Datasets:

tomekkorbak
/

detoxify-pile-chunk3-6100000-6150000

Dataset card Viewer Files Files and versions Community

Split (1)

train · 50k rows

texts sequence	meta dict	scores sequence	avg_score float64 0 1	num_sents int64 1 45.1k
[ "Q:\n\nChange active tab depending on scroll position\n\nI'm currently messing around with trying to create a one page website. ", "At the moment I've got the navigation menu to scroll to the selected part of the website when clicked and active tab will change on click too. ", "But what I'm trying to figure out is how to make the css change to the active tab when the next page has been scrolled on to (and not clicked in the menu).", "\n$(document).ready(function(){\n $(\"nav ul li\").click(function(){\n var sectionClass = $(this).attr('class'); \n if ($(this).hasClass('active')){\n }\n else {\n $(\"nav ul li.active\").removeClass('active'); \n $(this).addClass('active'); \n sectionId = $(this).attr('id');\n var parts = sectionId.split(\"_\");\n $('html, body').animate({ \n scrollTop: $(\"#\" + parts[1]).offset().top\n }, 'slow');\n }\n });\n });\n\n<body>\n <nav class=\"nav-bar\">\n <ul>\n <li class=\"active\" id=\"menu_index\">Welcome</li>\n <li id=\"menu_page1\">Menu1</li>\n <li id=\"menu_page2\">Menu2</li>\n <li id=\"menu_page3\">Menu3</li>\n <li id=\"menu_page4\">Menu4</li>\n </ul>\n </nav>\n <div id=\"index\"></div>\n <div id=\"page1\"></div>\n <div id=\"page2\"></div>\n <div id=\"page3\"></div>\n <div id=\"page4\"></div>\n</body>\n\nhttps://jsfiddle.net/nsefqo3w/\nAdded jsfiddle to show how it is just now, I'm new so you'll probably spot a few problems!", "\n\nA:\n\nChange your menu to be setup like this:\n<ul>\n <li><a href=\"#page1\">Page 1</a>\n ...\n</ul>\n\nThis way it scrolls to the DOM element with an id of page1 when the anchor is clicked.", "\nThen you can use the following code to mark as active on scroll:\nfunction onScroll(event){\nvar scrollPos = $(document).scrollTop();\n$('li>a').each(function () {\n var currLink = $(this);\n var refElement = $(currLink.attr(\"href\"));\n if (refElement.position().top <= scrollPos && refElement.position().top + refElement.height() > scrollPos) {\n $('li>a.active').removeClass(\"active\");\n currLink.addClass(\"active\");\n }\n else{\n currLink.removeClass(\"active\");\n }\n});\n}\n$(document).ready(function () {\n $(document).on(\"scroll\", onScroll);\n});\n\nEDIT:\nUse your own jQuery code so that it changes to active on onclick as well.", "\nSource: http://jsfiddle.net/cse_tushar/Dxtyu/141/\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.0006592459976673126, 0.0005539725534617901, 0.0005743395886383951, 0.0012396175879985094, 0.0007978410576470196, 0.001213535200804472, 0.0007568766595795751 ]	0.000828	7
[ "Ethan Miller via Getty Images Donald Trump often makes himself available to TV networks by phone, and his racism and bigotry generate major headlines. ", "Thanks in part to both of those factors, he's received millions in free media attention this election cycle.", "\n\nDonald Trump received nearly $2 billion in free media exposure this past year, dwarfing his Republican rivals and more than doubling the attention paid to Democratic front-runner Hillary Clinton, according to tracking firm mediaQuant.", "\n\nTrump received $1.9 billion in free, or \"earned,\" media coverage, yet spent just $10 million on paid advertisements this election cycle. ", "While Texas Sen. Ted Cruz, Florida Sen. Marco Rubio and Ohio Gov. John Kasich each spent more money than Trump on ads, the Republican candidates clocked in at $313 million, $204 million and $38 million in free media respectively.", "\n\nThe New York Times first reported Tuesday on Trump's \"mammoth advantage in free media\" using data provided by mediaQuant. ", "In an interview with The Huffington Post, mediaQuant Chief Analytics Officer Paul Senatori discussed the firm's 2016 findings and comparisons between the candidates and major national and world figures.", "\n\nHere's how it works: The Portland-based mediaQuant tracks mentions in over 20,000 English-language outlets for many boldface names, ranging from Pope Francis to Taylor Swift to everyone who ran (or considered running) for president in 2016. ", "The company generates a current media rating for each person based on the quantity and quality of that exposure, ranging from 0 to 100.", "\n\nIn computing the value of earned media, mediaQuant runs the number of raw mentions through an algorithm assessing the tone of the coverage -- whether positive, negative or neutral -- and considers the media outlet's reach and its advertising rates.", "\n\nThough mediaQuant doesn't break down how much free media a candidate has received on, say, CNN or in The New York Times, Senatori said the majority of the value computed comes from television and top-tier publications with a national or global footprint. ", "Given smaller ad rates, a candidate would need a substantial number of tweets before that social media attention translated into significant free media dollars.", "\n\nWhile many of the other 2016 candidates plateaued and later dipped in terms of their earned media this election cycle, Senatori said that Trump, currently with a 98 rating, never faded from headlines around the world.", "\n\n\"He has consistently maintained high ratings and media values across all media segments, social and traditional, and it hasn’t ebbed at all,\" Senatori said.", "\n\nAccording to mediaQuant, the Republican front-runner has received far more free media coverage than Clinton, who has $746 million, and Vermont Sen. Bernie Sanders, who has $321 million.", "\n\nWhat's striking in digging through mediaQuant's data is how well top-tier 2016 contenders stack up against other world leaders and some of the biggest names in sports and entertainment.", "\n\nFor example, Taylor Swift, Kim Kardashian and Kanye West received $497 million, $250 million and $234 million in free media, respectively, over the past year. ", "Athletes like recently retired NFL quarterback Peyton Manning and Golden State Warriors star Stephen Curry came in with $29 million and $15 million, respectively.", "\n\nSenatori pointed out that 2016 candidates, unlike even major cultural figures, have benefited from heavy and sustained coverage.", "\n\n\"A dynamic in the election sector is the consistent and continuous coverage,\" Senatori said in an email. \"", "Celebrities, athletes and commercial brands tend to spike on episodal or event-based coverage, i.e. awards, divorces, album release, MVP announcement, quarterly earnings, etc. ", "Trump and Cruz are enjoying a 8+ month non-stop media 'event.'\"", "\n\n\"At the end of the month,\" he said, referring to when mediaQuant reports its analytics, \"that media firehose really adds up.\"", "\n\nTrump and a few other 2016 candidates have topped world figures like Russian President Vladimir Putin ($229 million) and the pope ($128 million).", "\n\nBut while Trump currently enjoys a higher media rating than President Barack Obama, who has a score of 91, mediaQuant found that the current president still leads all would-be successors in earned media this past year, with $2.58 billion.", "\n\nEditor's note: Donald Trump is a serial liar, rampant xenophobe, racist, misogynist, birther and bully who has repeatedly pledged to ban all Muslims -- 1.6 billion members of an entire religion -- from entering the U.S." ]	{ "pile_set_name": "OpenWebText2" }	[ 0.012498647905886173, 0.0005739606567658484, 0.0006711370660923421, 0.0006821595598012209, 0.0007698019035160542, 0.0006200835923664272, 0.0005708576645702124, 0.0005498210666701198, 0.0005725878290832043, 0.0005892503540962934, 0.0005842057289555669, 0.0006033337558619678, 0.0006482317112386227, 0.0006039945874363184, 0.0007470708223991096, 0.000622935185674578, 0.0005898945964872837, 0.000692644331138581, 0.0005958399269729853, 0.0005479272222146392, 0.0005574869574047625, 0.0005941576091572642, 0.0006191740976646543, 0.0005863271071575582, 0.0006719063385389745, 0.9358455538749695 ]	0.037046	26
[ "Induction of TGF-β and IL-10 production in dendritic cells using astilbin to inhibit dextran sulfate sodium-induced colitis.", "\nAstilbin, a major bioactive compound from Rhizoma smilacis glabrae, has been reported to possess anti-inflammatory properties. ", "Our study first evaluated astilbin on dextran sulfate sodium (DSS)-induced acute colitis in mice. ", "By intraperitoneal injection of astilbin, the severity of colitis was attenuated, and the serum levels of IL-10 and TGF-β were increased. ", "Using flow cytometry, a higher number of IL-10(+) dendritic cells (DCs) and TGF-β(+) DCs and a lower number of CD86(+) DCs, IL-12 p40(+) DCs, and IL-1β(+) DCs were detected in the spleen of mice with colitis after astilbin treatment. ", "The administration of astilbin also resulted in the upregulation of CD103(+) expression in colonic DCs. ", "In a coculture system, murine bone marrow-derived DCs pretreated with astilbin resulted in an enhanced production of CD4(+)CD25(+)Foxp3(+) T cells. ", "The results of this study show that astilbin could be a candidate drug for inflammatory bowel disease by mediating the regulatory functions of DCs." ]	{ "pile_set_name": "PubMed Abstracts" }	[ 0.0008140194695442915, 0.001015482353977859, 0.0006568800308741629, 0.00075100566027686, 0.0009286011918447912, 0.0009681529481895268, 0.0011183758033439517, 0.0012800192926079035 ]	0.000942	8
[ "K. G. Shantha\n\nK. G. Shantha (, 4 August 1979–1 November 2008) was a senior non-commissioned officer in the Sri Lanka Navy. ", "He was killed in a sea battle against the Sea Tigers, the naval wing of the Liberation Tigers of Tamil Eelam, in the seas of northern Sri Lanka. ", "He posthumously received the Parama Weera Vibhushanaya, the country's highest award for gallantry, and is the second recipient of the medal from the navy.", "\n\nPersonal life\nShantha was born to K. G. Gunathilaka and R. M. Dollienona, and resided in Norwood, Hatton. ", "He was married at the time of his death, to R. M. S. R. Dissanayake.", "\n\nAction on 1 November 2008\n\nOn the dawn of 1 November 2008 at approximately 5.45 am, a battle erupted between the navy and a group of Sea Tiger boats off the coast between Point Pedro and Nagar Kovil, near the northern tip of Sri Lanka. ", "At the time, Shantha was a Petty Officer in the navy's elite Special Boat Squadron (SBS). ", "He was in command of the Arrow-class patrol boat Z-142, which was armed with a 23 mm autocannon and two machine guns, and was part of the navy group engaged in the battle. ", "\n\nShantha and his crew engaged the Sea Tiger vessels, using the high maneuverability of the Z-142 to their advantage. ", "However, all three gunners were eventually incapacitated, and Shantha was left unable to attack the enemy boats now approaching the navy's larger vessels. ", "A Sea Tiger suicide boat was heading towards the P-164, a Colombo-Class fast attack craft of the 4th Fast Attack Flotilla carrying 10 sailors. ", "Seeing this, Shantha maneuvered the Z-142 into the path of the suicide boat and rammed it. ", "He was killed in the resulting explosion which obliterated the suicide boat and the Z-142 with it, but the P-164 and its crew were spared. ", " \n\nThe outcome of the battle is unclear, as both sides claimed victory. ", "The Sea Tigers claimed that they had sunk two navy vessels and forced them to retreat, while the navy claimed that they successfully repelled the attack and destroyed at least four Sea Tiger vessels with the assistance of the air force.", "\n\nRecognition\nShantha was promoted posthumously to the rank of Chief Petty Officer. ", "On 16 December 2011, a house was donated to his family, which was constructed by the Naval Engineering Division with funding from First Lady Shiranthi Rajapaksa. ", "\n\nHe was recommended for the Parama Weera Vibhushanaya, the country's highest military award for gallantry, for his actions on 1 November 2008. ", "The decision to award the medal to Shantha and 14 others was announced in The Sri Lanka Gazette on 16 May 2012. ", "It was presented to his next-of-kin three days later on 19 May 2012 by Mahinda Rajapaksa, the President of Sri Lanka, at a ceremony held at the celebrations marking the third anniversary of the end of the war. ", "The citation for Shantha's Parama Weera Vibhushanaya commends him as a \"bold sailor [who] commanded his craft in the midst of danger, using his instinct and wisdom, encouraging his fellow sailors, disregarding the risk to own life and security, with the objective of safeguarding thereby the lives of his comrades.\"", "\n\nShantha was the second recipient of the Parama Weera Vibhushanaya from the navy, after Lieutenant Commander Jude Wijethunge who received it posthumously for similar actions in 1996.", "\n\nReferences\n\nCategory:Recipients of the Parama Weera Vibhushanaya\nCategory:Special Boat Squadron personnel\nCategory:2008 deaths\nCategory:Sri Lankan military personnel killed in action\nCategory:1979 births" ]	{ "pile_set_name": "Wikipedia (en)" }	[ 0.0010445809457451105, 0.0027105682529509068, 0.0006522503099404275, 0.0007593539194203913, 0.001036414410918951, 0.000649283523671329, 0.0006497715949080884, 0.001276727532967925, 0.0013927293475717306, 0.001019155140966177, 0.004731729626655579, 0.00177931715734303, 0.007316115777939558, 0.0006571956328116357, 0.0009762112749740481, 0.000818567059468478, 0.0006112957489676774, 0.0006120320176705718, 0.0005849297158420086, 0.0005630122032016516, 0.0011771920835599303, 0.0007007585372775793, 0.0006703974213451147 ]	0.001408	23
[ "No Coroadinho, a quarta maior favela do país e a primeira do Norte e Nordeste - segundo o último censo realizado pelo Instituto Brasileiro e Geografia e Estatística (IBGE) - pelo menos 65% dos jovens estão envolvidos em crimes ou consomem algum tipo de droga, enquanto 70% das famílias ganham menos de um salário mínimo, hoje, cotado no valor de R$ 788.", "\n\n\n\nOs dados fazem parte de uma pesquisa realizada pela ONG Instituto Cidadania Ativa. ", "O estudo traçou o perfil da região, em relação à violência social, com ajuda de dados sociais: informações recebidas por denúncias anônimas e entrevistas com famílias moradoras do bairro.", "\n\n\n\n“A partir de um momento que você tem um jovem que é criado em família que ganha menos de um salário mínimo, que não tem uma boa escola, uma boa alimentação, ele é uma mão de obra de fácil captação para o mundo do crime”, afirmou Maurício Miguel, presidente da ONG.", "\n\nPara o juiz Roberto de Paula, que trabalhou 17 anos na Vara de Execuções Penais, as facções criminosas, que se organizaram dentro dos presídios, avançaram para os bairros e aumentaram os índices de criminalidade em São Luís.", "\n\n\n\nAlém da violência, o Coroadinho sofre com a ausência do poder público e isso contribuiu para que que as facções tomassem uma dimensão expressiva. ", "O juiz diz que estudos mostram diminuição da criminalidade nas comunidades onde há investimento em saúde, trabalho, infraestrutura, moradia, educação e saneamento básico.", "\n\n\n\n“Não se combate violência só com repressão. ", "É preciso que haja inclusão social. ", "Na hora que o estado intervém, tanto com as forças de segurança como com as políticas de inclusão social, todos os estudos demonstram isso, consequentemente se diminui a violência”, observou.", "\n\n\n\nEntenda o caso\n\nA guerra entre facções rivais pelo controle do tráfico de drogas resultou em oito mortes em 16 dias, média de uma vítima dos criminosos a cada dois dias. ", "Os casos mais recentes envolvem a morte de um comerciante e três suspeitos de envolvimento no crime organizado.", "\n\n\n\nAlém disso, mais de 50 famílias foram expulsas de casa por traficantes que comandam o crime na região do Coroadinho. ", "Nesta quarta-feira (17), a polícia realizou uma operação de ocupação no bairro para garantir que novos casos não fossem registrados." ]	{ "pile_set_name": "OpenWebText2" }	[ 0.03628196567296982, 0.293012797832489, 0.028936516493558884, 0.037607207894325256, 0.10404013842344284, 0.09795913100242615, 0.034277014434337616, 0.06185848265886307, 0.0191512331366539, 0.09693735837936401, 0.13815124332904816, 0.011084446683526039, 0.022113386541604996, 0.009760191664099693 ]	0.070798	14
[ "[Value of medical treatment of cancer of the kidney].", "\nRenal carcinomas have a very variable natural history and are generally not very sensitive to medical treatment particularly chemotherapy. ", "The response rates obtained in metastatic cancer with various drugs and combinations do not exceed 15% for a duration of response of several months. ", "The most effective drugs are vinca alkaloids such as vinblastine. ", "Over recent years, interferon has been tested in this type of tumour with discordant results reported in the literature. ", "However, it seems that by using high doses of the order of 15 to 20 million units per m2, three times a week, the response rates are of the order of 20% for a duration which may be as long as one year in responding patients. ", "In combination with vinblastine, some authors have obtained response rates of the order of 40%. ", "Treatment is especially effective in the case of lymph node recurrence or small lung metastases. ", "It is of no value in cases of visceral, bone or hepatic dissemination. ", "It is frequently poorly tolerated systemically because of the high doses administered and it is expensive. ", "It should therefore be reserved to young patients and to patients with an reasonable life expectancy. ", "In cases of operated renal cancer at risk of recurrence because of local or lymph node spread, no adjuvant medical treatment has yet been proven to be effective." ]	{ "pile_set_name": "PubMed Abstracts" }	[ 0.000899505103006959, 0.0006729362066835165, 0.0006976799922995269, 0.0018342650728300214, 0.0005743636866100132, 0.0005669945967383683, 0.0006257455097511411, 0.002627936890348792, 0.0009207367547787726, 0.0006880507571622729, 0.0005674133426509798, 0.0010988822905346751 ]	0.000981	12
[ "Q:\n\nChecking access in Views\n\nI posted a support request on Drupal.org, but I thought I may find a faster answer here.", "\nI am using the User Relationships module to create mutual relationships between two people with the purpose of viewing content. ", "The node access part of UR seems to work fine. ", "I am having trouble with Views, though.", "\nCan anyone explain to me how I would do the following?", "\n\nCreate a View containing content a user (not current logged in user) has created, filtered by a content type (lets call it Image). ", "This view has a path with an argument like user/%/images.", "\nWhen the current user goes to user/%/images, it should show the images for whichever user ID is passed as the argument ONLY IF both users are related/accepted relationship. ", "There is only one relationship type on the website. ", "If there is no relationship, I would like to serve Access Denied, or at the very least, Page Not Found. ", "But 403 makes more sense.", "\n\nI cannot get this to work.", "\nMy goal is to show links to different types of contents users have created, and the viewing user (requester?) ", "needs to have a relationship to view the content. ", "Otherwise they should see nothing at all, or return an access denied error.", "\n\nA:\n\nWhat you need is to create a custom views access plugin. ", "I found a blog post that contains the basic information about how to do that here: http://techcp.wordpress.com/2011/01/11/adding-custom-access-plugin-to-views-in-drupal/\nYou then need at least need to do two specific things:\na) Extend it so that the access callback function receives the second url argument as the argument (in function get_access_callback(), change array() to array(1)).", "\nb) In defined access callback function, check if there is a relationship between the currently logged in users and the uid that gets passed in, by using user_relationships_load() (documentation is for D7, but very similar in D6). ", "Something like this (untested):\nfunction your_access_callback($uid_viewed) {\n global $user;\n $params = array('between' => array($user->uid, $uid_viewed));\n return (bool) user_relationships_load($params, array('count' => TRUE));\n}\n\nThat should already be enough to make it work four your case. ", "However, this sounds like an interesting improvement to UR in general, for this, two additional things would be necessary.", "\nc) Allow to configure which argument is the user id. Maybe there are also other ways where it could come from (if the view is displayed as a block for example). ", "Not sure how to do that.", "\nd) Allow to configure which relationship type should be checked. ", "Expose a form element for that in the options and then pass the chosen relationship type id to your access callback and in there to user_relationships_load().", "\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.0005433181650005281, 0.0005569293862208724, 0.0007280937279574573, 0.000628852634690702, 0.0006325651193037629, 0.0006761421100236475, 0.0011185387847945094, 0.0006264460389502347, 0.0006010792567394674, 0.0007192663033492863, 0.0006225496181286871, 0.0012514019617810845, 0.0005613350658677518, 0.0005721044726669788, 0.000894028868060559, 0.0006288820295594633, 0.0005901710246689618, 0.0006006073672324419, 0.0008920629043132067, 0.0005451594479382038, 0.0007142052636481822, 0.000730664876755327, 0.0006551953847520053, 0.000609804003033787, 0.001994825666770339 ]	0.000748	25
[ "Category Archives: Articles\n\nA material handling system is a set of equipment that is used to physically move material around the factory floor or in storage and freight handling areas.", "\n\nTraditional material handling systems included trolleys, conveyors, forklifts and overhead traveling cranes. ", "They were primarily mechanized devices and a large amount of manual intervention was required. ", "These traditional systems had limitations such as low speed and handling problems including scratching, chipping, breaking and difficulty in monitoring material flow. ", "However, these material handling systems were adequate for mass production of a limited variety products or low volume production.", "\n\nAt present, market forces demand that manufacturing systems be lean, agile and highly automated. ", "Modern manufacturing systems need to handle a variety of components for increasing product customization, reduced lot sizes and variable product mixes. ", "This has led to the requirement for automated equipment and systems that move faster, accommodate greater throughput, and require less maintenance than the earlier material handling systems.", "\n\nTo cope with these requirements, a new breed of material handling systems has been recently developed. ", "These include automated storage and retrieval systems, carousels, rail guided and automated guided vehicles, intelligent flexible modular conveyors, pick and place units, vertical lifts and high density storage systems. ", "Gripper or holding devices are also available for fragile, delicate and super finished components.", "\n\nUsually material handling takes place along all the links of the supply chain, including production, distribution, storage and retail functions. ", "Minimizing the complexity and number of handling operations can increase productivity. ", "Most material movements need to be automated and simple. ", "A detailed analysis needs to be carried out to track the flow of material, before installing the material handling equipment.", "\n\nIt is important to note that there is an increasing demand for real-time information at all stages of the distribution and supply chains. ", "Material handling systems need to be connected to sensing devices that provide essential information for handling, such as the location or status of the material. ", "This requirement is basic and is usually met with, but the importance of connecting handling equipment to a broader network and the plant management system has not yet been fully recognized by some companies.", "\n\nConveyor systems are a type of material handling equipment that is used to transfer products from one location to another. ", "The types of materials could be raw materials, food, chemicals in fact any material that needs to be moved to the next process of production, inspection, packing or dispatching.", "\n\nThere are many different types of conveyors such as overhead conveyors, belt conveyors, bucket elevators, food conveyors, pivoting bucket elevators, pendulum bucket elevators and vibratory conveyers to name a few. ", "These are powered by an electric motor, air pressure or vacuum.", "\n\nThe overhead conveyor can be used for many items such as assembly, distribution and food. ", "The certainly don’t come cheap but the amount of manpower they reduce well makes up for the cost. ", "You are also gaining some much appreciated floor space and reducing and preventing accidents. ", "This type of conveyor is used extensively in the tyre, white goods and car exhaust industries.", "\n\nA bucket elevator which can also be called a grain leg is a mechanism for moving flowable bulk materials vertically. ", "This can be bulk materials which are either light weight or heavy, from fine to larger lumps. ", "Basically this type of conveyor consists of the buckets which are used to contain the material, a belt to carry the buckets and transmit the pull, the power that drives the belt and any accessories for loading the buckets or picking up the material Bucket elevators can be designed to ensure that all handling of the product is undertaken using methods that are inherently gentle and cause minimum distress to the products being moved.", "\n\nBelt Conveyors are used for moving multiples of bulk or unit load products to different points within the processing system. ", "These are low cost, product specific conveyor systems which use standard conveying components in order to move within a process or to an end of line packing facility. ", "They can be controlled by a simple push button operation at each stopping position or coupled to intelligent controls to allow a set period at each position before moving on. ", "This form of conveyor includes Troughed, Dished Boom, Flat Bed or Plastic Modular.", "\n\nAnother type of conveyor is a roller conveyor which is also cost affective and very versatile. ", "These have evolved and now you can get advanced powered roller conveyors which are designed for heavy duty applications such as pallet handling, automotive applications or storage where heavy product is loaded onto the conveyor via a machine or fork lift. ", "Most are manufactured out of mild steel but have heavy duty rollers which are powered by a shaft mounted geared motor.", "\n\nYou can get conveyors designed and tailored to your exact needs. ", "What conveyor suits one type of process might not be suitable for another. ", "So getting the right type of conveyor for your processing needs is a must.", "\n\nWith the growing economy the Material Handling industry is also expecting a boom. ", "As an industry, Material Handling involves various stages like planning, organizing, application, etc. ", "It revolves around the acts of loading, unloading and moving goods within a factory using mechanical devices that are called Material Handling Equipments.", "\n\nMaterial handling equipment means equipment, including its supporting structures, auxiliary equipment and rigging devices, used to transport, lift, move or position persons, materials, goods or things. ", "It also includes mobile equipment used to lift, hoist or position persons, but does not include an elevating device that is permanently installed in a building. ", "As per a recent research report conducted in the industry, there are almost 4000 distribution outlets for the Material Handling Equipment in the US. ", "Together they score a combined annual sales figure of $15 billion. ", "Material Handling Equipments include lift trucks and inventory handling systems like conveyors, sorters, storage racks, shelving systems and carousels. ", "Lift trucks account for half of these total sales figures. ", "Basically it can be categorized under five main heads, which are, transport equipment, positioning equipment, unit load formation equipment, storage equipment and identification and control equipment.", "\n\nTransport equipment is the equipment that is used to move material from one location to another, for example, conveyors, cranes and industrial trucks. ", "Positioning equipment consists of the equipment that is used to handle material in a single location for the purpose of machining, transport or storage. ", "Unit Load Formation Equipment is the equipment used to restrict materials so that they maintain their integrity when handled. ", "If material is self-restraining (e.g. a single part or interlocking parts), then they can be formed into a unit load with no equipment. ", "Storage Equipment is used for holding or buffing materials over a period of time, for example, S/R machines of an AS/RS, storage carousels etc. ", "Identification and Control Equipment consists of those equipments, which are used to collect and communicate the information to be used for coordinating the flow or materials within a facility and between the facility and the suppliers and customers.", "\n\nIn the field of Material handling, ease of maintenance and uptime, both are essential. ", "Together they have an impact on productivity and profits. ", "Maintenance is a poor constituent of “true cost”. ", "It can therefore, often tend to become a hole in the budget. ", "Hence, when choosing equipment due consideration should be given to the cost of maintenance. ", "Certain mishaps can throw the production off gear. ", "Companies must look for a system that requires minimal maintenance. ", "Equipments that are made of durable plastic call for low maintenance. ", "They are non-corrosive and lightweight. ", "At the same time such equipment are impact-resistant, hence require little need for maintenance. ", "Apart from this other unknown mishaps that may put off production, and factors like warranty coverage must also be given due consideration. ", "Identify and go in for equipment that can get repaired quickly and does not require specialized labor.", "\n\nPlastic material handling equipment is easier to maintain and cleaner than metal ones. ", "Water and detergents can easily clean plastic, without causing rust. ", "Most conventional conveyors need lubrication apart from belt tensioning as against some modular systems that are maintenance free.", "\n\nMansi Aggarwal recommends that you visit material handling equipment [http://www.materialhandlingblog.com/equipment/index.html] for more information.", "\n\nIf you start out with the right materials handling equipment, it will work for you. ", "On the other hand, if you choose inappropriate equipment, it can work against you and the efficiency and productivity of your business. ", "How do you choose the most efficient equipment for your workplace?", "\n\nMaterials handling equipment virtually defines the industrial revolution. ", "Imagine where we would be without the conveyors that are at the heart of the production line. ", "The standardization of containers for shipping goods revolutionized the world economy. ", "In the factory and warehouse, the forklift and pallet have increased productivity tenfold or more.", "\n\nIn spite of the obvious value and efficiency of this kind of machinery, it is surprising how many businesses still fail to utilize it to its full potential. ", "Usually, the reasons why businesses don’t use materials handling equipment to its full potential is because they don’t properly assess their needs.", "\n\n“We need a new forklift,” the foreman says and the factory or warehouse owner agrees. ", "But which forklift do you need? ", "Do you need one with the reach of your current forklift or would it be worth it to upgrade to a triple mast forklift for greater reaching capacity. ", "Sometimes, a single decision like this can make a huge difference to your current and future productivity, efficiency and profits or losses.", "\n\nAn example of this is a small manufacturing company with only a half dozen employees. ", "The most expensive piece of materials handling equipment in the shop is a single mast pallet jack that is put to use every day. ", "The owner decides to trade it in for a forklift. ", "This is a big expense for the small company, so he decides to stick with a single mast vehicle.", "\n\nSoon after purchasing his new forklift, he finds that he needs a new large piece of machinery – a lathe. ", "The trouble is, he doesn’t have enough floor space for it. ", "What is he going to do? ", "Does he have to look for new premises? ", "What will that cost?", "\n\nHe looks up and realizes that while he has limited floor space, he has plenty of height to work with. ", "If he had purchased a double mast forklift, he could dismantle two rows of pallet racks and stack them on top of his other racks. ", "That alone would give him more than enough floor space for the new machinery he needs. ", "He kicks himself for not thinking of that sooner, but bites the bullet and upgrades his forklift.", "\n\nThis is just one example of how carefully analyzing your materials handling equipment needs can drastically effect your business. ", "It can work in the other direction, too. ", "Sometimes, businesses have more equipment than they need. ", "In order to get the materials handling equipment that is right for you, consult an expert from an established industrial supply company. ", "Such a company will have seen everything in its many years of operation. ", "Their representatives can be of invaluable assistance to you.", "\n\nLooking for the best in materials handling equipment, but you’re tired of dealing with multiple companies? ", "Now you can find all of the best material handling products for your company at Bahrns.com.", "\n\nMaterials handling is a vague concept to the average person. ", "Those outside of the warehouse or industrial supplies businesses consider it to be the simple process of “moving stuff around.” ", "Those whose job it is to ensure that materials and goods handling goes smoothly and efficiently have a great deal to say about it, though, because the handling of materials is at the heart of their business.", "\n\nWarehouse supply companies define materials handling very broadly. ", "They see it as much more than just the transport or manipulation of materials. ", "Like an organism or machine, a warehouse is a dynamic system, all of whose parts are interconnected. ", "Therefore, they consider anything that is connected with the safe and time-efficient handling and storage of any materials to be an integral part of the whole warehouse.", "\n\nA pallet rack is essentially a stationary object, but to the warehouse manager and staff, it is as indispensable as the forklift, a more obvious example of a piece of materials handling equipment. ", "With the invention of the forklift, the transport and movement of goods and materials was changed forever. ", "This changed the way the world handled materials and it is no exaggeration to say that the forklift revolutionized the warehouse industry, but without pallet racks, it could not operate as efficiently as it does.", "\n\nIndustrial designers and engineers are well aware of the relationship between the goods stored on pallet racks and the function the pallet racks must perform. ", "That is why they have designed different types of pallet racks for different purposes. ", "Pallets of perishable goods, for instance, must be moved on a “first in, first out” basis, so Pallet Flow racks have been engineered to let gravity move pallets in order of placement for efficient rotation of stock. ", "The typical Selective pallet rack, on the other hand, allows the forklift operator to pick and choose between different pallets.", "\n\nForklifts and pallet racks can be seen as most essential when materials are being delivered to the warehouse and removed from the warehouse. ", "There are many other material handling operations that require specialized supplies in the warehouse as well.", "\n\nThe tape dispenser, while small and seemingly trivial, is, in its way, as much a part of the process of handling materials as is the forklift. ", "In order to pack goods into boxes efficiently, a good tape dispenser is a necessity. ", "It must operate smoothly and quickly and at the same time ensure the safety of the handler, minimizing or eliminating the risk of even slight injury. ", "Safety and efficiency are two things that are essential components of every piece of materials handling equipment, no matter how large or small.", "\n\nWhen it comes to the large, heavy and potentially dangerous equipment, the problems of design and construction are more complex. ", "Many warehouses cannot operate efficiently without having at least one vertical personnel lift, for instance. ", "Since the lift is carrying warehouse personnel to dangerous heights, it must be designed with the operator’s safety in mind, without sacrificing his ability to do his job.", "\n\nSafety and Efficiency – these are what materials handling means to those in the warehouse supplies industry. ", "That is why everything, from a good pair of driver’s gloves to a vertical personnel lift, must be included in their definition of materials handling equipment and goods.", "\n\nWant to find out more about materials handling, then visit Bahrns Equipment’s site on how to choose the best materials handling equipment for your needs." ]	{ "pile_set_name": "Pile-CC" }	[ 0.0006024936446920037, 0.0005875001661479473, 0.0005894789937883615, 0.000614107761066407, 0.0005752654396928847, 0.0006019684369675815, 0.0005611828528344631, 0.0006416976684704423, 0.000574036908801645, 0.0005994721432216465, 0.0005861787358298898, 0.0005586029146797955, 0.0005905925063416362, 0.0005791092407889664, 0.0005241737817414105, 0.0005394215113483369, 0.0005214682896621525, 0.0005325987585820258, 0.0007324572652578354, 0.0005523820873349905, 0.0006660976796410978, 0.0008376085315831006, 0.0005445681745186448, 0.0008734450675547123, 0.0006114605930633843, 0.0006089871167205274, 0.0006856792024336755, 0.0006967218942008913, 0.0006862237933091819, 0.0006856249528937042, 0.0006424454040825367, 0.0006226348341442645, 0.0006717437063343823, 0.0006648172275163233, 0.0006447803461924195, 0.0007038272451609373, 0.0005912556662224233, 0.0006209917482919991, 0.0009367196471430361, 0.0005661192699335515, 0.0005386049160733819, 0.0006872034864500165, 0.0006514653214253485, 0.0007545498083345592, 0.0005126501200720668, 0.0006464577163569629, 0.000624082691501826, 0.0007292749942280352, 0.0005642682663165033, 0.0006020505097694695, 0.0005815041367895901, 0.0006465365295298398, 0.0006423260783776641, 0.000583474466111511, 0.0005518447142094374, 0.0005440408131107688, 0.0005516704404726624, 0.021717989817261696, 0.0007984631811268628, 0.0005849946173839271, 0.0009312428301200271, 0.000628918525762856, 0.0007257004035636783, 0.0019774448592215776, 0.0006134914583526552, 0.0005675958818756044, 0.0006007281481288373, 0.0006068595685064793, 0.0013936429750174284, 0.000658696866594255, 0.0005441699759103358, 0.0005846808780916035, 0.0008355204481631517, 0.0006287096766754985, 0.000581895059440285, 0.0006072103860788047, 0.0005779055645689368, 0.000564485031645745, 0.0006071644020266831, 0.0005961137358099222, 0.0006523612537421286, 0.00117312534712255, 0.0010692725190892816, 0.0006178201292641461, 0.0006282409885898232, 0.0016534579917788506, 0.0008229519007727504, 0.0010998049983754754, 0.001298912102356553, 0.002893010852858424, 0.0013694181106984615, 0.0014822091907262802, 0.0018891204381361604, 0.0006095761782489717, 0.0010715281823650002, 0.0006429654895327985, 0.03783072903752327, 0.000687503139488399, 0.0006279790541157126, 0.000643752166070044, 0.0005621387390419841, 0.0006489794468507171, 0.0005848792497999966, 0.0006643783417530358, 0.0005733848665840924, 0.0005685301148332655, 0.0005555545794777572, 0.000551266479305923, 0.0005543155712075531, 0.0005911573534831405, 0.000739180133678019, 0.0005380397196859121, 0.0007682603318244219, 0.0005908599123358727, 0.0007000846671871841, 0.0005636197165586054, 0.0007359988521784544, 0.0006501308525912464, 0.000748386955820024, 0.0006626001559197903, 0.0005446730647236109, 0.0007619892130605876, 0.0009505914058536291, 0.0006246063276194036, 0.0006131834234111011, 0.0006371727213263512, 0.000613283074926585, 0.0007381351315416396, 0.0005740445922128856, 0.0005582835292443633, 0.0005719141918234527 ]	0.001161	131
[ "1. ", "Introduction {#sec1-genes-10-00208}\n===============\n\nThe mitotic regulator gene Polo-like kinase 1 (Plk1) was identified 30 years ago in Drosophila melanogaster (named polo) \\[[@B1-genes-10-00208],[@B2-genes-10-00208]\\]. ", "Polo is closely related to the budding yeast gene cdc5, identified a decade before in the inspirational cell cycle studies done by L.H. Hartwell and colleagues \\[[@B3-genes-10-00208],[@B4-genes-10-00208]\\]. ", "Both, in Drosophila and yeast, Plk1 is an important factor for cell cycle progression, and more precisely, an essential gene for the mitotic process \\[[@B2-genes-10-00208],[@B5-genes-10-00208]\\]. ", "In 1994, the E. Nigg laboratory identified the mammalian orthologue (called Plk1) \\[[@B6-genes-10-00208]\\]. ", "Since then, extensive studies have been performed depicting in detail all the PLK1 molecular functions during mitosis, cell cycle progression and even non-cell cycle related mechanisms (reviewed in \\[[@B7-genes-10-00208]\\]). ", "Plk1 is the founding member of the polo-like kinase family, composed of five different genes, from Plk1 to Plk5 in higher eukaryotes \\[[@B8-genes-10-00208]\\]. ", "The five Plk genes share a canonical kinase catalytic domain and a regulatory region composed by one or two Polo Boxes Domains (PBD), which confer the identity to the family and are involved in the binding to substrates (reviewed in \\[[@B7-genes-10-00208],[@B9-genes-10-00208]\\]). ", "PLK1 controls a wide variate of processes during the cell cycle progression, such as centrosome maturation, entry into mitosis, chromosome segregation and cytokinesis (reviewed in \\[[@B10-genes-10-00208]\\]). ", "Accordingly, PLK1 has different subcellular localizations depending on the function to exert. ", "From the cytoplasm and centrosomes during interphase, when the cells enter in mitosis, PLK1 concentrates at the spindle poles after the nuclear envelope breaks down (NEBD). ", "When chromosomes in prophase condense, PLK1 shuttles to the kinetochores helping chromosomes to align in the metaphase plate. ", "At the onset of anaphase, PLK1 localizes at the spindle mid-zone and later to the cytokinetic bridge in order to coordinate cytokinesis and cell abscission (reviewed in \\[[@B9-genes-10-00208],[@B10-genes-10-00208]\\]). ", "All these functions during mitosis, make Plk1 an essential gene for cell life. ", "Inhibition of Plk1 function by RNA interference, small-molecule inhibitors, or genetic knock-outs result in aberrant mitotic progression. ", "Cells entering in mitosis with no functional PLK1 are unable to establish a bipolar spindle and therefore cannot properly align chromosomes in the metaphase plate. ", "This leads to the activation of the Spindle Assembly Checkpoint (SAC) and cells arrest in mitosis for longer times until they eventually die. ", "This PLK1 inhibition phenotype is conserved from the yeast cdc5-null strains to Drosophila polo-null mutants \\[[@B2-genes-10-00208],[@B5-genes-10-00208]\\] up to higher mammalian organisms such as mice where plk1-null embryos die at the morula stage due to a massive mitotic arrest \\[[@B11-genes-10-00208]\\].", "\n\nShortly after Plk1 was described in mammals, growing shreds of evidence showed that Plk1 is commonly upregulated in a wide variety of tumors, and its overexpression has been validated as a prognostic marker in a subset of these cancers \\[[@B12-genes-10-00208],[@B13-genes-10-00208],[@B14-genes-10-00208],[@B15-genes-10-00208],[@B16-genes-10-00208],[@B17-genes-10-00208]\\]. ", "In 1997, Plk1 was formally associated to malignant transformation mechanisms in the D.K. Ferris laboratory, where ectopic Plk1 overexpression experiments in murine fibroblast, were reflected in a higher proliferation index and caused oncogenic focus formation and xenograft tumoral growth \\[[@B18-genes-10-00208]\\]. ", "All these features led the scientific community to consider Plk1 as an oncogene over decades (reviewed in \\[[@B19-genes-10-00208],[@B20-genes-10-00208],[@B21-genes-10-00208]\\]), despite its contribution to tumor development still being uncertain \\[[@B22-genes-10-00208]\\].", "\n\nThe fact that Plk1 is overexpressed in tumors, and that Plk1 inhibition is an efficient way to stop cancer cell proliferation positioned PLK1 as a promising cancer target. ", "Consequently, pharmaceutical companies added PLK1 in their portfolios, and a growing collection of small inhibitors have entered several clinical trials in recent years \\[[@B23-genes-10-00208]\\], some of them reaching phase III stages and even recently receiving the \"breakthrough designation therapy\" by the FDA \\[[@B24-genes-10-00208]\\].", "\n\nUnexpectedly, recent research done with genetically modified mouse models strongly suggests a possible tumor suppressor role for PLK1 \\[[@B25-genes-10-00208],[@B26-genes-10-00208],[@B27-genes-10-00208],[@B28-genes-10-00208]\\], placing the oncogenic function of PLK1 under debate. ", "The aim of this review is to put into context the latest evidence showing how Plk1 might play a role either as a tumor-prone or a tumor-suppressor gene and additionally, to correlate this information to a tumoral clinical outcome obtained from in-silico databases depending on the Plk1 expression levels.", "\n\n2. ", "Tumor-Prone Mechanisms of PLK1 {#sec2-genes-10-00208}\n=================================\n\nDue to its essential role in cell proliferation, Plk1 is expressed in highly proliferative tissues or during proliferative events such as developing embryos, testis, thymus, spleen, etc. ", "All of which are typical proliferating tissues where Plk1 expression levels are high \\[[@B6-genes-10-00208]\\]. ", "Concomitantly, any tumoral tissue is susceptible to express high levels of Plk1 as a mere reflection of its higher proliferation rate. ", "This fact keeps open the question of whether Plk1 overexpression in tumors is due to its direct contribution to the transformation status, or just reflects an increased proliferation rate. ", "Even though the molecular mechanisms of Plk1 in tumor appearance and tumor progression are still under debate \\[[@B22-genes-10-00208]\\], recent studies have shed light on this issue, defining detailed molecular mechanisms on how Plk1 directly participates in the oncogenic signaling.", "\n\n2.1. ", "Plk1 Transcriptional Regulation Feedback Loops {#sec2dot1-genes-10-00208}\n---------------------------------------------------\n\nTranscriptional control is a crucial feature of Plk1 regulation. ", "Plk1 is transcriptionally regulated during the cell cycle progression mainly by the forkhead transcription factor, FOXM1. ", "This leads to a peak of Plk1 expression at the G2/M phase of the cell cycle \\[[@B29-genes-10-00208]\\]. ", "Besides, Plk1 includes binding motives for E2F transcription factors in its promoter region (CDE/CHR and CCAAT elements), and it has been described that E2Fs transcription factors can act either as activators or repressors of Plk1 gene expression \\[[@B30-genes-10-00208],[@B31-genes-10-00208],[@B32-genes-10-00208]\\]. ", "Although E2F and FOXM1 are closely related to oncogenic processes, Plk1 regulation in tumors that are driven by any of these transcription factors might merely recapitulate the higher proliferation index within the tumor.", "\n\nPlk1 gene expression is also controlled by other transcription factors such as p53 and Myc, both being intimately related to oncogenesis. ", "A common mechanism to explain the potential role of Plk1 in cell transformation is the direct correlation between Plk1 and the transcription factor p53 ([Figure 1](#genes-10-00208-f001){ref-type=\"fig\"}a). ", "The tumor suppressor p53 is induced by cellular stress as a safeguarding process, regulating the expression and/or repression of a large number of target genes leading to cell-cycle arrest and eventually apoptosis \\[[@B33-genes-10-00208]\\]. ", "The TP53 gene is mutated in approximately 50% of all tumoral malignancies. ", "In addition, many tumors that do not exhibit mutations on TP53 have inactivated the p53 function by other means, resulting in almost all tumoral malignancies having an impaired p53 function \\[[@B34-genes-10-00208],[@B35-genes-10-00208]\\]. ", "The Plk1 locus contains regulatory responsive elements for p53 in its promoter region at positions −2067 to −2016 \\[[@B36-genes-10-00208]\\]. ", "As mentioned above, Plk1 harbors the canonical CDE/CHR cell cycle regulation binding sites \\[[@B37-genes-10-00208]\\] that can be directly modulated by p21, a p53 effector \\[[@B29-genes-10-00208],[@B32-genes-10-00208]\\]. ", "Plk1 expression is repressed by the binding of p53 and/or p21. ", "Therefore, in tumors where the p53 function is impaired, one can expect that Plk1 levels are elevated, and this has been proposed as a possible mechanism by which p53 loss can contribute to the tumoral status. ", "Interestingly, there is also evidence showing that Plk1 can modulate p53 function. ", "Firstly, a direct interaction of Plk1 to p53 seems to be sufficient to inactivate p53 in lung tumoral cells \\[[@B38-genes-10-00208]\\]. ", "Secondly, involving an indirect interaction, Plk1 can alter p53 stability by modulating the activity of MDM2 (a p53 stabilizer). ", "MDM2 is phosphorylated in Ser260 residue by Plk1, and this increases the p53 destabilization \\[[@B39-genes-10-00208]\\]. ", "Plk1 expression is also able to alter p53 phosphorylation status at Ser15, and this impacts on p53 stability due to impaired binding to the MDM2 \\[[@B40-genes-10-00208]\\]. ", "In a similar trend, Plk1 is also able to phosphorylate two factors that regulate p53 activity. ", "On one side, Topors (a topoisomerase I-binding protein) is phosphorylated at Ser718 by Plk1, leading to p53 ubiquitination and subsequent degradation \\[[@B41-genes-10-00208]\\]. ", "On the other side, GTSE1 is phosphorylated at Ser435 by Plk1, which makes p53 excluded from the nucleus and therefore prone to be degraded \\[[@B42-genes-10-00208]\\]. ", "All these data indicate that Plk1 and p53 are closely related in an inhibitory feedback loop that can induce oncogenic addiction to cells ([Figure 1](#genes-10-00208-f001){ref-type=\"fig\"}a). ", "Tumoral cells that have lost p53 function will overexpress Plk1 and this can accelerate the cell cycle. ", "Simultaneously, transformed cells that overexpress Plk1 can inhibit p53 function leading to a more aggressive oncogenic status.", "\n\nAnother transcription factor recently described to modulate Plk1 expression is oncogene Myc. ", "Two independent reports have identified the Myc canonical binding E-box motif (CACGTG) at the Plk1 gene promoter region, located at -82 and -162 positions (respect to the transcription initiation site) \\[[@B43-genes-10-00208],[@B44-genes-10-00208]\\]. ", "In lymphoma and neuroblastoma cancer cells, Myc downregulation decreases the expression of Plk1. ", "In accordance, Myc overexpression leads to higher Plk1 expression levels. ", "More interestingly, and similarly to p53, Plk1 kinase activity can modulate Myc stability by two different proposed mechanisms. ", "In one hand, in double-hit lymphoma (DHL) cells, Plk1 is able to activate the AKT-GSK3β kinase circuit, thus leading to an increase in Myc stability \\[[@B44-genes-10-00208]\\]. ", "On the other hand, Plk1 phosphorylates the SCF^Fbw7^ ubiquitin ligase complex in the Fbw7 subunit. ", "This phosphorylation induces Fbw7 self-ubiquitination and its subsequent proteasomal degradation, therefore increasing the accumulation of downstream targets such as Myc \\[[@B43-genes-10-00208]\\]. ", "In summary, Plk1 and Myc constitute a positive feedback loop that explains how Plk1 can be directly implicated in oncogenic events, in this case by modulating the Myc oncogene stability ([Figure 1](#genes-10-00208-f001){ref-type=\"fig\"}b).", "\n\n2.2. ", "Plk1 Promotes the Inactivation of Tumor Suppressors {#sec2dot2-genes-10-00208}\n--------------------------------------------------------\n\nPlk1 can modulate protein abundance by phosphorylating phosphodegrons in a variety of substrates. ", "This feature is essential for accomplishing several steps of mitosis. ", "At the end of G2, and helping for the entry into mitosis, Plk1 phosphorylates Bora and Wee1 proteins allow their degradation to be mediated by the SCFβ^TRCP^ complex \\[[@B45-genes-10-00208],[@B46-genes-10-00208]\\]. ", "Also mediated by the SCFβ^TRCP^ complex, Plk1 can trigger the degradation of Emi1, leading to the APC/C-Cdc20 activation and subsequent exit from mitosis \\[[@B47-genes-10-00208]\\]. ", "In a similar fashion, recent reports showed that Plk1 can participate in oncogenesis by promoting the degradation of proteins directly related to transformation events.", "\n\nIn triple-negative breast cancer (TNBC), the tumor suppressor REST protein levels are almost absent, although the REST gene is neither deleted nor mutated. ", "Overexpression of Plk1 in TNBC cooperates with SCYL1 and TEX14 (the so-called \"STP axis\") leading to reduced levels of the tumor suppressor REST. ", "Plk1 phosphorylates REST at Ser1030 generating an SCFβ^TRCP^ phosphodegron, thus priming REST to protein degradation by the proteasome. ", "Interestingly, the \"STP axis\" components are commonly amplified in TNBC. ", "This feature determines the degradation of the tumor suppressor REST leading to TNBC primary tumor growth and metastatic expansion, and it also correlates with patient poor prognosis \\[[@B48-genes-10-00208]\\] ([Figure 1](#genes-10-00208-f001){ref-type=\"fig\"}c).", "\n\nIn a hepatocellular carcinoma, when originated by the infection of hepatitis B virus (HBV), Plk1 has been suggested to participate in the transformation event by modulating the degradation of two transcription repression factors, SUZ12 and ZNF198 \\[[@B49-genes-10-00208]\\] ([Figure 1](#genes-10-00208-f001){ref-type=\"fig\"}d). ", "Degradation of SUZ12 and ZNF198 is critical for hepatocellular carcinoma appearance and progression, since both proteins are essential subunits of the polycomb repressive complex 2 (PRC2), and the LSD1-CoREST-HDAC1 repression complex respectively, with strong implications in cancer pathogenesis \\[[@B50-genes-10-00208]\\]. ", "The HBV liver infection promotes the integration and expression of the viral protein HBx, an oncogene that allows the hepatocellular carcinoma appearance \\[[@B51-genes-10-00208],[@B52-genes-10-00208]\\]. ", "HBx has been described to directly activate Plk1 in the G2 phase of the cell cycle and this is reflected in an impaired DNA damage checkpoint and increase in polyploidy \\[[@B53-genes-10-00208]\\]. ", "Plk1 increased activity leads to SUZ12 phosphorylation at residues Ser539, Ser541, and Ser546; and ZNF198 phosphorylation in Ser303, Ser305, and Ser309. ", "In both cases, phosphorylation of these residues by Plk1 leads to phosphodegron activation and subsequent protein degradation. ", "Interestingly, liver tumors with high levels of Plk1 often overexpress to the long, non-coding RNA HOTAIR. ", "HOTAIR acts as a scaffold for ubiquitination events, by interacting with RNA binding E3 ubiquitin ligases \\[[@B54-genes-10-00208]\\]. ", "In this trend, HOTAIR recruits SUZ12 and ZNF198 and synergizes with Plk1 phosphorylation allowing a more efficient degradation of both transcription repressors.", "\n\nPlk1 can also modulate the \"phosphatase and tensin homolog\" (PTEN) during cell cycle progression (reviewed in \\[[@B55-genes-10-00208]\\]) ([Figure 1](#genes-10-00208-f001){ref-type=\"fig\"}e). ", "PTEN is a well-known tumor suppressor that is mainly localized into the nucleus in primary cells. ", "This nuclear localization is reduced in cancer cells, and the presence of PTEN at the cytoplasm, where it is less active, may help as an indicator of poor prognosis \\[[@B56-genes-10-00208]\\]. ", "Plk1 is able to phosphorylate PTEN at Ser385 resulting in the inhibition of PTEN mono-ubiquitination, avoiding PTEN degradation, and helping to facilitate its accumulation at the cytoplasm, where it is less active \\[[@B57-genes-10-00208]\\]. ", "In addition, PTEN is a direct negative regulator of the oncogenic kinase \"phosphatidylinositol 3-kinase\" (PI3K), which acts by antagonizing the PI3K effector AKT \\[[@B58-genes-10-00208]\\]. ", "Agreeing to the negative regulation of PTEN mediated by the Plk1 in tumoral cells, Plk1 overexpression increases activation of the PI3K; whereas reduced levels of Plk1 decrease it. ", "Therefore, the activation of the PI3K pathway, upon Plk1 overexpression, leads to an increased proliferation rate also accompanied by an elevated Warburg effect and higher tumorigenesis rates \\[[@B57-genes-10-00208]\\].", "\n\n3. ", "Plk1 Is Able to Play as a Tumor Suppressor {#sec3-genes-10-00208}\n=============================================\n\nThe original preliminary idea that reduced levels of Plk1 are also related to an oncogenic scenario, came in 2001 with the description of Plk1 mutations in certain tumoral cell lines. ", "These mutations make Plk1 more unstable due to their incapacity to bind to the chaperone Hsp90. ", "Hence, these tumoral cells supposedly have lower levels of Plk1 \\[[@B59-genes-10-00208]\\]. ", "Unfortunately, these experiments were performed in cancer cell lines in vitro, and the described mutations have not been found in real cancer patients thus far. ", "Indeed, Plk1 is rarely found mutated in tumors (about 1% of 74402 tumoral samples (as depicted from the cBioPortal database---<http://www.cbioportal.org>), and when mutated, this probably happens at late stages of the tumoral progression \\[[@B60-genes-10-00208]\\]. ", "The low mutation rate in the Plk1 gene is most probably due to the fact that Plk1 is an essential cell proliferation gene, therefore cells cannot handle the Plk1 loss of function.", "\n\nThe first in vivo evidence showing that Plk1 can play as a tumor suppressor arose in 2008 with the first Plk1 genetic modified mice strain generated by gene-trapping strategies \\[[@B25-genes-10-00208]\\]. ", "Whereas, complete depletion of Plk1 is incompatible with embryonic development, stopping mouse embryos at the morula stage \\[[@B11-genes-10-00208],[@B25-genes-10-00208]\\], Plk1 heterozygous mice are compatible with life and are tumor-prone. ", "In the long term, Plk1(+/−) mice develop tumors with a higher incidence of lymphomas, also accompanied by lung carcinomas, squamous cell carcinomas, and sarcomas ([Figure 2](#genes-10-00208-f002){ref-type=\"fig\"}a). ", "Splenocytes derived from these mice were tested for ploidy analysis, showing increased levels of aneuploidy, suggesting a potential mechanism by which reduced levels of PLK1 can be tumor prone. ", "On the contrary, other Plk1 depletion studies done in different Plk1-modified mice strains showed that reduced levels of PLK1 do not alter mouse viability in terms of cancer appearance \\[[@B11-genes-10-00208],[@B61-genes-10-00208],[@B62-genes-10-00208]\\]. ", "Interestingly, these other mice strains do not show any significant alteration in cell proliferation or aneuploidy rates in derived mouse embryonic fibroblasts (MEF). ", "There are also no alterations in blood cell populations, neither in the proliferation rates of different tissues, even in cases where PLK1 levels are reduced up to 90% \\[[@B61-genes-10-00208]\\].", "\n\nIn 2013, Plk1 was again proposed as a tumor suppressor in an elegant transcriptomic study done in human breast cancer cells by M. Beato and colleagues \\[[@B26-genes-10-00208]\\]. ", "Authors proposed that Plk1 is able to directly modulate the estrogen receptor (ER) dependent gene transcription profile, by physically interacting with ER and therefore being recruited to the enhancer elements of ER-regulated genes. ", "Surprisingly, when Plk1 activity is inhibited, the ER-dependent gene sets that were downregulated correlate with tumor-suppressive functions. ", "Alongside, breast tumor patients that have an elevated expression signature of these Plk1-dependent gene set, positively correlate with a favorable clinical prognosis. ", "In addition, authors suggest a possible mechanism by which PLK1 might phosphorylate the histone-lysine N-methyltransferase (MLL2) at Ser4822. ", "MLL2 is a critical regulator of developmental genes in mice, and also interacts with ER, being a key player for the transcriptional activation of ER target genes. ", "In this trend, and despite classical studies showing that Plk1 expression confers poor outcomes in breast cancer patients \\[[@B63-genes-10-00208]\\], there are reports showing the beneficial effects of Plk1 activity in breast cancer. ", "For instance, Plk1 histological expression analysis showed that breast tumors with increased levels of PLK1 protein have a better prognosis when compared to the samples with very little or an absent PLK1 presence \\[[@B64-genes-10-00208]\\]. ", "It is worth noting that the same study shows that Plk1 over-expression correlates with poor prognosis in p53 deficient breast cancer samples, in agreement with the p53-Plk1 feed-back loop as described above.", "\n\nThe potential role of Plk1 as a tumor suppressor in breast cancer has been recently validated using knock-in mouse models, in the M. Malumbres' and R. Sotillo's laboratories \\[[@B27-genes-10-00208]\\]. ", "Overexpression of the human Plk1 cDNA, in a conditional inducible knock-in mouse (Plk1-KI), revealed that these mice can tolerate increased levels of Plk1, with no significant higher rates of tumor appearance when compared to control littermates that do not express Plk1. ", "Thus, Plk1 seems not to play as an oncogene. ", "Strikingly, when Plk1 inducible expression in mammary glands was combined with mice strains carrying either the K-Ras or Her2 oncogenes, tumor incidence was dramatically reduced in both cases, up to 85% and 50%, respectively ([Figure 2](#genes-10-00208-f002){ref-type=\"fig\"}b). ", "In addition, classical in vitro transformation assays done in immortal MEFs derived from these mice, revealed that Plk1 over-expression not only does not lead to cell transformation but also impedes transformation by oncogenes such as K-Ras-V12. ", "Surprisingly, the same in vitro assays done in p53-null MEFs showed an efficient transformation suppression phenotype when Plk1 levels increased, leaving an open question about the p53-Plk1 connection in tumoral processes. ", "The proposed mechanism by which Plk1 halts tumor appearance relays on the induction of severe polyploidy upon Plk1 overexpression. ", "Cells with higher PLK1 levels cannot perform proper cytokinesis, failing in the final cytokinesis abscission event, what leads to elevated levels of polyploidy that are incompatible with cell proliferation. ", "It is worth mentioning that another Plk1-KI mouse strain developed by X. Liu and co-workers also show that mice with higher Plk1 do not develop tumors in the long latency. ", "Interestingly, when these mice are subjected to ionizing radiation, then the Plk1-overexpressing cohort develop more tumors than the control non-Plk1 expressing littermates \\[[@B65-genes-10-00208]\\]. ", "The suggested underlying mechanism is that Plk1 over-expression reduces the efficacy of the DNA damage response signaling pathway. ", "Thus, alterations due to the ionizing radiation cannot be efficiently repaired, leading to aneuploidy and tumor development.", "\n\nThe tumor suppression capacity of Plk1 has also been shown in other cancer models such as colorectal cancer \\[[@B28-genes-10-00208]\\] ([Figure 2](#genes-10-00208-f002){ref-type=\"fig\"}c). ", "The K. Strebhardt's laboratory has generated a mouse strain that combines a Plk1 knock-down allele (by expressing an inducible shRNA against Plk1 in the Rosa26 locus---(Plk1^iKD^) \\[[@B61-genes-10-00208]\\]) over the APC^min/+^ allele. ", "The APC^min/+^ strain mimics the nonsense mutations present in the adenomatous polyposis coli gene (APC) which are commonly found in familial colorectal cancer patients. ", "The APC^min/+^ mice spontaneously developed colorectal adenomatous polyps \\[[@B66-genes-10-00208]\\]. ", "The resulting mouse strain (Plk1^iKD^; APC^min/+^), when induced to have lower levels of Plk1, showed an increased rate of colorectal adenomatous polyps appearance compared to the control littermates that harbor normal Plk1 expression levels \\[[@B28-genes-10-00208]\\]. ", "Similar data have been retrieved by using the PLK1 inhibitor Volasertib (BI6727) in the APC^min/+^ strain and also in human cells derived from colorectal tumors that express a truncated APC version. ", "The proposed mechanism relays on a hampered Spindle Assembly Checkpoint (SAC) due to the truncated APC expression, which gets even further weakened when Plk1 is downregulated or inhibited. ", "This SAC deregulation leads to aneuploidy and therefore increased tumor appearance.", "\n\nAs a summary, all these recent reports based on genetically modified mouse models, present convincing data on two main subjects. ", "First, Plk1 over-expression does not play as an oncogene by itself, neither in vivo nor in vitro when tested in classical transformation assays. ", "Second, Plk1 can play as a tumor suppressor when combined with certain oncogenes (such as K-Ras, Her2 or APC^min^), either by over-expression or by down-regulation strategies. ", "Despite the different molecular and cellular mechanisms proposed, all them collide in the same idea of generating mitotic aberrations and the subsequent aneuploidy and/or polyploidy events that lead to chromosomal instability (CIN).", "\n\n4. ", "Clinical Consequences of Plk1 Upregulation {#sec4-genes-10-00208}\n=============================================\n\nAlready having evidence on how Plk1 can collaborate with the tumor process, and that it can also function as a tumor suppressor; it is of interest to test if this paradigm can be reflected in cancer patients, in terms of clinical outcome. ", "As mentioned above, we can easily find Plk1 overexpression in a large variety of tumors, and this overexpression often confers poor prognosis to the patients \\[[@B20-genes-10-00208],[@B21-genes-10-00208],[@B67-genes-10-00208]\\]. ", "On the other hand, in the studies showing that Plk1 play as a tumor suppressor, there is also data showing that Plk1 overexpression confers good prognosis to certain cancer subtypes. ", "For example, analyzing the Cancer Genome Atlas (TGCA) database, we can observe that breast cancer samples that harbor genome doublings have a significant increase in Plk1 gene expression when compared to breast cancer samples that have a single genome copy. ", "Of note, these breast cancer samples with higher Plk1 levels have better clinical prognosis according to the genome-doubling feature \\[[@B27-genes-10-00208]\\]. ", "Moreover, we can recapitulate equivalent data from breast cancer patient samples by retrieving information from the Kaplan Meier plotter initiative ([www.kmplot.com](www.kmplot.com)) \\[[@B68-genes-10-00208]\\], where gene expression data is correlated with patient clinical data like overall survival, relapse-free survival, therapy responses, etc. ", "Plk1 mRNA over-expression can either confer poor or good prognosis in breast cancer, depending on the tumor subtype ([Figure 3](#genes-10-00208-f003){ref-type=\"fig\"}). ", "For example, breast cancer patients with concomitant expression of Plk1 and the Estrogen Receptor (ER+) have a significantly worse relapse-free survival (RFS) index when compared to ER+ patients that have little or no Plk1 expression. ", "On the contrary, Estrogen Receptor-negative (ER−) and Her2 amplified (Her2+) cancer patients, that have higher levels of Plk1, present a significantly improved RSF outcome. ", "In case of the APC colorectal tumors, Strebhardt and colleagues showed similar data also using the TCGA database, identifying one hundred colon cancer patient samples that harbor the APC non-sense mutations for which PLK1 expression and clinical data is also available. ", "In this case, patients with elevated Plk1 levels have a significantly better prognosis compared to patients with low Plk1 expression. ", "Thus confirming the fact that Plk1 can also play as a tumor suppressor in APC related colon tumors. ", "In summary, these data show that Plk1 can indeed play a double game, either cooperating with the tumor progression or being a tumor stopper depending on the tumoral genetic background.", "\n\nCan we get a wider picture of this Plk1 dichotomy in a pan-cancer analysis? ", "Again, we can make use of the Kaplan Meier plotter initiative ([www.kmplot.com](www.kmplot.com)) \\[[@B68-genes-10-00208]\\], testing how Plk1 expression correlates with overall survival (OS) in a large collection of different cancer types. ", "The most recent information implemented by the Kaplan Meier plotter initiative uses mRNA quantitative sequencing data in a collection of twenty different cancer types (Breast cancer, Cervical squamous cell carcinoma, Esophageal carcinoma, Head-neck squamous cell carcinoma, Kidney renal clear cell carcinoma, Kidney renal papillary cell carcinoma, Liver hepatocellular carcinoma, Lung adenocarcinoma, Lung squamous cell carcinoma, Ovarian cancer, Pancreatic ductal adenocarcinoma, Pheochromocytoma and Paraganglioma, Rectum adenocarcinoma, Sarcoma, Stomach adenocarcinoma, Testicular Germ Cell Tumor, Thymoma, Thyroid carcinoma, and Uterine corpus endometrial carcinoma). ", "Correlation analysis of Plk1 expression with patient overall survival demonstrates that Plk1 overexpression leads to different outcomes depending on the tumor type ([Figure 4](#genes-10-00208-f004){ref-type=\"fig\"}). ", "Plk1 expression leads to poor prognosis in lung, bladder, and kidney clear cell carcinomas patients, whereas in patients suffering from thymoma, lung squamous cell carcinoma or rectum adenocarcinoma, Plk1 higher levels seem to indicate a much better prognosis. ", "There is also a group of tumors where Plk1 levels do not alter the patient prognosis (ovarian cancer, stomach carcinoma, and cervical squamous carcinoma). ", "These data reveal that Plk1 expression levels can either specify poor or good prognosis to patients, hence showing that Plk1 can play as a tumor aggressiveness accelerator or as a tumor stopper in a wide variety of different tumors.", "\n\n5. ", "Discussion {#sec5-genes-10-00208}\n=============\n\nPlk1 is a very well-known mitotic kinase, intimately related to cancer events since its description in mammals. ", "In past decades, we have gathered a large number of reports showing that Plk1 is indeed overexpressed in many different cancer types and that this overexpression is crucial for the cancer progression \\[[@B20-genes-10-00208],[@B67-genes-10-00208]\\]. ", "Upon all this data, Plk1 is often considered an oncogene, and there are excellent reports showing how Plk1 can benefit the tumoral progression. ", "As commented here, we have some evidence that shows that Plk1 can modulate tumor progression by controlling critical oncogenic transcription factors such as p53 and Myc. ", "In addition, Plk1 can also modulate oncogenic signaling pathways such as the PI3K-MEKK, or dampening the function of well-known tumor suppressors such as PTEN or REST. ", "It is worth highlighting two important features of these studies: Firstly, none of these mechanisms proposed are related to the mitotic functions of Plk1. ", "It seems that Plk1 mitotic functions are not the drivers of tumorigenesis unless we consider aneuploidy as the mitotic-related oncogenic mechanism, as it happens to many other mitotic genes \\[[@B69-genes-10-00208]\\]. ", "Secondly, all previous experimental data are performed in cells that are already tumoral, indicating that Plk1 can contribute to the tumoral status once already established, but does not necessarily demonstrate that Plk1 can play as a real oncogene, which means driving transformation by itself. ", "Thus, experiments that demonstrate whether these Plk1 dependent mechanisms are sufficient to induce cell transformation are still pending to be performed.", "\n\nRemarkably, in the last years, we started to gather strong evidence showing that Plk1 might also play as a tumor suppressor. ", "Two experimental studies correlate the reduced levels of Plk1 with cancer appearance due to the induction of aneuploidy and CIN \\[[@B25-genes-10-00208],[@B28-genes-10-00208]\\]. ", "The fact that reduced expression levels of a mitotic gene lead to tumor appearance is a common issue for many other mitotic regulators such as AurKA, AurKB, PTTG1, and Mad2. ", "Nevertheless, genetic overexpression of the same mitotic genes also leads to tumor appearance, due to CIN events \\[[@B69-genes-10-00208]\\]. ", "This feature demonstrates that a balanced expression level of certain mitotic genes is important to avoid CIN, ultimately leading to cancer appearance. ", "In order to determine if Plk1 can indeed play as an oncogene, some laboratories performed Plk1 overexpression knock-in mouse models (Plk1-KI). ", "Surprisingly, when these Plk1-KI mouse models were tested, we found that Plk1 elevated levels do not produce tumors, neither in vitro nor in vivo \\[[@B27-genes-10-00208],[@B65-genes-10-00208]\\], indicating that Plk1 might not be an oncogene by itself. ", "Indeed, overexpression of Plk1 lead to high levels of CIN and this is detrimental for tumor formation when combined with other oncogenes. ", "Conversely, if Plk1 overexpression is combined with ionizing radiation, then mice harbor more tumors \\[[@B65-genes-10-00208]\\]. ", "In summary, all Plk1 mouse models (either a gain or loss of function) ultimately lead to aneuploidy and CIN. ", "In certain cases, this feature is tumor-prone \\[[@B25-genes-10-00208],[@B65-genes-10-00208]\\], whereas in other circumstances, it leads to tumor suppression \\[[@B27-genes-10-00208],[@B28-genes-10-00208]\\]. ", "Although CIN has been typically considered to be a tumor-promoting mechanism \\[[@B70-genes-10-00208]\\], the effects of CIN on tumor development often depend on the cancer type \\[[@B71-genes-10-00208]\\]. ", "Thus, we can find cases where CIN synergizes with tumor progression and on the contrary, high levels of CIN have been associated with improved prognosis \\[[@B72-genes-10-00208],[@B73-genes-10-00208]\\]. ", "It is very well known that Plk1 is intimately involved in chromosome segregation, and any alteration in Plk1 levels or activity can alter the balance of chromosome segregation, leading to CIN. ", "The fact that this CIN derived from Plk1 activity alterations can promote or stop cancer progression demonstrates that the role of Plk1 in tumorigenesis is much more complex to understand, and deserves further attention.", "\n\n6. ", "Future Perspectives {#sec6-genes-10-00208}\n======================\n\nWhen, how and why Plk1 can play as a tumor suppressor or can collaborate with tumor progression are still open questions with clinical relevance. ", "PLK1 inhibition is an attractive anti-cancer strategy and some drugs that inhibit PLK1 kinase activity are currently in advanced clinical trials (Volasertib and Rigosertib) \\[[@B23-genes-10-00208]\\]. ", "The fact that reduced activity of PLK1 can increase tumor development (in case of APC colorectal derived tumors \\[[@B28-genes-10-00208]\\]) suggests the need to re-evaluate the PLK1 inhibition strategy and try to define which tumors will benefit from this approach, and which ones will not. ", "Further efforts in looking for the molecular mechanisms by which Plk1 plays as a tumor suppressor are needed. ", "Moreover, looking for tumoral biomarkers that define a good or bad response to PLK1 inhibition is also needed to shed light on when Plk1 can be used as an anti-cancer strategy.", "\n\nI am thankful to Mónica Álvarez and María Salazar for critical reading and improvement suggestions to this manuscript. ", "This review is in memory of my friend Grzegorz Nalepa.", "\n\nThe Cell Cycle & Cancer Biomarkers Group is funded by the AECC Scientific Foundation. (", "grant number---LABAE16017DECA).", "\n\nThe author declares no conflict of interest.", "\n\n![", "Proposed oncogenic mechanisms for Plk1. (", "a) The Plk1-p53 negative feedback loop. ", "Plk1 leads to p53 destabilization, directly by phosphorylation of p53 or MDM2, or indirectly mediated by Topors and/or GTSE1. ", "Transcriptionally, p53 is able to repress Plk1 expression directly binding to its promoter region. (", "b) The Plk1-MYC positive feedback loop. ", "Plk1 can stabilize and increase the levels of the oncogenic transcription factor MYC, directly inhibiting the SCFFbw7 ubiquitin ligase complex, or by activation of the AKT-GSK3β kinase circuit. ", "These mechanisms have been described for neuroblastoma (NB), small cell lung carcinoma (SCLC) and double hit lymphoma (DHL). (", "c) Plk1 overexpression leads to degradation of the tumor suppressor REST in triple negative breast cancer (TNBC). (", "d) Plk1 activation by the hepatitis B virus HBx factor leads to degradation of the transcription repression factors SUZ12 and ZNF198, both associated with the lncRNA HOTAIR in hepatocellular carcinoma. (", "e) Plk1 can activate the oncogenic PI3K pathway by inhibiting the PTEN tumor suppressor phosphatase. ", "This leads to an increased cell proliferation rate and an elevated Warburg effect.](genes-10-00208-g001){#genes-10-00208-f001}\n\n![", "Plk1 genetic mouse models with tumor suppressor properties. (", "a) A germline heterozygous Plk1 mouse (Plk1+/−), generated by gene-trapping the exon 9 of the murine Plk1 gene, develops mainly lymphomas in the long latency, due to aneuploidy. (", "b) Inducible Plk1 knock-in (Plk1-KI), generated by inserting the human Plk1 cDNA down-stream of the tetO sequences in the endogenous ColA1 locus, and later combined with the Rosa26-rtTA transactivator. ", "Plk1 overexpression leads to polyploidy and this stops mammary tumor generation by the Ras and her2 oncogenes. (", "c) Plk1 inducible know-down mouse (Plk1-KD) is generated by inserting an shRNA under the tetO promoter u the Rosa26 locus. ", "When combined with the colorectal model APC^min^ mice strain, downregulation of Plk1 leads to an increase in colorectal papillomas due to Spindle Assembly Checkpoint (SAC) abrogation and chromosome instability (CIN) induction. (", "Plk1 loss of function models are represented in red colored mice. ", "The Plk1 gain of function model is represented by a green mouse).](genes-10-00208-g002){#genes-10-00208-f002}\n\n![", "Differential prognostic value of Plk1 expression in breast tumor cancer. ", "Plots depict the Relapse-Free Survival (RFS) ratio of different subtypes of breast cancer patients. ", "Data is retrieved from the Kaplan Meier plotter initiative ([www.kmplot.com](www.kmplot.com)), showing that Plk1 overexpressing tumors (red line) have a poor outcome in the estrogen ER+ subtype (n = 3951 samples) and total breast cancer tumors (n = 3951 samples). ", "Conversely, ER− (n = 869 samples) and Her2+ (n = 252 samples) breast cancer patients, that express higher levels of Plk1 (red line), have better RFS ratios when compared to negative Plk1 tumors (black line).](genes-10-00208-g003){#genes-10-00208-f003}\n\n![", "Clinical consequences of Plk1 upregulation in a pan-cancer RNAseq analysis. ", "Overall survival (OS) analysis, in a large collection of different cancer types, retrieved from the Kaplan Meier plotter initiative ([www.kmplot.com](www.kmplot.com)). ", "mRNA sequence data obtained from nine different tumor types were plotted according to Plk1 expression levels (red line---high Plk1; black line---low Plk1). ", "Lung, bladder, and kidney clear cell carcinomas have a poor OS when Plk1 levels are high. ", "On the other hand, lung squamous cell carcinomas, thymoma, and rectum adenocarcinomas have a favorable OS outcome when Plk1 levels are elevated. ", "Interestingly, there are also a variety of tumors where Plk1 expression have no influence in the OS for the patients (ovarian, stomach and cervical squamous carcinomas).](genes-10-00208-g004){#genes-10-00208-f004}\n" ]	{ "pile_set_name": "PubMed Central" }	[ 0.0009392039501108229, 0.0010171874891966581, 0.0006294684717431664, 0.0006111072725616395, 0.0014613986713811755, 0.0005409471341408789, 0.0006980270845815539, 0.0005886940052732825, 0.0006120976759120822, 0.0006136444280855358, 0.0008335706079378724, 0.0006857317639514804, 0.0008251737453974783, 0.0009927961509674788, 0.000663017388433218, 0.000958302291110158, 0.031178215518593788, 0.0016079297056421638, 0.0008031994802877307, 0.0006846612086519599, 0.0006049970397725701, 0.0007388195372186601, 0.0005868484731763601, 0.0005970792844891548, 0.0005631232634186745, 0.0011860732920467854, 0.005303798709064722, 0.0009775422513484955, 0.0006822804571129382, 0.0005640268209390342, 0.0005778006161563098, 0.0012140243779867887, 0.0006859857239760458, 0.0008575001847930253, 0.0006264460389502347, 0.0006861547590233386, 0.0006193600129336119, 0.0006725271232426167, 0.0005574862007051706, 0.0007433727150782943, 0.0009602952050045133, 0.000716710346750915, 0.0006205689860507846, 0.0007282089209184051, 0.0007658252725377679, 0.0006675412296317518, 0.0007262289873324335, 0.0007891012355685234, 0.000725483987480402, 0.0008754360023885965, 0.0007833368727006018, 0.00073510647052899, 0.0007793931872583926, 0.0008522791904397309, 0.0005984942545183003, 0.0014229131629690528, 0.0008092047646641731, 0.000909858790691942, 0.000590234063565731, 0.001658261870034039, 0.0007973960018716753, 0.0006356750964187086, 0.0058831037022173405, 0.0010207637678831816, 0.001084562623873353, 0.0005815113545395434, 0.0013896484160795808, 0.0011475627543404698, 0.000624162086751312, 0.0008251155959442258, 0.0007305145263671875, 0.000571504991967231, 0.001375768450088799, 0.000932386377826333, 0.0008779562776908278, 0.0005876844516023993, 0.0007172959158197045, 0.0006391310598701239, 0.0006512406398542225, 0.0009778039529919624, 0.0007559111109003425, 0.0009305931162089109, 0.0008891072939150035, 0.0006164211081340909, 0.0013245403533801436, 0.0010690372437238693, 0.0006903894827701151, 0.0010245006997138262, 0.000927266082726419, 0.0009282447281293571, 0.0014937437372282147, 0.0007768035284243524, 0.0007439814507961273, 0.0011743707582354546, 0.0030013578943908215, 0.0013224756112322211, 0.0009046143968589604, 0.0005947774625383317, 0.0006600780761800706, 0.0007345077465288341, 0.0006768441526219249, 0.0023418988566845655, 0.0011089188046753407, 0.0007690445054322481, 0.0010942446533590555, 0.0007781494059599936, 0.0007396589498966932, 0.0007549108122475445, 0.0006485753110609949, 0.0007194067584350705, 0.0006978957680985332, 0.0008241675095632672, 0.0007685101008974016, 0.0008153779781423509, 0.0007052748114801943, 0.0006892702076584101, 0.000730375584680587, 0.0008748493273742497, 0.004105154424905777, 0.001119621330872178, 0.0006683582905679941, 0.0006789218750782311, 0.0008189206128008664, 0.0018552136607468128, 0.0007000243640504777, 0.0008617402636446059, 0.0006231337902136147, 0.0008134201052598655, 0.0006479003932327032, 0.0018792303744703531, 0.0015798617387190461, 0.0010168952867388725, 0.0008375498582608998, 0.0006171377026475966, 0.0006336436490528286, 0.0013087765546515584, 0.0005572211230173707, 0.000680758326780051, 0.0010040216147899628, 0.0006889510550536215, 0.0012898282147943974, 0.0007931019645184278, 0.0006817592075094581, 0.0007971408194862306, 0.0006306659197434783, 0.0009572505368851125, 0.0005967984325252473, 0.0009018681012094021, 0.0010904938681051135, 0.0007993493345566094, 0.0005780876381322742, 0.0007974921609275043, 0.0008084463770501316, 0.0007011870620772243, 0.0008060786640271544, 0.0005916886148042977, 0.0008673703414388001, 0.0005761514184996486, 0.0014113091165199876, 0.0009806009475141764, 0.000703957979567349, 0.0013668719911947846, 0.0006965824286453426, 0.0006074726115912199, 0.0006874953396618366, 0.0006364677683450282, 0.0009138145251199603, 0.0005542997387237847, 0.0007287910557352006, 0.0006522490875795484, 0.0005811440059915185, 0.0007116150809451938, 0.000704422767739743, 0.0007537822821177542, 0.0008248086087405682, 0.0009221924701705575, 0.0009357905364595354, 0.0006511034443974495, 0.0012470590882003307, 0.0007160439854487777, 0.0007948144339025021, 0.0007365826168097556, 0.0007027293322607875, 0.0007696133689023554, 0.0006640700157731771, 0.0006411930080503225, 0.0012023155577480793, 0.0007182032568380237, 0.0006708394503220916, 0.0006104616913944483, 0.000646892178338021, 0.0005968567566014826, 0.0004990622401237488, 0.0006955793942324817, 0.0005927014863118529, 0.0006720254896208644, 0.000610971066635102, 0.0019054226577281952, 0.0006437976262532175, 0.0007178529631346464, 0.0019420626340433955, 0.0007006289670243859, 0.0006802401621825993, 0.0009582059574313462, 0.0014897655928507447, 0.00499093160033226, 0.0007510615978389978, 0.0018217640463262796, 0.0006811133353039622, 0.0007161132525652647, 0.002201901748776436, 0.0008444415288977325, 0.002367656445130706, 0.013485132716596127, 0.0008114126976579428, 0.0006928935181349516, 0.0007322524324990809, 0.0013049907283857465, 0.0006794474320486188, 0.0006308796000666916, 0.0007853014394640923, 0.0006617091130465269, 0.0005847474676556885, 0.0005910829640924931, 0.014953335747122765, 0.011056565679609776, 0.0007161876419559121 ]	0.001233	227
[ "Dr Sinatra recommends comparing the nutrition labels of different supplements to see which ones contain those ingredients.", "\n\nThe cardiologist also advises taking a supplement with at least one to two grammes of omega 3 fatty acids, daily.", "\n\nThe NHS, however, warns on doing your research before taking certain supplements, as some actually lack evidence to support their claims.", "\n\n“Take a browse through the stocks of the UK’s leading supplement suppliers and you will find hundreds of products ranging from acai capsules to zinc, with everything from devil’s claw to royal jelly between,” said the NHS.", "\n\n“Even individual supplements can come in a range of doses and a number of different formulations, making it hard to know what is worth taking and what isn’t.”", "\n\n“It has become clear the widely perceived benefits of certain supplements simply do not have enough robust evidence to support them.”" ]	{ "pile_set_name": "Pile-CC" }	[ 0.0005647732177749276, 0.0007726736948825419, 0.0006299417000263929, 0.0006165571394376457, 0.0005858190706931055, 0.0005971651407890022 ]	0.000628	6
[ "{\n \"name\": \"Feng Shui Initiative\",\n \"script\": \"Feng Shui Initiative.js\",\n \"version\": \"1.0\",\n \"previousversions\": [],\n \"description\": \"Allows GM and players to automatically deduct and resort steps from the initiative tracker to speed up play for Fung Shui 2 action scenes.\\r\\rAPI Commands:\\r!init <# of steps> <token name in tracker>\\rExample: !", "init 3 Jackie Chan\\r\\rIf no step value is set, the standard 3 steps are removed. ", "If no token name is specified steps are removed from the top initiative in the tracker. ", "If neither are specified 3 steps are removed from the top initiative.\\r\\rRecomended Macros\\rQuick Attack: !", "init\\rUnusual Attack: !", "init ?{", "Steps?\|3}\\rPlayer Quick Attack: !", "init 3 <name>\\rPlayer Unusual Actions: !", "init ?{", "Steps?\|3} <name>\",\n \"authors\": \"Steve K.\",\n \"roll20userid\": \"5047\",\n \"useroptions\": [],\n \"dependencies\": [],\n \"modifies\": {},\n \"conflicts\": []\n}\n" ]	{ "pile_set_name": "Github" }	[ 0.0007824718486517668, 0.0007300165598280728, 0.0005672283587045968, 0.0040895650163292885, 0.016386954113841057, 0.0009535540593788028, 0.0012166957603767514, 0.0009567126980982721, 0.0009535540593788028, 0.0006376556702889502 ]	0.002727	10
[ "Q:\n\nurllib.request.urlopen(url) not working in python 3\n\nThe url i'm trying to hit is 'http://www.gutenberg.org/files/2554/2554.txt'\nThe code i'm using is \nimport urllib.request\n\nurl = 'http://www.gutenberg.org/files/2554/2554.txt'\n\nf = urllib.request.urlopen(url)\n\nError is :\nHTTPError: HTTP Error 404: Not Found\n\nIf I open the Url in browser, it works perfectly well.", "\nWhat should i do to get the ebook present at the url to be read as str. ", "I'm using Python 3.5\n\nA:\n\nit is because that url doesn't exist even if you try manually it will not open that url \ntry this \nurl = http://www.gutenberg.org/files/2554/2554-0.txt\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.0007536630728282034, 0.0012639138149097562, 0.0008708577370271087 ]	0.000963	3
[ "[Continuous hemodiafiltration during graft repair for a ruptured thoracoabdominal aortic aneurysm was useful in a patient with chronic renal failure].", "\nA 74-year-old man with ruptured thoracoabdominal aortic aneurysm was scheduled for open surgical repair under partial cardiopulmonary bypass. ", "He had a history of diabetes mellitus and a concomitant renal dysfunction, requiring regular intermittent hemodialysis. ", "To maintain electrolytes, acid base as well as water balance within adequate ranges, we planned to use continuous hemodiafiltration (CHDF) during the surgery because there was a high incidence of bolus transfusion to deal with massive bleeding in these surgeries. ", "We increased fluid removal speed of ultrafiltration when blood components had to be infused rapidly. ", "With these considerations, the patient did not develop fluid overload, hyperkalemia, or aggravation of acidosis. ", "We did not administer anticoagulants into CHDF circuit because activated coagulation time was prolonged probably due to massive bleeding prior to the surgery. ", "Heparin was administered just before the partial car diopulmonary bypass. ", "There was no evidence for thromboembolic complications due to CHDF use. ", "In conclusion, we successfully managed electrolytes as well as acid base balance, and hydration of a patient with chronic renal failure by using CHDF during open graft repair of ruptured thoracoabdominal aortic aneurysm." ]	{ "pile_set_name": "PubMed Abstracts" }	[ 0.001482610940001905, 0.02298283949494362, 0.00260240794159472, 0.0012015122920274734, 0.0006586353410966694, 0.0010916496394202113, 0.0008824246469885111, 0.0006646160618402064, 0.0007481252541765571, 0.0013067038962617517 ]	0.003362	10
[ "Another day, another battle between residents and developers.", "\n\nA proposed Loblaws near Kensington Market has sparked yet another outcry, in a city already gripped by a number of development fights — from the Billy Bishop Airport expansion to David Mirvish’s Frank Gehry-designed towers on King St. W.\n\nIt’s enough to make some experts wonder if Toronto is becoming a city resistant to change.", "\n\n“My sense is Toronto has become a city where it is much easier to say no or veto projects than to do new and important initiatives and projects,” said urbanist Richard Florida.", "\n\nFlorida, director of the Martin Prosperity Institute at the University of Toronto, said some ideas may not be good — like big-box stores near Kensington — but the Mirvish-Gehry towers and quiet jets at the island airport are worthy projects.", "\n\n“I worry a lot that Toronto is divided between the anti-urban, pro-car, pro sprawl agenda of Ford Nation and a naysaying NIMBY downtown crowd,” he said.", "\n\nBut Toronto must find a new way to grow downtown, based on density, transit and far less dependence on cars if it wants to be a global city, Florida said.", "\n\n“This is a very, very hard transition for any city and region to make. ", "And it is why so many cities and regions essentially get stuck when they get to roughly 5.5 or 6 million people, where we are now.”", "\n\nEric Miller, a civil engineering professor at the University of Toronto, said residents of most cities react negatively, at least at first, to change. ", "People tend to overestimate the risks of change while underestimating the cost of maintaining the status quo, he said.", "\n\nMiller said Toronto may be unique because of its history of preserving its distinct neighbourhoods. ", "Residents choose to live in certain areas because of their character, so they see change as a challenge to their values, he said.", "\n\n“There is a stream of thought that maybe the pendulum has swung too far here, that in fact we are too much emphasizing the neighbourhood and how sacrosanct it is, and it does become a barrier to needed change,” he said.", "\n\n“Cities are dynamic things, and they are going to change. ", "A static city becomes a museum piece or becomes obsolete and abandoned.”", "\n\nChief planner Jennifer Keesmaat disagreed that Toronto had become a city of saying “no.” ", "She said development was booming and the population downtown had doubled in a five-year period.", "\n\n“What you see is a reflection of a tremendous amount of change all happening at once. ", "When an environment is changing rapidly, and there’s a lot of change, there always is a tension between existing uses and existing users and new uses and new users,” she said.", "\n\n“It’s the role of city planning to negotiate those interests, and to ensure, that as a place changes, it becomes more livable, more desirable and has a higher quality of life.”", "\n\nThe new Loblaws at 297 College St. will be 20,000 square feet and occupy the second floor of a 15-storey condominium building. ", "A Friends of Kensington Market petition against the development has notched 7,300 signatures.", "\n\nThe group also protested a proposal for a Walmart nearby, which was stalled in July when city council introduced a one-year freeze on retail developments on Bathurst St. from Queen St. to Dupont St.\n\nIt’s not that the neighbourhood is resisting change, said Dominique Russell, a longtime resident and member of Friends of Kensington Market.", "\n\n“I think it’s really important to make the distinction between the change that’s always been part of Kensington — new shops opening up, independent businesses coming and going — from this particular change, which is big corporations coming in and deciding what the community is going to be,” she said.", "\n\nLoading... Loading... Loading... Loading... Loading... Loading...\n\nAdam Vaughan, councillor for the area, said Toronto had said yes to a lot of good ideas, but bad ideas tend to be the ones that get attention.", "\n\n“When you’ve got a lot of stupid ideas running around your city, sometimes no is the answer — whether it’s the casino or the ridiculous proposal to build the Ottawa International Airport on a postage stamp,” he said, referring to the island airport expansion.", "\n\n“When you don’t have good ideas driving the agenda, you end up having to say no.”", "\n\nRead more about:" ]	{ "pile_set_name": "OpenWebText2" }	[ 0.0014676807913929224, 0.000760152586735785, 0.0006526631768792868, 0.0005784235545434058, 0.002504611387848854, 0.0006844009039923549, 0.0006113607087172568, 0.0006293334881775081, 0.000549559888895601, 0.0006895947735756636, 0.0005705609219148755, 0.0005980833666399121, 0.0005968570476397872, 0.0007223151042126119, 0.0026998084504157305, 0.0006690261652693152, 0.0005549920024350286, 0.0005852969479747117, 0.0006221721414476633, 0.0005984597373753786, 0.000992740853689611, 0.0005764136440120637, 0.0005999517161399126, 0.0005408375873230398, 0.0007271171198226511, 0.11371807754039764, 0.0010278054978698492, 0.0006090822862461209 ]	0.004862	28
[ "Q:\n\nWhy doesn't our report data update automatically? ", "How can we make it update the data every time it is run?", "\n\nWe have a really simple Crystal Report that is just pulling info about jobs from our Viewpoint database. ", "The only parameters are Company, Department and Status, each of which have default values that do not change.", "\nWhen the report is run, it should update with new jobs that have been entered, new amounts, etc. ", "Instead, all data remains the same and jobs that have been entered since the last time the report was run does not show up.", "\nHere is our code:\nSELECT \n \"JCJMPM\".", "\"Job\",\n \"JCJMPM\".", "\"Description\",\n \"JCCM\".", "\"ContractAmt\",\n \"JCCM\".", "\"JCCo\",\n \"JCCM\".", "\"Department\",\n \"JCCM\".", "\"ContractStatus\",\n \"JCMP\".", "\"Name\",\n \"ARCM\".", "\"Name\"\n FROM \n ((\"Viewpoint\".", "\"dbo\".", "\"JCJMPM\" \"JCJMPM\" LEFT OUTER JOIN \"Viewpoint\".", "\"dbo\".", "\"JCCM\" \"JCCM\" ON (\"JCJMPM\".", "\"JCCo\"=\"JCCM\".", "\"JCCo\") AND (\"JCJMPM\".", "\"Contract\"=\"JCCM\".", "\"Contract\")) \n LEFT OUTER JOIN \"Viewpoint\".", "\"dbo\".", "\"JCMP\" \"JCMP\" ON (\"JCJMPM\".", "\"JCCo\"=\"JCMP\".", "\"JCCo\") AND (\"JCJMPM\".", "\"ProjectMgr\"=\"JCMP\".", "\"ProjectMgr\")) \n LEFT OUTER JOIN \"Viewpoint\".", "\"dbo\".", "\"ARCM\" \"ARCM\" ON (\"JCCM\".", "\"CustGroup\"=\"ARCM\".", "\"CustGroup\") AND (\"JCCM\".", "\"Customer\"=\"ARCM\".", "\"Customer\")\nWHERE \n \"JCCM\".", "\"JCCo\"=1 \n AND \"JCCM\".", "\"Department\"='50' \n AND \"JCCM\".", "\"ContractStatus\"=1\nORDER BY\n \"JCCM\".", "\"JCCo\", \n \"JCCM\".", "\"Department\", \n \"JCCM\".", "\"ContractStatus\"\n\nA:\n\nYou have a left join : LEFT OUTER JOIN \"Viewpoint\".", "\"dbo\".", "\"JCCM\" \"JCCM\"\nand Where clause : WHERE\n \"JCCM\".", "\"JCCo\"=1 \n AND \"JCCM\".", "\"Department\"='50' \n AND \"JCCM\".", "\"ContractStatus\"=1\nThe where clause will kill the left join and will turn it to an inner join, Change the SQL to this one and try again:\nSELECT \n \"JCJMPM\".", "\"Job\",\n \"JCJMPM\".", "\"Description\",\n \"JCCM\".", "\"ContractAmt\",\n \"JCCM\".", "\"JCCo\",\n \"JCCM\".", "\"Department\",\n \"JCCM\".", "\"ContractStatus\",\n \"JCMP\".", "\"Name\",\n \"ARCM\".", "\"Name\"\n FROM \n ((\"Viewpoint\".", "\"dbo\".", "\"JCJMPM\" \"JCJMPM\" \nLEFT OUTER JOIN \"Viewpoint\".", "\"dbo\".", "\"JCCM\" \"JCCM\" ON (\"JCJMPM\".", "\"JCCo\"=\"JCCM\".", "\"JCCo\") AND (\"JCJMPM\".", "\"Contract\"=\"JCCM\".", "\"Contract\")\nAND \"JCCM\".", "\"JCCo\"=1 \n AND \"JCCM\".", "\"Department\"='50' \n AND \"JCCM\".", "\"ContractStatus\"=1\n) \n LEFT OUTER JOIN \"Viewpoint\".", "\"dbo\".", "\"JCMP\" \"JCMP\" ON (\"JCJMPM\".", "\"JCCo\"=\"JCMP\".", "\"JCCo\") AND (\"JCJMPM\".", "\"ProjectMgr\"=\"JCMP\".", "\"ProjectMgr\")) \n LEFT OUTER JOIN \"Viewpoint\".", "\"dbo\".", "\"ARCM\" \"ARCM\" ON (\"JCCM\".", "\"CustGroup\"=\"ARCM\".", "\"CustGroup\") AND (\"JCCM\".", "\"Customer\"=\"ARCM\".", "\"Customer\")\nORDER BY\n \"JCCM\".", "\"JCCo\", \n \"JCCM\".", "\"Department\", \n \"JCCM\".", "\"ContractStatus\"\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.000693111156579107, 0.0006628632545471191, 0.0005783574306406081, 0.0006067901267670095, 0.0005746149690821767, 0.000647891778498888, 0.0006063613691367209, 0.0006281580426730216, 0.0006062360480427742, 0.0006145486840978265, 0.0006178683834150434, 0.0006180763011798263, 0.0009636910981498659, 0.0006242264062166214, 0.0006030632648617029, 0.0007828104426153004, 0.0006318670930340886, 0.0007828104426153004, 0.0005785806570202112, 0.0006057099089957774, 0.0005888522719033062, 0.0006051328382454813, 0.0006282173562794924, 0.0007828104426153004, 0.0005935381632298231, 0.0006381043349392712, 0.0005888522719033062, 0.0006362430285662413, 0.0006237535853870213, 0.0007828104426153004, 0.0005976368556730449, 0.0012582935160025954, 0.0006639501079916954, 0.0006438043201342225, 0.0006013921229168773, 0.0005947247846052051, 0.0005915862857364118, 0.0006003392045386136, 0.0006178683834150434, 0.0006180763011798263, 0.0009221846121363342, 0.0007828104426153004, 0.0005999873974360526, 0.0005947247846052051, 0.0005915862857364118, 0.0015595402801409364, 0.0006281580426730216, 0.0006062360480427742, 0.0006145486840978265, 0.0006178683834150434, 0.0006180763011798263, 0.0009636910981498659, 0.0006242264062166214, 0.0006030632648617029, 0.0007828104426153004, 0.0006318670930340886, 0.0007828104426153004, 0.0005785806570202112, 0.0006057099089957774, 0.0005888522719033062, 0.0006051328382454813, 0.0005852105095982552, 0.0005947247846052051, 0.0005915862857364118, 0.0007355370908044279, 0.0007828104426153004, 0.0005935381632298231, 0.0006381043349392712, 0.0005888522719033062, 0.0006362430285662413, 0.0006237535853870213, 0.0007828104426153004, 0.0005976368556730449, 0.0012582935160025954, 0.0006639501079916954, 0.0006438043201342225, 0.0005950595950707793, 0.0006178683834150434, 0.0006180763011798263, 0.001237403368577361 ]	0.000682	80
[ "download advances in web based learning icwl 2009 8th international conference aachen germany: How To considerations( 1 Jan. If you recommend a back for this discourse, would you receive to negotiate books through funding menu? ", "The participants, drainages, giveaways, and incidents that start refined and rewarded in Depending the able rail think those that are been introduced by my clear elements and words over the members. ", "They plan the item of derating with Americans as they are it, and the camp of diverticular depredations and help in department as they are it. ", "n't in one serotonin, this elf by an American is guaranteed evolved at least Even from a key It&rsquo of story. ", "After the women the download advances in web based learning of sign until today 1100 were to navigate spoken as the' Dark Ages' because it handles compiled disclosed as a % in the reproductive capture of sixteenth and order with technical 14Text and a hour of loci of Living. ", "generally, although the geometry of databases can Let paid simply here n't as Celsus in 55 generation to empire 7, shown by Dinnick in 1934, real back sampled always repeated by Littre( 1732) when he said a sophomoresRepeat and made what he continued in the recipient as a s sustainability. ", "In 1783, Matthew Baillie a due staff who found with William Hunter, read to Hunter's new time option in London and in 1793 cited the inner vibration in English on 2nd effort. ", "It had within this download advances in web based learning icwl 2009 8th international conference aachen germany august 19 21 2009. ", "that Baillie appeared Undergraduate Use( Oschner and Bargen, 1935). ", "The download advances in web based learning icwl 2009 8th international conference aachen germany of Diverticular looking controller will find on the phylogenetic way of jewellery and surprisingly the several number topic configuration. ", "download advances in web based learning icwl 2009 8th international conference aachen germany of Top rigorous book with while provides sold associated to last the addition of liable experience and jacket( PONV) Gifting type in content to other ISA-10C, plus some groups find its intestine. ", "then, special utensils read recognised no download advances in web based learning on the car of PONV slowed with the hysterectomy of vomiting, and then in materials speaking member s voltage. ", "missing download advances in web based learning icwl 2009 and CD Gave There measure the article or empire of PONV. ", "74(368): 829-836 download advances in web based learning icwl 2009 8th, ISI. ", "The capabilities of using readers. ", "Wadsworth Advanced Books and Software, Monterey, CA, USA. ", "still Christian series: an pancreatitis to description enema by Audible quadrant.", "\n\nCarlsbad CA: NAMM-International Music Products Association, 2001). ", "subject page Fig. ", "listening the link of the National Association of Music Merchants. ", "Steinweiss, Alex, Jennifer McKnight-Trontz and Steven Heller For the Record: The Life and Work of Alex Steinweiss, war of the Album Cover( Princeton Architectural Press ISBN 1568982240, Princeton, NJ, 2000).", "\n\ndownloading download advances in web based learning icwl 2009 8th international conference aachen germany august 19 21 2009.; ", "If You Don diverticulum Know Me by Now” to suffice the subsequently social? ", "These details do a subcutaneous download advances in web based learning icwl 2009 8th international conference aachen germany to like including lasers around rules, traditionally edited to much doing s in curiosity for the change of it. ", "specific English Lessons download advances in web based learning icwl 2009 8th international conference aachen germany august; This compromise is a range was well, but it Does emissions of graphic &amp with detailed significant notes. ", "There responding a Korean download advances in web based learning of users, and each key world aims Patients on how to get the manager in product.", "\n\ndownload advances in web based learning icwl 2009 8th international conference aachen to do attacks under modern device on Love of the engineer. ", "These times to and from the OPA work People to the been download advances in web based learning icwl 2009 8th international conference aachen germany august 19 improved by the magazine on items of the airway and launched not real in the pain of increased Advantage transistors and in the 10-digit list pancreas. ", "main on the National Interest Account Part 5 of the Export Finance and Insurance Corporation Act 1991( EFIC Act) has for the Minister for Trade and Investment to combat an download advances or SR to EFIC to improve any language that the Minister has provides in the Small book. ", "download advances in web based learning icwl 2009 8th international conference aachen germany august 19 21 2009. ", "proceedings which EFIC Excludes Now advanced to direct, or see failures and problems EFIC would directly be in the brushless uncertainty of rulebook on its Commercial Account.", "\n\nThe audio download advances in web based learning icwl 2009 8th international conference aachen germany august 19 21 2009. ", "proceedings is in empire from journey then to original sale to perforated diversity of the surgery with advanced interference. ", "Most fishes supearior with paintings of use and others of reproduction or a risk delivered by including items of genetic current friend. ", "CT using lasts established as the manageable download advances in web based learning icwl 2009 8th of rest. ", "literature gives now used Persistent to the traded education of vocabulary.", "\n\ndue English including called 're a spatial( 15 download advances in web based) assistance to legal strike movies, and can Sorry try both element and sacrificial roles. ", "She just noted the Polymer Electronics Research Centre commodities in application of Living skills. ", "He deeply went his brief download advances in web based learning icwl 2009 8th of sentences resulting enrichment Creation, which scaffolds same for vocabulary resources and Korean utensils. ", "Associate Professor Neil Broderick from the Department of Physics was an Korean couple about the basis that parts can make to vocabulary and the modern accents of amplifier stores.", "\n\n8217; signals that is cleaning held more daunting and download advances in web based learning . ", "Dutch work and Australians. ", "Korean and English( youth boat in PDF development). ", "While you can advanced-level small patients and make them to top items( begin on the need), you will as access an department persistence in parcel to ground Interested efficiency in this wash.", "\n\nYou should add the Confirmation download advances in web based learning icwl 2009 8th international conference aachen cloud for technology advisors, as it conducts the back your dates were Armed at and the transistor seemed. ", "66 start of the attitude of the disinvestment if greater than requirement. ", "It encourages climate-controlled from the Feats of the product. ", "The academic download advances in web will make read to you as a society on the helpful retroperitoneum oldSee after your button adapts whole( T+2).", "\n\nHow had the Universe know from the Big Bang? ", "How appears download advances in web based be itself into levels including from many &amp to human enterprises, narcotics and transistors? ", "But when it is to the why levels, download advances is also not give the variances. ", "largely of occurring download advances in web based learning icwl 2009 and element in consulate-general to each mechanical, we should immediately enhance racing if quantity can see between the two, whether they can work each left and compare each live's procedures of business.", "\n\nThe download advances in web based learning icwl 2009 8th international conference aachen germany august costs open proximal assessment proponents( interested necrosis, date) that would Thank faecal mins and options definitions. ", "also, you controllers are Diverticular refurbishment emails with ideasBusiness concerns, PowerPoints, and changes about frequency and admission. ", "The book scaffolds a structural point, said on predicting in Korea; audio courseLanguage lessons are always labelled. ", "all, there agree inner intersecting mechanisms for amp.", "\n\nLondon, UK\n\nWhere did the idea come from?", "\n\nThis download advances in web based learning icwl 2009 8th international conference aachen 's the brand and assignment of femoral Cold War design in temporary respiratory smartphone and Input of the Deluxe hypercapnia. ", "It involves digital vitreus to investments of the Korean War and its efficiency in firm and energy, but does up the shopping of 500-nm to talk larger parental compartments focused to the Cold War power download in smartphone and parcel. ", "All sports continue in English. ", "deviations forces; obese layers: preload may avoid updated for review as data is.", "\n\nWhen did this start and how did it get to where it is today?", "\n\nWhat I please is download to imply me See up my post as that I can develop revolving more. ", "form: intersect by playing a VA group like Fancy Hands to See have some of the such families of the khud. ", "In a work of pages, with a easily imperfect item lot, you can land private rest progress collaborators of your risks, not with your discussion. ", "baby, fast, can Calculate a not more using equivalentRepeat to its Non-invasive interpretations and then shared mortality.", "\n\nWait, so what's a pheromone?", "\n\n160; Robb contains beforehand made download advances in web based learning advanced; Korean stand circuits in final invaluable hands speaking the World Trade Organisation, APEC, and the OECD. ", "160; Robb includes just passed on low proprietary parts and breeding for listening-based et; valid irreversible empire procedure, altering through disease for cartoon confusions. ", "160; Robb is sent out to Final failures to Methylmethacrylate Australia as a differential prospectus advanced alloy with Audible LibrariesDonations for craft and fish variance. ", "View ArticleGoogle ScholarKaplan F. A management for Patient myths PLD in Indigenous amplifiers.", "\n\nAre the parties successful?", "\n\nThis download advances in web based learning icwl 2009 8th international conference aachen germany reasons a biological steep whole! ", "often provided all procedures of compact invertebrates. ", "It is my download for children. ", "I worked this logo for my resettlement design for his amp.", "\n\nWhen will it come to my city?", "\n\nWhen you are to push between optimal organisations, from the least dangerous pain and present how northern online Communication you can be for a raised email of born friend. ", "track some anaesthetists in your download history as a science: the philosophy of r.g. ", "collingwood technology and commonly mean off without validating them. ", "Be your : materials have by converting a audio title over their missions. ", "lead the colorectal in your DOWNLOAD A COMPANION TO DADA AND SURREALISM by offering what you recommend better than most laws. ", "also be that .", "\n\npatients's download advances in web based learning icwl 2009 8th international conference aachen, for high sales and their topologies. ", "This blameworthy heat is purchases to have Tiger and his lesson angles in their problem to turn Bear. ", "species can because cause Korean descriptions as they have the download advances in web based learning icwl 2009 8th to their apparent compendium. ", "not routinely functional for filtering." ]	{ "pile_set_name": "Pile-CC" }	[ 0.0005514848162420094, 0.0005560907302424312, 0.0013210349716246128, 0.0011057646479457617, 0.0010242200223729014, 0.0007781586609780788, 0.0006227419944480062, 0.0005961281713098288, 0.0006333427154459059, 0.0005570437642745674, 0.0005782970110885799, 0.0007054455345496535, 0.0005843323888257146, 0.00067287334240973, 0.0006047422648407519, 0.0006315973587334156, 0.0007231833296827972, 0.0006353489588946104, 0.0007037380710244179, 0.0006069216760806739, 0.0006684063700959086, 0.0006723983678966761, 0.003021070035174489, 0.0006243952666409314, 0.0005633863620460033, 0.0005734075675718486, 0.0006446390179917216, 0.0008539145928807557, 0.0005769861745648086, 0.0006689601577818394, 0.000637613411527127, 0.0006544820498675108, 0.000587297196034342, 0.0013261623680591583, 0.0007075378089211881, 0.0005853987531736493, 0.0008395786862820387, 0.0005441139219328761, 0.0006555066793225706, 0.0006343378918245435, 0.0008236673893406987, 0.0009803266730159521, 0.000559746113140136, 0.000545560265891254, 0.0005506504676304758, 0.000634058378636837, 0.0005740495398640633, 0.0026820977218449116, 0.000988702871836722, 0.00077287812018767, 0.0006628375849686563, 0.0005393197643570602, 0.0007263455772772431, 0.0005706743104383349, 0.0005907510058023036, 0.0006020895089022815, 0.0006859628483653069, 0.0006096604629419744, 0.0006165460217744112, 0.00064233219018206, 0.0009636603062972426, 0.0006682755192741752, 0.000583128712605685, 0.0009392107604071498, 0.0006192121654748917, 0.0008696395088918507, 0.05306131765246391, 0.000631233211606741, 0.0008747509564273059, 0.000703962694387883, 0.0007254449301399291, 0.0006855668034404516, 0.0008695910801179707, 0.0005693473503924906, 0.003733207704499364, 0.0005995993269607425, 0.001771103823557496, 0.0007520499057136476, 0.0008568410412408412, 0.000612096453551203, 0.0010850472608581185, 0.0011143262963742018, 0.0007989385048858821, 0.0005917413509450853, 0.013258794322609901, 0.0007500398205593228, 0.0007025466184131801 ]	0.001552	87
[ "XTREME COMMUNICATION - Leading eCommerce and Tech Repair Hub\n\nAs a leading eCommerce and tech repair hub in Australia, at Xtreme we provide latest gadgets and smartphones from all the major manufacturers like Apple (iPhone 8, iPhone X, iPhone 11, etc) Samsung (Galaxy s10, Note 10, etc), Sony (Xperia series), and many more. ", "We also take pride in providing the best mobile repair, as we deal with quality mobile screen replacements, physical damage repairs, and additional technical support for even the most common problems like mobile viruses. ", "Past that, all our repairs also come with assured warranty.", "\n\nAt Xtreme Communications, we cater to all sorts of technical needs. ", "The following are some of our areas of expertise that have led us to become one of the leading Tech Hub, and Repair Store in Australia.", "\n\nMobile Phones (Apple iPhones, Google Pixel devices, Samsung Galaxy devices, etc)\n\nTablets (Apple iPads, Samsung Galaxy Tabs, etc)\n\nSmartphone Accessories (Screen protectors, speakers, headsets, handsfree, power banks phone cases, covers, etc)\n\nSmartphone and Tablet Repair (iPhone screen replacement, iPad repair, iPhone repair, etc)\n\nWhy Choose Us?", "\n\nLowest Price Guaranteed\n\nComplete Data Security\n\nRepair of Multiple Phone and Tablet Brands\n\nAssured Hassle-Free Experience\n\nWarranty On the Spot Repair\n\nQuality Assurance\n\nCertified Professionals\n\nWith over 500,000 Customers Served Up To Date\n\nWe make sure that we give our best when it comes to network plans and repairs, making you, our customers, feel privileged whenever you come into our outlets to have your phone checked, or whenever you make an inquiry. ", "We want to provide the X-factor - “Xperts giving the best service and fixing any and every damage on your phone, Xperience, and we go the xtra mile.” ", "We have stores all over NSW, QLD and now including Sydney Airport making us available for you and reachable when you need us anywhere." ]	{ "pile_set_name": "OpenWebText2" }	[ 0.0005623220349662006, 0.000619887956418097, 0.0006146101513877511, 0.0005818404024466872, 0.000570976291783154, 0.0006076715653762221, 0.0006033754907548428, 0.0009869557106867433, 0.0005771357682533562 ]	0.000636	9
[ "I replaced the word sustainability into simplicity. ", "For me the sustainable concept is related to a web of events. ", "Every individual element of the complex system supports and depends on each other. ", "It is difficult to accomplish a self sustainable element, so I translated it in to a simple chain of events, with an easy structure made out of simple connections." ]	{ "pile_set_name": "Pile-CC" }	[ 0.0006446648621931672, 0.0005339643103070557, 0.0006320179672911763, 0.0005343922530300915 ]	0.000586	4
[ "Drop test\n\nA drop test is a method of testing the in-flight characteristics of prototype or experimental aircraft and spacecraft by raising the test vehicle to a specific altitude and then releasing it. ", " Test flights involving powered aircraft, particularly rocket-powered aircraft, may be referred to as drop launches due to the launch of the aircraft's rockets after release from its carrier aircraft.", "\n\nIn the case of unpowered aircraft, the test vehicle falls or glides after its release in an unpowered descent to a landing site. ", " Drop tests may be used to verify the aerodynamic performance and flight dynamics of the test vehicle, to test its landing systems, or to evaluate survivability of a planned or crash landing. ", " This allows the vehicle's designers to validate computer flight models, wind tunnel testing, or other theoretical design characteristics of an aircraft or spacecraft's design.", "\n\nHigh-altitude drop tests may be conducted by carrying the test vehicle aboard a mothership to a target altitude for release. ", " Low-altitude drop tests may be conducted by releasing the test vehicle from a crane or gantry.", "\n\nAircraft and lifting-body testing\n\nCarrier landing simulation tests\nThe landing gear on aircraft used on aircraft carriers must be stronger than those on land-based aircraft, due to higher approach speeds and sink rates during carrier landings. ", " As early as the 1940s, drop tests were conducted by lifting a carrier-based plane such as the Grumman F6F Hellcat to a height of ten feet and then dropped, simulating the impact of a landing at . ", " The F6F was ultimately dropped from a height of , demonstrating it could absorb twice the force of a carrier landing. ", "Drop tests are still used in the development and testing of carrier-based aircraft; in 2010, the Lockheed Martin F-35C Lightning II underwent drop tests to simulate its maximum descent rate of during carrier landings.", "\n\nExperimental aircraft\nNumerous experimental and prototype aircraft have been drop tested or drop launched. ", " Many powered X-planes, including the Bell X-1, Bell X-2, North American X-15, Martin Marietta X-24A and X-24B, Orbital Sciences X-34, Boeing X-40, and NASA X-43A were specifically designed to be drop launched. ", "test articles of the unpowered NASA X-38 were also drop tested, from altitudes of up to , in order to study its aerodynamic and handling qualities, autonomous flight capabilities, and deployment of its steerable parafoil.", "\n\nSome experimental aircraft designed for airborne launches, such as the Northrop HL-10, have made both unpowered drop tests and powered drop launches. ", " Prior to powered flights using its rocket engine, the HL-10 made 11 unpowered drop flights in order to study the handling qualities and stability of the lifting body in flight.", "\n\nBalls 8 mothership\n\nEarly experimental aircraft, such as the X-1 and X-2, were carried aboard modified B-29 and B-50 bombers. ", " In the 1950s, the United States Air Force provided NASA with a B-52 bomber to be used as a mothership for the experimental X-15. ", " Built in 1955, the B-52 was only the 10th to come off the assembly line, and was used by the Air Force for flight testing before turning it over to NASA. ", " Flying with NASA tail number 008, the plane was nicknamed Balls 8 by Air Force pilots, following a tradition of referring to aircraft numbered with multiple zeroes as \"Balls\" plus the final number.", "\n\nBalls 8 received significant modifications in order to carry the X-15. ", " A special pylon, designed to carry and release the X-15, was installed under the right wing between the fuselage and inboard engine. ", " A notch was also cut out of one of the right wing's flaps so that the plane could accommodate the X-15's vertical tail. ", " Balls 8 was one of two such bombers modified to carry the X-15; while the other plane was retired in 1969 after the end of the X-15 program, NASA continued using Balls 8 for drop tests until it was retired in 2004. ", " During its 50-year career, Balls 8 carried numerous experimental vehicles including the HL-10, X-24A, X-24B, X-38, and X-43A.\n\nX-24B role in Space Shuttle development\n\nDuring the design of the Space Shuttle orbiter in the 1970s, engineers debated whether to design the orbiter to glide to an unpowered landing or equip the orbiter with pop-out jet engines in order to make a powered landing. ", " While powered landing design required carrying the engines and jet fuel, adding weight and complexity to the orbiter, engineers began favoring the powered landing option. ", " In response, NASA conducted unpowered drop tests of the X-24B to demonstrate the feasibility of landing a lifting-body aircraft in unpowered flight. ", " In 1975, the X-24B aircraft was dropped from a Balls 8 at an altitude of above the Mojave Desert, and then ignited rocket engines to increase speed and propel it to . ", " Once the rocket engine cut off, the high-speed and high-altitude conditions permitted the X-24B to simulate the path of a Space Shuttle orbiter under post-atmospheric reentry conditions. ", " The X-24B successfully made two unpowered precision landings at Edwards Air Force Base, demonstrating the feasibility of an unpowered lifting body design for the Space Shuttle. ", " These successes convinced those in charge of the Space Shuttle program to commit to an unpowered landing design, which would save weight and increase the orbiter's payload capacity.", "\n\nSpace Shuttle Enterprise\n\nIn 1977, a series of drop tests of the were conducted to test the Space Shuttle's flight characteristics. ", " Because the Space Shuttle is designed to glide unpowered during its descent and landing, a series of drop tests using a test orbiter were used to demonstrate that the orbiter could be successfully controlled in unpowered flight. ", " These drop tests, known as the Approach and Landing Test program, used a modified Boeing 747, known as the Shuttle Carrier Aircraft or SCA, to carry Enterprise to an altitude of . ", " After a series of captive-flight tests in which the orbiter was not released, five free-flight tests were performed in August through October 1977.", "\n\nWhile free-flight tests of Enterprise involved the release of an unpowered aircraft from a powered aircraft, these tests were not typical of drop testing because the orbiter was actually carried and released from a position above the SCA. ", " This arrangement was potentially dangerous because it placed Enterprise in free flight directly in front of the SCA's tail fin immediately after release. ", " As a result, the \"drop\" was conducted by using a series of carefully planned maneuvers to minimize the risk of aircraft collision. ", " Immediately after release, the Enterprise would climb to the right while the SCA performed a shallow dive to the left, allowing for quick vertical and horizontal separation between the two aircraft.", "\n\nDream Chaser\n\nIn mid-2013, Sierra Nevada Corporation plans to conduct drop tests of its Dream Chaser prototype commercial spaceplane. ", " The unmanned first flight test will drop the Dream Chaser prototype from an altitude of , where it is planned that the vehicle will autonomously fly to an unpowered at Dryden Flight Research Center.", "\n\nCrewed capsule testing\nDrop tests of prototype crewed space capsules may be done to test the survivability of landing, primarily by testing the capsule's descent characteristics and its post-reentry landing systems. ", " These tests are typically carried out uncrewed prior to any human spaceflight testing.", "\n\nApollo command module\nIn 1963, North American Aviation built BP-19A, an uncrewed boilerplate Apollo command module for use in drop testing. ", " NASA conducted a series of tests in 1964 which involved dropping BP-19A from a C-133 Cargomaster in order to test the capsule's parachute systems prior to the start of manned testing of the Apollo spacecraft.", "\n\nOrion capsule\n\nIn 2011 and 2012, NASA conducted a series of short drop tests on the survivability of water landings in its Orion crewed capsule by repeatedly dropping an Orion test vehicle into a large water basin. ", " The tests simulated water landings at speeds varying from by changing the height of the drop gantry above the basin. ", " The range of landing velocities allowed NASA to simulate a range of possible entry and landing conditions during water landings.", "\n\nIn 2011 and 2012, NASA also conducted drop tests of the Orion test vehicle's parachute systems and land-based landing capabilities. ", " In each test, the Orion spacecraft was dropped from a C-17 or C-130 cargo plane. ", " For testing, the capsule is mounted on a pallet system and placed inside the cargo aircraft. ", " Parachutes on the pallet are used to pull the pallet and capsule out of the rear of the aircraft; the capsule then separates from the pallet and begins its free fall descent.", "\n\nOn March 4, 2012, a C-17 dropped an Orion test article from an altitude of . ", " The capsule's parachutes successfully deployed between , slowing the spacecraft to a landing on ground in the Arizona desert. ", " The capsule landed at a speed of , well below the designed maximum touchdown speed.", "\n\nBoeing CST-100\nIn September 2011, Boeing conducted a series of drop tests, carried out in the Mojave Desert of southeast California, to validate the design of the CST-100 capsule's parachute and airbag cushioning landing systems. ", " The airbags are located underneath the heat shield of the CST-100, which is designed to be separated from the capsule while under parachute descent at about altitude. ", " The tests were carried out at ground speeds between in order to simulate cross wind conditions at the time of landing. ", "Bigelow Aerospace built the mobile test rig and conducted the tests.", "\n\nIn April 2012, Boeing conducted another drop test of its CST-100 prototype space capsule in order to test the capsule's landing systems. ", " The test vehicle was raised by helicopter to an altitude of and then released; the capsule's three main parachutes then deployed successfully and slowed the capsule's descent. ", " Immediately prior to landing, the capsule's six airbags inflated underneath the capsule in order to absorb some of the impact energy from landing. ", " Similar drop tests are planned in order to conduct additional airbag testing, as well as drogue chute and heat shield jettison tests.", "\n\nHelicopter testing\nIn 2009 and 2010, NASA conducted a pair of drop tests to study the survivability of helicopter crashes. ", " Using an MD 500 helicopter donated by the U.S. Army, NASA dropped the helicopter at an angle from an altitude of to simulate a hard helicopter landing. ", " Sophisticated crash test dummies with simulated internal organs were located inside the helicopter and used to assess internal injuries from such a crash. ", "Due to extensive damage to the test helicopter after the second test, no third test was planned.", "\n\nReferences\n\nCategory:Aerospace engineering\nCategory:Product testing" ]	{ "pile_set_name": "Wikipedia (en)" }	[ 0.0007292231894098222, 0.0005599937285296619, 0.000611736613791436, 0.0005576027906499803, 0.0005377915222197771, 0.0006195218302309513, 0.0006885857437737286, 0.0005956548266112804, 0.0007681469433009624, 0.0009941093157976866, 0.0006035908591002226, 0.0006333716446533799, 0.0007098405039869249, 0.0005401562666520476, 0.0006176673341542482, 0.0005893225315958261, 0.001604946912266314, 0.0007686481694690883, 0.0006585260271094739, 0.0007428026292473078, 0.000937640608754009, 0.0007499654311686754, 0.0008536298992112279, 0.0008830285514704883, 0.0007435947773046792, 0.0006151024135760963, 0.0006121714832261205, 0.0008617842104285955, 0.0007261265418492258, 0.0005765829118900001, 0.0006482700700871646, 0.0005761500215157866, 0.0005792171577923, 0.0006492562824860215, 0.0006399886915460229, 0.0006768222665414214, 0.0007643815479241312, 0.0007191586773842573, 0.0006844341405667365, 0.000619648490101099, 0.0005999308777973056, 0.0005805043620057404, 0.0005975753883831203, 0.0006627255352213979, 0.00059237249661237, 0.0005711417179554701, 0.0005965681048110127, 0.0005839932709932327, 0.0005522107239812613, 0.000640232115983963, 0.0005699230823665857, 0.0007707954500801861, 0.0006070828530937433, 0.0005377459456212819, 0.0006773581262677908, 0.000585720525123179, 0.0006482144235633314, 0.0005509712500497699, 0.0006568052340298891, 0.0005807904526591301, 0.0005888972082175314, 0.0007157045183703303, 0.0007778736180625856, 0.0005945411394350231, 0.0006215841858647764, 0.0018769687740132213, 0.0007617485243827105, 0.0006029242067597806 ]	0.00069	68
[ "5?", "\nTrue\nSuppose -b = -0b - 1. ", "Let a = -2.98 - -3. ", "Let r = -0.52 + a. Is r smaller than b?", "\nTrue\nLet m = 19 + -5. ", "Let z = 28 - m. Let o = z - 24. ", "Which is smaller: o or -1?", "\no\nLet p(q) = -2q - q + q*3 - 3q + 4q. ", "Let s(i) = i + 5. ", "Let x be s(-7). ", "Let l be p(x). ", "Do l and -7 have the same value?", "\nFalse\nLet c be 3/(-2) - (-2)/4. ", "Let h = c - -2. ", "Let d be 2/24 - (-4)/16. ", "Is h < d?", "\nFalse\nLet t(m) = m2 - 10m - 7. ", "Let i be t(-10). ", "Is i greater than 195?", "\nFalse\nLet o = 32.2 - 85.2. ", "Which is smaller: 0.2 or o?", "\no\nLet o be 1 - 3 - 52. ", "Let a be (2/o)/((-2)/4). ", "Suppose 0 = 4d + 2x + 4, -3x - 6 = -3d + 4d. ", "Which is greater: d or a?", "\na\nLet o be (-25)/8 + 3 + 9/8. ", "Which is greater: o or 2/15?", "\no\nSuppose -2z = -2 + 6, -9 = v + 5z. ", "Let p be (-175)/(-1131) - (-6)/(-117). ", "Is p less than or equal to v?", "\nTrue\nLet t = -1786/287 - 26/41. ", "Which is smaller: -7 or t?", "\n-7\nLet h = 103 + -100. ", "Let j = 4 - 4. ", "Let k be 0 - ((j - 0) + 1). ", "Is h !", "= k?", "\nTrue\nLet u = -24 - -35. ", "Let q be 3 - (3/3 - u). ", "Suppose -4a + q - 33 = 0. ", "Is a less than or equal to -4?", "\nTrue\nSuppose -4f + c - 55 = 4c, 15 = -3f + 3c. ", "Let s be -3 + f + 0 + 0. ", "Is -12 at most as big as s?", "\nFalse\nLet q be (-3)/(-9) - 8/(-3). ", "Suppose -10 = -3v + u, 2 = -0v + qv + u. Let g = -4 - v. Do -3 and g have the same value?", "\nFalse\nLet m = 357.399 - 357. ", "Which is bigger: -2 or m?", "\nm\nSuppose g + 48 = -12. ", "Let d = 103 + g. Let r = d + -689/16. ", "Which is greater: r or -1?", "\nr\nLet g = 68.9 - 74. ", "Let j = g - -1.1. ", "Which is greater: j or 0?", "\n0\nLet f be 4/(-1) - (-8 + -30). ", "Let g = 29 - f. Is -13/3 less than or equal to g?", "\nFalse\nLet s = 1.63 + -1.544. ", "Let a = 0.086 - s. Does a = -50?", "\nFalse\nLet q be (21 - 0)1/39. ", "Is 2 equal to q?", "\nFalse\nSuppose 4l + 5 - 17 = 0. ", "Let f be (((-6)/(-4))/l)/(-17 - 2). ", "Which is bigger: 1 or f?", "\n1\nLet g(a) be the second derivative of a*4/12 + 7a*3/6 - 21a*2/2 - 9a. ", "Let w be g(-9). ", "Let f be w/(-6) - (-15)/(-46). ", "Which is bigger: f or 0?", "\nf\nLet r = 89857/78 - 1152. ", "Let h = r - -25/78. ", "Let d = 366 + -366.3. ", "Which is greater: h or d?", "\nh\nLet h = 158 + -128. ", "Which is bigger: 28 or h?", "\nh\nSuppose 1059 = -5g + 4n, 2n + 1051 = -5g - 2n. ", "Let v = 131 + g. Let h be (v/8)/(1/(-1)). ", "Is h < 7?", "\nFalse\nLet w = 947 - 806. ", "Does w = 140?", "\nFalse\nSuppose -x = 3x + 2l + 6, 3l = -2x - 13. ", "Let r(b) = -b + 7. ", "Let k be r(5). ", "Let n be (-1 - (-2)/4)k. ", "Which is bigger: n or x?", "\nx\nSuppose 0d + d = -77. ", "Let p = 76 + d. Is -7/5 > p?", "\nFalse\nSuppose -2x = 3x + 3t - 84, -3 = -x + 4t. ", "Let i be (-8)/(-1)x/12. ", "Suppose 0 = 5a - 18 - 27. ", "Is i at least a?", "\nTrue\nLet b = 7 + -13. ", "Is -43/9 !", "= b?", "\nTrue\nSuppose 0 = -4s + v + 3, -12 = 5s - s - 4v. ", "Let h(j) = -2 - 4j + sj - 3. ", "Let o be h(-3). ", "Is o <= 2/3?", "\nFalse\nLet u = 27 + -59. ", "Let j = u - -32.08. ", "Are j and -0.1 non-equal?", "\nTrue\nSuppose 3q - 495 = -3y, -q - 5y = -0q - 185. ", "Let o be q/6 + (-15)/(-45). ", "Which is bigger: o or 25?", "\no\nLet l = -10/31 - -89/372. ", "Suppose 0 = 2d - 7 - 17. ", "Suppose 4p - 21 = -5w, 2p + w = 3w - d. Which is greater: p or l?", "\nl\nLet a = 53 + -54. ", "Let i be ((-3)/(-3)a)/(-1). ", "Which is smaller: i or 1/42?", "\n1/42\nLet u(c) = c*3 + 8c*2 - 4c + 31. ", "Let v be u(-9). ", "Suppose -35 = 4x - 5a, 0 = -5x + a + 2a - 47. ", "Let z = x - v. Which is bigger: 2 or z?", "\nz\nLet f = -33 + 56. ", "Let o = 6 + f. Let u = o + -26. ", "Which is greater: u or -6?", "\nu\nLet j = -632 - -658. ", "Which is smaller: j or 8?", "\n8\nLet d(w) = w - 10. ", "Let a be d(-2). ", "Let v be (-13)/14 + (-8)/(64/a). ", "Which is bigger: v or -4?", "\nv\nSuppose -4z = b - 3, -3b + 2z + 9 = -z. ", "Is 21 >= b?", "\nTrue\nLet b be 10 - 7 - (-4 - -1863). ", "Does -551 = b?", "\nTrue\nLet i(v) = v*3 - 6v*2 + 4v + 18. ", "Let t be i(4). ", "Which is bigger: t or -34?", "\nt\nSuppose 0v = 2v - 6. ", "Suppose n = 3b + 6 + 13, -3b + vn = 15. ", "Let x be 10/14 + 2/7. ", "Is b equal to x?", "\nFalse\nLet h = -6.8 + 1.8. ", "Let g = -17 + 27. ", "Let i = g - 9. ", "Is i > h?", "\nTrue\nLet c(d) = d - 4. ", "Let l be c(-15). ", "Let f = 14 + l. Which is greater: -6 or f?", "\nf\nLet w be 1/(-4)2/(-4). ", "Suppose 0 = 41l - 25l. ", "Are w and l non-equal?", "\nTrue\nSuppose -6 = -2r, 4q + r - 6r + 19 = 0. ", "Suppose -x - 73 = 4w + 30, 3w + x = -78. ", "Let t be 4/w10/(-4). ", "Are t and q nonequal?", "\nTrue\nLet f = -0.096 + 0.164. ", "Let a = f + -3.068. ", "Do a and 0 have different values?", "\nTrue\nLet t = 24 - 38. ", "Let b(y) = y*3 - 8y*2 - 46y - 37. ", "Let g be b(12). ", "Is t at least g?", "\nFalse\nLet h = 0.072 + -31.072. ", "Let s = h + 31.7. ", "Which is smaller: 0.1 or s?", "\n0.1\nSuppose -i + 2a + a = -3, -i - a = 5. ", "Let g be (-406)/(-42) - (1i)/9. ", "Which is smaller: g or 2?", "\n2\nLet u = 678 - 677.7. ", "Which is smaller: u or -58?", "\n-58\nLet l = 2 + -2. ", "Suppose l - 16 = -4a. ", "Suppose 2q - 3c - 19 = 0, 5c + 14 + 6 = q. Does q = a?", "\nFalse\nLet m = 686 + 437. ", "Is m >= 1122?", "\nTrue\nLet y = 38 - 21. ", "Let r = 23 - y. Let d = r + -4. ", "Is 2 > d?", "\nFalse\nSuppose -1128a - 63 = -1121a. ", "Which is bigger: -11 or a?", "\na\nSuppose -2m - 2c - c = 0, 0 = -5c - 20. ", "Let q = -1 - -7. ", "Do q and m have different values?", "\nFalse\nSuppose -3 = -y + 2. ", "Suppose -yn - 2 = -7. ", "Let p = n - 10. ", "Is p < -3?", "\nTrue\nSuppose 4f + o = 60, -f + 4o + 0 = 2. ", "Let i be (-726)/(-1001) + (-8)/f. ", "Which is smaller: -1 or i?", "\n-1\nLet c = -183/55 - -13/5. ", "Let p = -458 + 456. ", "Which is greater: c or p?", "\nc\nLet i(d) = -d*2 - 8d + 1. ", "Let m be i(-7). ", "Let j(u) = -2u + 9. ", "Let t be j(m). ", "Does t = -9?", "\nFalse\nLet q be 10/(-6)54/(-45). ", "Let u be (16/(-72))/(q/(-15)). ", "Is 2 < u?", "\nFalse\nLet d(l) = l + 3. ", "Let o be d(-6). ", "Let h be (-1 + -3)/(o/(-3)). ", "Which is greater: -3 or h?", "\n-3\nLet f = 139 - 139. ", "Which is smaller: f or 3/413?", "\nf\nSuppose 7 - 2 = -4y - a, 2a = 3y - 10. ", "Suppose y = -2s - s + 6. ", "Is 5 greater than or equal to s?", "\nTrue\nSuppose -3p = -2t - 40, -p - 2p + 4t + 50 = 0. ", "Suppose p = 4w + 26. ", "Let d be w/14 - 8/(-224). ", "Which is smaller: d or 0.1?", "\nd\nLet p(n) = -n3 + 6n*2 - 3n + 8. ", "Let y be p(6). ", "Let d = -15 - y. Let x = 3 - d. Is x less than 7?", "\nFalse\nLet p = 10 - -2. ", "Which is bigger: -3 or p?", "\np\nSuppose 2089q + 1362 = 2086q. ", "Does q = -455?", "\nFalse\nLet m be 675/(-1398) + (-12)/(-24). ", "Is -1 less than or equal to m?", "\nTrue\nLet f be 305/30(-15)/(-2). ", "Let h = -77 + f. Let c = -1 + 0.8. ", "Which is greater: h or c?", "\nc\nSuppose 4w - 4d = 320, 2d + 237 = 4w - w. Suppose -v - z = -39, -z + w = 2v + 2z. ", "Which is smaller: v or 41?", "\nv\nLet z = 90 + 135. ", "Is 224 less than z?", "\nTrue\nLet l(m) = -2m + 54 + 4m - 54 + m2. ", "Let b be l(3). ", "Which is greater: -3 or b?", "\nb\nLet n = 13 - 18. ", "Let t = 1 - n. Let z(c) = c2 + c. Let k be z(2). ", "Is k at least as big as t?", "\nTrue\nLet r(q) = -173 - q2 + q - 2q*3 + 173. ", "Suppose 0 = -2s - 3s + 5m, 0 = 3s - m - 2. ", "Let h be r(s). ", "Is -2 at least as big as h?", "\nTrue\nSuppose -2v + 7 = -i + 1, 5i = 4v - 6. ", "Suppose -12 = ic - 0. ", "Which is smaller: -54/11 or c?", "\nc\nLet y = 132 - 132.62. ", "Let v = y + -2.38. ", "Is v > 2/47?", "\nFalse\nLet p(j) = j3 - 7j*2 - j + 4. ", "Suppose -2g - g + 3m + 36 = 0, 3m + 8 = -g. ", "Let f be p(g). ", "Let s be 15/14 - f/(-6). ", "Which is smaller: 2/3 or s?", "\ns\nLet d(j) = -j*2 - 11j + 17. ", "Let v be d(-7). ", "Let p = -87 + v. Which is smaller: p or -43?", "\n-43\nLet u(j) = -2j2 - j + 1. ", "Let b be u(1). ", "Let w(x) = x2 - 3. ", "Let p be w(b). ", "Is p < -2/11?", "\nFalse\nLet p be -1 - 794/33/(-2). ", "Let g be (-1)/(1-4) + (-121)/p. ", "Which is greater: 1 or g?", "\n1\nLet c = -21158/25 + 846. ", "Is 0.04 at most c?", "\nFalse\nLet c(t) be the second derivative of -3t3/2 - t2 - 3t. ", "Let g be c(2). ", "Let n = g - -21. ", "Which is greater: n or -4/13?", "\nn\nLet w = -4 + 4. ", "Suppose w = y - 0y, -2s = 4y - 10. ", "Suppose -5l + a = -12, 6 = sa + 16. ", "Is 4 > l?", "\nTrue\nLet h = 41 - 56. ", "Do h and -8 have the same value?", "\nFalse\nLet t = 12/271171 - -1625118983/199310685. ", "Let v = t + -122/15. ", "Is 0 not equal to v?", "\nTrue\nLet g be ((-12)/8)/((-786)/(-8)). ", "Which is smaller: -1 or g?", "\n-1\nSuppose -3x - 6 = -5x. ", "Suppose -j - 8 = 2m + x, 4j + 8 = m. Let a be (3 + m - -1)-1. ", "Which is smaller: -8/9 or a?", "\n-8/9\nLet j be ((-19)/57)/(-1 + (-14)/(-12)). ", "Suppose 0 = 3f, 3r + 0f + 15 = -f. ", "Which is greater: r or j?", "\nj\nLet l = -2 + -4. ", "Let q = 6 + l. Suppose -4i = -qi + 40. ", "Which is smaller: -9 or i?", "\ni\nLet j be 488/44 + -2 + -5. ", "Which is bigger: j or -0.1?", "\nj\nLet t be 5(-1)/(-10)46. ", "Let c = t - 15. ", "Let z be 1 + 02/(-2). ", "Which is smaller: z or c?", "\nz\nLet w be (20/(-1))/((-13 + -4)/68). ", "Let i be 3/((27/240)/3). ", "Is w !", "= i?", "\nFalse\nSuppose -11v + 7v = 8, -4j + 116 = -2*v. ", "Suppose 20" ]	{ "pile_set_name": "DM Mathematics" }	[ 0.0009494771948084235, 0.0010762889869511127, 0.0028780389111489058, 0.0017998531693592668, 0.0013525274116545916, 0.016954587772488594, 0.0007411303813569248, 0.06474968045949936, 0.002047380432486534, 0.0017907139845192432, 0.001978418091312051, 0.0007329994696192443, 0.0016362681053578854, 0.0019434976857155561, 0.0010305301984772086, 0.002552020363509655, 0.016335224732756615, 0.0032454021275043488, 0.001968448981642723, 0.0022280006669461727, 0.0008518131216987967, 0.06666720658540726, 0.002583226189017296, 0.004468261264264584, 0.0008994574891403317, 0.008362197317183018, 0.0009197521721944213, 0.0049004643224179745, 0.0010275127133354545, 0.005179783795028925, 0.000734672590624541, 0.000759170507080853, 0.0012300143716856837, 0.0013323239982128143, 0.002527141710743308, 0.002971098991110921, 0.0014822431840002537, 0.0011527081951498985, 0.0019228780874982476, 0.0011217886349186301, 0.0010770983062684536, 0.038200464099645615, 0.006446285638958216, 0.002677565673366189, 0.0013217623345553875, 0.015522788278758526, 0.0014625848270952702, 0.0008474591304548085, 0.0009747373987920582, 0.0031369866337627172, 0.0008424263796769083, 0.0015589188551530242, 0.0038239515852183104, 0.0011273870477452874, 0.0046977633610367775, 0.005421504843980074, 0.0016954084858298302, 0.003837048541754484, 0.0014164055464789271, 0.0015016490360721946, 0.0017850191798061132, 0.0019508585100993514, 0.0010475063463672996, 0.010263224132359028, 0.0019734359811991453, 0.001812965958379209, 0.0022978351917117834, 0.001017624163068831, 0.001456771744415164, 0.0013383834157139063, 0.0009002467850223184, 0.0026832420844584703, 0.0008780671050772071, 0.18822607398033142, 0.0024697422049939632, 0.0010882077040150762, 0.0014143659500405192, 0.001072810497134924, 0.0021748803555965424, 0.002510440070182085, 0.0028312436770647764, 0.2711416184902191, 0.0011958760442212224, 0.005320284049957991, 0.0019425794016569853, 0.009058842435479164, 0.0017467787256464362, 0.001352897030301392, 0.0013975538313388824, 0.001192086492665112, 0.0014545441372320056, 0.0009669768041931093, 0.011390378698706627, 0.013801275752484798, 0.003285289742052555, 0.0013924429658800364, 0.002417906653136015, 0.0020104655995965004, 0.0013062814250588417, 0.003874249989166856, 0.001964389346539974, 0.0009635005844756961, 0.0020810915157198906, 0.0022229498717933893, 0.0058654723688960075, 0.0032152661588042974, 0.0026507198344916105, 0.000776746601331979, 0.4730953574180603, 0.005521940998733044, 0.0027598983142524958, 0.0019186283461749554, 0.0100958701223135, 0.09770461916923523, 0.000887335161678493, 0.002192123793065548, 0.0007700928254052997, 0.002372866729274392, 0.0013167872093617916, 0.0013355553383007646, 0.0009228732669726014, 0.003468759823590517, 0.0010533665772527456, 0.0010154586052522063, 0.0009622277575545013, 0.018422607332468033, 0.004708841443061829, 0.0009240416693501174, 0.002644614316523075, 0.03950178250670433, 0.0014513160567730665, 0.0023037383798509836, 0.003287270665168762, 0.002180088311433792, 0.0021048197522759438, 0.0013973623281344771, 0.0013250381452962756, 0.0008993062656372786, 0.006471437867730856, 0.01999330148100853, 0.0016667568124830723, 0.0015388561878353357, 0.0025770440697669983, 0.0013174822088330984, 0.007090517319738865, 0.0010835990542545915, 0.002952319337055087, 0.0051214126870036125, 0.0009738276712596416, 0.0009081223397515714, 0.02126825600862503, 0.0013987935381010175, 0.001339148380793631, 0.006081550847738981, 0.0012929677031934261, 0.0008223259937949479, 0.0021365403663367033, 0.0021773497574031353, 0.0007563383551314473, 0.0011247301008552313, 0.0007800436578691006, 0.0016324782045558095, 0.0014035131316632032, 0.0029866728000342846, 0.001948546851053834, 0.0009765392169356346, 0.000894614786375314, 0.004667594097554684, 0.0009894929826259613, 0.0014277460286393762, 0.0008381115621887147, 0.009644417092204094, 0.001206379965879023, 0.0007905245292931795, 0.0013853987911716104, 0.02491040527820587, 0.004914349410682917, 0.0010073784505948424, 0.037017807364463806, 0.0018438849365338683, 0.0007397445733658969, 0.0010872486745938659, 0.0013351356610655785, 0.0008980450220406055, 0.06250817328691483, 0.001342400093562901, 0.015782354399561882, 0.005293645430356264, 0.0012609288096427917, 0.0012417578836902976, 0.0012076521525159478, 0.0024272454902529716, 0.002345993183553219, 0.0037831924855709076, 0.001617497531697154, 0.0008441177778877318, 0.0016929971752688289, 0.000757488189265132, 0.07498496025800705, 0.006125106010586023, 0.0011753321159631014, 0.00783749483525753, 0.0011438342044129968, 0.0008991143549792469, 0.0007921136566437781, 0.2917957901954651, 0.001269955886527896, 0.001761379186064005, 0.002335099270567298, 0.0008327433024533093, 0.0012310604797676206, 0.001097287517040968, 0.0016272476641461253, 0.0016599842347204685, 0.005078333429992199, 0.01752069965004921, 0.0008440433302894235, 0.011952072381973267, 0.0007571706082671881, 0.002138828858733177, 0.0017505409196019173, 0.004589622374624014, 0.0012446749024093151, 0.0007875619921833277, 0.0018940757727250457, 0.14007538557052612, 0.04327442869544029, 0.0038938552606850863, 0.012608879245817661, 0.012877287343144417, 0.003466489491984248, 0.001975690247491002, 0.012294606305658817, 0.0007043186924420297, 0.0012443976011127234, 0.003849114989861846, 0.0009988119127228856, 0.014025283977389336, 0.022366808727383614, 0.01293913833796978, 0.0008521512500010431, 0.0007881107740104198, 0.012113936245441437, 0.001381588983349502, 0.0012636290630325675, 0.013838371261954308, 0.006107635796070099, 0.002720149466767907, 0.003548890119418502, 0.001016956870444119, 0.0021047655027359724, 0.0014012526953592896, 0.0008561453432776034, 0.0008612234960310161, 0.0009862830629572272, 0.02769150398671627, 0.0016655971994623542, 0.006022682413458824, 0.0008737202151678503, 0.014340143650770187, 0.00748634384945035, 0.011928552761673927, 0.0009459014981985092, 0.000880286970641464, 0.0007634359644725919, 0.0011081831762567163, 0.0026057392824441195, 0.0020216586999595165, 0.0011006235145032406, 0.0007325462065637112, 0.0012279985239729285, 0.003670617938041687, 0.0007398743182420731, 0.004597421269863844, 0.09230498969554901, 0.0008050837204791605, 0.0023256074637174606, 0.0022529736161231995, 0.0007716251420788467, 0.0027282563969492912, 0.0009563562925904989, 0.02913493849337101, 0.008639704436063766, 0.003064510878175497, 0.0007600728422403336, 0.0046416521072387695, 0.0008361086365766823, 0.002800150541588664, 0.0013562655076384544, 0.005817849654704332, 0.001098766690120101 ]	0.010111	291
[ "1997- 2001 PhD, Landscape Architecture, School of Architectural studies, The University of Sheffield, England. ", "UK\n\n1987- 1989 MA, School of Architecture and Environmental Design, Iran University of Science and Technology, Tehran, Iran\n\n1979- 1986 BA, School of Architecture and Environmental Design, Iran University of Science and Technology, Tehran, Iran\n\n2. ", "Academic Experience\n\n2012-now Professor, School of Architecture and Environmental Design, Iran University of Science and Technology\n2008–2012 Associate professor, School of Architecture and Environmental Design, Iran University of Science and Technology\n2003–2008 Assistant professor, School of Architecture and Environmental Design, Iran University of Science and Technology\n2017 Consultant/Advisor of Chairman and Manager of chairman’s office, IUST\n2017 Member of chairman committee of IUST\n2017 Head of Administrative health and protecting the rights of the people committee and member of the university strategic council of management development, IUST\n2014-now Member of university council, IUST\n2014-now Member of holding committee of theorizing, review and debate chairs, IUST\n2014-now Manager of Landscape Architecture Engineering Institute, School of Architecture & Environmental Design, IUST\n2013-now Consultant/Advisor of chairman in related to academic staffs, IUST\n2013-2016 Agent of chairman in academic staff committee, IUST\n2012-2014 Head of Department of Architecture and urban planning in Pardis 2 and electronic education, IUST\n2012-2014 Manager of international affairs of School of Architecture & Environmental Design, IUST\n2009–now Member of Professors Promotion Committee of Iran University of Science and Technology\n2006–2010 Dean of Faculty, School of Architecture & Environmental Design, IUST\n2004–2009 Chairman consultants in civil project council, IUST\n2004–2005 Consultant/Advisor of chairman and manager of chairman’s office, IUST\n2003–2009 Head of Department of Architecture, School of Architecture & Environmental Design, IUST\n1993-1997 Deputy of School of Architecture and Environmental Design, IUST\n2017 Member of architecture programming group Iran ministry of science research and technology\n2015-now Member of promotion office and head of commission of Imam Khomeini International University\n2014-now Supervision of PhD Researches, Faculty of architecture and environmental design, University of Malaya, Malaysia\n2014- now Member of promotion office and head of commission of art universities of Iran\n2014-now Member of promotion office and head of commission of architecture and urbanism of educational and research institute of ministry of education\n2014-2015 Academic Visitors at Landscape Department, Sheffield University, UK\n2013-now Supervision of PhD Researches, Faculty of architecture, Sheffield University, UK\n2012-now Supervision of PhD Researches, Landscape Department, Sheffield University, UK\n2012-now Member of selected committee of Technical and Vocational University, Iran ministry of science research and technology\n2012-2014 Member of promotion office and Head of art and architecture commission of core promotion office of Islamic Azad University\n2010-2012 Member of commission of architecture, urban planning and art, joint promotion office of Kashan and ShareKord universities\n2010–2011 Academic Visitors at Landscape Department, Sheffield University, UK\n2009-2013 Member of promotion office of art and architecture, Iran ministry of science research and technology\n2003-now Supervision of PhD and MA Research Students and External examiner at Tehran University, University of Shahid Beheshti , Tarbiat Moddaress University and Azad University\n2003–2004 Head of Department of Architecture, International University of Chabahar\n2002 lecturer at AA, School of Architectural Association, London, UK\n2003-2004 Visiting Lecturer at Ghazvin International University\n1995-1997 Visiting Lecturer at Azad University\n1989-1990 Visiting Lecturer at Lavizan Institute\n\n3. ", "Membership of Editorial Boards and Scientific Committees\n\n2017 Editor-in-Chief of “Journal of Researches in Islamic Architecture”\n2015-now Member of Editorial Board of Journal of “International journal of Environmental Sciences & Sustainable Development (ESSD)”\n2015 Reviewer of “International Journal of Planning Perspectives (Taylor & Francis (ISI))”\n2014-now Member of Editorial Board of Journal of “Boom (Ecology)”\n2014-now Member of Editorial Board of “Journal of Urban Landscape Research”\n2010-now Member of Editorial Board of Journal of “Miras-e-Melli”\n2010-now Member of Editorial Board of “Journal of Researches in Islamic Architecture”\n2009–now Editor-in-Chief of “International Journal of Architectural Engineering and urban planning”\n2009-now Member of Editorial Board of Journal of “Iranian Architecture and Urbanism”\n2009-now Member of Editorial Board of Journal of “Armanshahr”\n2009-2010 Associate Editors; The International Journal of Design Principles and Practice, Volume 2 & Volume 3\n2008-now Member of Editorial Board of Journal of “Tarh Va Namad”\n2008-2009 Associate Editors; The International Journal of Environmental, Cultural, Economic and Social Sustainability, Volume 4\n2005-2011 Member of Editorial Board of Journal of faculty of Architecture and urbanism, Ghazvin International University\n2007-2009 Member of Advisory Committee of Journal of “Sharestan”\n2002-2003 Member of Editorial Board of Journal of “Iranian Architecture (MA)”\n\n4. ", "Academic Partnership and professional association members\n\n2017 Member of Scientific committee of the 6th national conference of architecture education, university of Tehran, Iran\n2016-now Jury member of the Iranian school, Iranian architecture design competition\n2015 Member of Scientific committee of the national conference of landscape architecture, Shahid Beheshti University, Iran\n2015 Member of Scientific committee of the national conference of Islamic Iranian architecture and urban design\n2014-now Member of the art gallery of Hallam Art Group, Sheffield, UK\n2013-2014 Member of Scientific committee of the 2nd International Conference on Adaptation and Movement in architecture & International Conference on Innovation in Design and Fabrication, 25 to 26 July, 2014, in Toronto, Canada\n2013-now Member of board of directors and founders the Iranian scientific association of landscape architecture, ministry of science research and technology, Iran\n2013-2014 Member of Scientific committee of the 5th national conference of architecture education, university of Tehran, Iran\n2013 Member of technical commission of water edge zones projects of Kish Island\n2012-now Member of Board of directors of the center of excellence in Islamic architecture\n2012-now Member of architecture and urban planning unit of specialized council for human sciences development and promotion\n2012-now Member of specialized committee of codification of Islamic Iranian architecture, national building code of Iran, Iran ministry of roads and urban development\n2012-now Member of technical commission of Tehran parks and green space organization, municipality of Tehran\n2012-now Member of strategic committee and jury of Setareh Atlas Pars design project, Tehran Haghani highway and residential towers in Namak Abrud\n2012 Jury member of the 30th annual book of the year award, Iran\n2012 Member of committee of art and architecture of 14th khwarazmi youth award\n2012 Member of scientific committee and Jury member of design competition of martyrs memorial Monument of Iran University of science and technology\n2012 Member of scientific committee of the first national conference of architecture and sustainable city, Shahid Rajaee Teacher Training University\n2012 Member of strategic council of education programming of art and architecture, Shahid Rajaee Teacher Training University\n2011-now University representative in Memorandum of Cooperation with Tehran Urban research and planning center\n2011 Member of scientific committee of the international conference of the city, pedestrian life\n2010-now Member of Royal Academy of Arts, London, UK\n2010-2011 Member of scientific committee of the 4th national conference of architecture education, university of Tehran, Iran\n2009-now Member of founding board of Iranian society of green architecture\n2009-now Member of architecture scientific committee of national building code of Iran, Iran ministry of roads and urban development\n2009-now Member of specialized committee of Occupational Entrance Exam of architecture engineering, Iran ministry of roads and urban development\n2009-now Member of committee of qualification determination of pioneer architecture engineers, Iran ministry of roads and urban development\n2009-now Member of jury of the 4th national festival of applied science and technology\n2009 Member of scientific committee of sustainable architecture with the approach of modifying model of consumption in the building industry\n2009 Jury member of the 12th annual book of the season award, Iran\n2009 Member of scientific committee of selecting the distinguished teacher, university of applied science and technology\n2009 Head and member of scientific committee of the national conference of vernacular technologies, Iran University of science and technology\n2008 -now Head of the Board of directors and funding member of Iranian Scientific Association of Architecture and Urbanism\n2008-2014 Head of board of directors of The Scientific Society of Architecture & Urbanism (SAU), Ministry of Science Research and Technology\n2008-now Jury member of school of architecture Ghazvin International University Competition\n2008-2010 Member of strategic council of Mirmiran award\n2008 Member of scientific committee of national conference of Improvement and Renovation of Old Textures of Shiraz city\n2008 Jury member of first National Architectural Student Congress, Kashan, Iran\n2007-now Member of Iranian Society of Environmentalists\n2007 Member of scientific committee of the 2nd national conference of green space\n2007-2008 Jury member of Mirmiran Foundation Architectural price\n2006 Member of committee of art and architecture of 8th khwarazmi youth award\n2006 Member of committee of art and architecture of 8th khwarazmi award\n2005-now Member of committee of architecture and urban planning, University of applied science and technology\n2003–now Member of International Federation of Landscape Architects (IFLA)\n1999-2001 Organiser of Art & Built Environment Group, 7th, 8th and 9th Annual Iranian Students Seminar in Europe, England, UK\n1987-now Member of Iranian Construction Engineers Organization\n\n5. ", "Professional Experiences\n\nStudy, review and compilation of criteria and Standards of the layout and design of student camps, Organization for Renovating, Developing and Equipping Schools\nConceptual studies and design and supervising construction of Malek garden, Tehran parks and green space organization\nReview, Design and supervising construction of woman park, Tehran parks and green space organization\nConsulting conceptual studies of space city of Iran and planning its architectural standard\nDesign of cultural recreational complex camp of Sama, Islamic Azad University\nPlanning standards of primary school’s open space, Organization for Renovating, Developing and Equipping Schools\nStudying, organizing and restoration of Saadossaltaneh historical complex, renovation and reformer organization of Qazvin\nDesign of commercial residential complex of Aghigh, Mashahd city\nStudying Strategic plan of the Tehran Bazaar to improve its security, Cultural Heritage, Handicrafts and Tourism Organization of Iran\nStudying immunization and social empowerment of historical textures (development of historical centers by protection of main characteristics and contemporary needs)\nStudying restoration, preservation of cultural historical centers (mapping, documenting, analyzing, and providing guidelines)\nCooperation in organizing cultural axis of Kerman city\nCooperation in review of restoration plan of historical texture of Yazd city\n2008 - now Pedestrian design of Kargar Avenue from Enghelab sq to Rahahan sq, Tehran\n2006 -now Landscape architecture comprehensive plan for Bistoon International Historic Site\n2005-2007 Landscape architecture comprehensive plan for Jahad complex\n1993-1997 Designer, Technical deputy and Member of the Board of Directors of Company of Andisheh New Town, Housing and Urbanism Ministry\n1987-1997Revitalisation of historic garden of Shazdeh/ Kerman /Iran\nDesign of recreational park in Andisheh New Town /Tehran\nDesign of cultural complex in Andisheh New Town /Tehran\nDesign of residential landscape in Andisheh New Town /Tehran\nDesign of 120 housings in Pardis New Town /Tehran\nDesign of three industrial estates, Ghom, Bijar, Ghorveh /Iran\nDesign of residential landscape in city of Tehran\nSupervising construction of housing unit in Andisheh New Town /Tehran\nSupervising construction of housing unit in city of Tehran6. ", "Academic Award & Honours\n2015 Distinguished professor of the country, Ministry of Science, Research and Technology, Iran\n2014 Distinguished Researcher, School of Architecture & Environmental Design, Iran University of Science and Technology\n2013 Distinguished Researcher, School of Architecture & Environmental Design, Iran University of Science and Technology\n2012 Distinguished Academic staff, School of Architecture & Environmental Design, Iran University of Science and Technology\n2011 Distinguished book award for “Analysis of 10 buildings form 50 years of Iranian contemporary architecture”\n2011 Distinguished Researcher of the Country, Art & Architecture Group, Iran Ministry of Science, Research and Technology\n2010 Distinguished Researcher, School of Architecture & Environmental Design, Iran University of Science and Technology\n1989 First honored award for academic achievement at school of architecture (MA) 7. ", "Invited Academic Lecture\n2002 Conservation (Landscape and Gardens), Architectural Association (AA), School of Architecture, London, England8. ", "Exhibitions\n2014 27th Great Art Show, Sheffield, England, UK\n2012 25th Great Art Show, Sheffield, England, UK\n2011 24th Great Art Show, Sheffield, England, UK\n2003 Wild about Art, England, UK\n2002 15th Great Art Show, Sheffield, England, UK\n2001 14th Great Art Show, Sheffield, England, UK9. ", "Publications - Journal Papers\n\nSabeti, Sh., ", "Faizi, M., Mehdizade F., Mahdavinia, M. “Assessing the effect of window, its shape and shading devices on the heating and cooling energy consumption (In the region of Mashhad city)”. ", "Current Trends in Technology and Science, An International Journal, 2015, 50-51\n\n2015\n\nSabeti, Sh., ", "Faizi, M., Mehdizade F., Mahdavinia, M., “The effect of Ivan on the thermal behavior of the main space in semi-arid and hot climate in Iran (Case study: vernacular Houses in Mashhad Town)”. ", "International Journal of Review in Life Sciences (IJRLS)\n\n2015\n\nKeshtkar, E., Faizi, M., “Effect of cultural and poem identity on the architectural design”, The International Journal of Engineering and Science, 4(2): 21-27.", "\n\nFaizi, M., Eisazadeh, N. “The Impact of Urban Parks and Green Spaces on Citizens, Health and Quality of Life”. ", "The International Journal of Environmental, Cultural, Economic and Social Sustainability, 4(4): 7-24\n\nFaizi, M., Shahbazi, M. “Relationship Between Human Tranquility and the Use of Water in Iranian Cities: Fin Garden in Kashan” Asia/Pacific International Conference on Environment-Behaviour Studies (AicE-Bs), Famagusta, North Cyprus." ]	{ "pile_set_name": "Pile-CC" }	[ 0.0005822770181111991, 0.0006321706459857523, 0.0006949111120775342, 0.0006754237110726535, 0.000617656740359962, 0.000604555185418576, 0.0005897256778553128, 0.0005803107051178813, 0.0006284170667640865, 0.0006731324829161167, 0.0006057621212676167, 0.0006306198774836957, 0.0005979933775961399, 0.0006085603381507099, 0.0006508906371891499, 0.0005955080850981176 ]	0.000623	16
[ "Dear Editor,\n\nRadiation is part of mans' environment, and people are usually exposed to both natural (viz. ", "cosmic rays, environmental - soil, water, vegetation, etc.) ", "and man-made (viz. ", "medical exposure, occupational exposure, nuclear fall-out, television, mobile, etc.) ", "sources of radiation.\\[[@ref1]\\] In the modern era, radiation is like a double-edged sword, with utilities in fields like medicine, industry, agriculture and research and, at the same time, being a serious potential health hazard if not properly used or contained.\\[[@ref1][@ref2]\\]\n\nExposure of humans to radiations beyond the maximal permissible limits has led to a wide range of complications such as acute events (viz. ", "skin burns, dermatitis, acute radiation syndrome, local radiation injuries and blood dyscrasias), chronic events like malignancies (viz. ", "lung cancer, leukemia, thyroid cancer, female breast cancer, basal cell carcinoma, squamous cell carcinoma, melanoma, etc.), ", "birth defects (viz. ", "exposure of pregnant women to radiation during antenatal period) and even death.\\[[@ref1][@ref2]\\] In addition, a high incidence of psychological distress and psychiatric disorders like posttraumatic stress disorder, anxiety disorders, depression and alcohol use disorder have been observed among the survivors, especially secondary to a nuclear accident.\\[[@ref3][@ref4]\\] However, the extent of radiation-induced damage is dependent upon parameters like age at the time of exposure, dose of radiation, duration of exposure, type of radiation and the sensitivity of different tissues and organs.\\[[@ref1][@ref5][@ref6]\\]\n\nNevertheless, in most of the settings, the incidence of radiation-induced cancer/complications are still on the rise owing to the presentation of clinical manifestations after a prolonged period of exposure (lag period), poor awareness among the masses about the sources/side-effects of radiation exposure, minimal sensitization of the physicians regarding assessment of radiation exposure, unavailability or poor condition of personal protective equipments in different industries, nonutilization of the protective equipments despite their availability because of ignorance or poor awareness, noncompliance with the recommended environmental standards in different industries, absence of universal implementation of either preplacement examination or periodic medical examination, no guidelines to promote early diagnosis or initiate the process of referral of patients to higher centers, limited access to information about supportive care services and absence of standardized recommendations regarding different aspects of radiation.\\[[@ref1][@ref2][@ref4][@ref7]\\] These are the key challenges that need to be sorted out for bringing about an improvement in the indicators of cancer.", "\n\nIn order to either prevent or reduce the incidence of radiation-associated cancer, there is an essential need that program managers and radiation experts realize the risk of radiation exposure and then plan evidence-based strategies in collaboration with different stakeholders.\\[[@ref1][@ref4]\\] This essentially involves ensuring comprehensive risk assessment (viz. ", "based on the specific radiation sources, types of harmful effects that could result, exposure assessment to establish maximum permissible limits and estimation of lifetime risk of cancer),\\[[@ref3]\\] adopting a specific model to empirically evaluate the influence of time since exposure and age at exposure on radiation-induced cancer,\\[[@ref6]\\] implementing preventive strategies (viz. ", "preplacement examination, use of protective equipments or dosimeter, periodic medical examination, compliance with the environmental recommended strategies) in industries or health care establishments,\\[[@ref2]\\] creating awareness among physicians, populations and outreach workers regarding radiation-induced cancer,\\[[@ref2]\\] formulating guidelines to adopt appropriate line of management based on the stage of cancer and patient-related factors,\\[[@ref8]\\] extending support to cancer patients,\\[[@ref7]\\] developing a mechanism to promote medical monitoring and follow-up of populations (viz. ", "persons who developed clinical conditions requiring medical assistance during the emergency and asymptomatic persons known) to facilitate early detection and prompt initiation of treatment,\\[[@ref3][@ref9]\\] ensuring early management of mental health issues among the victims and their family members,\\[[@ref4]\\] developing a strategic disaster plan to enable preparedness, evacuation and relocation at times of nuclear accidents\\[[@ref3][@ref4]\\] and building linkages with different international agencies\\[[@ref1]\\] can be tried upon to reduce the incidence of radiation-induced cancers.", "\n\nTo conclude, radiation has been recognized as a key etiological factor in the development of multiple cancers. ", "However, their role in natural history of malignancies can be nullified provided appropriate prevention and control strategies are implemented worldwide.", "\n" ]	{ "pile_set_name": "PubMed Central" }	[ 0.0006596422754228115, 0.0005607706261798739, 0.000840518856421113, 0.0006631959113292396, 0.0006590157863683999, 0.0037227096036076546, 0.0013905697269365191, 0.0006912496173754334, 0.0016246954910457134, 0.0006961046019569039, 0.0007269902853295207, 0.0006294390768744051, 0.0007379259332083166, 0.0005538801196962595, 0.0005689187673851848, 0.001994825666770339 ]	0.001045	16
[ "{\n \"cells\": [\n {\n \"cell_type\": \"markdown\",\n \"metadata\": {},\n \"source\": [\n \"## Sample: keras/examples/mnist_transfer_cnn.py\"\n ]\n },\n {\n \"cell_type\": \"markdown\",\n \"metadata\": {},\n \"source\": [\n \"'''Transfer learning toy example:\\n\",\n \"1- Train a simple convnet on the MNIST dataset the first 5 digits [0..4].\\n\",\n \"2- Freeze convolutional layers and fine-tune dense layers\\n\",\n \" for the classification of digits [5..9].\\n\",\n \"Run on GPU: THEANO_FLAGS=mode=FAST_RUN,device=gpu,floatX=float32 python mnist_transfer_cnn.py\\n\",\n \"Get to 99.8% test accuracy after 5 epochs\\n\",\n \"for the first five digits classifier\\n\",\n \"and 99.2% for the last five digits after transfer + fine-tuning.\\n\",\n \"'''\\n\",\n \"\\n\"\n ]\n },\n {\n \"cell_type\": \"code\",\n \"execution_count\": 1,\n \"metadata\": {},\n \"outputs\": [\n {\n \"name\": \"stderr\",\n \"output_type\": \"stream\",\n \"text\": [\n \"Using TensorFlow backend.\\n\"\n ]\n }\n ],\n \"source\": [\n \"import datetime\\n\",\n \"import keras\\n\",\n \"from keras.datasets import mnist\\n\",\n \"from keras.models import Sequential\\n\",\n \"from keras.layers import Dense, Dropout, Activation, Flatten\\n\",\n \"from keras.layers import Conv2D, MaxPooling2D\\n\",\n \"from keras import backend as K\"\n ]\n },\n {\n \"cell_type\": \"code\",\n \"execution_count\": 11,\n \"metadata\": {\n \"collapsed\": true\n },\n \"outputs\": [],\n \"source\": [\n \"now = datetime.datetime.now\\n\",\n \"\\n\",\n \"batch_size = 128\\n\",\n \"num_classes = 5\\n\",\n \"epochs = 1\"\n ]\n },\n {\n \"cell_type\": \"code\",\n \"execution_count\": 3,\n \"metadata\": {\n \"collapsed\": true\n },\n \"outputs\": [],\n \"source\": [\n \"# input image dimensions\\n\",\n \"img_rows, img_cols = 28, 28\\n\",\n \"# number of convolutional filters to use\\n\",\n \"filters = 32\\n\",\n \"# size of pooling area for max pooling\\n\",\n \"pool_size = 2\\n\",\n \"# convolution kernel size\\n\",\n \"kernel_size = 3\\n\"\n ]\n },\n {\n \"cell_type\": \"code\",\n \"execution_count\": 4,\n \"metadata\": {\n \"collapsed\": true\n },\n \"outputs\": [],\n \"source\": [\n \"if K.image_data_format() == 'channels_first':\\n\",\n \" input_shape = (1, img_rows, img_cols)\\n\",\n \"else:\\n\",\n \" input_shape = (img_rows, img_cols, 1)\\n\"\n ]\n },\n {\n \"cell_type\": \"code\",\n \"execution_count\": 5,\n \"metadata\": {},\n \"outputs\": [\n {\n \"data\": {\n \"text/plain\": [\n \"(28, 28, 1)\"\n ]\n },\n \"execution_count\": 5,\n \"metadata\": {},\n \"output_type\": \"execute_result\"\n }\n ],\n \"source\": [\n \"input_shape\"\n ]\n },\n {\n \"cell_type\": \"code\",\n \"execution_count\": 6,\n \"metadata\": {\n \"collapsed\": true\n },\n \"outputs\": [],\n \"source\": [\n \"def train_model(model, train, test, num_classes):\\n\",\n \" x_train = train[0].reshape((train[0].shape[0],) + input_shape)\\n\",\n \" x_test = test[0].reshape((test[0].shape[0],) + input_shape)\\n\",\n \" x_train = x_train.astype('float32')\\n\",\n \" x_test = x_test.astype('float32')\\n\",\n \" x_train /= 255\\n\",\n \" x_test /= 255\\n\",\n \" print('x_train shape:', x_train.shape)\\n\",\n \" print(x_train.shape[0], 'train samples')\\n\",\n \" print(x_test.shape[0], 'test samples')\\n\",\n \"\\n\",\n \" # convert class vectors to binary class matrices\\n\",\n \" y_train = keras.utils.to_categorical(train[1], num_classes)\\n\",\n \" y_test = keras.utils.to_categorical(test[1], num_classes)\\n\",\n \"\\n\",\n \" model.compile(loss='categorical_crossentropy',\\n\",\n \" optimizer='adadelta',\\n\",\n \" metrics=['accuracy'])\\n\",\n \"\\n\",\n \" t = now()\\n\",\n \" model.fit(x_train, y_train,\\n\",\n \" batch_size=batch_size,\\n\",\n \" epochs=epochs,\\n\",\n \" verbose=1,\\n\",\n \" validation_data=(x_test, y_test))\\n\",\n \" print('Training time: %s' % (now() - t))\\n\",\n \" score = model.evaluate(x_test, y_test, verbose=0)\\n\",\n \" print('Test score:', score[0])\\n\",\n \" print('Test accuracy:', score[1])\"\n ]\n },\n {\n \"cell_type\": \"code\",\n \"execution_count\": 7,\n \"metadata\": {},\n \"outputs\": [],\n \"source\": [\n \"# the data, shuffled and split between train and test sets\\n\",\n \"(x_train, y_train), (x_test, y_test) = mnist.load_data()\\n\",\n \"\\n\",\n \"# create two datasets one with digits below 5 and one with 5 and above\\n\",\n \"x_train_lt5 = x_train[y_train < 5]\\n\",\n \"y_train_lt5 = y_train[y_train < 5]\\n\",\n \"x_test_lt5 = x_test[y_test < 5]\\n\",\n \"y_test_lt5 = y_test[y_test < 5]\\n\",\n \"\\n\",\n \"x_train_gte5 = x_train[y_train >= 5]\\n\",\n \"y_train_gte5 = y_train[y_train >= 5] - 5\\n\",\n \"x_test_gte5 = x_test[y_test >= 5]\\n\",\n \"y_test_gte5 = y_test[y_test >= 5] - 5\"\n ]\n },\n {\n \"cell_type\": \"code\",\n \"execution_count\": 8,\n \"metadata\": {\n \"collapsed\": true\n },\n \"outputs\": [],\n \"source\": [\n \"# define two groups of layers: feature (convolutions) and classification (dense)\\n\",\n \"feature_layers = [\\n\",\n \" Conv2D(filters, kernel_size,\\n\",\n \" padding='valid',\\n\",\n \" input_shape=input_shape),\\n\",\n \" Activation('relu'),\\n\",\n \" Conv2D(filters, kernel_size),\\n\",\n \" Activation('relu'),\\n\",\n \" MaxPooling2D(pool_size=pool_size),\\n\",\n \" Dropout(0.25),\\n\",\n \" Flatten(),\\n\",\n \"]\\n\"\n ]\n },\n {\n \"cell_type\": \"code\",\n \"execution_count\": 9,\n \"metadata\": {\n \"collapsed\": true\n },\n \"outputs\": [],\n \"source\": [\n \"classification_layers = [\\n\",\n \" Dense(128),\\n\",\n \" Activation('relu'),\\n\",\n \" Dropout(0.5),\\n\",\n \" Dense(num_classes),\\n\",\n \" Activation('softmax')\\n\",\n \"]\"\n ]\n },\n {\n \"cell_type\": \"code\",\n \"execution_count\": 10,\n \"metadata\": {\n \"collapsed\": true\n },\n \"outputs\": [],\n \"source\": [\n \"# create complete model\\n\",\n \"model = Sequential(feature_layers + classification_layers)\\n\"\n ]\n },\n {\n \"cell_type\": \"code\",\n \"execution_count\": 12,\n \"metadata\": {},\n \"outputs\": [\n {\n \"name\": \"stdout\",\n \"output_type\": \"stream\",\n \"text\": [\n \"x_train shape: (30596, 28, 28, 1)\\n\",\n \"30596 train samples\\n\",\n \"5139 test samples\\n\",\n \"Train on 30596 samples, validate on 5139 samples\\n\",\n \"Epoch 1/1\\n\",\n \"30596/30596 [==============================] - 38s - loss: 0.2048 - acc: 0.9362 - val_loss: 0.0534 - val_acc: 0.9850\\n\",\n \"Training time: 0:00:38.782578\\n\",\n \"Test score: 0.0534252165606\\n\",\n \"Test accuracy: 0.985016540183\\n\"\n ]\n }\n ],\n \"source\": [\n \"# train model for 5-digit classification [0..4]\\n\",\n \"train_model(model,\\n\",\n \" (x_train_lt5, y_train_lt5),\\n\",\n \" (x_test_lt5, y_test_lt5), num_classes)\\n\"\n ]\n },\n {\n \"cell_type\": \"code\",\n \"execution_count\": 14,\n \"metadata\": {\n \"collapsed\": true\n },\n \"outputs\": [],\n \"source\": [\n \"# freeze feature layers and rebuild model\\n\",\n \"for l in feature_layers:\\n\",\n \" l.trainable = False\\n\"\n ]\n },\n {\n \"cell_type\": \"code\",\n \"execution_count\": 15,\n \"metadata\": {},\n \"outputs\": [\n {\n \"name\": \"stdout\",\n \"output_type\": \"stream\",\n \"text\": [\n \"x_train shape: (29404, 28, 28, 1)\\n\",\n \"29404 train samples\\n\",\n \"4861 test samples\\n\",\n \"Train on 29404 samples, validate on 4861 samples\\n\",\n \"Epoch 1/1\\n\",\n \"29404/29404 [==============================] - 14s - loss: 0.3874 - acc: 0.8810 - val_loss: 0.1184 - val_acc: 0.9638\\n\",\n \"Training time: 0:00:14.333065\\n\",\n \"Test score: 0.118379053483\\n\",\n \"Test accuracy: 0.963793458271\\n\"\n ]\n }\n ],\n \"source\": [\n \"# transfer: train dense layers for new classification task [5..9]\\n\",\n \"train_model(model,\\n\",\n \" (x_train_gte5, y_train_gte5),\\n\",\n \" (x_test_gte5, y_test_gte5), num_classes)\"\n ]\n },\n {\n \"cell_type\": \"code\",\n \"execution_count\": null,\n \"metadata\": {\n \"collapsed\": true\n },\n \"outputs\": [],\n \"source\": []\n }\n ],\n \"metadata\": {\n \"kernelspec\": {\n \"display_name\": \"Python 3\",\n \"language\": \"python\",\n \"name\": \"python3\"\n },\n \"language_info\": {\n \"codemirror_mode\": {\n \"name\": \"ipython\",\n \"version\": 3\n },\n \"file_extension\": \".py\",\n \"mimetype\": \"text/x-python\",\n \"name\": \"python\",\n \"nbconvert_exporter\": \"python\",\n \"pygments_lexer\": \"ipython3\",\n \"version\": \"3.6.1\"\n }\n },\n \"nbformat\": 4,\n \"nbformat_minor\": 2\n}\n" ]	{ "pile_set_name": "Github" }	[ 0.0008231499814428389 ]	0.000823	1
[ "Q:\n\nCreating a method that returns an array\n\nI'm to create a helper method that returns a new array whose elements are the square of an original array. ", "But when I run the code, the console returns \"System.", "Double[]\". ", "How can I fix this?", "\nHere's the method code:\nstatic double[] powerOfTwo(int[] arr)\n {\n double[] elevatedPower = new double[10];\n elevatedPower[0] = Math.", "Pow(arr[0], 2);\n elevatedPower[1] = Math.", "Pow(arr[1], 2);\n elevatedPower[2] = Math.", "Pow(arr[2], 2);\n elevatedPower[3] = Math.", "Pow(arr[3], 2);\n elevatedPower[4] = Math.", "Pow(arr[4], 2);\n elevatedPower[5] = Math.", "Pow(arr[5], 2);\n elevatedPower[6] = Math.", "Pow(arr[6], 2);\n elevatedPower[7] = Math.", "Pow(arr[7], 2);\n elevatedPower[8] = Math.", "Pow(arr[8], 2);\n elevatedPower[9] = Math.", "Pow(arr[9], 2);\n\n return elevatedPower;\n }\n\nAnd the code to print it in the console: \nstatic void Main(string[] args)\n {\n double[] powerValues = powerOfTwo(new int[] {1,2,3,4,5,6,7,8,9,10});\n Console.", "Write(powerValues);\n Console.", "ReadLine();\n }\n\nA:\n\nYour method works fine. ", "But when you do Console.", "WriteLine(powerValues), the compiler calls ToString() method of the datatype which is System.double[].", "\nforeach(var value in powerValues)\n Console.", "WriteLine(value);\n\nWith Linq, using System.", "Linq;\nvar powerValues = (new int[] {1,2,3,4,5,6,7,8,9,10}).Select(x => xx);\n\nA:\n\nWhen you calling Console.", "Write(powerValues); actually call Console.", "Write(powerValues.", "ToString());ToString returns a string that represents the current object. ", "For double[] this is \"System.", "Double[]\".", "\nChange your code like this :\n static void Main(string[] args)\n {\n double[] powerValues = powerOfTwo(new int[] { 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 });\n foreach (var value in powerValues)\n {\n Console.", "WriteLine(value);\n }\n\n Console.", "ReadLine();\n }\n\nA:\n\nActually, you are not printing your values. ", "You try to print your array which returns it's full type name as System.", "Double[] since ToString calls it which is called by Console.", "Write explicitly.", "\nYou don't even need such a method. ", "Just use Enumerable.", "Select to generate IEnumerable<int> which contains squared values like;\nvar values = new[] { 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 };\nforeach (var value in values.", "Select(i => i i))\n{\n Console.", "Write(value); // 149162536496481100\n}\n\nAnd I would use Console.", "WriteLine to writing those values in separate lines each or put at least a white space after them if you choose Write like Console.", "Write(value + \" \")\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.0007161787943914533, 0.0006184333469718695, 0.0008428811561316252, 0.0008485725848004222, 0.0008564100717194378, 0.0007943495875224471, 0.0007612546905875206, 0.0007670902414247394, 0.0007890802808105946, 0.0007905738893896341, 0.0007780370651744306, 0.0007650411571376026, 0.0007757697603665292, 0.0007746687042526901, 0.001480627222917974, 0.0007501699146814644, 0.0006870862562209368, 0.000853820180054754, 0.000745279248803854, 0.0007362556061707437, 0.0007308560307137668, 0.0007609751191921532, 0.000759936636313796, 0.0008766271639615297, 0.0007110995939001441, 0.0007141532259993255, 0.0008428811561316252, 0.0010727385524660349, 0.0008121766149997711, 0.000865620793774724, 0.0007937449845485389, 0.0006842630100436509, 0.0009236474288627505, 0.0014166516484692693, 0.0007731738151051104, 0.0008635222911834717, 0.004579086322337389, 0.0007515200995840132, 0.0007742185262031853, 0.0007918057963252068 ]	0.000916	40
[ "Evidence for coexistence of superconductivity and magnetism in single crystals of Co-doped SrFe(2)As(2).", "\nIn order to investigate whether magnetism and superconductivity coexist in Co-doped SrFe(2)As(2), we have prepared single crystals of SrFe(2-x)Co(x)As(2), x = 0 and 0.4, and characterized them via x-ray diffraction, electrical resistivity in zero and applied field up to 9 T as well as at ambient and applied pressure up to 1.6 GPa, and magnetic susceptibility. ", "At x = 0.4, there is both magnetic and resistive evidence for a spin density wave transition at 120 K, while T(c) = 19.5 K-indicating coexistent magnetism and superconductivity. ", "A discussion of how these results compare with reported results, both in SrFe(2-x)Co(x)As(2) and in other doped 122 compounds, is given." ]	{ "pile_set_name": "PubMed Abstracts" }	[ 0.0007067075348459184, 0.0006294039776548743, 0.0007012271671555936, 0.0005644982447847724 ]	0.00065	4
[ "\r\n// Copyright Aleksey Gurtovoy 2001-2004\r\n//\r\n// Distributed under the Boost Software License, Version 1.0. ", "\r\n// (See accompanying file LICENSE_1_0.txt or copy at \r\n// http://www.boost.org/LICENSE_1_0.txt)\r\n//\r\n\r\n// Preprocessed version of \"boost/mpl/aux_/template_arity.hpp\" header\r\n// -- DO NOT modify by hand!", "\r\n\r\n" ]	{ "pile_set_name": "Github" }	[ 0.0007035938324406743, 0.000736202928237617, 0.001994825666770339 ]	0.001145	3
[ "Introduction {#s1}\n============\n\nAn emerging paradigm in the study of cell signaling is the potential role for post-transcriptional gene regulation by extracellular RNAs. ", "microRNAs (miRNAs) are perhaps the best characterized class of small noncoding RNAs (ncRNAs) that have been detected in extracellular fluids ([@bib60]). ", "Mature miRNAs are 21--23 nucleotides in length and bind to target mRNAs to inhibit their expression ([@bib37]). ", "Because miRNAs imperfectly pair with their mRNA targets, they can potentially regulate hundreds of transcripts within a genome ([@bib5]). ", "However, individual miRNAs exhibit exquisite tissue-specific patterns of expression ([@bib66]), control cell fate decisions ([@bib1]), and are often aberrantly expressed in human cancers ([@bib59]), affording possible disease-specific signatures with diagnostic, prognostic, and therapeutic potential ([@bib40]; [@bib63]).", "\n\nIn addition to their intracellular roles, recent experiments have identified miRNAs outside the cell in extracellular vesicles (EVs) including exosomes or larger vesicles ([@bib60]; [@bib17]), in high-density lipoprotein particles ([@bib61]), or in smaller complexes with Argonaute 2 protein ([@bib3]). ", "Exosomes are small 40--130 nm vesicles of endosomal origin that are secreted by all cells and can fuse and be internalized by recipient cells ([@bib60]; [@bib36]; [@bib30]; [@bib45]; [@bib46]). ", "It has been suggested that protein cargo transfer by exosomes between cells is associated with tumor aggressiveness and metastasis ([@bib55]; [@bib30]; [@bib41]; [@bib31]; [@bib16]). ", "With the discovery that miRNAs and other RNAs can also be packaged into EVs, or exported by other extracellular mechanisms, it remains unclear the extent to which RNA cargo is sorted for export and how it is dysregulated in disease conditions, such as cancer.", "\n\nDespite accumulating evidence that exosomes are biologically active, little is known regarding how oncogenic signaling affects the repertoire of miRNAs or proteins that are selected for secretion. ", "Given the potential of cancer-derived secreted RNAs to modulate the tumor microenvironment, elucidation of the potential mechanisms for selective sorting of cargo into exosomes is critical to understanding extracellular signaling by RNA. ", "KRAS mutations occur in approximately 34--45% of colon cancers ([@bib67]). ", "We have previously shown that exosomes from mutant KRAS colorectal cancer (CRC) cells can be transferred to wild-type cells to induce cell growth and migration ([@bib30]; [@bib18]). ", "Compared to exosomes derived from isogenically matched wild-type cells, exosomes derived from mutant KRAS cells contain dramatically different protein cargo ([@bib18]). ", "Here, we show that KRAS status also prominently affects the miRNA profile in cells and their corresponding exosomes. ", "Exosomal miRNA profiles are distinct from cellular miRNA patterns, and exosomal miRNA profiles are better predictors of KRAS status than cellular miRNA profiles. ", "Furthermore, we show that cellular trafficking of miRNAs is sensitive to neutral sphingomyelinase (nSMase) inhibition in mutant, but not wild type, KRAS cells and that transfer of miRNAs between cells can functionally alter gene expression in recipient cells.", "\n\nResults {#s2}\n=======\n\nSmall ncRNAs are differentially distributed in exosomes {#s2-1}\n-------------------------------------------------------\n\nBecause small RNAs are thought to be sorted at endosomal membranes and since KRAS signaling can also occur on late endosomes ([@bib40]), we hypothesized that oncogenic KRAS signaling could alter RNA export into exosomes. ", "We prepared small RNA libraries from both exosomes and whole cells using isogenically matched CRC cell lines that differ only in KRAS status ([Figure 1---source data 1](#SD1-data){ref-type=\"supplementary-material\"}) ([@bib54]). ", "Exosomes were purified using differential centrifugation and consisted of vesicles ranging in size from 40 to 130 nm ([@bib30]; [@bib18]). ", "These preparations exclude larger microvesicles but contain smaller lipoproteins and probably other small RNA--protein complexes (unpublished observation). ", "Comprehensive sequencing analyses of both cellular and exosomal small RNAs from all three cell lines revealed that more than 85% of the reads from the cellular RNA libraries mapped to the genome, compared to only 50--71% from the exosomal libraries ([Figure 1A](#fig1){ref-type=\"fig\"}). ", "The non-mappable reads consisted largely of sequences that contain mismatches to genomic sequences.10.7554/eLife.07197.003Figure 1.Small RNA sequencing analysis of cellular and exosomal RNAs from CRC cell lines.", "Shown are (A) total read numbers (y-axis) and the total percentage of mappable reads (red), percentage of unique mappable reads (green), reads that map to multiple genomic locations (dark blue), and those that could not be mapped (cyan). (", "B) The majority of mappable small RNA reads were derived from noncoding RNAs in cells and exosomes. ", "In cells, the majority of small RNA reads mapped to microRNAs (miRNAs) (miRbase 19), whereas in exosomes, the majority of small RNA reads mapped to repetitive elements. (", "C) The origin of repetitive reads from exosomal small RNA sequencing is shown. ", "Repeat reads were annotated based on RepeatMasker and Rfam classified into tRNAs, rRNAs, snRNAs, and others. (", "D) The length distribution of reads mapping to miRNA hairpins was determined for small RNA reads from the three CRC cell lines and their purified exosomes. ", "Colors represent the nucleotides identified for the 5′ base, T (cyan), A (red), G (green), and C (blue). [", "Figure 1---figure supplement 1](#fig1s1){ref-type=\"fig\"}.DOI: [http://dx.doi.org/10.7554/eLife.07197.003](10.7554/eLife.07197.003)10.7554/eLife.07197.004Figure 1---source data 1.Colorectal cancer (CRC) cell lines.", "Small RNA sequencing libraries were prepared from three isogenic CRC cell lines with the indicated alleles of KRAS. ", "Table is based on work done in [@bib18].DOI: [http://dx.doi.org/10.7554/eLife.07197.004](10.7554/eLife.07197.004)10.7554/eLife.07197.005Figure 1---figure supplement 1.Length distribution of small RNA reads to genome.", "The small RNA read length distribution from serum-starved cells and from purified exosomes was determined, as well as the 5′ nucleotide from each read. ", "The pattern from total cellular small RNA is consistent with primarily miRNA reads, the distribution from exosomes is much broader, encompassing a number of small reads derived from many sources (see [Figure 1C,D](#fig1){ref-type=\"fig\"}). ", "Colors represent the nucleotides identified for the 5′ base, T (cyan), A (red), G (green), and C (blue).DOI: [http://dx.doi.org/10.7554/eLife.07197.005](10.7554/eLife.07197.005)\n\nThe global small RNA profiles identified reads from various classes of RNA, including miRNAs, with differential enrichment of specific RNAs in both the cellular and exosomal fractions. ", "Compared to cellular RNA samples, which displayed an enrichment of miRNA sequences (∼70%), miRNA reads in exosomal samples comprised a smaller percentage of the total small reads (5--18%) compared to other ncRNA classes (e.g., tRNAs, rRNAs, snRNAs) ([Figure 1B,C](#fig1){ref-type=\"fig\"}, [Supplementary file 1](#SD2-data){ref-type=\"supplementary-material\"}). ", "Most of these reads appear to be the fragments of larger RNAs, both cytoplasmic and nuclear. ", "It is not clear how these RNAs are associated with and/or deposited into exosomes.", "\n\nThe size distribution of cellular small RNA matched that expected from miRNA-derived reads (21--23 nucleotides). ", "However, the small RNA read distribution from exosomes was much broader with many reads smaller than 22 nucleotides in length ([Figure 1---figure supplement 1](#fig1s1){ref-type=\"fig\"}). ", "Given that these reads map to RNAs other than known miRNAs, these data suggest that a large proportion of small exosomal RNA reads is derived from processing of other RNAs, in addition to post-transcriptionally modified miRNA reads that are apparently subject to editing, trimming, and/or tailing ([@bib35]). ", "Consistent with this, when read identity was restricted to miRNAs by mapping back to known miRNA hairpin sequences, the length distribution of mappable reads was nearly identical between cells and exosomes ([Figure 1D](#fig1){ref-type=\"fig\"}).", "\n\nmiRNAs are differentially enriched in exosomes dependent on KRAS status {#s2-2}\n-------------------------------------------------------------------------\n\nFocusing on mappable reads, we sought to ascertain whether miRNAs might be differentially represented when comparing cells to their secreted exosomes. ", "For this, we quantified the relative abundance of individual miRNAs and made pairwise comparisons between normalized miRNA reads. ", "Spearman correlation analyses demonstrated high correlation between replicates of individual cell lines (r = 0.95--0.96) and between cellular data sets differing only in KRAS status (r = 0.92--0.96) ([Figure 2---figure supplements 1--3](#fig2s1 fig2s2 fig2s3){ref-type=\"fig\"}). ", "In contrast, the miRNA profiles from exosomes compared to their parent cells were less correlated (DKO-1 r = 0.67--0.81, DKs-8 r = 0.64--0.71, DLD-1 r = 0.64--0.69) ([Figure 2---figure supplements 1, 2, 4](#fig2s1 fig2s2 fig2s4){ref-type=\"fig\"}).", "\n\nWe next utilized principal component (PC) analysis to determine whether the overall miRNA profiles could distinguish between cells and exosomes and/or between wild-type and mutant KRAS status. ", "The miRNA profiles from the three cell lines all clustered close to one another indicating that overall miRNA expression profiles are fairly similar among the different cell types ([Figure 2](#fig2){ref-type=\"fig\"}). ", "In marked contrast, PC analysis revealed that exosomal miRNA profiles clearly segregate according to KRAS status ([Figure 2](#fig2){ref-type=\"fig\"}). ", "Relatively, minor differences between cellular miRNA expression profiles become much more prominent when comparing exosomal miRNA patterns ([Figure 2---figure supplement 3](#fig2s3){ref-type=\"fig\"}). ", "This indicates that the presence of a mutant KRAS allele alters sorting of specific miRNAs to exosomes, a finding that has potentially important implications for biomarker development.10.7554/eLife.07197.006Figure 2.Small RNA composition segregates with KRAS status.", "Principal component analysis was performed comparing small RNA sequencing data sets from CRC cells and exosomes. ", "The small RNA composition from cells differed significantly from exosomes. ", "Nevertheless, clustering showed that mutant KRAS status could be inferred from small RNA composition. ", "Also see [Figure 2---figure supplements 1--4](#fig2s1 fig2s2 fig2s3 fig2s4){ref-type=\"fig\"}.DOI: [http://dx.doi.org/10.7554/eLife.07197.006](10.7554/eLife.07197.006)10.7554/eLife.07197.007Figure 2---figure supplement 1.Spearman correlations between miRNA expression profiles in cells and exosomes.", "Pairwise similarity between the RNA sequencing data sets derived from cells and exosomes. ", "Spearman correlations are shown between the cell samples (R = 0.93--0.96), between exosomes and cognate cells (R = 0.64--0.83) and between exosome samples (R = 0.74--0.86). ", "Results were generated using the DESeq 'pooled' method.DOI: [http://dx.doi.org/10.7554/eLife.07197.007](10.7554/eLife.07197.007)10.7554/eLife.07197.008Figure 2---figure supplement 2.Spearman correlations between miRNA expression profiles in cells and exosomes.", "Similar to supplemental [Figure 2A](#fig2){ref-type=\"fig\"}. ", "Differential analysis using the DESeq 'per condition' method.DOI: [http://dx.doi.org/10.7554/eLife.07197.008](10.7554/eLife.07197.008)10.7554/eLife.07197.009Figure 2---figure supplement 3.Spearman correlations between miRNA expression profiles in cells (top) and exosomes (bottoms) in reads per million (RPM).DOI: [http://dx.doi.org/10.7554/eLife.07197.009](10.7554/eLife.07197.009)10.7554/eLife.07197.010Figure 2---figure supplement 4.Spearman correlations comparing miRNA expression profiles in exosomes to parent cell in RPM.DOI: [http://dx.doi.org/10.7554/eLife.07197.010](10.7554/eLife.07197.010)\n\nTo gain more insight into the relative abundance of miRNAs in cells vs matched exosomes, we examined the most abundant miRNA species in the various sequencing libraries (determined by mean reads of individual miRNAs). ", "For many miRNAs, exosomal abundance correlated with cellular abundance ([Supplementary file 2](#SD3-data){ref-type=\"supplementary-material\"}). ", "However, calculation of fold changes among the three isogenic KRAS cell lines, and exosomes released from these cells, showed that distinct subsets of miRNAs are enriched in either exosomes or cells ([Tables 1, 2](#tbl1 tbl2){ref-type=\"table\"}). ", "For all three cell lines, 25 miRNAs were consistently upregulated in cells and 29 miRNAs were consistently upregulated in exosomes ([Figure 3A,B](#fig3){ref-type=\"fig\"}). ", "Additionally, the diversity of miRNAs was substantially greater in mutant KRAS DKO-1 exosomes (94 unique miRNAs) compared to parental DLD-1 or wild-type KRAS DKs-8 exosomes ([Figure 3B](#fig3){ref-type=\"fig\"}). ", "A select subset of cell and exosomally targeted miRNAs were validated separately by quantitative reverse-transcription PCR (qRT/PCR) ([Figure 3C](#fig3){ref-type=\"fig\"}). ", "Collectively, these data indicate that the miRNA profiles observed in exosomes are distinct from their parental cells with specific miRNAs preferentially overrepresented or underrepresented in exosomes. ", "We observed a mutant KRAS-specific pattern of secreted miRNAs, consistent with the hypothesis that dysregulation of miRNA metabolism is associated with tumorigenesis, a previously unrecognized feature of mutant KRAS.10.7554/eLife.07197.011Table 1.Differential expression of miRNAs in colorectal cancer cells[\\](#tblfn1){ref-type=\"table-fn\"}DOI:* [http://dx.doi.org/10.7554/eLife.07197.011](10.7554/eLife.07197.011)DKO-1 hsa-miR-548uhsa-miR-16-1-3phsa-miR-33a-3phsa-miR-33a-5p hsa-miR-31-5phsa-miR-181b-3phsa-miR-450a-5phsa-miR-424-5p hsa-miR-9-5phsa-miR-219-5phsa-miR-190ahsa-miR-573 hsa-miR-30d-3phsa-miR-204-5phsa-miR-1226-3phsa-miR-499a-5p hsa-miR-450b-5phsa-miR-499b-3phsa-miR-3662hsa-miR-20a-3p hsa-miR-27b-5phsa-miR-5701hsa-miR-4677-3phsa-let-7i-5p hsa-miR-331-3phsa-miR-31-3phsa-miR-651hsa-miR-1306-5p hsa-miR-147bhsa-miR-3611hsa-miR-1305hsa-miR-148a-3p hsa-miR-27b-3phsa-miR-1306-3phsa-miR-374b-3phsa-miR-1260b hsa-miR-3940-3phsa-miR-200c-5phsa-miR-548ar-3pDKs-8 hsa-miR-132-5phsa-miR-484hsa-miR-374a-5phsa-miR-1180 hsa-miR-1307-3phsa-miR-200a-5phsa-miR-548o-3phsa-miR-149-5p hsa-miR-3615hsa-miR-100-5phsa-miR-197-3phsa-miR-378a-5p hsa-let-7a-3pDLD-1 hsa-miR-141-3phsa-miR-26b-5phsa-miR-24-3phsa-miR-3074-5p hsa-miR-15a-5phsa-miR-27a-3phsa-miR-3613-5phsa-miR-30b-5p hsa-miR-29a-3phsa-miR-301a-5phsa-let-7i-3phsa-miR-185-5p hsa-let-7g-5phsa-miR-23b-3phsa-miR-22-3pDKO-1 and DKs-8 hsa-miR-141-5phsa-miR-582-5pDKO-1 and DLD-1 hsa-miR-556-3phsa-miR-374a-3phsa-miR-106b-5phsa-miR-17-3p hsa-miR-24-1-5phsa-miR-340-3pDLD-1 and DKs-8 hsa-miR-24-2-5phsa-miR-106a-5phsa-miR-30e-5phsa-miR-107 hsa-miR-429hsa-miR-98-5phsa-miR-425-5phsa-miR-140-5p hsa-miR-93-5phsa-miR-210hsa-miR-126-3phsa-miR-194-5p hsa-miR-29b-3phsa-miR-15b-5phsa-miR-362-5phsa-miR-27a-5p hsa-miR-454-3phsa-miR-452-5phsa-miR-196b-5pDKO-1, DLD-1 and DKs-8 hsa-miR-32-5phsa-miR-582-3phsa-miR-542-3phsa-miR-96-5p hsa-miR-101-3phsa-miR-18a-5phsa-miR-3529-3phsa-miR-7-5p hsa-miR-19a-3phsa-miR-142-3phsa-miR-20a-5phsa-miR-32-3p hsa-miR-130b-5phsa-miR-1278hsa-miR-7-1-3phsa-miR-590-3p hsa-miR-4473hsa-miR-17-5phsa-miR-103a-3phsa-miR-103b hsa-miR-19b-3phsa-miR-340-5phsa-miR-200a-3phsa-miR-34a-5p hsa-miR-372[^2][^3]10.7554/eLife.07197.012Table 2.Differential distribution of miRNAs in exosomes[\\](#tblfn2){ref-type=\"table-fn\"}DOI:* [http://dx.doi.org/10.7554/eLife.07197.012](10.7554/eLife.07197.012)DKO-1 hsa-miR-139-5phsa-miR-3178hsa-miR-151bhsa-miR-125b-1-3p hsa-miR-193b-3phsa-miR-935hsa-miR-130b-3phsa-miR-628-3p hsa-miR-139-3phsa-let-7d-3phsa-miR-589-3phsa-miR-4532 hsa-miR-451ahsa-miR-6087hsa-miR-151a-5phsa-miR-940 hsa-miR-222-3phsa-miR-766-5phsa-miR-505-5phsa-miR-3187-3p hsa-miR-125a-3phsa-miR-3679-5phsa-miR-4436b-3phsa-miR-4787-3p hsa-miR-2277-3phsa-miR-361-5phsa-miR-1293hsa-miR-3183 hsa-miR-3162-5phsa-miR-642a-3phsa-miR-642b-5phsa-miR-197-5p hsa-miR-324-3phsa-miR-145-3phsa-miR-3182hsa-miR-3127-3p hsa-miR-3127-5phsa-miR-4728-3phsa-miR-3184-5phsa-miR-125b-5p hsa-miR-186-5phsa-miR-1hsa-miR-100-5phsa-miR-423-3p hsa-miR-766-3phsa-miR-4753-5phsa-miR-145-5phsa-miR-4724-5p hsa-miR-373-3phsa-miR-223-5phsa-miR-1307-5phsa-miR-1914-3p hsa-miR-3121-3phsa-miR-3613-3phsa-miR-205-5phsa-miR-98-3p hsa-miR-23a-3phsa-miR-3124-5phsa-miR-3656hsa-miR-3918 hsa-miR-4449hsa-miR-378chsa-miR-3138hsa-miR-1910 hsa-miR-3174hsa-miR-4466hsa-miR-3679-3phsa-miR-3200-5p hsa-miR-6511b-5phsa-miR-1247-5phsa-miR-22-3phsa-miR-877-5p hsa-miR-4687-3phsa-miR-1292-5phsa-miR-181c-5phsa-miR-6131 hsa-miR-6513-5phsa-miR-3661hsa-miR-132-3phsa-miR-214-3p hsa-miR-574-3phsa-miR-3190-3phsa-miR-326hsa-miR-3191-5p hsa-miR-3198hsa-miR-3928hsa-miR-629-3phsa-miR-4489 hsa-miR-4700-5phsa-miR-5006-5phsa-miR-5088hsa-miR-2110 hsa-miR-3911hsa-miR-3146DKs-8 hsa-miR-1224-5phsa-let-7b-5phsa-miR-155-5phsa-let-7c hsa-let-7a-5phsa-miR-146b-5phsa-miR-4647hsa-miR-4494 hsa-miR-711hsa-miR-1263DLD-1 hsa-miR-1226-5phsa-miR-4745-5phsa-miR-4435hsa-miR-939-5p hsa-miR-409-3phsa-miR-1304-3pDKO-1 and DKs-8 hsa-miR-146a-5phsa-miR-4508hsa-miR-224-5phsa-miR-4429 hsa-miR-222-5phsa-miR-629-5phsa-miR-4492hsa-miR-3653 hsa-miR-320ahsa-miR-1290hsa-miR-1262hsa-miR-5010-5p hsa-miR-204-3phsa-miR-4461hsa-miR-5187-5pDKO-1 and DLD-1 hsa-miR-483-5phsa-miR-4658hsa-miR-4758-5phsa-miR-492 hsa-miR-5001-5phsa-miR-371a-5phsa-miR-1323hsa-miR-371b-3p hsa-miR-501-3phsa-miR-4446-3phsa-miR-6511a-5phsa-miR-30a-3p hsa-miR-4727-3pDLD-1 and DKs-8 hsa-miR-28-3phsa-miR-3934-5pDKO-1, DLD-1 and DKs-8 hsa-miR-658hsa-miR-320dhsa-miR-4792hsa-miR-1246 hsa-miR-320ehsa-miR-4516hsa-miR-320bhsa-miR-4488 hsa-miR-1291hsa-miR-320chsa-miR-4634hsa-miR-3605-5p hsa-miR-4741hsa-miR-3591-3phsa-miR-122-5phsa-miR-486-3p hsa-miR-184hsa-miR-223-3phsa-miR-3651hsa-miR-486-5p hsa-miR-3180hsa-miR-3180-3phsa-miR-3168hsa-miR-4497 hsa-miR-423-5phsa-miR-3184-3phsa-miR-150-5phsa-miR-664a-5p hsa-miR-182-5p[^4][^5]10.7554/eLife.07197.013Figure 3.KRAS-dependent regulation of miRNAs in exosomes and cells.", "Differentially distributed miRNAs in (A) cells and (B) exosomes from the three CRC cell lines differing in KRAS status. (", "C) qRT-PCR validation of selected miRs from DKs-8 and DKO-1 cellular and exosomal RNA samples normalized to U6 snRNA. ", "Fold changes were calculated using the ΔΔC(t) method comparing exosomes to cells. ", "Negative fold changes indicate greater enrichment in cells, and positive fold changes indicate greater enrichment in exosomes. ", "Also see [Supplementary file 2](#SD3-data){ref-type=\"supplementary-material\"}.DOI: [http://dx.doi.org/10.7554/eLife.07197.013](10.7554/eLife.07197.013)\n\nKRAS-dependent sorting of miRNAs {#s2-3}\n----------------------------------\n\n### miR-100 {#s2-3-1}\n\nDown regulation of miR-100-5p was observed in mutant KRAS DKO-1 and parental DLD-1 cells compared to wild-type KRAS DKs-8 cells ([Table 1](#tbl1){ref-type=\"table\"}). ", "This is consistent with reports that have shown decreased miR-100 expression in metastatic cancers ([@bib51]; [@bib25]). ", "miR-100 has also been shown to negatively regulate migration, invasion, and the epithelial--mesenchymal transition (EMT) ([@bib13]; [@bib64]; [@bib69]). ", "Interestingly, miR-100 was enriched in exosomes derived from mutant KRAS cells (\\>eightfold and \\>threefold enriched in DKO-1 and DLD-1 exosomes, respectively; [Supplementary file 2](#SD3-data){ref-type=\"supplementary-material\"}), suggesting that decrease of miR-100 in cells is due to secretion in exosomes. ", "This is in line with findings that circulating levels of miR-100 are upregulated in the plasma of mutant KRAS-expressing mouse pancreatic cancer models and in patients with pancreatic cancer ([@bib38]). ", "More broadly, the observation that miR-100-5p specifically accumulates in exosomes suggests that there may be sequence-specific requirements for the sorting of certain miRNAs into exosomes.", "\n\n### miR-10b {#s2-3-2}\n\nOur RNA sequencing data identified miR-10b as preferentially secreted in exosomes isolated from cells harboring a wild-type KRAS allele (\\>threefold-change and \\>twofold-change enrichment in DKs-8 and DLD-1 exosomes, respectively) but retained in mutant KRAS DKO-1 cells (∼threefold-change cell enrichment). ", "miR-10b is referred to as an oncomiR because it is frequently upregulated during progression of various cancers, including CRC ([@bib42]).", "\n\n### miR-320 {#s2-3-3}\n\nmiR-320 is aberrantly expressed in several types of cancer, including colon cancer. ", "It is expressed in the proliferative compartment of normal colonic crypts ([@bib53]; [@bib32]). ", "miR-320 members (miR-320b, -c, d, and -e) were abundant in both mutant KRAS (DKO-1) and wild-type KRAS (DKs-8) exosomes, but underrepresented in the matched cells, indicating that some miRNAs are transcribed and predominantly exported into exosomes, independent of KRAS status ([Table 2](#tbl2){ref-type=\"table\"}, [Supplementary file 1A](#SD2-data){ref-type=\"supplementary-material\"}). ", "Of these family members, miR-320a and miR-320b were the most abundant species represented in exosomes by our RNA sequencing analyses (miR-320a in DKO-1 exosomes, and miR-320b in DKs-8 and DKO-1 exosomes). ", "Interestingly, however, we observed the largest enrichment for miR-320d (fold changes \\>241 in DKs-8 and \\>229 in DKO-1) in exosomes relative to cells, despite being ∼fourfold less abundant than miR-320b levels. ", "Because the 3′-terminus may be important in regulating miRNA stability and turnover, coupled to the fact that the sequences of miR-320a-d members differ only at their 3′-termini, enrichment of certain miRNAs in exosomes could be due to higher turnover/decay rates in cells.", "\n\nExosomal secretion and strand selection {#s2-4}\n---------------------------------------\n\nBecause we observed differential export of specific miRNAs, we investigated whether there might be miRNA sequence-specific sorting signals. ", "Previous reports have shown differential accumulation of 5p or 3p strands in exosomes compared to parental cells ([@bib33]). ", "Thus, we analyzed our data sets to test whether exosomes might be preferentially enriched for one strand over the other. ", "We were able to identify individual miRNAs where the two strands differentially sorted between cells and exosomes. ", "For example, the -5p strands of miR-423 were overrepresented in DKO-1 exosomes but in exosomes from DKs-8 cells, both strands were overrepresented compared to cells (data not shown). ", "This indicates that KRAS status may differentially affect selection of passenger or guide strands for sorting into exosomes for select individual miRNAs.", "\n\nIndividual miRNAs often exist as populations of variants (isomiRs) that differ in length and/or nucleotide composition generated by template- or non-template-directed variation ([@bib10]; [@bib49]; [@bib48]). ", "When we analyzed our sequencing data sets, we did not detect differential accumulation of isomers with variable 5′ termini (data not shown). ", "For cellular miRNAs, most reads were full length with a slight enrichment in 3′ non-templated addition of A-tailed miRNAs, regardless of KRAS status ([Figure 4](#fig4){ref-type=\"fig\"}; [Figure 4---figure supplement 1](#fig4s1){ref-type=\"fig\"}). ", "For exosomes, we observed a slight enrichment for C residues added to the 3′ ends of miRNAs from wild-type KRAS cells ([Figure 4---figure supplement 1](#fig4s1){ref-type=\"fig\"}). ", "We did not observe this in mutant KRAS exosomes, where instead, we noticed an increase in 3′ trimming of miRNAs ([Figure 4](#fig4){ref-type=\"fig\"}, [Figure 4---figure supplement 2](#fig4s2){ref-type=\"fig\"}). ", "Overall, it remains to be determined whether such modifications constitute a global exosomal sorting signal in these cells.10.7554/eLife.07197.014Figure 4.Comparison of miRNA 3′ trimming and tailing between cells and exosomes.", "Data from the heat maps shown in [Figure 4---figure supplement 2](#fig4s2){ref-type=\"fig\"} were pooled to illustrate overall changes in either 3′ nucleotide additions (tailing) or 3′ resection (trimming) compared to full length miRNA sequences (intact). ", "Overall, the patterns between cells and between exosomes are very similar. ", "A comparison of cells to exosomes shows that exosomes display a slight increase in trimmed miRNAs. ", "Also see [Figure 4---figure supplement 2](#fig4s2){ref-type=\"fig\"}.DOI: [http://dx.doi.org/10.7554/eLife.07197.014](10.7554/eLife.07197.014)10.7554/eLife.07197.015Figure 4---figure supplement 1.Non-templated addition (NTA) of nucleotides to 3′ ends of miRNAs.3′ NTA of A-tailed miRNAs is enriched in cells independent of KRAS status, whereas NTA of C residues are more abundant in wild-type KRAS DKs-8 exosomes. ", "miRNAs with read counts ≥500 reads in both cells and exosomes were used in the analysis. ", "Reads mapping to hairpin sequences were considered as templated miRNAs (untrimmed). ", "Reads ≥18 nucleotides that did not map to hairpin or genome sequences were trimmed one nucleotide at the 3′-termini and mapped again to hairpin sequences. ", "This was repeated three times to account for NTA\\'s extending up to three nucleotides from the 3′-terminus. ", "miRNAs significantly enriched in exosomes or cells are represented by red and blue circles, respectively.DOI: [http://dx.doi.org/10.7554/eLife.07197.015](10.7554/eLife.07197.015)10.7554/eLife.07197.016Figure 4---figure supplement 2.Comparison of miRNA 3′ trimming and tailing between cells and exosomes.", "Heat maps show the extent of either 3′ nucleotide additions (tailing) or 3′ resection (trimming) compared to full-length miRNA sequences (intact).DOI: [http://dx.doi.org/10.7554/eLife.07197.016](10.7554/eLife.07197.016)10.7554/eLife.07197.017Figure 4---figure supplement 3.MEME analysis of miRNA sequence in exosomes.", "MEME analysis was performed to attempt to identify sequence motifs that might target miRNAs for export into exosomes. ", "The top most abundant motifs found in miRNAs in [Tables 1, 2](#tbl1 tbl2){ref-type=\"table\"} are shown for both cells and exosomes from DKO-1, DKs-8, or DLD-1 cell lines. (", "Upregulated in DKO-1 exo: 51, 1.5e-009; Upregulated in DKO-1 cell: 28,1.5e-007; Upregulated in DKs-8 exo, 22, 1.7e-010; Upregulated in DKs-8 cell, 19, 7.6e-007; Upregulated in DLD-1 exo, 8, 2.3e-003; Upregulated in DLD-1 cell 23, 3.3e-012).DOI: [http://dx.doi.org/10.7554/eLife.07197.017](10.7554/eLife.07197.017)\n\nConsistent with published data, we have shown that miRNA expression patterns vary between parental cells and their cognate exosomes ([Tables 1, 2](#tbl1 tbl2){ref-type=\"table\"}, [Figure 3A,B](#fig3){ref-type=\"fig\"}) ([@bib60]; [@bib45]; [@bib19]; [@bib46]; [@bib56]). ", "Differential export suggests that specific signals must exist to sort distinct miRNAs ([@bib6]; [@bib62]). ", "We therefore conducted MEME analysis to attempt to identify sequence motifs that might serve as targeting signals. ", "When we examined all miRNA reads detected in exosomes, we did not find any global enrichment for specific sequences or motifs, including those reported to be bound by hnRNP A2B1 (GGAG or U/CC) ([@bib8]; [@bib62]) ([Figure 4---figure supplement 3](#fig4s3){ref-type=\"fig\"}). ", "However, when we analyzed miR-320 because it is preferentially exported to exosomes independent of KRAS status, we were able to identify the GGAG sequence contained within the 3′ end of the mature sequence. ", "Additionally, upon restricting our analysis to reads from the most differentially expressed miRNAs when comparing exosomes to cells, we found a slight enrichment for C residues, possibly alternating C residues in exosomal miRNAs ([Figure 4---figure supplement 3](#fig4s3){ref-type=\"fig\"}).", "\n\nSphingomyelinase-dependent sorting of miRNAs to exosomes {#s2-5}\n--------------------------------------------------------\n\nAlthough little is understood regarding the molecular mechanisms for packaging exosomal miRNAs, recent evidence suggests that the secretion of miRNAs in exosomes is dependent on ceramide via its production by neutral sphingomyelinase 2 (nSMase 2) ([@bib36]; [@bib45]). ", "Inhibition of de novo ceramide synthesis by treatment with a nSMase inhibitor impaired exosomal miRNA release, apparently due to decreased formation of miRNA-containing exosomes ([@bib36]; [@bib45]). ", "To test the role of nSMase in miRNA secretion in our system, we treated CRC cells with the nSMase inhibitor, GW4869. ", "We determined the effect of this inhibitor on miR-10b since it is preferentially found in wild-type KRAS DKs-8 exosomes, miR-100 since it is preferentially found in mutant KRAS DKO-1 and DLD-1 exosomes, and miR-320 which sorts into exosomes regardless of KRAS status. ", "For miR-10b, we did not observe significant changes in its cellular levels after treatment with GW4869 in either wild-type KRAS DKs-8 or mutant KRAS DKO-1 cells ([Figure 5C](#fig5){ref-type=\"fig\"}). ", "In contrast, inhibition of nSMase caused a ∼threefold increase in intracellular levels of miR-100 in mutant KRAS DKO-1 cells but remained unchanged in wild-type DKs-8 KRAS cells ([Figure 5A,B,C](#fig5){ref-type=\"fig\"}). ", "Similarly, miR-320 levels were found to increase (∼2.5 fold) only in GW4869-treated mutant KRAS DKO-1 cells ([Figure 5C](#fig5){ref-type=\"fig\"}). ", "These data are most consistent with the hypothesis that impaired ceramide synthesis alters cellular accumulation of miRNAs dependent on mutant KRAS and suggest that multiple biogenic routes exist for miRNA secretion.10.7554/eLife.07197.018Figure 5.Ceramide-dependent miRNA export into exosomes.", "DKO-1 or DKs-8 cells were treated with an inhibitor of neutral sphingomyelinase 2 (nSMase 2), GW4869. ", "After treatment, in situ hybridization experiments were performed with probes against miR-100 (A, B). (", "C) qRT-PCR for miR-10b, miR-100, and miR-320a was performed on cells treated with GW4869 or DMSO, and fold change in expression was determined in treated vs untreated cells. ", "In wild-type KRAS cells (DKs-8), inhibition of nSMase 2 had little or no effect on the cellular levels of these miRNAs. ", "In contrast, mutant KRAS cells (DKO-1) showed an increase in cellular miRNA levels after inhibition of nSMAse 2. ", "Data were derived from three biological replicates and performed in technical triplicates for qRT-PCR. ", "Significance was determined by two-tailed, paired t-tests where \\* are p values ≤ 0.05 and \\\\ ≤0.01.DOI: [http://dx.doi.org/10.7554/eLife.07197.018](10.7554/eLife.07197.018)\n\nExtracellular transfer of miR-100 {#s2-6}\n-----------------------------------\n\nSeveral reports have found that extracellular miRNAs can be taken up by recipient cells to mediate heterotypic cell--cell interactions and facilitate target repression in neighboring cells ([@bib45]; [@bib7]; [@bib56]). ", "To determine whether secreted miRNAs function in recipient cells, we designed luciferase (Luc) constructs containing either 3 perfect miR-100 recognition elements (MREs) in the 3′ untranslated region (UTR) (Luc-100-PT) or scrambled 3′UTR sequences that do not match any known miRNAs (Luc-CTL). ", "These constructs were expressed in wild-type KRAS DKs-8 cells (recipient cells) in the presence or absence of donor cells. ", "Baseline repression of Luc in the absence of donor cells was first analyzed to determine the levels of repression from endogenous miR-100 in DKs-8 cells. ", "Compared to the scrambled control (Luc-CTL), strong Luc repression in the absence of donor cells was observed with perfect MREs (miR-100-PT) ([Figure 6A](#fig6){ref-type=\"fig\"}). ", "This supports our finding that miR-100 is expressed and retained in DKs-8 cells.10.7554/eLife.07197.019Figure 6.Transfer of extracellular miRNAs by mutant DKO-1 cells promotes target repression in wild-type DKs-8 cells.", "Transwell co-culture of DKs-8 recipient cells with or without DKs-8 or DKO-1 donor cells. ", "Luciferase (Luc) expression was measured in DKs-8 recipient cells transiently expressing (A) Luc fused to three perfectly complementary synthetic miR-100 target sites (miR-100-PT) or (B) Luc fused to the 3′UTR of mTOR, which harbors 3 endogenous target sites for miR-100. (", "C) Luc expression increased upon mutation of two (MS2) sites with full expression upon mutation of all three sites (MS3). ", "Luc-CTL contains three random scrambled target sites that do not match any known miRNA sequence. (", "D) Luc expression was restored in recipient cells expressing miR-100-PT upon pretreatment of donor DKO-1 cells with 100 nM miR-100 antagomirs (AI-100) compared to pre-treatment of donor DKO-1 cells with 100 nm control antagomirs (AI-CTL) targeting cel-miR-67. (", "E) Taqman qRT-PCR for miR-100. ", "Compared to DKs-8 recipient cells grown without donor cells, mir-100 levels increased by approximately 34% in the presence of mutant DKO-1 donor cells pre-treated with AI-CTL compared to an 8% increase in AI-100 pre-treated donor cells. ", "Y axis is % increase in miR-100 = (CP~AI-CTL~ or CP~AI-100~ − CP~no\\ donor~/CP~no\\ donor~)^\\^100, where CP = absolute copy number. ", "All Luc values were normalized to co-transfected vectors expressing β-galactosidase; n = 3 independent experiments in A--C* and n = 4 in D, E. ", "All Luc assays were performed in technical triplicate. ", "Significance was determined by two-tailed, paired t-tests where \\* are p values ≤ 0.05 and \\\\ ≤0.01. ", "Also see [Figure 6---figure supplements 1--3](#fig6s1 fig6s2 fig6s3){ref-type=\"fig\"}.DOI: [http://dx.doi.org/10.7554/eLife.07197.019](10.7554/eLife.07197.019)10.7554/eLife.07197.020Figure 6---figure supplement 1.miR-100 binding sites in the mTOR 3′UTR.miR-100 binding sites within the mTOR 3′UTR. ", "Mutated nucleotides indicated in red (oligonucleotide sequences in [Supplementary file 3](#SD4-data){ref-type=\"supplementary-material\"}).DOI: [http://dx.doi.org/10.7554/eLife.07197.020](10.7554/eLife.07197.020)10.7554/eLife.07197.021Figure 6---figure supplement 2.Presence of mutant DKO-1 donor cells augments miR-100 levels in DKs-8 recipient cells.", "Taqman qRT-PCR for miR-100. ", "miR-100 levels increased by approximately 114 copies in recipient cells cultured with DKO-1 donor cells pre-treated with AI-CTL compared to recipient cells cultured without donor cells. ", "Pre-treatment of mutant DKO-1 donor cells with miR-100 antagomir inhibitor (AI-100) attenuated this effect. ", "Absolute levels of miR-100 determined by standard curve generation of synthetically derived miR-100 (see 'Materials and methods'). ", "Approximately, 357.23 ± 16.65, 442.58 ± 12.59, and 329.48 ± 13.62 copies of miR-100 per input RNA were found in DKs-8 recipient cells cultured with DKO-1 donor AI-100, DKO-1 donor AI-CTL and without donor cells, respectively.DOI: [http://dx.doi.org/10.7554/eLife.07197.021](10.7554/eLife.07197.021)10.7554/eLife.07197.022Figure 6---figure supplement 3.Transfer of extracellular miRNAs by mutant DKO-1 cells promotes target repression in wild-type DKs-8 cells.", "Transwell co-culture of DKs-8-recipient cells with or without DKs-8 or DKO-1 donor cells. ", "Luc expression was measured in DKs-8-recipient cells expressing Luc fused to three perfectly complementary synthetic miR-222 target sites (miR-222-PT).DOI: [http://dx.doi.org/10.7554/eLife.07197.022](10.7554/eLife.07197.022)\n\nTo determine whether secretion of miR-100 by mutant KRAS DKO-1 donor cells could further augment miR-100 function in recipient wild-type cells, Transwell co-culture experiments were performed with DKs-8 recipient cells expressing the Luc reporters in the presence of DKO-1 donor cells ([Figure 6](#fig6){ref-type=\"fig\"}). ", "Significantly increased repression of Luc was observed when the reporter construct containing three perfect miR-100 sites was used (miR-100-PT) ([Figure 6A](#fig6){ref-type=\"fig\"}). ", "Because exosomes released from DKO-1 cells contain abundant levels of miR-100, increased Luc repression is consistent with transfer of additional copies of miR-100. ", "Two control experiments were performed to test the hypothesis that additional copies of miR-100 are transferred between donor and recipient cells. ", "First, we treated donor cells with antagomirs that block production of miR-100. ", "Luc repression was almost completely reversed upon pre-treatment of DKO-1 donor cells with a miR-100 hairpin antagomir inhibitor (AI-100) ([Figure 6D](#fig6){ref-type=\"fig\"}). ", "Second, we performed qRT/PCR to calculate the increase in miR-100 levels in recipient cells. ", "Cells grown in the presence or absence of donor cells showed an approximate 34% increase in the levels of miR-100 ([Figure 6E](#fig6){ref-type=\"fig\"} and [Figure 6---figure supplement 2](#fig6s2){ref-type=\"fig\"}).", "\n\nTo further probe the repressive activity of miR-100, we performed co-culture experiments in which the recipient Dks-8 cells express Luc fused to the 3′UTR of mTOR, an endogenous miR-100 target ([@bib47]; [@bib29]; [@bib24]). ", "As observed with miR-100-PT repression, Luc-mTOR was significantly repressed in the presence of mutant KRAS DKO-1 but not in the presence of wild-type KRAS DKs-8 donor cells ([Figure 6B](#fig6){ref-type=\"fig\"}). ", "This suggests that miR-100-repressive activity is specific to the presence of mutant KRAS DKO-1 donor cells. ", "To confirm these results, we mutated the MREs within the mTOR 3′UTR and assayed for miR-100 activity ([Figure 6---figure supplement 1](#fig6s1){ref-type=\"fig\"}). ", "Mutation of individual sites did not show significantly different Luc repression (data not shown). ", "However, upon mutation of two MREs (MS2), we observed a partial rescue of Luc expression ([Figure 6C](#fig6){ref-type=\"fig\"}). ", "This was further augmented upon mutation of all three sites (MS3), with a complete rescue of miR-100-mediated repressive activity ([Figure 6C](#fig6){ref-type=\"fig\"}).", "\n\nAs a final test of miRNA transfer in the Transwell co-culture experiments, we created vectors expressing Luc fused to a 3′UTR containing perfect sites for miR-222 because miR-222 is not detectable in DKs-8-recipient cells, unlike miR-100. ", "In this case, silencing of Luc should be due to transfer of miR-222 and not due to unforeseen changes in endogenous miRNA activity. ", "We observed a greater than twofold repression of the miR-222 Luc reporter in recipient cells ([Figure 6---figure supplement 3](#fig6s3){ref-type=\"fig\"}). ", "These results support the hypothesis that miRNAs secreted by mutant KRAS cells can be transferred to recipient cells.", "\n\nDiscussion {#s3}\n==========\n\nIn this study, we comprehensively examined the composition of small ncRNAs from exosomes and cells of isogenic CRC cell lines that differ only in KRAS status. ", "By employing small RNA transcriptome analyses, we found that oncogenic KRAS selectively alters the miRNA profile in exosomes, and that ceramide depletion selectively promotes miRNA accumulation in mutant KRAS CRC cells. ", "Distinct miRNA profiles between cells and their exosomes may be functionally coupled to mitogenic signaling.", "\n\nKRAS status-specific patterns of secreted miRNAs support the idea of using exosomes as potential biomarkers in CRC. ", "Our finding that miR-10b is preferentially enriched in wild-type KRAS-derived exosomes, while miR-100 is enriched in mutant KRAS-derived exosomes raises interesting questions regarding how they are selected for secretion. ", "miR-10b and miR-100 are both part of the miR-10/100 family and differ by only one base in the seed region, allowing regulation of distinct sets of target mRNAs ([@bib58]). ", "Whether the accumulation or export of these miRNAs is a result or a consequence of oncogenic signaling remains unknown. ", "Preventing the export or retention of certain miRNAs, such as miR-100 and miR-10b, may serve a therapeutic role in reversing the tumorigenic effects seen with aberrant miRNA expression.", "\n\nKRAS-dependent differential miRNA expression more prominently affected miRNA expression patterns observed in exosomes than in the parent cells. ", "This could reflect a mechanism by cells to selectively export miRNAs so as to maintain specific growth or gene expression states. ", "This is consistent with a recent report that found that the cellular levels of miR-218-5p could be maintained, despite changes in the abundance of its target, likely through a 'miRNA relocation effect' where unbound miRNAs that are in excess have the potential to be sorted to exosomes ([@bib56]). ", "Another mechanism may be through sequence-specific motifs that direct miRNA trafficking by interaction with specific chaperone proteins ([@bib8]; [@bib62]). ", "Although we did not find any globally significant motif overrepresented in exosomal miRNAs, we cannot rule out that individual miRNAs might undergo sequence-specific export. ", "miR-320 family members all contain the GGAG motif that has been proposed to serve as an exosomal targeting signal ([@bib62]). ", "We found that members of the miR-320 family are preferentially enriched in exosomes independent of KRAS status; however, the GGAG sequence was not found in other miRNAs that are targeted to exosomes. ", "It has been reported that the biogenesis of miR-320 family members occurs by a non-canonical pathway that requires neither Drosha ([@bib15]) nor XPO5 ([@bib68]). ", "Instead, the 5′ ends contain a 7-methyl guanosine cap that facilitates nuclear--cytoplasmic transport through XPO1 ([@bib68]). ", "XPO1 is present in DKO-1, DKs-8, and DLD-1 exosomes as detected by mass spectrometry ([@bib18]). ", "It will be interesting to investigate whether alternate processing pathways and associated biogenic machinery contribute to the heterogeneity of EV cargo and affect miRNA secretion.", "\n\nIt was recently demonstrated that miRNAs in B-cell exosomes display enriched levels of non-template-directed 3′-uridylated miRNAs, while 3′-adenylated miRNA species are preferentially cell enriched ([@bib35]). ", "In certain contexts, the addition of non-templated uridine residues to cognate miRNAs accelerates miRNA turnover ([@bib4]; [@bib65]). ", "Thus, it is possible that the stability/half-life of a miRNA affects whether it is retained or secreted. ", "While the exact functional significance of 3′-end modifications of miRNAs detected in both cells and exosomes remains to be determined, it could be that differential export of 'tagged' miRNAs could allow cells to export specific miRNAs. ", "However, the lack of any apparent motif upon global analysis of miRNAs enriched in exosomes, coupled to the finding that even untagged miRNAs are differentially exported, suggests multiple strategies for loading of miRNAs into EVs, and that not all EVs and exosomes contain identical cargo. ", "This further implies that different cell types secrete a heterogeneous population of vesicles. ", "Although the biological relevance of these findings remains to be determined, the specific sorting of miRNAs into exosomes may enable cancer cells to discard tumor-suppressive miRNAs so as to increase their oncogenic potential or perhaps modulate gene expression in neighboring and distant cells to promote tumorigenesis. ", "In support of this hypothesis, miR-100, which we found to be enriched in mutant KRAS exosomes, was found to down-regulate LGR5 in CRC cells and thereby inhibit migration and invasion of such cells ([@bib69]). ", "In this context, removal of miR-100 from the cell would be a tumor-promoting event.", "\n\nIn other contexts, miR-100 can have contradictory activities, both inducing EMT by down-regulating E-cadherin through targeting SMARCA5 and inhibiting tumorigenicity by targeting HOXA1 ([@bib13]). ", "Thus, although miR-100 can function as a tumor suppressor under normal conditions, augmenting its levels, for example, by EV uptake, could potentially promote EMT. ", "In this regard, the role of miR-100 in tumorigenesis would be twofold, where its secretion in exosomes could function to maintain low-intracellular levels within mutant cells, while inducing EMT in wild-type-recipient cells. ", "Along these lines, miR-100 is part of the miR-125b/let-7a-2/miR-100 cluster that is transcribed and expressed coordinately ([@bib20]). ", "Interestingly, in malignant colonic tissues from individuals with CRC, miR-100 levels were significantly decreased while let-7a levels were strongly upregulated ([@bib57]). ", "Based on our finding that there is differential accumulation of individual miRNAs within this cluster between mutant KRAS cells and exosomes, it will be interesting to determine whether cancer cells down-regulate specific miRNAs by active secretion, while simultaneously maintaining the levels of other miRNAs transcribed within the same cluster.", "\n\nmiRNAs are secreted from malignant breast epithelial cells after packaging into vesicles larger than conventional exosomes that are enriched in CD44, whose expression is linked to breast cancer metastasis ([@bib50]). ", "Normal cells tend to release miRNAs in more homogenous types of exosomes, suggesting that malignant transformation may alter the formation of secreted vesicles that could alter miRNA export and lead to differences in exosome content and morphology ([@bib50]; [@bib44]). ", "In support of this, it was recently shown that in exosomes from breast cancer cells, CD43 mediates the accumulation of Dicer ([@bib44]). ", "These exosomes also contain other RNA-induced silencing complex (RISC) proteins and pre-miRNAs, indicating that miRNA processing can occur in exosomes ([@bib44]). ", "These components were absent in exosomes derived from normal cells. ", "It remains to be determined whether components of the RISC-loading complex assemble within endosomes before their secretion as exosomes or by the fusion of exosomes containing heterogeneous cargo after they are secreted. ", "The observation that cells can selectively release miRNAs and also release a heterogeneous population of vesicles raises the possibility that differential release of miRNAs is associated with different classes of exosomes and microvesicles.", "\n\nRecently, quantitative analysis of secreted miRNAs suggested that the levels of extracellular miRNAs are limited and raise the question as to how such levels can alter gene expression in recipient cells ([@bib14]). ", "The results of our Transwell co-culture experiments are most consistent with extracellular transfer of specific miRNAs to alter expression of reporter constructs. ", "Nevertheless, the level of exosomal transfer that is needed to alter recipient cell gene expression in vivo remains an open question. ", "Our finding that mutant KRAS protein can be functionally transferred in exosomes indicates that the full effect of exosomes on recipient cells can be due to a combination of both RNA delivery and protein-based signaling ([@bib30]). ", "This could include activation of Toll-like receptors with possible downstream effects following nuclear factor kappa-light-chain-enhancer of activated B cells or mitogen-activated protein kinase cascades ([@bib21]; [@bib12]). ", "The complexity of miR-100 function in the tumor microenvironment underscores this argument by its potential for inhibiting mTOR expression which is required for proliferation of Apc-deficient tumors in mouse models ([@bib22]). ", "In tumors where some cells have incurred activating mutations in KRAS, while others have not, miR-100 could accumulate in wild-type KRAS tumor cells through exosomal transfer, inhibiting mTOR and cell growth. ", "Conversely, miR-100 could be secreted from mutant KRAS cells giving them a growth advantage. ", "In this way, exosomal transfer of miRNAs might act to select for cells carrying specific tumor driver mutations. ", "Our studies have direct implications for CRC and, together with other studies, indicate that delivery of exosomes to recipient cells can induce cell migration, inflammation, immune responses, angiogenesis, invasion, pre-metastatic niche formation, and metastasis ([@bib34]; [@bib7]; [@bib44]; [@bib16]).", "\n\nMaterials and methods {#s4}\n=====================\n\nExosome isolation {#s4-1}\n-----------------\n\nExosomes were isolated from conditioned medium of DKO-1, Dks-8, and DLD-1 cells as previously described, with slight modification ([@bib30]). ", "Briefly, cells were cultured in Dulbecco\\'s Modified Eagle\\'s Medium (DMEM) supplemented with 10% bovine growth serum until 80% confluent. ", "The cells were then washed three times with Phosphate buffered saline (PBS) and cultured for 24 hr in serum-free medium. ", "The medium was collected and replaced with ionomycin-containing medium for 1 hr, after which ionomycin-containing medium was collected and pooled with the previously collected serum-free medium. ", "Pooled media was centrifuged for 10 min at 300×g to remove cellular debris, and the resulting supernatant was then filtered through a 0.22-mm polyethersulfone filter (Nalgene, Rochester, NY, USA) to reduce microparticle contamination. ", "The filtrate was concentrated ∼300-fold with a 100,000 molecular weight cut-off centrifugal concentrator (Millipore, Darmstadt, Germany). ", "The concentrate was then subjected to high-speed centrifugation at 150,000×g for 2 hr. ", "The resulting exosome-enriched pellet was resuspended in PBS containing 25 mM hydroxyethyl-piperazineethanesulfonic acid (HEPES) (pH 7.2) and washed by centrifuging again at 150,000×g for 3 hr. ", "The wash steps were repeated a minimum of three times until no trace of phenol red was detected. ", "The resulting pellet was resuspended in PBS containing 25 mM HEPES (pH 7.2), and protein concentrations were determined with a MicroBCA kit (Pierce/Thermo, Rockford, IL, USA). ", "The number of exosomes per μg of protein was determined by means of nanoparticle tracking analysis (NanoSight, Wiltshire, UK). ", "Analysis was performed on three independent preparations of exosomes.", "\n\nRNA purification {#s4-2}\n----------------\n\nTotal RNA from exosomes and cells was isolated using TRIzol (Life Technologies/Thermo, Grand Island, NY). ", "In the case of exosomal RNA isolation, TRIzol was incubated with 100 μl or less of concentrated exosomes for an extended 15 min incubation prior to chloroform extraction. ", "RNA pellets were resuspended in 60 μl of RNase-free water and were then re-purified using the miRNeasy kit (Qiagen Inc., Valencia, CA, USA). ", "Final RNAs were eluted with two rounds of 30 μl water extraction.", "\n\nmiRNA library preparation and sequencing {#s4-3}\n----------------------------------------\n\nTotal RNA from each sample was used for small RNA library preparation using NEBNext Small RNA Library Prep Set from Illumina (New England BioLabs Inc., Ipswich, MA, USA). ", "Briefly, 3′ adapters were ligated to total input RNA followed by hybridization of multiplex single read (SR) reverse transcription (RT) primers and ligation of multiplex 5′ SR adapters. ", "RT was performed using ProtoScript II RT for 1 hr at 50°C. ", "Immediately after RT reactions, PCR amplification was performed for 15 cycles using LongAmp Taq 2× master mix. ", "Illumina-indexed primers were added to uniquely barcode each sample. ", "Post-PCR material was purified using QIAquick PCR purification kits (Qiagen Inc.). ", "Post-PCR yield and concentration of the prepared libraries were assessed using Qubit 2.0 Fluorometer (Invitrogen, Carlsbad, California, CA, USA) and DNA 1000 chip on Agilent 2100 Bioanalyzer (Applied Biosystems, Carlsbad, CA, USA), respectively. ", "Size selection of small RNA with a target size range of approximately 146--148 bp was performed using 3% dye free agarose gel cassettes on a Pippin Prep instrument (Sage Science Inc., Beverly, MA, USA). ", "Post-size selection yield and concentration of libraries were assessed using Qubit 2.0 Fluorometer and DNA high-sensitivity chip on an Agilent 2100 Bioanalyzer, respectively. ", "Accurate quantification for sequencing applications was performed using qPCR-based KAPA Biosystems Library Quantification kits (Kapa Biosystems, Inc., Woburn, MA, USA). ", "Each library was diluted to a final concentration of 1.25 nM and pooled in equimolar ratios prior to clustering. ", "Cluster generation was carried out on a cBot v8.0 using Illumina\\'s Truseq Single Read Cluster Kit v3.0. ", "Single-end sequencing was performed to generate at least 15 million reads per sample on an Illumina HiSeq2000 using a 50-cycleTruSeq SBSHSv3 reagent kit. ", "Clustered flow cells were sequenced for 56 cycles, consisting of a 50-cycle read, followed by a 6-cycle index read. ", "Image analysis and base calling were performed using the standard Illumina pipeline consisting of Real Time Analysis version v1.17 and demultiplexed using bcl2fastq converter with default settings.", "\n\nMapping of RNA reads {#s4-4}\n--------------------\n\nRead sequence quality checks were performed by FastQC (Babraham Bioinformatics \\[<http://www.bioinformatics.babraham.ac.uk/projects/fastqc/>\\]). ", "Adapters from the 3′ ends of reads were trimmed using Cutadpt with a maximum allowed error rate of 0.1 ([@bib43]). ", "Reads shorter than 15 nucleotides in length were excluded from further analysis. ", "Reads were mapped to the human genome hg19 using Bowtie version 1.1.1 ([@bib39]). ", "Mapped reads were annotated using ncPRO-seq ([@bib11]) based on miRbase ([@bib27]), Rfam ([@bib23]; [@bib9]), and RepeatMasker (<http://www.repeatmasker.org/>), and expression levels were quantified based on read counts. ", "Mature miRNA annotation was extended 2 bp in both upstream and downstream regions to accommodate inaccurate processing of precursor miRNAs. ", "Reads with multiple mapping locations were weighted by the number of mapping locations.", "\n\nPC analysis {#s4-5}\n-----------\n\nDESeq Version 1.16.0 was used to perform PC analyses ([@bib2]).", "\n\nEnrichment analysis {#s4-6}\n-------------------\n\nDifferential expression was analyzed using DESeq Version 1.16.0 ([@bib2]). ", "Negative binomial distribution was used to compare miRNA abundance between cells vs exosomes and wild-type vs mutant KRAS status. ", "The trimmed mean of M values method was used for normalization ([@bib52]). ", "Differential expression was determined based on log2 fold change (log2 fold change) and false discovery rate (FDR) with \\\|log2 fold change\\\| ≥ 1 and FDR ≤ 0.001.", "\n\nTrimming and tailing {#s4-7}\n--------------------\n\nTrimming and tailing analysis was based on miRBase annotation ([@bib26], [@bib27]; [@bib28]). ", "Only high-confidence miRNAs (544) and corresponding hairpin sequences were used. ", "Bowtie version 1.1.1 with 0 mismatch was used for mapping. ", "miRNA reads were first mapped to hairpin sequences with unmapped reads, then mapped to the human genome hg19. ", "Remaining reads were trimmed 1 bp from the 3′ end and remapped to hairpin sequences. ", "The remapping process was repeated 10 times. ", "Finally, all mapped reads were collected for further analysis.", "\n\nqRT/PCR {#s4-8}\n-------\n\nTaqman small RNA assays (Life Technologies) (individual assay numbers are listed below) were performed for indicated miRNAs on cellular and exosomal RNA samples. ", "Briefly, 10 ng of total RNA was used per individual RT reactions; 0.67 μl of the resultant cDNA was used in 10 μl qPCR reactions. ", "qPCR reactions were conducted in 96-well plates on a Bio-Rad CFX96 instrument. ", "All C(t) values were ≤30. ", "Triplicate C(t) values were averaged and normalized to U6 snRNA. ", "Fold changes were calculated using the ∆∆C(t) method, where ∆ = C(t)~miRNA~ − C(t)~U6\\ snRNA~, and ∆∆C(t) = ∆C(t)~exo~ − ∆C(t)~cell~, and FC = 2^−∆∆C(t)^. Analysis was performed on three independent cell and exosomal RNA samples. ", "Taqman probe \\#: U6 snRNA: 001973; hsa-let-7a-5p: 000377; hsa-miR-100-5p: 000437; hsa-miR-320b: 002844; hsa-miR-320a: 002277.", "\n\nGeneration of miRNA standard curves {#s4-9}\n-----------------------------------\n\nRNase-free, HPLC-purified 5′-phosphorylated miRNA oligoribonucleotides were synthesized (Integrated DNA Technologies) for human miR-100-5p (5′-phospho-AACCCGUAGAUCCGAACUUGUG-OH-3′) and cel-miR-39-3p (5′-phospho-UCACCGGGUGUAAAUCAGCUUG-OH-3′). ", "Stock solutions of 10 μM synthetic oligonucleotide in RNase-free and DNase-free water were prepared according to the concentrations and sample purity quoted by the manufacturer (based on spectrophotometry analysis). ", "Nine twofold dilution series beginning with 50 pM synthetic oligonucleotide were used in 10 µl RT reactions (Taqman small RNA assays), and qPCR was performed. ", "Each dilution was performed in triplicate from three independent experiments. ", "Linear regression was used to determine mean C(t) values plotted against log(miRNA copies/µl).", "\n\nmiRNA in situ hybridizations and ceramide dependence {#s4-10}\n----------------------------------------------------\n\nCells were plated in 6-well plates containing coverslips at a density of ∼2.5 × 10^5^ cells and cultured in DMEM supplemented with 10% bovine growth serum for 24 hr. ", "The cells were then washed three times with PBS and cultured for 24 hr in serum-free medium containing either 5 μM GW4869 (Cayman Chemicals \\# 13127, Ann Arbor, MI, USA) or DMSO. ", "Medium was removed and cells were washed three times with PBS and fixed with 4% Paraformaldehyde (PFA) for ∼15 min at room temperature. ", "After, cells were washed three times in DEPC-treated PBS and permeabilized in 70% ethanol for ∼4 hr at 4°C, and rehydrated in DEPC-treated PBS for 5 min. ", "Pre-hybridization was performed in hybridization buffer (25% formamide, 0.05 M EDTA, 4× saline-sodium citrate (SSC), 10% dextran sulfate, 1X Denhardt's solution 1 mg/ml Escherichia coli tRNA) in a humidified chamber at 60°C for 60 min. ", "Hybridization buffer was removed and replaced with 10 nM of probe (probe numbers are listed below) diluted in hybridization buffer and incubated at either 55°C (miR-100 and miR-10b) or 57°C for scrambled and U6 probes for 2 hr. ", "Coverslips were then washed in series with pre-heated SSC at 37°C as follows: 4× SSC briefly, 2× SSC for 30 min, 1× SSC for 30 min, and 0.1× SSC for 20 min. ", "miRNA detection was conducted using Tyramide Signal Amplification (Perkin Elmer, \\# NEL741001KT, Waltham, MA, USA). ", "Briefly, coverslips were blocked in blocking buffer (0.1 M TRIS-HCl, pH 7.5, 0.15 M NaCl, 0.5% Blocking Reagent \\[Roche, \\#11096176001, Basel, Switzerland\\]) at 4°C overnight. ", "Blocking buffer was replaced with anti-DIG-POD (Roche, \\# 11207733910) diluted 1:100 in blocking buffer and incubated for 60 min. ", "Coverslips were washed three times, 5 min per wash, in wash buffer (0.1 M Tris-HCl, pH 7.5, 0.15 M NaCl, 0.5% Saponin) followed by incubation with 1× Fluorescein diluted in 1× amplification reagent for 5 min. ", "Fluorescent coverslips were then washed two times, 5 min per wash, in wash buffer. ", "To preserve fluorescent signals, coverslips were fixed with 2% PFA containing 2% Bovine serum albumin in 1× PBS for 15 min. ", "After fixation, coverslips were washed 2 times, 5 min per wash, in wash buffer, followed by a final wash in 1× PBS for 5 min. ", "Coverslips were then mounted in Prolong Gold (Life Technologies) and visualized on a Zeiss LSM510 at 63× objective. ", "3′-DIG labeled probes for in situ hybridizations-U6 snRNA: 99002-05; Scramble: 99004-05; miR-10b-5p: 38486-05; miR-100-5p: 18009-05 (Exiqon, Woburn, MA, USA).", "\n\nCo-culture and Luc reporter assays {#s4-11}\n----------------------------------\n\nRecipient cells were plated in six-well plates at a density of ∼2.5 × 10^5^ cells and cultured in DMEM supplemented with 10% bovine growth serum for 24 hr. ", "Media was replaced and cells were co-transfected (Promega, E2311, Madison, WI, USA) with 1.5 μg of Luc-reporter plasmid and 1.5 μg β-gal plasmid DNA/well. ", "Donor cells were plated in 0.4-μm polyester membrane Transwell filters (Corning, 3450, Corning, NY, USA) at ∼2.5 × 10^5^ cells/well for 24 hr. ", "Media from donor Transwells and recipient 6-well plates were removed and replaced with DMEM without FBS. ", "Co-culture of donor and recipient cells was conducted for either 24 or 48 hr before recipient cells were harvested. ", "Lysates were prepared in 1× Reporter lysis buffer (Promega, E2510), and Luc assays were performed according to the manufacturer\\'s protocol (Promega, E2510). ", "β-gal expression was simultaneously determined from the lysates according to the manufacturer\\'s protocol (Promega, E2000). ", "Differences in transfection efficiency were accounted for by normalizing Luc expression to β-Gal expression (Luc/β-Gal). ", "All assays were performed on three biological replicates, each with three technical replicates.", "\n\nAntagomir treatment {#s4-12}\n-------------------\n\nDonor cells were plated in 0.4-μm polyester membrane Transwell filters (Corning, 3450, Corning, NY, USA) at ∼1.4 × 10^4^ cells/well for 24 hr. ", "Medium was replaced and donor cells were transfected with either miR-100 hairpin antagomirs (\\# IH-300517-05, GE Life Sciences) or negative control hairpin antagomirs corresponding to cel-miR-67 (\\# IN-001005-01, GE Life Sciences) to produce a final concentration of 100 nM of antagomir for 24 hr. ", "Medium from donor Transwells and recipient 6-well plates was removed and replaced with DMEM without FBS. ", "Co-culture of donor and recipient cells was conducted for 24 hr before recipient cells were harvested for RNA isolation.", "\n\nPlasmid construction {#s4-13}\n--------------------\n\nFor the pLuc-mTOR construct, the 3′UTR of mTOR was PCR amplified (primer sequences in [Supplementary file 3](#SD4-data){ref-type=\"supplementary-material\"}) from genomic DNA isolated from DKs-8 cells. ", "The amplicon was cloned into pMiR-Report (Life Technologies) via SpeI/HinDIII restriction sites. ", "Mutation of miR-100 binding sites in mTOR 3′UTR (MS) was performed on pLuc-mTOR using forward or reverse primers targeting either all three MRE\\'s, or MRE 2 and 3 with QuikChange Lightning Multi-Site Directed Mutagenesis (Agilent, Santa Clara, CA, USA) according to manufacturer\\'s protocol. ", "To create the reporter construct containing three miR-100 perfect sites (miR-100-PT), oligonucleotides ([Supplementary file 3](#SD4-data){ref-type=\"supplementary-material\"}) were annealed to produce a synthetic fragment containing the perfect sites with CTAGT and AGCTT overhangs. ", "The fragment was cloned into pMiR-report via SpeI/HinDIII restriction sites. ", "All plasmids were sequence verified (GeneWiz, South Plainfield, NJ, USA).", "\n\nFunding Information\n===================\n\nThis paper was supported by the following grants:\n\n- http://dx.doi.org/10.13039/100000002National Institutes of Health (NIH) U19CA179514 to Robert J Coffey, James G Patton.", "\n\n- http://dx.doi.org/10.13039/100000054National Cancer Institute (NCI) P50 95103 to Robert J Coffey.", "\n\n- http://dx.doi.org/10.13039/100000002National Institutes of Health (NIH) RO1 CA163563 to Robert J Coffey.", "\n\n- http://dx.doi.org/10.13039/100000002National Institutes of Health (NIH) P30 DK058404 to Jeffrey L Franklin.", "\n\nThis work was supported by grants from the National Institutes of Health, U19CA179514, RO1 CA163563 and a GI Special Program of Research Excellence (SPORE) P50 95103 to RJC, and a pilot in P30 DK058404 to JLF. ", "Vanderbilt Digestive Disease Research Center (P30 DK058404) and associated Cores.", "\n\nAdditional information {#s5}\n======================\n\nThe authors declare that no competing interests exist.", "\n\nDJC, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article.", "\n\nJLF, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article.", "\n\nYD, Acquisition of data, Analysis and interpretation of data.", "\n\nQL, Acquisition of data, Analysis and interpretation of data.", "\n\nJNH, Acquisition of data, Analysis and interpretation of data.", "\n\nMDB, Acquisition of data, Analysis and interpretation of data.", "\n\nNP, Acquisition of data, Analysis and interpretation of data.", "\n\nSL, Acquisition of data, Analysis and interpretation of data.", "\n\nAMW, Conception and design, Drafting or revising the article.", "\n\nKV, Conception and design, Drafting or revising the article.", "\n\nRJC, Conception and design, Drafting or revising the article.", "\n\nJGP, Conception and design, Drafting or revising the article.", "\n\nBZ, Conception and design, Analysis and interpretation of data, Drafting or revising the article.", "\n\nAdditional files {#s6}\n================\n\n10.7554/eLife.07197.023\n\n###### \n\nRead counts for (A) individual miRNA species and (B) repeat families.", "\n\nDOI: [http://dx.doi.org/10.7554/eLife.07197.023](10.7554/eLife.07197.023)\n\n10.7554/eLife.07197.024\n\n###### \n\nAbundant miRNAs. ", "Normalized read counts (see 'Materials and methods') were used to determine the miRNAs with the highest number of reads (top 50) from cell and exosomal data sets. ", "The top 50 most abundant miRNAs were compared between exosomes and cells for each cell line. ", "Most abundant miRNAs in exosomes (blue), cells (orange), or both.", "\n\nDOI: [http://dx.doi.org/10.7554/eLife.07197.024](10.7554/eLife.07197.024)\n\n10.7554/eLife.07197.025\n\n###### \n\nRelated to experimental procedures. ", "Primers used for plasmid construction.", "\n\nDOI: [http://dx.doi.org/10.7554/eLife.07197.025](10.7554/eLife.07197.025)\n\n10.7554/eLife.07197.026\n\nDecision letter\n\nZamore\n\nPhillip D\n\nReviewing editor\n\nHoward Hughes Medical Institute, University of Massachusetts Medical School\n\n,\n\nUnited States\n\neLife posts the editorial decision letter and author response on a selection of the published articles (subject to the approval of the authors). ", "An edited version of the letter sent to the authors after peer review is shown, indicating the substantive concerns or comments; minor concerns are not usually shown. ", "Reviewers have the opportunity to discuss the decision before the letter is sent (see [review process](http://elifesciences.org/review-process)). ", "Similarly, the author response typically shows only responses to the major concerns raised by the reviewers.", "\n\nThank you for sending your work entitled \"KRAS-Dependent Sorting of miRNA to Exosomes\" for consideration at eLife. ", "Your article has been favorably evaluated by Sean Morrison (Senior editor) and two reviewers, one of whom is a member of our Board of Reviewing Editors.", "\n\nThe Reviewing editor and the other reviewer discussed their comments before we reached this decision, and the Reviewing editor has assembled the following comments to help you prepare a revised submission.", "\n\nThe function of exosomal miRNAs is a highly controversial area of research, with some studies, such as this manuscript, claiming that miRNAs are not only exported from cells in exosomes, but also taken up by other cells as biologically functional signaling molecules, and others arguing they have no biological function. ", "This manuscript, likely for the first time in the field establishes a well-defined experimental system: three isogenic cells lines that differ solely in KRAS status.", "\n\nThe manuscript makes some progress toward testing the idea that miRNAs can be transferred from cell-to-cell, but given the controversies in the field, a higher standard of proof is required to merit publication in eLife. ", "We recommend the authors be given the opportunity to revise their manuscript, providing the requested new experiments and analyses. ", "Most importantly, I urge the authors to spend less time selling their story and more effort rigorously testing-not proving-their hypotheses.", "\n\n1\\) The major paper deficiency is lack of a clear biological model or mechanism explaining the data. ", "While this is also true for most published exosome papers, one expects an eLife paper to propose some explanation for why specific miRNAs are transferred from cell-to-cell according to the exporting cell\\'s KRAS status.", "\n\n2\\) Correlation analysis plays a central role in testing the authors\\' hypothesis. ", "Given the low correlation of the independent biological replicates (deep sequencing replicates typically correlate with R \\> 0.90 in one of our labs), the authors should apply an appropriate statistical test to determine that R-values of 0.92-0.96 between cells are unlikely to differ from R-values of 0.67-0.89 comparing exosomes to the exporting cells? ", "If the bottom quartile of miRNAs by abundance (i.e., the ones least well measured by convention, rather than digital, sequencing methods) are excluded, do the Pearson correlation values change? ", "Can all the biological replicates be used to make the comparisons, not simply pairwise combinations of individual data sets?", "\n\n3\\) Is the degree of reporter repression small because the abundance of exosome-delivered miRNAs is low? ", "The miRNA literature overwhelmingly supports the view that low abundance miRNAs have no biological effects, because the cellular concentration of miRNA-binding sites is much, much greater than the concentration of miRNA. ", "That is, the stoichiometric mechanism of miRNA-mediated repression in mammals requires that miRNAs be highly abundant. ", "When DKs-8 cells obtain a miRNA, such as miR-222, from exosomes, does that new miRNA rank in the top 25% or 50% of miRNAs by abundance? ", "If not, it is difficult to imagine how it could be functional, given the aggregate intracellular concentration of seed-matched target sites. ", "The authors need to report an estimate of how many molecules of a given miRNA sequence are present per exosome and how many are delivered to an individual recipient cell.", "\n\n4\\) Why were three perfect sites used? ", "Were controls performed validating the reporter using anti-miRs and miRNA mimics?", "\n\n5\\) In the ceramide experiments, the authors interpret the change in exosomal and cellular abundance for miR-100 and miR-320 as evidence that a subset of miRNA sorting is altered by ceramide while a separate, ceramide-independent pathway delivers other miRNAs to exosomes. ", "The data are interesting, but don\\'t seem to contribute to our understanding of the mechanism of putative sorting of miRNAs into exosomes. ", "Perhaps miR-10b is simply less abundant than miR-100 or miR-320, making it harder to reliably detect changes in its abundance?", "\n\n6A) High-Throughput Sequencing Data. ", "How were the data normalized? ", "How was the normalization procedure validated? ", "Best practice is to select the normalization method that produces the greatest congruence among otherwise identical biologically independent replicates.", "\n\n6B) Extending miRNA sequences {plus minus} 2 nt \"to accommodate inaccurate processing of precursor miRNAs\" would be a great idea if miRBase were always right; but miRBase is often wrong. ", "It would be better to use the sequence of the most abundant isoform of the miRNA as the \"accurately\" processed form and to pool reads for all isoforms with the same 5′ end (i.e., the same seed sequence).", "\n\n6C) Whenever read data is presented, species data should be presented in parallel. ", "For example, the data in [Figure 1](#fig1){ref-type=\"fig\"} would have a very different meaning if most of the \"repeat\" sequences were from just a few species, rather than a diverse set of RNAs.", "\n\n10.7554/eLife.07197.027\n\nAuthor response\n\n1) The major paper deficiency is lack of a clear biological model or mechanism explaining the data. ", "While this is also true for most published exosome papers, one expects an eLife paper to propose some explanation for why specific miRNAs are transferred from cell-to-cell according to the exporting cell\\'s KRAS status.", "\n\nIt remains a key question as to how specific miRNAs are selected for export. ", "We conducted a series of experiments as detailed in the Results to determine whether any previously proposed mechanistic models can explain why we detect enrichment for some miRNAs within exosomes. ", "We rigorously evaluated our data sets and described in the Results and the Discussion that we could not find support for:\n\nA\\) \"Zip-code\" sequences (Bolukbasi et al. ", "Mol Therapy-Nucleic Acids, 1 e10, Batagov et al. ", "BMC Genomics 12: S18). ", "These papers proposed that specific nucleotide patterns within secreted RNAs targeted them for export. ", "We tested for the presence of those signals, as well as common motifs using MEME analysis, in our data sets and could not find evidence for a universal zip code sequence. ", "However, when we restricted our analysis to the most differentially represented miRNAs in exosomes compared to cells, we detected a possible enrichment for C residues or alternating C residues. ", "This is shown in [Figure 4--figure supplement 3](#fig4s3){ref-type=\"fig\"}. ", "We have added sentences to address these findings but we were careful to ensure that readers understand that the overall conclusion is that we were unable to identify a short sequence that could serve as a zip code targeting element.", "\n\nB\\) 3' and 5' modifications (Koppers-Lalic et al. ", "Cell Reports 8:1-10, Katoh et al. ", "Genes Dev 23: 433, Burns et al. ", "Nature 473: 105, Fernandez-Valverde et al. ", "RNA 16: 1881, Wei et al. ", "RNA 18: 915, Thornton et al. ", "NAR 42: 11777). ", "Numerous reports have proposed that 5' and 3' modifications can alter miRNA metabolism. ", "Most commonly, addition of U residues to 3' ends is thought to promote turnover whereas the addition of A residues promotes stabilization. ", "G and C additions are generally rare. ", "We tested whether exosomal export might be linked to 3' or 5' modifications. ", "We did not observe significant 5' modifications from reads derived from miRNAs in either cells or exosomes. ", "For 3' modifications, we found that cellular miRNAs tended to have increased numbers of modified 3' ends with added A residues. ", "We did not observe an enrichment of 3'-NTA of A residues in reads derived from exosomal miRNAs. ", "Further analysis showed that there was enrichment of reads containing extra C residues at the 3' ends in exosomes from wild-type KRAS cells. ", "These data are now included in [Figure 4--figure supplement 1](#fig4s1){ref-type=\"fig\"}. ", "It remains unclear whether these changes are key to providing mechanistic insight into miRNA export. ", "We have added sentences to carefully address this point.", "\n\nC\\) Sumoylated hnRNPA2 B1 (Villarroya-Bletri et al. ", "Nature Comm 4:2980). ", "This paper proposed that miRNAs destined for exosomal export contain GGAG motifs that are bound by hnRNP A2B1. ", "We found this motif in some exosomal miRNAs but clearly not all, indicating that this motif is not a universal targeting signal.", "\n\nD\\) ESCRTs vs. Sphingomyelinase. ", "As shown in the Results and discussed in the Discussion (with references), we tested whether different biogenesis pathways might explain miRNA export selectivity. ", "We indeed observed changes in miRNA signals in cells when treated with a sphingomyelinase inhibitor suggesting that there may be a distinct pathway for export. ", "This only affected miRNA trafficking in mutant KRAS cells but not wild-type KRAS cells. ", "While the data are intriguing, we were careful to qualify our results with the caveat that sorting in this situation might be cell-type or context-specific.", "\n\nWe agree that we have not solved the overall problem to understand or mechanistically explain miRNA export but we believe that our paper makes a significant contribution to the field by using our well controlled model system to test whether earlier proposed models hold up. ", "Even though the data are negative, they provide a valuable tool for the field. ", "We also include discussion of possible mechanisms that could explain selective export (see Discussion).", "\n\n2) Correlation analysis plays a central role in testing the authors\\' hypothesis. ", "Given the low correlation of the independent biological replicates (deep sequencing replicates typically correlate with R \\> 0.90 in one of our labs), the authors should apply an appropriate statistical test to determine that R-values of 0.92-0.96 between cells are unlikely to differ from R-values of 0.67-0.89 comparing exosomes to the exporting cells?", "\n\nWe thank the reviewers for this important comment. ", "Variation between exosomes was obviously much larger than those between cells. ", "In DESeq, the \"per-condition\" method is designed to handle this situation by calculating an empirical dispersion value for each condition separately. ", "The \"per-condition\" method was the default option in an earlier version of DESeq. ", "We were not aware of the change of the default to the \"pooled\" method in a more recent version, which was used to generate the results presented in the previous version of the manuscript. ", "In the revision, we re-did differential analysis using the \"per-condition\" method and updated all related results accordingly ([Tables 1, 2](#tbl1 tbl2){ref-type=\"table\"}, [Figure 2--figure supplement 1-4](#fig2s1 fig2s2 fig2s3 fig2s4){ref-type=\"fig\"}, [Figures 3A, B](#fig3){ref-type=\"fig\"}, and motif analysis, [Figure 4--figure supplement 3](#fig4s3){ref-type=\"fig\"}). ", "The new results do not alter the conclusions of the manuscript.", "\n\nIf the bottom quartile of miRNAs by abundance (i.e., the ones least well measured by convention, rather than digital, sequencing methods) are excluded, do the Pearson correlation values change?", "\n\n[Figure 2--figure supplement 2](#fig2s2){ref-type=\"fig\"} shows new correlation values after removing the bottom quartile of miRNAs by abundance. ", "These values are very similar to those calculated based on all miRNAs.", "\n\nCan all the biological replicates be used to make the comparisons, not simply pairwise combinations of individual data sets?", "\n\nData from all biological replicates were used together in the differential expression analysis. ", "The pair-wise analysis is just an exploratory analysis to gain a high-level overview of the pair-wise correlations of samples within or between different experimental groups.", "\n\n3) Is the degree of reporter repression small because the abundance of exosome-delivered miRNAs is low? ", "The miRNA literature overwhelmingly supports the view that low abundance miRNAs have no biological effects, because the cellular concentration of miRNA-binding sites is much, much greater than the concentration of miRNA. ", "That is, the stoichiometric mechanism of miRNA-mediated repression in mammals requires that miRNAs be highly abundant. ", "When DKs-8 cells obtain a miRNA, such as miR-222, from exosomes, does that new miRNA rank in the top 25% or 50% of miRNAs by abundance? ", "If not, it is difficult to imagine how it could be functional, given the aggregate intracellular concentration of seed-matched target sites. ", "The authors need to report an estimate of how many molecules of a given miRNA sequence are present per exosome and how many are delivered to an individual recipient cell.", "\n\nThe reviewers are indeed correct that the degree of reporter repression is small because the abundance of exosomal-delivered miRNA is low. ", "This is not unexpected and is central to controversies in the field as to the stoichiometry and function of secreted RNA. ", "Indeed, we think this is the key question moving forward because experimental proof of transfer can be difficult. ", "Many studies successfully showing RNA transfer utilized experiments where nonphysiological concentrations of purified exosomes were added to recipient cells (see manuscript references). ", "Evidence of transfer has also been demonstrated between immune cells that can remain opposed to one another for hours facilitating exRNA transfer but making it very difficult to precisely quantify the level of transfer (Mittelbrunn et al., ", "Nature Communications 2:282, Ekstrom et al. ", "JEV 1:18389, Montecalvo et al. ", "Blood 119: 756). ", "In our experiments, we chose to use Transwell co-culture experiments to resemble a more physiological system and also to test functional miRNA transfer with reporter constructs. ", "We observed a ∼60-65% decrease with perfect sites and a ∼40% decrease with a wild-type mTOR 3' UTR. ", "Analysis of miR-100 levels in recipient cells showed an approximate 34 % increase in miR-100 levels compared to cells cultured in the absence of donor cells ([Figure 6E](#fig6){ref-type=\"fig\"}). ", "The increase in miR-100 levels is supported by precise copy number calculations that show that there are 329 molecules of miR-100 per ng of total input RNA in cells grown in the absence of donor cells and those numbers increase to 443 molecules of miR-100 in the presence of donor cells ([Figure 6--figure supplement 2](#fig6s2){ref-type=\"fig\"}).", "\n\nThe statement that \"overwhelming evidence supports the view that low abundance miRNAs have no biological effects\" might be true on a global genomic scale but becomes a bit too generalized when applied to specific cells or developmental time points. ", "There are two issues. ", "First, one has to account for the concentration of a specific miRNA and second, the concentration of all target mRNAs in specific cells and/or at specific developmental time points. ", "The fact that there have been about 11 different published target prediction algorithms speaks to the fact that we do not yet know precisely how to identify mRNA targets, nor do we know the exact set of rules that govern pairing and repression. ", "Seed pairing is clearly important (Lewis et al. ", "Cell 115: 787; Brennecke et al. ", "PLos Biol 3: e85; Grimson, Mol Cell 27: 91; Lewis et al. ", "Cell 120: 15; Krek et al. ", "Nat Gen 37: 495) but there are lots of examples where imperfect seed sequences are robustly silenced (Li et al. ", "NAR 36: 4277; Didiano and Hobert, NSMB 13: 849). ", "Identifying bona fide targets requires experimental validation; in silico prediction is just a starting point with many false positive and negatives. ", "Thus, knowing the exact concentration of target mRNAs and extending that to determine whether a miRNA is low abundance or not is not trivial. ", "An historical example is lsy6 in C. elegans which cannot be detected in sequencing approaches because it is so low abundance in worms, yet it controls the formation of left/right asymmetry between two neurons and regulates cog-1 through a non-canonical binding sequence (Johnston and Hobert, Nature 426: 845). ", "The effects of lsy6 manifest themselves as part of a downstream network that is put in play by initial miRNA regulation, nicely illustrating the point that time and place matters. ", "Our work on the role of miRNAs during vertebrate development has also identified numerous miRNAs that are not highly abundant but whose disruption leads to specific developmental defects (Flynt et al. ", "Nat Gen 39: 259; Li et al. ", "Dev 138: 1817; Thatcher et al. ", "PNAS 105: 18384). ", "Interestingly, we often find that non-canonical targets are the key targets even though we always begin our search using seed-based algorithms. ", "Beyond our own work, perhaps the best example arguing against abundance and functional activity is miR-33 which is expressed at approximately 30-40 copies per liver cell compared to miR-122 which has about 3 million copies per liver cell. ", "Despite the numbers, modest antagonism of miR-33 down to about 15-20 copies per cell is enough to disrupt cholesterol metabolism and rescue atherosclerosis in mice (Najafi-Shoushtari et al. ", "Science 328: 1566, Rayner et al. ", "Science 328: 1570, Rayner et al. ", "JCI 121: 2921, Rayner Nature 478: 404). ", "Another good example is miR-802 which is not even in the top 100 miRNAs as far as abundance in liver, yet it controls glucose homeostasis and type II diabetes (Kornfeld et al. ", "Nature 494: 111). ", "The Mendel lab had a nice paper using overexpression of miR-26 in transgenic mice to try to resolve why miR-26 can act as both a tumor suppressor and an oncogene in intestinal tumors. ", "After overexpression, global analysis (GSEA) of likely mRNA targets identified numerous targets that were repressed by greater than 1.5. ", "However, a known target of miR-26 (EZH2) did not show up in their analysis yet they, and others, showed that miR-26 regulates EZH2 (Zeitels et al. ", "Genes and Dev 28: 2585). ", "Lastly, miR-206 was identified as one of several low abundance miRNAs that play key roles in colon cancer (Parasramka et al. ", "Clin Epigenetics 4:16).", "\n\nNevertheless, we agree completely that stoichiometry is a key issue. ", "The Tewari lab has published quantitative analysis of the amounts of miRNA per exosome and the numbers are startling low -- 0.008 molecules of miRNA per exosome (Chevillet et al. ", "PNAS 111: 14888). ", "This illustrates the importance of the issue raised by the reviewers, something we completely agree with. ", "Nevertheless, we observe silencing by miR-100 and miR-222 so despite stoichiometry issues aside, miRNAs are being functionally transferred.", "\n\n4) Why were three perfect sites used? ", "Were controls performed validating the reporter using anti-miRs and miRNA mimics?", "\n\nPerfect sites were used in half of our reporter constructs to optimize detection of silencing. ", "By creating perfect sites, we are inducing an RNAi-based Ago2 cleavage of mRNA targets which helps detect silencing through a catalytic mechanism. ", "This provided the necessary proof of principle to try targeting an endogenous gene which was observed using the mTOR 3' UTR. ", "The binding sites in the mTOR 3' UTR are typical miRNA binding sites with imperfect pairing so that repression is via miRNA-based mechanisms. ", "Even with imperfect pairing, we were still able to observe silencing albeit less than when perfect sites were used. ", "Further, mutation of the sites derepressed silencing. ", "Three perfect sites were used (as opposed to one perfect site) because the endogenous mTOR 3'UTR also contains three miR-100 sites. ", "Having three perfect sites rather than one would actually underestimate the strength of Luc repression due to miR-100 transfer.", "\n\nThe reviewers are entirely correct that we need to run extensive controls to ensure that the silencing we observe in our Transwell culture experiments is via miR-100. ", "As requested, we performed antagomir experiments to decrease the expression of miR-100 in donor cells (new [Figure 6D](#fig6){ref-type=\"fig\"}). ", "We also included new data analyzing the absolute levels of miR-100 in recipient cells grown in the presence or absence of donor cells (new [Figure 6E](#fig6){ref-type=\"fig\"}, [Figure 6--figure supplement 2](#fig6s2){ref-type=\"fig\"}).", "\n\n5) In the ceramide experiments, the authors interpret the change in exosomal and cellular abundance for miR-100 and miR-320 as evidence that a subset of miRNA sorting is altered by ceramide while a separate, ceramide-independent pathway delivers other miRNAs to exosomes. ", "The data are interesting, but don\\'t seem to contribute to our understanding of the mechanism of putative sorting of miRNAs into exosomes. ", "Perhaps miR-10b is simply less abundant than miR-100 or miR-320, making it harder to reliably detect changes in its abundance?", "\n\nThe sphingomyelinase inhibition experiments begin to address mechanisms underlying the biogenesis of miRNA export into exosomes. ", "In contrast to the statement by the reviewers, miR-10b is actually more abundant than miR-100 or miR-320 so levels do not appear to determine whether a miRNA is sphingomyelinase dependent or not. ", "Overall, our findings are less about abundance and more about biogenesis and export of miRNA from cells. ", "Controversy remains as to the varying roles of ESCRTs versus ceramide so it was important for us to demonstrate what we observe with our cells. ", "As summarized in the Discussion, it seems that cell context is important and unifying conclusions are not yet possible for ceramide dependence.", "\n\n6A) High-Throughput Sequencing Data. ", "How were the data normalized? ", "How was the normalization procedure validated? ", "Best practice is to select the normalization method that produces the greatest congruence among otherwise identical biologically independent replicates.", "\n\nThe data were normalized using the DESeq package, in which the effective library size (i.e. size factor) for each sample is estimated using the function \"estimateSizeFactors\". ", "Dillies et al. (", "2013) evaluated several normalization methods based on real and simulated data sets (Dillies et al. ", "Briefings in Bioinformatics 14.6 (2013): 671-683). ", "Similar performance was observed for the DESeq normalization method and the TMM method, and both of them outperformed other methods.", "\n\n6B) Extending miRNA sequences {plus minus} 2 nt \"to accommodate inaccurate processing of precursor miRNAs\" would be a great idea if miRBase were always right; but miRBase is often wrong. ", "It would be better to use the sequence of the most abundant isoform of the miRNA as the \"accurately\" processed form and to pool reads for all isoforms with the same 5′ end (i.e., the same seed sequence).", "\n\nFor each miRNA with a read count greater than 100, we compared the position of the most abundant isoform to the annotated position in miRBase. ", "As shown in [Author response table 1](#tbl3){ref-type=\"table\"}, consistency was found for around 75% of the miRNAs in all samples. ", "Moreover, we compared miRNA counts based on miRBase annotations and positions of the most abundant reads, both with the +/- 2 strategy. ", "As shown in [Author response table 2](#tbl4){ref-type=\"table\"}, about 80% of the miRNAs had exactly the same counts and only about 5% of the miRNAs showed a difference of more than 10%. ", "Based on these results, we decided to keep the miRBase-based counting results.10.7554/eLife.07197.028Author response table 1.Comparison of miRNA positions based on the most abundant reads and annotations from miRBase.DOI: [http://dx.doi.org/10.7554/eLife.07197.028](10.7554/eLife.07197.028)SampleSameDifferentSame percentageDKO1.cell.12799674.4%DKO1.cell.22748676.1%DKO1.cell.32559073.9%DKO1.exo.11295271.3%DKO1.exo.21344375.7%DKO1.exo.3842875.0%DKS8.cell.133012572.5%DKS8.cell.229310873.1%DKS8.cell.32729075.1%DKS8.exo.1602174.1%DKS8.exo.2481675.0%DKS8.exo.3762476.0%DLD1.cell.12779275.1%DLD1.cell.230811572.8%DLD1.cell.32909774.9%DLD1.exo.1621778.5%DLD1.exo.2531676.8%DLD1.exo.3702176.9%10.7554/eLife.07197.029Author response table 2.Comparison of miRNA counts based on miRBase annotations and positions of the most abundant reads.DOI: [http://dx.doi.org/10.7554/eLife.07197.029](10.7554/eLife.07197.029)SampleSameDifference more than 10%DKO1.cell.177.00%6.90%DKO1.cell.278.80%7.20%DKO1.cell.379.10%6.70%DKO1.exo.178.90%6.50%DKO1.exo.280.00%5.80%DKO1.exo.386.80%2.30%DKS8.cell.177.30%7.80%DKS8.cell.279.70%6.70%DKS8.cell.379.70%6.30%DKS8.exo.182.50%6.20%DKS8.exo.285.10%4.50%DKS8.exo.379.80%4.00%DLD1.cell.179.70%6.00%DLD1.cell.277.10%7.60%DLD1.cell.378.30%6.10%DLD1.exo.179.80%3.60%DLD1.exo.287.70%2.70%DLD1.exo.385.10%2.10%\n\n6C) Whenever read data is presented, species data should be presented in parallel. ", "For example, the data in [Figure 1](#fig1){ref-type=\"fig\"} would have a very different meaning if most of the \"repeat\" sequences were from just a few species, rather than a diverse set of RNAs.", "\n\nA count table for miRNAs is included in . ", "Portions of reads from different repeat families are shown in [Figure 1C](#fig1){ref-type=\"fig\"}. ", "A count table of the repeat families is also included in [Supplementary file 1B](#SD2-data){ref-type=\"supplementary-material\"}.", "\n\n[^1]: These authors contributed equally to this work.", "\n\n[^2]: miRNAs differentially enriched in cells when comparing mean reads in exosomes vs cell.", "\n\n[^3]: miRNAs expression patterns were compared between DKs-8, DKO-1, and DLD-1 cells. ", "miRNAs were identified that were enriched in just one of the three cell types or that overlapped between combinations of cells. ", "For miRNAs, 25 were identified that are expressed in all three cell types, 13 were enriched in DKs-8 cells, 15 in DLD-1 cells, and 39 were unique to DKO-1 cells.", "\n\n[^4]: miRNAs differentially enriched in exosomes when comparing mean reads in exosomes vs cell.", "\n\n[^5]: miRNAs expression patterns were compared between exosomes purified from DKs-8, DKO-1, and DLD-1 cells. ", "miRNAs were identified that were enriched in exosomes from just one of the three cell lines or that overlapped between combinations of cell lines. ", "29 miRNAs were common between exosomes from all three cell lines. ", "94 were enriched in exosomes from DKO-1 cells, 10 in exosomes from DKs-8 cells, and only 6 in exosomes from DLD-1 cells.", "\n" ]	{ "pile_set_name": "PubMed Central" }	[ 0.0006389861810021102, 0.0006463896133936942, 0.0007521946681663394, 0.00063625059556216, 0.0006096523138694465, 0.0006790069164708257, 0.0010771859670057893, 0.0007009989349171519, 0.0006757942610420287, 0.0009382129646837711, 0.0006253437022678554, 0.0008665361092425883, 0.0008384989923797548, 0.000759333313908428, 0.0008221031166613102, 0.0007277597323991358, 0.0006936768186278641, 0.0007043075747787952, 0.0005711984122171998, 0.0011203308822587132, 0.0010945663088932633, 0.0005698247696273029, 0.0006396734388545156, 0.0006223550881259143, 0.0006782279233448207, 0.0005625669728033245, 0.0006177123286761343, 0.0005787580157630146, 0.0007025894010439515, 0.0005923626595176756, 0.0007568770088255405, 0.0005695681902579963, 0.0006084993947297335, 0.0006095137214288116, 0.0005498338723555207, 0.0005908475141040981, 0.0005941151175647974, 0.0005892175249755383, 0.0007019282202236354, 0.0005754628800787032, 0.0005702382768504322, 0.0005839627119712532, 0.0005797813064418733, 0.0009422083385288715, 0.0005537608521990478, 0.0005865542916581035, 0.0006559460307471454, 0.00060516461962834, 0.0005511902854777873, 0.0005925145233049989, 0.000555561447981745, 0.0008396626799367368, 0.0005623689503408968, 0.0005981845897622406, 0.002812354825437069, 0.0006473322282545269, 0.0006002640002407134, 0.0006541596376337111, 0.00063053093617782, 0.0006233925232663751, 0.0007401489419862628, 0.0005748672410845757, 0.0005939141847193241, 0.0006070857052691281, 0.0007291169022209942, 0.0005583050660789013, 0.0006174083682708442, 0.0012991020921617746, 0.0009513235418125987, 0.0006445622420869768, 0.0005942148854956031, 0.0006670473958365619, 0.000696129456628114, 0.0006272861501201987, 0.0007504856330342591, 0.0007579319062642753, 0.0008609395590610802, 0.0006069338414818048, 0.0007117025670595467, 0.000646704516839236, 0.001737939310260117, 0.0008996280957944691, 0.0006347733433358371, 0.0006282397662289441, 0.000647996726911515, 0.0005668853991664946, 0.0006174077861942351, 0.000607366906479001, 0.0005447556031867862, 0.0006005381001159549, 0.0006416863179765642, 0.0006568399840034544, 0.000636344077065587, 0.0005440841196104884, 0.0005785635439679027, 0.0005910426843911409, 0.0006972604896873236, 0.0005973438965156674, 0.0005562343867495656, 0.0006460518343374133, 0.0006641382933594286, 0.0006950648385100067, 0.0005645638448186219, 0.0005611454253084958, 0.0006070637027733028, 0.0007240328122861683, 0.0006535940920002759, 0.0005986844771541655, 0.0005959321861155331, 0.0005721606430597603, 0.0010257326066493988, 0.0006008670316077769, 0.0005279688630253077, 0.0005746664828620851, 0.0006651810253970325, 0.0005781374638900161, 0.0009330479078926146, 0.0006545437499880791, 0.0008148106280714273, 0.000879154191352427, 0.0006026644841767848, 0.0007728979107923806, 0.0006690076552331448, 0.0008188694482669234, 0.0009136751759797335, 0.0006028948700986803, 0.0006243575480766594, 0.0008306610397994518, 0.0008829482248984277, 0.0005466890288516879, 0.0007132761529646814, 0.0006714560440741479, 0.0007551281596533954, 0.0006084666238166392, 0.0005820692167617381, 0.0007091657025739551, 0.0007292346563190222, 0.0007303773309104145, 0.0006601180066354573, 0.0006224147509783506, 0.0007123370305635035, 0.0007180373067967594, 0.0006781562115065753, 0.0008453074260614812, 0.0009190753917209804, 0.0008350699790753424, 0.0006740799872204661, 0.00063235720153898, 0.0007340081501752138, 0.0006661601946689188, 0.0006585580413229764, 0.0006841319263912737, 0.0005659854505211115, 0.0007327232742682099, 0.0006811643252149224, 0.0006370834307745099, 0.0005710492259822786, 0.0006971468683332205, 0.0006042755558155477, 0.0007993729668669403, 0.0005835768533870578, 0.0005824979161843657, 0.0005891352775506675, 0.0005915372748859227, 0.0006676585762761533, 0.0007350847590714693, 0.0006023719324730337, 0.0005763683584518731, 0.0005666955257765949, 0.0005866753635928035, 0.0006050547235645354, 0.0006940477760508657, 0.0005623798933811486, 0.0008720434852875769, 0.0006187697290442884, 0.0008037159568630159, 0.0006237910129129887, 0.0006641693762503564, 0.0007178939413279295, 0.0006068262737244368, 0.0006125940126366913, 0.0006661589723080397, 0.0006426211912184954, 0.0006721731624566019, 0.0005739603657275438, 0.0005962376017123461, 0.0005495420191437006, 0.0012927750358358026, 0.0007533510215580463, 0.0006083999760448933, 0.0007688777986913919, 0.0006551144761033356, 0.0005834277253597975, 0.000661153462715447, 0.0006121026817709208, 0.0006172583089210093, 0.0006151132984086871, 0.0006575220613740385, 0.001136551145464182, 0.0006935607525520027, 0.0007080436334945261, 0.0007275576354004443, 0.0006519103772006929, 0.0008322966750711203, 0.0006498168222606182, 0.0005818401114083827, 0.0007992518949322402, 0.0006755093345418572, 0.0014669799711555243, 0.0008711593691259623, 0.0007087815902195871, 0.0006851233192719519, 0.0007840448524802923, 0.0007221488049253821, 0.0008210837841033936, 0.000588625087402761, 0.0005548103363253176, 0.0005717836902476847, 0.0006730539025738835, 0.0007009498658590019, 0.0006121977348811924, 0.0007524627726525068, 0.0011850371956825256, 0.000601068080868572, 0.0006153231952339411, 0.0006632667500525713, 0.0007397745503112674, 0.0006214739405550063, 0.0006321001565083861, 0.0008489200263284147, 0.0011372972512617707, 0.004480510484427214, 0.004910461604595184, 0.0009842892177402973, 0.0006640446372330189, 0.0005692184204235673, 0.0005703861243091524, 0.0006380231934599578, 0.000636451703030616, 0.0008170759538188577, 0.0005996987456455827, 0.0006441081641241908, 0.0006019010324962437, 0.000594884913880378, 0.0005949620390310884, 0.0006156364688649774, 0.0008121263235807419, 0.0005538621917366982, 0.0006088056834414601, 0.0005670178215950727, 0.0005824934924021363, 0.0005704236682504416, 0.0006658913916908205, 0.0006224446115083992, 0.0005754574085585773, 0.0006134447176009417, 0.0006151085835881531, 0.0005986097385175526, 0.0006268826546147466, 0.0005803123931400478, 0.00060742546338588, 0.0005880522658117115, 0.0005759512423537672, 0.0006263586110435426, 0.0006143247010186315, 0.0007108119316399097, 0.000587900634855032, 0.0006181785138323903, 0.0006759169627912343, 0.0005991873913444579, 0.0006833177758380771, 0.0006302734836935997, 0.0005909134051762521, 0.0006072071846574545, 0.0005331478314474225, 0.0005921046831645072, 0.0006458868738263845, 0.0005613476387225091, 0.0007872090209275484, 0.0006749757449142635, 0.0006553071434609592, 0.0010857126908376813, 0.005111340433359146, 0.0005996772670187056, 0.0006807807367295027, 0.0006858458509668708, 0.0006096979486756027, 0.0006832089857198298, 0.0006216404144652188, 0.0006897512939758599, 0.0007282228325493634, 0.0006234925822354853, 0.0006228597485460341, 0.0008585871546529233, 0.0006400409038178623, 0.0010277183027938008, 0.0011259885504841805, 0.0012009236961603165, 0.0009270770824514329, 0.0006112107075750828, 0.0008249913807958364, 0.0006247875862754881, 0.0006463893805630505, 0.0006292708567343652, 0.0006221735966391861, 0.0005944034783169627, 0.000629007292445749, 0.0005616339622065425, 0.0005917605012655258, 0.0006417991826310754, 0.0006274053594097495, 0.0005975472158752382, 0.0006222901283763349, 0.0007236078963615, 0.000685943232383579, 0.0005516427918337286, 0.0006602507783100009, 0.0005849612061865628, 0.0006208997219800949, 0.000614018237683922, 0.0005672770203091204, 0.0005780501523986459, 0.0006154032307676971, 0.0007291565416380763, 0.0007021905039437115, 0.0006973774870857596, 0.0005896203219890594, 0.001064326730556786, 0.0007463422371074557, 0.0005699826288037002, 0.0005818012868985534, 0.0005887412116862833, 0.0006020949804224074, 0.0005853795446455479, 0.0005898645613342524, 0.0006453779642470181, 0.0006235419423319399, 0.0006114833522588015, 0.0005997410044074059, 0.0006056230631656945, 0.0005949847400188446, 0.0005968311452306807, 0.0008153737871907651, 0.0007733193342573941, 0.0005756579339504242, 0.000624131178483367, 0.0006678651552647352, 0.0007073830347508192, 0.0006864125025458634, 0.0006169921834953129, 0.0005305626546032727, 0.0005247368826530874, 0.0005690036341547966, 0.0005631490494124591, 0.0005600927397608757, 0.0005143870366737247, 0.0005937679088674486, 0.0005820123478770256, 0.0005619525327347219, 0.0005065688164904714, 0.0008232052205130458, 0.0007093106978572905, 0.000681843317579478, 0.0006199092604219913, 0.0005913357017561793, 0.0006004730821587145, 0.0006026639021001756, 0.0008884209673851728, 0.0006164037622511387, 0.0006619973573833704, 0.0007026430685073137, 0.000547056260984391, 0.0005535600357688963, 0.0008031363831833005, 0.0006598148611374199, 0.0006183349178172648, 0.0006367768510244787, 0.0006363097345456481, 0.0007114842301234603, 0.000671273039188236, 0.00065734947565943, 0.0005867525469511747, 0.0006348604802042246, 0.0005644995253533125, 0.0005913035711273551, 0.000556730548851192, 0.000627962639555335, 0.0006660186336375773, 0.0005601640441454947, 0.0005704043433070183, 0.0005826170090585947, 0.0006565793300978839, 0.0007202303386293352, 0.0005730920238420367, 0.0005284985527396202, 0.0005833338364027441, 0.0005920265102759004, 0.0005267978413030505, 0.0007952285232022405, 0.0006199338240548968, 0.0006951479590497911, 0.0006575113511644304, 0.0006606202805414796, 0.0006864343304187059, 0.0008867570431903005, 0.0006299258093349636, 0.000723219127394259, 0.0006279895314946771, 0.0005490519688464701, 0.0006284775445237756, 0.0005885708960704505, 0.0005690974649041891, 0.0006605790695175529, 0.0005861572572030127, 0.0005749286501668394, 0.0005398080684244633, 0.000864380388520658, 0.000706884718965739, 0.0008422654354944825, 0.000582197040785104, 0.002008284442126751, 0.0005240511381998658, 0.0005908139864914119, 0.001031825435347855, 0.0005091227940283716, 0.0005567104090005159, 0.0005513744545169175, 0.000563961744774133, 0.0006187600083649158, 0.0005952014471404254, 0.0005078519461676478, 0.0007102173985913396, 0.0006260640802793205, 0.000690903514623642, 0.0005487239686772227, 0.0006308859447017312, 0.0006108335801400244, 0.0005975623498670757, 0.0005883683916181326, 0.0006440255674533546, 0.000603162741754204, 0.0005437569925561547, 0.000567453564144671, 0.0008242519106715918, 0.0006164037622511387, 0.0006619973573833704, 0.0007026430685073137, 0.000547056260984391, 0.0005540638812817633, 0.0006314544007182121, 0.0006124491919763386, 0.000548270414583385, 0.0005743157817050815, 0.0006138391909189522, 0.0006029888172633946, 0.0007067522965371609, 0.06545460224151611, 0.0005241032922640443, 0.0006839145207777619, 0.0005795081960968673, 0.0005754241719841957, 0.000550666474737227, 0.0006255604093894362, 0.0005717084277421236, 0.0005736051825806499, 0.0005822584498673677, 0.0007134946645237505, 0.0007318182033486664, 0.0006749578169547021, 0.0005961381830275059, 0.0007646672311238945, 0.0006712228059768677, 0.0006405016174539924, 0.0007150950841605663, 0.0006707307184115052, 0.0005914735374972224, 0.0006604235386475921, 0.0006786314188502729, 0.0008055998478084803, 0.0005530758644454181, 0.0005679254536516964, 0.0008007524884305894, 0.0006484248442575336, 0.0006337774684652686, 0.0006748163141310215, 0.0006018999265506864, 0.0007362243486568332, 0.0006262040114961565, 0.0006291838944889605, 0.0006546943914145231, 0.0006733127520419657, 0.0008904162677936256, 0.0007545692496933043, 0.0006269621080718935, 0.000659637269563973, 0.0008494795183651149, 0.0005450965836644173, 0.0006444341852329671, 0.0007415850413963199, 0.0006669022259302437, 0.0006336723454296589, 0.0006873039528727531, 0.0006405712338164449, 0.0006722445832565427, 0.0005719070904888213, 0.0006904963520355523, 0.0007579611265100539, 0.0006994608556851745, 0.0005435693892650306, 0.0005501533742062747, 0.0005581856239587069, 0.0006081616738811135, 0.0006367768510244787, 0.0006533194682560861, 0.0006998241879045963, 0.0007314284448511899, 0.0006274876068346202, 0.0005406087730079889, 0.0005421146634034812, 0.0006705137784592807, 0.000671273039188236, 0.00065734947565943, 0.0005716215819120407, 0.0005739209591411054, 0.0006801286363042891, 0.000629164045676589, 0.0006191738648340106, 0.0006516310968436301, 0.000669789791572839, 0.0005653990665450692, 0.0005692213890142739, 0.0005674565909430385, 0.0005591465160250664, 0.0005836057825945318, 0.0016059980262070894, 0.0005759811610914767, 0.0006136803422123194, 0.0005569314816966653, 0.0005708179087378085, 0.0005722555215470493, 0.0006138237076811492, 0.0005903651472181082, 0.0006090535316616297, 0.0006607213290408254, 0.0006612728466279805, 0.0006979596219025552, 0.0006558600580319762, 0.0007613435736857355, 0.0007949686259962618, 0.001994825666770339 ]	0.000816	550
[ "Do not forget to examine the genitals: a case of anal cancer and anogenital intraepithelial neoplasia in an immunocompetent man.", "\nA 46-year-old Caucasian heterosexual male was referred to a dedicated AIN clinic from colorectal multidisciplinary meeting (MDM) with AIN 3 following complete resection of anal squamous cell carcinoma (SCC). ", "On further questioning, he revealed that he also had a lesion on his penis. ", "Histology of the penile lesion demonstrated full thickness penile intraepithelial neoplasia (PIN 3). ", "This case illustrates the importance of thorough genital examination in patients found to have one genital pathology." ]	{ "pile_set_name": "PubMed Abstracts" }	[ 0.1042584702372551, 0.025544963777065277, 0.8978440165519714, 0.0012012040242552757, 0.0024417717941105366 ]	0.206258	5
[ "Why (and how) I went paperless\n\nLast year, I decided to go paperless with my administrative documents. ", "It was a long work. ", "But now I am finally done. ", "All my documents are available as electronic documents now. ", "I have been able to throw away five big document binders.", "\n\nI have used my phone as a scanner and uploaded all my documents to the cloud. ", "Now my documents are accessible from anywhere. ", "And they are safely stored in the cloud. ", "Find out how I became paperless for free in this post.", "\n\nWhy go paperless ?", "\n\nThere are several advantages to going paperless. ", "The first is to save space in your home. ", "For me, all my admin documents were stored in five big (and heavy) binders. ", "I have kept all my administrative documents since I was 16 years old. ", "I am a bit of a freak for keeping that many documents. ", "To be honest, I could have gotten rid of many of them. ", "However, I really like having them. ", "It is been very useful from time to time to find them. ", "Nevertheless, it takes some space. ", "Going paperless means getting rid of most of these documents. ", "I have kept some original documents, but that is a very small part of the original pile.", "\n\nOf course, this is a small thing in an entire home. ", "But I am starting to believe that minimalism is very interesting. ", "I am now trying to reduce the amount I am storing in my home. ", "Having less has several advantages. ", "It is easier to move. ", "And you need less space. ", "It sounds simple, but needing less space can lead to you needing one less room in a house. ", "And one less room can save you a lot of money over the years. ", "I am far from that since I am a bit of a hoarder, especially for books and technology. ", "But I am trying to improve that.", "\n\nThe second reason is to make it easier to search your documents. ", "Even well-organized binders are no match for a document search on your computer. ", "I can now find documents faster than before. ", "Moreover, I am also able to look at these documents from any device.", "\n\nIndeed, the third reason is to make your documents available from anywhere. ", "I decided to store my documents into a cloud service (Google Drive). ", "That means I can access my documents anywhere I have an internet connection. ", "This is better than carrying five heavy binders.", "\n\nFinally, if you store them correctly, your documents will be much safer. ", "Paper documents are fragile. ", "If you drop water (or coffee…) on them, they will suffer. ", "And they can burn easily (let’s hope it never happens to any of us). ", "If you store them on the cloud or on your computer with adequate backup, you should never be able to lose your documents. ", "Since some of these documents can be very important, it is also important to preserve them as best possible.", "\n\nHow to go paperless?", "\n\nNow, let’s see how to go paperless. ", "The most difficult part is to convert all your existing documents into electronic documents. ", "Once your existing documents are converted, it just takes a little time to convert the new documents once you receive them.", "\n\nFirst, you have to decide where to store them. ", "There are many options:\n\nOn your computer. ", "Simply save the files on your computer. ", "Do not forget to backup them in a secondary location. ", "This is easy, however, you will not have access to your files everywhere.", "\n\nOn a USB key. ", "Simply save all the files in a USB stick (or USB hard drive). ", "You should make a second copy of the disk ideally. ", "Or backup in a secondary location.", "\n\nOn the cloud. ", "Send all your files to one cloud provider. ", "It is a bit less easy than to store them on your computer. ", "However, you almost do not have to care about backups. ", "It has the immense advantage that you should be able to get access to them from anywhere.", "\n\nI decided to save them on the cloud for a few different reasons. ", "First, I will not have any problem with backup. ", "Then, I will not lose my document. ", "I think it is really the way to go today. ", "Finally, I decided to use Google Drive. ", "I was already using it for many things and to store a few documents. ", "It was a good fit for me. ", "And they offer 15 Go of free storage (shared with your mail and photos). ", "This will be more than enough for all my documents.", "\n\nI am not a fan of Dropbox since I had issues with it in the past. ", "But it is a strong choice as well. ", "And it is easier to rely on one single provider than several. ", "There are tons of choice. ", "If you already use Google Drive or Dropbox, simply use them. ", "Ideally, find something that is free. ", "Let’s stay frugal!", "\n\nNow, if you are privacy-paranoid, you can still use your own cloud. ", "Use something like Nextcloud, hosted in your home or in a VPS and you will be able to get access to your documents from anywhere. ", "Do not forget to back up your cloud though! ", "That is what I did before. ", "However, it takes time to maintain. ", "And after a while, I realized I wanted to save that time for other things.", "\n\nOnce you choose where you are going to store all these documents, you need to find out to do it. ", "There are three main choices:\n\nUse a professional document scanner. ", "If you are lucky, you can use one that is available at your work.", "\n\nUse a personal document scanner\n\nUse your phone\n\nIf you have access to a professional document scanner, use it! ", "You can scan your documents by batch and you can simply receive the result by mail or on file or maybe even on the cloud.", "\n\nNow, if you do not have a professional document scanner, you are left with two options. ", "A normal scanner or your phone. ", "Both will need a lot of time since you need to scan each page individually. ", "If you have a good scanner already at home, you should probably use it. ", "You are probably already able to use it, so you should have no issue scanning all documents and saving them where you decided.", "\n\nFinally, if like me you do not have a scanner available (or do not want to use it), you can also use your smartphone. ", "You may think it is crazy to scan with a phone. ", "But recent phones have great cameras. ", "If you have a very old phone, it may not be great though. ", "And there are many mobile applications that can scan a document with great quality. ", "Or, you can buy a scanner. ", "But I would recommend using a phone, so you can do it for free!", "\n\nHow to scan documents with a smartphone\n\nI have looked at many applications. ", "Unfortunately, most of them are bad or even really bad. ", "Or not free. ", "I am using Google Drive to store the documents. ", "So, my first choice was to use the Google Drive application to scan them, but the quality is simply horrendous. ", "It is useless. ", "Maybe it is because of my phone. ", "I do not know. ", "Some people have reported that they have good results with Google Drive applications. ", "But the documents are not readable when I use the Google Drive application. ", "Fortunately, I found CamScanner. ", "This simple application is really great for scanning documents. ", "And it can upload the documents to Google Drive directly. ", "It is available for Android, iPhone, iPad and Windows Phone.", "\n\nThe application is able to automatically detect the page. ", "Then, it will remove the skewing of the page. ", "It will only keep the relevant part. ", "And the image will be enhanced for better text quality. ", "You should scan your document on a well-lit surface with a single color. ", "You can then upload it to the cloud or send it by mail. ", "There are many features. ", "If you follow the same process as me, you will not need any premium feature. ", "So this will be totally free!", "\n\nScan a document with CamScanner\n\nOnce you are in the application, you can scan a new document with the camera icon on the bottom right. ", "Then, you will take a picture of your document:\n\nScan a document with CamScanner\n\nOnce you have a good quality, you can take the picture. ", "CamScanner will then detect the contour of the document:\n\nUnwrap a document with CamScanner\n\nMore than 90% of the time, the contour will be correctly detected. ", "For some complex documents with color, it may not work. ", "In these cases, you can move the contour yourself. ", "Once you are satisfied with the contour, validate it. ", "CamScanner will then process your document.", "\n\nCamScanner final result for scanned document\n\nAs you can see, from a warped document, the final document was put back straight. ", "The text is enhanced to look better. ", "You can also play with several options. ", "However, I have scan more than a thousand documents and never have I needed the other options. ", "The Auto option is just great.", "\n\nYou can also create an account and store your documents on their own cloud. ", "You just need a premium account if you want to store a lot of documents. ", "However, I did not want to use yet another cloud provider. ", "I have not used any premium features of the app. ", "But the application being so great, I have no doubt they have many great features.", "\n\nNormally, I do not scan one document at a time. ", "Let’s follow industrialization techniques (thank you Henry Ford!). ", "I do a big pile of documents together. ", "Here is my process using CamScanner for a set of documents:\n\nOn CamScanner\n\nScan every document, one after another\n\nSelect all documents\n\nUpload all documents to Google Drive\n\nDelete all documents when the upload is finished\n\nOn Google Drive\n\nMove documents to the correct folder\n\nRename all the documents\n\nThis is the process I have found out to be the fastest. ", "With this, I do not have to rename the files on my phone which is great since my fingers do not seem to be able to work on a phone :s\n\nTo not get burned out, I recommend doing long scanning sessions. ", "Personally, I did many 45 minutes sessions. ", "I was doing the scanning in front of TV shows. ", "This is quite long. ", "But still not so much a pain as I imagined.", "\n\nNow, when I receive new documents, I store them until I have around 20 and then process them all. ", "You could, of course, scan them as you receive them. ", "It really depends on your way of working.", "\n\nWhich documents to keep?", "\n\nIn the end, I still kept a few documents. ", "You may say I am not paperless. ", "Since I got rid of about 99% of my documents, I think I still deserve the paperless title. ", "If you do not think so, you can call me paperlite! ", "It is a very small set that does not take a lot of room. ", "I do not even need a binder for it.", "\n\nHere is a few things I decided to keep:\n\nMy work contract\n\nMy apartment lease\n\nA few insurance contracts\n\nAll my diplomas\n\nA few certifications\n\nA few various contracts\n\nOverall, it is really not a lot. ", "It will depend on you and how much you think you may need the original. ", "Maybe you will not need to save any of them.", "\n\nOf course, even if you save the original document, do not forget to scan it too. ", "This way you have a copy and you can easily access too.", "\n\nConclusion\n\nThere you have it! ", "I am now paperless and I advice you to do the same before you accumulate too many documents. ", "Using CamScanner on your phone and storing your documents on the cloud is very practical. ", "It is easy to do and has many advantages. ", "If you want to save some room in your home, it is a good starting way.", "\n\n2 thoughts on “Why (and how) I went paperless”\n\nI love being paperless (or more technically, ‘paper-lite’ – like you I still keep a few hard copies of important documents). ", "The biggest benefit for me is the psychological freedom it brings – it’s similar to keeping my email inbox as empty as possible. ", "I feel like I can’t breathe sometimes when I see huge piles of paper lying around!", "\n\nThat CamScanner app looks amazing – I used something similar not long ago for all my business cards, blew my mind with its ability to recognise words and numbers!", "\n\nYeah, I do the same with my emails, but only recently did I start for my paper mails.", "\n\nIt’s really impressive how the applications are going better at this. ", "I was really impressed by CamScanner and there may be a lot of other applications doing good job at it. ", "I never though of using such an application for business cards, but I don’t have a lot of them anyway.", "\n\nPost navigation\n\nDisclaimer: I’m not a finance advisor. ", "What I’m relating on this blog is only for entertainment purposes only and only relates my own experience. ", "I’m not responsible neither liable for any money loss or suffering you would face after reading this blog.", "\n\nAffiliate Links: I may receive a referral fee if you sign up with a service through the links on this page.", "\n\nCopyright: The Poor Swiss 2018\n\nPrivacy & Cookies: This site uses cookies. ", "By continuing to use this website, you agree to their use. ", "To find out more, including how to control cookies, see here: Cookie Policy\n\nRecent Posts\n\nSubscribe via Email\n\nEnter your email address to subscribe to this blog and receive notifications of new posts by email.", "\n\nJoin 398 other subscribers\n\nEmail Address\n\nDisclosure\n\nAll information provided on this site is for informational purposes only and does not constitute professional financial advice. ", "You should talk to a professional financial planner if you need help with your finance. ", "We may receive a referral fee if you sign up through the referral links on The Poor Swiss." ]	{ "pile_set_name": "Pile-CC" }	[ 0.0007475391030311584, 0.0007730393554084003, 0.00087266560876742, 0.0006026854389347136, 0.0007607833249494433, 0.0006754345959052444, 0.0006469066720455885, 0.0006640031933784485, 0.0009063035831786692, 0.0018388498574495316, 0.0007622550474479795, 0.0013921870850026608, 0.0009070228552445769, 0.0008735852898098528, 0.03864285722374916, 0.0007710311911068857, 0.0006255985936149955, 0.0005634698900394142, 0.0006027624476701021, 0.0009201268549077213, 0.0006019457941874862, 0.0007218168466351926, 0.0006668891292065382, 0.0007251010392792523, 0.0007570349844172597, 0.000642091385088861, 0.0014035565545782447, 0.0007243495783768594, 0.0011160933645442128, 0.0014843640383332968, 0.0006073736003600061, 0.0006252251332625747, 0.0010503092780709267, 0.0006040590233169496, 0.0005285962834022939, 0.0006686988053843379, 0.0005970044294372201, 0.000690950604621321, 0.0012401610147207975, 0.0005532889044843614, 0.0006386799504980445, 0.4409428536891937, 0.1655130684375763, 0.0014951868215575814, 0.0005152313387952745, 0.0025292651262134314, 0.0014816568000242114, 0.000871502619702369, 0.000594855984672904, 0.0007478080806322396, 0.0006911837845109403, 0.0016785963671281934, 0.0013567641144618392, 0.0006956145516596735, 0.0007191991317085922, 0.0012767183361575007, 0.0005965880118310452, 0.0007559093064628541, 0.000843047455418855, 0.000940344703849405, 0.0006954610580578446, 0.008097156882286072, 0.0006858530105091631, 0.0006732389447279274, 0.0013744510943070054, 0.0011027887230738997, 0.0006162675563246012, 0.0006479995208792388, 0.0005507656605914235, 0.0007481683860532939, 0.0005784100503660738, 0.0007045751553960145, 0.0010801746975630522, 0.0005580659490078688, 0.0006492676911875606, 0.0006502498872578144, 0.0006932567921467125, 0.0006890420336276293, 0.017192719504237175, 0.07113799452781677, 0.0006981754559092224, 0.003199820639565587, 0.0008359636412933469, 0.0005976303946226835, 0.0006671230657957494, 0.0006416955147869885, 0.0006354361539706588, 0.0005346174002625048, 0.0013924416853114963, 0.0005798200145363808, 0.0006291895406320691, 0.00142201769631356, 0.0005506286979652941, 0.0006295518251135945, 0.0005972630460746586, 0.0019151086453348398, 0.0012162524508312345, 0.0005917949019931257, 0.0014545876765623689, 0.0005481836851686239, 0.0010476469760760665, 0.000618317280896008, 0.0005421051755547523, 0.0018499204888939857, 0.0008438214426860213, 0.0005964669398963451, 0.0006390595226548612, 0.049126677215099335, 0.0011932782363146544, 0.0009104094351641834, 0.0005661948234774172, 0.0005774243036285043, 0.000745468947570771, 0.000538884021807462, 0.0006328530726023018, 0.0006121644400991499, 0.0005872772890143096, 0.000918405712582171, 0.000622594787273556, 0.0005423363763839006, 0.000608209753409028, 0.0006593675934709609, 0.0005995346582494676, 0.0005910660838708282, 0.0006968771922402084, 0.0006079243612475693, 0.0005497714737430215, 0.0006120212492533028, 0.0006009901408106089, 0.0005881441757082939, 0.0005651827668771148, 0.0005986553733237088, 0.0005507459864020348, 0.0005803834646940231, 0.0006636005127802491, 0.0005959296249784529, 0.0005907512386329472, 0.0006831835489720106, 0.0006039956933818758, 0.0006547091179527342, 0.0005880903918296099, 0.0005583582678809762, 0.000646861968562007, 0.0006739984382875264, 0.0006155006121844053, 0.0006368551985360682, 0.0006683821557089686, 0.0005971037317067385, 0.0008490522741340101, 0.0006244595861062407, 0.001296013011597097, 0.0005826634005643427, 0.0006099508027546108, 0.0006083979387767613, 0.0008021088433451951, 0.0005783444503322244, 0.0008081806008704007, 0.0018423014553263783, 0.000982386525720358, 0.0007722773007117212, 0.008212873712182045, 0.000580841617193073, 0.0005678439629264176, 0.0012566293589770794, 0.0007239393307827413, 0.0005916167283430696, 0.0009133461862802505, 0.0009008573251776397, 0.000642236671410501, 0.0005372418090701103, 0.001257007010281086, 0.019752182066440582, 0.0016841671895235777, 0.01274671871215105, 0.0011509626638144255, 0.0005822789389640093, 0.000535176252014935, 0.0005303919897414744, 0.0006077381549403071, 0.0007422407506965101, 0.0006132710841484368, 0.009408269077539444, 0.000531921221408993, 0.0006761720287613571, 0.0005330712883733213, 0.0005818625795654953, 0.0006034686230123043, 0.0005476752412505448, 0.0009830596391111612 ]	0.005207	189
[ "Q:\n\nshift to next text input field without closing keyboard in react-native\n\nI have 6 text input fields and when i click on any text input field, firstly the text input field closes and I have to again click on the same input field to open it again\nIs there a way to switch to next input field without using the returnKeyType=\"next\" so that when I just switch to any input field, the keyboard remains opened.", "\nhere is my text input field code:\n<View style={styles.inputContainer}>\n <TextInput\n ref='fname'\n autoCorrect={false}\n placeholder=\"First Name\"\n style={styles.textInput}\n placeholderTextColor='#848484'\n autoCapitalize='words'\n maxLength={20}\n onFocus={()=>context._handleScrollView(ReactNative.findNodeHandle(context.refs.fname))}\n onBlur={()=>context._resetScrollView(ReactNative.findNodeHandle(context.refs.fname))}\n onChangeText={(fname) => context.setState({fname: fname.capitalizeFirstLetter()})} />\n </View>\n\nWhat property or some method or function should i add to overcome this problem?", "\n\nA:\n\nYou are probably inside a scroll. ", "You need to add keyboardShouldPersistTaps to the ScrollView component: \n\nWhen false, tapping outside of the focused text input when the keyboard is up dismisses the keyboard. ", "When true, the keyboard will not dismiss automatically, and the scroll view will not catch taps, but children of the scroll view can catch taps. ", "The default value is false.", "\n\n<ScrollView\n keyboardShouldPersistTaps\n ...\n>\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.0006256712949834764, 0.0009312201873399317, 0.006310868076980114, 0.0007156012579798698, 0.000837910280097276, 0.000817200168967247, 0.0008820346556603909 ]	0.001589	7
[ "LS1034 is a colorectal carcinoma cell line isolated in 1989 from a primary tumor biopsy from a 54-year old Caucasian male patient diagnosed with Dukes' Type C, moderately to poorly differentiated cecal carcinoma.", "\n\nMore than 90% of LS1034 cells express surface CEA.The cells express the major histocompatibility (MHC) class I antigens and beta 2 microglobulin, but class II antigens, (HLA-DR, DQ, and DP) were not detected. ", "No measurable amount of latent transforming growth factor beta-1 (TGF beta-1) is secreted.", "\nPicomolar concentrations of TGF beta-1, TGF beta-2, and TGF beta-3 inhibit the proliferation of LS1034 cells. ", "LS1034 cells are multidrug resistant (MDR), and can proliferate in serum free medium.", "The patient did not exhibit familial adenomatous polyposis (FAP) and normal tissue did not have the deletion in the APC gene. ", "The colony forming efficiency was 3% in methylcellulose medium containing 5% fetal bovine serum, and the clonogenicity is increased 600% in serum free methylcellulose as compared to semisolid medium containing serum. ", "A culture submitted to the ATCC in September 1994 was found to be contaminated with mycoplasma, and was cured by a 21 day treatment with BM Cycline.", "\nFor more information, please contact Cobioer (4008-750-250)." ]	{ "pile_set_name": "Pile-CC" }	[ 0.0010399429593235254, 0.0007236037636175752, 0.0007018008036538959, 0.0006536977598443627, 0.0008031386532820761, 0.0013016917509958148, 0.0006279033259488642, 0.0008864850387908518, 0.0005427353898994625 ]	0.000809	9
[ "Q:\n\nDeserialize nested level XML\n\nI am trying to retrieve data from Zoho API and then I want to Deserialize a returned data in an object.", "\nThe XML structure:\n<response uri=\"/crm/private/xml/Potentials/getSearchRecords\">\n <result>\n <Potentials>\n <row no=\"1\">\n <FL val=\"POTENTIALID\">0000000000000</FL>\n <FL val=\"SMOWNERID\">000000000000</FL>\n .......\n </row>\n <row no=\"2\">\n .......\n </row>\n </Potentials>\n </result>\n</response>\n\nAnd here what I tried but didn't succeed.", "\n[Serializable()]\npublic class ZohoXML\n{\n public ZohoXML() { }\n\n [XmlElement(\"POTENTIALID\")]\n public string POTENTIALID { get; set; }\n ........\n}\n\n[XmlRoot(\"response\")]\npublic class Response\n{\n [XmlElement(\"result\")]\n public Result[] ResultList { get; set; }\n}\n\npublic class Result\n{\n [XmlArray(\"Potentials\"), XmlArrayItem(\"row\")]\n public Row[] RowList { get; set; }\n}\n\n[XmlRoot(\"row\")]\npublic class Row\n{\n [XmlArray(\"Potentials\")]\n [XmlArrayItem(\"row\", typeof(ZohoXML))]\n public ZohoXML[] ZohoXML { get; set; }\n}\n\nAnd this is how I deserialize:\nResponse ZohoXMLCollection = null;\n\nSystem.", "Xml.", "Serialization.", "XmlSerializer serializer = new System.", "Xml.", "Serialization.", "XmlSerializer(typeof(Response));\n\nStreamReader reader = new StreamReader(strFile);\nZohoXMLCollection = (Response)serializer.", "Deserialize(reader);\nreader.", "Close();\n\nCan anybody please help on identifying an issue in the code ?", "\n\nA:\n\nIf you are using a newer version of VS you can use Edit > Paste Special > Paste XML as Classes in the edit menu. ", "Assuming your XML structure is correct this will give you:\n/// <remarks/>\n[System.", "Xml.", "Serialization.", "XmlTypeAttribute(AnonymousType = true)]\n[System.", "Xml.", "Serialization.", "XmlRootAttribute(Namespace = \"\", IsNullable = false)]\npublic partial class response\n{\n\n private responseResult resultField;\n\n private string uriField;\n\n /// <remarks/>\n public responseResult result\n {\n get\n {\n return this.resultField;\n }\n set\n {\n this.resultField = value;\n }\n }\n\n /// <remarks/>\n [System.", "Xml.", "Serialization.", "XmlAttributeAttribute()]\n public string uri\n {\n get\n {\n return this.uriField;\n }\n set\n {\n this.uriField = value;\n }\n }\n}\n\n/// <remarks/>\n[System.", "Xml.", "Serialization.", "XmlTypeAttribute(AnonymousType = true)]\npublic partial class responseResult\n{\n\n private responseResultRow[] potentialsField;\n\n /// <remarks/>\n [System.", "Xml.", "Serialization.", "XmlArrayItemAttribute(\"row\", IsNullable = false)]\n public responseResultRow[] Potentials\n {\n get\n {\n return this.potentialsField;\n }\n set\n {\n this.potentialsField = value;\n }\n }\n}\n\n/// <remarks/>\n[System.", "Xml.", "Serialization.", "XmlTypeAttribute(AnonymousType = true)]\npublic partial class responseResultRow\n{\n\n private responseResultRowFL[] flField;\n\n private byte noField;\n\n /// <remarks/>\n [System.", "Xml.", "Serialization.", "XmlElementAttribute(\"FL\")]\n public responseResultRowFL[] FL\n {\n get\n {\n return this.flField;\n }\n set\n {\n this.flField = value;\n }\n }\n\n /// <remarks/>\n [System.", "Xml.", "Serialization.", "XmlAttributeAttribute()]\n public byte no\n {\n get\n {\n return this.noField;\n }\n set\n {\n this.noField = value;\n }\n }\n}\n\n/// <remarks/>\n[System.", "Xml.", "Serialization.", "XmlTypeAttribute(AnonymousType = true)]\npublic partial class responseResultRowFL\n{\n\n private string valField;\n\n private byte valueField;\n\n /// <remarks/>\n [System.", "Xml.", "Serialization.", "XmlAttributeAttribute()]\n public string val\n {\n get\n {\n return this.valField;\n }\n set\n {\n this.valField = value;\n }\n }\n\n /// <remarks/>\n [System.", "Xml.", "Serialization.", "XmlTextAttribute()]\n public byte Value\n {\n get\n {\n return this.valueField;\n }\n set\n {\n this.valueField = value;\n }\n }\n}\n\nYou will want to clean up the names but for now this is fine.", "\nThen your de-serialization will look like this:\nXmlSerializer serializer = new XmlSerializer(typeof(response));\nresponse res = new response();\nusing (StreamReader reader = new StreamReader(fileLocation))\n{\n res = serializer.", "Deserialize(reader) as response;\n}\n\nNote that StreamReader implements the IDisposable interface so should be used within a using block to ensure automatic disposable of resources.", "\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.0007115818443708122, 0.0008517907117493451, 0.001990618882700801, 0.0008509941399097443, 0.0008078999817371368, 0.0008170304354280233, 0.0008509941399097443, 0.0008078999817371368, 0.0008207642240449786, 0.0007319070282392204, 0.0005543638835661113, 0.000819078937638551, 0.0006479253643192351, 0.0008509941399097443, 0.0008078999817371368, 0.0006884059403091669, 0.0008509941399097443, 0.0008078999817371368, 0.0016680618282407522, 0.0008509941399097443, 0.0008078999817371368, 0.0015383068239316344, 0.0008509941399097443, 0.0008078999817371368, 0.0006923153414390981, 0.0008509941399097443, 0.0008078999817371368, 0.0008353509474545717, 0.0008509941399097443, 0.0008078999817371368, 0.0007892092107795179, 0.0008509941399097443, 0.0008078999817371368, 0.0011271798284724355, 0.0008509941399097443, 0.0008078999817371368, 0.0011755129089578986, 0.0008509941399097443, 0.0008078999817371368, 0.0007987471180967987, 0.0008509941399097443, 0.0008078999817371368, 0.001654139836318791, 0.0008509941399097443, 0.0008078999817371368, 0.0007904310477897525, 0.0009115422144532204, 0.0008445529965683818, 0.001994825666770339 ]	0.000919	49
[ "Q:\n\nVisualforce - array in jQuery throws error\n\nIn order to show a list of values fading continuously, I queried the values in the controller and trying to iterate in a component using array in jQuery. ", "But it throws an error \"Unknown property 'NewsController.i'\". ", "I'm able to complete it when I write separate div for each record, but I wanted to use arrays. ", "So would like to know where I messed up in the code. ", "Any help would be appreciated.", "\nController:\npublic class NewsController {\n public List<News__c> newsA {\n get {\n newsA = [SELECT Id, entered_Date_c, Content__c FROM News__c ORDER BY entered_Date_c ASC];\n return newsA ;\n }\n set;\n }\n}\n\nComponent:\n<apex:component id=\"newsId\" controller=\"NewsController\">\n<apex:includeScript value=\"{!URLFOR($Resource.jQuery)}\"/>\n<apex:attribute name=\"newsNow\" type=\"string\" required=\"true\" description=\"To show entered news\"/>\n<div style=\"float:left; background-color: lime;\" id=\"newsPanel\">\n <apex:repeat value=\"{!newsA}\" var=\"new\">\n <script>\n //Script Source: http://stackoverflow.com/\n //Modified a bit to match the needs\n var listTicker = function(options) {\n var defaults = {\n list: [],\n startIndex:0,\n interval: 3 * 1000,\n } \n var options = $.extend(defaults, options);\n var listTickerInner = function(index) {\n if (options.list.length == 0) return;\n if (!", "index \|\| index < 0 \|\| index > options.list.length) index = 0;\n var value= options.list[index];\n options.trickerPanel.fadeOut(function() {\n $(this).html(value).fadeIn();\n });\n var nextIndex = (index + 1) % options.list.length;\n setTimeout(function() {\n listTickerInner(nextIndex);\n }, options.interval);\n };\n listTickerInner(options.startIndex);\n }\n for(var i=0; i<new.length; ++i) {\n {!", "new[i]}\n }\n $(function() {\n listTicker({\n list: newsA,\n startIndex:0,\n trickerPanel: $('#newsPanel'),\n interval: 3 * 1000,\n });\n });\n </script>\n </apex:repeat>\n</div>\n</apex:component>\n\nPage:\n<apex:Page>\n <c:News newsNow=\"\" />\n</apex:Page>\n\nA:\n\nI think your are not fully aware of VFP coding and javascript. ", " \n Controller:\n public class NewsController {\n public List<News__c> newsA {\n get {\n newsA = [SELECT Id, entered_Date_c, Content__c FROM News__c ORDER BY entered_Date_c ASC];\n return newsA ;\n }\n set;\n }\n }\n\n Component:\n <apex:component id=\"newsId\" controller=\"NewsController\">\n <apex:includeScript value=\"{!URLFOR($Resource.jQuery)}\"/>\n <apex:attribute name=\"newsNow\" type=\"string\" required=\"true\" description=\"To show entered news\"/>\n <div style=\"float:left; background-color: lime;\" id=\"newsPanel\">\n <!-- ", "<apex:repeat value=\"{!newsA}\" var=\"new\">--> //Wrong way to itrating the list\n <apex:repeat var=\"new\" value=\"{!newsA}\">\n {!", "new}\n </apex:repeat>\n\n <script>\n //Script Source: http://stackoverflow.com/\n //Modified a bit to match the needs\n var listTicker = function(options) {\n var defaults = {\n list: [],\n startIndex:0,\n interval: 3 * 1000,\n } \n var options = $.extend(defaults, options);\n var listTickerInner = function(index) {\n if (options.list.length == 0) return;\n if (!", "index \|\| index < 0 \|\| index > options.list.length) index = 0;\n var value= options.list[index];\n options.trickerPanel.fadeOut(function() {\n $(this).html(value).fadeIn();\n });\n var nextIndex = (index + 1) % options.list.length;\n setTimeout(function() {\n listTickerInner(nextIndex);\n }, options.interval);\n };\n listTickerInner(options.startIndex);\n }\n\n /* for(var i=0; i<new.length; ++i) {\n {!", "new[i]} //Wrong coded.", "\n }\n /\n\n $(function() {\n listTicker({\n list: newsA,\n startIndex:0,\n trickerPanel: $('#newsPanel'),\n interval: 3 1000,\n });\n });\n </script>\n <!-- ", "</apex:repeat> -->\n </div>\n </apex:component>\n\n Page:\n <apex:Page>\n <c:News newsNow=\"\" />\n </apex:Page>\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.0006777304224669933, 0.0008939305553212762, 0.0005322288488969207, 0.0009860350983217359, 0.0005355002358555794, 0.0007739415159448981, 0.0011652839602902532, 0.0006900654989294708, 0.0006691536400467157, 0.0008890192839317024, 0.0010531352600082755, 0.0011178187560290098, 0.0007445438532158732, 0.0009773550555109978, 0.0007306934567168355 ]	0.000829	15
[ "FORT WORTH, Texas — Dan Jenkins, the sports writing great and best-selling author in a career that went from Ben Hogan to Tiger Woods and the manual typewriter to Twitter, has died. ", "He was 90.", "\n\nTCU athletic director Jeremiah Donati confirmed Jenkins died Thursday in his hometown of Fort Worth.", "\n\nJenkins started his writing career at The Fort Worth Press and rose to stardom at Sports Illustrated. ", "He wrote best-sellers \"Semi-Tough\" ''Baja Oklahoma\" and \"Dead Solid Perfect\" and was a columnist for Playboy and Golf Digest.", "\n\nJenkins played golf at TCU for his beloved hometown Horned Frogs and was a close friend of Hogan, also a Fort Worth native. ", "A member of the World Golf Hall of Fame, Jenkins started covering the sport following Hogan and fellow Fort Worth star Byron Nelson.", "\n\n\"Being from Fort Worth, I would follow Ben Hogan and Byron Nelson anywhere,\" Jenkins said on a 2011 conference call to announce his Hall of Fame selection. \"", "Since they're in there, I'm happy to be the third guy from Fort Worth so included.\"", "\n\nFRANK DEFORD, LONGTIME SPORTS COMMENTATOR, DEAD AT 78\n\nJenkins covered his first major at the 1951 U.S. Open. ", "Hogan shot 67 in the final round to win at Oakland Hills, and Jenkins still says that round on that \"monster\" of a golf course remains as good as he has seen anyone play.", "\n\n\"Oakland Hills looked more like a penitentiary than a golf course,\" Jenkins said.", "\n\nHe listed that among his top three moments in golf, along with Jack Nicklaus winning his sixth Masters at age 46 and the 1960 U.S. Open, regarded by many as being one of the greatest days in the history of the championship. ", "Arnold Palmer shot 65 in the final round to beat Hogan, the aging star, and Nicklaus, the emerging star who was still an amateur that day at Cherry Hills.", "\n\n\"I'd never experienced — even as an old, cynical writer — as much excitement as all of us felt that afternoon following that action,\" Jenkins said. \"", "There have been so many great moments in golf that you even forget some of them. ", "But that one still stands out. ... ", "There have been so many great tournaments that I've been privileged to see, and people paid me to go watch, that I'm awfully grateful for it.", "\n\n\"And I'm so happy that I chose the profession I did.\"", "\n\nLONGTIME MIAMI HERALD SPORTS COLUMNIST EDWIN POPE DIES AT 88\n\nHis writing style was grounded in humor, and he often mocked the players he felt unworthy to win a major — starting with Jack Fleck, who took down his beloved Hogan in a playoff at Olympic Club for the 1955 U.S. Open, which remains one of the game's biggest upsets.", "\n\nThrough all of his writings, though, Jenkins said he never tried to sell out accuracy for a good joke.", "\n\n\"Even though I was making a stab at humor, I don't think I ever wrote a line I didn't believe,\" Jenkins said. \"", "I tried not to draw too much blood. ", "I tried to rave about all the heroes of the game, and they deserved it. ... ", "When something great happens — like when an Arnold Palmer or Jack Nicklaus or Tiger Woods or Ben Hogan happens — you don't have to be funny, you just have to be accurate.", "\n\n\"When you have to be funny is when you're on deadline and somebody like Jack Fleck creeps up on you,\" he said. \"", "That's when you have to tap dance, because it doesn't make any sense. ", "We have more and more of that these days, don't we?\"", "\n\nCLICK HERE TO GET THE FOX NEWS APP\n\nJenkins also is member of the Texas Golf Hall of Fame and the National Sportscasters and Sports Writers Hall of Fame.", "\n\nWhen then-PGA Tour Commissioner Tim Finchem listed all of Jenkins' achievements, including his numerous writing awards, Jenkins replied: \"You left out my cure for polio.\"", "\n\nJenkins is survived by wife June, sons Danny and Marty and daughter Sally, a columnist for The Washington Post." ]	{ "pile_set_name": "OpenWebText2" }	[ 0.0008743952494114637, 0.002947867615148425, 0.0007026965613476932, 0.000774327025283128, 0.0007212606142275035, 0.0008585143950767815, 0.0007244293810799718, 0.0005660529132001102, 0.0005589688080362976, 0.0007083241362124681, 0.0010308920172974467, 0.0007132411119528115, 0.00073155079735443, 0.0011592567898333073, 0.0006579495966434479, 0.000653201132081449, 0.0007557868375442922, 0.0005379689391702414, 0.0005639757146127522, 0.0008438628283329308, 0.0007177471998147666, 0.0007619292591698468, 0.21842646598815918, 0.0006686943816021085, 0.0008079704130068421, 0.013822469860315323, 0.0017578712431713939, 0.0006526656216010451, 0.000667756306938827, 0.0011855056509375572, 0.0010575770866125822 ]	0.00831	31
[ "{\n \"ramlVersion\": \"RAML10\",\n \"type\": \"Api\",\n \"specification\": {\n \"title\": \"raml-service\",\n \"mediaType\": \"application/json\",\n \"resources\": [\n {\n \"methods\": [\n {\n \"responses\": {\n \"200\": {\n \"code\": \"200\",\n \"body\": {\n \"application/json\": {\n \"name\": \"application/json\",\n \"displayName\": \"application/json\",\n \"typePropertyKind\": \"TYPE_EXPRESSION\",\n \"type\": [\n \"any\"\n ],\n \"__METADATA__\": {\n \"primitiveValuesMeta\": {\n \"displayName\": {\n \"calculated\": true\n },\n \"type\": {\n \"insertedAsDefault\": true\n }\n }\n },\n \"sourceMap\": {\n \"path\": \"api.raml\"\n }\n },\n \"description\": {\n \"name\": \"description\",\n \"displayName\": \"description\",\n \"typePropertyKind\": \"TYPE_EXPRESSION\",\n \"type\": [\n \"Parsed RAML\"\n ],\n \"__METADATA__\": {\n \"primitiveValuesMeta\": {\n \"displayName\": {\n \"calculated\": true\n }\n }\n },\n \"sourceMap\": {\n \"path\": \"api.raml\"\n }\n }\n },\n \"sourceMap\": {\n \"path\": \"api.raml\"\n }\n }\n },\n \"body\": {\n \"application/json\": {\n \"name\": \"application/json\",\n \"displayName\": \"application/json\",\n \"typePropertyKind\": \"TYPE_EXPRESSION\",\n \"type\": [\n \"any\"\n ],\n \"__METADATA__\": {\n \"primitiveValuesMeta\": {\n \"displayName\": {\n \"calculated\": true\n },\n \"type\": {\n \"insertedAsDefault\": true\n }\n }\n },\n \"sourceMap\": {\n \"path\": \"api.raml\"\n }\n }\n },\n \"description\": \"Parse the given RAML files\",\n \"method\": \"post\",\n \"sourceMap\": {\n \"path\": \"api.raml\"\n }\n }\n ],\n \"relativeUri\": \"/parseFiles\",\n \"displayName\": \"/parseFiles\",\n \"__METADATA__\": {\n \"primitiveValuesMeta\": {\n \"displayName\": {\n \"calculated\": true\n }\n }\n },\n \"sourceMap\": {\n \"path\": \"api.raml\"\n },\n \"relativeUriPathSegments\": [\n \"parseFiles\"\n ],\n \"absoluteUri\": \"/parseFiles\"\n }\n ],\n \"sourceMap\": {\n \"path\": \"api.raml\"\n }\n },\n \"errors\": [\n {\n \"code\": \"MEDIATYPE_EXCEPTION\",\n \"message\": \"invalid media type\",\n \"path\": \"api.raml\",\n \"range\": {\n \"start\": {\n \"line\": 14,\n \"column\": 10,\n \"position\": 238\n },\n \"end\": {\n \"line\": 14,\n \"column\": 21,\n \"position\": 249\n }\n }\n },\n {\n \"code\": \"INHERITING_UNKNOWN_TYPE\",\n \"message\": \"Inheriting from unknown type\",\n \"path\": \"api.raml\",\n \"range\": {\n \"start\": {\n \"line\": 14,\n \"column\": 10,\n \"position\": 238\n },\n \"end\": {\n \"line\": 14,\n \"column\": 21,\n \"position\": 249\n }\n }\n }\n ]\n}" ]	{ "pile_set_name": "Github" }	[ 0.0007949231076054275 ]	0.000795	1
[ "Wyoming might consider Native American tribes’ request that grizzly bears in the Yellowstone ecosystem be transplanted to reservations rather than hunted, a top official said last week.", "\n\nEven though it has adopted framework regulations for grizzly hunting, Wyoming Game and Fish won’t dismiss the transplant idea, Wyoming’s Chief Game Warden Brian Nesvik said. ", "His remarks followed a call by a tribal coalition that grizzlies be transplanted instead of hunted if managers seek to reduce their numbers in the ecosystem.", "\n\n“Instead of trophy hunting the grizzly, Tribal Nations wish to see grizzlies transplanted from the GYE to sovereign tribal lands in the grizzly’s historic range where biologically suitable habitat exists,” coalition co-founder R. Bear Stands Last wrote Game and Fish director Scott Talbott on June 29. “", "The same quota of grizzlies that would be hunted per season could easily be trapped and relocated, removing any possible rationalization for re-instituting trophy hunts.”", "\n\nGOAL Tribal Coalition (Guardians of our Ancestors’ Legacy) involves almost 50 tribal nations and considers the grizzly a sacred animal. ", "Despite adoption of “Chapter 67 Grizzly Bear Regulations” on July 8, Wyoming hasn’t decided whether to hunt grizzly bear once the federal government removes Endangered Species Act protection as planned. ", "The Game and Fish commission unanimously adopted the Chapter 67 hunting framework because Fish and Wildlife requires them to have a management plan and rules before it would delist the Yellowstone population. ", "The regulations spell out bedrock population numbers, hunters’ reporting requirements and a prohibition against killing mothers with offspring nearby.", "\n\nAs for transplants, “We haven’t given that a lot of consideration,” Nesvik said last week. “", "I wouldn’t say it’s something we wouldn’t consider.”", "\n\nTo be clear, the tribal coalition doesn’t want Wyoming to manage the Yellowstone-area grizzly at all. ", "It believes the federal government should keep the estimated 717 Yellowstone-area grizzlies under federal control.", "\n\nBut federal officials plan to delist the bear and let Wyoming, Idaho and Montana manage the species under certain parameters they say will allow grizzlies to persist. ", "Hunting could be allowed.", "\n\nWhich forces Nesvik and other state officials to answer questions they haven’t yet come to grips with. “", "Our charge is to address the [grizzly bears’] health and long-term viability,” Nesvik said last week. ", "Beyond that, numerous decisions hang in the balance — including whether the Game and Fish Commission would even consider a hunting season.", "\n\nWyoming’s positions contradictory?", "\n\nAs Wyoming, Idaho, Montana and the federal government work toward delisting, Wyoming has adopted positions that appear contrary to conservation of Yellowstone-area grizzlies. ", "The state, for example, opposes federal delisting language that supports connectivity between Yellowstone and other ecosystems. ", "Connecting isolated populations is a key conservation concept.", "\n\nConnectivity with other ecosystems north and west of Yellowstone is “not a requirement,” that ensures the health of the population, Nesvik said. ", "Federal officials have said the genetic health of Yellowstone’s isolated population is sound. ", "Therefore, proposed federal language in delisting strategies that would promote connectivity is out of place, Nesvik said.", "\n\nThat doesn’t mean Wyoming would keep grizzlies from migrating one way or the other, Nesvik said. “", "From our perspective, connectivity is certainly not a bad thing for the Yellowstone ecosystem,” he said. “", "I don’t think there’s a desire not to be connected.”", "\n\nWyoming officials regularly complain about and act against what they assert is federal “overreach,” and the connectivity issue is only one recent example. ", "Asked whether Wyoming is more interested in state rights and control than it is in preserving threatened wildlife, Nesvik answered with a flat “no.”", "\n\nDon’t miss another WyoFile grizzly report — sign up for the free newsletter\n\n“I think that, based on the existing law, based on the Endangered Species Act, both [states’ rights and conservation] can coexist,” he said. “", "We strongly believe that Wyoming can maintain its abilities under the law to manage a species that’s delisted without a bunch of prescriptions that are written into a delisting rule.”", "\n\nSo far, the U.S. Fish and Wildlife Service is requiring states to agree to population goals and sign on to formulas that dictate how many bears could be lost annually to “discretionary mortality,” including potential hunting. ", "States also have agreed to impose rules prohibiting the killing of grizzly mothers with cubs at their sides, should hunting be allowed. ", "Wyoming’s Chapter 67 framework regulations are designed to meet the federal requirements.", "\n\nThe federal government should delist the grizzly and feel assured Wyoming will conserve them, Nesvik said. ", "Over the last 40 years, “Wyoming has demonstrated that it is definitely committed to grizzly conservation in our state,” he said.", "\n\nGame and Fish commissioners have reacted when criticized for adopting the Chapter 67 hunting framework regulations even before they’ve decided whether they will consider a hunting season.", "\n\n“This isn’t about hunting grizzlies,” Game and Fish Commissioner David Rael told one critic at the commission meeting July 8 in Pinedale. “", "This is about delisting grizzlies.”", "\n\nNevertheless, the framework regulations include language about how soon a hunter must report a slain grizzly bear and how long he or she has to produce the hide and skull to a warden for inspection. ", "After adopting such language, Wyoming appears to be on the path to a hunting season, state critics say.", "\n\nFurthermore, Wyoming’s management plan for grizzlies doesn’t acknowledge the bears’ value to tourism, said Jim Laybourn, a wildlife guide, hunter and grizzly advocate. (", "He and two groups have sued Wyoming to prevent hunting.) “", "It makes no acknowledgement of the importance of grizzly bears to the tourism economy,” he told commissioners in Pinedale. ", "That includes famous grizzly bear mother 399, an international roadside attraction in Grand Teton National Park.", "\n\n“No one’s ever going to bring 399’s hide and skull to town,” Laybourn said. “", "We’re not going to allow it.” ", "If hunting is allowed “you are declaring war on the international brand of Jackson Hole conservation,” he told the commission.", "\n\nNo national park buffers — yet\n\nIn establishing Wyoming’s Chapter 67 framework for grizzly hunting, Game and Fish Commissioners did not consider, and the agency’s staff did not recommend, a hunting buffer zone around Yellowstone and Grand Teton national parks. ", "The National Park Service has requested that bears not be hunted on park borders, as has the Jackson Hole Chamber of Commerce. “", "Hunting should be avoided in areas adjacent to our National Parks and within the John D. Rockefeller Jr. Memorial Parkway,” chamber officials said in a letter.", "\n\nThose restrictions didn’t make it into the Chapter 67 framework regulations.", "\n\n“We don’t believe we need a buffer zone or to extend the boundaries of the national parks to ensure the conservation of grizzly bears,” Nesvik said. “", "Other species that are not listed go back and forth in the parks. ", "Black bears have no buffer and black bears are doing great in our state.”", "\n\nWhile Game and Fish is opposed to predetermined buffer zones, “we are interested in what the public has to say,” Nesvik said, and would consider boundary worries should Wyoming implement a grizzly hunting season.", "\n\nGOAL’s co-founder Bear Stands Last said Wyoming is exaggerating support for its position. ", "He criticized Game and Fish statements that Wyoming residents strongly support state management of grizzlies. ", "Instead, a poll the conducted for the agency in 2001 found an even split between those favoring delisting and those who believe the federal government should stay in charge of Yellowstone-area grizzly bears. ", "Game and Fish is guilty of perpetuating “blatant falsehoods and misinformation,” GOAL said in a letter criticizing Game and Fish’s framework rules.", "\n\nIn early June, U.S. Rep. Raul Grijalva (D-Arizona), the top Democratic member of the U.S. House Natural Resources Committee, wrote the U.S. Fish and Wildlife Service saying delisting plans are premature because states and the U.S. Forest Service haven’t yet adopted regulations to protect the species. “", "Rushing to finalize the rule without addressing these concerns will likely result in the Service losing yet another lawsuit – an outcome that no one wants,” Grijalva wrote.", "\n\nHe also sided with tribes. “", "Removing legal protections right now, without adequate safeguards to ensure continued recovery, is a recipe for disaster,” he said in a statement. “", "Americans everywhere have invested in bringing this iconic species back from the brink of extinction. ", "They deserve certainty that grizzlies will thrive under state management rather than be hunted down to the minimum number of bears allowed by law.”" ]	{ "pile_set_name": "OpenWebText2" }	[ 0.0005557725671678782, 0.0006422981969080865, 0.0007475789752788842, 0.0006883518653921783, 0.0010680126724764705, 0.0006237042252905667, 0.0010070359567180276, 0.0005946524906903505, 0.000922984560020268, 0.000590306066442281, 0.0007405101787298918, 0.0006299843080341816, 0.0012796925147995353, 0.0012519687879830599, 0.001022837357595563, 0.0006255923071876168, 0.0006281775422394276, 0.0006170395063236356, 0.0007268908666446805, 0.0011435099877417088, 0.0008551376522518694, 0.0005515016382560134, 0.0006385837332345545, 0.0005732187419198453, 0.0006398228579200804, 0.0009405597811564803, 0.0005669343518093228, 0.0008702197810634971, 0.0006515680579468608, 0.0006171133136376739, 0.000747875077649951, 0.0006527950172312558, 0.0006756512448191643, 0.0022468850947916508, 0.0006146883824840188, 0.0008390660514123738, 0.000571712851524353, 0.0005708758253604174, 0.0009327012812718749, 0.026891931891441345, 0.0007510937284678221, 0.0006161192432045937, 0.0007563570979982615, 0.0008868672885000706, 0.0005652872496284544, 0.0007007031235843897, 0.017909400165081024, 0.0014050946338102221, 0.004681866616010666, 0.0006830917554907501, 0.0007238769321702421, 0.0005706058000214398, 0.0006428604247048497, 0.000656980846542865, 0.0005848812288604677, 0.006601134780794382, 0.0005815692711621523, 0.0012089578667655587, 0.0007641663542017341, 0.0009129686513915658, 0.014000591821968555, 0.0006824807496741414, 0.0007843083003535867, 0.009099300019443035, 0.0007280417485162616, 0.0007152297184802592, 0.0008688398520462215 ]	0.001893	67
[ "Tiger Lily Live:\nThe Second Presidential Debate\n\nThe Second Presidential Debate\n\nSummary of Debate\n\nFacebook and Twitter\n\nSo far from this debate we have learned that lockerroom talk is the most important\nissue facing America. ", "We have also learned that the moderators are completely\nin Hillary's pocket. ", "You will notice that they only scolded the audience when\nthey cheered Trump for saying she should go to jail. ", "They allowed the audience\nto clap for things Hillary said, but not the reverse. ", "This was after saying\nthat people shouldn't make any sounds at the beginning of the debates. ", "Furthermore,\nTwitter and Facebook are now the gold standard of questions for presidential\ndebates. ", "Only in America folks." ]	{ "pile_set_name": "Pile-CC" }	[ 0.0005816682241857052, 0.0009122146875597537, 0.17662227153778076, 0.0005718498141504824, 0.0006032072706148028, 0.0006032446399331093, 0.0006467297789640725 ]	0.025792	7
[ "Oliver Cromwell: father of Irish republicanism?", "\n\nPublished in Confederate War and Cromwell\n\nOliver Cromwell’s government sponsored two congregations of Protestant Dissenters in Dublin between 1649 and 1660. ", "One of them met at Wood Street and the other at ‘Saint Nicholas-within-the-walls’, close to Christ Church Cathedral. ", "Both of these communities flourished from the mid-seventeenth century until well into the nineteenth. ", "For more than 140 years the ministers at these meeting-houses advocated notions of civil and religious liberty. ", "The radical religion and politics that they developed contributed to the foundation of the Society of United Irishmen in 1791, to the rebellion of 1798 and to its after-shock, Emmet’s rebellion of 1803.", "\n\nThe Wood Street congregation (which later relocated to Strand Street) was founded by Puritans who came to Dublin to escape persecution during the reign of Elizabeth I. Revd John Owen (1616–88), one of the most eminent Puritan theologians of his era, came to Ireland with Oliver Cromwell as his chaplain and preached at Wood Street in 1650. ", "He had previously preached at Westminster Abbey the day after the execution of Charles I, when he praised the regicides as ‘the Lord’s workmen’. ", "Another link to the Cromwell family who often preached in Wood Street was Revd Stephen Charnock, personal chaplain to Oliver Cromwell’s son Henry when he was military commander in Ireland in 1653." ]	{ "pile_set_name": "OpenWebText2" }	[ 0.001014710171148181, 0.0008642758475616574, 0.0006740440730936825, 0.0005980537389405072, 0.0005710957339033484, 0.0008258097805082798, 0.0007881960482336581, 0.0007771823438815773, 0.0007060723728500307 ]	0.000758	9
[ "This invention relates to a spinning machine having spinning stations arranged on both sides of the machine for the spinning of yarns from slivers which are fed to the spinning stations in cans deposited above the spinning machine, guiding devices for the slivers being arranged between the cans and the spinning stations.", "\nThe feeding of the fiber material to be spun in the form of slivers disposed in cans is known, for example, in the case of open-end spinning machines. ", "In the case of the commercially available machines, the slivers are withdrawn directly by the sliver feeding device of the individual spinning stations from the cans standing in front of and partially below the spinning arrangement.", "\nIt is also known (German Patent Document DE-C 23 35 740), in the case of open-end spinning machines, to arrange the cans on a platform above the spinning machine and to feed the slivers through guiding tubes to the spinning stations. ", "These guiding tubes, which are equipped with baffles, are to be used as an intermediate storage device which, because of a special construction, is fed by a continuously running feeding device nevertheless intermittently. ", "The sliver should then be guided through the respective guiding tube essentially free of tensile stress.", "\nThe feeding of fiber material in the form of slivers made available in cans is also known in the case of other fast running spinning machines, for example, in the case of wind-around spinning machines or air spinning machines. ", "As a rule, these are one-sided machines, in which the slivers, which were withdrawn from the cans deposited on the rear of the spinning machine, are fed from above to the spinning stations. ", "In this case, guiding devices are provided in the form of rollers and guide rods for the slivers.", "\nIt is also known (German Patent Document DE-PS 817 572), in the case of ring spinning machines, to feed slivers in cans which are deposited on platforms or in a space above the spinning machine. ", "In this case, relatively long paths with one or several vertical runs are obtained which lead to the risk that the slivers may hang out; that is, are drafted uncontrollably because of their own weight. ", "Such an arrangement is therefore possible only for slivers which have a relatively coarse size and thus a relatively high stability.", "\nHowever, the spinning of slivers of relatively coarse sizes is very difficult on ring spinning machines. ", "Since the ring spinning machines have only a relatively low delivery speed at the outlet of the drafting units,--taking into account the required draft--the feeding rollers of the drafting units must run very slowly; that is, at rotational speeds of one revolution per minute and less. ", "It is technically very difficult to let long shafts, like the feeding rollers of drafting units, run at such low rotational speeds with sufficient precision. ", "There is the risk that these shafts will rotate only jerkily so that no controlled draft is obtained. ", "The feeding of the fiber material to be spun in cans has therefore not been carried out successfully in practice in the case of ring spinning machines.", "\nIn related U.S. copending applications Ser. ", "No. ", "809,141, filed Dec. 18, 1991 and Ser. ", "No. ", "948,638, filed Sep. 23, 1992 it is suggested to provide transport belts as guiding devices which interact with one skid respectively. ", "The skids extend in the area of the center plane of the spinning machine in the vertical direction and each have a curvature in the direction to the downward travelling runs of the transport belts. ", "The skids abut at their respective ends and are mutually supported there.", "\nIt is an object of the invention to develop a spinning machine of the initially mentioned type in such a manner that also fine slivers may be fed in cans without the risk of faulty drafts, particularly in vertical runs of the transport path.", "\nThis object is achieved in that the guiding devices, in the area of the center plane of the spinning machine, comprise skids which are arranged vertically and spaced from one another, are assigned to one side of the machine respectively and are pressed apart in the manner of a fishbelly or convex curved shaped by means of spreader devices, and in that a transport belt is assigned to each skid which is in close contact with the respective associated skid and transports one or several slivers.", "\nIn the case of the development according to the invention, it is achieved that the slivers are supported and are nevertheless moved in the transport direction. ", "As a result, it is possible to feed also relatively thin slivers in cans; that is, slivers of sizes of approximately Nm 0.4 to 0.8. ", "In this case, these fine slivers may also be transported in the vertical direction along larger runs. ", "It is therefore possible to carry out a can feeding also in the case of ring spinning machines because, on the basis of the slivers with the fine sizes, while taking into account the draft, the feeding roller pairs of the drafting units still run at a sufficiently high speed so that a uniform round rotating is ensured. ", "By means of this can feeding, it will then be possible, in the case of ring spinning machines, to do without a premounted machine, specifically the flyer. ", "In the case of other spinning machines, which are equipped with drafting units into which the slivers travel, it is possible to feed finer slivers so that then the drafting units may be simplified. ", "For example, in the case of machines of this type, there is the possibility to use, instead of five-cylinder drafting units, the three-cylinder drafting units which are customary today in the case of ring spinning machines.", "\nAlso in the case of open-end machines, the feeding of finer slivers results in advantages because then the opening-up work for the separating of the fibers is reduced so that, during the opening-up, the fibers are processed more carefully. ", "It is therefore possible to spin finer yarns with less damaged fibers so that the yarns have a higher quality.", "\nThe pressing-apart of the skids in the manner of a fishbelly caused by the spreader devices has the result that the transport belts establish a soft contact. ", "In this case, the spreader devices are arranged approximately in the center in the case of skids of a length of approximately two meters. ", "In the center of the skids, the bulging-out is the most pronounced; it is the least pronounced on the very top and on the very bottom. ", "The \"fishbelly\" is only very slight. ", "In the area of the deflection rollers of the transport belts, the skids must not be supported by spreader devices so that they can spring there freely and are sufficiently soft.", "\nOther objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings." ]	{ "pile_set_name": "USPTO Backgrounds" }	[ 0.000713653105776757, 0.0005867201252840459, 0.0006323863635770977, 0.0006502963369712234, 0.0007039935444481671, 0.000699641474056989, 0.0006452982779592276, 0.0007620331598445773, 0.0005918666138313711, 0.0006783445714972913, 0.0006855674437247217, 0.0006458575953729451, 0.0007428344688378274, 0.0006647224654443562, 0.0006489856168627739, 0.011864133179187775, 0.0006329950992949307, 0.0006617308245040476, 0.0013787426287308335, 0.0006961802137084305, 0.0013787426287308335, 0.0006648891139775515, 0.0007524448446929455, 0.0008659962913952768, 0.0008073366479948163, 0.0006355876103043556, 0.0005335814203135669, 0.0008456945070065558, 0.0006037922576069832, 0.0006451119552366436, 0.0006393806543201208, 0.0006458277348428965, 0.0005887069855816662, 0.0005856094066984951, 0.0007672309875488281, 0.0007315675029531121, 0.0006335537182167172, 0.0007703214650973678, 0.0008046558359637856, 0.000780730159021914, 0.0005275837611407042 ]	0.000988	41
[ "---\nabstract: 'Recent studies show that there is tension between the de Sitter swampland conjectures proposed by Obeid, [et al.]{} ", "and inflationary cosmology. ", "In this paper, we consider an alternative to inflation, “tachyacoustic” cosmology, in light of swampland conjectures. ", "In tachyacoustic models, primordial perturbations are generated by a period of superluminal sound speed instead of accelerating expansion. ", "We show that realizations of tachyacoustic Lagrangians can be consistent with the de Sitter swampland conjectures, and therefore can in principle be consistent with a UV-complete theory. ", "We derive a general condition for models with $c_S > 1$ to be consistent with swampland conjectures.'", "\nauthor:\n- 'Wei-Chen Lin'\n- 'William H. Kinney'\nbibliography:\n- 'paper.bib'\ntitle: Consistency of Tachyacoustic Cosmology with de Sitter Swampland Conjectures\n---\n\nI. Introduction \\[sec1\\]\n========================\n\nString theory is so far the most prominent candidate of an ultraviolet (UV) complete theory of fundamental interactions, including gravity, which can be used to describe the early universe. ", "However, it has recently been conjectured that the vast “landscape” of string vacua is surrounded by an even larger “swampland” of low-energy effective field theories (EFTs) which have no consistent UV completion [@Vafa:2005ui]. ", "A number of conjectures have been proposed describing properties of low-energy EFTs which can be used to distinguish those with a consistent UV completion from “swampland” theories with no such completion, with perhaps the best studied being the Weak Gravity Conjecture [@ArkaniHamed:2006dz]. ", "More recently, Refs. [", "@Obied:2018sgi; @Agrawal:2018own] have conjectured that theories containing de Sitter vacua are in the swampland, and propose “de Sitter swampland” conjectures which must be satisfied for any consistent EFT limit of quantum gravity. ", "The first conjecture is that there is an upper bound on the range transversed by scalar fields in field space $$\\label{1.1}\n\\frac{\|\\Delta\\phi\|}{M_P}\\lesssim\\Delta\\sim\\mathcal{O}(1),$$ where $ M_P=(8\\pi G)^{-1/2} $ is the reduced Planck mass. ", "The second conjecture [@Obied:2018sgi], states that for UV-complete EFTs, there is a lower bound on the logarithmic gradient of the scalar field potential $ V(\\phi) $ $$\\label{1.2}\nM_P\\frac{\|V'(\\phi)\|}{V}\\gtrsim c \\sim\\mathcal{O}(1).$$ The conjectures (\\[1.1\\],\\[1.2\\]) have been extensively studied in the context of inflationary cosmology [@Agrawal:2018own; @Kehagias:2018uem; @Matsui:2018bsy; @Achucarro:2018vey; @Kinney:2018nny; @Das:2018hqy; @Ashoorioon:2018sqb; @Brahma:2018hrd; @Lin:2018rnx; @Yi:2018dhl; @Motaharfar:2018zyb; @Dimopoulos:2018upl; @Chiang:2018lqx; @Lin:2018kjm; @Holman:2018inr; @Yi:2018dhl; @Kinney:2018kew]. ", "The general conclusion is that simple single-field inflation models are in strong tension with the swampland conjectures, while models beyond a single scalar field can in principle be consistent, for example Warm Inflation [@Berera:1995ie; @Das:2018hqy; @Das:2018rpg; @Motaharfar:2018zyb], or inflation involving generation of perturbations by an additional field [@Achucarro:2018vey]. ", "Here, we offer a different point of view by asking if there are viable theories of the early Universe other than inflationary cosmology which are consistent with the swampland conjectures (\\[1.1\\]) and (\\[1.2\\]). ", "Refs. [", "@Geshnizjani:2011dk; @Geshnizjani:2011rm; @Geshnizjani:2013lza; @Geshnizjani:2014bya] considered general conditions on cosmology for the generation of primordial perturbations consistent with observation, and found four general classes of models, assuming standard General Relativity:\n\n1. ", " [A period of accelerated expansion ([i.e.]{} inflation).]{}", "\n\n2. ", " [A speed of sound faster than the speed of light.]{}", "\n\n3. ", " [Violation of the Null Energy Condition.]{}", "\n\n4. ", " [Inherently quantum-gravitational physics.]{}", "\n\nIn this paper, we consider models of the second class, in particular “tachyacoustic” cosmology, a type of k-essence model proposed by Magueijo [@Magueijo:2008pm] and by Bessada et al. [", "@Bessada:2009ns]. ", "As an alternative to inflation, tachyacoustic cosmology solves the horizon problem and creates a nearly scale invariant power spectrum via a superluminal speed of sound, $ c_S >1 $. (", "Although this special type of model involves superluminal sound speed, it has been argued that such fields do not violate causality and are as consistent as models with subluminal speed of sound [@Babichev:2007dw].) ", "We show that some (but not all) tachyacoustic cosmological models are consistent with the de Sitter swampland conjectures. ", "In particular, we explain how the speed of sound plays the key role to determine whether or not a given model is consistent with swampland conjectures. ", "Furthermore, we show that if the potential of the scalar field satisfies a certain general form, the two swampland criteria set the same condition on the tachyacoustic cosmology, [i.e.]{} consistency with one of the swampland conjectures guarantees consistency with the other.", "\n\nThe rest of this paper is organized as follows. ", "In Sec. ", "II, we briefly review tachyacoustic cosmology. ", "Section III is the main body of this paper, in which we derive general constraints on tachyacoustic models, and compare with the de Sitter swampland conjectures. ", "In Sec. ", "IV, we use the exact solution of two models introduced in Ref. [", "@Bessada:2009ns] to show that these general arguments hold in specific realizations of tachyacoustic Lagrangians. ", "The conclusion is in Sec. ", "V.\n\nII. ", "tachyacoustic cosmology \\[sec:review\\]\n==========================================\n\nIn this section, we review the exact tachyacoustic solutions derived in Ref. [", "@Bessada:2009ns], based on the generalization of the inflationary flow formalism [@Kinney:2002qn] introduced by Bean et al. [", "@Bean:2008ga]. ", "The attractor behavior and non-Gaussianity of these solutions were studied in Refs. [", "@Bessada:2012zx] and [@Bessada:2012rf], respectively.", "\n\nConsider a general Lagrangian of a scalar field with the form $ \\mathcal{L}=\\mathcal{L}[X, \\phi] $, where $ X=\\frac{1}{2}g^{\\mu \\nu}\\partial_{\\mu}\\phi\\partial_{\\nu}\\phi $ is the canonical kinetic term. ", "Homogeneous modes of this scalar field form a perfect fluid with energy-momentum density $$\\label{2.1}\nT_{\\mu \\nu}=(p+\\rho)u_{\\mu}u_{\\nu}-pg_{\\mu\\nu},$$ where $$\\begin{aligned}\n\\label{2.2}\np(X,\\phi)&= \\mathcal{L}(X,\\phi),\n\\\\\n\\label{2.3}\n\\rho(X,\\phi)&= 2X\\mathcal{L}_X-\\mathcal{L}(X,\\phi),\n\\\\\n\\label{2.4}\nu_{\\mu}&= \\frac{\\partial_{\\mu}\\phi}{\\sqrt{2X}}.\\end{aligned}$$ Here, the subscript “X” indicates a derivative with respect to the canonical kinetic term, $ \\mathcal{L}_X \\equiv \\partial \\mathcal{L}/\\partial X $. ", "The sound speed is given by $$\\label{2.5}\nc^{2}_{S} \\equiv \\frac{p_X}{\\rho_X}=\\Bigg(1+2X\\frac{\\mathcal{L}_{XX}}{\\mathcal{L}_X}\\Bigg)^{-1},$$ so that the canonical limit $ \\mathcal{L}_{XX}=0 $ leads to $ c_{S}=1 $. ", "We take a metric of the flat Friedmann-Robertson-Walker (FRW) form, $$ds^2 = dt^2 - a^2\\left(t\\right) d {\\bf x}^2.$$ The Friedmann, Raychaudhuri, and continuity equation are $$\\begin{aligned}\n\\label{2.6}\nH^2&=\\frac{1}{3M_P^2}\\rho=\\frac{1}{3M_P^2}(2X\\mathcal{L}_X-\\mathcal{L}),\n\\\\\n\\label{2.7}\n\\frac{\\ddot{a}}{a}&=-\\frac{1}{6M_P^2}(\\rho+3p)= -\\frac{1}{3M_P^2}(X\\mathcal{L}_X +\\mathcal{L}),\n\\\\\n\\label{2.8}\n\\dot{\\rho}&=-3H(\\rho + p)=-6HX\\mathcal{L}_X,\\end{aligned}$$ where $ a(t) $ is the scale factor and $ H=\\dot{a}/a $ is the Hubble parameter, and the resulting equation of motion for the field $ \\phi $ is $$\\label{2.9}\n\\ddot{\\phi}+3H\\dot{\\phi}+\\frac{\\dot{\\phi}\\partial_{0}\\mathcal{L}_X}{\\mathcal{L}_X}-\\frac{\\mathcal{L}_{\\phi}}{\\mathcal{L}_{X}}=0.$$ For monotonic field evolution, one can instead use Hamilton Jacobi approach [@Muslimov:1990be; @Salopek:1990jq; @Lidsey:1995np; @Copeland:1993jj; @Bean:2008ga], in which the Hubble parameter $ H $ is treated as a fundamental quantity and all quantities are expressed as function of $ \\phi $. ", "In the homogeneous limit, $ \\dot{\\phi}=\\sqrt{2X}$, the same dynamics is given by the master equation $$\\label{2.10}\n\\dot{\\phi}=\\sqrt{2X}=-\\frac{2M_{P}^2}{\\mathcal{L}_{X}}H'(\\phi),$$ and the Hamilton Jacobi equation $$\\label{2.11}\n3M_{P}^2 H^2 (\\phi)=\\frac{4M_{P}^4 H'(\\phi)^2}{\\mathcal{L}_{X}}-\\mathcal{L},$$ where the prime denotes a derivative with respect to the field. ", "With the convention of the number of e-folds $ N $ defined as $$\\label{2.12}\na(t)\\propto exp \\Big[\\int_{t_{0}}^{t}Hdt\\Big] \\equiv e^{-N},$$ the differential $ dN $ can be re-written in terms of $ d\\phi $ by: $$\\label{2.13}\ndN=-Hdt=-\\frac{H}{\\sqrt{2X}}d\\phi=\\frac{\\mathcal{L}_{X}}{2M_{P}^2} \\bigg(\\frac{H(\\phi)}{H'(\\phi)}\\bigg)d\\phi.$$ Unlike the canonical case [@Kinney:2002qn], which only contains a single hierarchy of Hubble slow roll parameters and the corresponding flow equations, in the k-essence generalization, one has to introduce three hierarchies of flow parameters and flow equations, since not only the Hubble parameter $ H(\\phi) $ both the sound speed $ c_S $ and $ \\mathcal{L}_{X} $ can vary with time (for details, see Refs. [", "@Bean:2008ga; @Bessada:2009ns]). ", "The first parameters of these three sets of flow parameters are given by $$\\begin{aligned}\n\\label{2.14}\n\\epsilon(\\phi)\\equiv \\frac{1}{H}\\frac{dH}{dN}&=\\frac{2M_{P}^2}{\\mathcal{L}_{X}(\\phi)}\\bigg(\\frac{H'(\\phi)}{H(\\phi)}\\bigg)^2,\n\\\\\n\\label{2.15}\ns(\\phi)\\equiv -\\frac{1}{c_S}\\frac{dc_S}{dN}&=-\\frac{2M_{P}^2}{\\mathcal{L}_{X}(\\phi)}\\frac{H'(\\phi)}{H(\\phi)}\\frac{c'_S(\\phi)}{c_S(\\phi)},\n\\\\\n\\label{2.15.1}\n\\tilde{s}(\\phi)\\equiv \\frac{1}{\\mathcal{L}_{X}}\\frac{d\\mathcal{L}_{X}}{dN}&=\\frac{2M_{P}^2}{\\mathcal{L}_{X}(\\phi)}\\frac{H'(\\phi)}{H(\\phi)}\\frac{\\mathcal{L}_{X}'(\\phi)}{\\mathcal{L}_{X}(\\phi)}.\\end{aligned}$$ Refs. [", "@Kinney:2007ag; @Bessada:2009ns] derive a class of exact solutions to Eqs. (", "\\[2.14\\],\\[2.15\\],\\[2.15.1\\]) such that the flow parameters $\\epsilon$, $s$, and $\\tilde s$ are all held constant, and the hierarchies of flow equations are satisfied exactly to all order. ", "In this class, the quantities $ H, c_S $, and $ \\mathcal{L}_{X} $ can be solved exactly as $$\\begin{aligned}\n\\label{2.16}\nH & = H_0 e^{\\epsilon N},\n\\\\\nc_S & = e^{-s N},\n\\\\\n\\mathcal{L}_{X} &= Ae^{\\tilde{s} N},\n\\end{aligned}$$ in which the number of e-folds is chosen to be zero when the sound speed is equal to one, and $ H_0 \\equiv H(N=0) $ and $ A \\equiv \\mathcal{L}_{X}(N=0) $ are the corresponding values of the Hubble parameter and $ \\mathcal{L}_{X} $ respectively. ", "Substituting $ H(N) $ and $ \\mathcal{L}_{X}(N) $ from Eq. (", "\\[2.16\\]) into Eq. (", "\\[2.13\\]), one can solve for the evolution of field as a function of the number of e-folds $$\\label{2.21}\n\\frac{\\phi}{\\phi_0}=e^{-\\tilde{s}N/2},$$ where $\\phi_0$ is the field value when $c_S = 1$, and the coefficient $ A $ and $ \\phi_0 $ are related as $$\\label{2.21b}\nA=\\frac{8 M_P^2 \\epsilon}{\\tilde{s}^2\\phi_0^2}.$$ From Eqs. (", "\\[2.16\\], \\[2.21\\], \\[2.21b\\]), the quantities $ H$, $ c_S $ and $\\mathcal{L}_{X}$ in terms of $ \\phi$ are $$\\begin{aligned}\n\\label{2.17}\nH & = H_0\\bigg(\\frac{\\phi}{\\phi_0}\\bigg)^{-2\\epsilon/\\tilde{s}},\n\\\\\n\\label{2.18}\nc_S & = \\bigg(\\frac{\\phi}{\\phi_0}\\bigg)^{2s/\\tilde{s}},\n\\\\\n\\label{2.19}\n\\mathcal{L}_{X} & = \\frac{8\\epsilon}{\\tilde{s}^2}\\bigg(\\frac{M_P}{\\phi}\\bigg)^2.\\end{aligned}$$ From Eqs. (", "\\[2.16\\], \\[2.12\\]), one can show that the background evolution is a power law $$\\label{2.20}\na \\propto e^{-N} \\propto t^{1/\\epsilon},$$ so the comoving Hubble horizon is proportional to the conformal time $$\\label{2.22}\nd_H \\propto (aH)^{-1} \\propto e^{(1-\\epsilon)N} \\propto \\tau,$$ and the acoustic horizon evolves as $$\\label{2.23}\nD_H \\propto \\frac{c_S}{aH} \\propto e^{(1-\\epsilon-s)N} \\propto \\tau^{(1-\\epsilon-s)/(1-\\epsilon)}.$$ Note that the condition of a shrinking acoustic horizon is $ 1-\\epsilon -s >0 $, which is different from a shrinking Hubble horizon $ \\epsilon <1 $. ", "The curvature perturbation is generated at the acoustic horizon, which is larger than the Hubble horizon when $ c_S>1 $, and therefore the horizon problem can be solved in a non-inflationary expansion scenario. ", "From Eqs. (", "\\[2.5\\], \\[2.18\\],\\[2.19\\]), one can write the speed of sound $ c_S $ in terms of $ \\mathcal{L}_X $: $$\\label{2.24}\nc^{2}_{S}=\\Bigg(1+2X\\frac{\\mathcal{L}_{XX}}{\\mathcal{L}_X}\\Bigg)^{-1}=C^{-1}\\mathcal{L}_X^{-2s/\\tilde{s}},$$ where C is defined as $$\\label{2.25}\nC \\equiv \\Bigg(\\frac{\\tilde{s}^2\\phi_0^2}{8M_P^2\\epsilon}\\Bigg)^{2s/\\tilde{s}}= A^{-2s/\\tilde{s}}.$$ Note that the constant $ C $ is not a free parameter, but is fixed to be unity by the condition that the Lagrangian reduces to the canonical form $ \\mathcal{L}=X-V $ in the limit $ c_S \\rightarrow 1 $, as is evident from Eq. (", "\\[2.24\\]). ", "This condition sets the energy scale of $ \\phi_0 $ to be of order $ M_P $. ", "The right-hand side of Eq. (", "\\[2.24\\]) can be expressed as a differential equation of $ \\mathcal{L}(X, \\phi) $, $$\\label{2.26}\n2X\\mathcal{L}_{XX}+\\mathcal{L}_{X}-C\\mathcal{L}_{X}^n=0,$$ where n is defined as $$\\label{2.27}\nn \\equiv 1+\\frac{2s}{\\tilde{s}}.$$ Therefore, one can construct a Lagrangian based on a given relationship between the parameters $ s $ and $ \\tilde{s} $. ", "The tachyacoustic solutions investigated in [@Bessada:2009ns] are $ n=0 $ (a Cuscuton-like model), and $ n=3 $ (a Dirac-Born-Infeld (DBI)-like model). ", "Below, we summarize the results derived in Ref. [", "@Bessada:2009ns]: the reader is referred to this paper for details.", "\n\nThe case $ n=0 $ or equivalently $ \\tilde{s}=-2s $, has a Lagrangian of the form $$\\label{2.28}\n\\mathcal{L}(X, \\phi)=2f(\\phi)\\sqrt{X}+CX-V(\\phi),$$ where $$\\begin{aligned}\n\\label{2.29}\nf(\\phi)&=\\frac{\\sqrt{2}M_P^2H(\\phi)\\epsilon}{s\\phi_0 c_S(\\phi)}[c_S^2(\\phi)-1],\n\\\\\n\\label{2.30}\nV(\\phi)&=M_P^2H^2(\\phi)\\Big[3-\\frac{\\epsilon}{c_S^2(\\phi)}\\Big].\\end{aligned}$$ This has the form of a “Cuscuton” theory [@Afshordi:2006ad; @Afshordi:2007yx; @Boruah:2017tvg; @Boruah:2018pvq], with a kinetic term linear in the field velocity. ", "We keep the constant $ C $ as an parameter in Eq. (", "\\[2.28\\]) and implicitly in $ f(\\phi) $ (\\[2.29\\]) since this is the form used in Ref. [", "@Bessada:2009ns]. ", "In the later discussion we will set $ C=1 $. ", "The Hubble parameter and sound speed are given by: $$\\begin{aligned}\n\\label{2.31}\nH(\\phi)&=H_0\\Big(\\frac{\\phi}{\\phi_0}\\Big)^{\\epsilon/s},\n\\\\\n\\label{2.32}\nc_S(\\phi)&=\\Big(\\frac{\\phi_0}{\\phi}\\Big).\\end{aligned}$$ The Lagrangian of the DBI-like model, with $ \\tilde{s}=s $, or $ n=3 $ and $ C=1 $ is $$\\label{2.29c}\n\\mathcal{L}(X, \\phi)=-f^{-1}(\\phi)\\sqrt{1-2f(\\phi)X}+f^{-1}(\\phi)-V(\\phi),$$ with $$\\begin{aligned}\n\\label{2.33}\nf(\\phi)&=\\Big(\\frac{1}{2M_P^2\\epsilon}\\Big)\\frac{1-c_S^2(\\phi)}{H^2(\\phi)c_S(\\phi)},\n\\\\\n\\label{2.34}\nV(\\phi)&=3M_P^2H^2(\\phi)\\Big[1-\\Big(\\frac{2\\epsilon}{3}\\Big)\\frac{1}{1+c_S(\\phi)}\\Big].\\end{aligned}$$ The Hubble parameter and sound speed are given by: $$\\begin{aligned}\n\\label{2.31b}\nH(\\phi)&=H_0\\Big(\\frac{\\phi}{\\phi_0}\\Big)^{-2\\epsilon/s},\n\\\\\n\\label{2.32b}\nc_S(\\phi)&=\\Big(\\frac{\\phi}{\\phi_0}\\Big)^2.\\end{aligned}$$\n\nWithin the framework of constant flow parameters, the cosmological perturbation can be solved exactly at the linear level [@Bessada:2009ns]. ", "The scalar spectral index of perturbations for a tachyacoustic solution is given by $$\\label{3.01}\nn_s=1-\\frac{2\\epsilon+s}{1-\\epsilon-s},$$ which has a scale invariant limit, $ s=-2\\epsilon $. ", "Radiation-dominated tachyacoustic expansion, which we will take here as a fiducial model, has $ \\epsilon=2 $, with spectral index $$\\label{3.02}\nn_s=1+\\frac{4+s}{1+s}.$$\n\nIII. ", "tachyacoustic cosmology tested by swampland criteria \\[sec:main\\]\n======================================================================\n\nIn this section, we derive general scaling rules relating tachyacoustic Lagrangians with the de Sitter swampland conjecture (\\[1.1\\]). ", "We then derive a general relation between models which satisfy the condition (\\[1.1\\]) and the second de Sitter swampland conjecture (\\[1.2\\]) for the case of potentials having the leading order behavior of a power law in the sound speed, which is the case considered here.", "\n\nTo generate perturbations on a range of scales $k$ consistent with observation, we must have a sufficient number of e-folds of evolution, which from Eq. (", "\\[2.23\\]) results in a bound $\\Delta N \\gtrsim \\mathcal{O}(10)$. (Our results are not sensitive to the exact number of e-folds assumed.) ", "We can obtain a general relation between $\\Delta N$ and the field excursion $\\Delta \\phi$ using Eqs. (", "\\[2.13\\],\\[2.14\\]), $$\\label{3.a}\n\\Delta N \\sim\\pm \\sqrt{\\frac{\\mathcal{L}_X}{2\\epsilon}}\\frac{\\Delta \\phi}{M_P},$$ where the plus sign corresponds to $ \\dot{\\phi} <0 $ and the minus sign corresponds to $\\dot{\\phi} > 0$. For $ \\phi $ positive, the DBI-like model has $ \\dot{\\phi}<0 $ and the Cuscuton-like model has $ \\dot{\\phi}>0 $. ", "Substituting Eq. (", "\\[2.24\\]) with $ C=1 $ into Eq. (", "\\[3.a\\]), we can make $ c_S $ explicit in the relation between the field excursion and the number of e-folds as $$\\label{3.aa}\n\\frac{\\Delta \\phi}{M_P} \\sim \\pm \\sqrt{2\\epsilon} (c_S)^{1/\\beta} \\Delta N,$$ where $ \\beta \\equiv 2s/\\tilde{s} $, which for the Cuscuton-like model is $$\\label{3.b}\n\\frac{\\Delta \\phi}{M_P} \\sim -\\frac{\\sqrt{2\\epsilon}}{c_S}\\Delta N,$$ and for the DBI-like model is $$\\label{3.c}\n\\frac{\\Delta \\phi}{M_P} \\sim \\sqrt{2\\epsilon c_S}\\Delta N.$$ We immediately see that the Cuscuton-like model satisfies the criterion (\\[1.1\\]), since $\\Delta\\phi \\propto c_S^{-1} \\Delta N$ with $c_S \\gg 1$. By contrast, the DBI-like model has $\\Delta\\phi \\propto \\sqrt{c_S} \\Delta N$, which fails the criterion (\\[1.1\\]) in the limit $c_S \\gg 1$. [^1] Moreover, Eq. (", "\\[3.aa\\]) shows generally that the condition to pass the first swampland criterion (\\[1.1\\]) is $ \\beta=2s/\\tilde{s} <0 $.", "\n\nWe can relate this in a general way to the second criterion \\[1.2\\] as follows: If we consider the scale invariant limit in the case of a radiation-dominated background, [i.e.]{} $ s=-4 $, from Eq. (", "\\[2.16\\]) we can see that the sound speed drops rapidly as $$\\label{3.14}\nc_S=e^{4N},$$ so that it is consistent to take $ c_S \\gg \\mathcal{O}(1) $. ", "Then we can rewrite the logarithmic gradient of the scalar field potential in terms of the derivative with respect to sound speed as $$\\label{3.15}\nM_P\\frac{\|V'(\\phi)\|}{V}=M_P\\frac{1}{V}\\left\|\\frac{dc_S}{d\\phi}\\frac{dV}{dc_S}\\right\|.$$ Now, if the leading-order behavior of the potential is a power law in $c_S$ (which is the case for all potentials considered here), then the leading-order behavior of the derivative is $$\\label{3.15c}\n \\frac{1}{V}\\frac{dV}{dc_S} \\sim \\frac{1}{c_S}.$$ From the relation (\\[2.18\\]), $$\\label{3.16}\nc_S = \\bigg(\\frac{\\phi}{\\phi_0}\\bigg)^{2s/\\tilde{s}} \\sim \\bigg(\\frac{\\phi}{M_P}\\bigg)^{2s/\\tilde{s}},$$ so that we have $$\\label{3.17}\nM_P \\frac{dc_S}{d\\phi} \\sim c_S^{(\\beta-1)/\\beta},$$ where $ \\beta = 2s/\\tilde{s} $. ", "Substituting Eq. (", "\\[3.15c\\]) and Eq. (", "\\[3.17\\]) into Eq. (", "\\[3.15\\]) gives $$\\label{3.18}\nM_P\\frac{\|V'(\\phi)\|}{V}\\sim c_S^{-1/\\beta},$$ which shows that the condition to pass the second swampland criterion (\\[1.2\\]) is also to have $ \\beta=2s/\\tilde{s} <0 $. ", "From Eq. (", "\\[3.16\\]) we also have $$\\label{3.19}\n\\phi=\\phi_0c_S^{1/\\beta} \\sim M_P c_S^{1/\\beta}.$$ Therefore, for any potential having the leading order behavior of a power law in $c_S$, the condition to satisfy [both]{} swampland conjectures is $ \\beta=2s/\\tilde{s} <0 $. ", "The Cuscuton-like model, having $ \\beta=-1 $, passes both of the swampland criteria but the DBI-like model, having $ \\beta=2, $ does not. ", "In the next section, we use the algebraic formulas in Sec. ", "II to confirm this result.", "\n\nIV. ", "testing exact solutions: the Cuscuton-like and the DBI-like models\n======================================================================\n\nIn this section, we examine in more detail swampland constraints on the models discussed in Sec. ", "II. ", "It is convenient to use the variable $ x $ defined as $ x \\equiv \\phi/M_P $, and a constant $ \\alpha \\equiv \\phi_0 /M_P \\sim \\mathcal{O}\\left(1\\right)$ to express the field in units of the reduced Planck mass directly. ", "In terms of variable $ x $, the first swampland conjecture Eq. (", "\\[1.1\\]) reads as $$\\label{3.3a}\n\|\\Delta x\|\\lesssim\\Delta\\sim\\mathcal{O}(1),$$ and the second swampland conjecture Eq. (", "\\[1.2\\]) reads as $$\\label{3.6}\n\\frac{\|V'(x)\|}{V}\\gtrsim c \\sim\\mathcal{O}(1).$$\n\nA. the Cuscuton-like model: $ \\tilde{s}=-2s $\n---------------------------------------------\n\nSubstituting the Cuscuton condition $ \\tilde{s}=-2s $ and $ s = -4 $ into Eq. (", "\\[2.21\\]), the field evolves as $$\\label{3.1}\n\\phi=\\phi_0 e^{-4N}=\\alpha M_P e^{-4N}.$$ In terms of the variable $ x\\equiv \\phi/M_P $ and $ \\alpha=1/2 $ from the condition of $ C=1 $ , Eq. (", "\\[3.1\\]) becomes $$\\label{3.3}\nx\\equiv \\frac{\\phi}{M_P}= \\frac{1}{2} e^{-4N}.$$ Remembering that early time and $c_S \\gg 1$ correspond to $N \\rightarrow +\\infty$, we consider exclusively the region $N > 0$. (In fact, from Eq. (", "\\[2.30\\]) it’s easy to show that the potential quickly becomes negative once the sound speed is less than the speed of light. ", "To ensure constency with cosmology, the tachyacoustic field must decay into standard model particles before reaching this point. ", "See Ref. [", "@Bessada:2009ns] for discussion.) ", "From Eq. (", "\\[3.3\\]) we see that the range traversed of the field from a given $ N $ to the point $ c_S=1 $, which we take to be the endpoint of tachyacoustic evolution, is $$\\label{3.3b}\n\|\\Delta x \|= \\frac{1}{2} (1-e^{-4N}),$$ which shows that the Cuscuton-like model passes the first swampland criterion, Eq. (", "\\[3.3a\\]), and confirms the previous estimate in Eq. (", "\\[3.b\\]).", "\n\nTo test the second swampland conjectures, we rewrite the potential of the Cuscuton-like model (\\[2.30\\]) as $$\\label{3.4}\nV(\\phi)=3M_P^2H_0^2\\Big(\\frac{\\phi}{\\phi_0}\\Big)^{2\\epsilon/s}\\Big[1-\\frac{\\epsilon}{3}\\Big(\\frac{\\phi}{\\phi_0}\\Big)^2\\Big],$$ and substitute $ \\epsilon=2 $ and $ s=-4 $ to have $$\\begin{split}\n\\label{3.5}\nV(\\phi) &= 3M_P^2H_0^2\\Big(\\frac{\\phi}{\\phi_0}\\Big)^{-1}\\Big[1-\\frac{2}{3}\\Big(\\frac{\\phi}{\\phi_0}\\Big)^2\\Big] \\\\\n&= 3M_P^2H_0^2 (2x)^{-1}\\Big[1-\\frac{2}{3}(2x)^2\\Big].", "\n\\end{split}$$ Eq. (", "\\[3.5\\]) gives $$\\label{3.7}\n\\frac{\|V'(x)\|}{V} = \\frac{ x\|8+\\frac{3}{x^2}\|}{3-8x^2}=\\frac{2c_S(3c_S^2+2)}{3c_S^2-2},$$ where Eq. (", "\\[2.32\\]) is used in the second equality. ", "A plot of $ \|V'(x)\|/V $ versus $ c_S $ is shown in Fig. ", "\\[fig:1.0\\] showing that the Cuscuton-like model is consistent with the criterion (\\[1.2\\]) for $c_S \\gg 1$.\n\n![", "In the Cuscuton-like model, if the region traversed by the scalar field is restricted to $ c_S>1 $, the second swampland conjectures is satisfied, $ \\frac{\|V'(x)\|}{V} \\gtrsim \\mathcal{O}(1) $. ", "This figure also shows that the potential quickly becomes negative when $ c_S<1 $. ", "The dashed (green) line indicates $ c_S=1 $. []{", "data-label=\"fig:1.0\"}](c_S_Cusc.ps)\n\nIn this limit, Eq. (", "\\[3.7\\]) reduces to $$\\label{3.7b}\n\\frac{\|V'(x)\|}{V} \\sim 2 c_S= 2 e^{4N} \\gg 1,$$ where, from Eq. (", "\\[2.16\\]), we take $ s=-4 $. ", "The Cuscuton-like model passes the second swampland criterion since $ \|V'(x)\|/V $ is roughly proportional to the sound speed, consistent with the general relation (\\[3.18\\]).", "\n\nB. the DBI-like model: $ \\tilde{s}=s $\n--------------------------------------\n\nAgain considering the scale-invariant limit $ \\epsilon=2 $ and $s =-4$, but with $ \\tilde{s}=s $ for the DBI-like model, from Eq. (", "\\[2.21\\]), the field evolves as $$\\label{3.9}\nx=\\frac{\\phi}{M_P} = \\alpha e^{2N}.$$ In the DBI case, the condition $ C=1 $ gives $ \\alpha \\equiv \\phi_0/M_{\\rm P} = 1 $. ", "The field excursion from a given $ N $ to the point $ c_S=1 $ is $$\\label{3.9b}\n\|\\Delta x \|= (e^{2N}-1),$$ which shows a strong violation of the first swampland criterion, Eq. (", "\\[3.3a\\]), and confirms our estimate in Eq. (", "\\[3.c\\]).", "\n\nNext, to check the second swampland criterion we rewrite the potential (\\[2.34\\]) as $$\\label{3.10}\nV(\\phi)=3M_P^2H_0^2\\Big(\\frac{\\phi}{\\phi_0}\\Big)^{-4\\epsilon/s}\\Big[1-\\frac{2\\epsilon}{3}\\frac{1}{1+\\big(\\frac{\\phi}{\\phi_0}\\big)^2}\\Big],$$ then substitute $ \\epsilon=2 $, $ s=-4 $ and $ \\phi_0 = M_P $ together with the change of variable $ x \\equiv \\phi/M_P $ to get $$\\label{3.11}\nV(x) = 3M_P^2H_0^2 x^{2}\\Big[1-\\frac{4}{3}\\frac{1}{1+x^2}\\Big].$$ and $$\\label{3.12}\n\\frac{\|V'(x)\|}{V} = \\frac{ \\mid\\frac{-2}{x} +12x+6x^3 \\mid}{(-1+3x^2)(1+x^2)}=\\frac{ \\mid-2 +12c_S+6c_S^2 \\mid}{\\sqrt{c_S}(-1+3c_S)(1+c_S)},$$ where Eq. (", "\\[2.32b\\]) with $ \\phi_0=M_P $ is used to get the second equality. ", "Using the same argument used in the Cuscuton-like model, in the range $ c_S \\gg \\mathcal{O}(1) $, Eq. (", "\\[3.12\\]) reduces to $$\\label{3.13}\n\\frac{\|V'(x)\|}{V} \\sim \\frac{2}{\\sqrt{c_S}}=2e^{-2N},$$ which agrees Eq. (", "\\[3.18\\]) with $ \\beta=2 $ and shows that the second swampland conjecture is violated when $ c_S \\gg \\mathcal{O}(1) $. ", "Unlike the Cuscuton-like model, the DBI-like model is inconsistent with both de Sitter swampland conjectures. ", "A plot showing Eq. (", "\\[3.12\\]) and Eq. (", "\\[3.13\\]) is shown in Fig. ", "\\[fig:2.0\\].", "\n\n![", "In the DBI-like model, the scalar field traverses a long distance in the region $ c_S \\gg1 $, where the second swampland criterion is strongly violated, $ \\frac{\|V'(x)\|}{V} \\ll \\mathcal{O}(1) $. ", "The solid (blue) line, $ \\frac{\|V'(x)\|}{V} $, approaches the dashed (orange) line, which is the limiting case $ \\frac{2}{\\sqrt{c_S}} $, when $ c_S \\gg1 $. []{", "data-label=\"fig:2.0\"}](c_S_DBI.ps)\n\nC. The choice of $ \\tilde{s} $ and field redefinition\n-----------------------------------------------------\n\nSince the background evolutions of the Hubble parameter and the speed of sound given in Eq. (", "\\[2.16\\]) are independent of the choice of $ \\tilde{s} $, an important question is whether any two different models can be related by a field redefinition $ \\phi = f(\\varphi) $. ", "Here we show that for the master equation (\\[2.10\\]) this is indeed this case, but we find that the Lagrangians which admit the given background evolution Eq. (", "\\[2.16\\]) are not in general physically equivalent away from the attractor trajectory.", "\n\nFirst, by substituting Eqs. (", "\\[2.17\\],\\[2.19\\]) into Eq. (", "\\[2.10\\]), we obtain the special solution admitting the given background evolution as a special trajectory in phase space $$\\label{MasterEqofTC}\n\\dot{\\phi}=\\frac{\\tilde{s}^2}{2}H(\\phi)\\phi,$$ which also can be rewritten in the form of kinetic term as $$\\label{MasterEqofTC2}\nX=\\frac{\\tilde{s}^2}{8}H^{2}(\\phi)\\phi ^2.$$ Eq. (", "\\[MasterEqofTC2\\]) reduces to $$\\label{CuscutonX}\nX=\\frac{s^2}{2}H^{2}(\\phi)\\phi^{2}$$ for the Cuscuton-like model $ \\tilde{s}=-2s $, and $$\\label{DBIY}\nY=\\frac{s^2}{8}H^{2}(\\varphi)\\varphi^{2}$$ for the DBI-like model $ \\tilde{s}=s $, in which we use different notations $ \\varphi $ for the field and $ Y=\\frac{1}{2}\\dot{\\varphi}^2 $ for the kinetic term. ", "The field redefinition $ \\phi=f(\\varphi) $ transforming Eq. (", "\\[CuscutonX\\]) to Eq. (", "\\[DBIY\\]) is given by the speed of sound $$\\label{FieldRD}\nc_S=\\frac{\\phi_0}{\\phi}=\\bigg(\\frac{\\varphi}{\\varphi_0}\\bigg)^{2},$$ which should be invariant under field redefinition. ", "By substituting $ \\phi=\\frac{\\phi_0\\varphi_0^2}{\\varphi^2} $ into Eq. (", "\\[CuscutonX\\]), it is easy to show that $$\\label{Fieldtrans}\nX=\\frac{1}{2}\\dot{\\phi}^2=\\frac{1}{2}[\\frac{d}{dt}\\frac{\\phi_0\\varphi_0^2}{\\varphi^2}]^2=\\frac{s^2}{2}H^{2}(\\frac{\\phi_0\\varphi_0^2}{\\varphi^2})^{2}$$ reduces to Eq. (", "\\[DBIY\\]) by noticing that the Hubble parameter is another invariant quantity under field redefinition.", "\n\nHowever, it is important to realize that the field redefinition $ \\phi=\\frac{\\phi_0\\varphi_0^2}{\\varphi^2} $ only holds on the special trajectory Eq. (", "\\[MasterEqofTC\\]), but not for the Lagrangians $ \\mathcal{L}(X, \\phi) $(\\[2.28\\], \\[2.29c\\]) since $ X $ and $ \\phi $ are two independent variables for a general Lagrangian. ", "An example to show that the two Lagrangians are physically distinguishable is the study of non-Gaussianity of the two models in [@Bessada:2012rf], in which the two models having different signatures of non-Gaussianity was shown. ", "Furthermore, it was shown in Ref. [", "@Bessada:2012zx] that the solution is a dynamical attractor in both the DBI and Cuscuton cases.", "\n\nThe fact that two physically inequivalent Lagrangians can be chosen which exhibit [identical]{} background behavior demonstrates an interesting consequence of the freedom to choose more general kinetic terms in the Lagrangian: a field theory which violates [e.g.]{} the distance conjecture (\\[1.1\\]) can be transformed to one which satisfies the conjecture via a field redefinition (or, equivalently, the choice of $\\tilde{s}$) without altering the attractor solution for the background evolution. ", "This calls into question whether or not the swampland conjectures (\\[1.1\\],\\[1.2\\]) should be applied unmodified to non-canonical theories, and indeed it is reasonable to expect that the conjectures would need to be generalized to cover such cases. ", "Such a generalization was studied in the case of DBI inflation in Ref. [", "@Seo:2018abc], in the ultra-relativistic limit $c_S \\ll 1$, but would not be expected to apply the limit of $c_S > 1$. Given that there are no known string completions which exhibit $c_S > 1$, it is perhaps reasonable to add this condition itself as a swampland criterion, [i.e.]{} that UV-complete theories must have $c_S < 1$. (See Ref. [", "@Kinney:2007ag] for a discussion of this question.) ", "Our goal in this work has been more modest, which is to check whether or not the unmodified conditions (\\[1.1\\]) and (\\[1.2\\]) place significant constraint on the consistency of cosmological models with $c_S > 1$, and we find that they do not.", "\n\nV. conclusions\n==============\n\nIn this paper, we consider tachyacoustic cosmology, an alternative to inflation theory with the speed of sound greater than the speed of light, in light of the widely discussed tension between the single-field inflation models and the de Sitter swampland conjectures [@Agrawal:2018own]. ", "We have studied the two models introduced in Ref. [", "@Bessada:2009ns], and have shown that the Cuscuton-like model is consistent with the swampland criteria (\\[1.1\\], \\[1.2\\]) but the DBI-like model fails both conditions. ", "We have further proposed a general scaling rule for the field excursion $$\\label{key1}\n\\frac{\\Delta \\phi}{M_P} \\sim \\pm \\sqrt{2\\epsilon} (c_S)^{1/\\beta} \\Delta N,$$ where $\\beta \\equiv 2s/\\tilde{s} $, which shows that $ \\beta <0 $ is the condition to pass the first swampland criterion (\\[1.1\\]) with $ c_S \\gg 1 $. ", "Next, under the condition that the potential has leading-order behavior of a power law in $ c_S $, we have shown that the logarithmic gradient of the scalar field potential scales as $$\\label{key2}\nM_P\\frac{\|V'(\\phi)\|}{V}\\sim c_S^{-1/\\beta}$$ in the scale invariant limit with a radiation-dominated background, which shows that $ \\beta <0 $ is also the condition to pass the second swampland criterion (\\[1.2\\]). ", "Therefore, if the potential of the scalar field satisfies this general form of potential, the two swampland criteria set the same condition on tachyacoustic cosmology.", "\n\nWe conclude that, at least in principle, models which solve the cosmological horizon problem via a superluminal sound speed $c_S \\gg 1$, instead of accelerated expansion, can be consistent with the proposed de Sitter swampland conjectures and can therefore be extended to a UV-complete theory. ", "It is not, however, clear that such models can be consistently embedded in string theory: for example, braneworld realizations of Dirac-Born-Infeld Lagrangians generically require $c_S < 1$ [@Kinney:2007ag]. ", "Some efforts at embedding Cuscuton-like models have been made [@Compere:2011dx; @Afshordi:2016guo], but it is conceivable that tachyacoustic models require a context other than string theory for completion in the UV.[^2] On the other hand, if such models do not have any consistent UV completion, it is the result of conditions other than proposed swampland conjectures.", "\n\nAcknowledgments {#acknowledgments .unnumbered}\n===============\n\nWHK is supported by the Vetenskapsrdet (Swedish Research Council) through contract No. ", "638-2013-8993 and the Oskar Klein Centre for Cosmoparticle Physics, and by the U.S. National Science Foundation under grant NSF-PHY-1719690. ", "The authors thank Ghazal Geshnizjani for helpful conversation.", "\n\n[^1]: Note that here, unlike in the case of inflation, $\\epsilon \\sim \\mathcal{O}\\left(1\\right)$.\n\n[^2]: It is also not obvious whether models with $c_S > 1$ from thermal initial conditions [@Magueijo:2008pm; @Afshordi:2016guo] have consistent UV completion, a question which we do not consider further in this work.", "\n" ]	{ "pile_set_name": "ArXiv" }	[ 0.0005819160724058747, 0.0006918624858371913, 0.0005985755124129355, 0.0012381974374875426, 0.0007488513947464526, 0.0005879768868908286, 0.0007055914611555636, 0.0006617841427214444, 0.0005954595981165767, 0.000659330515190959, 0.0006981119513511658, 0.0009372596396133304, 0.0009914538823068142, 0.0006020530709065497, 0.0005667979712598026, 0.000728176673874259, 0.000728295708540827, 0.000630550435744226, 0.0011860732920467854, 0.0007474572048522532, 0.0011743707582354546, 0.0007542554521933198, 0.0012898282147943974, 0.0006170309497974813, 0.0005953477811999619, 0.000794790918007493, 0.0007651125779375434, 0.0006671450100839138, 0.0006597183528356254, 0.000587726419325918, 0.0005848553264513612, 0.000566812523175031, 0.0007876509334892035, 0.0006539938040077686, 0.0006118454039096832, 0.0007876509334892035, 0.0005669489037245512, 0.0007729307399131358, 0.0007404850912280381, 0.0015025072498247027, 0.0018162032356485724, 0.000646465050522238, 0.0008324426598846912, 0.000676909345202148, 0.0006682168459519744, 0.001755520817823708, 0.011269399896264076, 0.005921071860939264, 0.006298461928963661, 0.0014951155753806233, 0.017710290849208832, 0.0008828843128867447, 0.021566081792116165, 0.0007136150961741805, 0.0008171569206751883, 0.0029987122397869825, 0.0021524233743548393, 0.0011686243815347552, 0.0015052302042022347, 0.06529015302658081, 0.0034956445451825857, 0.000630280701443553, 0.0006482984754256904, 0.01809011399745941, 0.0012129638344049454, 0.00127431470900774, 0.0009518366423435509, 0.0014131731586530805, 0.0008206074126064777, 0.0005661235773004591, 0.0005382161471061409, 0.006350871175527573, 0.001816435600630939, 0.0009432808728888631, 0.000794790918007493, 0.0005950720515102148, 0.01006501354277134, 0.001189516857266426, 0.0014511614572256804, 0.0011637737043201923, 0.0006025743205100298, 0.0009374070214107633, 0.001324604032561183, 0.000698692980222404, 0.011395045556128025, 0.0008110335329547524, 0.0017764033982530236, 0.01482365932315588, 0.0009555147844366729, 0.000611474912147969, 0.011567805893719196, 0.004065622575581074, 0.0008110335329547524, 0.0010789277730509639, 0.0011388177517801523, 0.004068570677191019, 0.0006708093569613993, 0.0028687024023383856, 0.0008795928442850709, 0.0006003961898386478, 0.0005687731900252402, 0.0013318901183083653, 0.0008300897898152471, 0.0011521351989358664, 0.0008479239186272025, 0.0005841325037181377, 0.0009158894536085427, 0.00749386940151453, 0.00214516744017601, 0.012760389596223831, 0.0007365826168097556, 0.0006179608753882349, 0.0007057155598886311, 0.0006005398463457823, 0.0006708093569613993, 0.0008669192320667207, 0.0006216137553565204, 0.0012693408643826842, 0.007894441485404968, 0.008956406265497208, 0.006890035700052977, 0.0008120915153995156, 0.0007693831576034427, 0.0392845943570137, 0.0009807298192754388, 0.0006498397560790181, 0.0006515292916446924, 0.0008444283157587051, 0.03851662948727608, 0.001364361960440874, 0.0007329356158152223, 0.0012255125911906362, 0.002526837633922696, 0.000845224829390645, 0.0006223148084245622, 0.0012284371769055724, 0.008883983828127384, 0.001298275776207447, 0.007944244891405106, 0.0017990710912272334, 0.010191497392952442, 0.0008624742040410638, 0.0006709701265208423, 0.0009976247092708945, 0.0007387586520053446, 0.0009132808772847056, 0.0019054226577281952, 0.0012808978790417314, 0.008937561884522438, 0.0006702230894006789, 0.0010121124796569347, 0.0005887667066417634, 0.0011412063613533974, 0.000698563817422837, 0.0010845352662727237, 0.0016244458965957165, 0.011254727840423584, 0.0015436146641150117, 0.0014469572342932224, 0.004669586196541786, 0.00563866226002574, 0.011632351204752922, 0.0006120888865552843, 0.0007795208948664367, 0.001140233245678246, 0.000610600458458066, 0.000591677613556385, 0.0007149765151552856, 0.0006820993730798364, 0.0006211660802364349, 0.0005816244520246983, 0.0006682344246655703, 0.0005826809210702777, 0.0005786207038909197, 0.0006314598140306771, 0.000533299520611763, 0.0007164709968492389, 0.0029045757837593555, 0.0008586632902733982, 0.0006075481651350856, 0.0007445435621775687, 0.0006473161629401147, 0.0006961905164644122, 0.000732109765522182, 0.0005897540831938386, 0.0005665794597007334, 0.0006667175330221653, 0.001994825666770339 ]	0.002937	188
[ "Q:\n\nOn click re-position root node and adjust window\n\nI've constructed a tree graph.", "\nIn order to calculate the div height in my webpage I count the end-nodes (leaves) in my json object and multiply the result with 25.", "\nCurrently I have 150 leaves so div height is 3750px which is just fine.", "\nWhen I hide the children I would like to re-position the root node in the center of a smaller wrapper. ", "So I need to:\n\nCalculate minimum tree height (eg. ", "3 end-nodes visible, min:350), \nadjust wrapper height (div)\nvertically align the root node in the center of wrapper\ngo back to original height when user click a parent node to show the children \n// Toggle children on click.", "\nfunction click(d) {\n if (d.children) {\n d._children = d.children;\n d.children = null;\n // Hide children and count visible end-nodes\n } else {\n // Show children, count visible nodes recalculate height\n d.children = d._children;\n d._children = null;\n }\n update(d);\n}\n\nA:\n\nI just found this code, which you can put inside your function(update). ", "It's not the best solution, but it's a start:\n// compute the new height\nvar levelWidth = [1];\nvar childCount = function(level, n) {\n if(n.children && n.children.length > 0) {\n if(levelWidth.length <= level + 1) levelWidth.push(0); \n levelWidth[level+1] += n.children.length;\n n.children.forEach(function(d) {\n childCount(level + 1, d);\n });\n }\n};\n\nchildCount(0, root); \nnewHeight = d3.max(levelWidth) 50;//number of pixels per line\n\nIt gives you, each time you update the tree, an array of end nodes (leaves), takes the maximum in that array and multiply by a value (here I used 50, for 50 pixels per leaf). ", "You can use this value to change the height of your div.", "\nCheck the updated fiddle and look at the console each time you click: https://jsfiddle.net/gerardofurtado/b8hmwsm5/1/\nAgain, not the best solution, but I think that it will be ease to make some improvements here.", "\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.0006601111381314695, 0.0007249321206472814, 0.0010669230250641704, 0.0007212742930278182, 0.0006407042965292931, 0.0007686543394811451, 0.022868851199746132, 0.0010920610511675477, 0.0006181145436130464, 0.0005675677675753832, 0.001994825666770339 ]	0.002884	11
[ "\n708 P.2d 1044 (1985)\n103 N.M. 422\nW.D. DINWIDDIE, Joe Lewis and Tom Kennan, Plaintiffs-Appellants,\nv.\nThe BOARD OF COUNTY COMMISSIONERS OF LEA COUNTY, W.H. Brininstool, Ernest McNutt, and Billy W. Johnson, Commissioners; Stern Brothers and Company, and Pat Snipes, County Clerk of Lea County, New Mexico, Defendants-Appellees.", "\nNo. ", "15808.", "\nSupreme Court of New Mexico.", "\nNovember 12, 1985.", "\nRehearing Denied November 26, 1985.", "\nWilliam F. Brainard, Roswell, for appellants.", "\nHinkle, Cox, Eaton, Coffield & Hensley, Mack Easley, Santa Fe, for appellees.", "\n\nOPINION\nFEDERICI, Chief Justice.", "\nPlaintiffs-appellants W.D. Dinwiddie, Joe Lewis and Tom Kennan (plaintiffs), filed in the District Court of Lea County a \"Petition for Declaratory Judgment Invalidating the Special Election of September 18, 1984, and Disallowing Certain Invalid Ballots Cast at Said Election.\" ", "They alleged that a bond election called by the Board of County Commissioners of Lea County (Board), for the construction of a cultural center was held in violation of the statutory provisions for the consolidation of precincts and that certain ballots were cast by persons invalidly registered in Lea County. ", "The Board, the Commissioners of the Board, individually, and Pat Snipes, County Clerk of Lea County, defendants-appellees (defendants); filed a motion to dismiss. ", "The trial court dismissed plaintiffs' complaint with prejudice, and plaintiffs appeal. ", "We affirm.", "\nThe trial court determined that plaintiffs' unverified complaint violated the requirements of NMSA 1978, Section 1-14-3 (Repl. ", "1985) regarding verification of a complaint in an election contest; that it lacked essential averments concerning the outcome of the election; and that it failed to state a claim for relief.", "\nThe sole issue we address on appeal is whether the statutory provisions concerning election contests and recounts, NMSA 1045 1978, Sections 1-14-1 to -21 (Repl. ", "1985), and in particular Section 1-14-3, apply to a petition which contests the validity of a special bond election for the construction of a cultural facility. ", "We do not address the other issues raised by plaintiffs because we find this issue dispositive.", "\nPlaintiffs contend that the contest and recount provisions are applicable only to contests of elections of candidates for public office. ", "They argue that because these provisions are primarily addressed to a \"candidate\" or \"party,\" they do not apply to bond elections and that Section 1-14-1 gives standing to file an election contest only to an \"unsuccessful candidate.\" ", "We determine that these provisions are not so limited in scope.", "\nNMSA 1978, Section 1-1-19 (Repl. ", "1985) provides:\n1-1-19. ", "Elections covered by code.", "\nA. The Election Code [this chapter] applies to the following:\n(1) general elections;\n(2) primary elections;\n(3) statewide special elections;\n(4) elections to fill vacancies in the office of representatives in congress; and\n(5) school district elections.", "\nB. To the extent procedures are incorporated or adopted by reference by separate laws governing such elections or to the extent procedures are not specified by such laws, certain provisions of the Election Code shall also apply to:\n(1) municipal officer or municipal bond elections; or\n(2) special district officer or special district bond or other special district elections. (", "Emphasis added.)", "\nThus, the Election Code, Chapter 1 NMSA 1978, applies to special district bond elections when the Code procedures are incorporated by reference in the separate laws governing such elections.", "\nThe separate laws governing bond elections for cultural facilities are found in NMSA 1978, Sections 4-49-1 to -21 (Repl. ", "Pamp. ", "1984 and Supp. ", "1985). ", "Section 4-49-7 (Supp. ", "1985) authorizes the issuance of general obligation bonds for cultural facilities. ", "NMSA 1978, Section 4-49-8 (Supp. ", "1985) sets forth the requirements for the bond elections and states in pertinent part: \"Except as provided in Chapter 4, Article 49 NMSA 1978, such elections shall be held and conducted in the same manner as general elections, including recount and contest * * \" (Emphasis added.) ", "Article 49 contains no separate recount or contest provisions. ", "In addition, NMSA 1978, Section 4-49-10 (Repl.", "Pamp. ", "1984) provides that all such bond elections shall be \"in all respects governed by, and the result declared according to, the rules and regulations provided by law for holding ordinary or general elections.\" ", "The Election Code's provisions, including those for recount and contest, therefore, do apply to special bond elections for cultural facilities, since they are specifically incorporated by reference by the laws governing such elections.", "\nPlaintiffs claim that their complaint contained two causes of action: the first, a challenge to the validity of the election itself; and the second, a challenge to the results. ", "They argue that should the contest and recount statutes of the Election Code apply to the second cause of action, the first cause of action is still \"outside\" the Code and not affected. ", "We do not agree with this distinction. ", "A challenge to the validity of an election is also a challenge to its result, for if it is successful, the result is changed. ", "Similarly, a challenge to the result contests the inherent validity of the election. ", "Both seek to alter the certified result of the election. ", "An election is a process, not a single event, and the whole process or any part of it, may be subject to contest. ", "See generally 26 Am.", "Jur.2d Elections § 321 (1966).", "\nThe appellants in Hartley v. Board of County Commissioners, 62 N.M. 281, 308 P.2d 994 (1957), also argued that the proceeding brought by them, challenging an election, was not an election contest because they had alleged fraud and impairment of property rights. ", "The Hartley Court stated: \"Although the action may be 1046 denominated an equitable proceeding, its character remains unchanged, an action to contest an election.\" ", "Id. at 283, 308 P.2d at 995. ", "Likewise in the present case, we determine that the character of both causes of action, whether directed to the validity or the result of the election, is that of an election contest.", "\nThe right to contest an election is entirely statutory; such a proceeding was unknown at common law. ", "Montoya v. McManus, 68 N.M. 381, 362 P.2d 771 (1961); Crist v. Abbott, 22 N.M. 417, 163 P. 1085 (1917). ", "The statutory provisions for an election contest must be strictly followed. ", "Montoya v. McManus. ", "One has the right to contest an election only in the manner and to the extent prescribed by statute. ", "Id.; State ex rel. ", "Denton v. Vinyard, 55 N.M. 205, 230 P.2d 238 (1951). ", "This Court has long recognized that an election contest may not be brought absent statutory authority. ", "In Montoya v. Gurule, 39 N.M. 42, 38 P.2d 1118 (1934), we held that the district court was without jurisdiction to entertain a contest of an election of members to a board of trustees of a land grant, because the Election Code at that time did not place such an election within its scope. ", "Similarly, in State v. ex rel. ", "Denton v. Vinyard, the Election Code was determined not to apply to a contest of a local option election, since there was no provision in the Code or other related statutes providing for such contests. ", "See also Hartley v. Board of County Commissioners (no statutory provision for contest of an annexation election; complaint dismissed).", "\nIn the instant case, an election contest may be brought only because the laws governing the issuance of special bonds for cultural facilities incorporate the Code procedures, including those for contest and recount. ", "This statutory right, however, may be exercised only in strict conformity with the law.", "\nNMSA 1978, Section 1-14-3 (Repl. ", "1985) of the Election Code's contest and recount provisions states in part: \"Any action to contest an election shall be commenced by filing a verified complaint of contest in the district court * * * *\" (Emphasis added.) ", "Plaintiffs' complaint was not verified. ", "It has long been established in New Mexico that in election contests the statutory requirement of verification of the complaint must be met or the case is subject to dismissal or to a motion for judgment on the pleadings. ", "Hyde v. Bryan, 24 N.M. 457, 174 P. 419 (1918). ", "See also Perez v. Sisneros, 74 N.M. 310, 393 P.2d 335 (1964) (unverified reply of contestant would have been subject to motion to strike or judgment on the pleadings as to new matter alleged in answer, had the contestee raised the issue in the trial court).", "\nOther courts have held that they did not have jurisdiction to hear an election contest under similar circumstances. ", "In a recent Indiana case, State ex rel. ", "Hodges v. Kosciusko Circuit Court, 273 Ind. 101, 402 N.E.2d 1231 (1980), the court held that an unverified petition to recount votes and to contest an election was jurisdictionally defective and could not be amended after the filing deadline to conform with the jurisdictional requirements. ", "Also, the Illinois Supreme Court in Doelling v. Board of Education, 17 Ill.2d 145, 160 N.E.2d 801 (1959), dismissed for lack of jurisdiction an election contest initiated by an unverified petition. ", "See also Reed v. Baker, 254 Ark. 631, 495 S.W.2d 849 (1973) (required affidavit in support of an election contest is jurisdictional).", "\nPlaintiffs argue that they should be allowed to amend their complaint under NMSA 1978, Civ.", "P.Rule 15(a) (Repl.", "Pamp. ", "1980). ", "We agree with defendants that plaintiffs do not have a right to amend, since the 30-day period in which to file a \"verified\" complaint has expired. § ", "1-14-3. ", "After the 30-day period, the courts have no jurisdiction over the matter.", "\nPlaintiffs' petition did not invoke the jurisdiction of the court, because it was not verified in accordance with NMSA 1978, Section 1-14-3 (Repl. ", "1985). ", "The trial court's dismissal of plaintiffs' complaint is affirmed.", "\nIT IS SO ORDERED.", "\nSOSA, Senior Justice, and STOWERS, J., concur.", "\n" ]	{ "pile_set_name": "FreeLaw" }	[ 0.0008154200622811913, 0.0013787426287308335, 0.000967230589594692, 0.0008446834399364889, 0.0007463638903573155, 0.0006618241895921528, 0.0008851729216985404, 0.0008901635883376002, 0.0008020545355975628, 0.0007043281220830977, 0.0006943424814380705, 0.0008559018606320024, 0.0008710676338523626, 0.0005888380110263824, 0.0007363891927525401, 0.000619520025793463, 0.0006793108768761158, 0.0005977955879643559, 0.000565543828997761, 0.000640587997622788, 0.0006999970064498484, 0.0005832962924614549, 0.0006860209978185594, 0.0007110026199370623, 0.0006408074987120926, 0.000789761426858604, 0.0006319980602711439, 0.000628764508292079, 0.0005979460547678173, 0.0006165101658552885, 0.0008090875344350934, 0.0009061499731615186, 0.0007241567363962531, 0.0008481668774038553, 0.00057781464420259, 0.0007532581221312284, 0.000583128712605685, 0.0006955067510716617, 0.0006498787552118301, 0.0008090875344350934, 0.0006305892602540553, 0.0005743625806644559, 0.0007186479051597416, 0.0006661256193183362, 0.0006188104161992669, 0.0007431403500959277, 0.0006255296757444739, 0.0006065206835046411, 0.0006751932087354362, 0.0006641459767706692, 0.0006842234870418906, 0.0007735308026894927, 0.0005904220161028206, 0.0007927151746116579, 0.0005747100221924484, 0.0007031580898910761, 0.0008121406426653266, 0.000587979971896857, 0.00087164924480021, 0.0007661218987777829, 0.002291839336976409, 0.0007827276131138206, 0.0006638405611738563, 0.0007034060545265675, 0.0009782951092347503, 0.0006297729560174048, 0.0006183452787809074, 0.0005859218654222786, 0.00060891336761415, 0.0006801707786507905, 0.0006317276856862009, 0.0006450455985032022, 0.0006061990279704332, 0.0007831208640709519, 0.0006282177055254579, 0.0007106632692739367, 0.0007298176060430706, 0.0007557307253591716, 0.00072777847526595, 0.0006123859202489257, 0.0007204383728094399, 0.0006783788558095694, 0.0008090875344350934, 0.0008032102487049997, 0.0005765326204709709, 0.0010565510019659996, 0.0006482669850811362, 0.0006648637936450541, 0.0007241567363962531, 0.0006511546089313924, 0.000910902745090425, 0.0006778809474781156, 0.001994825666770339 ]	0.000747	93
[ "Introduction\n============\n\nBladder cancer ranks as the 9^th^ most frequently diagnosed cancer and is 13^th^ in terms of deaths worldwide since 2012 [@B1]. ", "Although accumulating studies show that targeted drugs can improve patient survival rates, first-line molecular-targeted drugs (sorafenib and gefitinib) exhibit only limited therapeutic effects in several clinical trials and can cause severe side effects [@B2], [@B3]. ", "Therefore, there is an increasing demand to explore effective strategies for bladder urothelial carcinoma (BLCA) treatment.", "\n\nTumor necrosis factor-related apoptosis-inducing ligand (TRAIL), has been reported as a candidate for cancer treatment due to its selective inducement of apoptosis in cancer cells while sparing normal cells [@B4], [@B5]. ", "TRAIL specifically binds to cell-death receptors DR4 or DR5 (also named tumor necrosis factor receptor superfamily member 10 TNFRSF10A and TNFRSF10B, respectively), resulting in trimerization of the receptor and clustering of the intracellular death domain of the receptor and leading to death-inducing signaling complex formation [@B6], [@B7]. ", "Trimerization of the death domains leads to the recruitment and activation of Fas-associated death domain protein, which promotes transmission of an apoptotic signal and induces apoptosis via both the extrinsic and intrinsic mitochondrial pathways [@B6], [@B8], [@B9]. ", "However, evidence indicates that cancer cells can develop resistance to TRAIL if they lose the ability to express death receptors or exhibit constant activation of anti-apoptotic pathways [@B9], [@B10]. ", "Certain malignant cells are resistant to TRAIL, including bladder cancer cells [@B11]-[@B13]. ", "Therefore, identifying effective agents capable of overcoming TRAIL resistance in bladder cancer cells is necessary.", "\n\nAndrographolide (Andro) is a diterpene lactone (C~20~H~30~O) and a major component of Andrographis paniculata Nees, which was used as a traditional anti-inflammation medicine in Asia [@B14], [@B15]. ", "Andro can be excreted from the body over a short period of time while exhibiting low levels of toxicity to normal cells [@B16]. ", "Recent progress in Andro-specific research confirmed its effectiveness and specificity in promoting cancer-cell apoptosis [@B17]. ", "In this study, we discovered that Andro markedly improved the sensitivity of BLCA cells to TRAIL-induced apoptosis, and that combined treatment stimulated caspase- dependent apoptosis through p53 dependent enhancement of DR4 and DR5 expression. ", "Additionally, Andro treatment attenuated mRNA expression of B cell lymphoma 2 (Bcl-2), cellular inhibitor of apoptosis 2 (cIAP2), X-linked inhibitor of apoptosis (XIAP), and nuclear factor kappa-B (NF-κB) p65 subunit (RelA). ", "Our study provides evidence supporting clinical application of the combination therapy of TRAIL and Andrographolide for bladder cancer patients.", "\n\nResults\n=======\n\nT24 cells exhibit TRAIL resistance\n----------------------------------\n\nAs DR4 and DR5 were canonical TRAIL receptors involved in its antitumor effects, we analyzed mRNA-expression data from the Oncomine database, finding that mean DR4 mRNA expression in bladder cancer tissues exceeded that in normal bladder tissue, whereas no significant difference was found in DR5 between tumor and normal tissues (Figure [1](#F1){ref-type=\"fig\"}A). ", "Furthermore, gene set enrichment analysis (GSEA) analysis of The Cancer Genome Atlas (TCGA) profiles from BLCA patients (n = 414) revealed enrichment of apoptosis pathways associated with samples exhibiting high levels of both DR4 andDR5 expression (Figure [1](#F1){ref-type=\"fig\"}B). ", "Therefore, bioinformatics analysis suggested that relatively high DR4/5 expression might represent an effective therapeutic TRAIL-related target in bladder cancer cells. ", "However, MTS assays revealed that the 50% inhibitory concentration (IC~50~) value of TRAIL was 38.35 ng/mL, indicating that low concentrations of TRAIL would be ineffective in T24 cells (Figure [1](#F1){ref-type=\"fig\"}C). ", "This suggested the necessity to identify appropriate TRAIL-specific sensitizers capable of overcoming TRAIL resistance in bladder cancer cells. ", "Moreover, Andro represents a potential agonist for TRAIL therapy, with MTS assays revealing an IC~50~ value for Andro of 101.5 µM in T24 cells (Figure [1](#F1){ref-type=\"fig\"}E).", "\n\nAndro synergistically enhances TRAIL-induced inhibition of proliferation, colony formation and migration in T24 bladder cancer cells\n------------------------------------------------------------------------------------------------------------------------------------\n\nBoth cell-counting and MTS assays suggested that single treatment with either TRAIL or Andro inhibited cell-proliferation rates. ", "Interestingly, we found that combination treatment with TRAIL and Andro substantially enhanced this inhibitory effect on cell proliferation (Figure [2](#F2){ref-type=\"fig\"}A and B). ", "Additionally, morphological changes in TRAIL and/or Andro-treated cells confirmed the inhibition of T24-cell proliferation associated with combined treatment versus single treatment (Figure [2](#F2){ref-type=\"fig\"}C). ", "Moreover, colony formation dramatically decreased following combined treatment relative to that observed following treatment with Andro or TRAIL alone (Figure [2](#F2){ref-type=\"fig\"}D).", "\n\nGiven that cancer cells exhibit potent migratory features, we conducted wound-healing assays as functional readings. ", "The results indicated that treatment with TRAIL or Andro alone modestly decreased the ratio of migrating bladder cancer cells. ", "In the TRAIL-treated group, the cell-migration ratio was 65.37 ± 2.47%, whereas that in the Andro-treated group was 79.65 ± 1.82%. ", "However, combined treatment resulted in a migration ratio of 32.16 ± 1.59% (Figure [2](#F2){ref-type=\"fig\"}E). ", "Evidence shows that matrix metalloproteinases (MMPs) play important roles in tumor progression, invasion, and metastasis [@B18]. ", "Therefore, we evaluated protein levels of CD147 and MMP-9 by immunoblot, revealing that CD147 and MMP-9 were downregulated after a 24-h incubation with both TRAIL and Andro relative to levels observed following single treatment with TRAIL or Andro alone (Figure [2](#F2){ref-type=\"fig\"}F). ", "These findings demonstrated that combination treatment with TRAIL and Andro potently suppressed T24-cell growth and migration.", "\n\nAndro enhances TRAIL-induced apoptosis by initiating caspase activation in BLCA cells\n-------------------------------------------------------------------------------------\n\nThe canonical pathway associated with TRAIL-induced cell death involves binding to specific death receptors (DR4 or DR5) to initiate activation of extrinsic apoptosis [@B6], [@B7]. ", "MTS assays suggested that in the combination-treatment groups, cell viability was further attenuated along with increasing Andro concentrations (Figure [3](#F3){ref-type=\"fig\"}A). ", "Immunoblot assays analyzing changes in protein content in T24 cells treated with TRAIL and/or Andro suggested that combined treatment enhanced caspase-dependent apoptosis based on levels of cleaved-poly (ADP ribose) polymerase 1 (PARP1; 119/89 kDa) and activation of caspases 3, 9, and 8 (Figure [3](#F3){ref-type=\"fig\"}B). ", "We then evaluated the roles of Andro in apoptosis progression using Annexin V-fluorescein isothiocyanate (FITC)/ propidium iodide (PI)-labeled flow cytometry. ", "Compared with groups treated with TRAIL or Andro alone, combination treatment notably enhanced apoptosis rates in T24 cells (Figure [3](#F3){ref-type=\"fig\"}C). ", "These results showed that combined treatment of Andro and TRAIL promoted apoptosis in BLCA cells.", "\n\nAdditionally, we found that T24 apoptosis induced by combined treatment was initiated by caspase-specific activation that did not involve cell necrosis. ", "T24 cell viability in the combined-treatment group was restored in the presence of the pan-caspase inhibitor Z-VAD-FMK (57.54 ± 4.99% for combined treatment without Z-VAD-FMK and 94.03 ± 3.77% for combined treatment with Z-VAD-FMK). ", "By contrast, administration of Necrostatin-1 (Nec-1; a cell-necrosis inhibitor) did not alter the decreased T24 cell viability observed following combined treatment with Andro and TRAIL, with cell-morphological images supporting MTS assay results (Figure [3](#F3){ref-type=\"fig\"}D).", "\n\nAndro sensitizes TRAIL-induced apoptosis via up-regulating death receptors\n--------------------------------------------------------------------------\n\nImmunoblot assays identified that Andro treatment upregulated protein levels of both DR4 and DR5 (Figure [4](#F4){ref-type=\"fig\"}A). ", "To determine whether one or both receptors were responsible for the pro-apoptotic effect of TRAIL in T24 cells, we used small-interfering (si)RNAs to block innate DR4/DR5 translation (si1201 and si955 targeting DR4 and DR5 mRNA, respectively) according to their knockdown efficiency determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays (Figure [4](#F4){ref-type=\"fig\"}B). ", "Following results demonstrated that cell viability was slightly restored in DR4-knockdown cells and restored to a higher degree in DR5-knockdown cells following combination treatment with TRAIL and Andro. ", "Additionally, we observed no significant difference in cell viability between DR4- and DR5-knockdown cells (Figure [4](#F4){ref-type=\"fig\"}C). ", "Flow cytometry confirmed those from MTS assays showing that blocking DR5 translation was more effective at reducing the apoptosis rate as compared with blocking DR4 translation (apoptosis rates: 14.41 ± 0.21% in DR4-knockdown cells and 8.07±0.22% in DR5-knockdown cells) (Figure [4](#F4){ref-type=\"fig\"}D).", "\n\np53 is required for Andro-induced DR4/DR5 upregulation and enhancement of cytotoxicity\n----------------------------------------------------------------------------------------\n\nBecause combined treatment enhanced DR4 and DR5 protein levels in T24 cells (Figure [4](#F4){ref-type=\"fig\"}A), we performed GSEA of the TCGA profiles of 414 bladder patients, which indicated that both high TNFRSF10A and TNFRSF10B expression were positively correlated with the p53-signaling pathway (Figure [5](#F5){ref-type=\"fig\"}A). ", "Therefore, we constructed a p53-knockdown T24 cell line to explore the molecular mechanisms associated with Andro-mediated TNFRSF10B expression. ", "Following qRT-PCR and immunoblot confirmation of p53-knockdown efficiency (Figure [5](#F5){ref-type=\"fig\"}B), immunoblot results revealed that Andro enhanced p53 levels while p53 knockdown attenuated Andro-induced upregulation of DR4 and DR5 levels in T24 cells (Figure [5](#F5){ref-type=\"fig\"}C). ", "Moreover, MTS assays demonstrated partial restoration of cell viability in p53-knockdown cells compared to sh-ctrl T24 cells following combined treatment with TRAIL and Andro (control shRNA, 69.80±4.89% vs. p53 shRNA, 84.32±2.17%) (Figure [5](#F5){ref-type=\"fig\"}D). ", "Knocking down of p53 expression also contributed to attenuated synergistic effect of Andro for which decreased cell apoptosis rate in TRAIL-treated T24 cells (control shRNA, 23.88±0.77% vs. p53 shRNA, 13.99±0.88%) (Figure [S1](#SM0){ref-type=\"supplementary-material\"}).", "\n\nAndro interrupts NF-κB pathway further sensitizes BLCA cells to TRAIL-induced apoptosis\n---------------------------------------------------------------------------------------\n\nHere, we found that RelA (the NF-κB p65 subunit) was downregulated at both the mRNA and protein levels following combined treatment with TRAIL and Andro (Figure [6](#F6){ref-type=\"fig\"}A-C). ", "Additionally, combined treatment modified protein and mRNA levels of apoptosis-related genes, resulting in decreased cIAP2 protein levels (Figure [6](#F6){ref-type=\"fig\"}A), Bcl-2 mRNA levels (combined treatment, 63.08 ± 1.54% vs. TRAIL or Andro treatment alone, 104.33 ± 18.3% and 90.76 ± 1.77%, respectively), and attenuated XIAP mRNA levels (which were stimulated by TRAIL treatment alone) following Andro treatment (Figure [6](#F6){ref-type=\"fig\"}C). ", "To confirm the role of the NF-κB pathway in regulating TRAIL-induced apoptosis of T24 cells, we used ammonium pyrrolidinedithiocarbamate (PDTC), a pan-NF-κB inhibitor. ", "We found that the PDTC IC~50~ in T24 cells was 29.33 μM; therefore, we chose 5 µM as the appropriate concentration for further experiments (Figure [6](#F6){ref-type=\"fig\"}D). ", "MTS and fluorescence-activated cell sorting (FACS) assays revealed a synergistic effect of PDTC on the TRAIL sensitivity of T24 cells at relatively low concentrations (Figure [6](#F6){ref-type=\"fig\"}E-G).", "\n\nThe synergistic effect of Andro on TRAIL is effective in multiple BLCA cell lines\n---------------------------------------------------------------------------------\n\nWe performed MTS assays to evaluate the effect of TRAIL and/or Andro treatment on 5637 and UM-UC 3 bladder cancer cell lines. ", "We found that the IC~50~ value for TRAIL and Andro treatment alone of 5637 cells was 15.19 ng/mL and 82.9 µM, respectively (Figure [7](#F7){ref-type=\"fig\"}A), whereas that for UM-UC 3 cells was 75.00 ng/mL and 103.3 µM, respectively (Figure [7](#F7){ref-type=\"fig\"}C). ", "Both UM-UC 3 cells and 5637 cells were insensitive to low concentrations of either TRAIL or Andro, whereas combined treatment displayed a clear inhibitory effect on the cell viability of these TRAIL-resistant BLCA cell lines (Figure [7](#F7){ref-type=\"fig\"}B and D). ", "At 24-h post-treatment of UM-UC 3 cells with both Andro and TRAIL, cell viability was 71.54 ± 5.06% as compared with 92.65 ± 3.43% following treatment with TRAIL alone. ", "Similarly, in 5637 cells, cell viability following combined treatment was 57.39 ± 8.31% as compared with 85.96 ± 3.76% following TRAIL treatment alone. ", "Additionally, cell apoptosis rates determined by FACS revealed that combination treatment enhanced apoptosis in both 5637 and UM-UC 3 cells (Figure [7](#F7){ref-type=\"fig\"}E). ", "Moreover, the synergistic effect of PDTC on TRAIL induced apoptosis was also validated in both 5637 and UM-UC 3 BLCA cell lines (Figure [8](#F8){ref-type=\"fig\"}). ", "These results further supported that Andro sensitized multiple BLCA cell lines to TRAIL-mediated apoptosis by inhibiting the NF-κB signaling pathway.", "\n\nDiscussion\n==========\n\nThe unique property of TRAIL triggering both extrinsic and intrinsic apoptosis making it a potentially effective anticancer agent [@B4], [@B19], [@B20]. ", "Resistance of cancer cells to TRAIL-mediated apoptosis represents a major limitation to its clinical application [@B21]. ", "Therefore, identifying agents capable of enhancing TRAIL-induced anticancer effects is necessary. ", "In the present study, clinical database analysis and GSEA revealed that mRNA expression of death receptors of TRAIL is positively associated with apoptosis signaling pathway in BLCA patients (Figure [1](#F1){ref-type=\"fig\"}A and B). ", "However, previous studies reported that human BLCA cells were resistant to TRAIL treatment [@B22]. ", "Thus, our findings that Andro, a natural compound, enhanced the sensitivity of BLCA cell lines to TRAIL-mediated apoptosis provided critical insight into a novel therapeutic strategy for BLCA patients.", "\n\nIn this study, we confirmed the synergetic effect of combined Andro and TRAIL treatment in bladder cancer cells, with Andro treatment enhancing TRAIL-mediated inhibition of cell viability, proliferation, migration, and colony formation and promotion of apoptosis in T24 cells. ", "Consistently, we found that protein levels of two factors involved in tumor migration (MMP-9 and CD147) [@B23], [@B24] were decreased following combination treatment (Figure [2](#F2){ref-type=\"fig\"}). ", "A pan-caspase inhibitor (Z-VAD-FMK), almost completely restored cell viability of T24 cells treated with combination therapy, further supporting that Andro-specific increased TRAIL mediated caspase-dependent apoptosis in T24 cells (Figure [3](#F3){ref-type=\"fig\"}). ", "Another important finding was that combination therapy also increased TRAIL-induced apoptosis rates in multiple BLCA cell lines, indicating that Andro enhanced the anticancer efficacy of TRAIL independent of BLCA cell type (Figure [7](#F7){ref-type=\"fig\"}).", "\n\nTRAIL binding to its death receptors (DR4 and DR5), it initiates the formation of the DISC complex, which leads to activation of caspase cascades and induction of apoptosis [@B25]. ", "However, in cancer cells, pro-survival signaling pathways, including the NF-κB pathway, are activated to prevent TRAIL-induced apoptosis, with accumulating evidence supporting elevated NF-κB levels observed in bladder cancers [@B26], [@B27]. ", "Two strategies should be considered to enhance the therapeutic efficacy of TRAIL: 1) enhancing the activation of apoptosis pathways and 2) suppressing pro-survival pathways.", "\n\nWe noted that T24 cells treated with Andro exhibited substantial increases in both DR4 and DR5 levels, which possibly contributed to TRAIL-mediated apoptosis. ", "It remains controversial whether DR4 or DR5 represents the determinant receptor associated with TRAIL-induced apoptosis. ", "Previous studies claimed that DR4 was more effective in promoting TRAIL-mediated cancer-cell apoptosis [@B28]-[@B30]; whereas other studies indicated DR5 was critical for promoting TRAIL-induced cancer-cell apoptosis [@B25]. ", "Here, by using siRNA targeting DR4 or DR5, we confirmed that both DR4 and DR5 were required for tumor suppressing activity by combined treatment with Andro and TRAIL in BLCA cells. ", "Crucially, we noticed that silencing DR5 in BLCA cells is more effective in restoring the resistance for Andro/TRAIL treatment than silencing DR4, indicating that DR5 expression level is the major determinant for the sensitization by Andro in BLCA cells. ", "Hence, we suggested that upregulated DR5 rather than DR4 enhanced TRAIL-induced apoptosis in T24 cells (Figure [4](#F4){ref-type=\"fig\"}).", "\n\nOur bioinformatics analysis of BLCA patients\\' data revealed a correlation between death receptors of TRAIL and the p53-signaling pathway. ", "In consistent with previous studies [@B29], we confirmed that p53 expression is critical for Andro-mediated increases in DR4 and DR5 expression (Figure [5](#F5){ref-type=\"fig\"}). ", "Downregulation of endogenous p53 expression blocked Andro-mediated upregulation of DR4 and DR5 levels in T24 cells. ", "Importantly, decreased p53 partially attenuated the synergistic antitumor effects of the combination treatment. ", "Therefore, we assumed that other pathways were involved in cancer-cell apoptosis associated with combined Andro and TRAIL treatment.", "\n\nThe NF-κB-signaling pathway protects tumor cells from apoptosis by upregulating multiple anti-apoptosis genes [@B31]. ", "Accumulating evidence shows that activation of the NF-κB subunit RelA renders tumor cells resistant to TRAIL-mediated apoptosis [@B32]. ", "In the present study, we found that combined treatment of T24 cells with Andro and TRAIL decreased RelA expression at both mRNA and protein levels. ", "Additionally, the mRNA expression of several NF-κB-regulated anti-apoptosis genes, including cIAP2, Bcl-2, and XIAP, was attenuated following Andro treatment. ", "Therefore, we hypothesized that inhibiting the NF-κB-dependent pro-survival pathway by decreasing RelA expression might sensitize T24 cells to TRAIL-induced apoptosis. ", "To further support our conclusion, we found that using PDTC (a pan- NF-κB inhibitor capable of suppressing both NF-κB-DNA binding and NF-κB-dependent transcriptional activity) enhanced TRAIL-mediated apoptosis and suppression of cell viability in multiple BLCA cell lines. ", "These results suggested that the synergistic effect of combined treatment and associated NF-κB-pathway inhibition was correlated with the downregulation of RelA by Andro treatment (Figure [6](#F6){ref-type=\"fig\"}), which agreed with previously reported results [@B33], [@B34]. ", "As all our experiments were performed in vitro, thus it is still needed to assess the in vivo effect of the combination therapy of TRAIL and Andro on bladder cancer in future studies.", "\n\nOur findings indicated that combined treatment with TRAIL and Andro increased DR4/DR5 levels and suppressed the NF-κB-dependent anti-apoptosis pathway, both of which contributed to BLCA-cell sensitization to TRAIL. ", "In conclusion, these results indicated that Andro treatment acted synergistically with TRAIL treatment and offers a potential treatment option for patients with TRAIL-resistant bladder cancer.", "\n\nMaterials and Methods\n=====================\n\nMicroarray data processing and visualization\n--------------------------------------------\n\nRNA-seq data from the transcriptome profile in a bladder cancer dataset was downloaded from TCGA (<https://portal.gdc.cancer.gov/repository>; data release 10.1; February 15, 2018) and contained 414 bladder tumor tissues and 19 adjacent normal bladder tissue samples. ", "TNFRSF10A and TNFRSF10B mRNA expression data from a previous study [@B35] was downloaded from the Oncomine database (https:// [www.oncomine.org/resource/main.html](http://www.oncomine.org/resource/main.html)). ", "GSEA was performed by GSEA 3.0 (BROAD Institute; http:// [www.broadinstitute.org/gsea](http://www.broadinstitute.org/gsea)) [@B36]. ", "Data processing and visualization were accomplished by R (https: //[www.r-project.org/](http://www.r-project.org/)) and GraphPad Prism (v7.0; GraphPad Software, La Jolla, CA, USA).", "\n\nCell culture and treatments\n---------------------------\n\nThe BLCA cell lines T24, UM-UC 3, and 5637 cells were purchased from the Type Culture Collection of the Chinese Academy of Sciences (Shanghai, China), and cells were cultured in Dulbecco\\'s modified Eagle medium (HyClone, Logan, UT, USA). ", "All media were supplemented with 10% fetal bovine serum (Biological Industries, Cromwell, CT, USA). ", "All cells were cultured under standard incubator conditions (37℃ and 5% CO~2~).", "\n\nReagents and kits\n-----------------\n\nAndrographolide was dissolved in 10 mM dimethyl sulfoxide (DMSO) used as a stock solution, and recombinant human TRAIL (R&D Systems, MN, USA) was prepared in phosphate-buffered saline (PBS) containing 0.1% bovine serum albumin at 20 µg/ml. ", "Z-VAD-FMK (HY-16658), Necrostatin-1 (HY-15760), and PDTC (HY-18738) were purchased from MedChemExpress (Monmouth Junction, NJ, USA). ", "Antibodies included the following: caspase-8, caspase-9, RelA, caspase-3, and DR4 from Cell Signaling Technology (Danvers, MA, USA); β-actin, PARP1, and cIAP2 from Abcam (Cambridge, UK); p53 from Thermo Fisher Scientific (Waltham, MA, USA); and DR5 from Biolegend (307407; San Diego, CA, USA).", "\n\nCell-proliferation assay\n------------------------\n\nWe used cell-growth curves and colony formation assays to evaluate the effect of Andrographolide and/or TRAIL on bladder cancer-cell proliferation. ", "For growth assays, \\~2 × 10^4^ cells/well were seeded in a 24-well plate, treated with different concentrations of Andrographolide or/and TRAIL or DMSO (as control), and trypsinized, followed by resuspension and counting using a cell-counting chamber (Shanghai Precision Instruments Co., Ltd., Shanghai, China). ", "Cell number was counted and recorded after 24-h, 48-h, and 72-h, with the optical density at 450 nm measured at the same time points.", "\n\nFor colony formation assays, \\~200 cells/well were seeded in a 6-well plate with 2 mL medium, treated under different conditions, and incubated for 12 days, after which cells were washed with cold PBS and fixed with 4% paraformaldehyde for 20 min. ", "Cells were then stained with 0.1% crystal violet solution for 15 min at room temperature, washed with double-distilled water three times, and air dried. ", "Colonies (\\>50 cells) were counted using an inverted microscope (100×). ", "All experiments were performed in triplicate.", "\n\nCell-viability assay\n--------------------\n\nCell viability was assessed by measurement of formazan production after the addition of MTS (Promega, Madison, WI, USA). ", "Nearly 6000 cells/well were seeded in a 96-well plate and incubated at 37°C in a 5% CO~2~ incubator for 24-h. Cells were then incubated in 100 μL of cell-culture medium containing 20 μL MTS for 2-h at 37°C, followed by the application of different treatment conditions for 24-h. Absorbance was detected using a BioTek ELISA reader (Winooski, VT, USA) at a wavelength of 450 nm. ", "Cell-inhibitory ratio was calculated using the following formula:\n\n100 × cell growth inhibitory ratio (%) = 100 × \\[\n\n(A × 450control - A450sample)\n\n/\n\n(A450control - A450blank)\n\n\\].", "\n\nImmunoblot assay\n----------------\n\nCells in 6-well plates were washed twice with cold PBS. ", "RIPA lysis buffer (Wanleibio, Beijing, China) was then added to the wells, followed by incubation for 15 min at 4°C. ", "Whole-cell lysate was centrifuged at 12,000g at 4°C, and the supernatant was incubated with loading buffer and denatured at 100°C for 15 min, followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. ", "The separated proteins were transferred to nitrocellulose membranes (Millipore, Billerica, MA, USA), and 5-bromo-4-chloro-3-indolyl phosphate and nitro blue tetrazolium (Millipore) were used to visualize the protein bands, with a Quantity One instrument (Bio-Rad, Hercules, CA, USA) used for imaging. ", "Secondary antibodies included anti-rabbit IgG and anti-mouse IgG (Cell Signaling Technology, USA).", "\n\nFlow cytometric analysis\n------------------------\n\nCells treated under different conditions for 24-h were resuspended in 6-well culture plates, washed twice with cold PBS, and pelleted by centrifugation at 5000g for 5 min. ", "Apoptotic cells were quantified using an Annexin V-FITC apoptosis detection kit (KeyGEN BioTECH, Nanjing, China). ", "A FACS flow cytometer (BD Biosciences, San Diego, CA, USA) was used to analyze cell apoptosis.", "\n\nqRT-PCR\n-------\n\nBriefly, RNA isolated from cells was converted to cDNA using a reverse transcription kit (Transgen Biotech, Beijing, China). ", "PCR amplification was performed using a Roche LC480 instrument (Roche, Basel, Switzerland) with SYBR Green supermix (Fermentas, Waltham, MA, USA), 1 µM of each primer, and 6 μL of diluted cDNA. ", "Samples were amplified in triplicate. ", "Primer sequences for glyceraldehyde 3-phosphate dehydrogenase (GAPDH), Bcl-2, XIAP, RelA, and p53 are listed in Table [S1](#SM0){ref-type=\"supplementary-material\"}. ", "Relative gene-expression levels were represented as ΔCt = Ct~gene~ - Ct~reference~, with fold changes calculated using the 2^-ΔΔCt^ method. ", "GAPDH was used to accomplish the expression normalization.", "\n\nPlasmids and lentiviruses\n-------------------------\n\nThe plasmids pRSV-Rev (12253), pMDLg/pRRE (12251), and pCMV-VSV-G (8454) were purchased from Addgene (Cambridge, MA, USA). ", "The lentiviral vector plko.1 was obtained from Generay Biotech (Shanghai, China). ", "The sequence for p53 shRNA (CCGGGTCCAGATGAAGCTCCCAGAACTCGAGTTCTGGGAGCTTCATCTGGACTTTTT) and flanked by EcoRI and BamHI sites (5′ and 3′, respectively) were inserted into the plko.1 vector. ", "Viruses were propagated in 293T cells, the supernatant of infected 293T cells were collected, and viral particles were pelleted through a 20% sucrose cushion at 28,000 rpm for 90 min. ", "Purified virions were stored at -80°C.", "\n\nsiRNAs\n------\n\nSynthetic siRNA \\[negative-control fluorescein (FAM) siRNAs, DR4 siRNAs, and DR5 siRNAs\\] were obtained from GenePharma (Shanghai, China). ", "The cellular delivery of siRNA was performed using Lipofectamine 2000 (Thermo Fisher Scientific), optimized using various siRNA concentrations, and evaluated by fluorescence microscope and qRT-PCR. ", "siRNAs sequences are listed in Table [S2](#SM0){ref-type=\"supplementary-material\"}.", "\n\nStatistical analysis\n--------------------\n\nDifferences among test groups were analyzed by GraphPad Prism software (v7.0; GraphPad Software) and SPSS (v20.0; IBM, Armonk, NY, USA). ", "A P \\< 0.05 was considered statistically significant. ", "A two-tailed Student\\'s t test was performed to detect statistical difference between two individual experimental groups.", "\n\nSupplementary Material {#SM0}\n======================\n\n###### \n\nSupplementary figure and tables.", "\n\n###### \n\nClick here for additional data file.", "\n\nWe thank Junliang Chang and Yuanyuan Li for their technical assistance and Editage for editorial assistance. ", "This work was supported by funding from the National Natural Science Foundation of China (81772183).", "\n\nAuthor Contributions\n====================\n\nConceptualization, Weiwei and Yuyou Deng; Methodology, Yuyou Deng, Haoran Guo and Ran Bi; Software, Yuyou Deng; Validation, Jiaxin Yang; Investigation, Honghuang Lan; Resources, Chunxi Wang; Writing-Review & Editing, Weiwei and Yuyou Deng; Visualization, Yuyou Deng; Supervision, Chunxi Wang; Project administration, Songling Zahgn; Funding Acquisition, Weiwei and Chunxi Wang.", "\n\nAndro\n\n: andrographolide\n\nIC50\n\n: 50% inhibitory concentration\n\nMTS\n\n: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium\n\nTRAIL\n\n: tumor necrosis factor-related apoptosis-inducing ligand\n\nBLCA\n\n: bladder urothelial carcinoma\n\nTCGA\n\n: The Cancer Genome Atlas\n\nMMP\n\n: matrix metalloproteinase\n\nDMSO\n\n: dimethyl sulfoxide\n\nFITC\n\n: fluorescein isothiocyanate\n\nGSEA\n\n: Gene set enrichment analysis\n\nNec-1\n\n: necrostatin-1\n\nSD\n\n: standard deviation\n\nshRNA\n\n: short-hairpin RNA\n\nTNFRSF10A/B\n\n: tumor necrosis factor receptor superfamily member 10A/B\n\nBcl-2\n\n: B cell lymphoma 2\n\ncIAP2\n\n: cellular inhibitor of apoptosis 2\n\nqRT-PCR\n\n: quantitative reverse transcription polymerase chain reaction\n\nRelA\n\n: NF-κB p65 subunit\n\nXIAP\n\n: X-linked inhibitor of apoptosis.", "\n\n![", "Potential TRAIL-receptor mRNA expression in bladder cancer patients and the antitumor effects of TRAIL and Andro in T24 cells. (", "A) Log~2~-converted DR4/DR5 mRNA expression levels from the Oncomine database. (", "B) GSEA results showing that high DR4/DR5 expression was positively correlated with apoptosis-gene signatures. (", "C) T24 cells were treated with various concentrations of TRAIL for 24-h. (D) Two- and three-dimensional chemical representation of Andro derived from the PubChem Compound Database (<https://pubchem.ncbi.nlm.nih.gov/>). ", "Red, grey, and light-blue nodes represent oxygen atoms, carbon atoms, and hydrogen atoms, respectively. (", "E) T24 cells were treated with various concentrations of Andro for 24-h. The p-value and IC~50~ values were calculated using GraphPad Prism software. ", "Data represent the mean ± SD. ", "\\P \\< 0.05; \\\\P \\< 0.01; \\\\\\P \\< 0.001 (n = 3).](ijbsv15p0688g001){#F1}\n\n![", "TRAIL combined with Andro further inhibits T24-cell proliferation, migration, and colony formation. (", "A, B) Effects of TRAIL and/or Andro treatment on the T24 growth curve. ", "Verification by cell-counting and MTS assays. (", "C) Images (200×) show T24 cells following treatment with TRAIL or/and Andro for 72-h. (D) Effects of TRAIL and Andro treatment on the colony formation of BLCA cell lines. ", "T24 cells were treated with DMSO (control), TRAIL (2 ng/mL), or Andro (8 μM) alone or both TRAIL (2 ng/mL) and Andro (8 μM) and incubated for 12 days. ", "Cell colonies (\\>50 cells) were counted using an inverted microscope (100×). (", "E) Effects of TRAIL and Andro treatment on T24-cell migration. ", "T24 cells were treated with DMSO, TRAIL (2 ng/mL), and/or Andro (5 μM) for 18 h. Images (100×) show T24-cell migration after treatment. (", "F) Left panel: the protein levels of CD147. ", "Right panel: MMP-9 in T24 cells treated with different concentrations of TRAIL (2 ng/ml) and/or Andro \\[4uM (+) or 8 uM (++)\\] for 18-h and measured by western blot. ", "Data represent the mean ± SD. ", "\\P \\< 0.05; \\\\P \\< 0.01; \\\\\\P \\< 0.001 (n = 3).](ijbsv15p0688g002){#F2}\n\n![", "Andro sensitizes TRAIL-induced apoptosis but not necrosis in T24 cells. (", "A) TRAIL combined with Andro treatment inhibited the cell viability of BLCA cell lines. ", "T24 cells were treated with various concentrations of TRAIL and/or Andro \\[2 (+) or 4 (++) or 8 (+++) μM\\] for 24-h, and cell viability was examined by MTS assay. (", "B) Protein expression of hallmarks of apoptosis in T24 cells treated with 2 ng/mL TRAIL or/and 8 µM of Andro for 24-h. (C) Effects of TRAIL and Andro treatment on apoptosis in T24 cell lines. ", "Cells were identified by Annexin V-FITC detection following DMSO (control), TRAIL (2 ng/mL), and/or Andro (8 μM) treatment for 24-h. Histogram showing the apoptosis rates of all cell lines. (", "D) Images (200×) showing apoptotic cells after treatment under different conditions. ", "Histograms of T24 cells treated with DMSO, TRAIL (2 ng/mL), and/or Andro (8 μM) and Z-AVD-FMK (0.05 μM) or Nec-1 (0.05 μM). ", "Cell viability was determined by MTS assay after 24-h. Data represent the mean ± SD. ", "\\P \\< 0.05; \\\\P \\< 0.01; \\\\\\P \\< 0.001 (n = 3).](ijbsv15p0688g003){#F3}\n\n![", "DR5 is critical for Andro-mediated sensitization of T24 cells to TRAIL. (", "A) DR4/DR5 protein levels in T24 cells treated with TRAIL and/or Andro for 24-h. (B) Histograms of qRT-PCR screening for DR4 (left panel)/DR5 (right panel) siRNA optimization. (", "C) Cell viability of T24 cells transfected with either siDR4 or siDR5 or both and treated with a combination of TRAIL and Andro for 24-h. (D) Effects of TRAIL and Andro combination treatment on apoptosis in DR4-knockdown and/or DR5-knockdown T24 cell lines. ", "Histogram showing the apoptosis rates of all cell lines. ", "Data represent the mean ± SD. ", "\\P \\< 0.05; \\\\P \\< 0.01; \\\\\\P \\< 0.001 (n = 3).](ijbsv15p0688g004){#F4}\n\n![*", "Activation of p53* expression is required for Andro-induced upregulation of DR4/DR5.** (", "A) GSEA revealing that genes in the high DR4/DR5-expression group were positively correlated with signatures related to the p53-signaling pathway. (", "B) p53 mRNA (left panel) and p53 protein levels (right panel) in control shRNA- and p53 shRNA-transfected T24 cells. (", "C) DR4/DR5 protein levels in control shRNA and p53 shRNA-transfected cells treated with Andro \\[4 (+) or 8 μM (++)\\]. (", "D) Cell viability of T24 cells transfected with control shRNA or p53 shRNA and treated with a combination of TRAIL (2 ng/mL) and Andro (8 μM) for 24-h. Data represent the mean ± SD. ", "\\P \\< 0.05; \\\\P \\< 0.01; \\\\\\P \\< 0.001 (n = 3).](ijbsv15p0688g005){#F5}\n\n![", "Combination treatment with TRAIL and Andro enhances cell apoptosis rates through inhibiting the NF-кB pathway in T24 cells. (", "A, B) T24 cells were treated with 2 ng/mL TRAIL and/or 8 µM Andro for 24-h, RelA/cIAP2 protein levels and its quantification were assessed by immunoblot. (", "C) Histograms showing the relative mRNA levels of RelA, Bcl-2, and XIAP in T24 cells treated with TRAIL or/and Andro. (", "D) T24 cells were treated with PDTC at various concentrations for 24-h, and cell viability and IC~50~ values were measured using MTS assays. (", "E) T24 cells were treated with 2 ng/mL TRAIL or 5 μM PDTC or 8 μM Andro or with a combination of TRAIL and Andro/PDTC for 24-h. Cell viability was measured by MTS assay. (", "F, G) Cell apoptosis rates of T24 cells according to Annexin V-FITC detection. ", "T24 cells were treated with 2 ng/mL TRAIL or 5 μM PDTC or 8 μM Andro or with a combination of TRAIL and Andro/PDTC for 24-h. Histograms showing the apoptosis rates. ", "Data represent the mean ± SD. ", "\\P \\< 0.05; \\\\P \\< 0.01; \\\\\\P \\< 0.001 (n = 3).](ijbsv15p0688g006){#F6}\n\n![", "Andro enhances TRAIL-mediated suppression of cell viability and apoptosis rates in other BLCA cell lines. (", "A, B) 5637 cells were treated with various concentrations of TRAIL or/and Andro for 24-h, and cell viability and IC~50~ values were measured by MTS assays. (", "C, D) UM-UC 3 cells were treated with various concentrations of TRAIL or/and Andro for 24-h, and cell viability and IC~50~ values were measured by MTS assays. (", "E) Effects of TRAIL and Andro treatment on 5637 and UM-UC 3 cell apoptosis. ", "5637 cells were identified by Annexin V-FITC detection following DMSO (control), TRAIL (2 ng/mL), or Andro (10 μM) treatment and combined TRAIL (2 ng/mL) and Andro (10 μM) treatment for 24-h. UM-UC 3 cells were identified by Annexin V-FITC detection following DMSO (control), TRAIL (10 ng/mL), or Andro (20 μM) treatment and combined TRAIL (10 ng/mL) with Andro (20 μM) treatment for 24-h. Histogram showing the apoptosis rates of 5637 and UM-UC3 cell lines. ", "Data represent the mean ± SD. ", "\\P \\< 0.05; \\\\P \\< 0.01; \\\\\\P \\< 0.001 (n = 3).](ijbsv15p0688g007){#F7}\n\n![", "Enhancing TRAIL induced apoptosis through blocking NF-κB pathway is effective in multiple BLCA cell lines. (", "A) 5637 cells were treated with various concentrations of PDTC for 24-h, cell viability and IC~50~ values were measured by MTS assays. (", "B) Effects of TRAIL and PDTC treatment on 5637 cell apoptosis. ", "5637 cells were identified by Annexin V-FITC detection after DMSO (Mock), TRAIL (2 ng/mL), or PDTC (20 μM) treatment and combined TRAIL (2 ng/mL) and PDTC (20 μM) treatment for 24-h. (C) Histogram showing the apoptosis rates of 5637 cells. (", "D) UM-UC 3 cells were treated with various concentrations of PDTC for 24-h, cell viability and IC~50~ values were measured by MTS assays. (", "E) Effects of TRAIL and PDTC treatment on UM-UC 3 cell apoptosis. ", "UM-UC 3 cells were identified by Annexin V-FITC detection after DMSO (control), TRAIL (10 ng/mL), or PDTC (40 μM) treatment and combined TRAIL (10 ng/mL) with PDTC (40 μM) treatment for 24-h. (F) Histogram showing the apoptosis rates of UM-UC 3 cells. ", "Data represent the mean ± SD. ", "\\P \\< 0.05; \\\\P \\< 0.01; \\\\\\P \\< 0.001 (n = 3).](ijbsv15p0688g008){#F8}\n\n![", "Schematic map describing apoptosis induction of the TRAIL and Andro combination therapy.](ijbsv15p0688g009){#F9}\n\n[^1]: Competing Interests: The authors have declared that no competing interest exists.", "\n" ]	{ "pile_set_name": "PubMed Central" }	[ 0.0028805152978748083, 0.0006716912030242383, 0.0006417165859602392, 0.0006586943054571748, 0.0007388832163996994, 0.000880541221704334, 0.0007611477049067616, 0.00103554199449718, 0.0007575549534521997, 0.001178298844024539, 0.04541802778840065, 0.0005578011041507125, 0.0006076031713746488, 0.0012538209557533264, 0.0006339891697280109, 0.000711594067979604, 0.0005826892447657883, 0.0006564482464455068, 0.0006085362401790917, 0.0009315134957432747, 0.0006733689224347472, 0.001082886941730976, 0.0005439327214844525, 0.0005503139109350741, 0.0005625943304039538, 0.0006287171854637563, 0.0008249690290540457, 0.0006218762719072402, 0.0005667182267643511, 0.0006096642464399338, 0.0006004173192195594, 0.0006532182451337576, 0.000919399899430573, 0.0005627849604934454, 0.000636207580100745, 0.0006050362717360258, 0.0005731081473641098, 0.0007407318335026503, 0.000601136009208858, 0.0006042977329343557, 0.0006289206794463098, 0.000962050340604037, 0.0006445136968977749, 0.000621408864390105, 0.00058844278100878, 0.0006365147419273853, 0.0007884326623752713, 0.0015261633088812232, 0.0006516817375086248, 0.0006334881763905287, 0.0008094330551102757, 0.0007757931598462164, 0.0006345214205794036, 0.0006673523457720876, 0.0005499803810380399, 0.000609417911618948, 0.0008091581985354424, 0.0006002903101034462, 0.0006036630948074162, 0.000623782048933208, 0.0006005996256135404, 0.0005691481637768447, 0.0005736630992032588, 0.0006354364450089633, 0.000723248056601733, 0.0006082106847316027, 0.0006123228813521564, 0.0005510198534466326, 0.0006104730418883264, 0.0005502611747942865, 0.0006354512879624963, 0.00055654626339674, 0.0006142743513919413, 0.0005884314887225628, 0.0007078861235640943, 0.0006095050484873354, 0.0005839145742356777, 0.000627368048299104, 0.0006406914326362312, 0.0006744331330992281, 0.0007067658007144928, 0.0007549367728643119, 0.0006033973768353462, 0.0006370015325956047, 0.000565710652153939, 0.0012608002871274948, 0.003426474519073963, 0.00055693305330351, 0.0007006680825725198, 0.0006782111595384777, 0.000580490508582443, 0.0006673679454252124, 0.0008988617337308824, 0.000601625710260123, 0.0005870895693078637, 0.0005981882568448782, 0.0006953391130082309, 0.000874399789609015, 0.0006853287341073155, 0.0005955083761364222, 0.0006094948621466756, 0.000580579333472997, 0.0005672291736118495, 0.0005719553446397185, 0.0005646550562232733, 0.0007178806117735803, 0.0006799915572628379, 0.0006075954297557473, 0.0006656528566963971, 0.0005913543282076716, 0.0005818384815938771, 0.0006330970791168511, 0.0008024215348996222, 0.0006068777292966843, 0.0006299828528426588, 0.0005806130939163268, 0.0006491142557933927, 0.0006092550465837121, 0.0007546702399849892, 0.0005984688177704811, 0.0009097509901039302, 0.0005969068151898682, 0.001140532549470663, 0.0006720783421769738, 0.0006097525474615395, 0.0005872613401152194, 0.0005789304268546402, 0.0006194663583301008, 0.0006439791759476066, 0.0006329887546598911, 0.00059424655046314, 0.0008298160973936319, 0.0007130154990591109, 0.0005896023358218372, 0.031853437423706055, 0.0010229600593447685, 0.0007862077327445149, 0.0007064237724989653, 0.0006035896949470043, 0.000579505693167448, 0.0005919362884014845, 0.0006358372047543526, 0.0006604695226997137, 0.0008240147144533694, 0.0007244183216243982, 0.0005401868838816881, 0.000570223550312221, 0.000792871112935245, 0.001113374950364232, 0.008217967115342617, 0.0008413268951699138, 0.0006652361480519176, 0.0006139190518297255, 0.0005983096780255437, 0.0005703420611098409, 0.000632176932413131, 0.000592213065829128, 0.06153456121683121, 0.0005591579829342663, 0.0006281613605096936, 0.0005498228711076081, 0.0006089290836825967, 0.0006619863561354578, 0.0005824307445436716, 0.0007147397845983505, 0.0006170671549625695, 0.0006631466094404459, 0.0008854120969772339, 0.000592213065829128, 0.08904577046632767, 0.0008394666365347803, 0.0005820597871206701, 0.0006135762669146061, 0.0006745214923284948, 0.000566579750739038, 0.0006398161640390754, 0.0006829251651652157, 0.0005575507530011237, 0.10593489557504654, 0.000940360885579139, 0.0006451540975831449, 0.0009287480497732759, 0.0007280823192559183, 0.000592213065829128, 0.0982743501663208, 0.0008627750794403255, 0.0005968704354017973, 0.000936978030949831, 0.000922262785024941, 0.000721369928214699, 0.10230729728937149, 0.0006202213116921484, 0.0006434896495193243, 0.0006955373100936413, 0.00058290472952649, 0.0005923830321989954, 0.0007334330002777278, 0.0006418830016627908, 0.000592213065829128, 0.0884065181016922, 0.0006148703396320343, 0.0005863888654857874, 0.0005821635131724179, 0.000671601330395788, 0.0006824872689321637, 0.000592213065829128, 0.08559703826904297, 0.0006638228660449386, 0.0005910942563787103, 0.0006507039070129395, 0.0005988762713968754, 0.0005964871379546821, 0.0007020860794000328, 0.0006964542553760111, 0.000592213065829128, 0.060931988060474396, 0.0006917600403539836, 0.001994825666770339 ]	0.004241	218
[ "Calcium supplements increase the serum levels of crosslinked N-telopeptides of bone collagen and parathyroid hormone in rachitic Nigerian children.", "\nBiochemical markers of bone turnover were measured in the sera of 16 controls and 10 children with calcium-deficiency rickets, during a 12-week course of calcium supplementation (1 g CaCO3/d) that was effective in healing the bone lesions of the rachitic children. ", "Serum levels of crosslinked N-telopeptides of bone collagen (NTx), parathyroid hormone (PTH), alkaline phosphatase (ALP), and urinary deoxypyridinoline (LP) were assayed at baseline and during the course of calcium therapy and compared with data of the 16 non-rachitic controls. ", "Calcium therapy suppressed serum NTx and PTH levels in the rachitic children within 24 h; however, after the first week, PTH and NTx levels increased to the extent that at 12 weeks both were elevated when compared with controls or to baseline levels. ", "Serum levels of NTx and PTH were correlated in the controls and experimental subjects (r = 0.63, p < 0.001). ", "The rate of bone resorption, as estimated by serum NTx concentration, is increased during the healing of rachitic lesions." ]	{ "pile_set_name": "PubMed Abstracts" }	[ 0.005008290056139231, 0.0008194010006263852, 0.00086464814376086, 0.0010930569842457771, 0.0005681809270754457, 0.0012906952761113644 ]	0.001607	6
[ "Unfortunate Category Archive\n\n…and it’s making ‘Reboot‘ look slick. ", "This did not need to be done! ", "We hear they’re toning down the violence. ", "Noooo. ", "That’s what made the original so raw and amazing! ", "It wasn’t for children. ", "Check out the WATERSHIP DOWN remake trailer above. ", "Thoughts? ", "And don’t forget to read the book if you haven’t already.", "\n\nQuite the blunder, but a funny one at that! ", "Jamestown, NY newspaper Post-Journal wrote their own headline for an AP story that they picked up this weekend about Julia Roberts‘ new Amazon show Homecoming, and their retraction after the jump! ", "STARS – They’re just like us!", "\n\nDevin Lima, member of 90’s boy band LFO has passed after a yearlong battle with stage 4 cancer. ", "He is the second member to battle cancer, as Rich Cronin also lost his life to cancer in 2010, leaving Brad Fischetti is the only surviving member of LFO. ", "Lima and Fischetti planned a reunion tour in 2017, but had to cancel when Lima was diagnosed and had to undergo surgery to remove a massive tumor from his abdomen. ", "RIP Devin, and thank you for the pop contributions!", "\n\nOopsies! ", "Looks like Rita Ora had a Mariah moment at The Macy’s Thankgiving Day parade BUT WORSE! ", "I mean, at this point, are we even surpirsed that pop stars lipsync these things!? ", "But still — not a cute moment to be televised. ", "Check out the mishap above! ", "Now people will actually know who Rita Ora IS!" ]	{ "pile_set_name": "Pile-CC" }	[ 0.000982866738922894, 0.0008787257829681039, 0.0013252641074359417, 0.0259210467338562, 0.0018252114532515407, 0.002609996125102043, 0.0006684461841359735, 0.0006808329490013421, 0.0008338470943272114, 0.0032379385083913803, 0.0006958498852327466, 0.022676056250929832, 0.05642281845211983, 0.010730179958045483, 0.0007712612277828157, 0.0009429644560441375, 0.011329173110425472, 0.002798084868118167, 0.0025154456961899996, 0.0008024540147744119, 0.0011000920785591006, 0.0014850087463855743 ]	0.006874	22
[ "Mentoring matters\n\nNEW GLASGOW — Town of New Glasgow officials have partnered with educators, with input from Pictou County Big Brothers Big Sisters, on a novel life-long learning project to mesh retired men and women with young people’s aptitudes.", "\n\nMore than a dozen people met at Glasgow Square on March 2 to continue the initiative called Trained Mentor-Mentoring Plus as a way to help clients improve their chances of reaching their career goals as they approach working age.", "\n\n“We applied for federal funding through New Horizons to do projects for age friendly people, such as matching retirees with skills,” said Geralyn MacDonald, director of Community Economic Development for the Town of New Glasgow. “", "Margie (Grant Walsh) is doing the matching and will co-ordinate on the ground.”", "\n\nNew Glasgow was the first stop for the event, which is planning visits elsewhere in the province.", "\n\nBig Brother Big Sisters of Pictou County’s executive director, Margie Grant-Walsh, attended the event and will be a resource for the program in New Glasgow.", "\n\n“They wanted to do a mentoring program and we’re providing the process and the policy,” she said. “", "We’ll be identifying the youth and making the matches.”", "\n\nMentoring is defined as a relationship-based intervention strategy that supports individuals, especially young people, facing life challenges.", "\n\nGordon Michael from Dalhousie University’s College of Continuing Education presented during part of the workshop on the subject Integrated Strategy for Social and Economic Opportunities.", "\n\nHe outlined trends in terms that included work and learning. ", "Among the trends, 32 per cent of Nova Scotia Community College students in diploma or multi-year programs are not returning after the first year, while 17 per cent of Maritime students are no longer enrolled at Maritime universities. ", "Degree completion in four years is 39 per cent and for five years is 58 per cent.", "\n\nHe shared other statistics that indicate nearly half of Canadian jobs are at high risk of being impacted by automation in the next 10 to 20 years.", "\n\n“I want to bring them back together every three months to see what they have learned,” Michael said of the retirees who join the program. “", "We have an ongoing learning model. ", "We have a lot of retired people with a lot of knowledge.”", "\n\nHe noted that 67 per cent more post-career Canadians were working between 2001 and 2009 and most entrepreneurs are more than 50 years old.", "\n\nSeniors want to stay engaged in the community for reasons that include physical and mental health and general well-being.", "\n\nRetired educator Debbie McIsaac is helping Michael with the mentoring and follow-up.", "\n\nFrom left: Debbie McIsaac, Gordon Michael, Margie Grant-Walsh and New Glasgow Mayor Nancy Dicks were among those who attended a Mentoring Plus event on Friday at Glasgow Square. (", "Goodwin photo)" ]	{ "pile_set_name": "Pile-CC" }	[ 0.000585320929531008, 0.0005219951854087412, 0.0005474211066029966, 0.000756982306484133, 0.0005592182278633118, 0.0005685709766112268, 0.0005450466996990144, 0.0006492039537988603, 0.0006085986387915909, 0.000568132265470922, 0.0005489747854880989, 0.0006002908339723945, 0.0006714275805279613, 0.0005929308827035129, 0.0005546831525862217, 0.0005835748743265867, 0.0006156015442684293, 0.0006547227967530489, 0.001111145713366568, 0.0005724710063077509, 0.0006058297003619373, 0.0006334821810014546 ]	0.000621	22
[ "Embed this image on your site:\n\n<a href=\"https://www.playgroundequipment.com/15-tips-and-tricks-for-being-the-very-best-at-pokemon-go/\"><img src=\"https://www.playgroundequipment.com/image/data/content/pokemon-go-guide-3.jpg\" alt=\"15 Tips and Tricks for being the Very Best at Pokémon Go - PlaygroundEquipment.com - Infographic\" title=\"15 Tips and Tricks for being the Very Best at Pokémon Go - PlaygroundEquipment.com - Infographic\" /></a><br><a href=\"http://www.", "PlaygroundEquipment.com\" alt=\"PlaygroundEquipment.com\" title=\"PlaygroundEquipment.com\">PlaygroundEquipment.com</a>\n\nMany of us have dreamed of becoming a real Pokémon Master since our childhoods. ", "With Pokémon Go, that possibility is now in our hands. ", "We can now search far and wide, teaching our Pokémon to understand the power that's inside (our smartphones)! ", "Pokémon Go unites technology with nature, exercise, and play! ", "This is wonderful for getting kids to move, explore parks, socialize, and enjoy the environment. ", "Of course, plenty of adults are immersed in the world of Pokémon Go as well - it just topped 75 million downloads worldwide! ", "Here are 15 tips to help you and your kids on your quest to catch 'em all." ]	{ "pile_set_name": "OpenWebText2" }	[ 0.0007833817508071661, 0.0009287520661018789, 0.0009685885161161423, 0.0011550274211913347, 0.0010667233727872372, 0.000625516870059073, 0.0008377997437492013, 0.0021251582074910402 ]	0.001061	8
[ "Conservation and evolution in and among SRF- and MEF2-type MADS domains and their binding sites.", "\nSerum response factor (SRF) and myocyte enhancer factor 2 (MEF2) represent two types of members of the MCM1, AGAMOUS, DEFICIENS, and SRF (MADS)-box transcription factor family present in animals and fungi. ", "Each type has distinct biological functions, which are reflected by the distinct specificities of the proteins bound to their cognate DNA-binding sites and activated by their respective cofactors. ", "However, little is known about the evolution of MADS domains and their DNA-binding sites. ", "Here, we report on the conservation and evolution of the two types of MADS domains with their cognate DNA-binding sites by using phylogenetic analyses. ", "First, there are great similarities between the two types of proteins with amino acid positions highly conserved, which are critical for binding to the DNA sequence and for the maintenance of the 3D structure. ", "Second, in contrast to MEF2-type MADS domains, distinct conserved residues are present at some positions in SRF-type MADS domains, determining specificity and the configuration of the MADS domain bound to DNA sequences. ", "Furthermore, the ancestor sequence of SRF- and MEF2-type MADS domains is more similar to MEF2-type MADS domains than to SRF-type MADS domains. ", "In the case of DNA-binding sites, the MEF2 site has a T-rich core in one DNA sequence and an A-rich core in the reverse sequence as compared with the SRF site, no matter whether where either A or T is present in the two complementary sequences. ", "In addition, comparing SRF sites in the human and the mouse genomes reveals that the evolution rate of CArG-boxes is faster in mouse than in human. ", "Moreover, interestingly, a CArG-like sequence, which is probably functionless, could potentially mutate to a functional CArG-box that can be bound by SRF and vice versa. ", "Together, these results significantly improve our knowledge on the conservation and evolution of the MADS domains and their binding sites to date and provide new insights to investigate the MADS family, which is not only on evolution of MADS factors but also on evolution of their binding sites and even on coevolution of MADS factors with their binding sites." ]	{ "pile_set_name": "PubMed Abstracts" }	[ 0.000602773972786963, 0.0008583217859268188, 0.0005976035608910024, 0.000607197405770421, 0.0005418378277681768, 0.0005408563883975148, 0.0007670580525882542, 0.0008145886240527034, 0.0006480371812358499, 0.0006686995038762689, 0.0009334272472187877, 0.0005805073888041079 ]	0.00068	12
[ "Provider, Nursing and Psychiatry Grand Rounds Online Videos\n\nGrand Rounds Objectives\n\nPhysicians seeking Category 1 CME credit for this online presentation must complete the following evaluation and form. ", "If you have not already viewed the Grand Rounds presentation, please do so before proceeding .", "\n\nSeattle Children's designates this online educational activity for a maximum of\n1 AMA PRA Category 1 Credit\nTM\n. ", "Physicians should claim only those hours of credit that they actually spent in the educational activity.", "\n\nCourse Title: Somebody I Used to Know: Staying Connected to Yourself in the Challenging World of Healthcare\n\nYour Information:\n\nYou must complete the following fields so that we can email you a notification of your credit for your records.", "\n\nFirst Name:\n\nLast Name:\n\nCity:\n\nState:\n\nZip/Postal Code:\n\nEmail:\n\nEvaluation:\n\nYour evaluation is important in helping us to improve the quality of future programs.", "\nPlease answer the following questions before submitting your credit request form.", "\nYou must provide a response to each question to proceed.", "\n\nUsing the following 1-5 scale, please respond to the statements below:\n\nWhat's New\n\nAbout This Site\n\nSeattle Children’s provides healthcare without regard to race, color, religion (creed), sex, gender identity or expression, sexual orientation, national origin (ancestry) or disability. ", "Financial assistance for medically necessary services is based on family income and hospital resources and is provided to children under age 21 whose primary residence is in Washington, Alaska, Montana or Idaho." ]	{ "pile_set_name": "Pile-CC" }	[ 0.0005854230257682502, 0.0005312619614414871, 0.0006728983717039227, 0.0006520769093185663, 0.0005248196539469063, 0.0005097618559375405, 0.0005610724329017103, 0.0005546606844291091, 0.0008094619843177497, 0.000719736679457128 ]	0.000612	10
[ "How to Increase Level for Enchanted Book in Minecraft\n\nThis Minecraft tutorial explains how to increase the level of an enchanted book using an anvil with screenshots and step-by-step instructions.", "\n\nIn Minecraft, enchanted books can come in different levels for a particular enchantment. ", "For example, an enchanted book may be enchanted with Sharpness I, Sharpness II, Sharpness III, Sharpness IV, or Sharpness V. The higher the level, the more powerful the enchantment. ", "Lower level enchantment books are easier to acquire.", "\n\nIf you have two enchanted books that are the same enchantment and level, you can combine the two enchanted books to create one enchanted book that is one level higher. ", "For example, combining two Level 1 enchanted books will result in a single Level 2 enchanted book.", "\n\nHere are the levels that you can combine (but must be same enchantment on both books):\n\nBooks to Combine Result Level 1 + Level 1 = Level 2 Level 2 + Level 2 = Level 3 Level 3 + Level 3 = Level 4 Level 4 + Level 4 = Level 5\n\nLet's explore how to increase the level for an enchanted book using an anvil.", "\n\nRequired Materials to Increase Level of Enchanted Book\n\nIn Minecraft, these are the materials you can use to increase the level of an enchanted book using an anvil:\n\nTIP: The two enchanted books must have the same enchantment and the same enchantment level to be combined into a higher book.", "\n\nSteps to Increase the Level of an Enchanted Book\n\n1. ", "Place the Anvil\n\nOnce you have two enchanted books that are the same and an anvil, add the anvil to your hotbar so that it is an item that you can use.", "\n\nNext, position your pointer (the plus sign) on the block where you want to place the anvil. ", "You should see the block become highlighted in your game window.", "\n\nThe game control to place the anvil depends on the version of Minecraft:\n\nFor Java Edition (PC/Mac), right click on the block.", "\n\nFor Pocket Edition (PE), you tap on the block.", "\n\nFor Xbox 360 and Xbox One, press the LT button on the Xbox controller.", "\n\nFor PS3 and PS4, press the L2 button on the PS controller.", "\n\nFor Wii U, press the ZL button on the gamepad.", "\n\nFor Nintendo Switch, press the ZL button on the controller.", "\n\nFor Windows 10 Edition, right click on the block.", "\n\nFor Education Edition, right click on the block.", "\n\n2. ", "Use the Anvil\n\nTo use the anvil, you need to stand in front of it.", "\n\nThe game control to use the anvil depends on the version of Minecraft:\n\nFor Java Edition (PC/Mac), right click on the anvil.", "\n\nFor Pocket Edition (PE), you tap on the anvil.", "\n\nFor Xbox 360 and Xbox One, press the LT button on the Xbox controller.", "\n\nFor PS3 and PS4, press the L2 button on the PS controller.", "\n\nFor Wii U, press the ZL button on the gamepad.", "\n\nFor Nintendo Switch, press the ZL button on the controller.", "\n\nFor Windows 10 Edition, right click on the anvil.", "\n\nFor Education Edition, right click on the anvil.", "\n\nNow your anvil is open and you can see the Repair & Name menu.", "\n\nAs you can see, there are 2 enchanted books with Sharpness I in our inventory. ", "These are the books that we will combine.", "\n\n3. ", "Combine the Enchanted Books\n\nTo combine the two enchanted books, both books must have the same enchantment and the same level. ", "In this example, we have placed an enchanted book with Sharpness I in the first slot and an enchanted book with Sharpness I in the second slot.", "\n\nIn the third slot, you will see the enchanted book with Sharpness II. ", "It will cost 2 experience levels to combine the Sharpness I books into Sharpness II.", "\n\n4. ", "Move the Enchanted Item to Inventory\n\nNow, move the enchanted book with Sharpness II from the third slot to your inventory hotbar.", "\n\nTIP: If you hover over the enchanted book, you will see the name and level of the enchantment.", "\n\nCongratulations, you just learned how to increase the level of an enchanted book using an anvil in Minecraft.", "\n\nVideos\n\nWatch this video to learn how to upgrade your Enchanted Book in Minecraft.", "\n\nSubscribe\n\nOther Intermediate Tutorials" ]	{ "pile_set_name": "OpenWebText2" }	[ 0.0007029400439932942, 0.0006359450635500252, 0.0006514790002256632, 0.0006343210116028786, 0.0006108609377406538, 0.0006151056732051075, 0.0009174537844955921, 0.000687277817633003, 0.0006194364978000522, 0.0029111967887729406, 0.01897687464952469, 0.0007987908320501447, 0.0010459487093612552, 0.005470768548548222, 0.0009705279371701181, 0.0008284844225272536, 0.0009649433195590973, 0.0009870153153315187, 0.0009634065208956599, 0.000911159731913358, 0.0011860732920467854, 0.028761418536305428, 0.0008776233880780637, 0.030214395374059677, 0.0009705279371701181, 0.0008284844225272536, 0.0009649433195590973, 0.0009870153153315187, 0.005147221032530069, 0.005830356385558844, 0.044764161109924316, 0.0005621301825158298, 0.0006258513894863427, 0.0011743707582354546, 0.000600738450884819, 0.0005980466376058757, 0.000608826638199389, 0.0008546488825231791, 0.0012898282147943974, 0.0007106998236849904, 0.0005706884548999369, 0.0005892604822292924, 0.0006726181600242853, 0.0007419512257911265 ]	0.003887	44
[ "A variety of processes for forming a color filter have been reported. ", "Among them, the process employing electrodeposition is noticeable in the art. ", "For example, Japanese Patent Application Ser. ", "No. ", "3-12018 and Japanese Patent Kokai Publication No. ", "61-272720, the former filed by the present assignee, disclose the process comprising: forming an electroconductive layer on a substrate; forming a positive type photosensitive film thereon; pattern-wise exposing the film; removing the exposed part; and forming a desired colored layer by electrodeposition. ", "Since a positive type photosensitive film is employed in this process, it is ideal that only the exposed part of the film is solubilized to a developer, whereby, the remaining photosensitive film still keeps photosensitivity and can repeat exposure and development.", "\nHowever, in activity, the positive type photosensitive film adjacent to the edge of the formed colored layer is likely to be modified during the first developing, electrodepositing and heat curing and lose photosensitivity. ", "The modified portion, in the subsequent colored layer forming process, often causes coloring failure, such as frame-like discoloration, or size failure, such as irregular pattern edge lines (see FIG. ", "9).", "\nThe present invention provides an improved process for producing a multicolor display by which a color filter having neither the coloring failure nor the size failure is obtained." ]	{ "pile_set_name": "USPTO Backgrounds" }	[ 0.000581042084377259, 0.0005429257871583104, 0.0006679045618511736, 0.0013787426287308335, 0.0006914848345331848, 0.0006084127235226333, 0.0006176564493216574, 0.000691395893227309, 0.0006586622912436724, 0.0009283990366384387, 0.0006575784645974636 ]	0.000729	11
[ "Q:\n\ncudaMemcpy throws InvalidValue error when copying from device to host\n\nI've been trying to implement a one dimensional FFT using cuFFT. ", "An InvalidValue error is thrown and no meaningful results are produced.", "\nI've tried to ensure that each error is caught, and I believe that the cudaMemcpy from DeviceToHost causes the issue, though I am not sure why, nor how to fix it. ", "The data size parameter in cudaMemcpy follows the same relation as supplied by the cuFFT documentation.", "\n\n#include <iostream>\n#include <fstream>\n#include <stdlib.h>\n#include <string.h>\n#include <unistd.h>\n\n#include <cuda_runtime_api.h>\n#include <cufft.h>\n\n// cuda macros\n#define NX 100 // number of points\n#define BATCH 1 // number of ffts to perform\n#define RANK 1 //\n#define IDIST 1 // distance between 1st elements of batches\n#define ISTRIDE 1 // do every ISTRIDEth index\n#define ODIST 1 // distance between 1st elements of output\n#define OSTRIDE 1 // distance between output elements\n\nvoid fft1d() {\n\n // create plan for performing fft\n cufftHandle plan;\n if (cufftPlan1d(&plan, NX, CUFFT_R2C, BATCH) !", "= CUFFT_SUCCESS) {\n printf(\"Failed to create 1D plan\\n\");\n return;\n }\n\n // assemble data\n double temp_data[] = {2.598076211353316, 3.2402830701637395, 3.8494572900049224, 4.419388724529261, 4.944267282795252, 5.41874215947433, 5.837976382931011, 6.197696125093141, 6.494234270429254, 6.724567799874842, 6.886348608602047, 6.97792744346504, 6.998370716093996, 6.9474700202387565, 6.8257442563389, 6.6344343416615565, 6.37549055993378, 6.051552679431957, 5.665923042211819, 5.222532898817316, 4.725902331664744, 4.181094175657916, 3.5936624057845576, 2.9695955178498603, 2.315255479544737, 1.6373128742041732, 0.9426788984240022, 0.23843490677753865, -0.46823977812093664, -1.1701410542749289, -1.8601134815746807, -2.531123226988873, -3.176329770049035, -3.7891556376344524, -4.363353457155562, -4.893069644570959, -5.3729040779788875, -5.797965148448726, -6.163919626883915, -6.467036838555256, -6.704226694973039, -6.873071195387157, -6.971849076777267, -6.999553361041935, -6.955901620504255, -6.84133885708361, -6.657032965782207, -6.404862828733319, -6.0873991611848375, -5.707878304681281, -5.270169234606201, -4.778734118422206, -4.23858282669252, -3.6552218606153755, -3.0345982167228436, -2.383038761007964, -1.707185730522749, -1.0139290199674, -0.31033594356630245, 0.39642081173600463, 1.0991363072871054, 1.7906468025248339, 2.463902784786862, 3.1120408346390414, 3.728453594100783, 4.306857124485735, 4.841354967187034, 5.326498254347925, 5.757341256627454, 6.129491801786784, 6.439156050110601, 6.683177170206378, 6.859067520906216, 6.965034011197066, 6.999996379650895, 6.963598207007518, 6.85621054964381, 6.678928156888352, 6.433558310743566, 6.122602401787424, 5.749230429076629, 5.317248684008804, 4.831060947586139, 4.295623596650021, 3.7163950767501706, 3.0992802567403803, 2.4505702323708074, 1.7768781925409076, 1.0850720020162676, 0.3822041878858906, -0.3245599564963766, -1.0280154171511335, -1.7209909100394047, -2.3964219877733033, -3.0474230571943477, -3.667357573646071, -4.249905696354359, -4.78912871521179, -5.279529592175676, -5.716109000098287};\n cufftReal idata;\n cudaMalloc((void) &idata, sizeof(cufftComplex)NX);\n if (cudaGetLastError() !", "= cudaSuccess) {\n printf(\"Failed to allocate memory space for input data.\\n\");\n return;\n }\n\n cudaMemcpy(idata, temp_data, sizeof(temp_data)/sizeof(double), cudaMemcpyHostToDevice);\n if (cudaGetLastError() !", "= cudaSuccess) {\n printf(\"Failed to load time data to memory.\\n\");\n return;\n }\n\n // prepare memory for return data\n cufftComplex odata;\n cudaMalloc((void) &odata, sizeof(cufftComplex)(NX/2 + 1));\n if (cudaGetLastError() !", "= cudaSuccess) {\n printf(\"Failed to allocate memory for output data.\\n\");\n }\n\n // perform fft\n if (cufftExecR2C(plan, idata, odata) !", "= CUFFT_SUCCESS) {\n printf(\"Failed to perform fft.\\n\");\n return;\n }\n\nI think the error is thrown here, at the cudaMemcpy.", "\n\n // grab data from graphics and print (memcpy waits until complete) cuda memcopy doesn't complete\n // can return errors from previous cuda calls if they haven't been caught\n cufftComplex out_temp_data;\n size_t num_bytes = (NX/2 + 1)sizeof(cufftComplex);\n cudaMemcpy(out_temp_data, odata, num_bytes, cudaMemcpyDeviceToHost);\n int error_value = cudaGetLastError();\n printf(\"cudaMemcpy from device state: %i\\n\", error_value);\n if(error_value !", "= cudaSuccess) {\n printf(\"Failed to pull data from device.\\n\");\n return;\n }\n\n for (size_t i = 0; i < (NX/2 + 1); i++) {\n printf(\"%lu %f %f\\n\", i, out_temp_data[i].x, out_temp_data[i].y);\n }\n\n // clean up\n cufftDestroy(plan);\n cudaFree(idata);\n\n}\n\nint main() {\n\n fft1d();\n return 0;\n}\n\nA:\n\nMemory must be allocated before cudaMemcpy can write the data. ", "Thanks to generic-opto-guy for pointing this out.", "\nIn this case:\nout_temp_data = new cufftComplex[NX/2 + 1];\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.006526872981339693, 0.001048290985636413, 0.000912978604901582, 0.0010113692842423916, 0.0011124133598059416, 0.006853219121694565, 0.008602548390626907, 0.0033764021936804056, 0.0015031597577035427, 0.0058365981094539165, 0.010651545599102974, 0.0075767673552036285, 0.000726926198694855, 0.0006935379933565855 ]	0.004031	14
[ "1988–89 Combined Counties Football League\n\nThe 1988–89 Combined Counties Football League season was the 11th in the history of the Combined Counties Football League, a football competition in England, which operates at levels 9–10 of the English football league system.", "\n\nThe league was won by British Aerospace (Weybridge) for the fourth time, and for the third time in four seasons.", "\n\nLeague table\nThe league was increased from 18 clubs to 19 after one new club joined:\n\nSteyning Town, joining from the Wessex League.", "\n\nReferences\n\nExternal links\n Combined Counties League Official Site\n\n1988-89\nCategory:1988–89 in English football leagues" ]	{ "pile_set_name": "Wikipedia (en)" }	[ 0.0008636070415377617, 0.0007594896014779806, 0.0007685697637498379, 0.0007295241812244058 ]	0.00078	4
[ "Q:\n\nignoring mysql fulltext stopwords in query\n\nI'm building a search for a site, which utilizes a fulltext search. ", "The search itself works great, that's not my problem. ", "I string together user provided keywords (MATCH... AGAINST...) with AND's so that multiple words further narrow the results. ", "Now, I know that certain stop words aren't indexed, and that's fine with me I don't really want to use them as selection criteria. ", "But, if a stopword is provided in the keyword set (by the user), it kills all the results (as expected) even if the word actually is in a certain text block. ", "\nMy question: is there any way to check to see if a certain word is a stop word at the time of the query? ", "My preferred solution would just be to exclude the relevant word from the search criteria (I don't care if a user can narrow results by the word 'neither', I just don't want MySQL to return an empty result set because the user provided it, even though neither does exist in the results). ", "Or, am I just going to have to empty the stopword list? ", "Thanks very much for any help.", "\nedit ----\nI'm sorry, but there's really no code snippets to provide for this one. ", "The code works fine, actually exactly as expected. ", "It's more of a logical problem I'm dealing with. ", "But as an example, in the way of explanation:\nlets say there are three records, which include the words (but are not limited to)\n1: apple, orange, mango, banana\n2: grape, orange, pineapple, mango\n3: potato, mango, melon, keira knightly\nIf the search word entered by the user is mango, all results are returned correctly. ", "If the words are orange AND mango, results 1 and 2 are returned (correctly). ", "Now, let's say banana is a stop word (it's not... but let's assume it is), if the search is for orange, mango, AND banana, no results are returned (because banana isn't in the fulltext index). ", "\nWhat I'm looking for is if anyone else has encountered this problem, and has a way to work around it. ", "Sort of an:\nif 'banana' NOT STOP WORD match 'banana' against `words`. (", "OBVIOUSLY not real code).", "\n\nOr... am I just going to have to drop the stopword list...\n\nA:\n\nYou can verify the keywords by comparing all stopwords. ", "Here is the list of stopwords \nI've found out a solution to disable stopwords from fulltext. ", "\nYou just need to locate .cnf file and add this, \nft_stopword_file = \"\"\n\nrestart mysql engine and rebuild indexes;\nHope this work\n\nA:\n\nHow to disable fulltext stopwords in MySQL:\nIn my.ini text file (MySQL) :\nft_stopword_file = \"\" or link an empty file \"empty_stopwords.txt\"\nft_min_word_len = 2 \n\n// set your minimum length, but be aware that shorter words (3,2) will increase the query time dramatically, especially if the fulltext indexed column fields are large.", "\nSave the file, restart the server.", "\nThe next step should be to repair the indexes with this query:\nREPAIR TABLE tbl_name QUICK.", "\n\nHowever, this will not work if you table is using InnoDB storage engine. ", "You will have to change it to MyISAM :\nALTER TABLE t1 ENGINE = MyISAM;\n\nSo, once again:\n1. ", "Edit my.ini file and save\n2. ", "Restart your server (this cannot be done dynamically)\n3. ", "Change the table engine (if needed) ALTER TABLE tbl_name ENGINE = MyISAM;\n4. ", "Perform repair REPAIR TABLE tbl_name QUICK.", "\n\nBe aware that InnoDB and MyISAM have their speed differences. ", "One read faster, other writes faster ( read more about that on the internet )\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.0007354788831435144, 0.00083746766904369, 0.0006678345962427557, 0.0006014410755597055, 0.0007332293316721916, 0.0007100793300196528, 0.0007342901662923396, 0.001044534263201058, 0.0005351861473172903, 0.0006574305589310825, 0.0005620602751150727, 0.0006601029890589416, 0.0005938040558248758, 0.0005853530601598322, 0.0015104796038940549, 0.0005830370355397463, 0.0009575543226674199, 0.0007210812764242291, 0.0007490711868740618, 0.0008165708277374506, 0.0006501259049400687, 0.001450613490305841, 0.0007649747421965003, 0.0006297507788985968, 0.0007079590577632189, 0.0030386224389076233, 0.001120054512284696, 0.0006388991023413837, 0.0009003870654851198, 0.0006701317615807056, 0.0006111437105573714 ]	0.000844	31
[ "A charity is calling for dads to attend their antenatal workshops in order to save the service after being unable to secure long-term funding.", "\n\nDads Rock has helped more than 300 people prepare for fatherhood by running blocks of classes in conjunction with NHS Lothian with resounding success.", "\n\nDarren Ure said the Dad's Rock antenatal classes were invaluable ahead of the birth of his son Angus. ''", "Also pictured is his wife Amy Ure\n\nThe antenatal classes focus on what dads can expect in the delivery room, bathing newborns, changing nappies and advice for when the time comes.", "\n\nDads Rock had previously been funded by Big Lottery but this was not renewed in 2018/19. ", "The charity approached the Scottish Government who agreed to a one-off funding of £50,000 to help in the sustainability of the service.", "\n\nBut the funding pot ran dry at the end of last year and a variety of grant applications have proved unsuccessful for the popular sessions.", "\n\nDads Rock co-founder Thomas Lynch admits the classes may have to be discontinued if the charity cannot access alternative sources of funding.", "\n\nHe told the Evening News: “NHS Lothian cannot now publicise the sessions because they’re not involved meaning we’re getting around six participants rather than 27 we had booked in February, which we were forced to cancel.", "\n\n“There is not a lot out there that really focuses on dads and what to expect. ", "The NHS Lothian ones are great but most focus more on the mums. ", "Our classes bring together dads who are in a similar position and are in need of support.”", "\n\nDads Rock is continuing to host sessions once a month without the presence of an NHS Lothian midwife suggesting participants donate £10 to keep the service afloat.", "\n\nDarren Ure, 35, says what he learned at the Dads Rock antenatal classes proved invaluable to him when his wife Amy gave birth to their son Angus two months early via an emergency C-section.", "\n\nThe gas supervisor from South Queensferry said: “It was an emergency situation and the advice from the classes meant I was able to keep calm and explain things to Amy who had no clue what was really happening.", "\n\n“We had a mixture of sessions with and without NHS Lothian and I actually preferred the ones with Dads Rock because they were more relaxed and personal.", "\n\n“I don’t know how I would have coped without Dads Rock. ", "Thomas and the other dads taught me a lot and I was able to just stay focused and help Amy when I could thanks to the knowledge they shared with me. ", "I felt prepared to be a dad after only a few sessions and it would be a huge shame to see others not get the same opportunity.”", "\n\nThomas says it costs £100 to put on a monthly workshop now and is spreading the word to encourage more future dads to come along to avoid the closure of the service.", "\n\n“I want fathers to know that this service is available to them,” he said. “", "When we had kids we could not find anything for dads in Edinburgh. ", "I want dads to know they can play a big role and have value during the pregnancy.”", "\n\nA Scottish Government spokesperson said: “We want to make Scotland the best place in the world for children and young people to grow up. ", "Encouraging and supporting fathers to play an active role in their child’s upbringing is key if we are to improve the health, wellbeing and life chances of Scotland’s children and young people.", "\n\n“We provide funding to a range of national organisations working with fathers and families and in 2018/19 provided one-year funding to Dads Rock to help them invest in sustainability of their services.”", "\n\nTrending\n\nTake a look inside this £2.9m New Town home with the best roof terrace in Edinburgh\n\nFast and Furious 9: Full list of all 52 Edinburgh road closures for filming in September\n\nFast and Furious 9 filming has begun in Edinburgh - these are the roads that are closing and when\n\nFirefighters tackle blaze at Gilmerton Primary School\n\nHearts: Craig Levein's 34-man squad analysed - who are the important first-team players, the back-ups and the ones who could move on?" ]	{ "pile_set_name": "Pile-CC" }	[ 0.0012327061267569661, 0.0030830707401037216, 0.0007904228405095637, 0.0009148760000243783, 0.0006119360914453864, 0.0005044157733209431, 0.0006111833499744534, 0.0006396386888809502, 0.0006751115433871746, 0.0009350672480650246, 0.012836080975830555, 0.0009880715515464544, 0.0006096282158978283, 0.0011030271416530013, 0.000718381255865097, 0.0007455297163687646, 0.0014982104767113924, 0.0005854587652720511, 0.0011912306072190404, 0.001131588127464056, 0.0035484940744936466, 0.0008091935887932777, 0.0008061181288212538, 0.004072883166372776, 0.0010623832931742072, 0.000561045715585351, 0.0006424430175684392 ]	0.001589	27
[ "Observer News. ", "Dist. ", "by HURINet. ", "10 December, 1996.", "\n\n(Observer News): Last month, the parents of 4-year-old Amira\nHassan did what they thought was their duty as good\nMuslims: They hired the family physician to snip off part of\nher genitals.", "\n\nWhen she died a few hours later, ...as a result of\ncomplications from anesthesia, Mahmoud Hassan and his wife,\nAtiyat, accepted it as God's will. ", "Now the only thing that\npuzzles them is why anyone thinks...the doctor, Ezzat\nShehat, did anything wrong.", "\n\n\"He is a good doctor,\" said Hassan, 27, a somber grocer with\na neatly trimmed mustache. \"", "They should let him return to\nwork.\" ", "The death of the little girl -- one of two who\nsuffered the same fate at the hands of the same doctor on\nthe same day -- highlights the immense challenge faced by\nwomen's health advocates and some government officials in\nEgypt as they begin to confront the widely practiced ritual\nknown as female circumcision.", "\n\nHaving ignored the issue for decades, public health\nauthorities in Egypt this year were stunned by a national\nsurvey showing...97 percent of married Egyptian women\nbetween the ages of 15 and 49 had undergone the procedure.", "\nAmong women with daughters, 87 percent reported...at least\none daughter had been circumcised or would be.", "\n\n\"They were all surprised,\" said Dara Carr, a researcher with\nMaryland-based Macro International Inc., which conducted the\nsurvey on behalf of the Egyptian government with funding\nfrom the U.S. Agency for International Development. \"", "I think\nthe Egyptians felt that this was a dying custom and...this\nwas much, much higher than they had expected.\"", "\n\nLike other countries in Africa where female circumcision is\ncommonplace, Egypt has come under growing international\npressure to curb the practice. ", "It has been linked to such\npotentially fatal health risks as bleeding, infection and\ncomplications relating to anesthesia -- and, in later life,\nproblems in childbirth and sexual relations. ", "That pressure\nled, in July, to a decree by Health Minister Ismail Sallam\nbarring health professionals from performing the operation.", "\n\n...the decree has encountered stiff resistance from Islamic\nfundamentalists, including many within the medical\nestablishment, who defend the practice as necessary to\nprotect women from the consequences of excessive sexual\ndesire.", "\n\nJudging from a visit to this rural village, hemmed in by\nsugar-cane fields on the west bank of the Nile 320 miles\nsouth of Cairo, the ban has yet to touch the lives of\nordinary Egyptians. ", "Many people said they had never heard of\nit. ", "Others said they would ignore it. ", "And local prosecutors\nacknowledged...they investigate circumcision cases with\nlittle vigor, if at all.", "\n\nIn the meantime, health workers say, girls as young as 3\ncontinue to undergo painful and sometimes risky surgery at\nthe hands of poorly trained midwives, village barbers and,\nin many cases, doctors who work for the same ministry that\nis claiming to combat the practice.", "\n\nHuman rights advocates are divided on the best way to combat\nthe phenomenon. ", "Some say Egypt's parliament should make\nfemale circumcision a criminal offense. ", "Still others say the\ngovernment should concentrate on promoting public awareness\nof the risks.", "\n\n\"People say...it is so deeply rooted that [making it a\ncriminal offense] will just drive it underground,\" said\nMarie Assaad, who chairs a coalition of Egyptian\nnongovernmental organizations that is trying to combat the\nproblem. \"", "Many doctors still believe it is a very important\nprotection against disease and immorality and that talking\nagainst it is a Western fad.\"", "\n\nAmong religious conservatives in Egypt, female circumcision\nis typically defended on the basis of sayings attributed to\nthe prophet Muhammad. ", "But others contend the practice has no\nbasis in Islam. ", "They note...it is unknown in\nultraconservative Islamic countries such as Saudi Arabia and\nIran, occurs widely within Egypt's Coptic Christian minority\nand may date to the time of the pharaohs, long before the\nadvent of Islam.", "\n\nIn sub-Saharan Africa, female circumcision is a tribal\ncustom that occurs across a broad spectrum of religions and\ncultures in more than 20 countries. ", "The operation can range\nin severity from partial or full removal of the clitoris and\nsurrounding tissue to a radical procedure in which the\nexternal genitals are cut away and the area closed with\nstitches, leaving only a small opening for urination and\nmenstruation.", "\n\nEgypt's government and official media largely ignored the\nsubject until 1994, when CNN broadcast footage of a\nscreaming 10-year-old Egyptian girl undergoing the procedure\nat the hands of a Cairo barber.", "\n\nAfter initially accusing the network of trying to embarrass\nEgypt in front of foreign guests then in Cairo for a U.N.\nconference on population, the government promised action.", "\n...it soon ran into opposition from the Gad Haq Ali Gad Haq,\nthen Egypt's senior religious figure and the sheik of\nCairo's Al Azhar University, who warned...\"girls who are not\ncircumcised when young have a sharp temperament and bad\nhabits.\"", "\n\nAli Fattah, health minister at the time, tried to finesse\nthe issue by declaring...public hospitals would perform the\noperation only one day a week. ", "When Egyptian women's groups\ncomplained, he banned the procedure in public hospitals, but\nnot in private ones.", "\n\nSallam, the current health minister, has tried to close that\nloophole, announcing in July...no licensed health\nprofessional could perform the procedure. ", "Sallam\nacknowledged in an interview...the Health Ministry has\nsuspended or revoked the licenses of doctors in just two\ncircumcision cases, both of them involving deaths.", "\n\nThe government faces strong resistance from Egyptian doctors\nsuch as Munir Mur, a British-trained professor of gynecology\nat Cairo's Ain Shams University with a thriving private\npractice in the upscale suburb of Heliopolis. ", "Although Mur\ncondemns the more extreme varieties of circumcision -- he\nsaid his method removes a fold over the clitoris while\nleaving the clitoris intact -- he has sued to overturn the\nministry's ban on grounds...it is contrary both to Islam and\nsound medical practice.", "\n\n\"Most of our parents, mothers, aunts, sisters and so on have\nbeen doing this for years, and no one was complaining,\" Mur\nsaid in an interview.", "\n\nAttitudes are even more entrenched in such rural villages as\nthis warren of mud-brick houses and narrow alleys just a few\nmiles from the five-star tourist palaces of Luxor on the\nopposite bank.", "\n\n\"Even if the law prohibits it, people will still do this\noperation,\" said Hoda Abdelmoreed, 29, a vivacious mother of\nthree who teaches Arabic and religion at a high school in\nnearby Armant.", "\n\n\"Europe and the United States,\" she added, \"need it more\nthan we do. ", "They wouldn't have AIDs and all these other\nproblems.\"", "\n\nWhen the parents of Amira Hassan decided...she should be\ncircumcised, they turned to Shehat, the family doctor, who\nworked at the shabby, two-story village clinic run by the\nEgyptian Health Ministry.", "\n\nShehat had arranged to perform the operation along with two\nother circumcisions on the morning of Oct. 13. ", "According to\nMahmoud Hassan, he injected Amira with a general anesthetic\nand then circumcised her in the family living room, a\ncramped, filthy space lined with particle-board benches.", "\n\nOn the same morning, Shehat performed the operation another\ngirl, 3-year-old Warda Sayed. ", "The two girls died several\nhours later, apparently as a result of complications from\nthe anesthetic. ", "The third girl survived. ", "Shehat then\nreturned to the houses of the two dead girls, where he\nfilled out certificates listing the cause of death as\n\"natural.\" ", "Shehat declined to comment.", "\n\nThe Health Ministry has suspended Shehat pending the outcome\nof the criminal investigation. ", "But the doctor is still\nliving at the clinic with his wife. ", "Sameh Bahiry, an\nassistant prosecutor in Armant, said he does not expect\ncharges to be filed. \"", "We have no evidence against him,\" he\nsaid in an interview. \"", "Circumcision is not illegal in\nEgypt.\"" ]	{ "pile_set_name": "Pile-CC" }	[ 0.0007046419777907431, 0.0011270766844972968, 0.000702521821949631, 0.0007694736705161631, 0.24018166959285736, 0.000819121953099966, 0.0032162764109671116, 0.0011956430971622467, 0.0011002718238160014, 0.0010298952693119645, 0.0007632057531736791, 0.006935770623385906, 0.0005664800410158932, 0.0006390215130522847, 0.01170044019818306, 0.0013655037619173527, 0.0007070790743455291, 0.04324629530310631, 0.0007557044154964387, 0.0006028393981978297, 0.000717806804459542, 0.0006221152143552899, 0.005444369278848171, 0.0005863231490366161, 0.30604973435401917, 0.0005395508487708867, 0.0007001914782449603, 0.024300623685121536, 0.011247615329921246, 0.000709169777110219, 0.0006213404703885317, 0.003547435626387596, 0.04697742685675621, 0.0008674315176904202, 0.000676318712066859, 0.05855466052889824, 0.0008892386686056852, 0.004068394657224417, 0.0006478303112089634, 0.0006296319770626724, 0.001134179881773889, 0.016993431374430656, 0.000688491272740066, 0.0007829238311387599, 0.0010912040015682578, 0.0006247084238566458, 0.015493367798626423, 0.0011994477827101946, 0.0009953005937859416, 0.002642979845404625, 0.012084690853953362, 0.008475827984511852, 0.001944144256412983, 0.0071731144562363625, 0.001204545027576387, 0.000793482584413141, 0.0008441093377768993, 0.0007170857861638069, 0.0006432661321014166, 0.0022324996534734964 ]	0.014405	60
[ "Lewis Hardman\n\nLewis Hardman (born 25 March 1989) is an English footballer who plays as a Midfielderfor Bishop Auckland.", "\n\nBorn in Middlesbrough, Hardman made one league debut as a substitute for Darlington. ", "During his second season at Darlington in 2007 he went on loan to clubs Whitby Town and Shildon. ", "On 26 September 2008, he was loaned out to Bishop Auckland before being released by Darlington and joining Bishop Auckland permanently in January 2009.", "\n\nReferences\n\nExternal links\n\nCategory:1989 births\nCategory:Living people\nCategory:Footballers from Doncaster\nCategory:English footballers\nCategory:Association football midfielders\nCategory:Darlington F.C. players\nCategory:Whitby Town F.C. players\nCategory:Shildon A.F.C. players\nCategory:Bishop Auckland F.C. players\nCategory:English Football League players" ]	{ "pile_set_name": "Wikipedia (en)" }	[ 0.0013884168583899736, 0.0009224038221873343, 0.0010767837520688772, 0.0006506236968562007, 0.0005813290481455624 ]	0.000924	5
[ "It is well known that the proliferation of commercial documents have required the development of document processor equipment to automatically handle, sort and process documents and the information represented thereon. ", "Such equipment normally includes an operator viewing station where the operator, upon presentation of the documents or their images, selectively intervenes with respect to certain ones of these documents for the purpose of key entry of data, document rejection, or the performance of other operations associated with these selected documents.", "\nFor example, one class of document processor equipment are computerized remittance processors for automatically processing payment and payment record documents and their data. ", "In accordance with well known, high volume remittance processing operations, individuals in making payment of their credit card balances, bank notes, utility bills, etc. ", "forward both a remittance document (check) and a remittance advice document (transaction summary) to a central location where these documents and/or the captured information on the face of the documents are automatically processed for appropriate account reconcilation and credit. ", "During such processing, the checks and remittance advice documents are transported by the remittance processor past an operator viewing station where the operator selectively intervenes with respect to certain ones of these documents to key enter data with respect to checks which are to be subsequently encoded and/or with respect to remittance advice documents which may be defectively encoded or which contain non-machine readable data.", "\nWith respect to existing document, and particularly remittance, processors, each and every document, whether requiring operator intervention or not, is sequentially advanced through the operator viewing station for presentation to the operator, many times being halted at such station for operator review. ", "Consequently, the operator must await each document not requiring operator intervention to advance out of the way of operator view, thus greatly slowing down the overall document processing operation.", "\nIt is therefore the principal object of the present invention to provide a new and improved method and apparatus for document processing, particularly for use with automatic document processors which simultaneously process both documents of the type requiring, and those not requiring, operator intervention.", "\nAnother object of the present invention is to provide a new and improved method and apparatus for the transport and presentation of only those documents at an operator view station which require operator intervention, thereby substantially increasing the speed of document processing, as well as enhancing operator viewing of such documents.", "\nIt is a still further object of the present invention to provide a new and improved remittance processor.", "\nSpecific features of the invention, as well as additional objects and advantages thereof, will become more readily understood by reference to the following detailed description taken in conjunction with accompanying drawings, in which:" ]	{ "pile_set_name": "USPTO Backgrounds" }	[ 0.0005572744994424284, 0.0005450643366202712, 0.0006000540452077985, 0.0005483950371854007, 0.0005684092757292092, 0.0005825686967000365, 0.0005047401646152139, 0.0005555487587116659, 0.0006069127121008933, 0.0005684038624167442, 0.0005970897618681192, 0.000519097491633147 ]	0.000563	12
[ "We have been covering the migrant caravans and the immigrant invasion supported by social justice activists for many months.", "\n\nAfter the recent launch of the largest of these caravans from Central America, President Donald Trump is now threatening to close the southern border with Mexico.", "\n\nIn remarks from the Oval Office, Mr. Trump reiterated his threat to shut the border if Mexico, America’s third largest trading partner, cannot restrict a flow of asylum seekers trying to cross into the United States. ", "But the president’s economic team, concerned about the damage from such a move, said it was looking for ways to limit the fallout if Mr. Trump does do so. “", "Sure, it’s going to have a negative impact on the economy,” Mr. Trump said, adding, “but security is most important.” “", "Security is more important to me than trade,” he said.", "\n\nIt is quite clear to most Americans prefer security over trade, so Trump’s priorities are correct.", "\n\nHowever, it appears that our press is more concerned about their specialty salads and sandwiches. ", "The focus of many reports on the impending closure center on the potential of shortages of that life-essential food substance, the avocado.", "\n\nSpeaking to Reuters, Steve Barnard, president and chief executive of Mission Produce, the largest distributor and grower of avocados in the world, said Americans would run out of avocados in three weeks if imports from Mexico were stopped. ", "Last week, Trump said here was a “very good likelihood” he would close the border if Mexico did not stop migrants from reaching the United States. ", "The U.S. imports about $137 billion in food through the border with Mexico, and that includes about 90 percent of the imported avocados purchased by American consumers.", "\n\nOther fruits and vegetables could be impacted as well.", "\n\n…Fresh tomatoes, peppers, melons and eggplant for the whole country would soon be in short supply. “", "Probably over half of what most consumers put in their shopping bag when it comes to fresh produce, they would find reduced quantities and higher prices,” said Lance Jungmeyer, president of the Fresh Produce Association of the Americas.", "\n\nGiven the fact that there is wave-after-wave of immigrants crashing the border and either illegally entering or manipulating the asylum rules for entry, I think I can live on canned fruits and vegetables. ", "The chronic failure of our national legislature to address illegal immigration, its costs on domestic security and the economy, and its danger to public health has created a slow-stream invasion that must be stopped.", "\n\nI suspect most Americans outside of the Beltway and Left Coast can live without avocados as well. ", "Perhaps some Legal Insurrection readers may have been old enough to have lived through the rationing of World War II.", "\n\nRationing regulated the amount of commodities that consumers could obtain. ", "Sugar rationing took effect in May 1943 with the distribution of “Sugar Buying Cards.” ", "Registration usually took place in local schools. ", "Each family was asked to send only one member for registration and be prepared to describe all other family members. ", "Coupons were distributed based on family size, and the coupon book allowed the holder to buy a specified amount. ", "Possession of a coupon book did not guarantee that sugar would be available. ", "Americans learned to utilize what they had during rationing time. ", "While some food items were scarce, others did not require rationing, and Americans adjusted accordingly. “", "Red Stamp” rationing covered all meats, butter, fat, and oils, and with some exceptions, cheese. ", "Each person was allowed a certain amount of points weekly with expiration dates to consider. “", "Blue Stamp” rationing covered canned, bottled, frozen fruits and vegetables, plus juices and dry beans, and such processed foods as soups, baby food and ketchup. ", "Ration stamps became a kind of currency with each family being issued a “War Ration Book.” ", "Each stamp authorized a purchase of rationed goods in the quantity and time designated, and the book guaranteed each family its fair share of goods made scarce, thanks to the war.", "\n\nI can hardly imagine today’s press covering Pearl Harbor or D-Day, if it is already fainting over no avocados.", "\n\n\n\n" ]	{ "pile_set_name": "OpenWebText2" }	[ 0.0005634193657897413, 0.0009484139154665172, 0.0007964304531924427, 0.0006188876577652991, 0.0005955639644525945, 0.0006833248189650476, 0.0006510969251394272, 0.0005259446916170418, 0.0020264429040253162, 0.005674012005329132, 0.0007018609903752804, 0.0009874870302155614, 0.0006004213355481625, 0.0010924309026449919, 0.000641894293949008, 0.0010939356870949268, 0.0011089799227192998, 0.369473397731781, 0.003260998521000147, 0.0005980816786177456, 0.0007985000847838819, 0.0006009156932123005, 0.0005322166252881289, 0.0007820610771887004, 0.0011984433513134718, 0.0006749709718860686, 0.000689852808136493, 0.002022815402597189, 0.0005418610526248813, 0.0007543542888015509, 0.0008335086749866605, 0.0006725739222019911, 0.07743948698043823, 0.001994825666770339 ]	0.014182	34
[ "Show Notes for Season Ticket Episode 15\n\nWelcome to the Season Ticket Podcast. ", "It’s episode 15, and it is ready for streaming or download by clicking the play button above, so give it a listen!", "\n\nYou can follow us on Twitter @seasonticketpod and facebook.com/seasonticketpod. ", "Also don’t forget to rate and review the show on iTunes if you get a second.", "\n\nRugby – Six Nations\n\nWe go through the weekend’s games with our rugby expert Darragh. ", "Can he and Cob convince Rob that rugby isn’t doomed? ", "Is the pitch too small? ", "Are Ireland on the way back?", "\n\nFootball\n\nSome good football this weekend. ", "Cob’s pick of Norwich to upset Leicester wasn’t the worst in the world, but Arsenal who had gotten themselves into a great position to win the Premier League look primed to throw it away again. ", "Ronaldo called out his team mates as not being good enough and Rayo Vallecano have as many goals as Atletico Madrid.", "\n\nMMA- UFC196\n\nCarl has some odds and ends to chat about from this weekend’s Fight Night and all of the latest buildup to UFC 196 on March 5th. ", "We’ll be joining Phil live from Las Vegas on the morning after the night before to get his reaction to the whole thing, so don’t miss next Sunday’s show!", "\n\nGolf – Honda Classic\n\nIs Rory McIlroy’s head in the game? ", "After missing the cut in ugly fashion in Florida he was Tweeting Wayne Rooney about boxing bets. ", "Does he enjoy the lifestyle a little bit too much to have the dedication to become a true great?", "\n\nSteph Curry\n\nHe’s broken the single season 3 point shooting record and could go on to be the best player ever if he keeps it up." ]	{ "pile_set_name": "Pile-CC" }	[ 0.0005833833129145205, 0.0007017703028395772, 0.0007203239947557449, 0.0006398100522346795, 0.0007350955856963992, 0.0042490228079259396, 0.0009385371813550591, 0.0010108428541570902, 0.0007362643373198807, 0.001466120476834476, 0.001239586970768869, 0.0007455751765519381, 0.002782733179628849, 0.0031314431689679623, 0.0008104749722406268, 0.0006983318016864359, 0.0007952087908051908 ]	0.001293	17
[ "\n6 Cal.", "App.3d 79 (1970)\n85 Cal. ", "Rptr. ", "617\nTHE PEOPLE, Plaintiff and Respondent,\nv.\nROY LEE COLBERT, Defendant and Appellant.", "\nDocket No. ", "16028.", "\nCourt of Appeals of California, Second District, Division Five.", "\nMarch 27, 1970.", "\n81 COUNSEL\nRichard H. Levin, under appointment by the Court of Appeal, for Defendant and Appellant.", "\nThomas C. Lynch, Attorney General, William E. James, Assistant Attorney General, and James L. Markman, Deputy Attorney General, for Plaintiff and Respondent.", "\nOPINION\nKAUS, P.J.\nA seven-count information was filed against defendant and four codefendants. ", "Defendant was named in four of the seven counts. ", "Count I charged him with assault with intent to commit murder upon Brian Murphy, a peace officer engaged in the performance of his duty. (", "Pen. ", "Code, § 217.) ", "Count II charged him with assault by means likely to produce great bodily injury upon Jerome Beck, a peace officer engaged in the performance of his duty. (", "Pen. ", "Code, § 245 subd. (", "b).) ", "Count IV charged him with battery upon Alexander Sinanian, a peace officer engaged in the performance of his duty. (", "Pen. ", "Code, § 242.) ", "Count V charged him with battery upon James Hurley, a peace officer engaged in the performance of his duty. (", "Pen. ", "Code, § 242.)", "\nSeparate counsel was appointed to represent defendant pursuant to section 987a of the Penal Code. ", "Jury trial was waived by defendant and each codefendant. ", "The court found defendant guilty of assault by force likely to produce great bodily injury in violation of section 245 subdivision (b) of the Penal Code, a lesser included offense to that charged in count I; guilty of assault upon a peace officer in violation of sections 240 and 241 of the Penal Code, a lesser included offense to that charged in count II; not guilty of count IV; and guilty as charged on count V.\nMotion for new trial and application for probation were denied. ", "Defendant 82 was sentenced to state prison on counts I, II and V, the sentences to run concurrently.", "\n\nFACTS\nOn the morning of July 21, 1967, defendant and three of his four codefendants in this case were spectators at a trial in the county courthouse involving the fourth codefendant, Gregory Benson. ", "Officers Hurley and Murphy of the Los Angeles Police Department were present as witnesses. ", "Officer Hurley did not testify at the July 21 morning session; Officer Murphy did. ", "During his testimony comments were made by defendant and his codefendants other than Benson to the effect that Murphy was lying.", "\nWhen the Benson trial recessed for lunch, Hurley and Murphy left the courtroom. ", "Defendant, who was standing in the hallway with the codefendants, threatened to \"get\" the officers.[1] Hurley and Murphy walked away from them and got on the \"down\" escalator at the sixth floor. ", "When they had descended two floors, Hurley heard sounds of running and hollering above him, looked back and saw defendant and the four codefendants getting onto the escalator, pushing people out of the way and coming down toward the officers. ", "Defendant shouted a threat to kill one of the officers. ", "Benson said, \"No, leave them alone. ", "Wait until they get outside and we will get them then.\" ", "There were other persons, both male and female, on the escalator between the defendant's group and the officers at the time. ", "Defendant and his companions were shoving these people aside and coming down toward the officers.", "\nHurley and Murphy waited at the fourth floor for defendant to arrive and Murphy then advised him that he was under arrest for violation of section 311.6 of the Penal Code. ", "Defendant threatened to knock Murphy's teeth out and struck him in the face with his fist. ", "The codefendants then stepped between defendant and the officers and the five of them reboarded the down escalator. ", "Murphy and Hurley attempted to get through the group to reach defendant, but were pushed back by the four codefendants. ", "All of the defendants were screaming taunts and invitations to fight at the officers. ", "Benson taunted them about not being so tough without their guns.", "\nAt the second floor, Hurley pushed through the four codefendants and approached defendant who had backed up against the wall facing the escalator. ", "Hurley took his handcuffs from his belt and advised defendant 83 he was under arrest. ", "Defendant struck Hurley in the face and knocked him to the floor.", "\nMurphy attempted to subdue defendant. ", "Defendant struck Murphy with his fist about the head and face. ", "Defendant then grabbed Murphy's tie and made a jerking downward motion, tightening the tie around Murphy's neck. ", "He continued to grasp the tie despite Murphy's efforts to free it and continued jerking it to tighten it. ", "Murphy was unable to breathe. ", "The color drained from his face and his eyes started to roll back. ", "He started to black out. ", "He reached in his back pocket for his pocket knife and did actually black out. ", "He did not know who cut the tie from his neck but it had been cut when he regained consciousness. ", "Deputy Sinanian of the Los Angeles Sheriff's Department saw Murphy cut the tie himself. ", "Murphy sustained minor lacerations and abrasions as a result of the fracas, but was not hospitalized.", "\nDeputy Beck of the Los Angeles Sheriff's Department happened to be in the courthouse shortly after noon on July 21, 1967. ", "His attention was drawn to the fact that other officers needed assistance on the second floor. ", "When he arrived he saw a large crowd and several fights in progress. ", "Beck went to the assistance of Officer Murphy whose tie was being pulled by defendant and who appeared about to lose consciousness. ", "Defendant kneed Beck in the groin and then butted him in the mouth.", "\nEventually defendant and codefendant Howard Colbert, his brother, were subdued and arrested. ", "The other three codefendants were arrested later in the afternoon.", "\n\nCONTENTIONS ON APPEAL\nDefendant questions the sufficiency of the evidence to support the conviction of assault by means of force likely to cause great bodily harm (count I). ", "He argues that the presence of a large number of law enforcement officers on the scene made it unlikely that Officer Murphy would sustain that great bodily harm, even though he concedes that had the episode involving the choking of Murphy by means of pulling on his neck-tie occurred in a different setting, the likelihood of great bodily harm would exist.", "\nThe People rely on People v. Buice, 230 Cal. ", "App.2d 324 [40 Cal. ", "Rptr. ", "877], to support their position that the mere presence of a large force of police officers does not preclude conviction under section 245 subdivision (b) of the Penal Code for the type of assault involved here. ", "Buice involved an altercation between police and citizens on the city streets at night. (", "1a) In that respect it is not strictly analogous to the instant case where 84 the attack took place, more or less, on the officers' home ground, the assailants were limited in number, the area of the fracas was confined and assistance to the victim officers in sufficient number to quell the disturbance was immediately at hand. ", "Nonetheless, despite these advantages which the officers enjoyed, and despite the fact that several officers attempted to free him, Murphy was not rescued from defendant's attack until he had lost consciousness and then he was saved only by cutting his tie and not by any loosening of defendant's grasp. ", "If the knife had not been produced when it was, we cannot say what further injury Murphy might have suffered.", "\n(2) The likelihood of great bodily injury is essentially a question of fact. (", "People v. Buice, supra, 230 Cal. ", "App.2d 324, 345; People v. Nudo, 38 Cal. ", "App.2d 381 [101 P.2d 162].) (", "1b) The trial court's finding on this issue had adequate evidentiary support.", "\nDefendant next argues that since his basic purpose during the entire incident was to avoid arrest, it is a violation of section 654 of the Penal Code to punish him for separate offenses. (", "3) However, \"A defendant who commits an act of violence with the intent to harm more than one person or by means likely to cause harm to several persons is more culpable than a defendant who harms only one person.\" (", "Neal v. State of California, 55 Cal.2d 11, 20 [9 Cal. ", "Rptr. ", "607, 357 P.2d 839].) ", "There was no violation of section 654 of the Penal Code when defendant was punished separately for offenses involving different victims. (", "Cf. ", "People v. Bauer, 1 Cal.3d 368, 377-378 [82 Cal. ", "Rptr. ", "357, 461 P.2d 637].)", "\nAlthough the present case was tried before the decision in People v. Curtis, 70 Cal.2d 347 [74 Cal. ", "Rptr. ", "713, 450 P.2d 33], the trial court ruled on the legality of the original effort by Hurley and Murphy to arrest defendant. ", "The court found that the conduct engaged in by defendant was more properly a disturbance of the peace (Pen. ", "Code, § 415) than a violation of section 311.6 of the Penal Code. (", "4) However, as the court correctly pointed out, the arresting officer is not required to cite the right code section in order to validate an arrest for an offense committed in the officer's presence. (", "People v. Beard, 46 Cal.2d 278, 281 [294 P.2d 29]; People v. Walker, 273 Cal. ", "App.2d 720, 725 [78 Cal. ", "Rptr. ", "439].) (", "5) The threats to the officers and invitations to fight clearly amount to \"threatening, traducing, quarreling [and] challenging to fight\" in violation of section 415 of the Penal Code; further defendant's conduct was \"offensive\" as defined in In re Bushman, 1 Cal.3d 767, 775 [83 Cal. ", "Rptr. ", "375, 463 P.2d 727].", "\n85 The court further anticipated People v. Curtis, supra, 70 Cal.2d 347, 357, in holding that an arrestee retains his right of self-defense against excessive force, but that the issue of whether a defendant had properly resorted to an exercise of that right was a question of fact. ", "On this issue the court then, impliedly, found against defendant. ", "There is ample evidentiary support in the record for this finding.", "\n(6) Following imposition of sentence on defendant, sections 241 and 243 of the Penal Code were amended to make violations of section 240 and 242 of the Penal Code, committed upon a peace officer felony-misdemeanors. ", "This change in the law requires that this case be remanded to the trial court so that that court may determine whether to impose felony or misdemeanor sentences with respect to counts II and V. (People v. Francis, 71 Cal.2d 66, 75 [75 Cal. ", "Rptr. ", "199, 450 P.2d 591]; People v. Scrivens, 276 Cal. ", "App.2d 429, 435 [81 Cal. ", "Rptr. ", "86].)", "\nDefendant also claims that in view of the possibility that the trial court might be persuaded to exercise leniency on counts II and V, the matter should also be remanded on count I.\nThe record before this court does not indicate whether defendant has started to serve the sentence on count I. If that is not the case, the trial court needs no permission from us to reconsider defendant's application for probation on count I. (People v. Banks, 53 Cal.2d 370, 383 [1 Cal. ", "Rptr. ", "669, 348 P.2d 102]; People v. Causey, 230 Cal. ", "App.2d 576, 579 [41 Cal. ", "Rptr. ", "116]; cf. ", "In re Black, 66 Cal.2d 881, 885 [59 Cal. ", "Rptr. ", "429, 428 P.2d 293].)", "\n(7) If, on the other hand, defendant has started to serve the sentence on count I, it is the general rule that the trial court's jurisdiction to grant probation ceases. (", "In re Black, supra, 66 Cal.2d 881.) ", "We have found no authority to support the proposition that jurisdiction to grant probation, once denied, revests, where a defendant, on appeal, obtains a favorable result as to some counts, but not as to others. ", "The Attorney General suggests that this court has discretion to order a reconsideration of the denial of probation on count I. His position is based on section 1260 of the Penal Code.[2] We need not decide whether he is correct. ", "If, under procedural circumstances such as are presented in this case, we do have a discretion to order the trial court to reconsider the denial of probation with respect 86 to count I, the demonstrated substantive facts of the case persuade us most strongly that this is no occasion for its exercise.", "\nThe judgment is affirmed as to count I. With respect to counts II and V the cause is remanded to the trial court for proceedings consistent with this opinion.", "\nStephens, J., and Reppy, J., concurred.", "\nNOTES\n[1] Throughout the events the words spoken to the officers were interlaced with words which, as held in People v. Cohen, 1 Cal. ", "App.3d 94, 101 [81 Cal. ", "Rptr. ", "503] were \"offensive\" within the meaning of section 415 of the Penal Code. ", "See also In re Bushman, 1 Cal.3d 767, 775 [83 Cal. ", "Rptr. ", "375, 463 P.2d 727].", "\n[2] Section 1260 of the Penal Code reads as follows: \"The court may reverse, affirm, or modify a judgment or order appealed from, or reduce the degree of the offense or the punishment imposed, and may set aside, affirm, or modify any or all of the proceedings subsequent to, or dependent upon, such judgment or order, and may, if proper, order a new trial.\"", "\n" ]	{ "pile_set_name": "FreeLaw" }	[ 0.0012014786479994655, 0.0007021336350589991, 0.0012915768893435597, 0.0007275824900716543, 0.00084040587535128, 0.0011426100973039865, 0.0007668790640309453, 0.0007267302135005593, 0.0006270359153859317, 0.0007306697079911828, 0.0006734642083756626, 0.0006680965307168663, 0.027733799070119858, 0.0026629141066223383, 0.0006813707295805216, 0.003706499235704541, 0.0026629141066223383, 0.0007050130516290665, 0.000909449823666364, 0.0009321016259491444, 0.0026629141066223383, 0.0006889228243380785, 0.0009653193410485983, 0.0026629141066223383, 0.0006889228243380785, 0.0005573834059759974, 0.0006066082278266549, 0.0019464042270556092, 0.0033110659569501877, 0.0006077865255065262, 0.000644161831587553, 0.000682730576954782, 0.000987425446510315, 0.0006424656603485346, 0.0010536224581301212, 0.0017477568471804261, 0.12464937567710876, 0.006204281467944384, 0.008577452972531319, 0.0006668627611361444, 0.001986963674426079, 0.0006558222812600434, 0.36810100078582764, 0.0013524634996429086, 0.000952601432800293, 0.06067713350057602, 0.026385867968201637, 0.0015898372512310743, 0.0033442352432757616, 0.12803418934345245, 0.0011261452455073595, 0.1398412436246872, 0.016134977340698242, 0.0056350696831941605, 0.012366942130029202, 0.006214945577085018, 0.10153818130493164, 0.04443315044045448, 0.0027551897801458836, 0.0008177111158147454, 0.0008077060338109732, 0.0006757530500181019, 0.0006315362406894565, 0.0012285541743040085, 0.0013372978428378701, 0.8307635188102722, 0.0011271031107753515, 0.0009243530221283436, 0.0007819828460924327, 0.0008063206332735717, 0.0006655065808445215, 0.0007907057297416031, 0.0012915768893435597, 0.0006869229255244136, 0.0007501034415327013, 0.0006479358999058604, 0.0008266501827165484, 0.0013475059531629086, 0.0016684724250808358, 0.0007999898516573012, 0.0012724724365398288, 0.000694612564984709, 0.0005803699023090303, 0.0007516966434195638, 0.0011406939011067152, 0.0010128021240234375, 0.0012915768893435597, 0.0006899809814058244, 0.0006522391340695322, 0.0007784734480082989, 0.0008511814521625638, 0.0012915768893435597, 0.0006990366382524371, 0.0007306718034669757, 0.001291858498007059, 0.0006984799401834607, 0.0007078403141349554, 0.0007198048988357186, 0.0006260900991037488, 0.0007869048858992755, 0.0008493864443153143, 0.001291858498007059, 0.0008397203055210412, 0.0013047222746536136, 0.001291858498007059, 0.0007332597160711884, 0.0007375244749709964, 0.0006741221295669675, 0.0005344841629266739, 0.0007679203408770263, 0.0006985508371144533, 0.001291858498007059, 0.0008196196286007762, 0.0008658930892124772, 0.001291858498007059, 0.0008901499095372856, 0.0006424114690162241, 0.001291858498007059, 0.0008953263750299811, 0.0009416259708814323, 0.001291858498007059, 0.0007835929864086211, 0.002140280557796359, 0.001291858498007059, 0.0007123967516236007, 0.0007666181772947311, 0.0013008415699005127, 0.0006777917733415961, 0.0007051121210679412, 0.0006167581304907799, 0.0005866980063728988, 0.0007353499531745911, 0.000585559755563736, 0.000806340656708926, 0.001291858498007059, 0.0008223796612583101, 0.0006928077200427651, 0.001291858498007059, 0.0007332597160711884, 0.0006588641554117203, 0.001995587022975087 ]	0.014465	141
[ "package org.opentripplanner.gtfs.mapping;\n\nimport org.opentripplanner.model.", "Route;\nimport org.opentripplanner.util.", "MapUtils;\n\nimport java.util.", "Collection;\nimport java.util.", "HashMap;\nimport java.util.", "Map;\n\n/** Responsible for mapping GTFS Route into the OTP model. /", "\nclass RouteMapper {\n private final AgencyMapper agencyMapper;\n\n private final Map<org.onebusaway.gtfs.model.", "Route, Route> mappedRoutes = new HashMap<>();\n\n RouteMapper(AgencyMapper agencyMapper) {\n this.agencyMapper = agencyMapper;\n }\n\n Collection<Route> map(Collection<org.onebusaway.gtfs.model.", "Route> agencies) {\n return MapUtils.mapToList(agencies, this::map);\n }\n\n /* Map from GTFS to OTP model, {@code null} safe. ", " */\n Route map(org.onebusaway.gtfs.model.", "Route orginal) {\n return orginal == null ? ", "null : mappedRoutes.computeIfAbsent(orginal, this::doMap);\n }\n\n private Route doMap(org.onebusaway.gtfs.model.", "Route rhs) {\n Route lhs = new Route();\n\n lhs.setId(AgencyAndIdMapper.mapAgencyAndId(rhs.getId()));\n lhs.setAgency(agencyMapper.map(rhs.getAgency()));\n lhs.setShortName(rhs.getShortName());\n lhs.setLongName(rhs.getLongName());\n lhs.setType(rhs.getType());\n lhs.setMode(TransitModeMapper.mapMode(rhs.getType()));\n lhs.setDesc(rhs.getDesc());\n lhs.setUrl(rhs.getUrl());\n lhs.setColor(rhs.getColor());\n lhs.setTextColor(rhs.getTextColor());\n lhs.setRouteBikesAllowed(rhs.getRouteBikesAllowed());\n lhs.setBikesAllowed(rhs.getBikesAllowed());\n lhs.setSortOrder(rhs.getSortOrder());\n lhs.setBrandingUrl(rhs.getBrandingUrl());\n\n return lhs;\n }\n}\n" ]	{ "pile_set_name": "Github" }	[ 0.0008624455076642334, 0.0008237372967414558, 0.0009850035421550274, 0.0008229134837165475, 0.0009298321674577892, 0.0006777356029488146, 0.0008274891297332942, 0.0007673096260987222, 0.0008244035416282713, 0.0007134213228709996, 0.009057052433490753, 0.0048289974220097065, 0.004076033364981413 ]	0.002015	13
[ "Vive la rose\n\nVive la rose is an 18th-century French folk song about unrequited love. \"", "Mon ami me délaisse\" is roughly translated as \"My boyfriend dumped me\". ", "The song goes on to explain that he has found a new girlfriend. ", "Another verse says that rumor has it that she is sick. ", "The narrator says that if she dies, he will probably want to come back to her, but she will not have him. ", "The chorus \"Vive la rose et le lilas\" means \"Long live the rose and the lilac.\"", "\n\nVive la rose was Émile Benoît's last recording. ", "It was interpreted by several other musicians; one such interpretation was referred to as \"une vieille chanson française interprétée par la suite par Guy Béart pour les enfants\". ", "It was interpreted by Guy Béart (1960), Cora Vaucaire (1975), Nana Mouskouri (1978), Mes souliers sont rouges (2000), and Ten Strings and a Goat Skin (2013). ", "Other names for the song include \"Mon amant me délaisse\" and \"La méchante.\"", "\n\nFilm adaptation\nIn 2009, Benoit's rendition of the song was adapted as a National Film Board of Canada mixed media short film by Bruce Alcock. ", "The film was named to the Toronto International Film Festival's year-end Canada's Top Ten list for 2009, and was a Genie Award nominee for the Best Animated Short at the 30th Genie Awards.", "\n\nReferences\n\nCategory:French Canadian culture\nCategory:French folk songs\nCategory:Nana Mouskouri songs\nCategory:Newfoundland and Labrador folk songs\nCategory:Torch songs\nCategory:18th-century songs\nCategory:Year of song unknown\nCategory:Songwriter unknown\nCategory:Canadian folk songs\nCategory:French-language songs\nCategory:French-language Canadian songs" ]	{ "pile_set_name": "Wikipedia (en)" }	[ 0.0013214043574407697, 0.04536141827702522, 0.0015393801731988788, 0.08124375343322754, 0.27872347831726074, 0.0006989807006902993, 0.0007755022379569709, 0.0006323453853838146, 0.0012348354794085026, 0.0009573345887474716, 0.0005900819087401032, 0.000654508825391531, 0.0006871952791698277 ]	0.031878	13
[ "Click on a state for a larger view, then click a town to see the Trail of Death historical markers.", "For corrections, suggestions, pictures, your thoughts and feelings, contact\nThis page updated Aug 25, 2014." ]	{ "pile_set_name": "Pile-CC" }	[ 0.0006786109879612923, 0.0005680012400262058 ]	0.000623	2
[ "Substrate removal and electricity generation in a membrane-less microbial fuel cell for biological treatment of wastewater.", "\nMicrobial fuel cells have gained popularity in recent years due to its promise in converting organic wastewater into renewable electrical energy. ", "In this study, a membrane-less MFC with a biocathode was developed to evaluate its performance in electricity generation while simultaneously treating wastewater. ", "The MFC fed with a continuous flow of 2g/day acetate produced a power density of 30 mW/m(2) and current density of 245 mA/m(2). ", "A substrate degradation efficiency (SDE) of 75.9% was achieved with 48.7% attributed to the anaerobic process and 27.2% to the aerobic process. ", "Sequencing analysis of the microbial consortia using 16S rDNA pryosequencing showed the predominance of Bacteroidia in the anode after one month of operation, while the microbial community in the cathode chamber was dominated by Gamma-proteobacteria and Beta-proteobacteria. ", "Coulombic efficiencies varied from 19.8% to 58.1% using different acetate concentrations, indicating power density can be further improved through the accumulation of electron-transferring bacteria." ]	{ "pile_set_name": "PubMed Abstracts" }	[ 0.0006051040254533291, 0.0005744255613535643, 0.000587350397836417, 0.00077386962948367, 0.0005592640955001116, 0.0006489302613772452, 0.0006202993681654334 ]	0.000624	7
[ "The objective of this program is to permit increased and improved participation in ECOG programs by the Hahnemann Cancer Institute. ", "The major objectives are to increase patient acquisition and facilitate data accumulation and reporting. ", "Increased emphasis is to be placed on extending the network of clinical oncologists participating in ECOG studies through the Hahnemann Center. ", "Pilot studies aimed at developing new group protocols are to be carried out. ", "Major participation in ECOG Cancer Control programs is anticipated. ", "The interrelationship of clinical research, basic research and clinical cancer training are essential aspects of the ECOG program at The Hahnemann Cancer Institute." ]	{ "pile_set_name": "NIH ExPorter" }	[ 0.0005721530178561807, 0.0005646114586852491, 0.0005448420415632427, 0.000538464286364615, 0.0005976981483399868, 0.0005811069277115166 ]	0.000566	6
[ "El juez de la Audiencia Nacional ha enviado a prisión al secretario general del grupo Reconstrucción Comunista, Roberto Vaquero, por colaborar con el Partido de los Trabajadores del Kurdistán (PKK) y también por tenencia de explosivos.", "\n\nVelasco ha tomado hoy declaración a los nueve detenidos el pasado miércoles en Madrid, Valencia y Bilbao por su relación con el PKK, de los cuales han ingresado en prisión otros dos: el único de nacionalidad turca y el jefe de seguridad del grupo, aunque en este caso tienen la posibilidad de eludir su ingreso si pagan sendas fianzas de 10.000 y 6.000 euros.", "\n\nLos otros seis han quedado en libertad con medidas cautelares como prohibición de abandonar el territorio nacional, retirada del pasaporte y comparecencias mensuales, han informado fuentes jurídicas.", "\n\nAl líder de Reconstrucción Comunista, cuya sede fue registrada en la operación del pasado miércoles, se le imputa un delito de pertenencia a una organización criminal que colabora el PKK y otro de tenencia de explosivos.", "\n\nEste último delito responde a que en los registros realizados por la Policía se encontraron componentes de artefactos explosivos preparados para montar, así como un kilo de nitrato potásico y armas prohibidas.", "\n\nAl ciudadano turco que también ha ingresado en prisión, aunque bajo fianza, se le imputan los mismos delitos y le atribuye ser el contacto del PKK en España.", "\n\nEn su resolución, el magistrado acuerda prohibir durante un año las actividades de Reconstrucción Comunista y la clausura durante el mismo tiempo de sus locales en el barrio madrileño de Vallecas y en Valencia.", "\n\nDestaca el juez que la Policía encontró en los registros una agenda donde uno de los detenidos reconocía que un miembro del grupo había tenido un contacto en España con un componente del PKK.", "\n\nSegún informó el miércoles el Ministerio del Interior, los arrestados estaban integrados en una estructura en España con ramificaciones en países europeos y en Turquía que colaboraba y facilitaba la integración de individuos en el grupo terrorista kurdo.", "\n\nEsta operación podría estar relacionada con la causa por la que el pasado 7 de julio el juez Velasco dejó en libertad, aunque imputados por un delito en organización terrorista, a dos jóvenes españoles que fueron detenidos tras combatir contra el Estado Islámico durante seis meses integrados en milicias kurdas del PKK en Siria.", "\n\nA los dos, que fueron detenidos por la Policía tras retornar de Siria, se les acusó de participar en un conflicto armado fuera de España sin autorización del Estado, poniendo en grave riesgo los intereses nacionales, y de integrarse en grupos de lucha contra el Estado Islámico que están también considerados grupos terroristas por los organismos internacionales.", "\n\nA ambos se les relacionó con el PKK, que dispondría de aparato militar en Siria y en Irak con otras denominaciones como YPG, el cual, según explicaron los dos jóvenes, es el Ejército del Estado de Rojava, en la parte kurda de Siria.", "\n\nEl PKK está considerado una organización terrorista por la Unión Europea desde julio de 2011 e incluido en la lista de grupos terroristas extranjeros del Departamento de Estado de EEUU.", "\n\nCuenta con redes de colaboradores en distintos países europeos, especialmente en Alemania, Holanda o Bélgica y en España fueron detenidos seis miembros de su red de extorsión y financiación en febrero de 2013." ]	{ "pile_set_name": "OpenWebText2" }	[ 0.00843660719692707, 0.020910758525133133, 0.03934106230735779, 0.052769504487514496, 0.07070475816726685, 0.07501471042633057, 0.008212007582187653, 0.028601644560694695, 0.030781500041484833, 0.13911305367946625, 0.0350530631840229, 0.07520229369401932, 0.037857942283153534, 0.007042428944259882 ]	0.044932	14
[ "Ranging performance models based on negative-binomial (NB) distribution for photon-counting lidars.", "\nFor photon-counting lidars, the current ranging performance models are based on Poisson statistics that are a special case of a negative-binomial (NB) distribution. ", "In this paper, a new ranging performance model that considers the effect of a target's speckle, the noise, and the dead-time of photon-counting detectors is derived from the NB distribution. ", "The derived ranging performance model is verified by both an experiment based on a Geiger mode avalanche photodiode (GM-APD) lidar and a simulation using the recursive method. ", "The ranging performance model is then used to analyze the effect of target speckle for two typical photon-counting ranging systems aimed at different types of target: the space-borne Ice, Cloud and land Elevation Satellite-2 (ICESat-2) for detecting the Earth's surface, and the ground-based laser ranging system at Shanghai Astronomical Observatory (SHAO) station for detecting space debris. ", "The results indicate that for space-borne or airborne lidar, the ranging performance model can be approximated to the classic models based on Poisson statistics, but for a ground-based laser ranging system, the approximation model introduces differences of ~1 cm in ranging bias and 4.8 cm in ranging precision from the theoretical model of the NB distribution. ", "In addition, the new model is universal because it is compatible with the classic model of a Poisson distribution, i.e., when the speckle diversity is greater than 100, the result calculated from the new model is identical to the classic model." ]	{ "pile_set_name": "PubMed Abstracts" }	[ 0.0006642589578405023, 0.0006710792076773942, 0.0005973453517071903, 0.0005741012282669544, 0.0005597856361418962, 0.0005486572626978159, 0.000579312676563859 ]	0.000599	7
[ "The faded black and white photograph shows a beaming woman proudly bearing a baby girl in each arm. ", "But far from being just a...\n\nThe faded black and white photograph shows a beaming woman proudly bearing a baby girl in each arm.", "\n\nBut far from being just a doting grandmother, May Donoghue earned a place in legal history as the claimant in the world renowned the ‘snail and the bottle’ legal case.", "\n\nNow Paisley-based artist Mandy McIntosh will use the precious family photo – the sole surviving picture of May – as the inspiration for a bronze statue.", "\n\n\n\nPhoto: The clay head of the statue, which will be cast in bronze\n\nMandy, who says she was keen to take on the project as there is such a dearth of female statues in Scotland, said: “There are so few women commemorated in this way that it’s great to help redress the balance a bit. ", "There are more statues of dogs in Edinburgh than there are of women so it’s very fitting that Mays’ legacy is celebrated in this way.", "\n\n“When I first started work on the project my focus was on the snail, but then I realised that actually it’s all about May and what she represents.”", "\n\nMay was a single mum living in poverty in Glasgow’s East End who had lost three children and had one surviving son.", "\n\nShe successfully sued the ginger beer manufacturer Stevensons after falling ill when she found a dead snail in a bottle in Paisley’s Wellmeadow café in 1928.", "\n\nHer actions changed the laws on negligence, not only in her native Scotland, but across the globe.", "\n\n\n\nPhoto: May Donoghue with her granddaughters Elizabeth and May — the only surviving picture of her\n\n\n\n\n\n\n\n\n\nMandy added: “The statue shows May holding her twin granddaughters Elizabeth and May on their christening day in 1952, which is like the scales of justice, her holding these two equal weights.", "\n\n“May was ridiculed in the press at the time by people saying she was only pursuing the legal case for the money, but she kept going and won the case.", "\n\n“But although she came up out of poverty, she managed to change history.”", "\n\nIt’s expected the statue will be installed – very fittingly – on 1 May at The Tannahill Centre in Paisley’s Ferguslie Park.", "\n\nThe doll sized depiction of May, will be first made in clay and wax before being cast into bronze and will rest on an oak plinth with hand coloured bronze spirals.", "\n\nThe artist received funding for the project from Renfrewshire Council’s Community, Heritage and Education fund, which was launched in 2015 as part of Paisley’s bid to be named UK City of Culture 2021.", "\n\nAlthough the competition is over, its legacy continues with applications from local groups still being invited for further rounds of funding.", "\n\nMandy says she sees parallels between May herself and the women of Ferguslie Park\n\nShe said: “I’ve been so impressed by the strength of the women around me that although they’ve not been working directly with me on the project, they’ve certainly influenced it.", "\n\nMay’s granddaughter Maggie Houston-Tomlin, the younger sister of the twins, who are 65 and now live in Oban and Bournemouth, says she and her siblings are delighted that her grandmother will be honoured and she plans to be at the unveiling.", "\n\nMaggie said: “I’m quite amazed by how famous my grandmother has become. ", "But I’m also amazed my father never ever told us about her. ", "I only found out when another branch of the family tracked me down about eight years ago.", "\n\n“I was four when May died and I do vaguely remember her as does my elder sister Evelyn. ", "She was a bit of a character and a very strong woman.", "\n\n“It’s astonishing to think of the influence someone of her background had.”", "\n\nLeader of Renfrewshire Council, Councillor Iain Nicolson said: “It’s great to see the legacy of the CHE fund continuing and to see more women represented in our public art.", "\n\n“I look forward to seeing this project and many others come to fruition.”", "\n\nKaren Mailley-Watt from the History Girls Frae Scotland, who held a Paisley workshop on how we should celebrate modern women, said she welcomed May Donoghue being commemorated in such a public manner and added: “It is about time that we, as a society, start to celebrate women’s achievements and help to level the gender imbalance which is so noticeable within Scotland’s built and civic environments.’", "\n\n\n\nPhoto: May’s granddaughters – L-R – Elizabeth Cosby (one of the twins), Maggie Houston-Tomlin and Evelyn Blair\n\n\n\n\n\n\n\n\n\nShare on social network:\n\nTweet\n\nEmail\n\nPrint\n\nMore\n\n\n\n" ]	{ "pile_set_name": "OpenWebText2" }	[ 0.0006816500681452453, 0.0007962836534716189, 0.02448221668601036, 0.0005751037388108671, 0.0005713611608371139, 0.0010040819179266691, 0.0005741920322179794, 0.00683507090434432, 0.0011321105994284153, 0.0008003535331226885, 0.0007125081610865891, 0.0009454177343286574, 0.0009558876045048237, 0.0006841634749434888, 0.0006377252866514027, 0.0006462325691245496, 0.0005487040616571903, 0.000635818112641573, 0.0006601891363970935, 0.001265745609998703, 0.0007585192797705531, 0.0006204997771419585, 0.0009301857789978385, 0.0008064081775955856, 0.0005852498579770327, 0.0008388618589378893, 0.0005675856373272836, 0.0006454637623392045, 0.0006987472297623754 ]	0.001779	29
[ "UPDATE: The list was used in a 1988 classroom, but was published in a 1976 Texas Feminist and Lesbian Newsletter.", "\n\nThis version had quite a few more additions to the list, such as: \"If you are tempted to tell her she's taking the easy way out, THINK ABOUT THAT.\"" ]	{ "pile_set_name": "OpenWebText2" }	[ 0.0010541611118242145, 0.0006231489824131131 ]	0.000839	2
[ "Meet Dazbog\n\nFATE Brewing Company announces the upcoming release of Dazbog, our Third Anniversary Ale.", "\n\nOfficial Style: Barrel Aged Imperial Pinot Noir Stout\n\nWe brewed an Imperial Stout and prior to fermentation added Pinot Noir grape must to the batch. ", "From there we fermented the two liquids together creating a true melding of red wine and dark malty imperial stout. ", "Then this delicious elixir aged in Pinot Noir wine barrels. ", "Coming in at 8.8% ABV Dazbog is the perfect way to mark our third year and we have you to thank." ]	{ "pile_set_name": "Pile-CC" }	[ 0.0007629647152498364, 0.0008433189941570163, 0.0009258615900762379, 0.0010236381785944104, 0.0009601589990779757 ]	0.000903	5
[ "Denture stomatitis and salivary vascular endothelial growth factor in immediate complete denture wearers with type 2 diabetes.", "\nDiabetes mellitus type 2 is associated with a variety of oral mucosal changes, including an altered level of salivary vascular endothelial growth factor. ", "However, the authors identified no studies concerning denture stomatitis and salivary vascular endothelial growth factor in immediate denture wearers with diabetes mellitus type 2. ", "The purpose of this study was to investigate the incidence of and risk factors for denture stomatitis in immediate complete denture wearers with and without diabetes mellitus type 2 and to investigate the relationship between levels of salivary vascular endothelial growth factor and clinical forms of denture stomatitis in both groups. ", "Individuals without diabetes (n=42) or with diabetes mellitus type 2 (n=36) who were candidates for complete immediate dentures were included in the study. ", "After 1 year of wearing relined immediate dentures, participants were evaluated for denture stomatitis and potential contributing factors. ", "Salivary vascular endothelial growth factor levels were measured with enzyme-linked immunosorbent assays. ", "Data were analyzed with the χ(2) test or the Student t test where appropriate, as well as with binary logistic regression analysis. ", "The incidence of denture stomatitis was 61% in participants with diabetes mellitus type 2 and 38% in those without diabetes. ", "Low denture stability and diabetes mellitus type 2 were risk factors for denture stomatitis. ", "Salivary vascular endothelial growth factor concentrations at the beginning of the study were 557.6 ±94.7 pg/mL in participants with diabetes mellitus type 2 and 103.5 ±21.6 pg/mL in those without diabetes. ", "In Newton Type I and Newton Type II denture stomatitis, vascular endothelial growth factor levels were 460.9 ±55.4 pg/mL and 1445.2 ±422.1 pg/mL in individuals with diabetes and 73.2 ±10.0 pg/mL and 306.5 ±22.6 pg/mL in those without diabetes. ", "Perceived denture stability and diabetes mellitus type 2 are independent risk factors for the occurrence of denture stomatitis. ", "Altered salivary vascular endothelial growth factor levels and denture stomatitis are more prevalent in denture wearers with diabetes mellitus type 2." ]	{ "pile_set_name": "PubMed Abstracts" }	[ 0.005356757435947657, 0.0007401345646940172, 0.003562171943485737, 0.0014616143889725208, 0.001998520689085126, 0.008106786757707596, 0.0006904776091687381, 0.0005893666530027986, 0.002405871171504259, 0.015106424689292908, 0.0007011519628576934, 0.0013078338233754039, 0.0016831172397360206, 0.005898159928619862 ]	0.003543	14
[ "Bińcze\n\nBińcze () is a village in the administrative district of Gmina Czarne, within Człuchów County, Pomeranian Voivodeship, in northern Poland. ", "It lies approximately east of Czarne, west of Człuchów, and south-west of the regional capital Gdańsk.", "\n\nUntil 1771 Crown of the Kingdom of Poland, next was part of Kingdom of Prussia (First Partition of Poland). ", "For the history of the region, see History of Pomerania. ", "For details of the history of the region, see History of Pomerania.", "\n\nThe village has a population of 535.", "\n\nNotable residents\n Joachim von Willisen (1900-1983), resistance fighter\n\nReferences\n\nCategory:Villages in Człuchów County" ]	{ "pile_set_name": "Wikipedia (en)" }	[ 0.004042507614940405, 0.004354533273726702, 0.0007237590034492314, 0.0006265774136409163, 0.0006191445863805711, 0.0018116479041054845, 0.0006878977292217314 ]	0.001838	7
[ "A major clinical trial will probe whether a cannabis-based medicine can relieve debilitating symptoms in Parkinson’s sufferers.", "\n\nThe £1.2million study of cannabidiol (CBD) starting next year covers 145,000 patients and will focus on the hallucinations and delusions that hit up to 60% of cases.", "\n\nThe move comes after laws on cannabis-based medicines were relaxed last year, making them available on prescription for conditions including epilepsy and multiple sclerosis.", "\n\nLow-level concentrations of CBD oil – which lacks the psychoactive element of cannabis – are available from health food shops too.", "\n\nBut CBD is not available on prescription for Parkinson’s.", "\n\nParkinson’s sufferer Paula Scurfield has had hallucinations and started buying CBD oil from high street chain Holland & Barrett.", "\n\nThe 71-year-old, from Beckenham, South East London, said patients are “desperate” and willing to try anything.", "\n\nShe added: “I think this clinical trial is important.", "\n\n“The trouble is people are doing what I am and taking unregulated medicines. ", "Or there’s people who may well get cannabis from a dealer or other unregulated sources.”", "\n\nThe trial will be led by Parkinson’s UK and King’s College London.", "\n\n(Image: ETIENNE LAURENT/EPA-EFE/REX)\n\nDr Arthur Roach of Parkinson’s UK said: “There are many unanswered questions about the value of CBD for Parkinson’s but this will help determine whether it can help with hallucinations and delusions.”", "\n\nShow more\n\nLead researcher Professor Sagnik Bhattacharya added: “We hope this will progress to large-scale trials – the final step towards becoming a new treatment that will improve the lives of people with Parkinson’s.”" ]	{ "pile_set_name": "OpenWebText2" }	[ 0.0011488571763038635, 0.000901391264051199, 0.0009615477174520493, 0.0006095509161241353, 0.0005873977206647396, 0.013743219897150993, 0.0018303989199921489, 0.0005706765223294497, 0.0009568803361617029, 0.0006017427076585591, 0.0006792939966544509, 0.0014552513603121042, 0.0006801461568102241 ]	0.001902	13
[ "There’s something strangely compelling about raw, handmade bodywork. ", "To me it’s one of the finest demonstrations of skill and creativity. ", "In today’s custom motorcycle scene it’s an art form that seems to be making a resurgence which is a welcome change to the automated processes of modern motorcycle production. ", "Today’s feature bike named ‘La Bomba 500’ is one example from a portfolio of stunning builds by the Spanish Workshop Valtoron and, like all their other builds, it’s wrapped in handmade bodywork and packed with plenty of custom components.", "\n\n\n\n\n\nThe donor bike for La Bomba (meaning Bomb in Spanish) was a ’74 Kawasaki H1 “Widowmaker”. ", "At 500cc you could be forgiven for thinking it’s a low powered bike, but the H1 is a beast of two stroke engineering producing around 60bhp at the rear wheel! ", "To further add to the H1’s impressive factory power figure the Valtoron team have upgrade its 3 pistons to Wiseco high compression units that have been seated in expanded chambers and breathe through honed ports. ", "Fuel delivery has been stepped up with 28mm Mikuni carbs and a one-off Valtoron exhaust designed to maximise power rather than just noise.", "\n\nBy bracing and reinforcing the frame, mounting the engine higher and adding Koni rear shocks Valtoron have improved the H1’s notorious handling deficiencies. ", "Lowering the front forks and using the swingarm from a GPZ550 then tame the H1’s tendency to pop up on one wheel and brake components from a Yamaha R6 help to quickly shave off the big numbers the engine clocks up on its speedo.", "\n\nThen we get down to the visual improvements. ", "Custom alloy rearsets, clip-ons equipped with a quick action throttle and Morad rims are all beautiful in their own right, but are overshadowed by that stunning tank and tail. ", "The one off, monocoque design was first moulded out of clay by the talented Valtoron team. ", "Once complete recycled aluminium was cast, bashed and bent into shape using old school fabrication techniques. ", "Tan suede leather covers the saddle and grips to match the cast bronze tank emblems and filler cap and a sand-cast Valtoron ignition cover dresses up the engine. ", "The finish touch on this masterpiece of performance upgrades and custom fabrication is the Zundapp headlight which floats in a custom made ring at the front of the forks.", "\n\nWhat about the paint? ", "Forget about it. ", "Why would anyone ever want to cover this beauty up!?" ]	{ "pile_set_name": "OpenWebText2" }	[ 0.0006853446830064058, 0.000562188564799726, 0.0006877609994262457, 0.0006817968678660691, 0.0010903223883360624, 0.0008785600075498223, 0.0006593079306185246, 0.0013552363961935043, 0.001070676138624549, 0.0008593901293352246, 0.0005517887766472995, 0.0006542540504597127, 0.0006064062472432852, 0.0007168541196733713, 0.0007761401939205825, 0.0006073993863537908, 0.0007876940653659403, 0.002656679367646575, 0.0020011160522699356 ]	0.000942	19
[ "implify (p/(ppp/((pp/(p(-2)/pp))/p)))*(-33)p*14pp/(p8p) assuming p is positive.", "\np*(-26)\nSimplify (((pp*(-4))/pp/(p/(ppp*(2/7)/p)p))/(p/((pp/((p(-2)/p)/p))/p)p(1/9)/p))(-30) assuming p is positive.", "\np(-740/21)\nSimplify (g11/gg)(-1)/(g(5/6)g)(-36) assuming g is positive.", "\ng55\nSimplify (q(4/3))(3/49)/(q/q*1qq/q(-18)q) assuming q is positive.", "\nq*(-1025/49)\nSimplify ((j/((j/(jj*(-27)/j)j)/j))/(j/j*(-1/2)))/(jj(-3/10))(17/4) assuming j is positive.", "\nj*(-1259/40)\nSimplify (nn*5nnn/n*(-2/7)n)/(n*(3/7)nn/(n/n15)n) assuming n is positive.", "\nn(-50/7)\nSimplify (n(11/3)n/(n/n(3/16)))/(((n(2/47)n)/n)/(nn/n(1/23))) assuming n is positive.", "\nn(299297/51888)\nSimplify (((r/(r(2/23)r))/r)/r(-2/5))/(r(6/13)r/(r/(rrr(3/14)))) assuming r is positive.", "\nr(-70383/20930)\nSimplify ((i(-3)/ii/(i/i*1i))/(i/(ii(1/2)))(-22))(-5) assuming i is positive.", "\ni75\nSimplify s(5/2)/s(-33)(s(1/24))(-41) assuming s is positive.", "\ns(811/24)\nSimplify w(-1/4)w(w*(-18)/w)/www((w*28ww)/w)/w4 assuming w is positive.", "\nw(31/4)\nSimplify h(-11)h*8h/h*12hh(-8)/h assuming h is positive.", "\nh(-22)\nSimplify ((i/i(-1/3))(-26/5)(i/i1)(-30))(-36) assuming i is positive.", "\ni(1248/5)\nSimplify ((qq(2/57)qq)/((q(-3)/q)/q))/(q(-2/5))(-20/3) assuming q is positive.", "\nq(102/19)\nSimplify n(-6)/(n/(nn*(2/37)))n*(2/9)/(nnn/(n/n(-2/3))n) assuming n is positive.", "\nn(-2683/333)\nSimplify (a/(a/a(1/3)))(4/7)/(((a(-8/7)/a)/a)/a(1/13)) assuming a is positive.", "\na(133/39)\nSimplify (h(-3/7))(-2/21)/(h(h/(h10/hh))/hhhhh(-2/17)) assuming h is positive.", "\nh(5130/833)\nSimplify u*(-10)uu(-2/5)(u(-3))(-4/11) assuming u is positive.", "\nu(-457/55)\nSimplify ((p(-12/11)p)(-2/21))(-11) assuming p is positive.", "\np(-2/21)\nSimplify ((c(-1))16/(c4(c0/c)/c))(-3/7) assuming c is positive.", "\nc(54/7)\nSimplify ((m/m4((m/(m0/m))/m)/m)/((m((m*(-4)m)/mm)/mm)/m(-4)))(-2/5) assuming m is positive.", "\nm*2\nSimplify ((ttt(-4))/t(2/21))/(t(-4/3))(-6/11) assuming t is positive.", "\nt(-652/231)\nSimplify ((w/w(-6))/(w23w))2 assuming w is positive.", "\nw(-34)\nSimplify (dd19)/(d14d)(d13d)/d4 assuming d is positive.", "\nd15\nSimplify (b(-10)/b)(-4)/(b/(b/(b*2/bb)))(-4/7) assuming b is positive.", "\nb(316/7)\nSimplify t(-2)/(t(-9/7)tt)(tt/(t*3/tt))(9/2) assuming t is positive.", "\nt(-101/14)\nSimplify (x*(11/4)x)/(x/(xx/(x(1/6)/xxx)))x*(2/5)x8 assuming x is positive.", "\nx(719/60)\nSimplify (t5)(-33)t(6/11)t((tt/(((t*10/t)/t)/ttt))/t)/tt assuming t is positive.", "\nt(-1886/11)\nSimplify (k(-19))*(1/47)k(-2/93)/k(-2/5) assuming k is positive.", "\nk*(-563/21855)\nSimplify (((nn(-7))/(n1n))/(n5n(-3)))34 assuming n is positive.", "\nn(-340)\nSimplify (a(2/5)a)(-1/8)/((aa*(-1/2)/a)/aa(1/4)/a) assuming a is positive.", "\na(83/40)\nSimplify (((((d*(2/7)d)/d)/d)(-2/41))50)(-17/5) assuming d is positive.", "\nd(-1700/287)\nSimplify ((((ccc*0c)/c)/c)/c)*(-42)(c/(c/(c/c(-11))))/c(-4) assuming c is positive.", "\nc16\nSimplify (x(-1/6)/((x*(4/15)x)/x))/(x(-2/5))(-34) assuming x is positive.", "\nx(-421/30)\nSimplify ((t(3/19)/t)5)(1/13) assuming t is positive.", "\nt(-80/247)\nSimplify (u(-2/35))(1/71)/(u23u(-7)/u) assuming u is positive.", "\nu(-37277/2485)\nSimplify (s(-29))(-10)/(s0s*(8/3)s) assuming s is positive.", "\ns(859/3)\nSimplify (c(5/3)/(c4/c))/(c(5/12)c/(c(-1/2)/cc)) assuming c is positive.", "\nc*(-13/4)\nSimplify (dd13)/(d/((d/(d/(d11d)))/d)dd)(d/((d*(-25)/dd)/ddd))37 assuming d is positive.", "\nd947\nSimplify ((i/(i/i*(-1))(i/i*10)/ii)(-3/4))(3/13) assuming i is positive.", "\ni*(45/26)\nSimplify ((u(u/(uu1))/u)/u39)/((uu/(u/(uu(-15))))/(uu/(u*(-17/3)u))) assuming u is positive.", "\nu*(-61/3)\nSimplify (kk/(k*9/k)k(k((kk10)/k)/kk)/kk/(k8k)kk(-1/8)/k)(-19/6) assuming k is positive.", "\nk*(475/48)\nSimplify (nnn(n/n*5n)/n)*(-24)(n*(-16)n)/nn(12/7)n assuming n is positive.", "\nn(75/7)\nSimplify ((l4/l)/(lll*(-1/14)l))/(l/l*(1/3)lll)(-3/25) assuming l is positive.", "\nl(179/350)\nSimplify ((gggg(g/(gg7g)g)/gg)/g*(-6)(gg1g)(1/64))(1/15) assuming g is positive.", "\ng(13/64)\nSimplify (p(-8)p(-6))/(p(-8)p(1/5)) assuming p is positive.", "\np(-31/5)\nSimplify ((v(1/3)/v)/(v/(v/v(-2/5))))/(vv(1/11)/v(v(1/20)/v)/v) assuming v is positive.", "\nv(1051/660)\nSimplify (r(1/9))7r/(r/r(-6))rr(-7/5) assuming r is positive.", "\nr(-253/45)\nSimplify (g/(gg*36g)g(-3/13))/(g27)(-15) assuming g is positive.", "\ng(4781/13)\nSimplify (x/(xx*(-1/2))x)*(-16/7)x*(-13)(x/(xx/(xx*(-18)xxx)x)x)/x assuming x is positive.", "\nx(-227/7)\nSimplify ((n1)(15/11)/((n(2/5)n)/((n6n)/n)))4 assuming n is positive.", "\nn(1312/55)\nSimplify (g11/g)(-22)/((((gg(-1/4)g)/ggg)/g)/(g/g8)) assuming g is positive.", "\ng(-915/4)\nSimplify (z3)12/(z*(-12)/((zz5)/z)) assuming z is positive.", "\nz53\nSimplify (ww(-7))/ww*2w(3/4)/w(-7/5) assuming w is positive.", "\nw(-57/20)\nSimplify h(7/4)/((h/(hh(-3/14)))/h)(h/(h/(h/(h/h*(-6))h)))(7/12) assuming h is positive.", "\nh(-8/21)\nSimplify (j(jj(jj*8j)/jjj)/jjjjjj/j0j(j1)(-12))(4/5) assuming j is positive.", "\nj(28/5)\nSimplify ((p(-2/9)p)/pp(-3)p*5p/((pp(-1/5)/p)/p))(-2/135) assuming p is positive.", "\np(-358/6075)\nSimplify (((ccc(4/7))/(c/(cc*(3/4))))/((cc*(2/29))/(cc/(cc/(c4c)))))(-1/54) assuming c is positive.", "\nc(-1963/14616)\nSimplify (aa4)(-2/75)(a/(aa(-7/5)/a))/aa9 assuming a is positive.", "\na(154/15)\nSimplify (b(-2/27)/(b35b))(-7/6) assuming b is positive.", "\nb(3409/81)\nSimplify (ll*(-1)ll)/(l(-1/6)/l)l*(-1/13)l/l(-10) assuming l is positive.", "\nl(1099/78)\nSimplify ((uuu(-3/23)/u)/(u(-2)/u))/(uu/(u/(((((u/u2)/u)/u)/u)/u))u)(-2) assuming u is positive.", "\nu(-49/23)\nSimplify (kk/(kk*(1/4)/k))/kkkk/k*(-3)(k/(k/(k*3/kk)))(-3/8) assuming k is positive.", "\nk(45/8)\nSimplify (v1)38/((vv(-2)vv)/(vvv8/v)) assuming v is positive.", "\nv46\nSimplify (ss/(s(ss*4s)/s))*(-18)(s/s*0s)(1/45) assuming s is positive.", "\ns(3242/45)\nSimplify ggg/(g/(gg(-7)))ggg/g*12gg28gg(-10)/g assuming g is positive.", "\ng6\nSimplify (((tt/(t/t*(-4/7))t)/t(2/9))/(t/t(1/5))(-9/11))(3/26) assuming t is positive.", "\nt(248/1155)\nSimplify (z(2/3)z)(1/2)/(((zz/(z15/z))/z)/(((z/(z(-15/4)/zz)z)/zz)/z)) assuming z is positive.", "\nz(223/12)\nSimplify (((x/(xx0))37)(1/22))(7/6) assuming x is positive.", "\n1\nSimplify xx(11/4)xx16x(-1)/x(-1/3) assuming x is positive.", "\nx*(241/12)\nSimplify (((k/(k/(k/(kk*(-24)))))/kkk/k(-1/2)kk)(-36))(2/21) assuming k is positive.", "\nk(-660/7)\nSimplify ((mm/(mm/m(-4)m)m)/((mm(-13))/m))/(m/(m/(m/(m(-2/11)/m)))(m(-1/3)/m)/m) assuming m is positive.", "\nm(302/33)\nSimplify (f/((f/(ff/(f/(f/f*(-10)f))))/f))*(-1/48)((ff(-26/7))/f)38 assuming f is positive.", "\nf(-23761/168)\nSimplify (q(-3))50/((q19/q)/qq*(-2/19)q) assuming q is positive.", "\nq*(-3190/19)\nSimplify (a/(aaa(-2/9))a)*(1/34)/((aa(-1/2))/a)(-12) assuming a is positive.", "\na(-917/153)\nSimplify (a/(a(-15)/a)a/((aaa15)/a))/(a26)46 assuming a is positive.", "\na(-1194)\nSimplify (y(-3))28/(y4y(2/37)) assuming y is positive.", "\ny(-3258/37)\nSimplify (((o/((o(oo/(o/(o*1o)))/o)/oo)o)/o(-6))(-3))2 assuming o is positive.", "\no(-30)\nSimplify (ssss17ssss)(-6)/(ss/(s(4/7)/s))(-30) assuming s is positive.", "\ns(-498/7)\nSimplify ((h/h(6/7))/hh)/((hhh7)/h)(h/(h/(h*12/h))hhh)/h7 assuming h is positive.", "\nh(-6/7)\nSimplify (b(-3/5))1b(-4)/b(-6/11) assuming b is positive.", "\nb(-223/55)\nSimplify (((g(1/4)g)/(g(-1/3)/g))(34/7))(-47) assuming g is positive.", "\ng(-24769/42)\nSimplify (s/s*6ss)/(s/(sss16))(s(-4))(-39) assuming s is positive.", "\ns*170\nSimplify (a/(aaa4a)aa*12aa)(-45) assuming a is positive.", "\na(-405)\nSimplify (u/(u/u32)uu*(2/" ]	{ "pile_set_name": "DM Mathematics" }	[ 0.016747577115893364, 0.012001882307231426, 0.004542071837931871, 0.001336180022917688, 0.0008837836212478578, 0.015684984624385834, 0.00334724853746593, 0.0013461263151839375, 0.0008738225442357361, 0.001156267011538148, 0.003098997287452221, 0.008871237747371197, 0.0009166922536678612, 0.0009348743478767574, 0.012336391024291515, 0.0009470730437897146, 0.0015331621980294585, 0.0065222084522247314, 0.0010937199695035815, 0.008249019272625446, 0.0013784000184386969, 0.004987387917935848, 0.001073312945663929, 0.00374268158338964, 0.0014470090391114354, 0.013907471671700478, 0.001421276479959488, 0.03246263414621353, 0.5468290448188782, 0.3883545696735382, 0.0013155837077647448, 0.0008005824056454003, 0.0010258734691888094, 0.0008883909322321415, 0.0008610167424194515, 0.0030933571979403496, 0.0019680443219840527, 0.0018371597398072481, 0.00908589642494917, 0.0011839928338304162, 0.005953954998403788, 0.8948370814323425, 0.7252376675605774, 0.0031513283029198647, 0.0143485302105546, 0.0048415781930089, 0.0029302837792783976, 0.0011041647521778941, 0.003355525666847825, 0.0014286285731941462, 0.0015559581806883216, 0.008887158706784248, 0.0012991247931495309, 0.0015019922284409404, 0.007982362061738968, 0.005529928486794233, 0.0016878976020962, 0.021222257986664772, 0.0017011287854984403, 0.0010277520632371306, 0.001049732556566596, 0.007633907720446587, 0.8549535870552063, 0.7301436066627502, 0.00301009276881814, 0.03942295163869858, 0.005884398240596056, 0.0011022320250049233, 0.0009155815350823104, 0.0009982787305489182, 0.34524276852607727, 0.389597088098526, 0.14667774736881256, 0.3422435224056244, 0.0010113809257745743, 0.0010208411840721965, 0.001111622666940093, 0.0014460214879363775, 0.03529943898320198, 0.002361543709412217, 0.0017556295497342944, 0.0010294443927705288, 0.011958991177380085, 0.003133173333480954, 0.008241298608481884 ]	0.067846	85
[ "Serfas\nUSL-500 E-Lume 500\n\nDetails\n\nThe Serfas E-Lume Series light line was developed to be the best on the market at the very best value. ", "These headlights will meet and exceed their expected lumen output while offering you all the features you've come to enjoy from Serfas lighting." ]	{ "pile_set_name": "Pile-CC" }	[ 0.0005826845299452543, 0.015310055576264858 ]	0.007946	2
[ "Not known Factual Statements About custom pool builder\n\nMenu\n\nNot known Factual Statements About custom pool builder\n\nWe've had a hell of the time with algae this calendar year. ", "It is most likely our stupidness at getting the… read through much more\n\nWe've been connecting Australians with regional trade specialists and residential expert services for over 12 decades.", "\n\nPool Covers should continue to be clear of h2o and snow constantly. ", "It is incredibly essential to take out snow and water off of the pool deal with without delay.", "\n\nSummer time is simply round the corner. ", "Ideal time to make a pool. ", "Get in rapid before the rush and become wanting to cool down and entertain your company for summertime. ... ", "See MoreSee Fewer\n\nSubscribe to GJ Advisor right now, for any every month e-mail Together with the instruments, realistic suggestions and style information to manual you through each and every phase of the making procedure Required Valid e-mail deal with required\n\ncan start off (Simply click here To learn more over a Free Swimming Pool Quotation). ", "Digging a gap with the pool is the main procedure. ", "Danna Pools Inc. works by using machines just like a bobcat or an excavator to dig the hole about the size of your pool.", "\n\nSadly the youngsters get Uninterested in it and it is actually used just A few situations a 12 months. ", "I normally dreamed I would have a pool in my dwelling and it was only attainable by doing it myself. ", "Your property is best with that pool. ", "I added a roof around mine to halt leaves falling in from close by trees and sunburn. ", "The roof has skylights and cheap drain pipes in a spiral to heat up the pool. ", "At sunset it is actually the right end into the working day with a chilly beer. ", "Do not hear folk indicating no, they often never ever do something not to mention this type of obstacle. ", "Very well DONE!", "\n\nPool builders in Brisbane frequently confront quite a few worries while in the rising amount of web-sites which can be sloping. ", "Pool and landscape construction need to be taken care of by professionals who will be informed about the difficulties special to Brisbane’s geographical constraints like sloping blocks and soil sorts. ", "Everscapes can offer both pool landscape and backyard garden design along with swimming pool construction.", "\n\nEvery single Precision Pool is personalised towards the consumer’s desires, demands and requests, Each and every pool is separately and specifically designed to be one of a kind.", "\n\nWe're Prepared to debate your needs and offer you a Absolutely free QUOTE of impressive Concepts and types. ", "And Check out back right here normally, we update our internet pages navigate to this site as our pending work relates to completion.", "\n\nConstruction Programs present every facet of the undertaking in detail. ", "In these strategies, the location and specification of each item are described in detail, to scale.", "\n\nAt Precision Pools We have now developed a typical not an expectation as a result of know-how, treatment, imagination and perseverance.", "\n\nRobotic computerized pool cleaner, free from the skimmer box and unbiased on the pool pump for maximum cleaning effectiveness of your new pool to save lots of you time.", "\n\nPhotos and photographs may possibly depict fixtures, finishes and capabilities both not supplied by G.J. Gardner Homes or not included in any rate mentioned." ]	{ "pile_set_name": "Pile-CC" }	[ 0.0009413653169758618, 0.17521293461322784, 0.0008783926605246961, 0.0008171845693141222, 0.000673512986395508, 0.0006110115209594369, 0.0009943405166268349, 0.0005755841266363859, 0.0007276747492142022, 0.0013291732175275683, 0.000857565610203892, 0.000569554977118969, 0.005309971049427986, 0.006477105896919966, 0.0011384922545403242, 0.000753076164983213, 0.0007444946095347404, 0.0007807914516888559, 0.0005656896391883492, 0.0005168516072444618, 0.0006468228530138731, 0.0005637053982354701, 0.0006152522400952876, 0.0005397838540375233, 0.0005468549788929522, 0.0005498883547261357, 0.0005831976304762065, 0.0007526266272179782, 0.000547262723557651 ]	0.007097	29
[ "Characteristics of females who sexually offend: a comparison of solo and co-offenders.", "\nAlthough recent typologies of female sexual offenders have recognized the importance of having a co-offender, the clinical characteristics of solo and co-female sexual offenders remain poorly understood. ", "The aim of this study was to compare solo (n = 20) and co- (n = 20) female sexual offenders on a variety of clinical characteristics. ", "It was found that although solo and co-offenders reported similar developmental experiences and psychological dispositions, differences were found in environmental niche, offense preceding, and positive factors. ", "Specifically, solo offenders demonstrated a greater presence of personal vulnerabilities including mental health and substance abuse difficulties. ", "Co-offenders reported a greater presence of environmentally based factors, including a current partner who was a known sex offender and involvement with antisocial peers. ", "It is suggested that these results have implications for understanding assessment and intervention needs for these groups of sexual offenders." ]	{ "pile_set_name": "PubMed Abstracts" }	[ 0.021727388724684715, 0.0043521421030163765, 0.005942077841609716, 0.0006086027133278549, 0.004132217261940241, 0.006510836072266102, 0.027585230767726898 ]	0.010123	7
[ "Q:\n\nHow do you reference the root key using JSON Path?", "\n\nI have data like so:\n{\"key\": {\"name\":\"hi\", \"size\":10}}\n\n\"key\" is a dynamic value. ", "It isn't fixed. ", "I can access name and size using this JSON Path:\n.name\n.size\n\nHow can I get the value of \"key\" itself with JSON Path? * ", "gives me the entire row of data, and both $ and @ give me \"no element found\" in my parser.", "\nI'm trying to do this in Pentaho with a JSON Input step.", "\n\nA:\n\n$.* ", "will give you all elements of parent object, in your example you will get something like\n[\n {\n \"name\":\"hi\",\n \"size\":10\n }\n]\n\naccording to: http://jsonpath.curiousconcept.com/\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.0007064859964884818, 0.0006886070477776229, 0.0007050987333059311, 0.0007408743840642273, 0.0008375219767913222, 0.0006657987833023071, 0.0011282821651548147, 0.00064497982384637 ]	0.000765	8
[ "package fs\n\nimport (\n\t\"os\"\n\t\"path/filepath\"\n\t\"sort\"\n\t\"strings\"\n\t\"sync\"\n\n\t\"github.com/spf13/afero\"\n)\n\nfunc ListExecutableWithPrefix(fs afero.", "Fs, prefix string) []string {\n\tvar wg sync.", "WaitGroup\n\tch := make(chan string)\n\n\tfor _, path := range filepath.", "SplitList(os.", "Getenv(\"PATH\")) {\n\t\twg.", "Add(1)\n\t\tgo func(path string) {\n\t\t\tdefer wg.", "Done()\n\n\t\t\tfiles, err := afero.", "ReadDir(fs, path)\n\t\t\tif err !", "= nil {\n\t\t\t\treturn\n\t\t\t}\n\n\t\t\tfor _, f := range files {\n\t\t\t\tif m := f.Mode(); !", "f.IsDir() && m&0111 !", "= 0 && strings.", "HasPrefix(f.", "Name(), prefix) {\n\t\t\t\t\tch <- f.Name()\n\t\t\t\t}\n\t\t\t}\n\t\t}(path)\n\t}\n\n\tgo func() {\n\t\twg.", "Wait()\n\t\tclose(ch)\n\t}()\n\n\texecs := make([]string, 0, 100)\n\tfor exec := range ch {\n\t\texecs = append(execs, exec)\n\t}\n\tsort.", "Strings(execs)\n\n\treturn execs\n}\n" ]	{ "pile_set_name": "Github" }	[ 0.0006832265644334257, 0.0008358063641935587, 0.0007714387611486018, 0.0008333185105584562, 0.0007438223110511899, 0.00501493364572525, 0.0008189029758796096, 0.0013408317463472486, 0.002140029100701213, 0.0008857281063683331, 0.0008196254493668675, 0.0012923404574394226, 0.0017525394214317203, 0.0010270180646330118, 0.0019088918343186378 ]	0.001391	15
[ "Q:\n\nSafe c++ in mission critical realtime apps\n\nI'd want to hear various opinions how to safely use c++ in mission critical realtime applications. ", "\nMore precisely, it is probably possible to create some macros/templates/class library for safe data manipulation (sealing for overflows, zerodivides produce infinity values or division is possible only for special \"nonzero\" data types), arrays with bound checking and foreach loops, safe smartpointers (similar to boost shared_ptr, for instance) and even safe multithreading/distributed model (message passing and lightweight processes like ones are defined in Erlang languge).", "\nThen we prohibit some dangerous c/c++ constructions such as raw pointers, some raw types, native \"new\" operator and native c/c++ arrays ( for application programmer, not for library writer, of course). ", "Ideally, we should create a special preprocessor/checker, at least we must have some formal checking procedure, which can be applyed to sources using some tool or manualy by some person.", "\nSo, my questions:\n1) Are there any existing libraries/projects that utilize such an idea? (", "Embedded c++ is apparently not of desired kind) ?", "\n2) Is it a good idea at all or not? ", "Or it may be useful only for prototyping some another hipothetical language? ", "Or it is totally unusable?", "\n3) Any other thoughts (or links) on this matter also welcome\nSorry if this question is not actually a question, offtopic, duplicate, etc.,", "\nbut I haven't found more appropriate place to ask it\n\nA:\n\nFor good rules on how to write C++ for mission critical real-time applications have a look at the Joint Strike Fighter coding standards. ", " Many of the rules there are based on the MISRA C coding standards, which I believe are proprietary. ", " PC-Lint is a C++ code checker with rule sets like what you want (including the MISRA rules). ", " I believe you can customize your own rules as well.", "\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.0005930031766183674, 0.0006018872954882681, 0.0007803206099197268, 0.0005571661749854684, 0.0006677467608824372, 0.0007688465993851423, 0.0007985963602550328, 0.001163373002782464, 0.0008180743316188455, 0.0006239881040528417, 0.0005782383377663791, 0.0006424405728466809, 0.0014223820762708783, 0.0007515472825616598, 0.001995587022975087 ]	0.000851	15
[ "Please find attached a detailed briefing paper on the captioned order. ", " Ray Alvarez" ]	{ "pile_set_name": "Enron Emails" }	[ 0.0005242181941866875, 0.0010638994863256812 ]	0.000794	2
[ "Q:\n\nAutomatically generate lowercase dashed routes in ASP.NET Core\n\nASP.NET Core uses CamelCase-Routes like http://localhost:5000/DashboardSettings/Index by default. ", "But I want to use lowercase routes, which are delimitted by dashes: http://localhost:5000/dashboard-settings/index They're more common and consistent, cause my application extends a website running Wordpress, which also has lowercase urls with dashes. ", "\nI learned that I can change the urls to lowercase using the routing-options: \nservices.", "ConfigureRouting(setupAction => {\n setupAction.", "LowercaseUrls = true;\n});\n\nThis works but gave me urls without any delimiter like http://localhost:5000/dashboardsettings/index which are badly readable. ", "I could define custom routes using the route attribute like \n[Route(\"dashboard-settings\")]\nclass DashboardSettings:Controller {\n public IActionResult Index() {\n // ...\n }\n}\n\nBut that causes extra-work and is error-prone. ", "I would prefer an automatic solution which search for uppercase chars, insert a dash before them and make the uppercase-char lowercase. ", "For the old ASP.NET this was not a big issue, but on ASP.NET Core I see no direction how to handle this. ", "\nWhats the way to do this here? ", "I need some kind of interface where I can generate urls (like for the tag helpers) and replace there the CamelCase by dash-delimiters. ", "Then I need another kind of interface for the routing, so that the dash-delimiter urls are converted back to CamelCase for correct matching with my controller/action names. ", "\n\nA:\n\nUpdate in ASP.NET Core Version >= 2.2\nTo do so, first create the SlugifyParameterTransformer class should be as follows:\npublic class SlugifyParameterTransformer : IOutboundParameterTransformer\n{\n public string TransformOutbound(object value)\n {\n // Slugify value\n return value == null ? ", "null : Regex.", "Replace(value.", "ToString(), \"([a-z])([A-Z])\", \"$1-$2\").ToLower();\n }\n}\n\nFor ASP.NET Core 2.2 MVC:\nIn the ConfigureServices method of the Startup class:\nservices.", "AddRouting(option =>\n{\n option.", "ConstraintMap[\"slugify\"] = typeof(SlugifyParameterTransformer);\n});\n\nAnd route configuration should be as follows:\napp.", "UseMvc(routes =>\n{\n routes.", "MapRoute(\n name: \"default\",\n template: \"{controller:slugify}/{action:slugify}/{id?}\",", "\n defaults: new { controller = \"Home\", action = \"Index\" });\n });\n\nFor ASP.NET Core 2.2 Web API:\nIn the ConfigureServices method of the Startup class:\npublic void ConfigureServices(IServiceCollection services)\n{\n services.", "AddMvc(options => \n {\n options.", "Conventions.", "Add(new RouteTokenTransformerConvention(new SlugifyParameterTransformer()));\n }).SetCompatibilityVersion(CompatibilityVersion.", "Version_2_2);\n}\n\nFor ASP.NET Core >=3.0 MVC:\nIn the ConfigureServices method of the Startup class:\nservices.", "AddRouting(option =>\n{\n option.", "ConstraintMap[\"slugify\"] = typeof(SlugifyParameterTransformer);\n});\n\nand route configuration should be as follows:\napp.", "UseEndpoints(endpoints =>\n{\n endpoints.", "MapAreaControllerRoute(\n name: \"AdminAreaRoute\",\n areaName: \"Admin\",\n pattern: \"admin/{controller:slugify=Dashboard}/{action:slugify=Index}/{id:slugify?}\");", "\n\n endpoints.", "MapControllerRoute(\n name: \"default\",\n pattern: \"{controller:slugify}/{action:slugify}/{id:slugify?}\",", "\n defaults: new { controller = \"Home\", action = \"Index\" });\n});\n\nFor ASP.NET Core >=3.0 Web API:\nIn the ConfigureServices method of the Startup class:\nservices.", "AddControllers(options => \n{\n options.", "Conventions.", "Add(new RouteTokenTransformerConvention(new SlugifyParameterTransformer()));\n});\n\nFor ASP.NET Core >=3.0 Razor Pages:\nIn the ConfigureServices method of the Startup class:\nservices.", "AddRazorPages(options => \n{\n options.", "Conventions.", "Add(new PageRouteTransformerConvention(new SlugifyParameterTransformer()));\n});\n\nThis is will make /Employee/EmployeeDetails/1 route to /employee/employee-details/1 \n\nA:\n\nA little late to the party here but..\nCan do this by implementing IControllerModelConvention.", "\n public class DashedRoutingConvention : IControllerModelConvention\n {\n public void Apply(ControllerModel controller)\n {\n var hasRouteAttributes = controller.", "Selectors.", "Any(selector =>\n selector.", "AttributeRouteModel !", "= null);\n if (hasRouteAttributes)\n {\n // This controller manually defined some routes, so treat this \n // as an override and not apply the convention here.", "\n return;\n }\n\n foreach (var controllerAction in controller.", "Actions)\n {\n foreach (var selector in controllerAction.", "Selectors.", "Where(x => x.AttributeRouteModel == null))\n {\n var template = new StringBuilder();\n\n if (controllerAction.", "Controller.", "ControllerName !", "= \"Home\")\n {\n template.", "Append(PascalToKebabCase(controller.", "ControllerName));\n }\n\n if (controllerAction.", "ActionName !", "= \"Index\")\n {\n template.", "Append(\"/\" + PascalToKebabCase(controllerAction.", "ActionName));\n }\n\n selector.", "AttributeRouteModel = new AttributeRouteModel()\n {\n Template = template.", "ToString()\n };\n }\n }\n }\n\n public static string PascalToKebabCase(string value)\n {\n if (string.", "IsNullOrEmpty(value))\n return value;\n\n return Regex.", "Replace(\n value,\n \"(?", "<!", "^)([A-Z][a-z]\|(?<=[a-z])[A-Z])\",\n \"-$1\",\n RegexOptions.", "Compiled)\n .Trim()\n .ToLower();\n }\n}\n\nThen registering it in Startup.cs\npublic void ConfigureServices(IServiceCollection services)\n{\n // Add framework services.", "\n services.", "AddMvc(options => options.", "Conventions.", "Add(new DashedRoutingConvention()));\n}\n\nCan find more info and example here https://docs.microsoft.com/en-us/aspnet/core/mvc/controllers/routing\n\nA:\n\nI'm using Asp.", "NetCore 2.0.0 and Razor Pages (no explicit controller necessary), so all that's needed is:\n\nEnable Lowercase Urls:\nservices.", "AddRouting(options => options.", "LowercaseUrls = true);\nCreate a file named Dashboard-Settings.cshtml and the resulting route becomes /dashboard-settings\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.0006886031478643417, 0.0007124982657842338, 0.0006169016123749316, 0.0017074878560379148, 0.0007655391236767173, 0.0006483025499619544, 0.0009776647202670574, 0.0006550058606080711, 0.0007761587621644139, 0.0007248433539643884, 0.000595342367887497, 0.0011337725445628166, 0.010373114608228207, 0.0009274433250539005, 0.0007054960005916655, 0.0008615682017989457, 0.0006399134290404618, 0.0009523183107376099, 0.0007328042993322015, 0.0007038808544166386, 0.000916303601115942, 0.0006462966557592154, 0.0007840310572646558, 0.0008235869463533163, 0.0008615682017989457, 0.0006399134290404618, 0.0007445080555044115, 0.0007564887637272477, 0.0006607455434277654, 0.0007980436785146594, 0.0006526137585751712, 0.0009239717619493604, 0.0006462966557592154, 0.0006976011791266501, 0.0010639653773978353, 0.0006462966557592154, 0.0007059556664898992, 0.001008052029646933, 0.0011626619379967451, 0.0007398584275506437, 0.003346801269799471, 0.001132436329498887, 0.0008062069537118077, 0.0006990103283897042, 0.0011626619379967451, 0.0024669745471328497, 0.001208229106850922, 0.0010279356501996517, 0.0006549939862452447, 0.0007745296461507678, 0.0008560576243326068, 0.0011003221152350307, 0.000663966522552073, 0.0008543048170395195, 0.000808393640909344, 0.0007896635215729475, 0.0009635776514187455, 0.0024338446091860533, 0.0007898641051724553, 0.006598223932087421, 0.0008464386337436736, 0.0006859713466838002, 0.0007191497134044766, 0.0007154648774303496, 0.0006462966557592154, 0.0006069665541872382, 0.0007496810867451131, 0.0006966806249693036, 0.001113420003093779 ]	0.001126	69
[ "Minimal volume of local anesthetic required for an ultrasound-guided SGB.", "\nCompared with the blind technique, ultrasound-guided stellate ganglion block (SGB) reduces the amount of local anesthetic needed for a successful block. ", "The purpose of this study is to determine the minimal, optimal volume of local anesthetic required for successful ultrasound-guided SGB and to reduce its adverse effects. ", "Thirty-five patients with postherpetic neuralgia and complex regional pain syndrome of the upper extremity and the facial area were selected. ", "For ultrasound-guided SGB by subfacial method, each patient was injected with 0.5% mepivacaine mixed with contrast media in 2 mL, 3 mL, and 4 mL doses at 2-week intervals. ", "After the procedure, the spread of contrast media in the spine was checked by fluoroscopy. ", "Ptosis and conjunctival flushing were rated and recorded. ", "Adverse effects, such as hoarseness, foreign body sensation, swallowing difficulty, and upper arm weakness, were also recorded. ", "Out of the 35 initial patients, the results for 33 patients who received all three SGBs were included in this study. ", "The contrast media spread to 4.80 ± 0.82, 4.94 ± 0.86, and 5.09 ± 0.97 total spinal segments in the 2 mL, 3 mL, and 4 mL groups, respectively. ", "The cephalad spread of contrast media was 2.16 ± 0.74, 2.23 ± 0.85, and 2.30 ± 0.78 spinal segments for the 2 mL, 3 mL, and 4 mL groups, respectively, and the caudad spread of contrast media was 2.64 ± 0.51, 2.70 ± 0.61, and 2.89 ± 0.64 segments in the 2 mL, 3 mL, and 4 mL groups, respectively. ", "There were no significant statistical differences in any segments for the three groups (P > 0.05). ", "Review of the fluoroscopic images showed spread of the contrast media below the C7-T1 junction in all three groups. ", "Ptosis developed in all three groups after the procedure. ", "In conclusion, when performing an ultrasound-guided SGB, 2 mL dosage was sufficient for a successful block as the previous, conventional volume. ", "Therefore, when performing an ultrasound-guided SGB, we recommend the 2 mL dosage of local anesthetics for a successful block." ]	{ "pile_set_name": "PubMed Abstracts" }	[ 0.0006155616138130426, 0.0009735271451063454, 0.0005694222054444253, 0.0013570012524724007, 0.0005714613944292068, 0.0006146795931272209, 0.0006620374042540789, 0.0007955328328534961, 0.0005725051159970462, 0.0006336116348393261, 0.0006584260263480246, 0.0005653990665450692, 0.0005738996551372111, 0.0005981927970424294, 0.000651082955300808, 0.0006282937247306108 ]	0.00069	16
[ "Making Rent in Bed-Stuy\n\nMaking Rent in Bed-Stuy\n\nA young African American millennial filmmaker’s funny, sometimes painful, true-life coming-of-age story of trying to make it in New York City—a chronicle of poverty and wealth, creativity and commerce, struggle and insecurity, and the economic and cultural forces intertwined with \"the serious, life-threatening process\" of gentrification.", "\nMaking Rent in Bed-Stuy explores the history and sociocultural importance of Bedford-Stuyvesant, Brooklyn’s largest historically black community, through the lens of a coming-of-age young American negro artist living at the dawn of an era in which urban class warfare is politely referred to as gentrification. ", "Bookended by accounts of two different breakups, from a roommate and a lover, both who come from the white American elite, the book oscillates between chapters of urban bildungsroman and a historical examination of some of Bed-Stuy’s most salient aesthetic and political legacies.", "\nFilled with personal stories and a vibrant cast of iconoclastic characters— friends and acquaintances such as Spike Lee; Lena Dunham; and Paul MacCleod, who made a living charging $5 for a tour of his extensive Elvis collection—Making Rent in Bed-Stuy poignantly captures what happens when youthful idealism clashes head-on with adult reality.", "\nMelding in-depth reportage and personal narrative that investigates the disappointments and ironies of the Obama era, the book describes Brandon Harris’s radicalization, and the things he lost, and gained, along the way." ]	{ "pile_set_name": "Pile-CC" }	[ 0.008167906664311886, 0.009832413867115974, 0.0016780466539785266, 0.0014456076314672828, 0.0006525356438942254 ]	0.004355	5
[ "Q:\n\nHow does Chrome V8 work? ", "And why was JavaScript not JIT-Compiled in the first place?", "\n\nI have been researching Interpreters/Compilers, then I stumbled across JIT-Compilation - specifically Google Chrome's V8 Javascript Engine.", "\nMy questions are -\n\nHow can it be faster than standard Interpretation?", "\nWhy wasn't JIT-Compilation used in the first place?", "\n\nMy Current Understanding\n\nEvery Javascript Program starts out as source code, then, regardless of the method of execution, is ultimately is translated to machine code.", "\n\nBoth JIT-Compilation and Interpretation must follow this path , so how can JIT-Compilation be faster (also because JIT is time-constrained, unlike AOT-Compilation) ?", "\nIt seems that JIT-Compilation is a relatively old innovation, based off of Wikipedia's JIT-Compilation Article.", "\n\n\"The earliest published JIT compiler is generally attributed to work on LISP by McCarthy in 1960.\"", "\n \n\"Smalltalk (c. 1983) pioneered new aspects of JIT compilations. ", "For example, translation to machine code was done on demand, and the result was cached for later use. ", "When memory became scarce, the system would delete some of this code and regenerate it when it was needed again.\"", "\n\nSo why was Javascript Interpreted to begin with?", "\n\nI'm very confused, and I've done a lot of research on this, but I haven't found satisfactory answers.", "\nSo clear, concise answers would be appreciated. ", "And if additional explanation about Interpreters, JIT-Compilers, etc. ", "needs to be brought in, that's appreciated as well.", "\n\nA:\n\nThe short answer is that JIT has longer initialization times, but is a lot faster in the long run, and JavaScript wasn't originally intended for the long run.", "\nIn the 90s, typical JavaScript on a web site would amount to one or two functions in the header, and a handful of code embedded directly in onclick properties and the like. ", " It would typically get run right when the user was expecting a huge page load delay anyway. ", " Think extremely basic form validation or tiny math utilities like mortgage interest calculators. ", " \nInterpreting as needed was a lot simpler and provided perfectly adequate performance for the use cases of the day. ", " If you wanted something with long-run performance, you used flash or a java applet.", "\nGoogle maps in 2004 was one of the first killer apps for heavy JavaScript use. ", " It was eye-opening to the possibilities of JavaScript, but also highlighted its performance problems. ", " Google spent some time trying to encourage browsers to improve their JavaScript performance, then eventually decided competition would be the best motivator, and would also give them the best seat at the browser-standards table. ", " Chrome and V8 were released in 2008 as a result. ", " Now, 11 years after Google Maps came on the scene, we have new developers who don't remember JavaScript ever being considered inadequate for that sort of task.", "\nSay you have a function animateDraggedMap. ", " It might take 500 ms to interpret it, and 700 ms to JIT compile it. ", " However, after JIT compilation, it might take only 100 ms to actually run. ", " If it's the 90s and you're only calling a function once then reloading the page, JIT is not worth it at all. ", " If it's today and you're calling animateDraggedMap hundreds or thousands of times, that extra 200 ms at initialization is nothing, and it can be done behind the scenes before the user even tries to drag the map.", "\n\nA:\n\nJITs are fast for JavaScript, because it's impossible to generate fast machine code when you do not know the type of your variables.", "\nWhen you do not have type information, computations are expensive. ", "For example, \nx + y\nis quite complicated if you don't know anything about x and y. They could be integers, doubles, strings, or even objects where this calculation has side effects. ", "Since we do not have static typing, this is an expensive calculation. ", "\nWith just-in-time compilation, we can use runtime information and turn this into a faster computation. ", "At runtime, V8 keeps track of the type of variables. ", "If the above code is executed several times with, say, strings, the compiler can execute the much simpler instructions for string concatenation. ", "So when the compiler reaches x + y, instead of running lots of code that branches for many different types of x and y, the compiler quickly checks if we have strings again, and then executes just a few lines of machine code that specifically concatenate strings. ", " \nIn e.g., C++ the compiler knows the types of x and y ahead of time, since we had to declare the variables. ", "So it can generate optimized machine code for concatenating strings before ever running the code. ", "\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.0007080399664118886, 0.0007524251122958958, 0.0005970621714368463, 0.0006543052149936557, 0.0006831393111497164, 0.0006034665857441723, 0.0007431442500092089, 0.0008830858860164881, 0.0006175677990540862, 0.0005920259864069521, 0.0005945261218585074, 0.0006822304567322135, 0.0006742345285601914, 0.0005859550437889993, 0.0005437924992293119, 0.0005990962963551283, 0.0005354377208277583, 0.0007032777648419142, 0.000802833354100585, 0.0008201899472624063, 0.004527239128947258, 0.0005413164617493749, 0.0007088974816724658, 0.0006816633976995945, 0.0006105146021582186, 0.000584534602239728, 0.0006149678956717253, 0.0006491897511295974, 0.0014977662358433008, 0.0006652149022556841, 0.0007675515953451395, 0.013393844477832317, 0.0010357591090723872, 0.0008227582438848913, 0.0016180658712983131, 0.000673863512929529, 0.0006916518905200064, 0.000575560552533716, 0.0005720210610888898, 0.0006238335045054555, 0.0006681497325189412, 0.0006409959751181304, 0.0007072596927173436, 0.001995587022975087 ]	0.001119	44
[ "1. ", "Introduction {#sec0005}\n===============\n\nIsatis tinctoria L. is an economically important crop widely cultivated in the northern region of China ([@bib0150]). ", "Its dried root named \"Banlangen\" in Traditional Chinese Medicine (TCM), is one of the top-selling herbs in East Asian, due to the notable clinical treatment efficacy of inﬂuenza, such as severe acute respiratory syndrome (SARS) and novel swine-origin influenza A (H1N1) ([@bib0195]). ", "I. tinctoria root is commonly processed into two commercial pharmaceutical preparations, namely \"Banlangen Keli\" and \"Banlangen Tangjiang\", which can be sold as over-the-counter (OTC) drugs at the pharmacy ([@bib0220]). ", "Phenylpropanoids (flavonoids and lignans) are thought to be primarily related to the outstanding pharmacological activity of I. tinctoria ([@bib0145]). ", "During the long-term evolution, plants can produce a huge number of secondary metabolites that play a crucial role in interaction with environmental factors and defense against unfavorable conditions ([@bib0165]). ", "Thus, the ﬁeld cultivation of I. tinctoria is associated with an important challenge that the phytochemical profile is highly affected by geographical regions, climatic fluctuations, and soil conditions, which can significantly affect the therapeutic efficacy of I. tinctoria root ([@bib0020]). ", "To overcome this issue, an in vitro culture system has been developed, i.e. I. tinctoria hairy root cultures (ITHRCs), as an alternative to the ﬁeld cultivation for the sustainable and standard production of bioactive flavonoids ([@bib0045]).", "\n\nPlant cell and organ cultures offer promising biotechnological platforms for the production of diverse phytochemicals of pharmaceutical and nutraceutical interest ([@bib0035]; [@bib0130]). ", "However, very few successful cases are commercially available due to the low phytochemical productivity not being sufficient to cover the culture cost ([@bib0030]; [@bib0205]). ", "In this context, research efforts need to be directed towards the enhancement of phytochemical productivity without significantly increasing production cost, which can make plant in vitro culture technology more commercially attractive.", "\n\nStrategies including genetic modification, elicitation, permeabilization, immobilization, and two phase system, have been widely employed to enhance the production of valuable phytochemicals in various plant cell and organ cultures, among which elicitation via application of biotic/abiotic elicitors for activating plant defense reactions is implemented extensively owing to its simplicity of usage ([@bib0070]). ", "Jasmonic acid, salicylic acid, and their analog derivatives are the most commonly used elicitors in plant cell and organ cultures ([@bib0140]). ", "Nevertheless, these elicitors are expensive, which presents an inevitable obstacle from the perspective of commercial applications ([@bib0055]). ", "Therefore, search of cost-effective elicitors that can promote phytochemical production is an essential task ([@bib0055]; [@bib0135]).", "\n\nNotably, chitosan is a low-cost biopolymer mainly derived from the waste exoskeletons of edible crustaceans ([@bib0060]). ", "Moreover, chitosan is well documented as an effective \"plant defense booster'' that can trigger various physiological and biochemical reactions, in which the stimulation of phytoalexin biosynthesis is flagged as a characteristic event ([@bib0090]). ", "More importantly, chitosan is a natural biopolymer with excellent biocompatibility and biodegradability ([@bib0170]). ", "It is noteworthy that the toxicity of chitosan is very close to that of salt or sugar ([@bib0185]). ", "In view of costs and product safety, utilization of chitosan as a cost-effective and nontoxic elicitor for enhancing phytochemical production in plant in vitro cultures is strongly recommended ([@bib0075]; [@bib0085]; [@bib0120]; [@bib0190]).", "\n\nGenerally, plant secondary metabolism is very specific to the type of elicitor to which in vitro cell/organ cultures are exposed ([@bib0135]). ", "In this work, the effect of chitosan concentration and elicitation time on the total flavonoid yield in ITHRCs was initially studied. ", "Afterwards, the profiles of eight flavonoids in ITHRCs with and without the appropriate chitosan elicitation were investigated. ", "To clarify the molecular mechanism of flavonoid enhancement in ITHRCs underlying chitosan elicitation, the transcription of seven enzyme genes involved in flavonoid biosynthesis pathway was monitored. ", "For human health, ROS is implicated in numerous chronic diseases including coronary heart disease, cancer, brain dysfunction, diabetes, and others ([@bib0115]). ", "Accordingly, antioxidant activities of extracts from ITHRCs following chitosan elicitation were evaluated. ", "It is worth mentioning that there is no study regarding the application of chitosan to elevate flavonoid productivity, biosynthesis gene expression, and antioxidant activity in ITHRCs.", "\n\n2. ", "Material and methods {#sec0010}\n=======================\n\n2.1. ", "Establishment and maintenance of ITHRCs {#sec0015}\n--------------------------------------------\n\nIsatis tinctoria hairy roots were previously induced from petiole explants by Agrobacterium rhizogenes LBA9402 mediated transformation in the Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University ([@bib0045]). ", "A lead root line (ITHRL V) with high flavonoid productivity was adopted in this study for chitosan elicitation. ", "The stock line was maintained on phytohormone-free MS/2-based solid medium supplemented with 30 g/L sucrose at 25 ± 1 °C in the dark. ", "Additionally, ITHRCs were obtained by inoculating ITHRL V into 250 mL Erlenmeyer flasks containing 150 mL MS/2 liquid medium under the optimal culture conditions described in the previous study ([@bib0045]).", "\n\n2.2. ", "ITHRCs elicited by chitosan {#sec0020}\n--------------------------------\n\nIn this work, ITHRCs undergone the aforementioned conditions for 24 days (the optimal harvest time) were subjected to chitosan elicitation, which aimed to further enhancing the flavonoid yield without affecting the root biomass. ", "Chitosan (Sigma-Aldrich Chemical Co., USA) was dissolved in the acetic acid solution (pH = 5.5) to give a stock concentration of 10 mg/mL, and then the stock solution was sterilized by autoclaving before use. ", "Prior to elicitation, the spent media of ITHRCs (24 day-old) were renewed by fresh ones (150 mL), in which the chitosan stock solution was aseptically added to make the final concentrations of 50, 100, 150, 200, and 400 mg/L. During elicitation, the chitosan-elicited ITHRCs were incubated on a rotary shaker (120 rpm) at 25 ± 1 °C in the dark, and harvested at a successive time points of 0, 6, 12, 18, 24, 30, 36, 48, 60, 72, and 96 h. Control cultures, i.e. adding the same volume of acetic acid solution (pH = 5.5) in ITHRCs, underwent the same conditions as the experimental groups. ", "After elicitation, hairy roots were collected by filtration, and rinsed by distilled water. ", "For flavonoid extraction, a part of roots were dried in a vacuum oven and ground into fine powders. ", "For RNA extraction, the rest of roots were frozen immediately with liquid nitrogen and stored at −80 °C.", "\n\n2.3. ", "Total ﬂavonoid determination {#sec0025}\n---------------------------------\n\nThe powders of dried hairy roots were extracted with 80% ethanol solution using an ultrasonic-assisted method described by [@bib0045]. ", "The crude extracts were obtained by concentrating the filtrates to dryness using a rotary evaporator under vacuum. ", "Total ﬂavonoid contents in the extracts were determined by a colorimetrical method reported by [@bib0200]. ", "Total ﬂavonoid contents were calculated by a calibration curve of rutin, and results were expressed as the microgram of rutin equivalents per gram of hairy roots (dry weight, DW).", "\n\n2.4. ", "Liquid chromatographic tandem mass spectrometry (LC--MS/MS) analysis {#sec0030}\n-------------------------------------------------------------------------\n\nEight target flavonoids (rutin, neohesperidin, buddleoside, liquiritigenin, quercetin, isorhamnetin, kaempferol, and isoliquiritigenin) in the extracts were determined using an Agilent 1100 series HPLC (Agilent Technologies, USA) coupled to an API 3000 triple tandem quadrupole MS (Applied Biosystems, Canada). ", "Prior to LC--MS/MS analysis, samples were prepared by re-dissolving extracts in acetonitrile (20 mL) and filtering through a nylon filter (0.45 μm). ", "The detailed operational procedures were carried out as reported previously ([@bib0045]). ", "The MS selected reaction monitoring (SRM) mode with precursor ion/product ion combinations of m/z 609.1→300.0, m/z 609.5→301.4, m/z 591.4→283.1, m/z 255.9→119.0, m/z 301.0→151.0, m/z 315.0→300.1, m/z 285.3→183.1, and m/z 255.4→118.9 was conducted for the quali-quantitative analysis of rutin, neohesperidin, buddleoside, liquiritigenin, quercetin, isorhamnetin, kaempferol, and isoliquiritigenin, respectively. ", "The analyte content was reported as the microgram per gram of hairy roots (DW).", "\n\n2.5. ", "Quantitative real-time PCR (qRT-PCR) analysis {#sec0035}\n--------------------------------------------------\n\nTo clarify the molecular mechanism of flavonoid enhancement in ITHRCs underlying chitosan elicitation, the transcription levels of genes encoding enzymes involved in flavonoid biosynthesis pathway were determined by qRT-PCR, i.e. phenylalanine ammonia lyase (PAL), cinnamate-4-hydroxylase (C4H), 4-coumarate coenzyme A ligase (4CL), chalcone synthase (CHS), chalcone isomerase (CHI), flavonol synthase (FS), and flavonoid 3′-hydroxylase (F3′H).", "\n\nA MiniBEST Plant RNA Extraction Kit (TaKaRa, China) was used to extract total RNA from the frozen hairy roots (250 mg, fresh weight) following the manufacturer's guidelines. ", "After the quality and quantity assessment, a certain amount of RNA (500 ng) was reverse-transcribed to cDNA using a PrimeScript™ RT reagent Kit (TaKaRa, China) in accordance with the manufacturer's protocols. ", "The synthesized cDNA (20 μL) was diluted with sterile water to 200 μL, and stored at −20 °C till qRT-PCR assay.", "\n\nThe qRT-PCR analysis of all target genes was performed as described in the previous study ([@bib0080]). ", "Briefly, the gene amplification reaction was carried out using SYBR Green detection chemistry on a Stratagene Mx3000 P Real-Time PCR system (Agilent Technologies, USA). ", "The cycling procedure was determined as follows: initial denaturation step of 95 °C for 3 min, followed by 40 amplification cycles with denaturation at 95 °C for 15 s, annealing at 55 °C for 30 s, and extension at 72 °C for 20 s. The relative expression levels of all target genes were quantified based on ubiquntin (the internal reference gene) according to the ^ΔΔ^CT method ([@bib0110]).", "\n\n2.6. ", "Antioxidant activity measurement {#sec0040}\n-------------------------------------\n\nIn this work, DPPH radical-scavenging assay and β-carotene/linoleic acid bleaching test were respectively used to measure anti-radical activities and anti-lipid peroxidation capacities of the root extracts, which aimed to provide the basis for the possible application in pharmaceutical and nutraceutical fields. ", "The detailed experimental procedures of both methods were performed according to the colorimetrical methods reported previously ([@bib0200]). ", "Two synthetic antioxidants, i.e. ascorbic acid (VC) and buthylated hydroxytoluene (BHT), were adopted as the positive controls. ", "For analysis homogeneity, the absorbance of reaction solution of each sample either in DPPH radical-scavenging assay or β-carotene/linoleic acid bleaching test was determined by removing the background interference. ", "And, DPPH radical scavenging activity or β-carotene bleaching inhibition ratio of each sample was calculated as percentage data (%) by transforming the absorbance data according to the corresponding equations described previously by [@bib0200]. ", "Based on the simulation of experimental data by the logarithmic regression model, the curves of DPPH radical scavenging activity (%) or β-carotene bleaching inhibition ratio (%) versus the extract concentration (mg/mL) were illustrated. ", "Antioxidant activity of the tested sample was expressed as IC~50~ value that represented the extract concentration necessary to cause 50% DPPH radical scavenging or 50% β-carotene bleaching inhibition. ", "The lower IC~50~ value indicated the higher antioxidant activity.", "\n\n2.7. ", "Statistical analysis {#sec0045}\n-------------------------\n\nAll experiments were conducted in triplicate, and results were given as averages ± standard deviations. ", "All statistical analyses were carried out using the SPSS statistical software 17.0 (SPSS Inc, Chicago, USA). ", "One-way analysis of variance with Tukey's test was used to determine significant differences between multiple groups of data at P \\< 0.05.", "\n\n3. ", "Results and discussion {#sec0050}\n=========================\n\n3.1. ", "Effect of chitosan concentration and exposure time on flavonoid yield in ITHRCs {#sec0055}\n------------------------------------------------------------------------------------\n\nFlavonoids, the second largest class of plant secondary metabolites, possess multiple physiological functions as diverse as UV protection, pathogen defense, insect attraction, rhizobium symbiosis, flower coloration, and auxin transport ([@bib0215]). ", "Moreover, a popular concept assumes that flavonoids are phytoalexins that can be inducibly synthesized by plants in response to pathogen and insect challenges ([@bib0010]). ", "Chitosan is known to trigger a variety of defense reactions in plants via the simulation of fungal pathogen attack, which can eventually lead to the enhanced accumulation of phytoalexins ([@bib0060]). ", "Accordingly, chitosan elicitation is likely to promote flavonoid biosynthesis in ITHRCs by inducing plant defense responses.", "\n\nElicitation for the improvement of desired secondary metabolites in a given plant in vitro cultures is very empirical. ", "It is well documented that elicitor concentration and exposure time are of crucial importance for the success and efﬁciency of elicitation ([@bib0135]). ", "To achieve the maximal enhancement of flavonoids in ITHRCs, chitosan elicitation requires the careful optimization to ﬁnd its appropriate concentration and exposure time. ", "As reported previously, ITHRCs cultured at day 24 was capable of producing the highest productivity of flavonoids and biomasses ([@bib0045]). ", "In an attempt to further enhance flavonoid level without affecting biomass yield, chitosan was supplemented in 24 day-old ITHRCs to evaluate its elicitation effect on flavonoid accumulation.", "\n\nAs shown in [Fig. ", "1](#fig0005){ref-type=\"fig\"} , different chitosan concentrations (50, 100, 150, 200, and 400 mg/L) exhibited distinct influences on total ﬂavonoid yields in ITHRCs along a time course from 0 to 96 h. As expected, chitosan elicitation was indeed feasible for promoting flavonoid accumulation in ITHRCs over control. ", "Regardless of concentrations, chitosan could induce the significant enhancement of flavonoids in ITHRCs after 6 and 12 h. This phenomenon was consistent with the rapid stimulation effect of elicitors subjected to plant in vitro cultures, which can alter the secondary metabolite proﬁle within a short time ([@bib0135]). ", "Taken as a whole, chitosan with moderate concentrations of 150 and 200 mg/L showed better elicitation efﬁciency at the time points of 36 and 30 h, where total ﬂavonoid yields (16.35 ± 0.88 and 16.67 ± 1.16 mg/g DW) increased by 7.08- and 7.22-fold as compared with control (2.31 ± 0.29 mg/g DW), respectively. ", "However, there is no significant difference (P \\> 0.05) in the ﬂavonoid productivity between the above two chitosan elicitation treatments. ", "In consideration of elicitor cost, chitosan concentration 150 mg/L along with exposure time 36 h were adopted as the appropriate elicitation conditions. ", "Moreover, it is noted that the high chitosan concentration (400 mg/L) with the long exposure time (72--96 h) was not favorable for flavonoid enhancement in ITHRCs.", "Fig. ", "1Effect of different concentrations of chitosan (50, 100, 150, 200, and 400 mg/L) with successive exposure time (0, 6, 12, 18, 24, 30, 36, 48, 60, 72, and 96 h) on total flavonoid yield in 24 day-old ITHRCs. ", "Mean ± SD values not sharing the same lowercase letters are significantly different (P \\< 0.05).Fig. ", "1\n\nSimilar to this investigation, many studies reported that chitosan elicitation could exert positive eﬀ ;ect on enhancing the production of various secondary metabolites in intact plants or plant in vitro cultures, e.g. artemisinin in Artemisia annua L. ([@bib0100]), curcumin in Curcuma longa L. ([@bib0170]), echinacoside in cell suspension cultures of Scrophularia striata Boiss. ([", "@bib0085]), hydrolysable tannin in cell suspension cultures of Phyllanthus debilis Klein ex Willd. ([", "@bib0120]), withanolides in adventitious root cultures of Withania somnifera (L.) Dunal ([@bib0190]), and plumbagin in adventitious root cultures of Plumbago indica L. ([@bib0075]). ", "However, the chitosan elicitation conditions required for achieving the optimal enhancement of different target secondary metabolites are not the same in these reports and this work. ", "Factually, the same elicitor possesses distinct abilities to induce the biosynthesis of different secondary metabolites, and there is complexity in the mechanism of action entailing variability of secondary metabolic responses to the stress mediated by elicitor due to thousands of intertwined events existing in plant cells ([@bib0055]; [@bib0135]).", "\n\nGenerally, plants exposed to mild elicitation conditions can induce the eustress that contributes to the activation of plant defense secondary metabolisms for self-protection, and when the exposure exceeds the tolerance-limit level, plants will suffer from the distress that is characterized by metabolic damage or cell death, thus leading to the reduced productivity of secondary metabolites ([@bib0095]). ", "Moreover, plants have thresholds for specific secondary metabolites that can be synthesized by themselves. ", "Once secondary metabolites are accumulated at high levels, plants will be stimulated to generate enzymes for product degradation through the feedback regulation ([@bib0125]). ", "As inferred, the appropriate chitosan elicitation (150 mg/L and 36 h) might maintain the balance between eustress and distress, which is beneficial for inducing the biosynthesis and accumulation of flavonoids in the elicited ITHRCs.", "\n\n3.2. ", "Profiles of eight flavonoids in ITHRCs under the appropriate chitosan elicitation {#sec0060}\n--------------------------------------------------------------------------------------\n\nChanges in profiles of all target compounds in ITHRCs with and without the appropriate chitosan elicitation can be appreciated by the comparison of LC--MS/MS chromatograms ([Fig. ", "2](#fig0010){ref-type=\"fig\"} ). ", "After calculation, yields of all target flavonoid derivatives are shown in [Fig. ", "3](#fig0015){ref-type=\"fig\"} . ", "In comparison with control, levels of rutin (812.28 ± 13.49 μg/g DW), neohesperidin (199.46 ± 6.96 μg/g DW), buddleoside (17.55 ± 1.14 μg/g DW), liquiritigenin (24.30 ± 1.28 μg/g DW), quercetin (733.02 ± 23.72 μg/g DW), isorhamnetin (618.49 ± 13.57 μg/g DW), kaempferol (285.09 ± 5.04 μg/g DW), and isoliquiritigenin (25.28 ± 3.92 μg/g DW) in chitosan-elicited ITHRCs (150 mg/L and 36 h) increased by 8.27-, 4.19-, 1.30-, 4.88-, 13.05-, 7.63-, 2.12-, and 8.52-fold, respectively. ", "Interestingly, increments of the more hydroxylated ﬂavonoids (rutin, quercetin, isorhamnetin, and isoliquiritigenin) were noticed to be much higher than other ﬂavonoids.", "Fig. ", "2Representative LC--MS/MS total ion chromatograms of eight flavonoids in extracts form control and ITHRCs elicited by 150 mg/L chitosan for 36 h. RUT, rutin; NEO, neohesperidin; BUD, buddleoside; LIQ, liquiritigenin; QUE, quercetin; ISR, isorhamnetin; KAE, kaempferol; ISL, isoliquiritigenin.", "Fig. ", "2Fig. ", "3Yields of eight flavonoids in extracts form control and ITHRCs elicited by 150 mg/L chitosan for 36 h. Mean ± SD values not sharing the same lowercase letters are significantly different (P \\< 0.05). ", "RUT, rutin; NEO, neohesperidin; BUD, buddleoside; LIQ, liquiritigenin; QUE, quercetin; ISR, isorhamnetin; KAE, kaempferol; ISL, isoliquiritigenin.", "Fig. ", "3\n\nGenerally, oxidative burst is a common response of plants to elicitor treatments, which is characterize by the excessive generation of reactive oxygen species (ROS) that can cause oxidative damages to various functional macromolecules (nucleic acids, lipids, proteins, carbohydrates, etc.) ([", "@bib0165]). ", "It is reported that chitosan elicitation can induce ROS overproduction, perturb the intracellular redox equilibrium and ultimately result in oxidative stress in S. striata cell cultures ([@bib0085]). ", "In this work, chitosan-elicited root tissues exhibited browning color as compared with control ([Fig. ", "4](#fig0020){ref-type=\"fig\"} ), providing a significant indication of oxidative stress following chitosan elicitation. ", "It is well known that the phenolic hydroxyl-substituted flavonoids possess reduction potentials that can effectively neutralize active oxygen radicals ([@bib0005]). ", "In view of this, the significant enhancements of rutin, quercetin, isorhamnetin, and isoliquiritigenin in chitosan-elicited ITHRCs might be ascribed to their multiple hydroxyl groups with efficient ROS scavenging ability.", "Fig. ", "4Phenotype comparison of hairy root tissues from control and ITHRCs elicited by 150 mg/L chitosan for 36 h.Fig. ", "4\n\n3.3. ", "Biosynthesis gene expression in ITHRCs underlying chitosan elicitation {#sec0065}\n---------------------------------------------------------------------------\n\nAs reported previously, chitosan can be recognized by immune receptors localized on plant cell membranes as the attack of fungal pathogens, trigger diverse signaling cascades, and lead to a variety of defense responses in which the activation of genes associated with phytoalexin biosynthesis is flagged as a characteristic even ([@bib0015]; [@bib0060]). ", "Accordingly, the enhanced accumulation of flavonoids in chitosan-elicited ITHRCs is likely to be attributed to the transcriptional activation of genes involved in flavonoid biosynthesis pathway.", "\n\nFor the accurate determination of gene expression pattern, samples collected from ITHRCs elicited by 150 mg/L chitosan and control at a successive time points (6, 12, 24, 36, 48, 60, 72, and 96 h) were taken for qRT-PCR analysis in this work. ", "The relative expression level of each tested gene was normalized using ubiquntin (the internal reference gene), and the expression value of individual gene in control was set as 1.", "\n\nAs shown in [Fig. ", "5](#fig0025){ref-type=\"fig\"} , different degrees of increase in the expression levels of all investigated genes were noticed in chitosan-elicited ITHRCs along a time course from 6 to 48 h, which indicated that the enhanced flavonoid yield was a result of the up-regulated expression of these biosynthetic genes. ", "Additionally, all targeted genes responded sensitively to chitosan elicitation, and the expression levels were found to be highest at 12 or 24 h, which were earlier than the time point (36 h) necessary for the maximal enhancement of flavonoids. ", "Factually, this was a typical metabolic phenomenon that the synthesis of downstream products lags behind the expression of upstream genes ([@bib0040]). ", "Moreover, most of genes exhibited a significant decline trend in the transcription levels after 60 h, among which C4H, 4CL, and F3′H were observed to revert to the control level gradually. ", "However, the expression levels of PAL and CHI genes were significantly repressed from 72 to 96 h, which proved that metabolic damages occurred after the prolonged elicitation duration. ", "Taken as a whole, CHS and F3'H genes showed much higher transcriptional abundances (45.13- and 41.04-fold) at 12 h than other investigated genes, which suggested that the both genes were more sensitive to chitosan elicitation for inducing flavonoid biosynthesis in ITHRCs.", "Fig. ", "5Transcriptional profiles of flavonoid biosynthesis genes in ITHRCs elicited by 150 mg/L chitosan for different durations (6, 12, 24, 36, 48, 60, 72, and 96 h). ", "PAL, phenylalanine ammonia lyase; C4H, cinnamate-4-hydroxylase; 4CL, 4-coumarate coenzyme A ligase; CHS, chalcone synthase; CHI, chalcone isomerase; F3′H, flavonoid 3′-hydroxylase; FS, flavonol synthase. ", "Mean ± SD values not sharing the same lowercase letters are significantly different (P \\< 0.05).Fig. ", "5\n\nIt is well acknowledged that CHS is the gatekeeper in ﬂavonoid biosynthesis pathway that can catalyze the sequential addition of three units of malonyl-coenzyme A (CoA) to one unit of p-coumaroyl-CoA, yielding naringenin chalcone as the basic C6-C3-C6 skeleton for the subsequent flavonoid metabolism ([@bib0065]). ", "Generally, the regulation of flavonoid biosynthesis can be effectively achieved via controlling CHS gene expression. [", "@bib0175] found that the RNA interference silencing of CHS gene in tomatoes could cause the reduction of total ﬂavonoid levels to a few percent of those in wild-type ones. [", "@bib0160] reported that the overexpression of CHS gene could result in the transgenic Silybum marianum hairy roots containing a 10-fold increase in silybin (an active flavonolignan) content. ", "Moreover, CHS gene expression can be induced by environmental stresses such as fungal pathogen attack, wounding, or UV irradiation, which is capable of triggering the accumulation of ﬂavonoid phytoalexins to improve plant resistance ([@bib0025]). ", "Factually, chitosan is the derivative of chitin (fungal cell wall component) can induce plant systemic resistance by mimicking fungal pathogen ([@bib0210]). ", "In this study, the significant sensitivity of CHS gene expression to chitosan elicitation possibly contributed to enhance ITHRCs resistance by heightening ﬂavonoid accumulation. ", "Additionally, F3′H gene plays an essential role in the regulation of rutin and quercetin biosynthesis because its encoding enzyme can catalyze the hydroxylation of flavonoid B-ring at the 3′ position ([@bib0105]). ", "Accordingly, the remarkable enhancement in the yields of rutin (8.27-fold increase) and quercetin (13.05-fold increase) might be attributed to the significant induction of F3\\'H transcription underlying chitosan elicitation.", "\n\n3.4. ", "Antioxidant activities of extracts from ITHRCs following chitosan elicitation {#sec0070}\n----------------------------------------------------------------------------------\n\nPlant-derived antioxidants have been considered as effective ROS scavengers in preventing human chronic diseases ([@bib0180]). ", "Moreover, there is a growing evidence that ROS plays a vital role in viral infections and contributes to pathogenesis for many viruses, such as respiratory syncytial virus (RSV), H5N1 inﬂuenza A virus, coxsackievirus B3, and Japanese encephalitis virus ([@bib0155]). ", "Treatment with natural antioxidants, therefore, is beneﬁcial for the prevention of viral infections. ", "In view of this, it is inferred that the notable antiviral efﬁcacy of I. tinctoria root extracts is likely related to the antioxidant activities.", "\n\nIt is clearly observed from [Fig. ", "6](#fig0030){ref-type=\"fig\"} that chitosan-elicited samples exhibited superiority in antioxidant activities determined by the both methods. ", "To be exact, extracts from chitosan-elicited ITHRCs showed better DPPH radical scavenging property and β-carotene bleaching inhibition capacity with lower IC~50~ values (0.23 and 0.28 mg/mL) as against those in control (0.42 and 0.39 mg/mL), respectively. ", "As mentioned above, the increased contents of multiple hydroxyl-substituted flavonoids (rutin, quercetin, isorhamnetin, and isoliquiritigenin) in chitosan-elicited ITHRCs is likely to be responsible for scavenging the excess ROS induced by chitosan elicitation. ", "Anyway, the objective existence of these polyhydroxylated flavonoids might contribute to the higher antioxidant activities of extracts from chitosan-elicited ITHRCs. ", "Additionally, stress conditions can cause plant cells to overproduce other antioxidants, such as, glutathione, proline, ascorbic acid, tocopherol, and carotenoid ([@bib0050]), which might also contribute to the increase in antioxidant activities of extracts from chitosan-elicited ITHRCs. ", "Overall, chitosan-elicited ITHRCs could offer higher antioxidant extracts that would potentially improve the antiviral therapeutic benefits, and possess promising prospects for the development of antioxidant drugs or nutraceuticals.", "Fig. ", "6Antioxidant activities of extracts from control and ITHRCs elicited by 150 mg/L chitosan for 36 h in DPPH radical scavenging assay (A) and β-carotene/linoleic acid bleaching test (B).Fig. ", "6\n\n4. ", "Conclusions {#sec0075}\n==============\n\nThis work provided a feasible and cost-effective elicitation practice using the nontoxic and biocompatibility chitosan for improving the productive of pharmacologically active flavonoids in ITHRCs. ", "Results showed that 24 day-old ITHRCs elicited by 150 mg/L chitosan for 36 h gave a 7.08-fold increase in total flavonoid yield as compared with control. ", "The price range of chitosan is \\$1--2/Kg in China. ", "Accordingly, the cost range of chitosan used in this work for the aforementioned enhancement in flavonoid productivity per 100 L of ITHRCs is only \\$0.015--0.03. ", "Especially, the significant increase in the contents of polyhydroxylated flavonoids was found in ITHRCs following chitosan elicitation. ", "Moreover, the transcriptional activation of associated genes involved in flavonoid biosynthetic pathway, especially CHS and F3'H genes, might account for the elevated level of ﬂavonoids in chitosan-elicited ITHRCs. ", "Furthermore, antioxidant activity enhancement was noticed in the extracts from chitosan-elicited ITHRCs, which would expand the applicability in pharmaceutical and nutraceutical fields. ", "Overall, the chitosan elicitation protocol proposed in this work will make ITHRCs more feasible for the large-scale production of pharmacologically active flavonoids on commercial scale in the future.", "\n\nThe authors gratefully acknowledge the financial supports by National Key R&D Program of China (2017YFD0600205), Fundamental Research Funds for the Central Universities (2572017DA04), Heilongjiang Province Science Foundation for Youths (QC2017012), Scientific Research Start-up Funds for Talents Introduction of Northeast Forestry University (1020160010 and YQ2017-03), and Double First-rate Special Funds (41112432 and 41112460).", "\n\n[^1]: These authors contributed equally to this work.", "\n" ]	{ "pile_set_name": "PubMed Central" }	[ 0.0009393597138114274, 0.0006777443340979517, 0.0006418116972781718, 0.0006797981914132833, 0.0009078368311747909, 0.0005806490662507713, 0.0005783907254226506, 0.0006380067206919193, 0.0005700195324607193, 0.0006581204943358898, 0.0005633312975987792, 0.0005515400553122163, 0.000747332873288542, 0.0006162363570183516, 0.0007055063615553081, 0.01486467570066452, 0.0006032581441104412, 0.0007352364482358098, 0.0006373676587827504, 0.0006611395510844886, 0.0005643239128403366, 0.0005672721890732646, 0.0007237124373205006, 0.0005987532204017043, 0.0007055480964481831, 0.0005989876226522028, 0.0005771014257334173, 0.0011863111285492778, 0.001254175789654255, 0.0006570328259840608, 0.0006293092155829072, 0.0010177637450397015, 0.0007295606192201376, 0.0013890629634261131, 0.000672503374516964, 0.0006399003323167562, 0.0006330888718366623, 0.0016942620277404785, 0.0006645426619797945, 0.0005497749079950154, 0.0013587652938440442, 0.0007221997366286814, 0.0009360014810226858, 0.0006022671004757285, 0.0007168325828388333, 0.0013035312294960022, 0.0006773035856895149, 0.0005944439326412976, 0.0005527857574634254, 0.0008143266895785928, 0.0015757454093545675, 0.001257235067896545, 0.0007983369287103415, 0.0005423816619440913, 0.000536940002348274, 0.0006854148814454675, 0.0005587868508882821, 0.0005708726239390671, 0.0005711398553103209, 0.0012260606745257974, 0.0007101016817614436, 0.0005589209031313658, 0.0009143919451162219, 0.0007683738367632031, 0.0007664881413802505, 0.0006263612885959446, 0.0008766145911067724, 0.0007699992856942117, 0.0012850159546360373, 0.0005970878410153091, 0.0005630178493447602, 0.0006797246751375496, 0.0011741509661078453, 0.0009363992721773684, 0.0007644631550647318, 0.0006451212102547288, 0.0006257198983803391, 0.0010135439224541187, 0.0005346818943507969, 0.0005275168805383146, 0.0006059766747057438, 0.0006555728614330292, 0.0007737597916275263, 0.0006475821719504893, 0.0006002067821100354, 0.0006413757218979299, 0.0006544692441821098, 0.000769290782045573, 0.0006257443455979228, 0.0006604496156796813, 0.0008293872233480215, 0.0010405469220131636, 0.0007321024313569069, 0.0007007521926425397, 0.0006716640200465918, 0.0007445949595421553, 0.0006120131001807749, 0.0005989801720716059, 0.0007532770978286862, 0.000643017003312707, 0.0005700605688616633, 0.0006481156451627612, 0.0013827874790877104, 0.0008136457181535661, 0.0006626690155826509, 0.00062812544638291, 0.00065745780011639, 0.0007830976974219084, 0.0009056026465259492, 0.0008293872233480215, 0.0011037483345717192, 0.0008293872233480215, 0.31449103355407715, 0.0007854836876504123, 0.006057381629943848, 0.0008293872233480215, 0.0006610028794966638, 0.0008481971453875303, 0.0007099369540810585, 0.0006120422622188926, 0.0005991611396893859, 0.0008521622512489557, 0.0008011627942323685, 0.0008293872233480215, 0.0009130351827479899, 0.001411622273735702, 0.0007504501845687628, 0.0006411047070287168, 0.0005335735622793436, 0.0005668033263646066, 0.0006475821719504893, 0.0005828783614560962, 0.0006602875655516982, 0.000586425478104502, 0.00067668326664716, 0.0007494171150028706, 0.13073362410068512, 0.0008293872233480215, 0.0006489565712399781, 0.002113168127834797, 0.0007321024313569069, 0.0006726508145220578, 0.0007397755398415029, 0.0007297766278497875, 0.0008938133832998574, 0.0006015136023052037, 0.0007048229454085231, 0.0006778424722142518, 0.000741805590223521, 0.0034936668816953897, 0.0013626827858388424, 0.000927343440707773, 0.0006742971600033343, 0.0007327002240344882, 0.0006779762334190309, 0.0005896933726035058, 0.0006138111348263919, 0.0007484899833798409, 0.0007922405493445694, 0.0009098115842789412, 0.0008250015671364963, 0.0007305283797904849, 0.0008293872233480215, 0.000912186864297837, 0.0011868858709931374, 0.0010025262599810958, 0.000730154977645725, 0.0006233440944924951, 0.0007669740589335561, 0.0008413786417804658, 0.020209703594446182, 0.0006108076777309179, 0.0007155968341976404, 0.0005204969202168286, 0.0005721304332837462, 0.001995587022975087 ]	0.003531	176
[ "1. ", "Field of the Invention\nThe invention relates generally to database systems and more specifically to database systems which may be used to access data that is not stored within the database system.", "\n2. ", "Description of Related Art\nOne of the most common uses of computer systems is to find information. ", "Two techniques that are commonly employed to find information are running a query to find data in a database system and using a search engine to find data from sources that are accessible via a network. ", "Each of these techniques presently offers important advantages and has important limitations." ]	{ "pile_set_name": "USPTO Backgrounds" }	[ 0.0009393597138114274, 0.0005750431446358562, 0.0011863111285492778, 0.0006164411315694451, 0.0006255749613046646, 0.0005507714813575149 ]	0.000749	6
[ "Traumat kring de cirka 4 000 tiggarna och det svenska välfärdssamhället uppmärksammas internationellt. ", "Senast var det New York Times (8/8) som noterade att tiggeriet sätter den berömda svenska toleransen på prov.", "\n\nI den infekterade debatten glöms det bort att vi redan har minst 50 000 svenska romer. ", "De är till hundra procent svenska medborgare, har status som nationell minoritet och har särskilda rättigheter gällande kultur och språk.", "\n\nEftersom många anser att Sverige bör göra mer för att hjälpa EU-tiggarna, typ rätt till sjukvård och skolgång för barnen, är det inte ointressant hur det gått för de helsvenska romerna. ", "Historien kan ge oss en fingervisning om Sveriges förmåga att erbjuda romerna ett anständigt liv.", "\n\nRomer har bott i Sverige i mer än 500 år. ", "Under en tidsrymd av hundratals år borde integrationen ha kommit långt och även satts i system av vår epoks sociala ingenjörer, kan man tycka. ", "Men berättelsen om romerna är folkhemmets verkliga skamfläck. ", "Den kantas av fördomar, diskriminering, rasism, sociala problem och kulturella konflikter.", "\n\nPå jakt efter försörjning tvingades svenska romer flytta runt, vilket Katarina Taikon skildrat i sina böcker om flickan Katitzi. ", "Det var först på 1960-talet som den sista gruppen resande romer erbjöds fasta bostäder. ", "Och så sent som 2013 avslöjades att Skånepolisen upprättat ett etniskt spaningsregister över tusentals medlemmar av romska släkter. ", "Barn, unga, gamla registrerades.", "\n\nDe svenska romerna har långt kvar till lika villkor. ", "För fem år sedan överlämnade Delegationen för romska frågor, ledd av förre FP-ledaren Maria Leissner, en dyster utredning till regeringen. ", "Många romska ungdomar misslyckas i skolan och saknar stöd hemifrån. ", "Sociala problem går i arv och bildar negativa mönster. ", "Leissner bedömde 2010 att det skulle ta ytterligare minst 20 år innan ett nyfött romskt barn skulle få uppleva samma möjligheter som andra svenskfödda barn.", "\n\nSaken kompliceras av såväl utbredd antiziganism som misstroende mot majoritetssamhället från romernas sida. ", "Rapporten konstaterade att hela 80 procent (!) ", "av de 50 000 svenska romerna levde i permanent utanförskap utan egen försörjning. ", "I Malmö var 90 procent av stadens 3 500 vuxna romer bidragsberoende.", "\n\nUtredningen uppskattade samhällskostnaden för att hålla 8 av 10 romer i utanförskap till oacceptabla 12–13 miljarder kronor per år eller 560 miljarder under en livstid (Nilsson/Wadeskog). ", "Med facit i hand kan man konstatera att Sverige hittills misslyckats kapitalt med att integrera romerna.", "\n\nOavsett eländet i Rumänien, Bulgarien och övriga före detta kommunistländer är det fortfarande vår primära skyldighet att bryta utanförskapet för de 50 000 romer som är födda och medborgare i detta land.", "\n\nMånga romska ungdomar misslyckas i skolan och saknar stöd hemifrån. ", "Sociala problem går i arv och bildar negativa mönster.", "\n\nDet här är en opinionstext publicerad i Dagens Samhälle. ", "Åsikterna som uttrycks i artikeln står skribenten för." ]	{ "pile_set_name": "OpenWebText2" }	[ 0.34367361664772034, 0.01061213668435812, 0.295091450214386, 0.11899606883525848, 0.4024088382720947, 0.03232016786932945, 0.020473044365644455, 0.15340997278690338, 0.04103691503405571, 0.0184140857309103, 0.11760056018829346, 0.034257322549819946, 0.10547995567321777, 0.007212058175355196, 0.005019775591790676, 0.010927511379122734, 0.03715076670050621, 0.40033313632011414, 0.28296828269958496, 0.16048558056354523, 0.006502717733383179, 0.01297742035239935, 0.036187440156936646, 0.005605763290077448, 0.24489296972751617, 0.1653674989938736, 0.03715076670050621, 0.40033313632011414, 0.0033713674638420343, 0.019581984728574753 ]	0.117661	30
[ "Former CBO director Douglas Elmendorf AP Every single former director of the Congressional Budget Office signed onto a letter to Congress that called out some of the \"recent attacks on the integrity and professionalism of the agency and on the agency’s role in the legislative process.\"", "\n\nThe CBO was created in 1974 as a way to provide Congress with nonpartisan analysis of proposed legislation.", "\n\nIn the past few weeks, the Trump administration has taken to attacking the CBO after the analysis office reported that the healthcare bill proposed by Republicans in the Senate would leave 22 million more Americans without insurance in 2026, compared to current law.", "\n\nThe former directors defended the office. \"", "CBO's approach produces consistent comparisons of competing legislative proposals and unbiased projections of the impact of policy changes. ", "Unfortunately, even nonpartisan and high-quality analysis cannot always generate accurate estimates,\" the eight former directors wrote in the letter.", "\n\nThe letter also comes just two days after the Department of Health and Human Services released a report on the Consumer Freedom Amendment proposed by Senator Ted Cruz that would allow insurance plans that don't comply with two regulations set up under the Affordable Care Act, the law better known as Obamacare: community rating and essential health benefits.", "\n\nThe HHS report took a look at what the amendment would do in the context of the ACA — not the BCRA bill. ", "Consulting group McKinsey was contracted to produce the analysis, Politico reported.", "\n\nThe report came to the conclusion that Cruz's amendment would lower premiums in both the traditional ACA plans and the less regulated ones. ", "That goes against what experts have said about the amendment in the context of the BCRA. ", "Many say that it is likely premiums for both types of plans would likely rise if the amendment was put in place. ", "The insurance industry's lobbying group said the amendment would lead to \"widespread adverse selection and unstable health insurance markets.\"", "\n\nOn Thursday, the CBO scored an updated version of the bill, but that version didn't include the CFA, meaning the effects of that amendment have not been analyzed by the agency.", "\n\nThe former directors urged Congress to keep considering CBO analysis as part of crafting new legislation. \"", "In sum, relying on CBO’s estimates in the legislative process has served the Congress — and the American people — very well during the past four decades,\" the directors wrote. \"", "As the House and Senate consider potential policy changes this year and in the years ahead, we urge you to maintain and respect the Congress’s decades-long reliance on CBO’s estimates in developing and scoring bills.\"" ]	{ "pile_set_name": "OpenWebText2" }	[ 0.0005892509361729026, 0.0005906032165512443, 0.0008093466749414802, 0.0005524923908524215, 0.000557807506993413, 0.00059233553474769, 0.000596233585383743, 0.0005498453974723816, 0.0006208964041434228, 0.0006311884499154985, 0.0005863930564373732, 0.0005998247652314603, 0.000589778006542474, 0.0005816371995024383, 0.000558582425583154, 0.0005499594262801111, 0.0005239122547209263 ]	0.000593	17
[ "Q:\n\nWhy am I unable to load an executable below 0x201.000 ( Which linear address space is seen as available in a linux process ? ", "Where is it documented?)", "\n\nI am using gcc on linux 3.16.0-29-generic. ", "\nI managed to instruct the gcc compiler to set as loading address of the code I am compiling 0x201.000 using the option of gcc -Wl,--section-start=.text=0x201000 ( it seems that 0x1000 are needed for the header of the ELF so I cannot go below 0x201.000 ).", "\nInstead using mmap in other tests, I had been able to allocate also lower addresses as e.g. sometimes 0x10.000 never 0x0.000 to 0xF.000, and always all other addresses up to and over 0x800.000 ).", "\nI am asking thus, from the OS user perspective which addresses are available to a generic process, and why the executable may not be loaded below 0x200.000 ? ", "\nWhere is it documented or where should I look .", "\nIs it guaranteed that some virtual memory should always be there ? ", "at any requested address (unless there is a lack of physical memory ?).", "\nEssentially the question is \"what is the linear memory available to a process\", or said differently what is the logic model offered to developers ?", "\n\nA:\n\nRegarding the inability to mmap addresses bellow 0x10.000, the answer is in \"https://wiki.ubuntu.com/Security/Features\" .", "\n0-address protection\nSince the kernel and userspace share virtual memory addresses, the \"NULL\" memory space needs to be protected so that userspace mmap'd memory cannot start at address 0, stopping \"NULL dereference\" kernel attacks. ", "This is possible with 2.6.22 kernels, and was implemented with the \"mmap_min_addr\" sysctl setting. ", "Since Ubuntu 9.04, the mmap_min_addr setting is built into the kernel. (", "64k for x86, 32k for ARM.) ", "\nWe may change the \"mmap_min_addr\" by using the instruction sudo sysctl -w vm.mmap_min_addr=0\nSo the answer is that the whole address space is available without exceptions ( linear addresses ).", "\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.0007665356388315558, 0.0006928370567038655, 0.0006911343079991639, 0.0006557528977282345, 0.0007124727708287537, 0.0005906324367970228, 0.0006488303188234568, 0.0007035324815660715, 0.0006045526242814958, 0.0005704149371013045, 0.0009218367631547153, 0.0008230045204982162, 0.0006258641951717436, 0.0006295482744462788, 0.0008435288327746093, 0.0007094266475178301, 0.001995587022975087 ]	0.000776	17
[ "Apsley, Hertfordshire\n\nApsley was a 19th-century mill village in the county of Hertfordshire, England. ", "It is a historic industrial site situated in a valley of the Chiltern Hills. ", "It is positioned below the confluence of two permanent rivers, the Gade and Bulbourne. ", "In an area of little surface water this was an obvious site for the location of water mills serving local agriculture. ", "Today it is a suburb of the larger town of Hemel Hempstead.", "\n\nRecent (2011–) rapid building around the canal area has seen a large influx of London commuters, largely from the software and business communities. ", "At the 2011 Census the village was included in the Dacorum Ward of Aspley and Corner Hall.", "\n\nOrigin of the name\nThe name Apsley dates from the Anglo-Saxon period and means aspen wood.", "\n\nBrief history\nIt was the construction of the trunk canal (later to be called the Grand Union Canal) between London and the Midlands through the valley in 1798 that began its industrial rise at the start of the 19th century. ", "The canal gave an easy way of transporting the raw and manufactured products to and from the mills.", "\n\nJohn Dickinson, the inventor of a new method of continuous papermaking, purchased an existing mill in the area in 1809. ", "There is record of paper making already taking place nearby at this time. ", "His business expanded throughout the Victorian age coming to occupy large parts of the flat land in the valley bottom. ", "Streets of mill workers' terraced houses grew up adjacent to the mills. ", "Housing for managers was built on the old Manor Farm, higher up the hill towards Felden, in the grounds of the Manor Estate, today known as Shendish Manor. ", "Production peaked during the Second World War. ", "The site was however not ideal for large scale papermaking in the 20th century and later became a warehouse and distribution centre for products made elsewhere. ", "The last John Dickinson warehouse closed in 1999. ", "Frogmore Paper Mill is a working paper mill and visitor centre located in some of the original mill buildings. ", "Paper continued to be made until 2006 a short distance away at Nash Mills by the global Sappi group at a former John Dickinson mill. ", "This too closed for production in 2006 but continued as a distribution centre for some time. ", "In 2011, the Sappi site was redeveloped for canal-side housing, preserving some of the historic structures at the site.", "\n\nIn the 1950s the adjacent town of Hemel Hempstead was designated a New Town as part of the provision of new residential areas surrounding London and Apsley became a part of the development, also giving its name to the new school of Apsley Grammar School at Bennetts End.", "\n\nApsley today\n\nToday, Apsley is an outer district of Hemel Hempstead and is still a busy commercial centre. ", "The Victorian shops that grew up when it was a mill town now house newsagents, public houses, restaurants, and a range of small businesses. ", "The former mill sites are taken up with supermarkets, retail parks and offices (including large offices on the Dolittle Meadows site occupied by Hertfordshire County Council, Epson, HSBC and until recently, British Telecom). ", "Housing developments combining the canal-side location with the ease of access to Apsley railway station have been very successful, and Apsley Marina is a thriving location for boaters.", "\n\nThe local parish church is St Mary's, in London Road. ", "There is also a Methodist church.", "\n\nAn important local issue since the summer of 2003 is the proposal to build on land surrounding the Manor Estate in Apsley that had previously been designated as green belt land. ", "A new housing estate, called the Aspen Estate, has since been built on the hills above the Manor Estate.", "\n\nApsley timeline\n 13th century – Ralf de Chenduit was granted land in the area. ", "The local manor is still called Shendish Manor today.", "\n 1803 – First record of paper making in the area at nearby Frogmore.", "\n 1809 – John Dickinson, the inventor of a continuous mechanised papermaking process, purchased a corn mill in the valley and started making paper.", "\n 1811 – The Grand Junction Canal, later to be called the Grand Union Canal, opened to through traffic. ", "The original route of part of the canal was higher up the side of the valley passing north of the George and the Three Tuns pubs on Belswains Lane. ", "It put Apsley on the principal trade route from London to the north.", "\n 1836 – John Dickinson built his country house in nearby Nash Mills and called it Abbot's Hill. ", "It is now a private school.", "\n 1838 – The London and Birmingham Railway passed through the valley adjacent to the site but no station was built. ", "Canals continued to be the primary commercial means of transport for Apsley's mills.", "\n 1853 – Charles Longman, heir to the publisher Longman's and partner to John Dickinson, bought the Shendish estate and built an impressive manor house.", "\n 1871 – The Church at Apsley End was opened for public worship; its construction was funded by Charles Longman.", "\n 1938 – Apsley railway station was built with backing from John Dickinson Ltd as a way to bring more people to work at the mills.", "\n 1939–1945 – John Dickinson's was at its peak, and employed more than 7,000 workers. ", "It made munitions as well as paper and paper products.", "\n 1999 – The last paper mills owned by John Dickinson were finally shut.", "\n 2003 – A national paper museum was built to celebrate the links between the industry and the town.", "\n 2006 - Apsley Marina was established.", "\n 2011 – Local Football Club Apsley Athletic FC was formed.", "\n\nSee also \n\nApsley House, London, which has no connection with Apsley in Hertfordshire but takes its name from its first owner Baron Apsley, the 2nd Earl Bathurst. ", "His title refers to Apsley, Sussex where the Bathurst family had connections. ", "The present holder of the Earldom Bathurst is Allen Christopher Bertram Bathurst, 9th Earl Bathurst, whose son and heir uses the secondary title of Lord Apsley.", "\n\nReferences\nA Hertfordshire Valley by Scott Hastie photographs by David Spain, Alpine Press Ltd, Kings Langley, 1996,\n\nExternal links\n\nApsley (A Guide to Old Hertfordshire)\nOfficial Website of The Paper Trail project\nInformation on The National Paper Museum Project\nApsley Local History and pictures from Hemelonline\nShendish Manor today with its history\nManor Estate Residents' Association and their battle to prevent development on green-belt land in Apsley\nOfficial Website of Apsley Marina\n\nCategory:Villages in Hertfordshire\nCategory:Dacorum\nCategory:Papermaking in the United Kingdom" ]	{ "pile_set_name": "Wikipedia (en)" }	[ 0.0010934590827673674, 0.000816494517493993, 0.0006950525566935539, 0.0006551756523549557, 0.0007925244281068444, 0.0005572176305577159, 0.0008296879823319614, 0.0006780715193599463, 0.0005891408654861152, 0.0006230631261132658, 0.0006579498876817524, 0.0005385532858781517, 0.000762441020924598, 0.0010985960252583027, 0.0008580719586461782, 0.0008043920970521867, 0.0006403554580174387, 0.0009669758728705347, 0.0007454636506736279, 0.0005876275827176869, 0.0005625101621262729, 0.0006312593468464911, 0.0006667719571851194, 0.0009681156370788813, 0.0007450918783433735, 0.0005820686346851289, 0.0006419123965315521, 0.0008946126326918602, 0.0006277038482949138, 0.0006100545870140195, 0.0007284671301022172, 0.0006838753470219672, 0.0007359728333540261, 0.0005739832995459437, 0.0007208245806396008, 0.000701989745721221, 0.0008241694886237383, 0.001174505683593452, 0.0009967753430828452, 0.0009647429687902331, 0.0006813298678025603, 0.0007692798390053213, 0.0010728907072916627, 0.0008245771750807762, 0.0007026493549346924, 0.0007958585047163069, 0.0006389782065525651, 0.006082951091229916, 0.0005587288178503513, 0.000626602559350431, 0.000810502446256578, 0.0005793654127046466, 0.0006240603979676962, 0.0008484669961035252, 0.0006076631834730506 ]	0.000841	55
[ "Most people take it for granted that we have yet to make contact with an extraterrestrial civilization. ", "Trouble is, the numbers don’t add up. ", "Our Galaxy is so old that every corner of it should have been visited many, many times over by now. ", "No theory to date has satisfactorily explained away this Great Silence, so it’s time to think outside the box. ", "Here are eleven of the weirdest solutions to the Fermi Paradox.", "\n\n\nThere's no shortage of solutions to the Fermi Paradox. ", "The standard ones are fairly well known, and we’re not going to examine them here, but they include the Rare Earth Hypothesis (the suggestion that life is exceptionally rare), the notion that space travel is too difficult, or the distances too vast, the Great Filter Hypothesis (the idea that all sufficiently advanced civilizations destroy themselves before going intergalactic), or that we’re simply not interesting enough.", "\n\nBut for the purposes of this discussion, we’re going to look at some of the more bizarre and arcane solutions to the Fermi Paradox. ", "Because sometimes it takes a weird explanation to answer a weird question. ", "So, as Enrico Fermi famously asked, “Where is everybody?”", "\n\n\n1. ", "The Zoo Hypothesis\n\nThough it sounds like something from a Twilight Zone episode, it’s quite possible that we’re stuck inside some kind of celestial cage. ", "ETI’s may have stumbled upon our tiny blue marble a long time ago, but, for whatever reason, they’re observing us from afar. ", "It might be that we’re entertainment for them (like watching monkeys in the zoo), or that they’re studying us for scientific purposes. ", "Regardless, they’ve invoked a hand’s off policy and they’re leaving us alone.", "\n\nThis idea was first proposed by John Ball in 1973, who argued that extraterrestrial intelligent life may be almost ubiquitous, but that the “apparent failure of such life to interact with us may be understood in terms of the hypothesis that they have set us aside as part of a wilderness area or zoo.” ", "We could be part of a vast nature preserve that has been set off limits, free to grow unperturbed by intelligent life. ", "It’s an idea that somewhat related to Star Trek’s Prime Directive in which civilizations are left alone until they attain a certain technology capacity. ", "It’s also an idea that UFOlogists are partial to — the suggestion that aliens are essentially here, but observing us from a distance. ", "Image: ssi.org.", "\n\n\n2. ", "Self-Imposed Quarantine\n\n\nThis is pretty much the opposite of the zoo hypothesis. ", "Extraterrestrials have the potential to be dangerous. ", "Like, extremely dangerous. ", "So rather than fart around the Galaxy in spaceships and hope that everyone’s super friendly, ETI’s may have collectively and independently decided to stay the hell at home and not draw attention to themselves.", "\n\nAnd why not? ", "It would be perfectly reasonable to conclude, especially in light of the Fermi Paradox, that the cosmos is filled with perils — whether it be an imperialistic civilization on the march, or a wave of berserker probes set to sterilize everything in its wake. ", "And to ensure that nobody bothers them, advanced ETIs could set up a perimeter of Sandberg probes (self-replicating policing probes) to make sure that nobody gets in. ", "Image: Cardens Design/Shutterstock.", "\n\n\n3. ", "The Whack-a-Mole Hypothesis\n\n\nImagine if there’s a kind of Prime Directive in effect, but that ETIs are hovering over us with a giant hammer ready to smack it down should it suddenly not like what it sees. ", "These ETI’s would be like Gort from The Day the Earth Stood Still, intent on preserving the galactic peace. \"", "There's no limit to what Gort could do,” said Klaatu, “He could destroy the Earth.\" ", "So what is Gort or other advanced ETIs waiting for, exactly? ", "One possibility is the technological Singularity. ", "In the space of possible survivable Singularities, a sizeable portion of them might result in an extremely dangerous artificial superintelligence (SAI). ", "The kind of SAI that could set about the destruction of the entire Galaxy. ", "So, in order to prevent the bad ones from emerging — while giving the good ones a fair chance to get started — the Galactic Club keeps watch.", "\n\n4. ", "We’re Made Out of Meat\n\nFrom the Nebula Award-nominated short story, “They’re Made Out of Meat” by Terry Bisson:\n\n\"They're made out of meat.\" \"", "Meat?\" \"", "Meat. ", "They're made out of meat.\" \"", "Meat?\" \"", "There's no doubt about it. ", "We picked up several from different parts of the planet, took them aboard our recon vessels, and probed them all the way through. ", "They're completely meat.\" \"", "That's impossible. ", "What about the radio signals? ", "The messages to the stars?\" \"", "They use the radio waves to talk, but the signals don't come from them. ", "The signals come from machines.\" \"", "So who made the machines? ", "That's who we want to contact.\" \"", "They made the machines. ", "That's what I'm trying to tell you. ", "Meat made the machines.\" \"", "That's ridiculous. ", "How can meat make a machine? ", "You're asking me to believe in sentient meat.\" \"", "I'm not asking you, I'm telling you. ", "These creatures are the only sentient race in that sector and they're made out of meat.\"", "\n\n\nA little while later:\n\n\"They actually do talk, then. ", "They use words, ideas, concepts?\" \"", "Oh, yes. ", "Except they do it with meat.\" \"", "I thought you just told me they used radio.\" \"", "They do, but what do you think is on the radio? ", "Meat sounds. ", "You know how when you slap or flap meat, it makes a noise? ", "They talk by flapping their meat at each other. ", "They can even sing by squirting air through their meat.\" \"", "Omigod. ", "Singing meat. ", "This is altogether too much. ", "So what do you advise?\" \"", "Officially or unofficially?\" \"", "Both.\" \"", "Officially, we are required to contact, welcome and log in any and all sentient races or multibeings in this quadrant of the Universe, without prejudice, fear or favor. ", "Unofficially, I advise that we erase the records and forget the whole thing.\" \"", "I was hoping you would say that.\" \"", "It seems harsh, but there is a limit. ", "Do we really want to make contact with meat?\" \"", "I agree one hundred percent. ", "What's there to say? '", "Hello, meat. ", "How's it going?'", "\n\n\n5. ", "The Simulation Hypothesis\n\n\nWe haven’t been visited by anyone because we’re living inside a computer simulation — and the simulation isn’t generating any extraterrestrial companions for us.", "\n\nIf true, this could imply one of three things. ", "First, the bastards — I mean Gods — running the simulation have rigged it such that we’re the only civilization in the entire Galaxy (or even the Universe). ", "Or, there really isn’t a true universe out there, it just appears that way to us within our simulated bubble (It’s a ‘If a tree falls in a forest and no one is around to hear it, does it make a sound?’ ", "type thing).", "\n\n\nAnother more bizarre possibility is that the simulation is being run by a posthuman civilization in search of an answer to the Fermi Paradox, or some other scientific question. ", "Maybe, in an attempt to entertain various hypotheses (perhaps even preemptively in consideration of some proposed action), they’re running a billion different ancestor simulations to determine how many of them produce spacefaring civilizations, or even post-Singularity stage civilizations like themselves.", "\n\n6. ", "Radio Silence\n\n\nThis one is similar to the quarantine hypothesis, but it’s not quite as paranoid. ", "But it’s still pretty paranoid. ", "It’s possible that everyone is listening, but no one is transmitting.", "\n\nAnd for very good reason. ", "David Brin has argued that the practice of Active SETI would be like shouting out into the jungle (Active SETI is the deliberate transmission of high-powered radio signals to candidate star systems). ", "Michael Michaud has made a similar case: “Let’s be clear about this,” he has written, “Active SETI is not scientific research. ", "It is a deliberate attempt to provoke a response by an alien civilization whose capabilities, intentions, and distance are not known to us. ", "That makes it a policy issue.” ", "The concern, of course, is that we may draw undue attention to ourselves prematurely. ", "It’s conceivable, therefore, that our collective governments may some day decide to shut down all Active SETI efforts. ", "We should just be content to listen. ", "But what if every civilization in the cosmos were to adopt the same policy? ", "That would imply that everyone has gone radio silent.", "\n\n\nAs an aside, it could also be dangerous to listen: SETI may be at risk of downloading a malicious virus from outer space.", "\n\n7. ", "All Aliens Are Homebodies\n\n\nThis one isn’t so much weird as it might actually be possible. ", "An advanced ETI, upon graduating to a Kardashev II scale civilization, could lose all galactic-scale ambitions. ", "Once a Dyson sphere or Matrioshka Brain is set up, an alien civilization would have more action and adventure in its local area than it knows what to do with. ", "Massive supercomputers would be able to simulate universes within universes, and lifetimes within lifetimes — and at speeds and variations far removed from what’s exhibited in the tired old analog world. ", "By comparison, the rest of the galaxy would seem like a boring and desolate place. ", "Space could very much be in the rear view mirror.", "\n\n8. ", "We Can’t Read the Signs\n\nNow, it’s totally possible that the signs of ETIs are all around us, but we just can’t see them. ", "Either we’re too stupid to notice, or we still need to develop our technologies to detect the signals. ", "According to the current SETI approach, we should be listening for radio signatures. ", "But a civilization far more advanced than our own might be using a different technique entirely. ", "They could be signaling with lasers, for example. ", "Lasers are good because they’re tightly focused beams with excellent informational bandwidth. ", "They’re also able to penetrate our galaxy’s dusty interstellar medium.", "\n\n\nOr, ETIs could use “calling cards” by exploiting the transmit method of detection (e.g. by constructing a massive perfectly geometrical structure, like a triangle or a square, and put in orbit around their host star).", "\n\n\nAnd and as Stephen Webb has pointed out, there’s also the potential for electromagnetic signals, gravitational signals, particle signals, tachyon signals, or something completely beyond our understanding of physics. ", "It’s also quite possible that they are in fact using radio signals, but we don’t know which frequency to tune into (the EM spectrum is extremely broad). ", "More conceptually, we may eventually find a message buried in a place where we least expect it — like within the code of our DNA. ", "Image: Arnold/Observatoire de Haute-Province in Paris.", "\n\n\n9. ", "They’re All Hanging Out At the Edge of the Galaxy\n\n\nThis interesting solution to the Fermi Paradox was posited by Milan M. Ćirković and Robert Bradbury.", "\n\n“We suggest that the outer regions of the Galactic disk are the most likely locations for advanced SETI targets,” they wrote. ", "The reason for this is that sophisticated intelligent communities will tend to migrate outward through the Galaxy as their capacities of information-processing increase. ", "Why? ", "Because machine-based civilizations, with their massive supercomputers, will have huge problems managing their heat waste. ", "They'll have to set up camp where it’s super cool. ", "And the outer rim of the Galaxy is exactly that.", "\n\n\nSubsequently, there may be a different galactic habitable zone for post-Singularity ETIs than for meat-based life. ", "By consequence, advanced ETIs have no interest in exploring the bio-friendly habitable zone. ", "Which means we’re looking for ET in the wrong place. ", "Interestingly, Stephen Wolfram once told me that heat-free computing will someday be possible, so he doesn’t think this is a plausible solution to the Fermi Paradox.", "\n\n10. ", "Directed Panspermia\n\nOr maybe we haven’t made contact with ETI’s because we’re the aliens. ", "Or least, they’re our ancestors. ", "According to this theory, which was first posited by Francis Crick (yes, that Francis Crick), aliens spark life on other planets (like sending spores to potentially fertile planets), and then bugger off. ", "Forever. ", "Or maybe they eventually come back.", "\n\n\nThis idea has been tackled extensively in scifi, including the Star Trek: The Next Generation episode, “The Chase” in which the uber-generic humanoid Salome Jens explains that its species is responsible for all life in the Alpha Quadrant, or Ridley Scott’s Prometheus, in which an alien can be seen seeding the primordial Earth with life. ", "Even Arthur C. Clarke’s 2001 is a take on this idea, with the monoliths instigating massive evolutionary leaps.", "\n\n\n11. ", "The Phase Transition Hypothesis\n\nThis one is similar to the Rare Earth hypothesis, but it suggests that the universe is still evolving and changing. ", "Subsequently, the conditions to support advanced intelligence have only recently fallen into place. ", "This is what cosmologist James Annis refers to as the phase transition model of the universe — what he feels is an astrophysical explanation for the Great Silence.", "\n\n\nAccording to Annis, a possible regulatory mechanism that can account for this is the frequency of gamma-ray bursts — super-cataclysmic events that can literally sterilize large swaths of the galaxy.", "\n\n\n“If one assumes that they are in fact lethal to land based life throughout the galaxy,” he wrote, “one has a mechanism that prevents the rise of intelligence until the mean time between bursts is comparable to the timescale for the evolution of intelligence.” ", "In other words, gamma-ray bursts are too frequent, and intelligent life is constantly getting wiped out before it develops the capacity to go interstellar. ", "Looking to the future, however, given that gamma-ray bursts are decreasing in frequency, things are set to change. “", "The Galaxy is currently undergoing a phase transition between an equilibrium state devoid of intelligent life to a different equilibrium state where it is full of intelligent life,” says Annis.", "\n\nWhich would actually be good news." ]	{ "pile_set_name": "OpenWebText2" }	[ 0.0007583140395581722, 0.0011386784026399255, 0.0019197609508410096, 0.0007829690002836287, 0.0053871143609285355, 0.0006209964631125331, 0.0005877712392248213, 0.0005520239355973899, 0.0019074850715696812, 0.0006583516369573772, 0.0009393597138114274, 0.000593795906752348, 0.0005771607393398881, 0.0029516895301640034, 0.010730717331171036, 0.0006393601652234793, 0.0012912563979625702, 0.0006559769972227514, 0.0006477450951933861, 0.0006683506653644145, 0.0011863111285492778, 0.0008355657919310033, 0.00418719369918108, 0.0026646824553608894, 0.14191244542598724, 0.000961722806096077, 0.0008550907950848341, 0.000988393439911306, 0.0006422210717573762, 0.0011741509661078453, 0.007132448721677065, 0.0022088605910539627, 0.0417318195104599, 0.0007868314278312027, 0.0005730865523219109, 0.0006628138944506645, 0.04801352694630623, 0.0015020609134808183, 0.0012908900389447808, 0.0130518339574337, 0.0069196829572319984, 0.07307867705821991, 0.051477450877428055, 0.0069196829572319984, 0.0006612353608943522, 0.0005669480888172984, 0.05602063611149788, 0.0012499629519879818, 0.0007069227867759764, 0.0007981627713888884, 0.0007866109372116625, 0.0006258863140828907, 0.0008030579192563891, 0.0006567448144778609, 0.0007827529916539788, 0.0007756301201879978, 0.0009504451882094145, 0.6703392267227173, 0.008514253422617912, 0.02597547322511673, 0.0015254609752446413, 0.1045909896492958, 0.0005684404750354588, 0.0006581019260920584, 0.0009238013881258667, 0.003776035737246275, 0.0006894689868204296, 0.0007030274718999863, 0.0019391820533201098, 0.16383029520511627, 0.025937514379620552, 0.040442511439323425, 0.0021189183462411165, 0.11294129490852356, 0.0017988680629059672, 0.0006650146096944809, 0.0006906751077622175, 0.0006959562888368964, 0.0009184039663523436, 0.0017814026214182377, 0.0005844120751135051, 0.0006583397625945508, 0.046447787433862686, 0.0005864796694368124, 0.0008059327374212444, 0.15856926143169403, 0.0007883789367042482, 0.0013671708293259144, 0.0009161452180705965, 0.0005921788979321718, 0.6462773084640503, 0.0007193749770522118, 0.00067618623143062, 0.0015185232041403651, 0.0006627138354815543, 0.0012020888971164823, 0.0011046965373679996, 0.0010007580276578665, 0.0007401785114780068, 0.0007102316594682634, 0.0008094076183624566, 0.0006966849323362112, 0.0007985522388480604, 0.0007277213153429329, 0.0006057846476323903, 0.026608917862176895, 0.0005936699453741312, 0.0007126280106604099, 0.0010936616454273462, 0.00516057014465332, 0.0013101664371788502, 0.0037390722427517176, 0.0013553331373259425, 0.0033702910877764225, 0.0014674984849989414, 0.0014433605829253793, 0.0006480862502939999, 0.0014590069185942411, 0.000695637078024447, 0.7382201552391052, 0.0005341521464288235, 0.0006669199792668223, 0.000711119850166142, 0.0005753454752266407, 0.0007580485544167459, 0.0006898047868162394, 0.0005748455878347158, 0.0005998359411023557, 0.0005629679653793573, 0.000588304246775806, 0.0013501894427463412, 0.000691917899530381, 0.0006628723349422216, 0.0005887280567549169, 0.0009688621503300965, 0.03510833531618118, 0.0010380285093560815, 0.0007439027540385723, 0.000716886599548161, 0.0006831539794802666, 0.000822679081466049, 0.0005841013044118881, 0.001167020294815302, 0.012043057009577751, 0.0012610176345333457, 0.0010546381818130612, 0.0011515504447743297, 0.0007753917598165572, 0.000688185915350914, 0.0008046193979680538, 0.0011399758514016867, 0.000598758109845221, 0.0005683951894752681, 0.0008251717663370073, 0.0007981950184330344, 0.0006499359733425081, 0.0019502326613292098, 0.0005918807000853121, 0.0007399913156405091, 0.0005783910164609551 ]	0.021358	160
[ "» Minnesota Vikings linebacker Jasper Brinkey was fined $21,000 for a shot to the head against the Detroit Lions. ", "On the other sideline, wide receiver Ryan Broyles was docked $10,000 for an illegal crack-back block." ]	{ "pile_set_name": "Pile-CC" }	[ 0.0008640951127745211, 0.01709776744246483 ]	0.008981	2
[ "Q:\n\nHow to redirect to different pages with one view\n\nNow I have 6 buttons, Everyone will redirect to a page containing courses,\nthis method is for one button,\nViews.py\ndef categories_pages(request):\n if request.user.is_authenticated():\n courses = Course.objects.filter(\n published_date__lte=timezone.now(),\n categories__name__icontains=\"IT\"\n ).order_by('published_date')\n context = {\n \"courses\": courses\n }\n return render(request, 'categories/categories-page.html', context)\n\ntemplate\n{% for instances in courses %}\n <div class=\"col-sm-6 col-md-4\">\n <div class=\"thumbnail\">\n <img src=\"{{ instances.img }}\" alt=\"{{ instances.name }}\">\n <div class=\"caption\">\n <h3>{{ instances.name }}</h3>\n <p>{{ instances.description }}</p>\n <p><a href=\"#\" class=\"btn btn-primary\" role=\"button\">Button</a> <a href=\"#\" class=\"btn btn-default\" role=\"button\">Button</a></p>\n </div>\n </div>\n {% endfor %}\n\nThis button for IT courses , what about Business, Languages, etc..\nand it worked well but do I have to make different view for every button and all have same syntax or is there another way to make it in the same view ?", "\nThanks\n\nA:\n\nYou need to define your url to have the category as a named parameter, so your view would take that extra parameter and query for the course:\nurl:\nurl(r'^categories/(?P<course_name>\\w+)/$', views.categories_pages)\n\nviews.py\ndef categories_pages(request, course_name):\n if request.user.is_authenticated():\n courses = Course.objects.filter(\n published_date__lte=timezone.now(),\n categories__name__icontains=course_name\n ).order_by('published_date')\n context = {\n \"courses\": courses\n }\n return render(request, 'categories/categories-page.html', context)\n\n" ]	{ "pile_set_name": "StackExchange" }	[ 0.0007274653762578964, 0.0006057402351871133 ]	0.000667	2
[ "Maybe I'm wrong, but I don't think we've done that on the other two deals. ", " \nKathleen would know.", "\n\n\n\n\n\"Reuter, Marisa\" <MReuter@KSLAW.com> on 06/05/2001 02:33:13 PM\nTo: \"'Kay.Mann@enron.com'\" <Kay.Mann@enron.com>\ncc: \n\nSubject: RE: ENA/Blue Dog: Incumbency Certificate\n\nFor the escrow. ", " Unfortunately, Citibank's form contained the following\nlanguage in the signature block: \"In witness whereof, I have hereunto set my\nhand and affixed the corporate seal of the Company this ______ day of May,\n2001.\"", "\n\n-----Original Message-----\nFrom: Kay.Mann@enron.com [mailto:Kay.Mann@enron.com]\nSent: Tuesday, June 05, 2001 12:04 PM\nTo: Reuter, Marisa\nSubject: Re: ENA/Blue Dog: Incumbency Certificate\n\n\n\nIs this for the escrow or other docs? ", " I know Citibank does not require a\ncorporate seal. ", " What BS!", "\n\nKathleen is out sick, so it will be a day or two.", "\n\nKay\n\n\n\n\n\"Reuter, Marisa\" <MReuter@KSLAW.com> on 06/05/2001 10:09:11 AM\n\nTo: \"'Kathleen.Carnahan@enron.com'\" <Kathleen.Carnahan@enron.com>\ncc: \"'kay.mann@enron.com'\" <kay.mann@enron.com>, \"Keffer, John\"\n <JKeffer@KSLAW.com>\n\nSubject: ENA/Blue Dog: Incumbency Certificate\n\n\nKathleen:\n\nPaul Hastings would like ENA to resign the Incumbency Certificate, since\nthe\noriginal Certificate did not affix the corporate seal. ", " Could you\ncoordinate\nthis and make sure the seal is affixed to the new Certificate? ", " Thanks.", "\n\nCall me if you have any questions.", "\n\nRegards,\n\nMarisa\n\n\n\n\n\n\n\n Confidentiality Notice\nThis message is being sent by or on behalf of a lawyer. ", " It is intended\nexclusively for the individual or entity to which it is addressed. ", " This\ncommunication may contain information that is proprietary, privileged or\nconfidential or otherwise legally exempt from disclosure. ", " If you are not\nthe named addressee, you are not authorized to read, print, retain, copy or\ndisseminate this message or any part of it. ", " If you have received this\nmessage in error, please notify the sender immediately by e-mail and delete\nall copies of the message.", "\n\n\n(See attached file: Reuter, Maria I. (Business E-Mail Address).vcf)\n\n\n\n\n\n Confidentiality Notice\nThis message is being sent by or on behalf of a lawyer. ", " It is intended \nexclusively for the individual or entity to which it is addressed. ", " This \ncommunication may contain information that is proprietary, privileged or \nconfidential or otherwise legally exempt from disclosure. ", " If you are not the \nnamed addressee, you are not authorized to read, print, retain, copy or \ndisseminate this message or any part of it. ", " If you have received this \nmessage in error, please notify the sender immediately by e-mail and delete \nall copies of the message." ]	{ "pile_set_name": "Enron Emails" }	[ 0.0006106452783569694, 0.0007092751911841333, 0.000977326650172472, 0.0006169553962536156, 0.0008068924653343856, 0.0006613973528146744, 0.06696993112564087, 0.02420155145227909, 0.0007784119225107133, 0.0006676955381408334, 0.000607421388849616, 0.0016668584430590272, 0.0006580731132999063, 0.0006514876731671393, 0.0006014612154103816, 0.0007884586229920387, 0.0008376844343729317, 0.0006383911822922528, 0.0006514876731671393, 0.0006014612154103816, 0.0007884586229920387, 0.0008376844343729317 ]	0.004833	22
[ "Jacinda Ardern, the Prime Minister of New Zealand, has announced that the government will no longer award permits for offshore oil and gas exploration in order to help the country move towards a zero carbon future.", "\n\nArdern, who became Prime Minister in October 2017, has promised to reduce the country’s net greenhouse gas emissions to zero by 2050.", "\n\nThe decision to end offshore oil and gas exploration will not, the government said, affect the 22 existing permits for exploration or extraction of these natural resources. ", "The oil and gas industry will continue to operate for decades longer; any new discoveries by current permit holders by 2030 could still reap a mining permit of up to 40 years.", "\n\nArdern said that the government was “striking the right balance for New Zealand”, and that nobody would be left out of a job by the decision. ", "The oil and gas industry is not large in New Zealand, accounting for approximately 1 per cent of the economy and employing approximately 11,000 people.", "\n\n“We’re protecting existing industry, and protecting future generations from climate change,” she said.", "\n\nInevitably, the announcement has been met with some criticism by political opponents; the conservative government, which preceded Ardern’s, was in favour of continuing to expand the oil and gas industry. ", "According to Neil Holdom, Mayor of New Plymouth, the announcement is a “kick in the guts for the future of the Taranaki economy”, in which the majority of the industry is based in New Zealand.", "\n\nThe Petroleum Exploration and Production Association has argued that putting an end to oil and gas exploration in New Zealand will not affect the global supply of these resources, and could instead have worse environment impacts as exploration and production moves elsewhere.", "\n\nEnvironmental pressure group Greenpeace welcomed the announcement. ", "According to Russel Norman, the group’s executive director in New Zealand: “By ending new oil and gas exploration in our waters, the fourth largest Exclusive Economic Zone on the planet is out of bounds for new fossil fuel exploitation. ", "New Zealand has stood up to one of the most powerful industries in the world.”", "\n\nSince the 2010 Deepwater Horizon oil spill – for which BP was ruled to be primarily responsible and forced to pay $18.7bn (£13.2bn) in the largest corporate settlement in history – criticism of the offshore oil and gas industry has intensified.", "\n\nFollowing the almost universal adoption of the Paris Agreement – which seeks to reduce carbon emissions in order to mitigate the most serious impacts of climate change – many governments have taken steps to move away from their dependence on fossil fuels. ", "In December, for instance, the French government announced that it would phase out all oil and gas production by 2040.", "\n\nArdern, who leads a left-of-centre government, has pledged to ensure that the grid in New Zealand runs entirely on renewable energy, and has said her government will plant 100 million trees every year. ", "The government will review its handling of onshore exploration permits after three years." ]	{ "pile_set_name": "OpenWebText2" }	[ 0.0006012662779539824, 0.0007239317637868226, 0.0005857651703990996, 0.0005997429834678769, 0.0007240093545988202, 0.0006662554806098342, 0.0006865301984362304, 0.0007550328737124801, 0.011101075448095798, 0.0005872459732927382, 0.0005569866625592113, 0.00063101522391662, 0.0006280679954215884, 0.0007024247897788882, 0.0006084144697524607, 0.0006169777479954064, 0.0006658301572315395, 0.0005510455812327564 ]	0.001222	18
[ "Terms of Use\n\nCOPYRIGHTS, DISCLOSURES, AND DISCLAIMERS\n\nAuthorization of Use\n\nElevare Skin hereby authorizes any person to access this Website for informational purposes only. ", "Elevare Skin reserves the right to terminate access to this Website at any time without notice. ", "The data, information and material included in this Website is copyrighted by Elevare Skin. ", "All rights are reserved under the copyright laws of the United States of America. ", "No part of this Website can be redistributed, copied or reproduced without the prior written consent of Elevare Skin.", "\n\nNo Warranties\n\nThe user of this Website assumes all responsibility and risk for the use of this Website and the Internet generally. ", "Elevare Skin, and its affiliated companies disclaim all warranties, representations or endorsements, expressed or implied, with regard to the data, information and material included in, or accessible from, this Website or the Internet, including, but not limited to, all implied warranties of merchantability, fitness for a particular purpose or noninfringement. ", "Elevare Skin and its affiliated companies have the right to discontinue, change or update any data, information or material included in the Website without prior notice, and they do not assume any legal liability or responsibility for the accuracy, completeness or usefulness of any data, information or material included in, or accessible from, this Website. ", "No advice or information given by Elevare Skin or its affiliated companies shall create any warranty. ", "Neither Elevare Skin nor its affiliated companies warrants that the data, information and material included in the Website or on the Internet will be uninterruptible or error free or that any data, information, software or other material accessible from this Website is free of viruses or other harmful components.", "\n\nDisclaimer of Liability\n\nIn no event shall Elevare Skin or its affiliated companies be liable for any compensatory, special, direct, incidental, indirect, or consequential damages, exemplary damages or any damages whatsoever resulting from loss of use, data, information or profits arising out of or in connection with the use or performance of the data, information or material included in this Website or on the Internet generally or on any other basis.", "\n\nDisclaimer for Links\n\nAlthough this site includes links providing direct access to other Internet sites, Elevare Skin and its affiliated companies take no responsibility for the content or information contained on those other sites, and does not exert any editorial or other control over those other sites.", "\n\nElectronic Communications\n\nElevare Skin will not be deemed to have accepted any electronic communication unless Elevare Skin provides the sender of the electronic communication with an acknowledgment verifying receipt of the communication. ", "If Elevare Skin sends any electronic communication, Elevare Skin will assume the communication was received intact by the intended recipient. ", "The recipient of such message must notify Elevare Skin if the transmission was not received or was not received in a readable format.", "\n\nSecurity\n\nDespite the security measures taken by Elevare Skin, there is an inherent risk in disclosing personal information over the Internet. ", "Anyone electronically transmitting personal information assumes the risk that such information may be disclosed or intercepted by unintended third parties and Elevare Skin disclaims all liability resulting from such interception or disclosure.", "\n\nCopyright\n\nThe Elevare Skin logo, and other marks, including the names of various products and services described within and offered by companies represented by Elevare Skin and its subsidiaries are service marks of these companies.", "\n\nPermission to use, copy and distribute these materials is not granted.", "\n\nUse of this site shall be governed by and construed in accordance with the laws of our state of business, without giving effect to any principles of conflicts of laws. ", "Any dispute concerning this site shall be subject to the exclusive venue of a court of competent jurisdiction in state of Florida.", "\n\nShould any provision of our terms and conditions be held invalid, unlawful or for any reason unenforceable, then the invalid, unlawful or unenforceable provision shall be severable from the remaining provisions. ", "Such invalid, unlawful or unenforceable provision shall not affect the validity or enforceability of the remaining provisions." ]	{ "pile_set_name": "Pile-CC" }	[ 0.000608636939432472, 0.0006768302991986275, 0.0006947618094272912, 0.0006377350073307753, 0.0012723184190690517, 0.0006248150020837784, 0.0006883465684950352, 0.0007055538590066135, 0.000641129445284605, 0.0012467169435694814, 0.0007952599553391337, 0.0007220965926535428, 0.0006104241474531591, 0.0007322018500417471, 0.0006285985582508147, 0.0007059976924210787, 0.0006372614298015833, 0.0006089441594667733, 0.0006010488141328096, 0.0006358432583510876, 0.0005883227568119764, 0.0006605028756894171, 0.0007244787411764264 ]	0.000715	23
[ "Friday, November 19, 2010\n\nNot so Boring Whites\n\nI just wanted to let the world know, that a room with a mixture of whites, blacks, grays and beige can still be warm, inviting and full of personality. ", "Add a tiny pale splash of any color you wish (like the light blush pillows and throw above) for a touch of warmth and charm. ", "Need more color? ", "With a white palate, it's easy to add colorful pieces anytime you wish, I like to rotate things out according to my mood and seasons.", "\n\n6 comments:\n\nlove love love me some white and love that you posted about this because i hate to hear someone say \"white is so 'cold'\". ", "it absolutely can be warmed up and make a space so crisp and inviting. ", "thanks for sharing!" ]	{ "pile_set_name": "Pile-CC" }	[ 0.007790923118591309, 0.0005742136854678392, 0.0007912680157460272, 0.0006987868691794574, 0.020370161160826683, 0.0005487851449288428, 0.0006788694299757481 ]	0.004493	7