Analysis of DEGs also suggested that hormone biosynthesis and signaling genes probably participate in BPH-induced defense (Figure [3](#F3){ref-type=\"fig\"}; Supplementary Table [S5](#SM5){ref-type=\"supplementary-material\"}). ",
"Therefore, we analyzed the expression patterns of hormone biosynthesis and signaling genes, along with the endogenous concentrations of phytohormones including IAA, JA, GA, SA, and ABA.",
"\n\n{#F3}\n\nFour IAA biosynthesis-related DEGs were identified by microarray analysis. ",
"Upon BPH infestation, *indole-3-glycerol phosphate synthase (IGS)* and *amidase (AMI)* were upregulated, while *nitrilase (NIT)* and *IAA-amino acid hydrolase* were downregulated. ",
"All auxin-responsive *IAA/AUX* and *ARF* genes were downregulated except *OsIAA18*, which might have resulted from the reduced levels of IAA after BPH feeding (Figure [4](#F4){ref-type=\"fig\"}; Supplementary Table [S5](#SM5){ref-type=\"supplementary-material\"}). ",
"Meanwhile, most *SAUR* genes were induced. ",
"IAA concentrations were more significantly reduced in non-Bt parent (in which *NIT1* was markedly suppressed upon BPH feeding) than in Bt rice line. *",
"AMI* was significantly induced in Bt rice line, while a slight decrease in expression was revealed in non Bt parent by qRT-RCR analysis, which is also in accordance with the change in IAA levels (Supplementary Table [S5](#SM5){ref-type=\"supplementary-material\"}; Figure [4](#F4){ref-type=\"fig\"}). ",
"Three of four JA biosynthesis pathway genes and one JA signaling gene were upregulated in both rice lines in response to BPH infestation, which is consistent with the qRT-PCR results. ",
"However, the endogenous JA levels did not significantly increase, and it even decreased in Bt rice (Figures [3](#F3){ref-type=\"fig\"}, [4](#F4){ref-type=\"fig\"}). ",
"Microarray analysis revealed that the expression of bioactive GA biosynthesis genes *GA20ox1* and *GA20ox2* was suppressed by BPH attacking, and a more severe effect was found in Bt rice. ",
"GA inactivation gene *GA2ox1* was upregulated, while *GA2ox3* was downregulated, in response to BPH infestation, whereas most of the predicted GA receptor genes (such as *GID1L2*) were downregulated. ",
"In non-transgenic parental plants, GA levels showed no obvious changes, even though the reduced *GA20ox1* expression and inducted *GA2ox1* expression were verified by qRT-PCR. ",
"Significant reductions in GA~1~ levels were found in Bt rice line, although no significant change in *GA20ox1* was detected by qRT-PCR (Supplementary Table [S5](#SM5){ref-type=\"supplementary-material\"}; Figure [4](#F4){ref-type=\"fig\"}). ",
"BPH attack did not alter SA concentrations in either line, although the expression of *phenylalanine ammonia-lyase (PAL)* and *isochorismate synthase 1 (ICS1)* was suppressed. ",
"On the contrary, ABA concentrations were significantly reduced upon BPH infestation, but ABA biosynthesis-related genes did not show significant changes in expression, except for Mo-cofactor. ",
"In addition, 14 SA signaling-related WRKY TF genes were significantly induced, while ABA signaling and -responsive genes were either up- or downregulated upon BPH infestation (Supplementary Table [S5](#SM5){ref-type=\"supplementary-material\"}; Figures [3](#F3){ref-type=\"fig\"}, [4](#F4){ref-type=\"fig\"}). ",
"As indicated by microarray analysis, ET and BR biosynthesis-related genes were suppressed in both rice lines, while a cytokinin (CK) deactivating enzyme gene was upregulated upon BPH infestation. ",
"ET and CK signaling-related genes were either up- or downregulated in both rice lines. ",
"Seven of 9 BR signaling-related *BAK1* genes *(Brassinosteroid insensitive 1-associated receptor kinase 1)* were suppressed in both Bt and non-Bt rice plants, while one (Os11g31540) was dramatically induced in the non-Bt parent. ",
"In addition, significant changes in the expression of genes encoding AP2 domain-containing proteins were only detected in non-Bt parent.",
"\n\n{#F4}\n\nDiscussion {#s4}\n==========\n\nIn this study, we determined that the general response to BPH infestation is similar in Bt rice KMD2 vs. non-Bt parent Xiushui 11, as only approximately 10% of genes exhibited differential expression patterns. ",
"According to the results of pathway analysis, inhibition of chlorophyll biosynthesis, nitrogen assimilation, lipid metabolism and amino acid biosynthesis was detected in both rice lines. ",
"Meanwhile, IAA and JA biosynthesis and GA deactivation pathways were induced (Table [3](#T3){ref-type=\"table\"}). ",
"The expression of genes encoding protein inhibitors, pathogen-related proteins and other stress response genes was induced in response to BPH infestation, which is similar to many biotic and abiotic stress responses (Figure [1](#F1){ref-type=\"fig\"}). ",
"Indeed, continuous ingestion of phloem sap by BPH reduces plant growth by inducing leaf senescence and disrupting photosynthesis. ",
"Suppression of genes involved in photosynthesis and cell growth by BPH was also detected in Minghui63 (Yuan et al., [",
"@B93]). ",
"A shift from basic metabolism to defense responses appears to be a common strategy used by plants suffering from biotic and abiotic stress.",
"\n\nThe defense response of plants to piercing-sucking pests resembles the response to pathogens (Goggin, [@B27]; Wang et al., [",
"@B80]). ",
"As explained above, PTI, together with the effectors secreted in watery saliva, promote the basal resistance response, including the activation of Ca^2+^ influx as well as phytohormone and MAPK cascade signaling pathways. ",
"In the current study, Ca^2+^ signaling appeared to function in the BPH response, as a series of *calmodulin* genes were upregulated in response to infestation. ",
"Ascorbate peroxidase (APx) and most peroxidase (POD) family genes (21) were suppressed in both rice lines, which might result in the accumulation of H~2~O~2~ as a second messenger (Supplementary Table [S2](#SM2){ref-type=\"supplementary-material\"}; Figure [S1](#SM6){ref-type=\"supplementary-material\"}). ",
"By contrast, seven *POD* genes were induced after BPH attacking, especially in non-Bt parent, which suffered heavier oxidative stress (Supplementary Table [S3](#SM3){ref-type=\"supplementary-material\"}; Figure [S1](#SM6){ref-type=\"supplementary-material\"}). ",
"The induction of *POD* is thought to be required for the scavenging of excessive ROS.",
"\n\nMany studies have demonstrated that JA, SA, and ET are involved in BPH resistance. ",
"However, this effect is positive or negative remains controversial. ",
"The present results show that in response to BPH exposure, JA biosynthesis was activated while SA and ET biosynthesis was suppressed. ",
"A similar result was reported by Wei et al. ([",
"@B83]), who suggested that JA biosynthesis-related genes are induced by the wounding caused by BPH. ",
"However, in the current study, JA and SA levels were not significantly altered upon BPH attack, except for a reduction in JA levels in the Bt rice line. ",
"Meanwhile, all JA and SA signaling-related genes were activated after BPH infestation (Figure [4](#F4){ref-type=\"fig\"}; Supplementary Table [S5](#SM5){ref-type=\"supplementary-material\"}). ",
"Auxin, ABA and GAs have been shown to be involved in defense responses to aphid feeding (Divol et al., [",
"@B21]; Park et al., [",
"@B58]). ",
"ABA and IAA signaling were proposed to be associated with the rice--BPH interaction (Zhang et al., [",
"@B96]). ",
"The present results show that IAA and GA levels decreased as a result of the repression of biosynthesis-related genes or the induction of inactivation-related genes. ",
"In accordance with these observations, a number of signaling genes were downregulated in response to BPH. ",
"Similar results were obtained for BR, another regulator of plant growth and development. ",
"Therefore, the reduced growth of rice plants under BPH attack might be regulated by IAA, GA, and BR. ",
"A recent study revealed that WRKY70 is involved in the trade-off between defense and growth through regulating JA and GA biosynthesis (Li et al., [",
"@B43]). ",
"In the current study, ABA concentrations decreased significantly in both rice lines in response to BPH attack, although ABA biosynthesis genes showed no difference in expression. ",
"Mo-factors, as well as ABA signaling and responsive genes, were either down- or upregulated in response to BPH attack. ",
"Meanwhile, *Asr* (Os01g73250) was specifically suppressed in Bt rice plants (Supplementary Table [S5](#SM5){ref-type=\"supplementary-material\"}; Figure [2](#F2){ref-type=\"fig\"}). ",
"Extensive feeding by phloem feeders is thought to trigger water stress and senescence, which alters the expression of ABA-induced genes (Divol et al., [",
"@B21]). ",
"Based on our results, we conclude that phytohormones play a role in balancing plant growth and defense responses in plants under stress conditions. ",
"The growth related hormonrs are sensitive to herbivore attack. ",
"Expression of growth-related hormone signaling genes changed via feedback regulation. ",
"Thus, the shift from growth to defense is started in BPH-infested plants. ",
"Subsequently, defense-related hormone signaling pathways, such as the JA, SA, and ABA signaling pathways, directly regulate defense/resistance genes and, consequently, the levels of defense-related compounds. ",
"In addition, IAA- GA-, and BR-mediated signaling might also participate in induced BPH defense, as crosstalk among plant hormones commonly occurs in most biological processes. ",
"JA, ABA, and ET interact with GA signaling by modulating the levels of DELLA repressors or *ent*-kaurene synthase A (Achard et al., [",
"@B1]; Zentella et al., [",
"@B95]; Qi et al., [",
"@B60]; Yang et al., [",
"@B88], [@B87]). ",
"The GAST family gene *OsGSR1* activates BR biosynthesis by directly regulating a BR biosynthetic enzyme (Wang et al., [",
"@B78]).",
"\n\nWe detected 400 genes with differential responses to BPH between Bt rice and non-Bt parent plants, which suggests that some variation associated with the plant--BPH interaction might have occurred during plant transformation. ",
"We investigated 50 DEGs that probably contribute to the changes that render Bt rice less suitable for BPH consumption, including three early nodulin genes, four lipid metabolic genes, 14 stress response genes, three TF genes and genes with other functions. ",
"Nodulins were first recognized as a group of proteins induced by *Rhizobium* infection in the root nodules of leguminous plants (Legocki and Verma, [@B41]; Govers et al., [",
"@B28]). *",
"OsENOD93*, which was first isolated from rice by Reddy et al. ([",
"@B61]), is highly expressed in roots and suspension-cultured cells without elicitor. ",
"The identification of nodulin-like genes in non-nodulating plants suggests a possible role for nodulin-like proteins in regulating plant growth and development, although the functions of most nodulin-like proteins remain unclear. ",
"Recent studies have highlighted the transporter activity of nodulin-like proteins (Denancé et al., [",
"@B18]). ",
"Members of the early nodulin-like (ENODL) family are related to phytocyanin, but they lack amino acid residues for copper binding (Mashiguchi et al., [",
"@B53]). ",
"A phytocyanin-related early nodulin-like gene from *Boea crassifolia, BcBCP1*, increases osmotic tolerance in transgenic tobacco (Wu et al., [",
"@B85]). ",
"The *ENOD93* gene identified in the present study encodes a protein with two transmembrane domains and the conserved ENOD domain, which might be involved in carbohydrate transport, as proposed by Chen ([@B12]). ",
"This gene was induced by BPH infestation more strongly in Bt rice than in non-Bt parent plants, as revealed by qRT-PCR, which contrasts with the results of microarray analysis. ",
"Whether this gene is involved in BPH defense requires further study.",
"\n\nPlant non-specific lipid transfer proteins (nsLTPs) transport phospholipids, as well as glycolipids, across membranes. ",
"The antimicrobial activity of nsLTPs was first discovered by screening plant extracts that inhibit the growth of pathogens *in vitro*. ",
"LTPs isolated from the leaves of barley, maize, Arabidopsis and spinach (*Spinacia oleracea*) have antimicrobial activity against the bacteria *Clavibacter michiganensis* subsp. *",
"sepedonicus* and *Ralstonia solanacearum* and the fungus *Fusarium solani* (Molina et al., [",
"@B54]; Segura et al., [",
"@B67]). ",
"Rice LTP expressed in *Escherichia coli* has activity against *Pyricularia oryzae* and the bacterium *Pseudomonas syringae*, and it delays the growth of *Xanthomonas oryzae* (Ge et al., [",
"@B26]). ",
"In addition to the pathogen response, *nsLTP* genes are also regulated by abiotic stress in maize (*Zea mays*) and wheat (*Triticum aestivum* L.) (Jang et al., [",
"@B37]; Wei and Zhong, [@B82]). ",
"Therefore, plant nsLTPs are thought to play an important role in plant defense. ",
"In the present study, 10 *LTP* genes were regulated by BPH infestation, nine of which showed differential responses to BPH damage between rice lines. *",
"LTPL159* and *LTPL82* (encoding 2S albumin storage protein according to Boutrot et al., [",
"@B8]) were more highly induced in non-Bt parent. ",
"The expression of four *LTPL* genes was more significantly reduced in Bt rice than in non-Bt parent. *",
"LTPL65* was repressed in the non-Bt parent but significantly upregulated in Bt rice plants. ",
"Therefore, we speculate that LTPs are involved in the BPH defense response, especially LTPL65. ",
"The hypothesis that LTPs are involved in plant systemic resistance signaling was previously proposed by Maldonado et al. ([",
"@B52]). ",
"Buhot et al. ([",
"@B9]) revealed that tobacco (*N. tabacum*) LTP1 can bind to JA, and formation of the LTP--JA complex facilitates its recognition by elicitin receptors, thus inducing long distance protection against *Peronospora parasitica*. ",
"Arabidopsis AZI1, an LTP-related hybrid proline-rich protein, was identified as a novel target of MPK3, which is involved in salt stress signaling (Pitzschke et al., [",
"@B59]). ",
"Moreover, major allergens in *Asparagus officinalis, B. oleracea* var. *",
"capitata* and *Zea mays* are LTP family proteins (van Ree, [@B75]; Palacín et al., [",
"@B56]; Carvalho and Gomes, [@B10]). ",
"Rice LTPL65 has a glycosyl phosphatidylinositol (GPI)-anchor in addition to its eight cysteine motif backbone, which helps this protein attach to the exterior side of the plasma membrane. ",
"Therefore, this protein is more like a signaling component than an allergen. ",
"The exact role of nsLTPs in BPH defense remains to be determined.",
"\n\nTFs are protein complexes that can help RNA polymerase bind to specific DNA sequences, thereby controlling the rate of gene transcription. ",
"WRKY genes have been implicated in multiple biotic and abiotic stress responses (Barah et al., [",
"@B4]; Wang et al., [",
"@B76]). ",
"In the present study, all WRKY genes responsive to BPH attack were upregulated, especially in non-Bt parent plants. ",
"WRKY genes are also induced by cabbage aphid attack in Arabidopsis, whereas they are repressed by both aphid and whitefly attack in cotton (Kusnierczyk et al., [",
"@B40]; Dubey et al., [",
"@B23]). ",
"Silencing of *SlWRKY70* attenuates *Mi-1*-mediated resistance against potato aphid and root-knot nematode, showing that *SlWRKY70* is required for *Mi-1* function (Atamian et al., [",
"@B3]). ",
"NAC, MYB, and zinc finger TF family members are primarily responsive to pathogen infection and abiotic stress (Huang et al., [",
"@B35]; Xia et al., [",
"@B86]; Liu et al., [",
"@B47]; Deng et al., [",
"@B19]; Sun et al., [",
"@B69]). ",
"AP2, NAC, and zinc finger family TFs, together with WRKY, are thought to be stress sensitive or involved in inducible defense responses, as more significant responses were detected in the more severely affected non-Bt parent. ",
"Meanwhile, *MYB* (Os04g56990) was induced upon BPH infestation, especially in Bt rice. ",
"One bHLH family TF gene was specifically repressed in Bt rice line (Os01g38610), while another was specifically repressed in non-transgenic parent plants (Os04g49450). ",
"The two TF genes that showed more significant responses in Bt rice (*bHLH* \\[Os01g38610\\] and *MYB* \\[Os04g56990\\]) are considered to represent candidate genes involved in the variation in Bt rice related to its impact on BPH performance. ",
"MYB and bHLH family TF genes were also identified as constitutive BPH resistance genes by Wang et al. ([",
"@B79]). ",
"MYB TF is thought to function in reallocating energy to enhance defense responses, as several members of this gene family play important roles in photosynthesis and related metabolism (Saibo et al., [",
"@B63]). ",
"R2R3-MYB and bHLH type TFs are also involved in the phyenylpropanoid pathway through regulating the biosynthesis of anthocyanin (Schwinn et al., [",
"@B66]). ",
"It was recently demonstrated that plants prioritize defense over growth through regulation by WRKY. ",
"Moreover, an R2R3-type MYB TF, NaMYB8, modulates the accumulation of phenylpropanoid polyamine conjugates, which are involved in herbivore defense (Kaur et al., [",
"@B39]). ",
"Identifying the targets of the candidate TFs requires further study.",
"\n\nConclusion {#s5}\n==========\n\nWe compared the expression profiles of Bt rice vs. its non-transgenic parent in response to BPH infestation, as a previous study revealed significantly longer nymphal developmental duration and lower fecundity in BPH fed on KMD2. ",
"Basic metabolism, as well as growth-related hormone biosynthesis and signaling, were inhibited in response to BPH attack, while defense-related hormone signaling was induced. ",
"Based on our results, we conclude that phytohormone signaling play an important role in the shift form plant growth to defense in plants under stress conditions. ",
"Further studies on the crosstalk between growth-related hormone signaling and defense-related hormone signaling may come to be a key to understand the mechanism of plants\\' fight against biological or abiological stresses.",
"\n\nWe found that 10% of genes showed differential responses to BPH between Bt rice and its non Bt parent, including 50 DEGs that are likely related to the impact of Bt rice on BPH performance. ",
"Among these, the early nodulin gene *ENOD93* and non-specific lipid transfer protein gene *LTPL65*, as well as two TF genes, are considered to represent candidate genes that contribute to the enhanced defense of Bt rice to BPH. ",
"Whether these genes could be used to improve rice BPH resistance remains to be investigated.",
"\n\nAuthor contributions {#s6}\n====================\n\nFW, YC, and GY conceived and designed and performed the experiments. ",
"FW and YC performed the microarray analysis and analyzed the data. ",
"FW, DN, CD, NH, and YL contributed to the preparation of experiment materials, and qRT-PCR, LC-MS analysis. ",
"FW wrote the manuscript.",
"\n\nFunding\n=======\n\nThis work was supported by the National Special Transgenic Project from the Chinese Ministry of Agriculture (2014ZX08011-001), and China National Science Fund for Innovative Research Group of Biological Control (Grant No. ",
"31321063).",
"\n\nConflict of interest statement\n------------------------------\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.",
"\n\nWe greatly thank Prof. Shu QY for the development of the Bt rice KMD2. ",
"We thank Ms. Wu XD, the technician of Core Facilities for Agriculture, Life and Environment Sciences of Zhejiang University, for her contribution in carrying through the LC-MS analysis of plant hormone. ",
"Microarray data used in this study have been deposited in the GeneExpression Omnibus database at the National Center under the accession nos. ",
"GSE74745.",
"\n\nSupplementary material {#s7}\n======================\n\nThe Supplementary Material for this article can be found online at: <http://journal.frontiersin.org/article/10.3389/fpls.2015.01181>\n\n###### \n\nClick here for additional data file.",
"\n\n###### \n\nClick here for additional data file.",
"\n\n###### \n\nClick here for additional data file.",
"\n\n###### \n\nClick here for additional data file.",
"\n\n###### \n\nClick here for additional data file.",
"\n\n###### \n\nClick here for additional data file.",
"\n\n[^1]: Edited by: Sagadevan G. Mundree, Queensland University of Technology, Australia\n\n[^2]: Reviewed by: Rita Sharma, Jawaharlal Nehru University, India; Tejinder Kumar Mall, Dow Agrosciences, USA\n\n[^3]: This article was submitted to Plant Biotechnology, a section of the journal Frontiers in Plant Science\n"
] | {
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"[General anesthesia in infants].",
"\nIt is generally accepted, that the progress in surgical treatment of congenital malformation is closely related to the progress in highly-specialised methods of newborn anaesthesia. ",
"The safe methods of anaesthesia have to be adapted to anatomical and physiological peculiarities of the earliest days of life as well as to different reaction to drugs and anaesthetics. ",
"The preoperative preparation in newborns used to be often very short, because most of the problems of the neonatal period are emergency surgical interventions and there is no time for treatment even of the serious disturbances of basic physiological functions. ",
"The purpose of this study was to estimate methods of general anaesthesia in newborns, which have been introduced in the Anaesthesiology Department of the National Research Institute of Mother and Child. ",
"The main element of these methods was general anaesthesia with muscle relaxants and controlled ventilation as a routine. ",
"The estimation was based on general analysis of 10 years practice when these methods of anaesthesia were used. ",
"During this time 515 anaesthesias to 408 both-sex newborns were given (Tab. ",
"I, Fig. ",
"1). ",
"85% of anaesthetized newborns were operated because of congenital malformations (Tab. ",
"I); 46% of operations were performed during their first week of life, 21% were operated in first 24 hours of life, mostly as an emergency (Fig. ",
"3). ",
"10% of operations were performed is prematures (body weight below 2500 g) (Fig. ",
"4). ",
"The \"routine\" anaesthesia was given in 82% cases. ",
"Awake intubation in unpremedicated newborns was performed. ",
"Anaesthesia was maintained with nitrous oxide-oxygen mixture (1:1 or 2:1). ",
"D-tubocurarine in 95% of cases was used. ",
"The initial dose 0,5 with matures and 0,25 mg with premature babies was used. ",
"If necessary supplementary doses were given. ",
"During anaesthesia, intermittent positive pressure ventilation (IPPV) with frequency at least 60/min. ",
"was used. ",
"During this ventilation, hyperventilation and positive end-expiratory pressure (PEEP) were obtained. ",
"Precordial stetoscope and thermometer probe was used as a routine. ",
"In some special cases eCG, end-expired CO2 (capnography), pletysmography were also recorded; blood gas analyses were checked. ",
"All intra- and postoperative complications as well as postoperative mortality have been analysed in details. ",
"During 3,3% of operations some complications had been observed. ",
"The total incidence of early psotoeprative complications was 20%. ",
"In this group the most frequent were respiratory complications (16,1%). ",
"Serious disturbances in pulmonary gas exchange during operation and early postoperative period were not found.(ABSTRACT TRUNCATED AT 400 WORDS)"
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"#bFair2DirectCare\n\nAs laws and policies continue to change and develop in our state and our nation, FREE is so proud to support the #bFair2DirectCare campaign. #",
"bFair2DirectCare is an online movement urging Governor Cuomo how important it is to make sure he allocates money in his budget to help non-profits pay their DSP salaries as the minimum wage goes up. ",
"Out DSPs are our front lines. ",
"Without them, our industry cannot exist.",
"\n\nTo support this cause, FREE has been asking individuals, Valued Team Members, and family members of people who receive services to share on camera, what this issue means to them, in hopes that their stories will reach the ears of our legislators."
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