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"China-EU economic ties go ahead despite headwinds\n\nDate：2017-01-03 Source：china daily Views：461482\n\nCore Tip：BRUSSELS - China and the European Union (EU) have gone through a bittersweet year in economy in 2016, stumbling over iss\n\nBRUSSELS - China and the European Union (EU) have gone through a bittersweet year in economy in 2016, stumbling over issues, such as the anti-dumping regime and \"analogue country,\" while continuously advancing in trade, investment and strategic cooperation.",
"\n\nProtectionism overshadows ties\n\nGrowing protectionism in Europe has resulted in mounting EU anti-dumping and anti-subsidy investigations against Chinese products.",
"\n\nBrussels' anxiety accumulated, as the continent has for years been clouded by sluggish economic growth, a lack of sufficient investment, a disappointing inflation record and a double-digit jobless rate in the wake of the debt crisis and the global financial crisis.",
"\n\nFacing the chronic problems, some EU countries started to vent their disappointment on China, a country which managed to maintain a medium-to-high economic growth amid an average sluggish global growth.",
"\n\nThey claimed Chinese imports would hit the bloc's manufacturing industry, especially traditional and energy-intensive sectors, as well as exacerbate unemployment across the continent.",
"\n\nThough a lack of evidence left the argument untenable, the bias affected Brussels' policy making.",
"\n\nThe European Commission imposed anti-dumping duties on Chinese steel products in October, attributing its steel sector's difficulties to China's overcapacity.",
"\n\nThe decision came just about two months before a deadline required by the World Trade Organization (WTO) rules which demand that the EU quit the \"analogue country\" method in its anti-dumping investigations on China.",
"\n\nThe move forced Beijing to launch dispute settlement procedures at the WTO.",
"\n\nAnti-dumping cases accounted for less than 2 percent of the total EU-China trade and it was not worthy for Brussels to put bilateral trade ties on edge, Pierre Defraigne, executive director of the Brussels-based think tank the Madariaga-College of Europe Foundation, told Xinhua.",
"\n\nObstacles to chinese investment\n\nThe impact of the growing protectionism was not confined to imports from China, but was spilling over to investment.",
"\n\nEnthusiastic Chinese investors were confused: Europe has been complaining about a lack of investment, but when they brought investment to Europe, they met a cold shoulder.",
"\n\nSkeptics, politicians or lobbyists cited the \"threat of Chinese capital\" as a major concern and groundlessly accused Chinese investment of harming EU interests, such as national security and intellectual property.",
"\n\nAmid rancorous voices, the German government in October announced a restart of investigation on the sale of the German semi-conductor maker Aixtron to a Chinese company, and to withdraw the clearance certificate it issued in September which confirmed the Chinese buyer's credibility, due to \"security concerns.\"",
"\n\nEuropean countries' worry over the Chinese investment coincides with a protectionist trend and a surge in populism on the continent, said Hannes Dekeyser, an expert with the European Institute for Asian Studies.",
"\n\nAmid the surge of protectionism in global trade and a gloomy outlook of an EU-U.S. free trade deal, Europe's foreign trade policy should focus more on Eurasia, especially China, Defraigne said.",
"\n\nTrade increases amid headwinds\n\nDespite the headwinds in China-EU economic ties, bilateral trade managed to reach a new high in 2016, overcoming global trade downturn affected by sluggish demand and weak growth.",
"\n\nData from Chinese customs show that bilateral trade value reached 2.94 trillion yuan ($423.34 billion) in the first 10 months.",
"\n\nOn a daily basis, trade in goods between the EU and China is worth well over 1.5 billion euros ($1.58 billion), according to the EU data.",
"\n\nIn 2016, the EU stands as China's biggest trading partner, while China is the EU's second largest trading partner after the United States.",
"\n\nChina and the EU have a solid foundation of cooperation and the two sides have enhanced cooperation on connectivity, investment plans, and other strategies including \"Made in China 2025\" and Germany's \"Industry 4.0,\" said Wang Yiwei, director of the Center for European Studies at China's Renmin University.",
"\n\nAnd the connection between the two sides is deepening with the progress of the China-proposed Belt and Road Initiative.",
"\n\nThe cooperation between China and 16 Central and Eastern European Countries has become a highlight under the Belt and Road Initiative, said Wang.",
"\n\nWang cited the fact that 25 Chinese cities have launched China-Europe express lines, which tremendously promoted the links between the two continents and contributed to the infrastructure construction and industrial development in the region.",
"\n\nExperts said it's time for European countries to downplay their baseless worries over China, but to brace for pragmatic cooperation in the future."
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"Le dernier sondage Léger semble confirmer la tendance qu’on observe depuis une dizaine de jours, soit une certaine hausse des appuis au PLQ (et, accessoirement, à Québec solidaire), ainsi qu’une chute correspondante des intentions de vote péquistes.",
"\n\nL’inversion de la tendance semble coïncider, grosso modo et contre toute attente, avec l’atterrissage de Pierre Karl Péladeau dans la campagne. ",
"Plusieurs ont d’abord cru que l’arrivée de M. Péladeau attirerait certains électeurs de la CAQ vers le PQ et enverrait certains électeurs péquistes vers QS — et il semble que l’effet se manifeste effectivement dans le cas de QS.",
"\n\nDans le cas de la CAQ, toutefois, l’exode a profité aux Libéraux. ",
"Quelques heures après l’annonce de la candidature de M. Péladeau, il semble que bien des électeurs caquistes aient compris qu’avec un Parti québécois ayant fait le pari du n’importe-quoi-pour-la-souveraineté, l’échéancier référendaire devenait le seul enjeu capable d’unir un caucus divisé, et qu’il serait donc, de facto, la priorité d’un futur gouvernement péquiste.",
"\n\nLe PQ a désespérément tenté de changer de sujet depuis.",
"\n\nLa stratégie consistait d’abord à affirmer qu’il n’y aurait «pas de référendum… tant que les Québécois ne seront pas prêts». ",
"Cette déclaration, répétée ad nauseam pendant le débat de jeudi dernier, a sans doute eu un effet nul sur les électeurs qui ne veulent rien savoir d’un troisième référendum sur l’indépendance du Québec.",
"\n\nSerait-il théoriquement possible que les Québécois soient «prêts» au cours du prochain mandat d’un gouvernement péquiste ? ",
"Jean-François Lisée semble certainement le croire, lui qui se dit «pressé de tenir un référendum le plus rapidement possible dans le prochain mandat».",
"\n\nComment un gouvernement péquiste saura-t-il quand les Québécois seront prêts ? ",
"Impossible de savoir. ",
"Un futur gouvernement péquiste s’emploierait-il, une fois au pouvoir, à «préparer les Québécois à être prêts» à tenir un troisième référendum ? ",
"Bien évidemment.",
"\n\nConstatant la quasi-impossibilité de changer de sujet, le PQ a ostentatoirement tenté de ramener la Charte des valeurs. ",
"Sans grand succès. ",
"Puis ce fut le tour de l’épouvantail d’une élection volée par le Canada anglais — une étrange stratégie si l’objectif était de faire oublier l’hypothèse d’un prochain référendum, considérant que la rhétorique était presque identique à celle du lendemain de l’échec de 1995. ",
"Cette stratégie semble toutefois s’être retournée contre ses auteurs.",
"\n\nDepuis 48 heures, la nouvelle ligne consiste apparemment à répéter qu’un vote pour Philippe Couillard est un vote pour Jean Charest. ",
"On verra ce que ça donne.",
"\n\n(Ça devient un peu compliqué. ",
"Selon le PQ, un vote pour Philippe Couillard est un vote pour Jean Charest, et un vote pour QS est un vote pour le PLQ. ",
"François Legault, lui, dit qu’un vote pour le PQ en chute libre est essentiellement un vote pour le PLQ. ",
"M. Couillard, lui, dit qu’un vote pour la CAQ est un vote pour le PQ. ",
"Le PQ dit qu’un vote pour le PQ n’est pas un vote pour un référendum, mais les Québécois croient plutôt le contraire. ",
"Françoise David répète qu’elle est souverainiste et affirme qu’un vote pour QS est un vote pour un référendum, mais les péquistes disent plutôt qu’ils sont les seuls vrais souverainistes, même s’ils ne tiendront pas de référendum. ",
"Pendant ce temps, comme le faisait remarquer Mathieu Charlebois, 25 % des partisans d’Option nationale sont indifférents ou opposés à la souveraineté du Québec, même si c’est l’unique raison d’être du parti.)",
"\n\nL’autre approche, plus défaitiste à certains égards, consiste à attaquer les électeurs allergiques à un troisième référendum sous prétexte qu’ils s’opposeraient en quelque sorte au principe même de la démocratie.",
"\n\nC’est évidemment ridicule. ",
"Personne ne conteste le caractère démocratique d’un référendum, et l’allergie qu’il suscite chez certains n’a rien à voir avec l’exercice de la consultation populaire.",
"\n\nCe qui repousse, c’est le détournement des ressources, du temps et des énergies du gouvernement vers un combat qui figure très loin dans la liste des priorités d’une majorité de la population.",
"\n\nLes électeurs anti-référendum refusent d’élire un gouvernement qui chercherait à provoquer des disputes avec Ottawa, qui dépenserait temps, ressources et énergie à mettre en place des consultations publiques aux conclusions prédéterminées, qui enrôlerait tous les ministères dans la mise en place des «conditions gagnantes» et dont le caucus de députés n’aurait que la souveraineté comme point de convergence.",
"\n\nTentant sans doute de répéter l’expérience de 2012 — où près de 24 % des électeurs qui ont voté pour le PQ l’ont apparemment fait pour des raisons stratégiques —, les ténors péquistes exhortent maintenant les électeurs souverainistes à délaisser Québec solidaire pour bloquer le Parti libéral. ",
"Les attaques sont inspirées par la crainte de la fameuse division du vote et sont de plus en plus créatives.",
"\n\nLe dernier sondage Léger devrait toutefois refroidir un peu ces angoisses : quand on demande aux répondants de choisir uniquement entre le PQ et le PLQ — éliminant ainsi l’effet de la CAQ, de QS, d’Option nationale et du Parti vert —, on obtient 48 % des voix pour les libéraux et 41 % pour le PQ. ",
"L’avance de 7 % du PLQ est exactement la même que quand on considère tous les partis (40 % contre 33 %). ",
"Il semblerait qu’en surface, du moins, la division du vote ne change pas grand-chose au sort des deux principaux partis.",
"\n\nAprès les femmes voilées, les étudiants ontariens, Québec solidaire, la division du vote et Jean Charest, voici toutefois une cible que le PQ ne risque pas d’attaquer : notre archaïque mode de scrutin. ",
"Celui que Claude Béland souhaiterait tant changer. ",
"Et celui qui «donne au PQ un avantage non négligeable», selon l’analyste Bryan Breguet.",
"\n\nGrâce à ce mode de scrutin que René Lévesque voulait changer, le Parti québécois pourrait encore espérer former un gouvernement, même majoritaire, avec moins de votes que les libéraux.",
"\n\nIl serait pour le moins ironique que le parti qui s’est le plus inquiété d’une fausse fraude électorale finisse par accéder au pouvoir grâce à une distorsion du système qui fausse réellement la volonté démocratique.",
"\n\n* * *\n\nÀ propos de Jérôme Lussier\n\nJérôme Lussier est juriste et journaliste. ",
"Au cours des dernières années, il a notamment travaillé à Radio-Canada et tenu un blogue au journal Voir, en plus d’avoir été conseiller politique à la Coalition Avenir Québec. ",
"Il blogue sur les enjeux sociaux et politiques contemporains à L’actualité depuis 2013. ",
"On peut le suivre sur Twitter : @jeromelussier."
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"#!",
"/bin/bash\n#\n# Copyright 2008, Google Inc.\n# All rights reserved.",
"\n#\n# Redistribution and use in source and binary forms, with or without\n# modification, are permitted provided that the following conditions are\n# met:\n#\n# * Redistributions of source code must retain the above copyright\n# notice, this list of conditions and the following disclaimer.",
"\n# * Redistributions in binary form must reproduce the above\n# copyright notice, this list of conditions and the following disclaimer\n# in the documentation and/or other materials provided with the\n# distribution.",
"\n# * Neither the name of Google Inc. nor the names of its\n# contributors may be used to endorse or promote products derived from\n# this software without specific prior written permission.",
"\n#\n# THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS\n# \"AS IS\" AND ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT\n# LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR\n# A PARTICULAR PURPOSE ARE DISCLAIMED. ",
"IN NO EVENT SHALL THE COPYRIGHT\n# OWNER OR CONTRIBUTORS BE LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL,\n# SPECIAL, EXEMPLARY, OR CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT\n# LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES; LOSS OF USE,\n# DATA, OR PROFITS; OR BUSINESS INTERRUPTION) HOWEVER CAUSED AND ON ANY\n# THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY, OR TORT\n# (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE\n# OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE.",
"\n\n# Executes the samples and tests for the Google Test Framework.",
"\n\n# Help the dynamic linker find the path to the libraries.",
"\nexport DYLD_FRAMEWORK_PATH=$BUILT_PRODUCTS_DIR\nexport DYLD_LIBRARY_PATH=$BUILT_PRODUCTS_DIR\n\n# Create some executables.",
"\ntest_executables=(\"$BUILT_PRODUCTS_DIR/gtest_unittest-framework\"\n \"$BUILT_PRODUCTS_DIR/gtest_unittest\"\n \"$BUILT_PRODUCTS_DIR/sample1_unittest-framework\"\n \"$BUILT_PRODUCTS_DIR/sample1_unittest-static\")\n\n# Now execute each one in turn keeping track of how many succeeded and failed. ",
"\nsucceeded=0\nfailed=0\nfailed_list=()\nfor test in ${test_executables[*]}; do\n \"$test\"\n result=$?",
"\n if [ $result -eq 0 ]; then\n succeeded=$(( $succeeded + 1 ))\n else\n failed=$(( failed + 1 ))\n failed_list=\"$failed_list $test\"\n fi\ndone\n\n# Report the successes and failures to the console.",
"\necho \"Tests complete with $succeeded successes and $failed failures.\"",
"\nif [ $failed -ne 0 ]; then\n echo \"The following tests failed:\"\n echo $failed_list\nfi\nexit $failed\n"
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"Budget an election gimmick\n\nThe budget is just an election gimmick so that people may vote for the BJP in the coming 2019 elections. ",
"People should not get carried away. ",
"Modi had made a lot of promises during the last four and half years of his tenure but did not fulfill any of them; not even the Rs 15 lakh which he promised to give every citizen of India. ",
"Who knows what will be in store for us next year in 2020 when the budget will be announced? ",
"It will be another hard five years for us if the BJP comes again to power.",
"\n\nJubel D’Cruz\n\nUnpardonable and condemnable garrulity!",
"\n\nRecently in a program held at the premises of Mumbai’s famous JJ Hospital, music of film ‘Gully Boy’ was released. ",
"Actor Ranveer Singh advised the organizers to make such loud noise that even dead bodies should get up from morgue of JJ Hospital. ",
"He also said not to worry about it since he had good contacts with police because he was Simbaa. ",
"Exhibiting such garrulity, in fact, proves the need for such people to learn good manners as a human being. ",
"Such garrulity shows the name and fame going to their head. ",
"Such people should be timely shown that their garrulous statements and irresponsible behaviour has no place here. ",
"You are in this field of art because of people. ",
"How can you dare to say anything to them? ",
"It is firstly wrong to organise such noisy programs in hospital area. ",
"Had Ranveer Singh even little empathy towards distressed patients treated at hospital, he would not have agreed to attend such program. ",
"It shows that what we see with eyes is not always true. ",
"We need to know true nature of these people. ",
"He held program in hospital area. ",
"He never thought of paying good will visit to patients admitted in hospital which was so close. ",
"How will he think of such things? ",
"The irresponsible comments he made about dead bodies, exhibit his lack of sense in understanding value of human life and the souls going through so much distress in hospital.",
"\n\nJayesh Rane\n\nHow did Pakistani goods reach here?",
"\n\nIndian Republic completed 71 years but the country has not yet become totally free from bondage. ",
"There have been numerous known and unknown revolutionaries, right from Babu Genu who was an ordinary mill worker, who sacrificed their life for freedom of this country. ",
"Only then, we saw dawn of freedom and people felt that it would bring righteous governance; but they were disappointed. ",
"Rulers, so also citizens are responsible for the same. ",
"On January 26, it was found that goods such as spices and eatables prepared by Pakistani companies were sold at a mall in Vasai (Dist. ",
"Palghar, Maharashtra). ",
"It was learnt that Shiv Sena members stopped this sale. ",
"Isn’t using goods made by an enemy country, like sedition? ",
"They will certainly have to leave if they don’t get buyers here. ",
"Shopkeepers, wholesalers should not bring goods made in enemy country for sale in our markets. ",
"We need to make firm resolve of not getting things made by enemy country in own country and even in own house by taking necessary action. ",
"Especially, in case of enemy like Pakistan, which is killing our soldiers on borders, we need to know that by buying those goods, we are in a way helping their economy. ",
"Traders should keep away their greed and see to it that consumers buy maximum indigenous products. ",
"Celebrating August 15 and January 26 as just a formality is of no use but every action should show Indian citizens’ patriotism. ",
"If we develop the quality of sacrificing own selfish interests, only then there will be true righteous governance in this country!",
"\n\nManisha Chandarana\n\n(The views expressed by the author in the article are his/her own.)"
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"You Are Here\n\nThe Cult of Childhood Fears: Introduction\n\nUnderdogs, I want to put a disclaimer on this series right away. ",
"If you are upset by certain harsh subjects, including: stalking, murder, death, suicide, and other things, please don’t read. ",
"This is an introduction into a series I am doing about things we grew up with, and how terrible they really are in life! ",
"For example, I will be taking in depth looks at fairy tales, nursery rhymes, and cartoons and the horror behind them.",
"\n\n*This post contains affiliate links. ",
"To see more info, go to the Promotions page for the disclaimer.",
"\n\nI went to school for creative writing and literature, and I have had an fascination about all of these strange and upsetting things that were supposed to be meant for children! ",
"The purpose of this post is to warn you that there will be very sensitive subject matters discussed about these childhood things that induced fears and terrible explanations. ",
"As a child, I remember being told some of these nursery rhymes and being very disturbed.",
"\n\nMy Grandparents were older, and they had an amazing collection of books. ",
"I grew up with Bryor Rabbit, and Grimm Fairytales. ",
"Even then, I understood that there was something very wrong with these stories that were being told to me. ",
"I also watched Loony Tunes and was shocked at how many of the characters killed themselves. ",
"I don’t know if you can watch these now, but when I was a kid, these were on all of the time. ",
"The shows would leave me depressed, upset, and feeling sick. ",
"Sometimes, I would cry about it. ",
"I would get so sad that I wouldn’t know how to describe and vocalize what I was feeling. ",
"I sort of understood that it wasn’t real, but what I was feeling about the very upsetting event was very real.",
"\n\nI often wonder why we plague children with such sad and disturbing stories. ",
"This isn’t anything new at all. ",
"Going back and looking at stories that were meant for children is like taking a ride on a horror roller coaster. ",
"I know at some point, people didn’t know, or care that children are not adults and do not have the understanding of an adult. ",
"Children weren’t expected to live long, so were these horrible stories to remind these kids that their short little lives would be cut short? ",
"Was this a way to help kids understand that there is only harsh and terrible things waiting for them if they make it past being a kid?",
"\n\nI call this a cult just for that reason. ",
"We have been brought up in a society where we have been brainwashed in more ways than one. ",
"Nothing is easier than including ideas to impressionable young children. ",
"A whole bunch of cartoons from the 80’s were nothing but 30 minute ads for toys and other things from their brand. ",
"Ideas are presented to children in a very pretty wrapping. ",
"At first, it seems nice, but when you look closer, the reality peeks through. ",
"It is a way of thinking that we have all been set up for, and if that isn’t cult like, I don’t know what is.",
"\n\nI hope you are excited to dive into the series with me. ",
"Again, I hope that you take this warning to heart. ",
"While all of this is readily available online and pretty much anywhere, I will be breaking it down more and looking deeper. ",
"Some of the things that I will be looking at are: Loony Tunes, Disney, Grimm Fairy Tales, and more. ",
"Stories are a powerful thing, and a tool that is used to pass history and to entertain. ",
"What about the darkness behind these stories? ",
"Join me to find out as we explore this world."
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"Ida Redbird\n\nIda Redbird (1892-1971) was a Maricopa potter from the Gila River Indian Community of the Gila River Indian Reservation in Arizona. ",
"She was the first president of the Maricopa Pottery Maker's Association and was widely credited with the revival of ancient Maricopa pottery techniques and forms. ",
"Her polished black-on-redware pottery was highly prized with collectors. ",
"Texas photographer Ted Sayles shot a series documenting Redbird sculpting her pottery. ",
"The series toured museums throughout the \nWestern United States\n\nEarly life\nIda Redbird was born March 15, 1892, in Laveen on the Gila River Indian Reservation in Arizona to Hoot Somegustava. ",
"Hoot, Ida's mother, is sometimes described as Tohono O'odham and at other times as Maricopa-Halchidhoma. ",
"Ida was the granddaughter of Kutox (also known as Kutŏ’x̣ or Uwȧ’nyȧ), who was Halchidhoma and wife of Charlie Redbird (also known as Matȧkwĭsnunyĕ’), who was Maricopa-Halchidhoma. ",
"Ida attended Phoenix Indian School, where her former teacher remembered her a being a shy, serious student, who learned pottery at a young age.",
"\n\nCareer\nIn the 1920s, Redbird acted as an interpreter for Leslie Spier's work Yuman Tribes of the Gila River. ",
"By the 1930s, her work became known and was selling to dealers from Los Angeles, though for mere pennies. ",
"Even though the Great Depression had reduced all wages, the price was still a pittance–a situation Redbird sought to change. ",
"Organizing other potters, and backed by Elizabeth Hart, a Home Extension Agent for the U.S. Indian Service, Redbird strove to improve their products so potters could increase their prices. ",
"Her efforts earned her the respect of fellow potters, who elected her first president of the Maricopa Pottery Maker's Association.",
"\n\nRedbird's pottery was typically a highly polished redware painted with designs in black slip. ",
"She built her pots with the paddle-and-anvil technique rather than a coil method. ",
"Her method was developed by ancient Hohokam artisans and used local clay from the Gila Riverbed. ",
"Once the vessel had dried for several days, a red clay from the Superstition Mountains was liquefied in and applied. ",
"When that slip dried, it was burnished with a stone and then fired outside. ",
"When the firing had been completed and while the piece was still hot, geometric shapes were painted on it with a boiled mesquite-bark dye.",
"\n\nIn 1940, E. B. \"Ted\" Sayles took images of Redbird and her pottery making techniques. ",
"Sales, who was curator of the Arizona State Museum in Tucson, took the photographs to Abilene, Texas, for a show at the Abilene Fine Arts Museum. ",
"They were also featured in Arizona Highways Magazine in January 1948. ",
"From 1941 until her death, Redbird taught summer classes and exhibited her works at the Heard Museum of Phoenix, Arizona. ",
"She and Mary Juan also held pottery classes at Casa Grande.",
"\n\nIn 1949, Redbird served as an interpreter for Lenora S. M. Curtin in her study of the Pima people, By the Prophet of the Earth. ",
" Curtin described Redbird as one of the two best potters of the Maricopa and noted that she was also a skilled herbalist. ",
"Guy Acuff regarded Redbird and Lena Mesquerre as two of the best Maricopa potters. ",
"Paul Huldermann, founder of the Scottsdale National Indian Arts Exhibition; Tom Cain, curator of the Heard Museum; Dr. Carl Guthe, a one-time president of the American Museum Association; and Kermit Lee, an Arizona Indian art collector all described her as one of the very best Southwestern Native American potters, but Redbird herself thought that Mary Juan was better than she. ",
"She exhibited at fairs, museums, and gatherings such as the All-Indian Fair in Lake George, New York and the 1968 Tohono O'odham Powwow held at Casa Grande.",
"\n\nDeath and legacy\nAfter completing work on some pots, Redbird sat them out to dry and laid down to take a nap on August 10, 1971. ",
"The tree under which she was sleeping on the reservation fell on her and killed her.",
"\n\nA special display of Redbird's works was held shortly after her death at the Heard Museum. ",
"Redbird was inducted into the Arizona Women's Hall of Fame in 1985. ",
"In 2015, Redbird's work was shown along with other Arizona Native American potters' work in an exhibition at the Amerind Museum and Art Gallery.",
"\n\nReferences\n\nCitations\n\nBibliography\n\n \n\n and \n \n \n and \n \n\n \n \n\nCategory:1892 births\nCategory:1971 deaths\nCategory:Gila River Indian Community\nCategory:Maricopa\nCategory:Native American potters\nCategory:People from Maricopa County, Arizona\nCategory:Women potters\nCategory:20th-century ceramists\nCategory:American women ceramists"
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"Massive transfusion practices around the globe and a suggestion for a common massive transfusion protocol.",
"\nMassive transfusion, the administration of 10 to more than 100 units of red blood cells (RBC) in less than 24 hours, can be a life saving therapy in the treatment of severe injury. ",
"The rapid administration of large numbers of RBC, along with sufficient plasma and platelets to treat or prevent coagulopathy, is frequently a disorderly process. ",
"Patient care and collaborative research might be aided with a common protocol. ",
"The authors polled trauma organizations and trauma centers to find examples of massive transfusion protocols. ",
"The goals and ease of use of these protocols were evaluated. ",
"Massive transfusion protocols exist at a relatively small number of large and well-organized trauma centers. ",
"Most of these protocols are designed to treat pre-existing and/or ongoing coagulopathy. ",
"The evidence would suggest that prevention of coagulopathy is superior to its treatment. ",
"Simple ratios such as 1:1:1 RBC:plasma:platelets have the benefit of ease of use and the relatively higher plasma and platelet doses appear to be associated with improved outcome. ",
"Such a standard protocol can foster multicenter research on resuscitation and hemorrhage control. ",
"The fixed volume ratios might allow the number and rate of administered units of RBC to be used as surrogates for blood loss and primary treatment effect."
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"Zandvoort, 2000\n\nDat zijn erfenis tot problemen gaat leiden, staat bij de dood van Karel Kramer – meneer Kramer, ook voor intimi – wel vast.",
"\n\nBij zijn begrafenis staan twee weduwes naast het graf, op een heuvel van de lommerrijke begraafplaats Westerveld bij het Noord-Hollandse Driehuis. ",
"Twee vrouwen met wie Kramer trouwde, kinderen kreeg en in een echtscheiding belandde. ",
"De weduwes loeren naar elkaar. ",
"Na zijn dood zullen ze 15 jaar lang een verbitterde strijd voeren om de erfenis. ",
"En om de vraag van wie meneer Kramer het meest gehouden heeft.",
"\n\nDe erfenis zelf is net zo problematisch. ",
"Kramer heeft een vastgoedbedrijf gebouwd rond een gat in de wet dat hij zelf heeft ontdekt en waar banken en rechters zich tot op de dag van vandaag geen raad mee weten.",
"\n\nMet de erfenis van meneer Kramer is, kortom, van alles mis.",
"\n\nDuitse grens, 1968\n\nHuberta Burgers is bloednerveus. ",
"Ze heeft zich door haar vriend laten overhalen om een auto vol smokkelwaar de grens over te rijden. ",
"In het bos bij Bentveld hebben ze in de vroege ochtend met z’n tweeën een huurauto volgeladen. ",
"Maar nu staat ze daar, 23 jaar oud, helemaal alleen bij de douane, met een kofferbak vol zilveren guldens en rijksdaalders. ",
"Ze heeft het benauwd.",
"\n\nDe zilveren muntjes die Huberta Burgers voor Karel Kramer naar Duitsland smokkelde. ",
"Foto NRC\n\nWat gaat ze doen in Duitsland, wil de douanier weten. ",
"Huberta, jong en knap, stamelt, glimlacht en mag doorrijden. ",
"Haar hart bonkt.",
"\n\nHet is haar vriend, de tien jaar oudere Karel Kramer uit Zandvoort, die de smokkelroute heeft uitgedokterd. ",
"Maandenlang rijden ze zakken vol Nederlands geld naar Duitsland, waar het wordt omgesmolten. ",
"Het zilver in de munten is meer waard dan de munten zelf. ",
"Soms stuurt hij haar alleen. ",
"Huberta is hopeloos verliefd en laat zich graag meeslepen in de avonturen die haar imposante, charismatische vriend bedenkt. ",
"Ze leert zo veel van hem.",
"\n\nDe smokkelroute levert Kramer in een paar maanden tijd misschien wel een miljoen gulden op. ",
"Zwart geld, dat hij in Zwitserland stalt. ",
"Daar is het uit zicht van de Belastingdienst, maar ook moeilijk te gebruiken. ",
"Hij zint op een nieuw plan.",
"\n\nZandvoort, 2017\n\nEen vrouw doet aarzelend de deur open van een rijtjeshuis in Zandvoort. ",
"Ze heet Ingrid van Poeke, ze woont hier met haar vrouw Angelica Scheer. ",
"Het huis is van hen, vertelt ze, maar de grond onder de woning niet. ",
"Die huurt ze van de ‘Stichting Vastgoed Beheer Nederland’. ",
"Particuliere erfpacht heet die constructie.",
"\n\nVan Poeke zucht. ",
"Ze woont hier fijn, maar kan de maandlasten bijna niet meer betalen. ",
"Zij is ziek geworden, waardoor het financieel allemaal heel krap is. ",
"En dan is er de kwestie met die man die opeens op de stoep stond.",
"\n\nIn het erfpachtcontract dat ze bij de koop argeloos tekende stond dat ze elk jaar 680 euro moesten betalen voor het gebruik van de grond – best redelijk. ",
"Maar kort na de verhuizing stond er opeens een net geklede en zorgvuldig gecoiffeerde man voor de deur. ",
"Hij heette Roderick en was van de vastgoedstichting. ",
"Hij wilde over de erfpacht praten, zei hij.",
"\n\nIn het contract stond dat de stichting die elke tien jaar naar eigen believen mocht verhogen. ",
"En binnenkort zou die van 680 naar 6.000 euro per jaar gaan, zei Roderick. ",
"Maar hij kon wel wat regelen. ",
"In een hoek van de kamer ging hij druk bellen met ‘de baas’. ",
"Toen hij ophing zei hij dat als ze direct zouden tekenen, hij de canon de komende tien jaar op slechts 4.000 euro per jaar kon houden. ",
"Overdonderd en bang voor nog meer kosten zetten de vrouwen hun handtekening.",
"\n\nBinnenkort loopt de termijn van tien jaar af. ",
"De vrouwen vrezen dat Roderick dan weer voor de deur staat met een volgende exorbitante verhoging. ",
"Dat kunnen ze echt niet betalen. ",
"Verhuizen kunnen ze evenmin, het huis is zo goed als onverkoopbaar. ",
"Sinds 2011 financieren de banken vrijwel geen huizen met particuliere erfpacht meer.",
"\n\nZandvoort, 1970\n\nNa de zilversmokkel heeft Karel Kramer een nieuw plan om rijk te worden. ",
"Hij handelt op kleine schaal in panden in Zandvoort en Haarlem en nu heeft hij iets interessants afgekeken van de gemeente Amsterdam. ",
"Erfpacht.",
"\n\nHet idee, vertelt hij aan Huberta: ik verhandel het huis, maar houd de grond. ",
"Voor het gebruik daarvan vraag ik jaarlijks een bedrag – de canon. ",
"Ik begin laag en schroef de bedragen gaandeweg op. ",
"Dat is straks een mooie pensioenvoorziening. „",
"Had-ie helemaal zelf bedacht”, zegt Huberta later met lichte trots. „",
"Hij was een echte zakenman.” ",
"Kramer vraagt zijn notaris of er nog iets in de wet staat dat dit verbiedt. ",
"Nee.",
"\n\nTrouwfoto van Karel Kramer met Huberta. ",
"Foto familie-archief\n\nKramer, kapiteinszoon en Nyenrode-alumnus, is een behendig handelaar. ",
"Al gauw staan er tientallen stukken grond, ‘blote eigendommen’, op de balans van zijn vastgoedbedrijven. ",
"Er komen meer panden bij, meer erfpachten, het geld stroomt binnen.",
"\n\nMet het geld komen de problemen. ",
"De jonge Huberta betrapt haar man met andere vrouwen in het echtelijk bed. ",
"Kramer stort zich in het Amsterdamse nachtleven, steeds vaker komt hij ’s nachts niet thuis. ",
"Wat doe je daar toch, vraagt ze. ",
"De huur innen, zegt hij dan. ",
"In de kastjes in huis bewaart hij rare poeders. ",
"Maar elke keer laat ze zich overhalen toch bij hem te blijven.",
"\n\nZe houdt van Kramer. ",
"Van zijn bravoure, zijn charme. ",
"Zonder hem wordt het leven onverdraaglijk saai en die erfpachten zorgen voor een riante hoeveelheid geld. „",
"Ik was verblind”, zegt ze later. ",
"Tegen beter weten in trouwt ze in 1973 met hem. ",
"Ze rijden in een Jaguar naar de plechtigheid. ",
"Ze krijgen twee zoons.",
"\n\nZandvoort, 2017\n\nOm de hoek bij Ingrid en Angelica woont Cees Leek, met z’n vrouw. ",
"Ook hij zit met erfpacht. ",
"Toen hij in 1970 zijn woning kocht moest hij jaarlijks 85 gulden overmaken naar zijn dorpsgenoot Karel Kramer, de eigenaar van de grond onder zijn huis. ",
"Voortdurend probeerde Kramer de pacht te verhogen. ",
"Eind jaren 70 ging die naar 600 gulden.",
"\n\nDe oude Kramer herinnert hij zich wel. ",
"Zijn dochter paste wel eens op de vier kinderen van diens tweede vrouw. ",
"Zelf heeft hij hem nooit ontmoet. ",
"Geen van de vijf, zes keren dat hij woedend aan zijn deur stond om over de steeds hoger wordende erfpacht te praten, heeft Kramer opengedaan. ",
"Er waren dorpsgenoten die z’n bloed wel konden drinken na zo’n verhoging, maar de man gaf geen krimp.",
"\n\nOm de hoek bij Ingrid en Angelica woont Cees Leek. ",
"Foto Olivier Middendorp\n\nInmiddels heeft Leek dezelfde problemen met die Stichting Vastgoed Beheer Nederland, die de stukken grond uit de erfenis van Kramer overnam. ",
"De stichting gaat verder waar Kramer stopte. ",
"Dezelfde Roderick die bij zijn buren op de stoep stond, wil nu zijn canon verdubbelen naar 2.610 euro per jaar. ",
"Maar ook al dreigt de stichting met uithuiszetting, dat gaat Cees Leek niet betalen.",
"\n\nIn september zitten Cees Leek, zijn advocaat en nog twee gedupeerde huiseigenaren daarom in de rechtbank Amsterdam tegenover vastgoedhandelaar Roderick. ",
"Zijn compagnon bij de vastgoedstichting, fiscalist Erik Bos, is er niet. ",
"Roderick is niet op z’n gemak. ",
"NRC berichtte kort voor de zitting over een grote faillissementsfraudezaak rond Harry Hilders, een steenrijke vastgoedbons uit Den Haag. ",
"Hij is de Roderick van P. uit het stuk, een van de hoofdverdachten. ",
"De zitting verloopt emotioneel. ",
"De rechter zegt dat hij het systeem van particuliere erfpacht „iets van een Russische roulette” vindt hebben.",
"\n\nZandvoort, 1985\n\nDe conflicten tussen Karel Kramer en zijn erfpachters verbleken bij het gevecht dat zijn weduwen over de erfpachtcontracten uitvechten. ",
"De kiem daarvoor legt Kramer zelf in 1985, als hij van Huberta scheidt. ",
"Die woont dan – op zijn kosten – met haar zoons in Zuid-Frankrijk. ",
"Daar is ze, zo voelt ze dat, na jaren ontrouw en leugens „volledig op een zijspoor” gezet.",
"\n\nDan komt Milcah, een flamboyant, goedlachs meisje van Surinaamse afkomst, Kramers leven binnen. ",
"Milcah is 17 wanneer ze de dan 49-jarige Kramer op Koninginnedag in Amsterdam tegenkomt, op een feestje in één van zijn panden op de Wallen. ",
"Ze valt niet op hem, veel te oud. ",
"Maar Kramer is wel in haar geïnteresseerd en doet een voorstel. ",
"Of ze hem niet thuis in Zandvoort wil helpen met de administratie? ",
"Erfpachtcanons uitrekenen, achterstanden bijhouden? ",
"Dat doet ze. ",
"Ze herinnert zich nog de pachters die de voordeur van het woonhuis kwamen intrappen, zo boos waren ze als de canon omhoog ging. ",
"Snapt ze wel, „die mensen schrokken zich natuurlijk wild”.",
"\n\nMilcah, graag stads gekleed in korte rokjes en met hoge laarzen, is altijd beschikbaar. ",
"Als Kramer zijn zoons in Frankrijk bezoekt, gaat ze mee „als kindermeisje”. ",
"Tot afschuw van Huberta die denkt dat haar ex een piepjonge scharrel heeft, of erger, een prostituee meeneemt.",
"\n\nHet leven van Kramer is in die jaren een chaos. ",
"Hij gebruikt drugs en er altijd hangen er vrouwen om hem heen, van alle leeftijden. ",
"Bij eentje verwekt Kramer nog een kind. ",
"Maar toch blijft Milcah. ",
"Ze vindt Kramer soms beangstigend – je moet geen ruzie met ’m krijgen – maar ook charismatisch, imposant en rijk. ",
"In 1990 trouwt ze met hem en ze krijgen vier kinderen.",
"\n\nTrouwfoto van Karel Kramer met Milcah.",
"\n\nFoto familie-archief Karel en Milcah Kramer en hun vier kinderen.",
"\n\nFoto familie-archief Karel en Milcah Kramer, bij hun huwelijk in 1990 (links) en met hun vier kinderen\n\nFoto familie-archief\n\nOver wat er daarna gebeurt, bestaan twee versies, één van Milcah en één van Huberta.",
"\n\nMilcahs versie gaat zo. ",
"Na een aantal jaar huwelijk wordt ze verliefd op een Egyptenaar, een knappe vent. „",
"Mijn eigen Dodi al Fayed.” ",
"In 1998 scheidt ze van Kramer, om met de Egyptenaar te trouwen. ",
"Ze blijft wel bij Kramer wonen, „voor de kinderen”.",
"\n\nDan wordt Kramer ziek, hij krijgt hersentumoren en het gaat snel. ",
"Een paar maanden voor zijn dood scheidt Milcah van haar Egyptenaar, om een krappe twee weken erna opnieuw met Kramer te trouwen op het stadhuis van Zandvoort. ",
"Rechtbankstukken melden dat op 24 augustus 2000 een huwelijksakte is getekend. ",
"De volgende dag wordt Milcah bestuurder van de bedrijven waarin Kramer zijn tientallen erfpachtcontracten heeft ondergebracht, daar tekent hij zelf voor.",
"\n\nEen week daarna maakt Kramer zijn laatste testament op. ",
"Daarin laat hij alle bezittingen, ook de stukken grond met erfpacht, aan zijn echtgenote over. ",
"Op 27 oktober overlijdt hij. ",
"Volgens Milcah wilde Kramer het zo, omdat hij „voor haar en de kinderen wilde zorgen”.",
"\n\nMaar er bestaat een andere versie van deze gebeurtenissen.",
"\n\nBiscarosse, 2017\n\nHuberta Burgers, 72 jaar, rangschikt chocolaatjes op een glazen tafeltje, puur en melk. ",
"Buiten is het dik 20 graden. ",
"De zon schittert in het water van het zwembad, maar de glazen schuifpui blijft dicht: „Veel te fris”. ",
"Ze is gewend geraakt aan Zuid-Franse temperaturen, ze wil nooit meer naar Nederland. ",
"Ze woont hier met haar nieuwe man Alain, haar twee zoons wonen in de buurt.",
"\n\nWeduwe Huberta Burgers: „Kramer heeft ooit tegen mij gezegd: je bent de enige vrouw van wie ik heb gehouden.”. ",
"Foto NRC\n\nEén voor één legt ze de bewijsstukken van haar levensverhaal, dat ze optekende in haar sleutelroman Remark vs Remark, op tafel. ",
"Eén: een zak met zilveren muntjes die ze voor Kramer naar Duitsland smokkelde. ",
"Twee: lange lijsten met de stukken grond met particuliere erfpacht. ",
"Drie: het rapport van een grafoloog, waaruit blijkt dat Kramers handtekening is vervalst, in de weken voor zijn dood.",
"\n\nHuberta’s versie van de gebeurtenissen luidt als volgt. ",
"Als de spilzieke, wulpse Milcah erachter komt dat de vader van haar kinderen ziek is, gooit ze het op een akkoordje met haar Egyptische minnaar. ",
"Zij gaat van hem scheiden, neemt een andere man in plaats van Kramer mee naar het gemeentehuis, zorgt zo dat er een vervalste handtekening op de trouwakte komt, wordt met nog een vervalste handtekening bestuurder van Kramers bedrijven, wacht tot hij zijn laatste adem uitblaast, strijkt de erfenis op en deelt die met de Egyptenaar. ",
"Listig, lucratief, simpel.",
"\n\nHuberta’s versie leest als een detectiveroman. ",
"En er zijn feiten die haar verhaal steunen. ",
"De Kamer van Koophandel schrapt Milcah drie jaar na Kramers dood als bestuurder van diens bedrijven, vanwege problemen met de handtekening. ",
"En na jaren van procederen oordeelt de rechter van rechtbank Haarlem op basis van een grafologisch rapport dat de handtekening op de huwelijksakte evenmin die van Karel Kramer is. ",
"En dat Milcah strafrechtelijk vervolgd moet worden wegens valsheid in geschrifte.",
"\n\nDe gebruikte handtekening lijkt zo weinig, zegt de grafoloog, dat je het niet eens een imitatie kan noemen. ",
"In het vonnis oordeelt de rechter dat er tussen Milcah en wijlen Karel Kramer „op 24 augustus 2000 geen huwelijksvoltrekking heeft plaatsgevonden”.",
"\n\nBoven: de vervalste handtekening van Kramer op de huwelijksakte van het tweede huwelijk tussen Milcah Bolwerk en Karel Kramer.",
"\n\nOnder: het oordeel van de rechter over de vervalste handtekening onder de huwelijksakte.",
"\n\nBeeld\n\nOok de Egyptische ex van Milcah stapt naar de rechter. ",
"Hij zwaait met een document, waarop Milcah verklaart dat ze hem bijna een half miljoen verschuldigd is. ",
"Een bewijs voor het akkoordje tussen hem en Milcah, vindt Huberta. ",
"Ook hij krijgt gelijk van de rechter, Milcah moet betalen.",
"\n\nHuberta is moe van vijftien jaar procederen, zegt ze in de Zuid-Franse zon. ",
"Kramers erfenis is inmiddels verdeeld over de zeven kinderen en Milcah, die tóch als erfgenaam is aangewezen. ",
"Huberta is ontevreden over de uitkomst. ",
"Milcah was toch niet getrouwd? „",
"Er is geen recht gedaan.” ",
"Milcah en haar ex hadden vervolgd moeten worden, hoe kunnen ze hier mee wegkomen?",
"\n\nHaarlem, 2017\n\nOp het naambordje van een galerijflat aan de rand van Haarlem staat de naam Kramer. ",
"Zo noemt Milcah zich nog steeds. ",
"Haar flat is schemerig, aan de muur hangt een groot, donker schilderij met een Romeinse soldaat dat ooit van Kramer was. ",
"In een hoekje staan dozen met pakken spacecakebeslag – een handeltje van haar zoon. ",
"Dat loopt niet zo lekker; klanten snappen niet dat de wiet niet is bijgeleverd. ",
"Hij en z’n broer roken een joint op het balkon.",
"\n\nWeduwe Milcah Bolwerk: „Het was zo’n imposante man. ",
"Ik zou wel naast ’m begraven willen worden.” . ",
"Foto Olivier Middendorp\n\nMilcah laat zich op de enorme bank zakken. ",
"Wat vindt ze van het verhaal van Huberta? ",
"Ze lacht. „",
"Huberta is gewoon jaloers.” ",
"Kramer koos voor haar. ",
"En bovendien: het is haar verdienste dat er überhaupt een erfenis is. ",
"Zonder haar stabiliteit had Kramer alles verbrast: „Huberta weet niet dat ik hem al die jaren van de drugs heb gehouden. ",
"Ik heb hem gered.”",
"\n\nZe is echt twee keer met hem getrouwd, zegt ze. ",
"Dat de rechter de laatste keer de handtekening vervalst vond, dat was gewoon pech. ",
"Misschien had ze meer bewijzen en tekstfragmenten van Kramer moeten inleveren bij haar advocaat. ",
"Maar hij was ziek, hij zat onder de pillen!",
"\n\nEn hoe zit het met die knappe Egyptenaar? ",
"Milcah zucht. „",
"Ik weet niet waarom ik met hem ben gegaan.” ",
"Het klopt dat er maar twee weken zaten tussen de scheiding van haar Egyptenaar en het tweede huwelijk met Kramer, zegt ze. ",
"Maar Kramer wilde het voor zijn dood goed regelen en daarvoor was hertrouwen het handigst. ",
"Haar Egyptische man vond dat ook een goed idee, ook al wilde hij helemaal niet scheiden.",
"\n\n„Hij dacht natuurlijk: straks hebben we veel geld, dan kunnen we samen wat opbouwen.” ",
"Ze schatert. „",
"Maar daar had ik geen zin in!” ",
"Ze ging niet naar hem terug. ",
"Dat ze de Egyptenaar uiteindelijk een half miljoen euro heeft betaald, wijt ze aan een moment van psychische zwakte. ",
"Toen heeft ze een keer een schuldbekentenis ondertekend, waarvan „die geldwolf” heeft geprofiteerd.",
"\n\nNog steeds bezoekt ze Kramers graf als ze zich slecht voelt, afgelopen weekeinde nog. ",
"Dat helpt haar. „",
"Hij was zo’n imposante man, hij heeft zelfs nog eens een inbreker doodgeschoten. ",
"Dat maakte hem interessant.” ",
"Ze zou wel naast ’m begraven willen worden, maar ze weet dat Huberta de grafrechten bezit. „",
"Die wil dat nooit.”",
"\n\nEn Huberta? ",
"Die treurt nog steeds over hoe het tussen haar en Kramer is gelopen. ",
"Waarom koos hij voor deze chaos, deze destructie? ",
"Zijn enige gelukkige momenten in zijn leven waren met mij, zegt ze. ",
"Het had zo anders kunnen lopen. ",
"Ze staat aan haar tafel in Zuid-Frankrijk, haar ogen glanzen: „Hij heeft ooit tegen mij gezegd: je bent de enige vrouw van wie ik heb gehouden.”",
"\n\nAmsterdam, 2017\n\nEn nu? ",
"Cees Leek wacht nog steeds op de uitspraak van de Amsterdamse rechter over de particuliere erfpacht. ",
"Roderick van P. laat via zijn advocaat weten niet te willen reageren op vragen.",
"\n\nDe zeven kinderen van Kramer hebben elk anderhalve ton gekregen uit de erfenis, vooral geld dat verdiend is met die particuliere erfpacht. ",
"Dat had veel meer kunnen zijn. ",
"De erfpachtcontracten werden voor een schijntje – 1,7 miljoen euro – doorverkocht aan Roderick van P., die profiteerde van de ruzie rond de erfenis. ",
"De zoons van Huberta staken het geld in huizen en investeringen. ",
"Twee zoons van Milcah kochten er bitcoins voor. ",
"De koers is zo hard gestegen dat één volgens haar al miljonair is, de ander is halverwege. ",
"Het is de nieuwe erfpacht, lacht Milcah. „",
"Ze worden slapend rijk, net als hun vader.”",
"\n\nReageren? ",
"Onderzoek@nrc.nl\n\nCorrectie (20 november): In een eerdere versie van dit verhaal stond dat begraafplaats Westerveld bij Santpoort ligt, dat moet Driehuis zijn. ",
"Dit is aangepast.",
"\n\nHuis met particuliere erfpacht is nauwelijks te verkopen\n\nParticuliere erfpacht heeft zich ontwikkeld tot een maatschappelijk probleem. ",
"De reden: Nederlandse banken zijn sinds 2011 heel terughoudend met het verstrekken van hypotheken voor huizen waar particulier erfpacht op rust. ",
"Daardoor zijn deze huizen zeer moeilijk verkoopbaar geworden. ",
"Dit beleid is in 2011 vastgelegd in de „Bancaire richtlijn financierbaarheid erfpachtrechten” van de Nederlandse Vereniging van Banken (NVB). ",
"De richtlijn is opgesteld omdat in bepaalde gevallen de jaarlijkse canons onbeperkt verhoogd kunnen worden – zoals in de contracten die Karel Kramer verzon en die nu worden geëxploiteerd door de Stichting Vastgoed Beheer Nederland. ",
"Op diverse plekken in Nederland wordt geprocedeerd over particuliere erfpacht, op initiatief van huizenbezitters in financiële problemen. ",
"Jeroen Corten en Eduard de Geer van kantoor Corten De Geer Advocaten zijn in erfpacht gespecialiseerd. ",
"Zij schatten dat tienduizenden huizenbezitters last kunnen krijgen van hun particuliere erfpacht. ",
"Honderden huizenbezitters, denken ze, zitten in acute problemen. ",
"Momenteel loopt in Amsterdam een rechtszaak tegen Stichting Vastgoed Beheer Nederland, dat de stukken grond met erfpacht van Karel Kramer overnam. ",
"In een vergelijkbare rechtszaak in Amsterdam over erfpachtvoorwaarden die problemen met financiering opleverden kreeg de erfpachter in oktober gelijk van de rechter. ",
"De voorwaarden werden door de rechter buiten werking gesteld.",
"\n\nEen versie van dit artikel verscheen ook in NRC Handelsblad van 18 november 2017"
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"He longed for the fury of the mating fever.",
"\nShe had the magic to touch his dragon heart.",
"\nUnlike the other Nox Incendi dragons, Torch Dorado never sought his treasure, the hoard that would bring peac..."
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"A/N: Everything you recognize belongs to JKR. ",
"This is my first attempt at writing Lily and James the first, so hopefully it didn't turn out too badly. ",
"This collection of stories is going to feature several HP characters, and each chapter is its own piece, so this is all the Lily/James I have.",
"\n\nBegin the Christmas fluff!",
"\n\n“Hurry up, James, we'll be late!”",
"\n\nLily Evans Potter stood impatiently at the door with her infant son bundled up in her arms. ",
"She glanced down at him. ",
"Only his little face was visible in the hat, snowsuit, and blanket that were keeping him warm. ",
"He was asleep against her shoulder. ",
"At only five months old, little Harry spent a great deal of his time sleeping. ",
"She hoped he would wake up when they got to the church.",
"\n\nJames came stumping down the stairs in a pair of Wellies and a heavy coat. “",
"I could be listening to Quidditch right now on the wireless, you know. ",
"Harry's too little to have any idea what's going on. ",
"Can't we just-”\n\n“No.” ",
"She rolled her eyes at her husband in exasperation. “",
"I want Harry to have a proper first Christmas. ",
"Get a move on.”",
"\n\nThe church wasn't far from their little cottage, and they strolled down the snow-covered road together. ",
"James seemed to relax as they walked, forgetting about his Quidditch match, and put an arm around Lily, reaching up to tickle Harry's chin with his other hand. ",
"She could hear the choir singing in the church, the carol faint on the night air, growing stronger as they got closer.",
"\n\nStill, still, still, one can hear the falling snow. ",
"For all is hushed, the world is sleeping, Holy Star its vigil keeping. ",
"Still, still, still, one can hear the falling snow.",
"\n\nThe children of the parish were doing their yearly Nativity Play, and Lily and James sat at the back to watch. ",
"They weren't very good, but that was a traditional part of Nativity Plays, and Lily smiled at the little ones as they struggled to say their lines, or said them in overly loud, nervous voices. ",
"They were all trying so hard, God love them.",
"\n\nJames seemed to find the entire thing very amusing, and Lily had to put her foot down hard over his to stop him laughing when the children stuttered over their lines.",
"\n\n“How will you feel when it's Harry up there messing up his lines?” ",
"she hissed, and that shut him up.",
"\n\nThe carol service followed the Nativity Play. ",
"James had never been to a carol service before, and didn't know the songs that were sung, but he stood next to Lily, holding Harry so that she could hold her candle and sing. ",
"Harry had finally woken up, and was looking around with wide green eyes, staring at his mother as she sang.",
"\n\n“Have we had enough proper Christmas yet?” ",
"James asked a few carols later. “",
"Harry's starting to fuss.”",
"\n\nLily reached over to her son, who immediately made a swipe for her finger and started gnawing on it. ",
"He was cutting his first teeth, and went from zero to fussy ridiculously fast. ",
"She took the baby away from James, cuddling him close, and they left the church.",
"\n\nBathilda Bagshot was just coming in as they left. ",
"They stopped to talk for a few minutes; Bathilda loved children and doted on Harry. ",
"Harry did not like being delayed in the cold, and protested in a loud cry.",
"\n\n“Better get the little dear home,” Bathilda said fondly, shooing them out. ",
"She was leaning heavily on her cane, clutching a slightly mouldy fur coat tightly at her chest. ",
"Lily reminded herself to bring over a potion for Bathilda's painful joints.",
"\n\n“Happy Christmas,” Lily said as they left.",
"\n\n“Happy Christmas, my dears.” ",
"Bathilda waved to them and then hobbled into the church.",
"\n\nJames took Harry back as they walked, holding him against one shoulder and reaching out to take Lily's hand with his free hand. ",
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"Q:\n\nstrtok_r results in segmentation fault\n\nThis code is to parse a csv file, but it results in segmentation fault.",
"\nI could see the similar code here: Nested strtok function problem in C\nThey look same but my code results in segmentation fault. ",
"Why?",
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"= NULL) {\n\n user = atoi(data_point_attr);\n data_point_attr = strtok_r(NULL, \",\", &end_attr);\n item = atoi(data_point_attr);\n data_point_attr = strtok_r(NULL, \",\", &end_attr);\n rating = atoi(data_point_attr);\n strtok_r(NULL, \",\", &end_attr);\n input.push_back({user, item, rating});\n maxUser = max(maxUser, user);\n maxItem = max(maxItem, item);\n }\n data_point = strtok_r(NULL, \";\", &end_str);\n }\n return 0;\n}\n\nA:\n\nyour inner loop is not needed AND toxic to your program.",
"\nThe inner loop extracts 3 tokens, then continues, extract the 4th token but reaches NULL in the middle, and atoi is passed NULL: segfault.",
"\nYou only need one loop (added assert statements for sanity though):\n while(data_point !",
"= NULL) {\n char *end_attr;\n char *data_point_attr = strtok_r(data_point, \",\", &end_attr);\n\n user = atoi(data_point_attr);\n data_point_attr = strtok_r(NULL, \",\", &end_attr);\n assert(data_point_attr !",
"= NULL);\n item = atoi(data_point_attr);\n data_point_attr = strtok_r(NULL, \",\", &end_attr);\n assert(data_point_attr !",
"= NULL);\n rating = atoi(data_point_attr);\n strtok_r(NULL, \",\", &end_attr);\n input.push_back({user, item, rating});\n maxUser = max(maxUser, user);\n maxItem = max(maxItem, item);\n\n data_point = strtok_r(NULL, \";\", &end_str);\n }\n\nA better solution would be to use a real C++ solution to split the strings.",
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"The medical examiner ruled Sherin, who was from India, died from homicidal violence but did not release additional details, CNN affiliate KTVT reported. “",
"Based on the autopsy report we were able to determine we could seek capital murder in this case,” Johnson said Friday.",
"\n\nMathews previously was charged with injury to a child, a first-degree felony punishable with a maximum 99 years in prison,police in the Dallas suburb of Richardson said.",
"\n\nFriday’s indictment adds abandoning a child and tampering with evidence, second-degree allegations punishable by two to 20 years in prison.",
"\n\nThe girl’s adoptive mother, Sini Mathews, 35, faces one count of abandoning a child. ",
"That stems from the couple’s decision to leave the girl at home on October 6 while they went out to dinner with their biological child, according to the indictment.",
"\n\nCNN reached out to attorneys for the couple for comment, but received no reply.",
"\n\nAttorney David Kleckner said in November at a hearing about custody of the couple’s biological child that Wesley Mathews is “a good father, a loving man and loves his family.”",
"\n\nSini Mathews has maintained her innocence, KTVT has reported.",
"\n\nFather’s later story to police\n\nMathews had initially told authorities he made Sherin stand outside because she wouldn’t drink her milk, and she disappeared.",
"\n\nIn a second interview about two weeks after Sherin went missing, the father gave a different account. ",
"He told a detective that he had been trying to get Sherin to drink her milk in the garage, and she wouldn’t listen to him, the affidavit states. ",
"She then began drinking the milk.",
"\n\n“Wesley Mathews then physically assisted the 3-year-old in drinking the milk,” last year’s affidavit states. “",
"The 3-year-old began to choke. ",
"She was coughing and her breathing slowed. ",
"Eventually Wesley Mathews no longer felt a pulse on the child and believed she had died.”",
"\n\nThe father said he removed the body from the home, the affidavit says.",
"\n\nWesley Mathews was jailed on $1 million bond last fall. ",
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"Reading Time: 2 minutes\n\nBy Sherina Harris and Emma Sandri\n\n\n\nRyerson University plans to request a forensic audit of the Ryerson Students’ Union (RSU) finances, the university said in a statement posted Wednesday.",
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"\n\n\n\nPurchases included $2,280.89 to the club EFS Toronto, $2,507.18 at a Cineplex Rec Room in Toronto and $1,375.21 at Nick’s Sport Shop. ",
"There were also purchases of $190.97 and $117.52 to Long & McQuade in Toronto, $347.34 to Haze Lounge Inc. in Mississauga, $696.90 on an Airbnb and $613.60 to Bar Everleigh Toronto, among others.",
"\n\n\n\n“The University takes these allegations very seriously. ",
"Protecting the interests of students is of primary concern to the University,” said the statement.",
"\n\n\n\nPresident Mohamed Lachemi previously told The Eye the university could not launch an independent investigation, but said the BoD had the authority to do this. ",
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"\n\n\n\n“I’m taking this very seriously as a president,” he said, adding that the RSU is a separate entity from the university with its own governing body.",
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"Q:\n\nSaving state of html page on page refresh\n\nLike i mentioned in my other questions, I am building my own web application.",
"\nNow i have this application --> Here's Plunker! ",
"You can see it better here. ",
"Where i have a tab in the header and i can navigate through multiple pages and load its content.",
"\n<!",
"DOCTYPE html>\n<html>\n <head>\n <link rel=\"stylesheet\" href=\"style.css\">\n <script src=\"https://code.jquery.com/jquery-1.12.4.min.js\"></script>\n <script src=\"script.js\"></script>\n </head>\n<body>\n <a href=\"link1\">Link 1</a>\n <a href=\"link2\">Link 2</a>\n <div id=\"content\">\n <!-- ",
"Page content displays here --> \n </div> \n</body>\n</html>\n\n$(document).ready(function(){ \n $('a').click(function(e){\n var page = $(this).attr('href'); \n $('#content').load(page + '.html'); \n return false; // don't follow the link\n }); \n});\n\nIt is working fine! ",
"But i am having problems with saving the state of the page.",
"\nFor example if i am on page 2 and i refreshed the browser, the page will go back to its start state. ",
"How can i let stay on the current page on refresh.",
"\nI am very thankful for every solution or tip!",
"\n\nA:\n\nYou have to take advantage of browser's History API. ",
"On each content load, you have to push state to the history.",
"\nOn hard refresh, you have to parse the url and fetch the correct content.",
"\nOne thing to keep in mind with this approach is that you have to jump through hoops to make it easy for search engine crawlers to index all your \"pages\".",
"\nAnother approach is to use Turbolinks.",
"\nCheers. ",
"\n\n"
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"\nEnglish: \n3D Printing allows you to realize your imagination, going from zero to one.",
"\nIn this video,\nwe're going to demonstrate the use of Snapmaker 2.0 3D Printer by printing a vase.",
"\nIt will cover the whole process of 3D printing usage including Heated Bed Calibration,\nLoading Filament, Generating G-code and Printing,\npresenting you an easy way to create something useful, artistic or even profitable.",
"\nBefore starting, you need to make some preparations.",
"\nFirst, make sure that the 3D printing module,\nprint platform and print sheet are properly attached to your machine.",
"\nFetch the accessories and tools as illustrated.",
"\nIf this is your first time to use the 3D printing feature,\na guide will pop up on the touchscreen and guide you through the steps.",
"\n\nChinese: \n3D打印功能可以将你的想象化为现实，从0到1，实现创造\n本期视频中\n我们将通过打印一个花瓶，为你演示\nSnapmaker 2.0 3D打印功能的使用方法\n通过观看视频，你将了解如何调平热床\n装填材料、生成代码、打印作品\n轻松创作出或实用、或美观，甚至是\n具有商业价值的3D打印作品\n开始3D打印前，你需要做如下准备\n首先，确保3D打印模组\n3D打印工作平台和打印钢板已经正确地安装在机器上\n取出如图所示的物品和工具\n若是第一次启用机器的3D打印功能\n机器触摸屏将自动弹出新手引导，指引你完成全部操作\n\nEnglish: \nBut the guide will only pop up the first time you use the 3D printing feature.",
"\nYou can still access the guide later on by going to Settings - Guide\nFor regular use of the 3D printer, please follow this video tutorial to set up your machine.",
"\nBefore your first printing,\nyou need to calibrate the heated bed to ensure the print sticks to the bed properly.",
"\nAt the home page of the touchscreen, swipe to the left and tap Calibration button.",
"\nTap \"Start\",\nand the machine will run an auto-leveling process.",
"\nNow, the 3D printing module will probe the bed in a grid.",
"\nWhen the 3D printing module finally moves to and hovers over the center of the heated bed,\nset a proper Z Offset as instructed.",
"\nTake out the calibration card/ A4 paper and place it under the nozzle.",
"\nTap the \"Up\" and \"Down\" buttons\nto fine-tune the Z Offset until you feel a slight resistance when pulling the paper,\n\nChinese: \n但新手引导仅会在首次使用时自动弹出一次\n如有需要，亦可通过点击触摸屏上的\n设置 - 引导，重新开启该功能的新手引导\n而日常的3D打印功能使用，请跟随本视频教程了解和学习\n在开始首次打印之前\n你需要先手动调平热床，确保打印物品与热床粘着牢固\n进入主界面后，向左划动触摸屏，点击调平按钮\n选择 开始\n机器将进入自动调平模式\n此时，3D打印模组将将在多个位置测量\n喷嘴尖端与热床之间的距离\n当打印模组最终移动到热床中央并悬停时\n需要手动校准Z轴高度\n取出调平卡或一张A4纸，置于喷嘴与热床之间\n通过点击 上 和 下 按钮\n微调Z轴高度，直到抽动纸张时能够感受到轻微的阻力\n\nEnglish: \nand see a curl when pushing forward.",
"\nWhen you finish calibrating, save the changes.",
"\nIn this video, we take the provided PLA filament as an example.",
"\nHang the filament over the filament holder.",
"\nCut the curved end of the filament with the diagonal pliers,\nand insert the filament into the 3D printing module.",
"\nEnter the \"Control\" page,\nchoose \"Nozzle\" tab,\nand the nozzle will be heated to the preset temperature.",
"\nTap \"Load\" when it finishes heating,\nand gently push the filament into the 3D printing module\nuntil you feel the motor pulling the filament in.",
"\nFilament squeezed out of the nozzle means a successful loading.",
"\nClean the nozzle with the tweezer,\nthen return to the home page.",
"\nOr, you can open the front cover of the 3D printing module,\ndirect the filament at the feed hole\nand push it in manually until you see the filament coming out.",
"\nAt last, close the front cover,\n\nChinese: \n并且推动时，纸张产生褶皱\n调平完成后，点击 保存 ，确认更改\n这里，我们以附赠的PLA耗材为例进行演示\n先将耗材悬挂于耗材支架上\n使用斜口钳剪除耗材末端的弯曲部分\n然后将耗材插入3D打印模组中\n点击主界面的 控制 按钮\n选择 喷嘴 选项卡\n喷嘴将自动加热至设定的温度\n完成加热后，即可点击 加载\n并将耗材缓慢推入3D打印模组中\n在感觉到耗材被向下拉入时，即可停止推动\n此时，喷嘴处将有少许材料挤出，表明装载成功\n用镊子清理喷嘴处的材料\n返回首页即可\n你也可以拨动3D打印模组上的卡扣，打开前盖\n直接将耗材对准入口\n并手动推入，直到喷嘴处有材料挤出\n最后，盖上前盖\n\nChinese: \n用镊子清理喷嘴处的材料，返回首页即可\n接下来，在电脑上打开Snapmaker Luban软件\n点击 连接 下的 Wi-Fi 按钮\n刷新设备列表，在下拉菜单中选定你的机器\n发送连接命令\n在触摸屏点击 是 ，即可连接机器与电脑\n上传准备好的STL或OBJ格式的模型文件\n你可以自由调节模型的位置、大小和方向\n也可以选择相应的打印材料，使用默认参数\n或点击加号，新增材料，并自行设置相关参数\n根据需要，选择预设的三个打印模式\n也可进入 自定义 版块\n选定其中一个模式作为基础，点击加号，\n添加自定义打印方案\n精确设置各项参数\n\nEnglish: \nclean the nozzle, and return to the home page.",
"\nNext, start the Snapmaker Luban software on your computer.",
"\nClick the \"Wi-Fi\" button at the \"Connection\" area,\nrefresh the list and select your machine.",
"\nSend a connection request to your machine,\nthen tap \"Yes\" on the touchscreen to complete the connection.",
"\nUpload a model file in .stl or .obj format.",
"\nYou can move, rotate the model and adjust its position.",
"\nAnd choose a printing material to use the default settings,\nor click the \"Plus\" button to add and edit a new material profile.",
"\nFor the part of printing settings, 3 recommended modes are provided.",
"\nYou can also enter the \"Customize\" area,\nchoose one mode as a basis, and click \"Plus\" button to create your own profile.",
"\nThen, every parameter can be set as needed.",
"\n\nEnglish: \nWhen the setting is done, click \"Generate G-code\" and choose \"Load G-code to Workspace\".",
"\nNow, send the G-code file to your machine via Wi-Fi.",
"\nTap \"Yes\" on the touchscreen to enter the preview page.",
"\nThe printing can also be accomplished with USB disk.",
"\nClick \"Export G-code to File\" and save the file to your USB disk.",
"\nInsert the disk into the controller,\nselect \"File\" and switch to \"USB\" Tab,\nthen find and open your G-code file.",
"\nNow, tap \"Start\" to begin your printing as everything is ready.",
"\nWhen the printing completes,\nwait until the temperatures of the nozzle and heated bed drop to the normal level.",
"\nFinally, detach the print sheet,\nand bend it slightly outward to remove the print.",
"\nYou can also insert the palette knife between the print sheet and the print,\npry it gently to complete your removement.",
"\n\nChinese: \n完成设置后，点击 生成G代码 ，并选择 将G代码加载到工作区\n将G代码通过Wi-Fi发送至机器\n随后，在触摸屏点击 是 ，即可进入打印预览页面\n除了使用Wi-Fi，你还可以通过U盘进行打印\n生成G代码后，将G代码导出到文件，并储存至U盘\n将U盘插入机器控制器\n在触摸屏主界面选择 文件 ，点击 USB 选项卡\n找到并打开G代码文件\n现在，一切准备就绪，点击 开始 按钮，即可进行3D打印\n打印完成后\n等待喷嘴及热床温度下降至室温\n最后，拆下钢板\n将其与物品连接处稍微向外弯折，打印物品便会与钢板脱离\n如果打印物品较小，可以取出铲刀，将刀尖慢慢插入物品与钢板的缝隙中\n轻轻撬动，也可轻松取下打印物品\n\nEnglish: \nThank you for watching!",
"\n\nChinese: \n感谢观看！",
"\n"
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"Field of the Invention\nThe subject disclosure relates to tunable antimicrobial-loaded polymer base formulations having a two-part, rapid and sustained, delivery of a drug.",
"\n2. ",
"Background of the Related Art\nIn the United States, there are millions of infections per year from resistant bacteria. ",
"Some of these infections even result in death. ",
"The monetary costs associated with these infections are billions of dollars, not to mention the burden of the actual infections themselves. ",
"In burn victims, wound infection is particularly troublesome as it is the leading cause of death in ICUs for burn victims, in the United States. ",
"Some of the bacterial or fungal pathogens are Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA) and Candida albicans. ",
"\nCurrent treatments are usually some combination of sterile gauze, systemic drug administration, and hydrogels to promote wound healing, provide moisture, and soothe the wound. ",
"For example, see U.S. Pat. ",
"No. ",
"4,931,279 to Bawa et al. ",
"However promising, these treatments have limitations. ",
"One such treatment is silver sulfadiazine, which is often the active antimicrobial agent in existing topical therapies. ",
"Silver sulfadiazine has high toxicity for keratinocytes and fibroblasts, key wound healing cells, thus preventing optimal wound healing. ",
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"Loss of chromosome 1p/19q in oligodendroglial tumors: refinement of chromosomal critical regions and evaluation of internexin immunostaining as a surrogate marker.",
"\nLoss of chromosome 1p/19q in oligodendrogliomas represents a powerful predictor of good prognosis. ",
"Expression of internexin (INA), a neuronal specific intermediate filament protein, has recently been proposed as a surrogate marker for 1p/19q deletion based on the high degree of correlation between both parameters in oligodendrogliomas. ",
"The aim of this study was to assess further the diagnostic utility of INA expression in a set of genetically well-characterized oligodendrogliomas. ",
"On the basis of a conservative approach for copy number determination, using both comparative genomic hybridization and fluorescent in situ hybridization, INA expression as a surrogate marker for 1p/19q loss had both reduced specificity (80%) and sensitivity (79%) compared with respective values of 86% and 96% reported in the previous report. ",
"The histologic interpretation and diagnostic value of INA expression in oligodendrogliomas should therefore be assessed with greater caution when compared with 1p/19q DNA copy number analysis. ",
"In addition, DNA copy number aberrations of chromosomes 10, 16, and 17 were detected exclusively in 1p/19q codeleted samples, suggesting that other regions of the genome may contribute to the 1p/19q-deleted tumor phenotype inthese samples."
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"Outline of the Current Survey of Production - Japan\n\nThis document describes the aspects of the Current Survey of Production in Japan.",
"\n\nThe Current Survey of Production has been conducted since 1948 on a monthly basis to monitor month-to-month changes in manufacturing and mining outputs in Japan and obtain basic data on the industries available for policymakers. ",
"The Current Survey of Production, the eleventh statistics designated according to the Statistics Law, is the only monthly survey that monitors industrial outputs in Japan. ",
"Since the first survey in 1948 it has been used by a range of government agencies, researchers, businesses, and other organizations and individuals. ",
"The survey covers around 1,800 items of goods among those under the charge of the Ministry of Economy, Trade and Industry. ",
"For the items, outputs, shipments, and inventories are reported. ",
"Raw materials, manufacturing facilities, and workforce used for the outputs are also surveyed. ",
"A survey period starts on the first day of a month and ends on the last day. ",
"Reports are available both in print and on the website of the METI."
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"[Haptoglobin in domestic mammals. ",
"V. Plasma haptoglobin level in cattle under pathological conditions].",
"\nThe haptoglobine concentration in the blood plasma of cattle tends to rise to more than 10 mg/100 ml in the presence of acute inflammation anywhere in the organism. ",
"They were 40 mg/100 ml and above in the presence of traumatic reticuloperitonitis. ",
"The absence of haptoglobin multiplication in the plasma is a high-probability indicator to the absence of that inflammatory process. ",
"chronic inflammation will only in exceptional cases entail plasma-haptoglobin multiplication. ",
"Concentrations will not be pathologically increased in cattle with positive reaction to haematological testing for leucosis."
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"PSX Extreme\n\nSite Stats\n\nA Crack In Time Progress Report\n\nIf history is any indication, the next Ratchet and Clank title will be extremely polished, wonderfully entertaining, and a true gem for another PlayStation platform.",
"\n\nRatchet and Clank Future: A Crack in Time is one of the most anticipated action/adventure titles, and let's not forget that it'll be exclusive to the PlayStation 3. ",
"In the latest Full Moon Show podcast, we learn a bit more about the current progress of this promising title. ",
"First of all, the game will be playable at this week's GamesCom event and they will lift the lid on a new trailer during Sony's press conference, too. ",
"Insomniac won't be there, but they're going to PAX in September and Brian Allgeier, creative director for the game, will introduce us to the all new weapons and gadgets we'll find in A Crack in Time. ",
"The project itself is in the \"final stages of development\" and should be ready to head into the manufacturing phase at some point in the near future. ",
"Right now, it's probably safe to say that we'll be seeing the game on store shelves on October 27, as promised. ",
"And if that does indeed happen, you can bet that it'll be a highly sought-after item for the holidays.",
"\n\nAs if October isn't full enough already. ",
"Well, at least we'll have a two-week grace period between the launch of Uncharted 2: Among Thieves (October 13) and A Crack in Time.",
"\n\nGood gravy gotta get cracking on finishing Quest for Booty (work's been awfully busy). ",
"I am so looking forward to playing ACiT. I was a late convert to the series. ",
"I didn't start playing the series until I saw one of my friends playing Going Commando and from that moment on I was hooked. ",
"I wonder what type of trophies it'll have.",
"\n\nMan, R&C, Uncharted 2, and Tekken6?!!! ",
"Damn you October! ",
"I can't handle it! ",
"Well my wallet can't, plus borderlands next month and MUA2. ",
"Must every year get better and better?!!!!!! ",
"I'm loving the cracked out kids to comment first tonight.",
"\n\ni hope insomniac well sony dont follow their usual suit and release R&C a month after its out in the US, they REALLY pissed me off when they did it for resistance 2.on a lighter note i watched a interview yesterday about ACIT and insomniacs new development team, and they reminded us how many games they have just on the ps3.in 4 years they have released 5 titles, JESUS CHRIST thats amazing.think about it, PD have spent how long on GT5?in roughly the same time insomniac have managed to create 5 and release 4 games now thats impressive.id love to see PD or GG or quantic dream or R* or any other studio really. ",
"when it comes to quality insomniac are second to none, but for the icing on the cake their always the first to finish to.i would have to say the worlds best development studios are.1st naughty dog2nd Insomniac.3rd sucker punch.",
"\n\nDo I have to play Quest for Booty before playing this one? ",
"I'm in the middle of Tools of Distruction right now and tried to download Quest for Booty but had problems and had to fight with Sony to get my 15 bucks back. ",
"I don't want to try and download it again, worried I might have the same results. ",
"Over a weeksof troubleshooting with Sony got no where and trying to get my money back was like pulling teeth. ",
"Don't want to go through that again.",
"\n\nthere not seperate story lines, quest for booty explains what hapend to clank and to some extent why he dissapeared.you dont have to play it to understand the story line to ACIT but it would help.just check arround your local game stores it should be on bluray disk by now, or even check ebay."
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"Significance Statement {#s1}\n======================\n\nEpileptogenic injuries disrupt adult neurogenesis, leading to the abnormal integration of adult-generated granule cells. ",
"The newborn cells exhibit a variety of pathologies, including dendritic abnormalities and migration defects. ",
"It was not known, however, whether all progenitors contributed equally to the accumulation of these abnormal cells or whether a distinct subset of progenitors was responsible. ",
"Here, we performed a clonal analysis study of progenitor cell activity following status epilepticus. ",
"Our results reveal that a small subset of progenitors produces the majority of ectopic granule cells, while cells with abnormal dendrites arise ubiquitously throughout the progenitor pool. ",
"Together, these findings demonstrate a newly understood complexity among progenitors in producing abnormal granule cells in epilepsy.",
"\n\nIntroduction {#s2}\n============\n\nHippocampal dentate granule cells (DGCs) are generated throughout life from progenitor cells located in the subgranular zone, a proliferative region located between the granule cell body layer and the hilus. ",
"A subset of progenitor cells in this region expresses the Gli1 transcription factor, a Krüppel family zinc finger protein activated by the sonic hedgehog signal transduction cascade ([@B1]; [@B43]). ",
"Sonic hedgehog is a key regulator of cell proliferation ([@B31]). ",
"Gli1-expressing type 1 progenitor cells are morphologically characterized by the presence of a radial process that projects into the dentate inner molecular layer. ",
"They exhibit the stem cell characteristics of self-renewal and multipotency, and give rise to intermediate progenitors (type 2 cells; transient amplifying cells), which, in turn, give rise to postnatally generated dentate granule cells. ",
"Type 1 cells can also give rise to astrocytes ([@B4]).",
"\n\nAdult-born DGCs are especially vulnerable to epileptogenic insults. ",
"Cells born in the weeks before and after an insult develop morphological and functional abnormalities ([@B44]; [@B24]; [@B63]; [@B40]; [@B50]). ",
"Following epileptogenic insults, adult-born DGCs populate the dentate hilus (hilar ectopic granule cells), a region they rarely occupy in normal animals ([@B52]). ",
"Afferent inputs to these ectopic DGCs are abnormal, and the cells can exhibit atypical bursting properties ([@B64]; [@B41]; [@B2]). ",
"DGCs with basal dendrites are also common in the epileptic brain, a feature typically absent from nonepileptic rodent DGCs. ",
"Basal dendrites are hypothesized to form recurrent circuits and promote hyperexcitability within the hippocampus ([@B48]; [@B54]).",
"\n\nAlthough it is well established that abnormal DGCs are derived from adult progenitor cells, it is not known whether all progenitors contribute equally to the production of abnormal cells, or whether distinct subsets of progenitors preferentially produce them. ",
"Answering this question will provide novel insights into the mechanisms underlying aberrant granule cell accumulation. ",
"Equal participation among progenitors suggests systemic changes in the factors regulating granule cell development, while unequal participation suggests regional disruption of neurogenic niches or intrinsic changes within individual progenitors. ",
"Here, we used a conditional Brainbow reporter line driven by an inducible *Gli1-CreER^T2^* promotor construct to trace the lineage of clones arising from Gli1-expressing granule cell progenitors in the pilocarpine model of epilepsy. ",
"Brains were rendered translucent using a novel clearing agent. ",
"Hippocampi were imaged in their entirety to identify and characterize groups of daughter cells, known as \"clonal clusters,\" each of which originates from a single labeled progenitor.",
"\n\nMaterials and Methods {#s3}\n=====================\n\nAnimals {#s3A}\n-------\n\nAll methods used involving animals were approved by the Institutional Animal Care and Use Committee of the Cincinnati Children\\'s Hospital Research Foundation and conform to National Institutes of Health guidelines for the care and use of animals. ",
"For the present study, hemizygous *Gli1-CreER^T2^* mice ([@B1]; <https://www.jax.org/strain/007913>) were crossed to mice homozygous for a *Gt(ROSA)26Sor^tm1(CAG-Brainbow2.1)Cle^*/J \"*Brainbow*\" reporter construct ([@B8]; <https://www.jax.org/strain/013731>) to generate double-transgenic *Gli1-CreER^T2^::Brainbow* mice. ",
"All animals were on a C57BL/6 background. ",
"A total of 30 double-transgenic mice were randomly assigned to the control or treatment \\[pilocarpine-induced status epilepticus (SE)\\] group for the present study. ",
"Postnatal tamoxifen treatment of these mice restricts CreER^T2^ expression to type 1 cells in the hippocampal subgranular zone ([@B1]; [@B40]; [@B22]). ",
"Tamoxifen-induced activation of Cre-recombinase causes random excision and/or inversion between multiple pairs of lox sites, leading to the expression of one of four possible different fluorescent proteins in progenitor cells and all their progeny ([@B34]). ",
"To facilitate morphological analyses, only cells expressing the cytoplasmic red fluorescent protein (RFP) or yellow fluorescent protein (YFP) were examined. ",
"Cells expressing cyan fluorescent protein (CFP) were excluded because morphological details were poorly revealed by this membrane-bound protein. ",
"GFP-expressing cells were not observed in any of the animals, consistent with prior work ([@B9]).",
"\n\nTamoxifen-induced cell labeling and pilocarpine treatment {#s3B}\n---------------------------------------------------------\n\nTo achieve sparse labeling of progenitor cells, mice were given three injections of tamoxifen (250 mg/kg, s.c.) ",
"on alternate days during postnatal week 7 ([Fig. ",
"1*A*](#F1){ref-type=\"fig\"}). ",
"At 8 weeks of age, all mice received methyl scopolamine nitrate in sterile saline solution (1 mg/kg, s.c.), ",
"followed 15 min later by either pilocarpine (420 mg/kg, s.c.; *",
"n* = 25) or saline solution (controls, *n* = 5). ",
"Animals were monitored behaviorally for seizures and the onset of SE (defined as continuous tonic--clonic seizures). ",
"Following 3 h of SE, mice were given two injections of diazepam, 10 min apart (10 mg/kg, s.c.), ",
"to alleviate seizure activity. ",
"Mice were given sterile Ringer's solution as needed to restore pretreatment body weight and were then returned to their home cages, where they were provided with food and water *ad libitum*. ",
"Mice were housed under a 14 h/10 h light/dark cycle to optimize breeding ([@B16]). ",
"Of the 25 mice randomly assigned to pilocarpine treatment, 12 (48%) survived to the end of the experiment, yielding a final group consisting of 7 males and 5 females. ",
"There was no mortality among the five control animals (three males and two females).",
"\n\n{#F1}\n\nTissue preparation for whole hippocampal imaging {#s3C}\n------------------------------------------------\n\nAt 16 weeks of age, animals were killed by intraperitoneal injection of 100 mg/kg pentobarbital. ",
"The mice were perfused through the ascending aorta with ice-cold PBS (0.1 [m]{.smallcaps} PBS) containing 1 U/ml heparin for 30 s at 10 ml/min, immediately followed by a 2.5% paraformaldehyde plus 4% sucrose solution in 0.1 [m]{.smallcaps} PBS at 25°C for 10 min. ",
"Brains were removed, dissected into left and right hemispheres, and post-fixed in the same solution overnight at 4°C. ",
"Brain hemispheres were cryoprotected in 10%, 20%, and 30% sucrose in PBS for 24, 24, and 48 h, respectively. ",
"The hemispheres were then frozen in isopentane cooled to −23°C with dry ice and stored at −80°C until sectioning. ",
"Brain hemispheres were thawed in PBS for scale clearing, and 300 µm coronal sections were cut on a tissue slicer (Campden Instruments). ",
"Sections were transferred to 24 multiwell tissue culture plates (Becton Dickinson), maintaining their septotemporal order. ",
"Sections were incubated for optical clearing in ScaleA2 for 2 weeks at 4°C ([@B19]). ",
"At least one hemisphere from each animal was used for clonal analysis, and in three cases both hemispheres were used (2 SE and 1 control). ",
"No significant differences in cluster composition were found between hemispheres within animals \\[Mann--Whitney rank sum test (RST)\\], so hemispheres were pooled by animal for statistical analysis. ",
"The remaining hemispheres were used for immunohistochemical characterization of Brainbow-labeled cells.",
"\n\nTissue preparation for immunohistochemistry {#s3D}\n-------------------------------------------\n\nUnused hemispheres from a subset of animals (*n* = 5) were sectioned coronally on a cryostat at 60 μm and mounted to gelatin-coated slides. ",
"Sections were immunostained with mouse anti-nestin (1:100; Millipore), chicken anti-glial fibrillary acidic protein (GFAP; 1:500; Chemicon), goat anti-doublecortin (1:250; Santa Cruz Biotechnology), mouse anti-calretinin (1:200; Millipore) or guinea pig anti-calbindin-[d]{.smallcaps}-28K (1:200; Sigma-Aldrich). ",
"Alexa Fluor 405 goat anti-mouse, 488 goat anti-chicken, 594 goat anti-mouse, 647 donkey anti-goat or Alexa Fluor 647 goat anti-guinea pig secondary antibodies were used (Invitrogen). ",
"Tissue was dehydrated in alcohol series and cleared in xylenes, and coverslips were secured with mounting media (Krystalon, Harleco).",
"\n\nConfocal microscopy {#s3E}\n-------------------\n\nScaleA2-cleared hippocampal sections were imaged on an A1R GasAsP confocal system attached to a motorized Eclipse Ti inverted microscope (Nikon Instruments). ",
"This system was used to capture three-dimensional image stacks through the *z*-depth of the tissue at 1 μm steps using a 10× Plan Apo λ objective (NA, 0.25) at 1× optical zoom (field size 1024 × 1024 pixels, 1.23 pixels/µm). ",
"These 10× image stacks were used to identify clonal clusters, defined here as cells expressing the same fluorophore and contained within a 150 μm radius of the clone center ([@B5]; [@B9]). ",
"Identified clonal clusters were then imaged using a 40× Plan Apo infrared- differential interference contrast water immersion objective (NA, 1.3) at 1× optical zoom (field size, 1024 × 1024 pixels, 0.31 pixels/μm). ",
"All cells selected for analysis were brightly labeled with RFP or YFP and had their somas fully contained within the tissue section. ",
"The investigator was blind to treatment group during all image collection and data analysis.",
"\n\nThree-dimensional hippocampal reconstructions {#s3F}\n---------------------------------------------\n\nConfocal *z*-series image stacks were converted into 8 bit RGB.tiff files. ",
"Reconstruct Software (John C. Fiala, the National Institutes of Health; [@B36]) was used to septotemporally align sections (10× images) for each hippocampus ([Fig. ",
"1*B*](#F1){ref-type=\"fig\"}). ",
"Aligned *z*-stacks were imported into Neurolucida software for analysis (version 11.01, Microbrightfield). ",
"Borders of the granule cell body layer were traced at *z*-intervals of 100 μm to recreate the whole hippocampus.",
"\n\nMorphological classification {#s3G}\n----------------------------\n\nHigher-magnification images (40×) were used to categorize cells within each cluster as follows: (1) type 1 cell, with a small cell body located in the subgranular zone and a single, radial process that projects through the granule cell layer and terminates in the inner molecular layer (type 1 progenitor cells express nestin and GFAP); (2) type 2/3 cells, with a cell body located in the subgranular zone and short, aspiny processes projecting parallel to the plane of the granule cell body layer (because their appearance is morphologically similar, we did not attempt to distinguish between type 2 and 3 cells, or the different subtypes of type 2 cells; type 2 and 3 cells express the cellular proliferation marker doublecortin); (3) immature granule cells, with a cell body in the granule cell body layer and aspiny dendrites that project radially through the granule cell body layer, but terminate prior to reaching the hippocampal fissure (typically with growth cones at the tips; these cells occasionally possessed short, aspiny basal dendrites and express calretinin); (4) normal mature granule cells, with their somas located in the granule cell body layer and spine-coated dendrites projecting to the hippocampal fissure (mature granule cells express calbindin); (5) hilar ectopic granule cells, with spiny dendrites and a cell body located in the hilus (at least two cell body distances, ∼20 μm, away from the granule cell layer-hilar border); (6) mature granule cells with basal dendrites, possessing all the features of normal mature granule cells (see point 4), but with at least one dendrite originating from the hilar side of the soma \\[i.e., ",
"arising from a region below the soma midline; cells with basal dendrites projecting into either the dentate hilus, or the dentate molecular layer (recurrent basal dendrites), were included in this measure. ",
"Only granule cells with clearly visible axons were scored for basal dendrites. ",
"Basal dendrites are often thin and difficult to visualize in deeper regions of the tissue. ",
"Well developed axons should be present on all mature granule cells. ",
"Confirming that these axons can be visualized limits the entry of false negatives into the dataset. ",
"If the axon can be visualized, then any basal dendrites, which are typically of higher caliber than the axon, should also be detectable\\]; and (7) astrocytes, defined as cells with a small cell body, located anywhere within the dentate gyrus and possessing numerous thin, aspiny process projecting outward in a stellate fashion (for review of granule cell developmental markers, see [@B27]; [@B4]).",
"\n\nStatistical analysis {#s3H}\n--------------------\n\nA Microsoft SQL Server (version 2012) was used to query the dataset for different clone compositions, and statistical analysis was performed using R (version 0.98.109) or SigmaPlot (version 12.5). ",
"Sex and treatment effects were determined using two-way ANOVA. ",
"Individual group differences were determined using the Holm--Sidak method for all ANOVA results. ",
"Parametric tests were used for data that met assumptions for normality and equal variance. ",
"Data that failed assumptions of normality and equal variance were either transformed, as noted in the text to meet these assumptions, or were analyzed using nonparametric alternative tests. ",
"The actual tests used are noted in the text. ",
"Values presented are the mean ± SEM (least square means for two-way ANOVA data) or median (range), as appropriate. ",
"Details of statistical tests are given in [Table 1](#T1){ref-type=\"table\"}.",
"\n\n###### \n\nStatistical tests\n\n Data Data structure Type of test Power\n ------------------------------------------- --------------------------------------------------------------------------------------------------------------- ------------------------------------------------- ----------------------------------------------\n Number of clonal clusters per hippocampus Normality test (Shapiro-Wilk): passed (*p* = 0.561)Equal variance test (Brown-Forsythe): passed (*p* = 0.614) Two-way ANOVA with treatment and sex as factors Treatment: 0.372Treatment × sex: 0.579\n Mean clone size Normality test (Shapiro-Wilk): passed(*p* = 0.658)Equal variance test (Brown-Forsythe): passed (*p* = 0.399) Two-way ANOVA with treatment and sex as factors Treatment: 0.516Treatment × sex: 0.259\n Control vs SE, type 1 Normality test (Shapiro-Wilk): failed (*p* \\< 0.050) Mann--Whitney RST 25--75% CIs, control: 7.76--37; SE: 0-3.5\n Control vs SE, type 2 Normality test (Shapiro-Wilk): failed (*p* \\< 0.050) Mann--Whitney RST 25--75%, control: 0-21.6; SE: 0--6.1\n Control vs SE, immature cells Normality test (Shapiro-Wilk): failed (*p* \\< 0.050) Mann--Whitney RST 25--75%, control: 0--23.4; SE: 0--4.5\n Control vs SE, mature cells Normality test (Shapiro-Wilk): failed (*p* \\< 0.050) Mann--Whitney RST 25--75%, control: 26.9--83.6; SE: 75.0--93.8\n Control vs SE, astrocytes Normality test (Shapiro-Wilk): failed (*p* \\< 0.050) Mann--Whitney RST 25--75%, control: 0--10.4; SE: 3.2--7.0\n Clusters with progenitors Normality test (Shapiro-Wilk): passed (*p* = 0.526) *t* test Power = 0.793\n Self-renewing (2 type 1) clusters Normality test (Shapiro-Wilk): failed (*p* \\< 0.050) Mann--Whitney RST 25--75%, control: 0--0.15; SE: 0--0\n Fully differentiated clusters Normality test (Shapiro-Wilk): passed (*p* = 0.536) *t* test Power = 0.790\n Ectopic cells Normality test (Shapiro-Wilk): failed (*p* \\< 0.050) Mann--Whitney RST 25--75%, control: 0--0; SE: 0--0\n Cells with basal dendrites Normality test (Shapiro-Wilk): failed (*p* \\< 0.050) Mann--Whitney RST 25--75%, control: 0--0; SE: 0--0\n\nThe statistical analysis for the frequency/distribution of ectopic cells and basal dendrites was performed using the binomial distribution (to compute probabilities of combinatorial events). ",
"The experiment-wise error was conservatively set at 0.001 ([@B11]). ",
"Corrections for multiple comparisons were performed using a Bonferroni correction. ",
"For clusters containing ectopic cells, the resultant *p* value for significance for the pilocarpine-treated animals was calculated to be 4.17 × 10^−6^ (0.001/240). ",
"Similarly, for clusters containing DGCs with basal dendrites, the probability of a single trial success was 0.0614, and the critical *p* value was calculated to be 5.41 × 10^−6^ (0.001/185).",
"\n\nFigure preparation {#s3I}\n------------------\n\nMaximum projections from *z*-series stacks were prepared using NIS-Elements Ar Microscope Imaging Software (version 4.0). ",
"Contrast, brightness, montage adjustments, and figure preparation were performed using Adobe Photoshop CS5 (version 12.0). ",
"Identical filtering and adjustments to brightness and contrast were performed for images meant for comparison. ",
"Tableau (version 8.0) and Microsoft Excel (version 2013) were used to create graphs and visualizations. ",
"The image in Figure 4 was cropped to remove neuronal structures above and below the cell of interest that would otherwise obscure it ([@B63]; [@B37]; [@B39]). ",
"This image is best viewed as a neuronal reconstruction, similar to traditional neuroanatomical techniques ([@B14]), rather than a standard photomicrograph.",
"\n\nResults {#s4}\n=======\n\n*In vivo* lineage tracing of individual Gli1-expressing progenitor cells in the adult mouse hippocampus {#s4A}\n-------------------------------------------------------------------------------------------------------\n\nTo study the proliferative activity of a cohort of Gli1-expressing granule cell progenitors in epilepsy, we treated double-transgenic *Gli1-CreER^T2^::Brainbow* reporter mice with tamoxifen at postnatal week 7 to trace the lineage of these cells. ",
"A small cohort of animals was perfused 2 d later, revealing an average of two type 1 cells per 300 μm hippocampal coronal section ([Fig. ",
"1](#F1){ref-type=\"fig\"}), an optimal labeling sparsity for identifying individual clones ([@B5]). ",
"Gli1 expression has been shown to mark multipotent type 1 stem cells, which give rise to type 2/3 stem cells and other differentiated progeny ([@B15]). ",
"Animals in the main study groups received either saline or pilocarpine 1 week after tamoxifen treatment ([Fig. ",
"1*A*](#F1){ref-type=\"fig\"}). ",
"Pilocarpine induces acute status epilepticus (SE) and the subsequent development of epilepsy a few weeks later ([@B62]). ",
"Animals were killed 2 months after pilocarpine treatment, when spontaneous seizures are typically frequent ([@B10]; [@B22]). ",
"Hippocampi were imaged in their entirety to identify all fluorescently labeled cells ([Fig. ",
"1*B*](#F1){ref-type=\"fig\"}). ",
"Brainbow fluorophore expression was strictly tamoxifen dependent; and was limited to dentate granule cells, astrocytes, and sub-granular zone progenitor cells ([Fig. ",
"1*C*](#F1){ref-type=\"fig\"}). ",
"We first assessed whether SE altered the number of clonal clusters per hippocampus (control, female, *n* = 2 mice, 4.0 ± 5.8 clusters per hippocampus; control, male, *n* = 3, 13.3 ± 4.8; SE, female, *n* = 5, 24.9 ± 4.2; SE, male, *n* = 7, 11.0 ± 2.9). ",
"The effect of SE was found to be dependent on animal sex ([Fig. ",
"2](#F2){ref-type=\"fig\"}; *p* = 0.025, two-way ANOVA). *",
"Post hoc* tests revealed a significant increase in female, but not male, mice in clusters per hippocampus relative to controls (*p* = 0.012, Holm--Sidak method) and significantly more clusters in females versus males within the pilocarpine-treated groups (*p* = 0.017, Holm--Sidak method). ",
"Differences between sexes could reflect differential numbers of progenitors prior to pilocarpine treatment and differential behavior of progenitors after treatment. ",
"Greater apoptosis of quiescent progenitor cells or entire clonal groups in males, for example, would reduce the number of clonal clusters. ",
"Sexually dimorphic changes in neurogenesis have been observed following early-life stress in rodents ([@B35]). ",
"The present findings suggest that dimorphic responses to adult SE also occur.",
"\n\n{#F2}\n\nStatus epilepticus increases the average number of cells per clonal cluster {#s4B}\n---------------------------------------------------------------------------\n\nIncreased hippocampal neurogenesis and cell survival have been consistently demonstrated in epilepsy models ([@B3]; [@B46]; [@B18]; [@B45]). ",
"In addition to an increase in the number of clonal clusters in female mice, the present work also revealed an increase in the mean size of individual clones. ",
"Specifically, mean clonal size increased from 3.0 ± 0.7 cells/cluster in controls to 5.1 ± 0.5 in SE mice \\[[Fig. ",
"1](#F1){ref-type=\"fig\"}, *p* = 0.033, SE mice (*n* = 12) vs control mice (*n* = 5), two-way ANOVA). ",
"In contrast to cluster number, however, no differences between males and females were found for cluster size (*p* = 0.822), nor was there an interaction between treatment and sex (*p* = 0.107). ",
"Similarly, no additional sex differences or interactions were found in pretests for all additional data presented here (data not shown), so males and females were binned for all further statistical analyses. ",
"Together, these data suggest that the increase in new granule cells after SE is likely due to increased proliferation among individual progenitors (increased cluster size) and/or reduced apoptosis of their progeny (more clusters, increased cluster size).",
"\n\nStatus epilepticus promotes terminal differentiation of hippocampal progenitor cells {#s4C}\n------------------------------------------------------------------------------------\n\nWhile neurogenesis is increased after an acute epileptogenic injury, it can decrease in chronic epilepsy ([@B20]; [@B12]). ",
"A growing body of literature demonstrates that progenitor cell pools can be depleted as progenitors proceed through multiple rounds of division, ultimately leading to terminal differentiation ([@B33]; [@B15]). ",
"Reduced neurogenesis in chronic epilepsy, therefore, could be a direct consequence of increased progenitor cell activity early in the disease.",
"\n\nTo assess whether this might be the case, we used morphological criteria to classify cells as type 1 progenitors, type 2/3 progenitors, immature granule cells, mature granule cells, or astrocytes ([Fig. ",
"2*A*](#F2){ref-type=\"fig\"}). ",
"The accuracy of this morphological classification was confirmed by immunocharacterization of the different cell types quantified ([Fig. ",
"2*B*](#F2){ref-type=\"fig\"}). ",
"This lineage analysis revealed a significant reduction in the progenitor cell pool in SE-exposed animals. ",
"Compared with control animals, SE animals exhibited an 84% reduction in type 1 cells \\[*p* = 0.013, SE mice (*n* = 12) vs control mice (*n* = 5), Mann--Whitney RST\\]. ",
"No difference in the percentage of type 2/3 cells was found \\[*p* = 0.870, SE mice (*n* = 12) vs control mice (*n* = 5), Mann--Whitney RST\\]. ",
"Overall, there was a 58% reduction in the percentage of clusters containing either type 1 or type 2/3 progenitors, dropping from 46.2 ± 8.1% in control animals to 18.6 ± 5.0% in animals exposed to SE \\[[Fig. ",
"2*E*](#F2){ref-type=\"fig\"}; *p* = 0.009, SE mice (*n* = 12) vs control mice (*n* = 5), two-tailed *t* test\\]. ",
"Symmetric self-renewing clusters (composed of two type 1 cells) decreased from a median of 4.5% (range, 0-16.7%) of clusters/animal in controls to nil in SE animals \\[*p* = 0.006, SE mice (*n* = 12) vs control (*n* = 5), Mann--Whitney RST\\]. ",
"The significant shift away from progenitors in animals exposed to SE was mirrored by a nonsignificant trend in the proportion of mature granule cells produced \\[*p* = 0.065, SE mice (*n* = 12) vs control mice (*n* = 5), Mann--Whitney RST\\] and a significant increase in the percentage of clusters that were \"fully differentiated,\" meaning the clusters contained only granule cells and astrocytes, and were devoid of progenitors \\[*p* = 0.010, SE mice (*n* = 12) vs control mice (*n* = 5), two-tailed *t* test). ",
"No differences in the proportions of immature granule cells (*p* = 0.299, Mann--Whitney RST) or astrocytes (*p* = 0.223, Mann--Whitney RST) were found.",
"\n\nEctopic DGCs appear in clonal clusters in which the majority of the cells are ectopic {#s4D}\n-------------------------------------------------------------------------------------\n\nHilar ectopic granule cells are a common pathology seen in temporal lobe epilepsy. ",
"These neurons are newly generated, arising after an epileptogenic brain insult, and are implicated in the development of epilepsy ([@B22]). ",
"The percentage of newborn cells found in the hilar region of SE-exposed animals was significantly increased relative to controls \\[[Fig. ",
"3](#F3){ref-type=\"fig\"}; *p* = 0.004; SE mice, 63 of 1238 DGCs (5.09%), control mice, 1 of 192 cells (0.52%); Mann--Whitney RST\\], which is consistent with the findings of previous studies ([@B44]). ",
"Clonal analysis revealed that ectopic cells were concentrated within a small number of clusters. ",
"Specifically, the 63 identified ectopic cells from animals exposed to status were contained within only 14 clusters ([Fig. ",
"3*B*](#F3){ref-type=\"fig\"}). ",
"Within these clusters, 76.8% of all cells were ectopic ([Fig. ",
"3*B*](#F3){ref-type=\"fig\"}).",
"\n\n{#F3}\n\nThe probability of finding a set number of ectopic cells, *S*, in a cluster containing a total of *N* cells was computed for all values of *S* from 1 to *N* (e.g., when *S* = *N*, 100% of the cells in the cluster are ectopic). ",
"The minimum number of ectopic cells *S*, at which the *p* value reaches the target *p* value for significance (*p* = 4.17 × 10^−6^; see Materials and Methods for calculations) was determined for every cluster and was compared with the observed number of ectopic cells. ",
"We found that 6 of the 14 clusters with ectopic cells exceeded the threshold *p* value for significance (binomial, *p* \\< 4.17 × 10^−6^; [Fig. ",
"3](#F3){ref-type=\"fig\"}). ",
"The binomial probability of finding 6 of 240 clusters exceeding this value is statistically minute (\\<1.33 × 10^−21^). ",
"Finding one cluster that exceeded the value would indicate that ectopic cells are not randomly distributed, and in the present study six such clusters were observed. ",
"These results provide overwhelming evidence that the accumulation of ectopic cells in certain clusters is not a random event.",
"\n\nDGCs with basal dendrites occur in clonal clusters in which the majority of the cells do not have a basal dendrite {#s4E}\n------------------------------------------------------------------------------------------------------------------\n\nAnother common pathology observed in the epileptic brain is the presence of dentate granule cells with basal dendrites ([@B57]; [@B7]). ",
"In the current study, 6.14% of granule cells from SE-exposed animals possessed basal dendrites. ",
"By contrast, only one cell with basal dendrites was found among the control animals (*p* = 0.034; SE mice, 43 of 700 DGCs; control mice, 1 of 101 cells; Mann--Whitney RST). ",
"The 43 basal dendrite-possessing granule cells from SE mice were distributed among 31 of 185 clonal clusters ([Fig. ",
"4](#F4){ref-type=\"fig\"}). ",
"Among these 31 clusters that contained a cell with a basal dendrite, 23 had only a single basal dendrite-possessing cell, 6 had two cells with basal dendrites, 1 had three cells with basal dendrites, and 1 had five cells with basal dendrites ([Fig. ",
"4](#F4){ref-type=\"fig\"}). ",
"Using the significance criterion described in Materials and Methods (similar to that used for ectopic cells), there were no clusters that contained a significant number of DGCs with basal dendrites ([Fig. ",
"4](#F4){ref-type=\"fig\"}). ",
"Indeed, even the biggest cluster---containing 17 DGCs with 5 harboring a basal dendrite---failed to reach significance even if the experiment-wise α value is relaxed to 0.05 (*p* = 0.054; threshold *p* value for α = 0.001, 5.41 × 10^−6^; for α = 0.05, 2.60 × 10^−4^).",
"\n\n{#F4}\n\nClonal clusters have more type 1 cells in dorsal hippocampus {#s4F}\n------------------------------------------------------------\n\nPrevious studies ([@B26]; [@B29]; [@B25]) have reported topographical differences within the hippocampus with respect to neurogenesis, cell densities, functional properties, and electrophysiological properties. ",
"To determine whether there are dorsal--ventral differences in progenitor cell behavior, we correlated cluster composition with cluster bregma level ([@B47]). ",
"Within SE animals, the number of type 1 cells was significantly correlated with bregma level, with greater numbers of cells identified in more dorsal regions ([Fig. ",
"5](#F5){ref-type=\"fig\"}; *p* = 0.0037, Spearman rank order correlation). ",
"This effect persisted when bregma levels were correlated with the proportion of type 1 cells at each level (type 1 cells/total cells), suggesting that differences in total cell numbers cannot account for the finding (*p* = 0.0238, Spearman rank order correlation). ",
"The numbers and proportions of mature, immature, type 1, type 2, astrocytic, ectopic, and basal dendrite-possessing cells were not significantly correlated with bregma level (data not shown). ",
"No significant correlations were found between bregma level and the number or proportion of any cell types in control animals (data not shown).",
"\n\n{#F5}\n\nDiscussion {#s5}\n==========\n\nAbnormal hippocampal granule cells are common in animal models of temporal lobe epilepsy ([@B49]) and in tissue from patients with the disease ([@B60]; [@B44]). ",
"Prior studies ([@B63]; [@B30]) have established that many of these abnormal cells are adult generated. ",
"In the present study, we queried whether two important abnormalities, ectopic DGCs and DGCs with basal dendrites, are derived with equal likelihood from the entire progenitor pool, or whether they are preferentially produced by a subset of progenitors. ",
"We found that ectopic granule cells were highly concentrated within distinct clonal clusters, with many containing only ectopic cells. ",
"By contrast, cells with basal dendrites were relatively evenly distributed among clones. ",
"These findings strongly suggest the existence of distinct mechanisms regulating ectopic cell migration and basal dendrite formation. ",
"A second key finding provides new insights into the bimodal changes in neurogenesis rates observed in epileptic animals. ",
"Neurogenesis increases acutely following an epileptogenic insult; however, animals with chronic epilepsy exhibit reduced neurogenesis. ",
"Depletion of the progenitor pool---potentially as a direct consequence of the early increase in neurogenesis---has been hypothesized to account for these changes ([@B20]). ",
"Our data provide direct evidence that this is occurring, with a 70% increase in the number of daughter cells/clone, and a corresponding decrease in the percentage of actively dividing and self-renewing clones ([Fig. ",
"6](#F6){ref-type=\"fig\"}).",
"\n\n{#F6}\n\nLimitations of the current study {#s5A}\n--------------------------------\n\nThe present study uses a clonal analysis methodology previously validated for the dentate gyrus ([@B5]). ",
"Nonetheless, it is expected that progenitor cells labeled with the same fluorophore will occasionally appear in close proximity to one another, leading to the false conclusion that they represent a single clonal cluster. ",
"Conclusions based on rare clonal events, therefore, should be made with caution if the observation could also be accounted for by a false merging of clusters. ",
"As an example, it is possible that some of the clones with mixes of ectopic and normally positioned cells shown in [Figure 3](#F3){ref-type=\"fig\"} are actually merged clonal clusters. ",
"Notably, however, our findings in control animals are remarkably similar to those of [@B5] using the Nestin-CreER^T2^ driver line to label progenitor cells. ",
"We found a similar distribution of cluster sizes ([Fig. ",
"1*D*](#F1){ref-type=\"fig\"}) in the animals and were able to reproduce key findings, such as the occurrence of symmetric cell divisions, yielding two type 1 cells. ",
"One difference we noted was a greater degree of neurogenesis among clusters using the Gli1 driver relative to the nestin driver used previously. ",
"The nestin driver produced a roughly equal ratio of neurons to astrocytes ([@B5]; [@B56]); whereas, neurons were much more common in the present work ([Fig. ",
"2*D*](#F2){ref-type=\"fig\"}). ",
"The higher ratio of neurons to astrocytes is consistent with studies using cell birth-dating and virus-labeling approaches ([@B58]), and may reflect differences between Gli1- and nestin-expressing stem cells.",
"\n\nA second notable caveat is that the present study examined only progenitor cells labeled in the week before SE, in order to examine the impact of status epilepticus on progenitor cells (rather than their offspring, as would be achieved with earlier labeling), and to ensure equivalent labeling of progenitor populations between control and epileptic animals. ",
"The progenitor pool changes after SE, so labeling after the insult will presumably label a population of progenitors that diverges from controls. ",
"Aberrant granule cell integration occurs over a protracted time course, and includes immature cells born weeks before SE, as well as cells born months later. ",
"Whether the current findings will extend to populations generated at other time points remains to be determined.",
"\n\nClonal analysis of adult subgranular zone neurogenesis following status epilepticus {#s5B}\n-----------------------------------------------------------------------------------\n\nIn the present study, we used an *in vivo*, genetic, sparse-labeling approach to mark stem cells for lineage tracing. ",
"This approach has been used previously to study neural stem cell behavior in the subventricular ([@B9]) and subgranular ([@B59]; [@B5]) proliferative zones in healthy animals. ",
"We combined this approach with recently developed tissue-clearing protocols, allowing us to generate three-dimensional reconstructions of the entire rodent hippocampus; and the Brainbow reporter line, allowing us to separate clonal groups by fluorochrome expression. ",
"Poor recombination with the Brainbow reporter in CNS tissue limited our study to two colors, rather than the potential seven colors evident in other tissues ([@B34]; [@B8]). ",
"Even with two colors, however, the strategy provided sufficient spatial resolution for the study.",
"\n\nAn additional advantage of the genetic approach is that it avoids disturbing the target tissue with direct brain injections, as is needed for retroviral strategies ([@B23]; [@B38]). ",
"Retrovirus also targets Sox2^+^ type 2 progenitor cells ([@B59]), while the Gli1 driver used here targets the parent type 1 cells ([@B1]), so the different strategies provide complimentary data.",
"\n\nLocalized regulation of ectopic granule cell formation {#s5C}\n------------------------------------------------------\n\nEctopic granule cells have been observed in a number of different epilepsy models. ",
"They are hyperexcitable ([@B52]; [@B2]) and have atypical connections within the hippocampal network ([@B53]), and their numbers correlate with the severity and duration of seizures ([@B22]). ",
"The mechanisms underlying ectopic cell migration, however, are unknown. ",
"A mechanistic understanding would provide new insights into the development of therapeutic strategies for epilepsy. ",
"A putative mechanism that could account for the current results is mislocation of progenitor cells from the subgranule zone to the hilus during epileptogenesis ([@B44]). ",
"Alternatively, epileptogenic stimuli could activate \"dormant\" progenitors trapped in the hilus during development ([@B17]; [@B51]). ",
"If one further presumes that daughter cells produced by hilar progenitors would not have access to the necessary cues directing them to migrate into the granule cell layer, the presence of entirely ectopic clonal groups could be accounted for. ",
"Alternatively, seizures might lead to the localized disruption of migratory cues, like reelin ([@B61]). ",
"Progenitor cells active in regions with disrupted cues would produce daughter cells that fail to migrate correctly, while progenitors in regions with intact cues would produce normal offspring. ",
"In support of this possibility, [@B44] observed trains of cells migrating on glial scaffolds into the hilus after seizures, suggesting that localized changes in non-neuronal cells might play a role. ",
"Additional studies will be needed to distinguish among these possibilities.",
"\n\nThe finding that clonal groups with ectopic cells tend to be made up of entirely ectopic cells is consistent with a Markov chain model ([@B32]). ",
"In a Markov model, there are two states a progenitor cell can assume: progenitors in state 1 give rise to DGCs correctly located in the cell body layer; whereas progenitors in state 2 give rise to ectopic DGCs. ",
"For the model, we assumed that, at every mitotic cycle, cells could either stay in the same state or transition between states. ",
"The transition matrix specifies the probabilities of these transitions. ",
"Our data show that the probability of a progenitor switching states is very low, and the probability that a progenitor will remain in the same state is close to 100%, implying that cells that begin producing ectopic cells will continue to do so, and that cells that initially produce normal cells also will continue to do so. ",
"Transitions between states appear to be very rare. ",
"Only 5 of 240 clusters from SE mice contained a mixture of ectopic and correctly located cells.",
"\n\nTemporal/global regulation of basal dendrite formation {#s5D}\n------------------------------------------------------\n\nBasal dendrites were distributed close to the predicted ratio among clonal clusters and tended to be present in clusters in which the majority of cells lacked this feature. ",
"Progenitors that produce DGCs with basal dendrites, therefore, mostly produce morphologically normal DGCs. ",
"This observation suggests a mechanism that could impact the development of daughter cells from any progenitor, while also leaving most daughter cells unaffected. ",
"Such a mechanism might affect the entire hippocampus, but only some of the time. ",
"Seizure activity clearly meets these criteria, as seizures are episodic in nature, and when these seizures generalize, as is typical for the pilocarpine model, the entire hippocampus will be affected. ",
"Recent work by [@B6] supports this idea, with the demonstration that limbic kindling disrupts granule cell integration more severely than kindling of nonlimbic regions.",
"\n\nThe idea that seizure activity might drive basal dendrite formation is supported by the work of [@B42]. ",
"They demonstrated that increasing neuronal activity in hippocampal slice cultures stabilized the normally transient basal dendrites that typically are present on immature granule cells. ",
"Under low-activity conditions, developing granule cells briefly possess basal dendrites 1 to 2 weeks after their birth, but subsequently reabsorb these processes as they mature. ",
"Increasing neuronal activity, however, allowed these processes to persist through cell maturity, perhaps through a neurotrophin-dependent mechanism ([@B13]; [@B6]). ",
"Whether a similar process occurs *in vivo* remains to be determined, but the present findings are consistent with the idea that episodic increases in activity (including seizures) might similarly stabilize granule cell basal dendrites, but only among granule cells that happen to be at this particular developmental stage at the time of the event.",
"\n\nDepletion of the granule cell progenitor pool {#s5E}\n---------------------------------------------\n\nIn the current study, we found a decrease in progenitor cell numbers and an increase in differentiated cells. ",
"A chronic decrease in neurogenesis has been observed previously in epileptic animals ([@B20]). ",
"Reduced neurogenesis could be the result of increased progenitor cell quiescence, loss of functional progenitor cell division, decreased survival of daughter cells, or an overall loss of progenitors. ",
"Our results provide evidence for the division-coupled loss of type 1 progenitor cells as a key contributor to the chronic decline in neurogenesis. ",
"We observed a decrease in quiescent and actively self-renewing progenitors, but an increase in mature granule cells within clonal groups in animals following status. ",
"Activation and terminal differentiation of quiescent progenitors would account for these observations. ",
"Indeed, [@B15] observed a similar loss of stem cells during the normal aging process in the mouse hippocampus. ",
"Using a genetic label, they showed that type 1 cells act as \"disposable stem cells\": once activated, they tend to terminally differentiate rather than continuing to cycle. ",
"Therefore, epileptic stimuli might accelerate the age-related loss of progenitor cells from the dentate. [",
"@B55] observed a similar reduction in the progenitor cell pool following intrahippocampal injection of the convulsant kainic acid. ",
"In contrast to the present results, however, they observed terminal differentiation of type 1 cells into astrocytes (see also [@B21]), rather than mature granule cells, as described here. ",
"This difference likely reflects the very different pathological responses, and impacts on neurogenesis, of the two epilepsy models ([@B39]).",
"\n\nConcluding remarks {#s5F}\n------------------\n\nOur results strongly suggest different mechanistic origins for ectopic DGCs and DGCs with basal dendrites. ",
"Ectopic DGCs are highly localized to specific clonal clusters, implicating the parent progenitor cell or the neurogenic niche in which the progenitor resides. ",
"By contrast, basal dendrites appeared to be randomly distributed among clones, suggesting that transient changes acting throughout the hippocampus drive this pathology. ",
"Both abnormalities are implicated in the development of epilepsy and associated comorbidities, and separate therapeutic strategies will likely be required to mitigate these different abnormalities.",
"\n\nAcknowledgments: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke, the National Institutes of Health, the Albert J. Ryan Foundation, or the American Heart Association. ",
"We thank Matthew Kofron and Micheal Muntifering (Confocal Imaging Core, Cincinnati Children's Hospital, Cincinnati, OH) for technical advice on imaging modalities used for this study. ",
"We also thank Keri Kaeding and Mary Dusing for useful comments on the earlier versions of this manuscript.",
"\n\nSynthesis {#s6}\n=========\n\nThe decision was a result of the Reviewing Editor Tallie Z. Baram and the peer reviewers coming together and discussing their recommendations until a consensus was reached. ",
"A fact-based synthesis statement explaining their decision and outlining what is needed to prepare a revision is listed below. ",
"The following reviewers agreed to reveal their identity: Jack Parent, Katelin Patterson.\\</synthesis-intro\\>\n\nThank you for sending us your paper, providing interesting insights into the manner in which multiple abnormalities in dentate granule cells (DGCs) arise after epilepsy inducing insults. ",
"The Reviewers and myself found the work This work is largely novel and exciting, capitalizing on state-of-the-art technologies including clonal analysis, the brainbow reporter, and Scale clearing. ",
"Most of the results are interesting and reasonably convincing. ",
"However, there are some limitations in the studies, analyses and interpretation that require further actions. ",
"For clarity, the Reviewers and I have divided these required action into new experiments, new analyses and clarification/ re-statements.",
"\n\nA. New experiments:\n\n1\\. Independent confirmation of the age and identity of the cells, addressing the issues raised in Point 9 of Reviewer 2 and Points 1 and 2 of Reviewer 1. ",
"In essence, once Tamoxifen induces recombination, the radial glial stem cells may theoretically continue to generate progeny such that the new DGCs/progenitors may be of mixed ages. ",
"New animals and immunostaining will need to show that, for example, cells that are considered mature DGCs have turned off DCX expression. ",
"The studies should include Gli1, to address the query raised by Reviewer 2 (point 3)\n\nThis is fundamental to the interpretation of the data.",
"\n\nB New Analyses: note that these might require additional experiments:\n\n1\\. By mouse rather than by hippocampus, as there is an apparent absence of systematic utilization of tissue (point 8, reviewer 2). ",
"This analysis is required.",
"\n\n2\\. By gender, if possible;\n\n3\\. By dorsal / ventral hippocampus if feasible\n\nC. Explain, clarify. ",
"Amend or rewrite:\n\nReviewer 1: points 3,4,5\n\nReviewer 2: points 2,5,6,7,10\n\nReviewer 1 comments:\n\nThis group used Gli1-CreERT2 mice crossed with a brainbow reporter line to perform clonal lineage analysis of adult hippocampal neural stem cells. ",
"With this approach they examined whether distinct subsets of neural progenitors give rise to adult-born dentate granule cells (DGCs) that migrate ectopically or exhibit persistent hilar basal dendrites (HBDs), two distinct pathologies in temporal lobe epilepsy. ",
"Radial glial-like cell (RGL) clones were tracked throughout the hippocampus in thick sections from Scale cleared brains, and the authors found that, while HBDs do not arise from distinct progenitors, the majority of ectopically located DGCs are concentrated within small clusters of progenitors that mainly consist of ectopic cells. ",
"These findings suggest that ectopic DGCs arise from distinct RGLs that then migrate abnormally together. ",
"Furthermore, they describe that, during the chronic phase of epilepsy, there is a significant decrease in the quiescent and self-renewing stem cell pools with a corresponding increase in the number of mature DGCs, thereby supporting the notion that the transient increase in neurogenesis after status epilepticus (SE) depletes the DG stem cell population.",
"\n\nThis work is largely novel and exciting as the group uses state-of-the-art technologies including clonal analysis, the brainbow reporter, and Scale clearing. ",
"Most of the results are interesting and reasonably convincing. ",
"However, there are some limitations in the analyses, with the main concern being the sole reliance on cell morphology. ",
"The major concerns are as follows:\n\n1\\. A major limitation is that the cell type analysis is based only on morphology without any immunohistochemical confrimation. ",
"It would be advantageous for the group to also thin section and immunostain some non-cleared samples with markers for RGLs, transit amplifying cells, immature DGCs, mature neurons and glia in order to confirm their results from the Scale clearing experiments.",
"\n\n2\\. The authors describe a trend towards increased clusters in epileptic animals that may suggest a survival effect. ",
"However, this increase could result from variability in recombination efficiency. ",
"It would be more convincing if the authors analyzed the number of clonal clusters at an earlier time point, such as 1 week, after SE to determine whether the number of clones is similar between groups at the early time point.",
"\n\n3\\. Figure 1 panel C2 was not adequately described in the text or legend.",
"\n\n4\\. In figure 4A it is difficult to visualize the HBD, which makes one question the sensitivity of the technique for detecting HBDs. ",
"Perhaps a more representative example could be shown. ",
"Another concern is that using the presence of a visible axon as a criterion for counting a HBD probably markedly reduces the sensitivity of the assay and may bias the analysis.",
"\n\n5\\. The tables do not add much to the data already in the figures. ",
"Perhaps the authors can add ectopic cells to Fig. ",
"2B and get rid of all of the tables, which are redundant with the figures. ",
"Also, in tables 1 and 3, the % change from control would be better expressed as positive numbers with increase or decrease, rather than as a negative number representing an increase, and denoting a \\\"100%\\\" change when one of the numbers is zero is not statistically accurate.",
"\n\nThis paper provides interesting insights into the manner in which multiple abnormalities in dentate granule cells arise after epilepsy inducing insults. ",
"It is well written and has clear objectives. ",
"Specifically, it asks whether atypical features found in DGCs after status arise from a small number of progenitor cells or if they originate from multiple lineages. ",
"They found that while ectopic cells seem to originate from selective \\\"hub\\\" progenitors, DGCs with hilar basal dendrites arise from multiple progenitors indiscriminately. ",
"The conclusion is that disparate mechanisms govern the creation of ectopic DGCs and the retention of HBDs after status.",
"\n\nReviewer 2:\n\n1\\. The authors mention that they used mixed genders of mice. ",
"Do the authors believe that mixing genders could change results in any way? ",
"Do female mice respond differently during various times of estrous to pilocarpine? ",
"Is there an effect on neurogenesis in the SGZ during different times of female mouse cycles (ref Galea et al., ",
"2006)? ",
"The authors should note if any sex difference were or were not found in their studies.",
"\n\n2\\. Mortality rates from pilocarpine\n\na\\. How many animals began the study versus how many survived until week 16?",
"\n\n3\\. Do constructs label all or only some of Gli1+ cells? ",
"It might be advantageous to co- label for Gli1 with brainbow to check for penetrance.",
"\n\n4\\. Were there ventral/ dorsal differences found for any studies mentioned?",
"\n\n5\\. How do you know for sure that clusters are from same clones? ",
"Is there precedent for methods used? (",
"150 micrometers apart etc) Especially in the case of status animals where they report fewer progenitor cells that may act to \\\"anchor\\\" the cluster.",
"\n\na\\. If only two colors were obtained/ analyzed, how can you ensure that \\\"clusters\\\" are arising from a single progenitor? ",
"Are they sparse enough? ",
"It is concerning that out of 7 colors available through brainbow, the authors were only able to visualize 4 and utilize 2 for quanitification. ",
"Have the author\\'s considered why they only get 4 colors in their hands? ",
"Additionally, amplification techniques should be attempted to at least be able to utilize the other 2 available colors (TSA kit for example).",
"\n\n6\\. When determining depleted progenitor pools in \\\"epileptic\\\" animals, how were the animals deemed epileptic? ",
"Video? ",
"EEG?",
"\n\na\\. There is a lot of cell death in the pilocarpine model. ",
"Could the drastic drop out of quiescence be simply from cell death?",
"\n\n7\\. Is one week of tamoxifen sufficient to turn on enough cells? ",
"On a similar note, authors mention in the introduction that DGCs born weeks before insults develop abnormally, yet chose to focus only on cells born within one week of status. ",
"Because it is fairly well established that DGCs need ∼4 weeks to develop fully (Parent et al., ",
"Gage et al) is it possible that DGCs at different developmental states behave differently? ",
"Why did the authors decide to focus on this subgroup of developing DGCs? ",
"While this may not affect the study of ectopic cells, work from Parent et al has shown HBDs arising at various DGC developmental stages all the way to maturity.",
"\n\n8\\. There were 5 control mice with 6 hippocampi and 12 SE mice with 14 hippocampi. ",
"Why were not all hemispheres used in study? ",
"Was there at least one hippocampi used from each mouse described? ",
"For mice that had both hippocampi analyzed, were hemispheric differences found or were they similar? ",
"Including two hippocampi from one mouse while including only one from all others with a low n might confound results if results in hemispheres from individual animals mimic each other.",
"\n\n9\\. Once tomoxifen is administered, does it only label the cells during a discrete time, or does it continue to label cells well after? ",
"If so, how far after does it continue to label cells? ",
"This may be important because immature DGCs often have a basal dendrite that they may loose later in life. ",
"With the increase in neurogeneis found (which has been well documented previously) is it possible that the authors are simply catching more immature DGCs with HBDs, or do they believe that these cells are indeed \\\"mature\\\" and have integrated abnormally into the system?",
"\n\n10\\. In the discussion under Temporal/ global regulation of basal dendrite formation, the authors note on line 402 that seizures are both episodic and affect the entire brain when they occur. ",
"This is incorrect as seizures can affect localized portions of the brain. ",
"Consider revising this statement.",
"\n\nAuthor Response {#s7}\n===============\n\nWe sincerely thank the reviewers for their encouraging words, helpful comments and suggestions. ",
"We have responded to each comment, point by point, below. ",
"We feel the revised manuscript is now much improved.",
"\n\nSynthesis Statement for Author (Required):\n\nThank you for sending us your paper, providing interesting insights into the manner in which multiple abnormalities in dentate granule cells (DGCs) arise after epilepsy inducing insults. ",
"The Reviewers and myself found the work This work is largely novel and exciting, capitalizing on state-of-the-art technologies including clonal analysis, the brainbow reporter, and Scale clearing. ",
"Most of the results are interesting and reasonably convincing. ",
"However, there are some limitations in the studies, analyses and interpretation that require further actions. ",
"For clarity, the Reviewers and I have divided these required action into new experiments, new analyses and clarification/ re-statements.",
"\n\nA. New experiments:\n\n1\\. Independent confirmation of the age and identity of the cells, addressing the issues raised in Point 9 of Reviewer 2 and Points 1 and 2 of Reviewer 1. ",
"In essence, once Tamoxifen induces recombination, the radial glial stem cells may theoretically continue to generate progeny such that the new DGCs/progenitors may be of mixed ages. ",
"New animals and immunostaining will need to show that, for example, cells that are considered mature DGCs have turned off DCX expression.",
"\n\nAuthor (AR): We agree with the reviewers and have performed additional experiments to confirm the validity of our morphology-based characterization. ",
"We have added Figure 2B to correlate the immunophenotyping of the different cell stages with our morphological classification. ",
"The results showed high concordance with our initial characterization criterion. ",
"This is now indicated in the text (page 14, paragraph 2) and in figure 2B.\n\nThe studies should include Gli1, to address the query raised by Reviewer 2 (point 3)\n\nThis is fundamental to the interpretation of the data (Reviewer 2, point 3: Do constructs label all or only some of Gli1+ cells? ",
"It might be advantageous to co- label for Gli1 with brainbow to check for penetrance).",
"\n\nAR: The experiment was designed to label only a subset of Gli1+ cells. ",
"This is required for the clonal analysis approach, as labeling of the entire Gli1+ progenitor cell population would produce too many clonal groups, making it impossible to identify individual clusters. ",
"Tamoxifen levels were titrated to achieve this: Higher tamoxifen doses label more progenitor cells, confirming that only a subset of cells were labeled in the present study. ",
"Since labeling of only a subset of Gli1+ progenitors is by design, we feel that demonstrating this using Gli1 antibodies would be redundant. ",
"If the reviewers still consider this experiment to be essential, however, we can conduct it.",
"\n\nB New Analyses: note that these might require additional experiments:\n\n1\\. By mouse rather than by hippocampus, as there is an apparent absence of systematic utilization of tissue (point 8, reviewer 2). ",
"This analysis is required (Reviewer 2, point 8): There were 5 control mice with 6 hippocampi and 12 SE mice with 14 hippocampi. ",
"Why were not all hemispheres used in study? ",
"Was there at least one hippocampi used from each mouse described? ",
"For mice that had both hippocampi analyzed, were hemispheric differences found or were they similar? ",
"Including two hippocampi from one mouse while including only one from all others with a low n might confound results if results in hemispheres from individual animals mimic each other.",
"\n\nAR: We agree with the critique and have now redone the statistics by mouse rather than hippocampus (page 12, paragraph 1; page 13, paragraph 2). ",
"At least one hemisphere was used for each mouse. ",
"For the three animals for which both hemispheres were examined, no differences between hemispheres were found. ",
"Hemispheres not used for clonal analyses were frozen and sectioned for immunohistochemical studies. ",
"This is now clarified in the text (page 7, paragraph 1).",
"\n\n2\\. By gender, if possible;\n\nAR: We have performed additional data analysis by comparing clusters from male and female mice in both control and epileptic groups. ",
"Interestingly, a sex difference was found for cluster number/hippocampus, now reported on page 12, paragraph 1. ",
"All other measures in the study were also examined for sex differences, and none were found; therefore sexes were binned for these analyses.",
"\n\n3\\. By dorsal / ventral hippocampus if feasible\n\nAR: We agree with the reviewers about the importance of dorsal-ventral analyses and have now added this into the main text (page 17, paragraph 1). ",
"To make this analysis more robust, dorsal-ventral differences were assessed by examining the relationship between different clonal features and the bregma level of the clone. ",
"This provides much better visualization of the data than a binary dorsal-ventral split, and revealed a significant correlation between type-1 cell numbers and bregma level in SE mice. ",
"The data is now presented in the new figure 5.",
"\n\nC. Explain, clarify. ",
"Amend or rewrite:\n\nReviewer 1, point 3. ",
"Figure 1 panel C2 was not adequately described in the text or legend.",
"\n\nAR: We thank the reviewer for catching this and have added the explanation to the figure legend. ",
"The key point of this image is that it demonstrates optimal separation of progenitor cells for clonal analysis.",
"\n\nReviewer 1, point 4. ",
"In figure 4A it is difficult to visualize the HBD, which makes one question the sensitivity of the technique for detecting HBDs. ",
"Perhaps a more representative example could be shown. ",
"Another concern is that using the presence of a visible axon as a criterion for counting a HBD probably markedly reduces the sensitivity of the assay and may bias the analysis.",
"\n\nAR: It is difficult to represent the three-dimensional image stacks used for data analysis as two-dimensional images for figures. ",
"While fine features such as axons and dendrites can be easily traced through the 3D image stacks, these features are often obscured by overlying structures in maximum projections, and can be averaged out by other types of 3D rendering software. ",
"To overcome these limitations, for the revised manuscript we now present a neuronal reconstruction for figure 4, in which the cell of interest is highlighted relative to processes from adjacent cells. ",
"We have used this approach in the past (Walter et al., ",
"J.Neurosci., ",
"2007) and note that these images should be viewed as neuronal reconstructions, similar to classical camera lucida drawings. ",
"This approached is described in the methods (page 11, paragraph 1) and figure legend.",
"\n\nThe rational for using a visible axon as a criterion for whether or not to score a cell for basal dendrites is to avoid false negatives that can result from poor cell labeling, or difficulty in imaging cells deep in the tissue. ",
"The mature granule cells scored for basal dendrites should all have axons (we are not aware of any reports of axon-less granule cells in animals with normal genetics). ",
"In our experience, we have found that basal dendrites can often be thinner than apical dendrites, making them easier to miss. ",
"Confirming that the axon can be visualized on the cell ensures that a basal dendrite, if present, would also be visible. ",
"It is reasonable to assume that such methodological limitations are randomly distributed throughout the data set, so excluding fainter cells should not bias the results, whereas including cells without visible axons would be expected to increase the number of false negatives in the data set. ",
"The text has been modified to clarify this point (page 9, paragraph 1)\n\nReviewer 1, point 5. ",
"The tables do not add much to the data already in the figures. ",
"Perhaps the authors can add ectopic cells to Fig. ",
"2B and get rid of all of the tables, which are redundant with the figures. ",
"Also, in tables 1 and 3, the % change from control would be better expressed as positive numbers with increase or decrease, rather than as a negative number representing an increase, and denoting a \"100%\" change when one of the numbers is zero is not statistically accurate.",
"\n\nAR: We thank the reviewer for catching these errors. ",
"We have corrected the graphs and removed the redundant tables. ",
"The information is now completely provided in all the text and figures. ",
"We decided not to include graphs for ectopic cells and basal dendrites in figure 2, because differences between control and SE mice for these measures are well established in the literature, and therefore wouldn\\'t add much to the figure. ",
"Descriptions of these findings in the text should now be adequate.",
"\n\nReviewer 2: points 2, 5, 6,7,10\n\nReviewer 2, point 2. ",
"Mortality rates from pilocarpine\n\na\\. How many animals began the study versus how many survived until week 16?",
"\n\nAR: 25 animals were treated with pilocarpine, and 12 of these mice survived to the end of the study. ",
"Overall survival was 48%. ",
"This is now described in the methods (page 6, paragraph 1).",
"\n\nReviewer 2, point 5. ",
"How do you know for sure that clusters are from same clones? ",
"Is there precedent for methods used? (",
"150 micrometers apart etc) Especially in the case of status animals where they report fewer progenitor cells that may act to \"anchor\" the cluster.",
"\n\na\\. If only two colors were obtained/ analyzed, how can you ensure that \"clusters\" are arising from a single progenitor? ",
"Are they sparse enough?",
"\n\nAR: This is an important point. ",
"Our criterion to include cells in a cluster was based on previous clonal analysis experiments of similar nature (Bonaguidi et al., ",
"2011; Calzolari et al., ",
"2015). ",
"These groups have validated this approach, and this is now clarified further in the text on page 8, paragraph 1. ",
"These groups used only a single fluorophore to label cells, so the current approach with two fluorophores will provide greater accuracy. ",
"Nonetheless, the technique is not foolproof. ",
"There will occasionally be progenitors labeled that are close together, leading to the false merging of separate clones. ",
"The large number of clones analyzed in the present study (291 total), however, provides a means to overcome this experimental noise. ",
"This limitation is now addressed in the discussion (page 18, paragraph 2).",
"\n\nIt is concerning that out of 7 colors available through brainbow, the authors were only able to visualize 4 and utilize 2 for quantification. ",
"Have the author's considered why they only get 4 colors in their hands? ",
"Additionally, amplification techniques should be attempted to at least be able to utilize the other 2 available colors (TSA kit for example).",
"\n\nAR: In our hands, the brainbow mouse only produced two useable colors in brain, YFP and RFP. ",
"We observed infrequent CFP-labeled cells, but the membrane-bound presentation of this fluorochrome made morphological analyses unreliable. ",
"In general, we have found it difficult to discriminate neighboring cells with membrane-bound reporters. ",
"We did not observe any GFP-labeled cells in our tissue, nor did we observe any color combinations. ",
"We believe this reflects poor recombination efficiency with this construct in brain tissue, since other investigators have reported better results in other tissues. ",
"Notably, Calzolari and colleagues (Nature Neuroscience 18:490-492, 2015) recently reported identical problems with this reporter line when used in brain. ",
"Finally, with regard to immunostaining, since our analyses indicate that the primary problem is lack of expression, rather than low expression, immunostaining is unlikely to increase the number or types of labeled cells. ",
"When fluorophore expression was present, it was generally of sufficient intensity to visualize the cells. ",
"We do not feel that these problems with the mouse line undermine the study, however, as clonal analyses have previously been conducted with only single fluorophores. ",
"In this regard, the brainbow line is still an advantage.",
"\n\nReviewer 2, point 6. ",
"When determining depleted progenitor pools in \"epileptic\" animals, how were the animals deemed epileptic? ",
"Video? ",
"EEG?",
"\n\nAR: Past studies in our hands and others demonstrate that pilocarpine-induced status epilepticus reliably leads to the development of epilepsy in 90-100% mice on a C57BL/6 background (Murphy et al., ",
"2011, Murphy et al., ",
"2012, Hester and Danzer, 2013). ",
"Given the high incidence of spontaneous recurrent seizures in this model, we did not conduct independent video-EEG studies. ",
"Morphological abnormalities in these animals (ectopic cells, cells with basal dendrites) provide further evidence that the animals were epileptic, as these abnormalities do not develop in normal animals. ",
"Nevertheless, in the interest of clarity, the text has been edited to refer to mice in the study as animals that have undergone status epilepticus, rather than as epileptic animals.",
"\n\na\\. There is a lot of cell death in the pilocarpine model. ",
"Could the drastic drop out of quiescence be simply from cell death?",
"\n\nAR: We agree with the reviewer that cell death could be a factor and have now included this point in the discussion (page 23, paragraph 2).",
"\n\nReviewer 2, point 7. ",
"Is one week of tamoxifen sufficient to turn on enough cells?",
"\n\nAR: We sacrificed a small cohort of mice two days after the last injection on week seven and analyzed the labeled cells. ",
"We found that on average two, type-1 progenitor cells were labelled per 300 m of the hippocampus (Fig 1 panel C2). ",
"This low induction was ideal for clonal analysis as it provided enough spatial resolution between developing clusters. ",
"Also, it revealed that sufficient numbers of cells were induced for the desired statistical power employed for this study.",
"\n\nOn a similar note, authors mention in the introduction that DGCs born weeks before insults develop abnormally, yet chose to focus only on cells born within one week of status. ",
"Because it is fairly well established that DGCs need \\~4 weeks to develop fully (Parent et al., ",
"Gage et al) is it possible that DGCs at different developmental states behave differently? ",
"Why did the authors decide to focus on this subgroup of developing DGCs? ",
"While this may not affect the study of ectopic cells, work from Parent et al has shown HBDs arising at various DGC developmental stages all the way to maturity.",
"\n\nAR: The reviewer is correct in noting that granule cells of different ages exhibit distinct responses to status epilepticus, and we have revised this discussion to clarify that our findings only apply to the cohort examined (page 19, paragraph 2). ",
"For the current design, we had a two-fold rationale. ",
"First, we wanted to examine the effects of status epilepticus on granule cell progenitors, not immature granule cells. ",
"Earlier tamoxifen treatment to generate immature granule cells for SE exposure would certainly be interesting, but addresses different experimental questions than those examined here. ",
"The second aspect of our approach --- to label progenitor cells just before SE rather than after --- was to ensure that control and experimental groups would have identical populations of progenitor cells at the time of status. ",
"If SE alters Gli1 expression for example, tamoxifen treatment after SE might label a different population of progenitor cells. ",
"The current design ensures that the results reflect SE-induced changes in the behavior of an initially identical progenitor pool, rather than studies of distinct progenitor pools.",
"\n\nReviewer 2, point 10. ",
"In the discussion under Temporal/ global regulation of basal dendrite formation, the authors note on line 402 that seizures are both episodic and affect the entire brain when they occur. ",
"This is incorrect as seizures can affect localized portions of the brain. ",
"Consider revising this statement.",
"\n\nAR: We thank the reviewer for catching this misstatement and have revised the text accordingly (page 22, paragraph 2).",
"\n\n[^1]: The authors declare no competing financial interests.",
"\n\n[^2]: Author Contributions: S.P.S., C.L.L., and A.A. performed research; S.P.S., C.L.L., J.J.M., and S.C.D. analyzed data; S.P.S., C.L.L., J.J.M., and S.C.D. wrote the paper; S.C.D. designed research.",
"\n\n[^3]: This research was supported by National Institute of Neurological Disorders and Stroke Grant 2R01-NS-065020 (to S.C.D.), an Albert J. Ryan Foundation Fellowship (to S.P.S.), and an American Heart Association Pre-Doctoral Award (to S.P.S.).",
"\n"
] | {
"pile_set_name": "PubMed Central"
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[
"Yurika Hirayama\n\nis a Japanese ski jumper and the 2011 World University Vice Champion.",
"\n\nCareer\nAt the age of 14, Hirayama started her career as a ski jumper at the FIS Race in Sapporo in 2005 where she placed eighth. ",
"In 2007, Hirayama placed 22nd at the Junior World Championships in Tarvisio but did not take part in races outside Japan until 2010. ",
"In 2010, at the Junior World Championships in Hinterzarten Hirayama placed 24th. ",
"In 2011/12, Hirayama took part in the World Cup competitions in Zao placing 35th and 34th. ",
"In 2012/13, Hirayama is present at the complete World Cup series (Lillehammer: 46th, Sochi: 36th and 38th, Ramsau: 27th, Schonach: 22nd and 30th).",
"\n\nReferences\n\nExternal links \n\n FIS Biography in English\n Hirayama's Blog in Japanese\n\nCategory:1990 births\nCategory:Living people\nCategory:Japanese female ski jumpers\nCategory:Universiade medalists in ski jumping\nCategory:Universiade silver medalists for Japan\nCategory:Competitors at the 2011 Winter Universiade"
] | {
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"Q:\n\nBentching after vomiting\n\nIf someone gets sick during a meal, assuming they are not incapacitated as a result, should they still Bentch, or do we say that they did not gain any nourishment and it's like they didn't eat (or at least like they didn't eat enough to constitute a meal)?",
"\n\nA:\n\nSee Har Tz'vi (OC 1:163) where he discusses this issue. ",
"He first quotes the Panim M'iros (2:27), Chasam Sofer (OC 127), and the Minchas Chinuch (313), who hold that hana'as mei'av is a necessary criterion for birkas hamazon. ",
"Therefore, these opinions hold, if someone ate half of a k'zayis, then vomited it up, then ate another half k'zayis, he would be exempt from birkas hamazon (see also Chullin 103b). ",
"The Har Tz'vi infers from these opinions that if someone ate a k'zayis at one time, there might be grounds to say that birkas hamazon is required. ",
"\nHowever, he then quotes the Gra (Kol Eliyahu, § 9), who writes that if someone vomited out all of what he ate, he is exempt from birkas hamazon because this is similar to a case of delaying bentching until after the food is digested (whereupon one can no longer bentch). ",
"\nThe responsum concludes by referencing the Imrei Binah (OC, § 14), who writes that even if a person kept a little bit of the k'zayis down, he should not bentch because kdei sviah does not remain in his digestive tract. ",
"\nSee also Torah Lishmah (§ 125), who writes that someone who vomits, if he won't be able to eat more and keep it down, should bentch without shem u'malchus.",
"\n\n"
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"Q:\n\nIn predicate logic, all $x$ in set $X$ who have quality A also have quality B\n\nHow do I convert the premise that\nall $x$ in set $X$ for which $A$ is true $\\implies B$ is also true\nthe main part where I am having trouble finding examples is \"all $x$ in set $X$ for which $A$ is true\"...I can do there exists $x$ in $X$ for which $A$ is true, but am confused as to what is equivalent to the subset of $X$ for which $A$ is true in predicate logic...\nI guess what I am asking is if I have to specify the truth set: $\\{x \\in X\\mid A(x)\\}$ in the predicate logic expression.",
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"The challenges of innovating\n\nShare\n\nCarlos Saldaña, IE Marketing Director\nThrough the years, the Marketing Department has seen how the world changed and has had to adapt or even foresee into the future. ",
"Now, their efforts towards making IE renowned as a mark of excellence and all over the world pass by the innovation in channels and formats and an international mindset.",
"\n\nWe use both our own and third-party cookies to enhance our services and to offer you the content that most suits your preferences by analysing your browsing habits. ",
"Your continued use of the site means that you accept these cookies. ",
"You may change your settings and obtain more information here."
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"The push to remove all Confederate iconography continues at one Texas high school where eligible students voted to replace its Old South logo with a politically correct “service dog” mascot.",
"\n\nStudents at the soon-to-be formerly named Robert E. Lee High in the North East Independent School District recently selected the rendering of a service dog, ending the era where their campus logo featured 13 stars and “Grumpy Gus,” a cartoon Confederate soldier bearing the signature red and gray campus colors.",
"\n\nOn Monday night, North East ISD officials unveiled the chosen image of the new canine mascot outfitted in a service dog vest. ",
"The school’s motto, the “Volunteers,” is displayed on the side of the vest. ",
"On the chest, the vest reads “LEE,” an acronym for the school’s future name, “Legacy of Educational Excellence” High.",
"\n\nThe service dog mascot and other changes will go into effect at the start of the 2018-19 school year when the high school officially becomes “LEE.” ",
"The school will maintain the red and gray colors.",
"\n\nThe San Antonio Express News reported that Lee High freshman, sophomores, and juniors along with eighth graders enrolled in the Nimitz and Jackson middle schools which are zoned for their graduates to attend the high school next year, selected the service dog logo from three proposed mascot designs, according to a letter sent to Lee High families by Principal Nicole Franco. ",
"Students cast their votes during lunch periods last week.",
"\n\nLast year, Breitbart Texas reported that the North East ISD board of trustees voted to re-imagine their campus named for Confederate General Robert E. Lee with a more welcoming 21st Century moniker. ",
"This decision came amid a nationwide push to strip all Confederate history from memory after violence erupted at a Charlottesville, Virginia, protest. ",
"School district officials wrestled with re-branding Lee High to a politically correct moniker that would not break the bank.",
"\n\nSuperintendent Brian Gottardy originally told trustees a full re-brand would cost more than $1.3 million, a far too hefty taxpayer price tag. ",
"Thus, Gottardy later presented a scaled down plan to the school board. ",
"It packaged proposed expenditures for athletics, school facilities, fine arts, and Junior ROTC into a more manageable $300,000.",
"\n\nSubsequently, the school board voted to rename the high school. ",
"Trustees accepted more than 2,000 submissions for new names, ultimately transforming Lee High to the cost-cutting “LEE.”",
"\n\nThe school board also voted to keep its long-standing motto, the “Volunteers,” now paired with the service dog imagery. ",
"However, they dumped the school spirit team names — the Rebel Rousers and the Dixie Drillers. ",
"LEE High will write a new school spirit song.",
"\n\nIn his presentation last year, Gottardy said that the campus would retain the many honors, trophies, and awards accumulated during its 60 years of operation as Robert E. Lee High. ",
"The superintendent also announced plans to honor the high school’s history under the Confederate general’s nomenclature by opening on-campus museum at a cost of $15,000. ",
"He said it would be open to the public.",
"\n\nIn 2015, a similar re-branding campaign erupted calling for the removal of all images and historical figures associated with the Confederacy after the tragic Charleston, South Carolina, church shooting of nine black parishioners. ",
"At that time, though, the same North East ISD school board bucked the trend and voted to keep the high school’s name as Robert E. Lee.",
"\n\nFollow Merrill Hope, a member of the original Breitbart Texas team, on Twitter."
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[
"Introduction {#Sec1}\n============\n\nChinese rice wine (CRW) is a Chinese traditional alcoholic beverage. ",
"It has been popular in China for thousands of years because of full-bodied aroma, soft taste, high nutritional value and low alcohol content^[@CR1],[@CR2]^. CRW fermentation usually uses grain as feedstock. ",
"Wheat Qu, as a starter for CRW production, contains a variety of microorganisms and their metabolites. ",
"Wheat Qu has a compound enzyme preparation to provide a variety of enzymes, which is needed for the CRW fermentation process. ",
"Therefore, the quality of Wheat Qu has a great impact on CRW^[@CR3]^. Additionally, yeast and amyloglucosidase were added separately to pre-saccharify feedstock for increasing alcohol. ",
"The fermentation of CRW needed two processes: saccharification of starch and fermentation of sugars. ",
"Starch can be saccharified to glucose and other sugars by amylase and amyloglucosidase. ",
"Meanwhile, protein can be hydrolyzed by proteases and carboxypeptidases to peptides and amino acids. ",
"Then, yeast can utilize these nutrients for cell growth, fermentation and flavor formation^[@CR1]^. Furthermore, with development of the CRW industry, the kinds of feedstocks for fermentation of CRW continue to expand^[@CR4]^. In recent years, some scholars have begun to use *Fagopyrum tataricum* as fermentation feedstock to study and optimize the fermenting process of CRW^[@CR5],[@CR6]^. *F. tataricum* grain, which was a functional food material, have many advantages, such as high biological value proteins, high crude fiber, balanced amino acid composition, and high vitamin B1, B2, and B6^[@CR7],[@CR8]^. In addition to rich nutrition, *F*. *",
"tataricum* also has functions of lowering blood lipid and blood sugar, regulating myocardial activity, clearing free radicals and other physiological functions^[@CR9]^. Studies have shown that *F*. *",
"tataricum* CRW has the function of reducing blood lipid, blood sugar and blood pressure^[@CR10]^. The use of *F*. *",
"tataricum* as feedstock can not only use its rich nutrition and physiological activity to increase the variety of CRW, but also meet the consumer's demand for low alcohol content^[@CR2]^.\n\nFlavor is an important feature of CRW. ",
"Alcohols, aldehydes, esters, acids, phenols and so on, contribute to the various volatile flavor formation. ",
"There are many reports describing the volatile and semi-volatile flavor compounds in CRW^[@CR11]^. A total of 66 volatile compounds were identified in glutinous rice CRW that rice was pretreated by enzymatic extrusion or steam-cooked, in the meanwhile, the alcohols, esters, and aromatic compounds contribute to the various volatile flavor formation^[@CR12]^. A total of 15 volatile compounds were detected and measured in the CRW from Shaoxing region, including 5 higher alcohols and 10 esters. ",
"Almost all of these compounds have already been detected in CRW^[@CR4]^. It is well known that bacteria can produce many flavor compounds and determine the quality of CRW. ",
"However, there are few reports about how bacterial communities change in CRW, and most bacteria can only be detected by cultivation-dependent methods, such as cell culture and colony counting^[@CR13],[@CR14]^. With the development of science and technology, Illumina-based metagenomic sequencing is widely used. ",
"Through this technique, Xie *et al*. ",
"revealed the community structure of Shaoxing rice wine at different fermentation times^[@CR15]^. Liu *et al*. ",
"used metagenomics and found that the Jiannanchun koji microbial community composition is stable and mainly distributed in *Proteobacteria*, *Firmicutes* and *Actinobacteria*, which accounted for more than 95% of the microbial community^[@CR16]^. However, studies on the microbial diversity and flavor of Chinese rice wine fermented with *F. tataricum* using the High-throughput sequencing (HTS) approach have not been reported yet.",
"\n\nWith the development of ecological techniques, there are increasing studies which focus on microbes and metabolic phenotype correlation in the food fermentation^[@CR17],[@CR18]^. Some statistic approach and models are applied to understand the role of microbiota and functions of the community in fermented foods. ",
"To associate the microbiota and volatile compounds in the fermentation of Daqu starter for Chinese liquor making, Pearson correlations coefficient (r) was calculated among the microbial genera and metabolites, and suggested that Lactobacillus were associated with esters, acids and alcoholsand Bacillus and Clavispora positively correlated with six pyrazines^[@CR19]^. In addition, in the acetic acid fermentation (AAF) of Zhenjiang aromatic vinegar, bidirectional orthogonal partial least squares (O2PLS) was applied to predict the relationship between microbiota assembly and flavors datasets. ",
"Finally, a functional core microbiota was selected by comparison of the comprehensive importance of microbiota correlated with flavours^[@CR20]^. In this study, we adopted Pearson correlations coefficient (r), correlation network and bidirectional orthogonal partial least squares (O2PLS) to predict relationship between microbial genera and flavor. ",
"Functional core microbiota were selected by comparison of the comprehensive significance of microbiota correlated with flavors in the fermentation process of CRW using *F. tataricum* grain as feedstock.",
"\n\nIn this paper, the volatile flavor compounds were determined by HS-SPME and GC-MS. ",
"Bacterial diversity was analyzed using MiSeq sequencing of the 16S rRNA gene clone library. ",
"Fungal diversity was analyzed using MiSeq sequencing of the internal transcribed spacer (ITS1) region. ",
"The objective of this study was to identify the flavor compounds in *F*. *",
"tataricum* grain CRW, and to predict the relationship between volatile compounds and microbial communities, and to estimate the functional significant microbiota by bioinformatics analysis. ",
"In order to produce high-quality CRW, we must make full use of the aroma producing microorganisms. ",
"So the analysis the relationship of flavor substances and microorganisms maybe provide some hints. ",
"This experiment provide theoretical support for future production of CRW by analyzing the microbial community dynamics and metabolic profile of CRW, predicting the association between microbes and flavors. ",
"In addition, *F. tataricum* as the feedstock can increase the variety of CRW and increase the added value of *F. tataricum*.",
"\n\nMaterials and Methods {#Sec2}\n=====================\n\nSample collection {#Sec3}\n-----------------\n\n*F. tataricum* were collected in April 2017, in Zhangjiakou, Hebei Province. ",
"Fermentation was carried out in winery's experimental tanks with a constant temperature of 28 °C after collecting the *F. tataricum*. ",
"The period of fermentation was 12 days. ",
"The samples were harvested every two days. ",
"During different fermentation stages of 0, 2, 4, 6, 8, 10, and 12 days, three parallel samples were collected each time. ",
"When sampling, the ferment was mixed evenly. ",
"The 300 g samples that at different locations in the pits were harvested into sterile bottles. ",
"A total of 21 samples of different fermentation days were collected. ",
"Each sample was divided into two parts: one part was centrifuged with 4000 r/min for 20 min and stored the supernatant at 4 °C immediately for the flavor test, and the other part was continues placed in sterile bottles and stored at −80 °C before DNA extraction. ",
"Dry ice was used to keep low temperature throughout the transportation process.",
"\n\nDetermination of Reducing Sugar, Alcohol, Acidity, Flavor Compounds and Organic Acids {#Sec4}\n-------------------------------------------------------------------------------------\n\nThe DNS method was adopted to determine the reducing sugar content with glucose as a reference standards. ",
"A 1.0 mL liquid sample was ten times diluted. ",
"Then, 1.0 mL of the dilution was shaken well with 1.0 mL of DNS solution and put in a boiling water bath for 5 min. ",
"When the mixture cooled to room temperature, it was diluted by water to a final volume of 10.0 mL, before absorbance at 540 nm was read^[@CR21]^. The alcohol degree was measured by density bottle method. ",
"By taking 100 mL wine into a distillation flask for rotary evaporation, the distillation was stopped when about 95 mL of distillate was collected. ",
"After cooling the distillate to room temperature, the volume was made up to 100 mL by water in a measuring cylinder. ",
"The alcohol content was measured by density bottle. ",
"Acidity was measured by titration. ",
"10 mL of wine was taken into a beaker, and 50 mL water without of carbon dioxide was added. ",
"After pH value was titrate to 8 with 0.1 mol/L NaOH, the volume of NaOH consumed was recorded. ",
"The acidity was calculate according to the formula below.$$\\documentclass[12pt]{minimal}\n \\usepackage{amsmath}\n \\usepackage{wasysym} \n \\usepackage{amsfonts} \n \\usepackage{amssymb} \n \\usepackage{amsbsy}\n \\usepackage{mathrsfs}\n \\usepackage{upgreek}\n \\setlength{\\oddsidemargin}{-69pt}\n \\begin{document}$${\\rm{X}}=\\frac{(V1-V2)\\times c\\times 0.090}{V}\\times 1000$$\\end{document}$$\n\nX: Acidity of the sample. ",
"The unit is g/L.\n\nV1: The volume of NaOH consumed by the sample. ",
"The unit is mL\n\nV2: The volume of NaOH consumed by the blank. ",
"The unit is mL\n\nc: The concentration of NaOH. ",
"The unit is mol/L\n\n0.090: The molar mass of lactic acid. ",
"The unit is g/mol\n\nV: The volume of sample. ",
"The unit is mL.\n\nThose methods all according to the standard of GB/T13662-2008 to evaluate the wine quality^[@CR22]^.\n\nThe flavor compounds in the samples were analyzed by headspace solid-phase microextraction and gas chromatography mass spectrometry (HS-SPME/GC-MS). ",
"Semi-quantification of volatile compounds was performed using 2-octanol as the internal standard^[@CR23]^. Each wine sample (8 mL) was placed in a 15 mL SPME glass vial together with 2.5 g sodium chloride and 150 μL 2-octanol (65.76 mg/L) . ",
"The sample was extracted by SPME fiber (50/30 μm DVB/CAR/PDMS) in water bath and ultrasonic wave for 45 min at 50 °C. ",
"After extraction, fiber was introduced into the injection port of the GC-MS system (at 230 °C for 5 min). ",
"Identification was carried out using a Shimadzua-QP2010 Plus-GC-MS. ",
"Each concentrated fraction was analyzed on a DB-wax column (30 m X 0.25 mm i.e., 0.25 µm film thickness). ",
"The carrier gas, helium, was circulated at 1 mL/ min in split-flow mode with a split ratio of 50/1. ",
"The oven temperature program was as follows: 35 °C (4 min), 5 °C/min to 150 °C (2 min), 3 °C/min to 210 °C. ",
"The injector and detector temperatures were 230 °C and the ion source temperature was set at 200 °C. ",
"The ion energy for the electron impact (EI) was always 70 eV. The chromatograms were recorded by monitoring the total ion currents in the 30-350 mass range. ",
"Data was collected in total ion mode. ",
"Semi-quantitative data of the flavor compounds were acquired with the following formula:$$\\documentclass[12pt]{minimal}\n \\usepackage{amsmath}\n \\usepackage{wasysym} \n \\usepackage{amsfonts} \n \\usepackage{amssymb} \n \\usepackage{amsbsy}\n \\usepackage{mathrsfs}\n \\usepackage{upgreek}\n \\setlength{\\oddsidemargin}{-69pt}\n \\begin{document}$${\\rm{C}}({\\rm{\\mu }}g/{\\rm{L}})=\\frac{{\\rm{Ac}}}{{\\rm{Ais}}}{\\rm{Cis}}({\\rm{\\mu }}g/{\\rm{L}})$$\\end{document}$$\n\nC: the relative concentration of flavor compounds;\n\nCis: the final concentration of internal standard in sample;\n\nAc: peak area of flavor compounds;\n\nAis: peak area of internal standard.",
"\n\nThe organic acids in the samples were analyzed by HPLC. ",
"Each wine sample (5 mL) was placed in a tube and centrifuged at 10,000 r/min for 15 min, then filtered through a 0.45 mm microporous membrane. ",
"Chromatographic conditions were based on the method described by Ye *et al*.^[@CR24]^. The determination of the organic acids was carried by HPLC. ",
"The separations were carried out on an Agilent 1260 Infinity II equipped with a 250 mm × 4.6 mm and 5 μm welch ultimate XB-C18 column. ",
"The column temperature was set at 30 °C. ",
"A mixture of phosphate buffer (0.01 mol/L (NH~4~)~2~HPO~4~) adjusted with a phosphoric acid solution to a pH of 3.0 was used as the mobile phase with a flow rate of 0.8 mL/min. ",
"The detection wavelength was 215 nm.",
"\n\nDNA extraction, PCR amplification and Illumina MiSeq sequencing {#Sec5}\n---------------------------------------------------------------\n\nMicrobial DNA was extracted from the samples using a M4015-01E.Z.N.A.^®^ soil DNA kit (Omega Bio-Tek, Norcross, GA, U.S.A.). ",
"The final DNA concentration and purity were determined using NanoDrop 2000 UV-vis spectrophotometer (Thermo Scientific, Wilmington, USA). ",
"DNA quality was checked by 1% agarose gel electrophoresis. ",
"The primers for bacterial and archaeal 16 S rRNA genes and the eukaryotic ITS rRNA genes were provided by Majorbio Biotechnology Company. ",
"The V3-V4 hypervariable regions of the bacterial 16 S rRNA gene were amplified by polymerase chain reactions (95 °C for 5 min; followed by 25 cycles of 95 °C for 30 s, 55 °C for 30 s and 72 °C for 40 s with a final extension of 72 °C for 10 min) with primers 338 F (5′-ACTCCTACGGGAGGCAGCAG-3′) and 806 R (5′-GGACTACHVGGGTWTCTAAT-3′)^[@CR25]^ using a thermocycler PCR system (GeneAmp 9700, ABI, USA). ",
"The ITS1 was amplified by PCR (95 °C for 2 min, followed by 30 cycles at 95 °C for 30 s, 61 °C for 30 s, and 72 °C for 45 s with a final extension at 72 °C for 10 min) with the ITS1F (5′-AxxxCTTGGTCATTTAGAGGAAGTAA-3′) and ITS2 (5′-BGCTGCGTTCTTCATCGATGC-3′)^[@CR26]^ primers. ",
"PCR products were purified according to a previous study^[@CR27]^. Purified amplicons were sent to the Majorbio Institute (Shanghai, China) for Illumina high-throughput sequencing on a MiSeq platform (Illumina, CA, USA).",
"\n\nProcessing of sequencing data {#Sec6}\n-----------------------------\n\nRaw fastq files were demultiplexed, quality-filtered by Trimmomatic and merged by FLASH using the following criteria: (i) the reads were truncated at any site receiving an average quality score \\< 20 over a 50 bp sliding window. (",
"ii) Primers were exactly matched, allowing 2 nucleotide mismatches, and reads containing ambiguous bases were removed. (",
"iii) Sequences whose overlap was longer than 10 bp were merged according to their overlap sequence^[@CR27],[@CR28]^.\n\nSequences were clustered into operational taxonomy units (OTUs) at a similarity cutoff of 97% (version 7.1 <http://drive5.com/uparse/>) and further assigned to phylotypes from the phylum to the genus level using classify. ",
"Alpha rarefaction was performed in QIIME (version 1.7.0) using the Chao1 estimates of species abundance^[@CR29]^, which is the observed species estimation of the amount of unique OTUs found in each sample, and the Shannon index^[@CR30]^. The cluster analysis was preceded by PCA^[@CR31]^. For the QIIME calculation, the beta diversity of the unweighted and weighted UniFrac distances was used for UPGMA clustering and principal coordinate analysis^[@CR32]^. To identify the differences in the bacterial communities between the two groups, similarities were analyzed using the Bray-Curtis dissimilarity distance matrices.",
"\n\nThe OTU abundance table was standardized by PICRUSt. ",
"According to the KEGG database, the KO, Pathway and EC information in the fermentation process was obtained, and the abundance of each functional category was calculated according to the OTU abundance. ",
"In addition, for the Pathway, 3 levels of information on the metabolic pathways were obtained using PICRUSt, and the abundance tables at each level were obtained.",
"\n\nThe significance of correlations between the microbial genera and flavor compounds were tested (pearson correlation) for associating the microbiota and flavor compounds. ",
"Benjamini--Hochberg method was used for adjusting the P values by FDR, and the cutoff of adjusted P values was set as 0.05. ",
"The association network was displayed using R language programming^[@CR33]^. O2PLS models were built using the OmicsPLS package of R^[@CR34]^. Permutation test was performed to establish the thresholds for identifying the most influential variables. ",
"Datasets were reshuffled 1000 times and the O2PLS model was established for each rearranged dataset. ",
"Setting the significant level (α) of 0.05 for the two datasets, the upper and lower α/2 quantiles of the loading values were used as the latent variables thresholds^[@CR35]^.\n\nResults {#Sec7}\n=======\n\nChanges of acid, reducing sugar and alcohol {#Sec8}\n-------------------------------------------\n\nThe data in Fig.",
" [1](#Fig1){ref-type=\"fig\"} showed that the concentration of acid and alcohol increased gradually. ",
"The biggest increase was from 0 day to the 2^nd^ day, and tended to be stable at the end of fermentation. ",
"The final acid and alcohol were 7.28 ± 0.05 g/L and 12.8 ± 0.1 g/L, respectively. ",
"The content of reducing sugar rapidly reduced from 35.49 ± 0.29 g/L to 28.47 ± 0.09 g/L in the first two days of fermentation and slowly reduced in the late stage of fermentation. ",
"The final content of reducing sugar was 18.52 ± 0.23 g/L. Detailed data are attached to Supplementary Table [S1](#MOESM1){ref-type=\"media\"}.Figure 1Changes of the acid, reducing sugar and alcohol found in Chinese Rice Wine brewed from *F. tataricum* during fermentation.",
"\n\nChanges of organic acids in the CRW during fermentation {#Sec9}\n-------------------------------------------------------\n\nThe amount of organic acids directly influences the aroma and taste of CRW. ",
"The data showed that malic acid, lactic acid, citric acid and succinic acid were the dominant acids. ",
"The highest total organic acid content was on the 10^th^ day, while the lowest organic acid content was on day 0. ",
"The succinic acid content was the highest and the lactic acid content was second one among organic acids. ",
"The succinic acid content showed an upward trend overall and rose sharply in the first two days, then slowly rose but fluctuated slightly, and finally reached 2753.95 ± 4.70 mg/L. The lactic acid content showed an upward trend in 0--8 days, and it rose sharply in the first two days, then slowly rose and reached 1776.59 ± 5.04 mg/L. But there was a slight downward trend on 8--12 days. ",
"Malic acid content rose to 87.60 ± 6.41 mg/L in the first two days. ",
"But after that it continuously reduced to 17.93 ± 0.22 mg/L. The citric acid content decreased sharply on the 2^nd^ day and then was steady. ",
"The tartaric acid content keep a continuous fluctuation throughout the fermentation. ",
"The oxalic acid, pyruvic acid and α-ketoglutaric acid contents had a similarly growing trend that was a slight increase in the first two days and then trended to steady. ",
"Detailed data are attached to Supplementary Table [S2](#MOESM1){ref-type=\"media\"}.",
"\n\nChanges of volatile compounds in the CRW during fermentation {#Sec10}\n------------------------------------------------------------\n\nA total of 107 volatile compounds were detected in the 21 samples at seven time points, including 19 alkanes, 21 alcohols, 31 esters, 7 ketones, 11 pyrazines, 5 acids, 4 phenols, and 9 other compounds (see Supplementary Table [S3](#MOESM1){ref-type=\"media\"}). ",
"The number of esters tended to increase from the 2^nd^ day to a peak on the 6^th^ day, which was 19. ",
"The number of esters were always higher than other volatile compounds, and the number of alcohols were the second highest. ",
"The kinds of alkanes reached maximum on the 6^th^ day, which was 7, and declined slightly at the 8^th^ day. ",
"The number of ketones, pyrazines, phenols, acids and other volatile compounds remained relatively stable with fluctuations in the fermentation process. ",
"On the last day, 37 compounds were detected, including 2 alkanes, 10 alcohols, 14 esters, 2 ketone, 3 pyrazines, 2 acids, 3 phenols, and 1 other compound. ",
"Among the esters, the relative concentrations of hexanoic acid ethyl ester, octanoic acid ethyl ester, decanoic acid ethyl ester, (E)-9-octadecenoic acid ethyl ester, 9,12-octadecadienoic acid ethyl ester, acetic acid phenylethyl ester and hexadecanoic acid ethyl ester were much higher than other esters. ",
"Ethyl alcohol can react with the acetyltransferase catalyst via esterification in the fermentation of CRW. ",
"Among the alcohols, 2-methyl-1-propanol, 3-methyl-1-butanol, 1-hexanol, 2,3-butanediol and phenylethyl alcohol, which existed in each period of fermentation in this study, were the main alcohols, which is in agreement with the previous report^[@CR36]^. Volatile phenols also had a high concentration during CRW fermentation using *F*. *",
"tataricum* grain as the feedstock. ",
"Among the phenols, 2-methoxy-4-vinylphenol was the main one, which had two maxima at the 4^th^ and 12^th^ days. ",
"Additionally, there were 11 pyrazine compounds identified in CRW samples.",
"\n\nChanges in bacterial communities during different fermentation stages {#Sec11}\n---------------------------------------------------------------------\n\nTo detect the intra- and inter variabilities in the bacterial community among the seven groups, we estimated a series of alpha diversity indices, including the Shannon and Simpson indices (see Supplementary Fig.",
" [S1](#MOESM1){ref-type=\"media\"}). ",
"As shown in the Fig.",
" [S1a](#MOESM1){ref-type=\"media\"}, the bacterial community diversity was highest on the 8^th^ day. ",
"The changing trend in the diversity increased gradually and then decreased. ",
"The Simpson diversity index showed that the highest community diversity was on the 12^th^ day (see Fig.",
" [S1b](#MOESM1){ref-type=\"media\"}).",
"\n\nSequencing of the bacterial communities acquired a total of 1,085,965 sequences, which passed the quality control filters. ",
"The 16S rRNA gene sequences indicated that 168 bacterial genera can be found in the fermentation broth and were distributed among 17 phyla and 108 families. ",
"Most microorganisms in the fermentation broth belonged to three bacterial phyla (*Firmicutes*, *Proteobacteria* and *Actinobacteria*) (see Fig.",
" [2a](#Fig2){ref-type=\"fig\"}). ",
"The phylum *Firmicutes* was dominant. ",
"At the genus level, the dominating genera was *Bacillus* (see Fig.",
" [2b](#Fig2){ref-type=\"fig\"}). *",
"Weissella* and *Paenibacillus* have a higher abundance than the other bacteria. *",
"Bacillus* decreased gradually from the 0 to 4^th^ day and then slightly increased from the 6^th^ day to the end of fermentation. *",
"Weissella* increased and appeared at its maximum on the 8^th^ day and then decreased. ",
"On the 8^th^ day, most of the top 20 genera were the most abundant, which indicated that the fermentation reached the highest level on the 8^th^ day. ",
"Conversely, most of the top 20 genera had the lowest abundance on the last day, except for *Bacillus*. ",
"Among the bacterial communities, *Bacillus* was the dominant bacteria, ranging from 90.05 to 98.21%. ",
"Compared with *Bacillus*, *Lactobacillus*, *Lactococcus* and *Weissella* had a different tendency. ",
"All of them are lactic acid bacteria (LAB). ",
"These groups of bacteria decreased sharply at the beginning of fermentation, increased on the 4^th^ day and eventually decreased slightly at the end of fermentation. ",
"In this study, the relative abundance of *Lactobacillus* was lower, while *Weissella* was higher. ",
"Therefore, *Weissella* was probably the main genus that generated acids and could inhibit the growth of other bacteria. *",
"Saccharopolyspora* belonged to *Actinomycetales*, which peaked after 10 days. ",
"Detailed information on the composition of bacteria is shown in the Supplementary Table [S4](#MOESM1){ref-type=\"media\"}.Figure 2Bacterial community distribution from D0 to D12. ",
"Relative abundance of the most abundant bacteria at the phylum (**a**) and genus (**b**) levels were analyzed. ",
"D0 stands for the day 0 sample and the remainder are deduced by analogy. ",
"The members of the other populations were placed in an artificial group designated as \"Others\".",
"\n\nBased on the 16 S rRNA gene sequencing data, PICRUSt was performed to predict the function of the microorganisms in fermented mash, which showed similar gene functions among all the 21 samples, which were categorized into 39 level 2 KEGG pathways that was shown at Fig.",
" [3](#Fig3){ref-type=\"fig\"} (human disease pathway has been deleted), in which Membrane Transport, Carbohydrate Metabolism,Amino Acid Metabolism, Replication and Repair,Cellular Processes and Signaling, Energy Metabolism,Poorly Characterized, Translation, Metabolism of Cofactors and Vitamins were the dominant KEGG pathways. ",
"Detailed information of the predicted gene functions related to KEGG pathways at levels 3 is shown in the Supplementary Table [S5](#MOESM1){ref-type=\"media\"}.Figure 3Relative abundance levels of the predicted gene function related to the KEGG pathways at levels 1 and 2.",
"\n\nChanges in fungal communities during different fermentation stages {#Sec12}\n------------------------------------------------------------------\n\nA total of 1,029,988 sequences for the fungal communities were obtained after quality control processing. ",
"Three phyla, 12 families and 12 genera were detected. ",
"Approximately 99% of the ITS region sequences could be assigned to the Ascomycota (see Fig.",
" [4a](#Fig4){ref-type=\"fig\"}). ",
"At the genus level, unclassfied_O\\_*Saccharomycetale*s had the highest percent relative abundance in the fermentation and remained basically stable with slight fluctuation. ",
"It was the dominant fungi genus, occupying more than 70% abundance during fermentation. (",
"See Fig.",
" [4b](#Fig4){ref-type=\"fig\"}). ",
"The relative abundance of Pichia peaked at day 0 and then decreased rapidly. ",
"There were fewer kinds of fungal genus participating in the fermentation of CRW. ",
"Detailed information of fungal is shown in the Supplementary Table [S6](#MOESM1){ref-type=\"media\"}.Figure 4Fungal community distribution from D1 to D12. ",
"Relative abundance of the most abundant fungi at the phylum (**a**) and genus (**b**) level were analyzed. ",
"D0 stands for the day 0 sample, and the remainder can be analogously deduced. ",
"The members of the other populations were placed in an artificial group designated as \"Others\".",
"\n\nAssociation between microorganisms and flavor compounds {#Sec13}\n-------------------------------------------------------\n\nA correlation analysis of the microbial and flavor substances during *F*. *",
"tataricum* grain fermentation was conducted. ",
"To obtain a closer correlation, the P value was adjusted. ",
"By filtering the data with a P adjust less than 0.05, we established 838 correlations (see Fig.",
" [5](#Fig5){ref-type=\"fig\"} and Supplementary Table [S7](#MOESM1){ref-type=\"media\"}). ",
"A total of 108 microbial genera may be involved in the formation of 72 flavor compounds (adjusted P \\< 0.05). ",
"Through the correlation analysis we predicted the following results. *",
"Aspergillus*, *Cladosporium*, norank_O\\_*Hypocreales*, unclassified_O\\_*Hypocreales*, *Lactococcus*, *Saccharomycopsis*, *Sporidiobolus*, *Pichia*, norank_O\\_*Malasseziales et al*. ",
"participated in the formation of the largest number of flavor compounds, which were up to 22. *",
"Bacillus*, *Staphylococcus*, *Cochliobolus*, *Perlucidibaca*, *Enterococcus* and norank_O\\_*Obscuribacterales* were only related to 2-methyl-propanoic acid, 3,7-dimethyl-nonane, 3-hydroxy-2-butanone, butanedioic acid diethyl ester, methyl-pyrazine and sulfurous acid ethylhexyl isohexyl ester, respectively.",
"Figure 5Correlation between the microorganisms and flavor compounds in *F. tataricum* grain.",
"\n\nPyrazines as the special flavor compounds that were rarely detected (include 2,6-dimethyl-pyrazine, 2-ethenyl-5-methyl-pyrazine, 2-ethyl-3,5-dimethyl-pyrazine, 2-ethyl-5-methyl-pyrazine, 2-ethyl-6-methyl-pyrazine, 3,5-diethyl-2-methyl-pyrazine, ethyl-pyrazine and trimethyl-pyrazine) were correlated with *Aspergillus*, *Cladosporium, Cladosporium*, norank_K\\_*Fungi*, *Lactococcus*, *Pichia*, norank_O\\_*Hypocreales*, unclassified_O\\_*Hypocreales*, norank_O\\_*Malasseziales*, *Saccharomycopsis*, *Sporidiobolus* and norank_O\\_*Tremellales*. ",
"A total of 88 correlations were establish between pyrazines and microorganism.",
"\n\nAssociation between functional significant microbiota and flavor compounds {#Sec14}\n--------------------------------------------------------------------------\n\nThe result of analysis based on O2PLS model shown that 14 genera had significance. ",
"Among them, unclassified_O\\_*Saccharomycetales* had upper quantiles. *",
"Lactococcus*, *Pediococcus*, *Aspergillus*, *Cladosporium*, *Cochliobolus*, *Sporidiobolus*, *Pichia*, *Saccharomycopsis*, *norank_O\\_Hypocreales*, *unclassified_O\\_Hypocreales*, *norank_K\\_Fungi*, *norank_O\\_Malasseziales* and *norank_O\\_Tremellales* had lower quantiles (Supplementary Table [S8](#MOESM1){ref-type=\"media\"}).",
"\n\nFurther analysis was performed to investigate the relationship of significant microbiota correlated with flavor compounds during CRW fermentation process. ",
"It was shown that these significant microbiota built association with 23 kinds of flavor compounds including 8 pyrazines, 4 ketones, 4 alkanes, 3 alcohols, 2 aldehydes, 9,12-octadecadienoic acid ethyl ester and 1-heptadecanamine. ",
"A total of 289 correlations had shown in Fig.",
" [6](#Fig6){ref-type=\"fig\"} and Supplementary Table [S9](#MOESM1){ref-type=\"media\"}. *",
"Pediococcus* only built correlation with 3-hydroxy-2-butanone. ",
"Four genera yeast (*Saccharomycopsis*, *Sporidiobolus*, unclassified_O\\_*Saccharomycetales* and *Pichia*) had similar correlation results, and only unclassified_O\\_*Saccharomycetales* additionally built correlation with 9,12-octadecadienoic acid ethyl ester. ",
"Eight kinds of pyrazines built correlations with functional significant microbiota except *Pediococcus*.Figure 6Association between functional significant microbiota and flavor compounds in *F. tataricum* grain.",
"\n\nDiscussion {#Sec15}\n==========\n\nThe metabolic activity of microorganisms involved in industrial fermentation depends on the fermentation conditions and availability of nutrients. ",
"In a natural environment or under artificial control, the microbial community is likely to produce various metabolites using different materials. ",
"This experiment adopted *F. tataricum* grain as the fermentation material, which is different from the southern CRW made from glutinous rice. ",
"Using Wheat Qu to brew wine is characteristic of CRW, and it is also a traditional operation process of the CRW fermentation process.",
"\n\nIn the fermentation process of CRW, the change of acid, alcohol and reducing sugar are the important physical and chemical indicators which indirectly reflect the vital activities of microorganisms^[@CR37]^. The results showed that ethanol was mainly produced in the first two days because a large amount of reducing sugar was utilized by the yeasts, as the reducing sugar rapidly reduced and the alcohol increased^[@CR38]^. Subsequently, the metabolism of yeasts were inhabited by alcohol. ",
"As a result, the utilization of sugar by yeasts was reduces and the ability to produce alcohol weaken^[@CR39]^. For acid, suitable environment promoted growth of acidogenic bacteria at first two days while the content of acid rose fast. ",
"As the fermentation proceeds, high alcohol and acid concentration restrained acid-producing microbes from growing, so that the acid content began to rise slowly.",
"\n\nMicro-substances such as alcohol, acid, ester and aldehyde contribute to the flavor of CRW^[@CR40]^. The experimental results showed that the alcohol had the highest proportion among the volatile compounds, and the higher alcohols had the highest proportion among the alcohol compounds. ",
"Some research indicated that there were two main pathways for higher alcohol metabolism: the Ehrlich metabolic pathway in which amino acids are converted to alcohols by deamination and the anabolic pathways that by the synthetic pathway of glucose^[@CR41]^. At the same time, the fermentation broth was rich in various microorganisms and enzymes. ",
"Therefore, lipid oxidation might be another way to produce alcohol compounds^[@CR42]^. The Ehrlich metabolic pathway not only produced volatile compounds (higher alcohols), but also decomposes some bitter amino acids (leucine), improving the flavor of CRW^[@CR43]^. In addition, the experimental results showed that changing trend of alcohol and alkane were opposite, so they might be mutually transformed.",
"\n\nEsters are the most important flavor components, which contribute fruit and floral aroma^[@CR44]^. One source of esters is the esterification of fatty acids and alcohols. ",
"Another source is the anabolism of microorganisms by the use of higher alcohols under the action of acetyltransferases^[@CR45]^. The results showed that ethyl ester was the most abundant ester, indicating that ethyl esters may play an important role in the composition of volatile components. ",
"Phenols, pyrazines had the similar trend with esters. ",
"Among them, 2-methoxy-4-vinylphenol was the most important phenolic, which can contribute aroma and had a low threshold (3 µg/L)^[@CR46]^. It was reported that the content of 2-methoxy-4-vinylphenol in Wheat Qu was high^[@CR47]^. It might be derived from Wheat Qu^[@CR48]^, but whether it was related to the metabolism of microorganisms in CRW has not been reported. ",
"Pyrazines are important flavor compounds in many fermented foods and alcoholic beverages, with baking, nuts and cocoa aroma. ",
"It is a heterocyclic nitrogen compound that can be used as a pharmaceutical, as well as in flavorings and spice intermediates.",
"\n\nKetones had a higher content than other flavor compounds in the beginning of fermentation. ",
"It indicated that feedstock such as Wheat Qu might contain ketones which also participated in the metabolism of microorganisms in fermentation^[@CR49]^.\n\nThe initial microbial community participating in fermentation were mainly brought in by the Wheat Qu, however, the process of making Wheat Qu was completely open, as a result, the kinds of microorganisms contained in the Wheat Qu were extremely complicated. ",
"The changes in the composition of the bacterial communities affected the quality of CRW, and thereby reflected its role in the CRW fermentation process. ",
"At the phylum level, the bacterial communities detected in CRW fermented with *F. tataricum* were similar to those fermented with rice in Zhejiang Province, but they were obviously different at the genus level^[@CR50]^. At the beginning of fermentation, most microorganisms were brought in from the feedstock, brewing water and the environment. ",
"In the first two days, as the nutrients were richer, microorganisms grew quickly in this environment. ",
"However, as the fermentation continued, alcohol and acid increased and oxygen decreased, which inhibited the microorganisms' growth.",
"\n\nIn this study, *Bacillus* was the dominating genus during the fermentation process. *",
"Bacillus* which can produce spores, has stronger environmental adaptability and resistance to acid and alcohol^[@CR51]^. This may be one of the reasons why it can exist with high relative abundance during fermentation. ",
"In addition, *Weissella* also has a higher abundance, and is the main genus of acid production by which inhibit the growth of other microorganisms. ",
"There is similarity in the fungal diversity of CRW that fermented by *F.tataricum* and rice. ",
"According to previous reports of Shaoxing CRW, Ascomycota occupied 99% of the total fungal population at the phylum level. ",
"In this study, the data showed the same result. ",
"At the genus level, there were fewer fungal communities participating in the fermentation of CRW. ",
"Unclassfied_O\\_*Saccharomycetales* and *Pichia* as major fungal genus may produce more volatile compounds or nutrients.",
"\n\nThis experiment used an association analysis to speculate that *Cochliobolus* and unclassified_O\\_*Saccharomycetales* were closely related to the formation of 9,12-octadecadienoic acid ethyl ester. ",
"In addition, *Cellvibrio* was associated with benzeneacetic acid ethyl ester, oxalic acid- 2-ethylhexyl hexyl ester and sulfurous acid ethylhexyl hexyl ester. *",
"Bdellovibrio* functions as a phage, which can stably decompose protein and use peptide and amino acids as a carbon source and energy source, which was related to the formation of pentadecanoic acid ethyl ester. ",
"This may be related to the ability of *Bdellovibrio* to produce various enzymes depending on the host cell. *",
"Rhizobium* is a heterotrophic bacterium that uses carbohydrate various salts and organic acids (mainly malic and succinic acid) as carbon sources and can utilize mannitol and other sugars to produce acids. ",
"During fermentation, it was related to the formation of pentadecanoic acid ethyl ester and ethyl 9-hexadecenoate.",
"\n\nAcetoin (3-hydroxy-2-butanone) is an important physiological metabolite excreted by many microorganisms, serves as a quality index of fermented products and is an important flavor in vinegar^[@CR52]^. Members of *Acetobacter*, *Lactococcus*, *Klebsiella*, *Enterobacter*, and *Bacillus* are considered acetoin biosynthesis bacteria in various fermentation processes^[@CR53],[@CR54]^. In our study, speculated the synthesis of acetoin was closely related to *Aspergillus*, *Cladosporium*, *Cochliobolus*, *Lactococcus*, *Pichia*, *Pediococcus*, norank_O\\_*Malasseziales*, *Saccharomycopsis*, *Sporidiobolus* and unclassified_O\\_*Saccharomycetales*. ",
"Biosynthesis of acetoin is a complex process.",
"\n\nPyrazine are rarely detected in southern CRW. ",
"It is produced mostly by non-enzymatic browning in the Maillard reaction^[@CR55]^. The occurrence of microbial metabolites of pyrazine compounds is rare, but not absent. ",
"A previous study showed that *Bacillus pumilus* is a high-yield bacterial strain for tetramethyl pyrazine biosynthesis^[@CR56]^. In this experiment, all the pyrazine built correlation with the same microbial genera.",
"\n\nAbout acids, most *Lactobacillus* species had the ability to produce lactic acid, ethanol and acetic acid. ",
"The genera *Pichia*, *Saccharomyces*, and *Zygosaccharomyces* can convert lactic acid to pyruvate. ",
"Moreover, they converted pyruvate to acetyl-CoA, acetaldehyde in liquor production^[@CR57]^. The citric acid-accumulating microorganisms mainly include several yeast strains and molds from the genera *Aspergillus*, *Penicillium*, and *Candida*^[@CR58]^. The malic acid-producing microorganisms were also mainly from *Saccharomyces* and *Aspergillus*^[@CR59],[@CR60]^. Except for the reported microbe communities, the possibly main microorganisms associated with organic acids in this experiment were *Saccharomycopsis* (which ferments one or more sugars, including galactose, glucose, maltose and sucrose, producing amino acids, organic acids, inorganic acids, etc.), *",
"Lactococcus* (which uses some carbohydrates to ferment acid; L(+)-lactic acid is the main product), *Pediococcus* (which produces acids by the fermentation of sugars; the main product is DL, or L(+)-lactate. ",
"Some strains can produce diacetyl butter or a cream aroma), *Streptomyces* (which can utilize glucose and have a strong starch and protein hydrolysis ability. ",
"It is the most important antibiotic-producing bacteria, and some strains can produce industrial protease, glucose isomerase, vitamin B12 and others), *Bacillus* (which has strong protease, amylase and lipase activity and can synthesize many organic acids, enzymes, physiological activities and other substances), *Acetobacter* (which can oxidize ethanol to produce acetic acid and can be further oxidized into carbon dioxide, which can cause a variety of low alcohol wine deterioration and can be used in brewing vinegar).",
"\n\nIn the high expression metabolic pathway, ABC transporters are members of a transport system superfamily that is one of the largest and is possibly one of the oldest families, with representatives in all the extant phyla from prokaryotes to humans^[@CR61]^. ABC transporters take up a large variety of nutrients, biosynthetic precursors, trace metals and vitamins, while exporters transport lipids, sterols, drugs, and a large variety of primary and secondary metabolites^[@CR62]^. Glycolysis/Gluconeogenesis is a series of reactions that degrade glucose and glycogen to pyruvate and ATP. ",
"It is a ubiquitous pathway of glucose degradation in all living organisms. ",
"Most monosaccharides, such as sugars and galactose, can be converted into one of these intermediates. ",
"The intermediates can be used directly. ",
"For example, the intermediate product, dihydroxy phosphate acetone (DHAP), is a combination that forms the source of fatty glycerol fatty acids. ",
"Metatranscriptomic analysis revealed pyruvate metabolism in yeasts (genera *Pichia, Schizosaccharomyces*, *Saccharomyces* and *Zygosaccharomyces*) and lactic acid bacteria (genus *Lactobacillus*), which was classified into two stages in the production of the flavor components, with the genus *Schizosaccharomyces* serving as the core functional microorganism and the genus *Lactobacillus* serving as the core functional microorganism^[@CR57]^. Specific expression of genes in metabolism also requires subsequent meta-analysis.",
"\n\nIn this experiment, the micro-ecological structure of *F. tataricum* grain wine was detected by high throughput sequencing, and HS-SPME/GC-MS and HPLC were used to determine the kinds and contents of the flavor substances. ",
"The correlation analysis predicted the relationship between the core of the flavor substances and the microorganisms. ",
"In addition to the known major microbial communities, there are many new microorganisms involved in the production of the core flavor compounds. ",
"Fermenting rice wine with *F. tataricum* can not only increase the variety of CRW, but also increase the added value of *F. tataricum*. ",
"How to improve the flavor and quality of CRW is important to every producer. ",
"To produce high-quality CRW, we must make full use of the aroma producing microorganisms. ",
"So the analysis of flavor substances and microorganisms' relationship maybe provide some hints. ",
"According to our knowledge, this is the first report to analyse the relationship between the structure and function of microbial community in *F. tataricum* fermentation.",
"\n\nSupplementary information\n=========================\n\n {#Sec16}\n\nsupplementary information\n\n**Publisher's note:** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.",
"\n\nSupplementary information\n=========================\n\n**Supplementary information** accompanies this paper at 10.1038/s41598-019-40337-8.",
"\n\nThis study was supported by National Key R&D Program of China (2016YFD0400500) and National Natural Science Foundation of China (No. ",
"31400161). ",
"We are also grateful to all wine producers that collaborate with this study.",
"\n\nJ.L.X. X.L. and Q.R. designed the research; H.J.W. and J.L.X. analyzed the results; H.J.W. and Z.W.W. performed the experiments; J.L.X. Y.S.W. and F.P.Z. participated in writing the manuscript and revision; L.P.S. amended the manuscript and reanalyzed the result; Q.R. and J.L.X. supervised the research.",
"\n\nAll data generated or analyzed during this study are included in this published article (and its Supplementary Information files). ",
"Sequence data at <https://www.ncbi.nlm.nih.gov/bioproject/> Accession: PRJNA483531.",
"\n\nCompeting Interests {#FPar1}\n===================\n\nThe authors declare no competing interests.",
"\n"
] | {
"pile_set_name": "PubMed Central"
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[
"[Study on mechanism of hepatotoxicity of Ploygoni Multiflori Caulis based on function inhibition of bilirubin-associated transporters in idiosyncratic rat].",
"\nTo explore the possible mechanism of liver injury, the effects of Ploygoni Multiflori Caulis and its extractive on the function of bilirubin-associated transporters were investigated in normal (N) and idiosyncratic (LPS) rats (M). ",
"The normal and LPS rats were respectively administrated powder of Ploygoni Multiflori Caulis, its extractive and same volume of 0.5% CMC-Na solution for 7 d. BSP, a substrate of the transporters of Oatp1a1 and Oatp1b2 was selected, and its pharmacokinetic parameters of intravenous injection were determined to examined the activity these transporters. ",
"Meanwhile the mRNA expressions of transporters were detected. ",
"Compared with N-blank control group, besides M-powder group, the Cmax has no significantly different from other groups, t1/2, AUC0-t and AUC0-∞ were significantly increased, and CL were significantly decreased. ",
"However, compared with N- blank control group, AST and ALT decreased significantly. ",
"The expression of Oatp1a1, Oatp1b2 and MRP2 mRNA was significantly decreased (P<0.05), but there was no act synergistically when Ploygoni Multiflori Caulis and extractive were combined with LPS. ",
"The function of Oatp1a1, Oatp1b2 and MRP2 in rats were significantly inhibited by Ploygoni Multiflori Caulis and extractive, which may be an important cause of hepatotoxicity."
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[
"Polymer light emitting diode (PLED) with a practically acceptable lifetime is an important issue for realization of its industrialization. ",
"Therefore, using oxygen- and moisture-stable high-work-function metals as the cathode such as Al, Cu, Ag, and Au has attracted extensive attentions recently. ",
"The crucial issue for using the high-work-function metals is the large electron-injection barrier from the metal cathode to emitting layer (EML). ",
"Water- or alcohol-soluble electron injection layer (EIL) based on hydroxyl, amino and ammonium-salt groups grafted conjugated polymer has been demonstrated to allow a use of high-work-function metal as the cathodes because the formation of interfacial dipole or space charge between EIL and the cathode can reduce electron-injection barrier (Huang, F., et al., ",
"Chem. ",
"Mater., ",
"16, 708 (2004). ",
"Wu, H. B., et al., ",
"Adv. ",
"Mater., ",
"16, 1826 (2004). ",
"Wu, H., et al., ",
"Org. ",
"Electron., ",
"6, 118 (2005). ",
"Huang, F., et al., ",
"Adv. ",
"Mater., ",
"19, 2010 (2007). ",
"Huang, F., et al., ",
"Adv. ",
"Mater., ",
"19, 2457 (2009). ",
"Oh, S. H., et al., ",
"Adv. ",
"Mater., ",
"20, 1624 (2008). ",
"Yang, R., et al., ",
"J. Am. ",
"Chem. ",
"Soc. ",
"128, 14422 (2006). ",
"Seo, J. H., et al., ",
"J. Am. ",
"Chem. ",
"Soc. ",
"130, 10042 (2008)). ",
"Consequently, the maximum external quantum efficiency ηext (and its corresponding luminous efficiency ηL) for blue, green, and red emission PLEDs based on fluorescent conjugated polymers and Al as the cathode were reported to reach 1.62% (1.3 cd/A) (Wu, H. B., et al., ",
"Adv. ",
"Mater., ",
"16, 1826 (2004)), 7.85% (23.8 cd/A) (Wu, H. B., et al., ",
"Adv. ",
"Mater., ",
"16, 1826 (2004)), and 2.94% (2.89 cd/A) (Huang, F., et al., ",
"Adv. ",
"Mater., ",
"19, 2457 (2009)), respectively. ",
"But, the brightness (and applied voltage) at the ηext for the three emissions are only 380 cd/m2 (9.7 V), 7,923 cd/m2 (8.8 V), and 1,040 cd/m2 (9.4 V), respectively, which may cause the extra energy consumption and thus is detrimental to the PLED application. ",
"Therefore, enormous efforts must be made on the study of useful water- or alcohol-soluble EIL.",
"\nIn addition to the hydrophilic groups above, crown ether groups may be expected to serve the same purpose. ",
"Polyfluorene grafted with 15-crown-4 moiety (PFC) is used as an EIL for poly(9,9-dihexylfluorene)-based device with Ca as the cathode to reduce turn-on voltage from 6.6 V (without PFC) to 4.1 V (with PFC) and enhance the maximum brightness Bmax (and ηL) from 880 cd/m2 (0.29 cd/A) to 2,800 cd/m2 (0.53 cd/A) due to a formation of interfacial dipole leading to a rise of vacuum level of metal cathode and thus lowering of the electron injection barrier (Yu, J. M., et al., ",
"J. Polym. ",
"Sci. ",
"Part A: Polym. ",
"Chem., ",
"47, 2985 (2009)). ",
"Crown ethers are a special class of ethers able to form stable complexes with ions of alkali, alkaline earth, and transition metals (Pedersen, C. J., J. Am. ",
"Chem. ",
"Soc., ",
"89, 2495 (1967). ",
"Gokel, G. W., et al., ",
"Chem. ",
"Rev., 104, 2723 (2004). ",
"Pedersen, C. J., Angew. ",
"Chem. ",
"Int. ",
"Ed. ",
"Engl., ",
"27, 1021 (1988)). ",
"A metal ion with diameter close to the cavity diameter of a crown ether can form a stable complex with it (Pedersen, C. J., Angew. ",
"Chem. ",
"Int. ",
"Ed. ",
"Engl., ",
"27, 1021 (1988)). ",
"For example, the cavities of 12-crown-4 (1.2-1.5 Å), 15-crown-5 (1.7-2.2 Å) and 18-crown-6 (2.6-3.2 Å) can form stable complexes with lithium ion (1.36 Å), sodium ion (1.94 Å) and potassium ion (2.66 Å), respectively (Pedersen, C. J., Angew. ",
"Chem. ",
"Int. ",
"Ed. ",
"Engl., ",
"27, 1021 (1988)). ",
"Due to the specific chelating selectivity of crown ether on metal ion, conjugated polymers grafted with various crown ethers on side chain are widely used as a fluorescent sensor for detecting metal ions such as 15-crown-4 grafted hyperbranched (or linear) oligo(fluorene vinylene) for Ru3+ and Fe3+ ions (Yu, J. M., et al., ",
"Macromolecules, 42, 8052 (2009)) or polyfluorene derivatives with benzo-18-crown-6 pendants for Pb2+ ion (Yu, M., et al., ",
"Macromol. ",
"Rapid Commun., ",
"28, 1333 (2007)).",
"\nSo far two kinds of electron injection layers have been used for the OLEDs, which are an inorganic slat and an organic small molecule matrix doped with an inorganic salts and/or an organic small molecule. ",
"Examples of the inorganic salt are vapor deposited Ba-containing compounds such as BaF2 (Cina, S., U.S. Pat. ",
"No. ",
"7,833,812 B2 (2010)), and metal oxides such as LiCoO2 and LiNiO2 (Qiu, Y., et al., ",
"U.S. Pat. ",
"No. ",
"7,501,755 B2 (2009)). ",
"One example of the doped organic small molecule matrix is triazine matrix doped with N,N′-di(naphthalene-1-yl)-N,N′-diphenyl-benzidine and SiO2 (SiOc or Sc) (Aziz, H., U.S. Pat. ",
"No. ",
"7,111,407 B2 (2010))."
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"An electron microscope study employing horseradish peroxidase.",
"\nElectron microscope observations were made of rat peroneal nerve after crushing using intravenously injected horseradish peroxidase (HRP) as a tracer protein to indicate changes in vascular permeability. ",
"At 1/2 h and 2 d after the crush there was gross leakage of HRP from damaged capillaries at the site of injury but none from vessels above or below this. ",
"Ultrastructurally vessels at the site of crush showed broken and separated endothelial cells. ",
"Proximally and distally there was little abnormal in the vessel walls; vesicles containing HRP were absent and tight-junctions between cells remained intact. ",
"Twenty-one days after the crush, leakage of HRP was found both at the site of crush and along the distal segment. ",
"The only change in vessel walls was an obvious increase in vesicles filled with HRP. ",
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"Stockingtops's review of Wok Inn, Uckfield\n\nGood Points\nA fantastic place, with a great atmosphere, lovely staff, traditional full service and nothing is too much trouble. ",
"The food is the best Chinese this side of China town.",
"\n\nBad Points\nIf it's very busy it can be difficult to get a table. ",
"It is also in the middle of nowhere.",
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"We use the Wok Inn near Uckfield at work as a reward. ",
"It is by far the best team motivator yet. ",
"There is an \"eat as much as you like\" option for a very cheap price. ",
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"I think we have now sampled everything on the menu.",
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"We all love the place.",
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"A computer-tailored dietary fat intake intervention for adolescents: results of a randomized controlled trial.",
"\nThe positive effects of computer-tailored dietary fat intake interventions have been demonstrated in adults, but few studies have investigated the impact on adolescents. ",
"The purpose is to evaluate the acceptability, feasibility and effectiveness of a computer-tailored dietary fat intake education program for adolescents. ",
"A random sample of 10 schools, 5 with general and 5 with technical-vocational education programs, were selected to participate. ",
"In each of the 10 schools, 2 classes of 7th graders were randomly assigned to the intervention (n = 153) or control (no-intervention, n = 151) condition. ",
"Students were exposed once in class to a 50-min theory-based computer-tailored dietary fat intake intervention. ",
"Questionnaires were completed 1 week before (food frequency questionnaire for dietary fat intake + psychosocial determinants) and 3 months after (process evaluation + food frequency questionnaire for dietary fat intake + psychosocial determinants) the intervention. ",
"About one in three students evaluated the intervention as interesting (34%), novel (38%), personally relevant (26%), credible (34%), and correct (38%). ",
"Half of the students evaluated the intervention messages to be too long, and one fourth did not read the intervention messages. ",
"A decrease in dietary fat consumption was shown in girls enrolled in technical-vocational schools (F = 3.5, p < or = .05) and in boys and girls undertaking general education who reported to have read the intervention messages (F = 3.6, p < or = .05); however, no intervention effects were detected for the total sample. ",
"Further improvements to the intervention for use in adolescents should be evaluated. ",
"Given that a positive impact was shown in most adolescents and that a computer-tailored dietary fat intake education program has the capability of reaching large groups at low cost, this study shows that using such interventions in adolescents has potential."
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" \\\\\n \\hline\n\\end{tabular}\n\nBut the combined column labels end up getting an extra space after their first character.",
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"\n\nA:\n\nYour syntax is wrong, it should be \\multicolumn{2}{c||}{Liberal Arts}. ",
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"OUR BLOG\n\nNews & Updates\n\nTips to leverage your business with photo editing services\n\nPublished: Aug 8th, 2017\n\nMost businesses, especially ecommerce sites have realized the importance of a visually appealing photographs and how they help them entice the customers to make purchases. ",
"This is where; photo editing services can come in handy. ",
"It is now become the crucial aspect of marketing, communication as well as branding.",
"\n\nWith the rise in the use of social media as a platform to market their services and products, images have become important for most businesses like ecommerce, retail, fashion, food etc.",
"\n\nProfessional photo editing companies can help to edit your images, thus making it visually more appealing and help build the identity for the brand. ",
"Let’s take a look at some of the tips on how to make the most of your business with the help of professional photo editing services.",
"\n\nHow image editing services can help your businesses?",
"\n\nIt helps to improve your business credibility:- You would have seen how customers are more attracted by real photographs than with stock photographs. ",
"With the help of professional photo editing services, you have the facility to make pictures of your original products look more appealing, without misguiding your customers with false pictures. ",
"Thus, this helps to increase the credibility of the business.",
"\n\nIt helps to build up your brand:- Editing the images to fit the brand and reflect its tone can be done by photo editing services such as cropping, adding patterns etc. ",
"This also helps to build your customer’s confidence in your brand.",
"\n\nIt helps to customize photographs for multiple platforms :- How an image is displayed in hoardings or paper advertisements vary from that on a digital platform. ",
"The product images across mobile platforms or social media varies. ",
"Professional photo editing services helps to overcome this difficulty by making sure that the photographs are edited to look equally appealing across all platforms.",
"\n\nIt helps to bring in more customers and increase sales :- With the help of photo editing, it is possible to improve the look and feel of images, thus making it more appealing. ",
"These high-quality images will help to entice more customers, leading to increased sales.",
"\n\nKey Takeaway: You can see here that if you leverage the key benefits of the editing services, you can transform your images from ordinary to captivating, thus benefiting your business."
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"Mobile Banking Compliance\n\nAccount for these four compliance areas if you offer mobile products and services.",
"\n\nIn my compliance world, I like to write about topics that are black and white. ",
"But this month I’m going to discuss mobile banking compliance, which currently features a few more shades of gray. ",
"Mobile banking compliance receives minimal guidance from the regulators, and regulations haven’t been updated to keep up with this technology.",
"\n\nSo, consider the following four areas as more credit unions offer mobile banking for members:\n\nRisk assessments;\n\nDisclosures;\n\nTerms and conditions; and\n\nAdvertising.",
"\n\nRisk assessments\n\nAs with any new product, you must account for mobile banking in your existing risk assessments, such as those covering the Bank Secrecy Act, identity theft red flags, vendor management, and online banking.",
"\n\nNCUA has specifically indicated that a credit union’s online banking risk assessment should cover mobile banking. ",
"A credit union should\nperform, review, update, and document a risk assessment as new information becomes available, before implementing new electronic financial services, or at least every 12 months, according to the January 2012 NCUA Report. “",
"The risk assessment should cover all forms of electronic banking, not just Internet-based transactions. ",
"Mobile banking is a good example.”",
"\n\nDisclosures\n\nExisting regulations such as the Electronic Funds Transfer (EFT) Act/Regulation E do apply to mobile banking, so you must provide proper disclosures. ",
"You may include the mobile banking Reg E disclosure as part of your account agreement, or you can provide it separately. ",
"Under Reg E, your initial disclosure contained in your account agreement may cover all EFT services (ATMs, debit cards, mobile banking, online banking, etc.) ",
"even if members haven’t arranged to receive all services at the time you provide the account agreement. ",
"Thus, if you include mobile banking in the account agreement, you don’t need to provide members a new Reg E disclosure when they actually sign up for and/or begin using mobile banking.",
"\n\nIf you have existing members who want to sign up for mobile banking and it wasn’t part of their initial Reg E disclosures, you’ll need to determine how to provide the disclosures. ",
"If your member already has Reg E services (such as a debit card) and received the initial Reg E disclosures for that service, then you only need to disclose the terms and conditions that differ.",
"\n\nTerms and conditions\n\nYou should have an agreement with your member for the use of mobile banking. ",
"Some credit unions think the required regulatory disclosures are enough, but that isn’t the case.",
"\n\nYou might include the regulatory disclosures in the agreement. ",
"But there are other contractual terms you might want to impose, such as security, access, notifications, illegal use, termination, liability, or indemnification.",
"\n\nAdvertising\n\nIf you’re advertising loans through mobile banking, you still must provide the proper disclosures. ",
"If you state the annual percentage rate (APR) for your credit card through a text message advertisement, you must provide the required additional disclosures including:\n\nAny minimum, fixed, transaction, activity, or similar charge that’s a finance charge;\n\nThe fact that the APR is variable if that’s the case; and\n\nAny membership or participation fee that may be imposed.",
"\n\nIf you’re advertising a deposit product and you include the annual percentage yield, not only do you need additional Truth in Savings disclosures, but you also need the official advertising statement. ",
"Will all of it fit into a text message?",
"\n\nAlthough there may be little explicit guidance on mobile banking compliance issues, look at existing regulations to see how they apply to mobile banking. ",
"The compliance issues still exist, even if they’re not all in black and white."
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"There’s something that doesn’t ring-true about the coverage of crisis in Iraq. ",
"Maybe it’s the way the media reiterates the same, tedious storyline over and over again with only the slightest changes in the narrative. ",
"For example, I was reading an article in the Financial Times by Council on Foreign Relations president, Richard Haass, where he says that Maliki’s military forces in Mosul “melted away”. ",
"Interestingly, the Haass op-ed was followed by a piece by David Gardener who used almost the very same language. ",
"He said the “army melts away.” ",
"So, I decided to thumb through the news a bit and see how many other journalists were stung by the “melted away” bug. ",
"And, as it happens, there were quite a few, including Politico, NBC News, News Sentinel, Global Post, the National Interest, ABC News etc. ",
"Now, the only way an unusual expression like that would pop up with such frequency would be if the authors were getting their talking points from a central authority. (",
"which they probably do.) ",
"But the effect, of course, is the exact opposite than what the authors intend, that is, these cookie cutter stories leave readers scratching their heads and feeling like something fishy is going on.",
"\n\nAnd something fishy IS going on. ",
"The whole fable about 1,500 jihadis scaring the pants off 30,000 Iraqi security guards to the point where they threw away their rifles, changed their clothes and headed for the hills, is just not believable. ",
"I don’t know what happened in Mosul, but, I’ll tell you one thing, it wasn’t that. ",
"That story just doesn’t pass the smell test.",
"\n\nAnd what happened in Mosul matters too, because nearly every journalist and pundit in the MSM is using the story to discredit Maliki and suggest that maybe Iraq would be better off without him. ",
"Haass says that it shows that the army’s “allegiance to the government is paper thin”. ",
"Gardener says its a sign of “a fast failing state.” ",
"Other op-ed writers like Nicolas Kristof attack Maliki for other reasons, like being too sectarian. ",
"Here’s Kristof:\n\n“The debacle in Iraq isn’t President Obama’s fault. ",
"It’s not the Republicans’ fault. ",
"Both bear some responsibility, but, overwhelmingly, it’s the fault of the Iraqi prime minister, Nouri Kamal al-Maliki.”",
"\n\nOf course, Kristof is no match for the imperial mouthpiece, Tom Friedman. ",
"When it comes to pure boneheaded bluster, Friedman is still numero uno. ",
"Here’s how the jowly pundit summed it up in an article in the Sunday Times titled “Five Principles for Iraq”:\n\n“Iraq’s Shiite prime minister, Nuri Kamal al-Maliki, has proved himself not to be a friend of a democratic, pluralistic Iraq either. ",
"From Day 1, he has used his office to install Shiites in key security posts, drive out Sunni politicians and generals and direct money to Shiite communities. ",
"In a word, Maliki has been a total jerk. ",
"Besides being prime minister, he made himself acting minister of defense, minister of the interior and national security adviser, and his cronies also control the Central Bank and the Finance Ministry. ",
"Maliki had a choice — to rule in a sectarian way or in an inclusive way — and he chose sectarianism. ",
"We owe him nothing.” (",
"Five Principles for Iraq, Tom Freidman, New York Times)\n\nLeave it to Friedman, eh? ",
"In other words, the reason Iraq is such a mess, has nothing to do with the invasion, the occupation, the death squads, Abu Ghraib, the Salvador Option, the decimated infrastructure, the polluted environment, or the vicious sectarian war the US ignited with its demented counterinsurgency program. ",
"Oh, no. ",
"The reason Iraq is a basketcase is because Maliki is a jerk. ",
"Maliki is sectarian. ",
"Bad Maliki.",
"\n\nSound familiar? ",
"Putin last week. ",
"Maliki this week. ",
"Who’s next?",
"\n\nIn any event, there is a rational explanation for what happened in Mosul although I cannot verify its authenticity. ",
"Check out this post at Syria Perspectives blog:\n\n“…the Iraqi Ba’ath Party’s primary theoretician and Saddam’s right-hand man, ‘Izzaat Ibraaheem Al-Douri, himself a native of Mosul…was searching out allies in a very hostile post-Saddam Iraq … Still on the run and wanted for execution by the Al-Maliki government, Al-Douri still controlled a vast network of Iraqi Sunni Ba’athists who operated in a manner similar to the old Odessa organization that helped escaped Nazis after WWII … he did not have the support structure needed to oust Al-Maliki, so, he found an odd alliance in ISIS through the offices of Erdoghan and Bandar. ",
"Our readers should note that the taking of Mosul was accomplished by former Iraqi Ba’athist officers suspiciously abandoning their posts and leaving a 52,000 man military force without any leadership thereby forcing a complete collapse of the city’s defenses. ",
"The planning and collaboration cannot be coincidental.” (",
"THE INNER CORE OF ISIS – THE INVASIVE SPECIES, Ziad Fadel, Syrian Perspectives)\n\nI’ve read variations of this same explanation on other blogs, but I have no way of knowing whether they’re true or not. ",
"But what I do know, is that it’s a heckuva a lot more believable than the other explanation mainly because it provides enough background and detail to make the scenario seem plausible. ",
"The official version–the “melts away” version– doesn’t do that at all. ",
"It just lays out this big bogus story expecting people to believe it on faith alone. ",
"Why? ",
"Because it appeared in all the papers?",
"\n\nThat seems like a particularly bad reason for believing anything.",
"\n\nAnd the “army melting away” story is just one of many inconsistencies in the official media version of events. ",
"Another puzzler is why Obama allowed the jihadis to rampage across Iraq without lifting a finger to help. ",
"Does that strike anyone else as a bit odd?",
"\n\nWhen was the last time an acting president failed to respond immediately and forcefully to a similar act of aggression?",
"\n\nNever. ",
"The US always responds. ",
"And the pattern is always the same. “",
"Stop what you are doing now or we’re going to bomb you to smithereens.” ",
"Isn’t that the typical response?",
"\n\nSure it is. ",
"But Obama delivered no such threat this time. ",
"Instead, he’s qualified his support for al-Maliki saying that the beleaguered president must “begin accommodating Sunni participation in his government” before the US will lend a hand. ",
"What kind of lame response is that? ",
"Check out this blurb from MNI News:\n\n“President Barack Obama Friday warned Iraqi Prime Minister Nouri al-Maliki that the United States wants him to begin accommodating Sunni participation in his government, or see the United States withhold the help he needs, short of U.S. troops on the ground, to ward off an attack on Baghdad. ",
"Obama added the emphasis of an appearance before TV cameras to his midday message, that while he will be considering options for some military intervention in the days ahead, the next move is up to Maliki.”",
"\n\n(Obama Warns Iraq’s Maliki,Looking for Sunni-Shia Accommodation, MNI)\n\nHave you ever read such nonsense in your life? ",
"Imagine if , let’s say, the jihadi hordes had gathered just 50 miles outside of London and were threatening to invade at any minute. ",
"Do you think Obama would deliver the same message to UK Prime Minister David Cameron?",
"\n\n“Gee, Dave, we’d really like to help out, but you need to put a couple of these guys in your government first. ",
"Would that be okay, Dave? ",
"Just think of it as affirmative action for terrorists.”",
"\n\nIt might sound crazy, but that’s what Obama wants Maliki to do. ",
"So, what’s going on here? ",
"Why is Obama delivering ultimatums when he should be helping out? ",
"Could it be that Obama has a different agenda than Maliki’s and that the present situation actually works to his benefit?",
"\n\nIt sure looks that way. ",
"Just take a look at what Friedman says further on in the same article. ",
"It helps to clarify the point. ",
"He says:\n\n“Maybe Iran, and its wily Revolutionary Guards Quds Force commander, Gen. Qassem Suleimani, aren’t so smart after all. ",
"It was Iran that armed its Iraqi Shiite allies with the specially shaped bombs that killed and wounded many American soldiers. ",
"Iran wanted us out. ",
"It was Iran that pressured Maliki into not signing an agreement with the U.S. to give our troops legal cover to stay in Iraq. ",
"Iran wanted to be the regional hegemon. ",
"Well, Suleimani: “This Bud’s for you.” ",
"Now your forces are overextended in Syria, Lebanon and Iraq, and ours are back home. ",
"Have a nice day.” (",
"5 Principles for Iraq, Tom Friedman, New York Times)\n\nInteresting, eh? ",
"Friedman basically admits that this whole fiasco is about Iran who turned out to be the biggest winner in the Iraq War sweepstakes. ",
"Naturally, that pisses off people in Washington, Tel Aviv and Riyadh to no end, so they’ve cooked up this goofy plan to either remove Maliki altogether or significantly trim his wings. ",
"Isn’t that what’s going on? ",
"And that’s why Obama is holding a gun to Maliki’s head and telling him what hoops he has to jump through in order to get US help. ",
"Because he’s determined to weaken Iran’s hegemonic grip on Baghdad.",
"\n\nFriedman also notes the Status of Forces agreement which would have allowed U.S. troops to stay in Iraq. ",
"Al Maliki rejected the deal which enraged Washington setting the stage for this latest terrorist farce. ",
"Obama intends to reverse that decision by hook or crook. ",
"This is just the way Washington does business, by twisting arms and breaking legs. ",
"Everybody knows this.",
"\n\nTo understand what’s going on today in Iraq, we need to know a little history. ",
"In 2002, The Bush administration commissioned the Rand Corporation “to develop a Shaping Strategy for pacifying Muslim populations where the US has commercial or strategic interests.” ",
"The plan they came up with–which was called “US Strategy in the Muslim World after 9-11”– recommended that the US, “Align its policy with Shiite groups who aspire to have more participation in government and greater freedoms of political and religious expression. ",
"If this alignment can be brought about, it could erect a barrier against radical Islamic movements and may create a foundation for a stable U.S. position in the Middle East.”",
"\n\nThe Bushies decided to follow this wacky plan which proved to be a huge tactical error. ",
"By throwing their weight behind the Shia, they triggered a massive Sunni rebellion that initiated as many as 100 attacks per day on US soldiers. ",
"That, in turn, led to a savage US counterinsurgency that wound up killing tens of thousands of Sunnis while reducing much of the country to ruins. ",
"Petraeus’ vicious onslaught was concealed behind the misleading PR smokescreen of sectarian civil war. ",
"It was actually a genocidal war against the people who Obama now tacitly supports in Mosul and Tikrit.",
"\n\nSo there’s been a huge change of policy, right? ",
"And the fact that the US has taken a hands-off approach to Isis suggests that the Obama administration has abandoned the Rand strategy altogether and is looking for ways to support Sunni-led groups in their effort to topple the Al Assad regime in Damascus, weaken Hezbollah, and curtail Iran’s power in the region. ",
"While the strategy is ruthless and despicable, at least it makes sense in the perverted logic of imperial expansion, which the Rand plan never did.",
"\n\nWhat is happening in Iraq today was anticipated in a 2007 Seymour Hersh article titled “The Redirection.” ",
"Author Tony Cartalucci gives a great summary of the piece in his own article. ",
"He says:\n\n“The Redirection,” documents…US, Saudi, and Israeli intentions to create and deploy sectarian extremists region-wide to confront Iran, Syria, and Hezbollah in Lebanon. ",
"Hersh would note that these “sectarian extremists” were either tied to Al Qaeda, or Al Qaeda itself. ",
"The ISIS army moving toward Baghdad is the final manifestation of this conspiracy, a standing army operating with impunity, threatening to topple the Syrian government, purge pro-Iranian forces in Iraq, and even threatening Iran itself by building a bridge from Al Qaeda’s NATO safe havens in Turkey, across northern Iraq, and up to Iran’s borders directly… It is a defacto re-invasion of Iraq by Western interests – but this time without Western forces directly participating – rather a proxy force the West is desperately attempting to disavow any knowledge of or any connection to.” (",
"America’s Covert Re-Invasion of Iraq, Tony Cartalucci, Information Clearinghouse)\n\nSo, now we’re getting to the crux of the matter, right? ",
"Now we should be able to identify the policy that is guiding events. ",
"What we know for sure is that the US wants to break Iran’s grip on Iraq. ",
"But how do they plan to achieve that; that’s the question?",
"\n\nWell, they could use their old friends the Baathists who they’ve been in touch with since 2007. ",
"That might work. ",
"But then they’d have to add a few jihadis to the mix to make it look believable.",
"\n\nOkay. ",
"But does that mean that Obama is actively supporting Isis?",
"\n\nNo, not necessarily. ",
"Isis is already connected to other Intel agencies and might not need direct support from the US. (",
"Note: Many analysts have stated that the Islamic State of Iraq and al-Sham (ISIS) receives generous donations from Saudi Arabia and Qatar, both of whom are staunch US allies. ",
"According to London’s Daily Express: “through allies such as Saudi Arabia and Qatar, the West (has) supported militant rebel groups which have since mutated into ISIS and other al‑Qaeda connected militias. ( ",
"Daily Telegraph, June 12, 2014)\n\nWhat’s important as far as Obama is concerned, is that the strategic objectives of Isis and those of the United States coincide. ",
"Both entities seek greater political representation for Sunnis, both want to minimize Iranian influence in Iraq, and both support a soft partition plan that former president of the Council on Foreign Relations, Leslie H. Gelb, called “The only viable strategy to correct (Iraq ‘s) historical defect and move in stages toward a three-state solution: Kurds in the north, Sunnis in the center and Shiites in the south.” ",
"This is why Obama hasn’t attacked the militia even though it has marched to within 50 miles of Baghdad. ",
"It’s because the US benefits from these developments.",
"\n\nLet’s summarize:\n\nDoes the US Government “support” or “not support” terrorism depending on the situation?",
"\n\nYes.",
"\n\nHave foreign Intel agencies supplied terrorist organizations in Syria with weapons and logistical support?",
"\n\nYes.",
"\n\nHas the CIA?",
"\n\nYes.",
"\n\nHas the Obama administration signaled that they would like to get rid of al Maliki or greatly reduce his power?",
"\n\nYes.",
"\n\nIs this because they think the present arrangement strengthens Iran’s regional influence?",
"\n\nYes.",
"\n\nWill Isis invade Baghdad?",
"\n\nNo. (",
"This is just a guess, but I expect that something has been already worked out between the Obama team and the Baathist leaders. ",
"If Baghdad was really in danger, Obama would probably be acting with greater earnestness.)",
"\n\nWill Syria and Iraq be partitioned?",
"\n\nYes.",
"\n\nIs Isis a CIA creation?",
"\n\nNo. ",
"According to Ziad Fadel, “ISIS is the creation of the one man who played Alqaeda like a yo-yo. ",
"Bandar bin Sultan.”",
"\n\nDoes Isis take orders from Washington or the CIA?",
"\n\nProbably not, although their actions appear to coincide with US strategic objectives. (",
"which is the point!)",
"\n\nIs Obama’s reluctance to launch an attack on Isis indicate that he wants to diminish Iran’s power in Iraq, redraw the map of the Middle East, and create politically powerless regions run by warlords and tribal leaders?",
"\n\nYes, yes and yes.",
"\n\nMIKE WHITNEY lives in Washington state. ",
"He is a contributor to Hopeless: Barack Obama and the Politics of Illusion (AK Press)."
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"This invention relates to a printing apparatus for printing a variety of information such as images and characters to a recording medium, such as a card, and more particularly to a printing apparatus that is capable of switching printing methods according to the characteristics of the recording medium or the information that is to be recorded.",
"\nConventionally, thermal transfer method printing apparatuses that record desired images and characters by thermally transferring with a thermal head via a thermal transfer film to a recording medium are used to create card shaped recording medium, like credit cards, cash cards, license cards and ID cards. ",
"As an example, Japanese Patent Publication (KOKAI) No. ",
"H9-131930 teaches a direct transfer method printing apparatus that directly transfers images and characters to a recording medium via thermal transfer film. ",
"The use of a thermal sublimate ink has the benefit of attaining high quality images because this type of ink is more expressive. ",
"However, a receptive layer to receive ink on the surface of a recording medium to which images, etc., ",
"are transferred is an essential element to enable this method of printing, so a problem exists in that either the type of recording medium that can be used is limited, or it is necessary to form the aforementioned receptive layer upon the surface of a recording medium.",
"\nGenerally, cards made of polyvinyl chloride (also known as PVC cards) are widely used as the recording medium because they can receive thermal sublimate ink. ",
"However, due to the fact that harmful substances are generated when these cards are burned, there has been consideration given to switching to cards made of polyethylene terephthalate (also known as PET cards). ",
"However, PET cards have a crystal-like quality so not only is it difficult to use them for thermal sublimate printing, but embossing them is also difficult. ",
"Thus, if it is necessary to emboss the surface of the recording medium, the use of PVC cards is presently unavoidable.",
"\nFurthermore, in recent years there are card shaped media of the type having IC chips or antennae embedded therein such as IC cards, which are being used in a variety of fields. ",
"Because of the embedding of such elements into the card, the surface of the card becomes uneven resulting in problems in transferring images.",
"\nJapanese Patent Publication (KOKAI) No. ",
"H8-332742 teaches the technology of an indirect transfer method printing apparatus that transfers an image to an intermediate transfer medium once, then transfers that image again to the recording medium, as a method for overcoming the aforementioned problems. ",
"According to this method, it is possible to overcome the problems such as the limitation of recording medium related to the receptive layer or the transferring of images to an uneven surface of the recording medium which had been considered demerits of the direct transfer method. ",
"Furthermore, this method has the advantage of being easier to print to the entire surface of the card shaped recording medium compared to the direct transfer method.",
"\nDisclosed in Japanese Patent Publication (KOKAI) No. ",
"H8-58125 is a thermal transfer printing apparatus that prints to both the front and back surfaces of a recording paper, configured to transfer ink to an intermediate transfer film using a thermal head and after forming an image, to re-transfer the ink image to a recording paper surface by a heat roller, and configured to transfer ink to the back side of a recording paper with a thermal head that is different from the aforementioned thermal head.",
"\nHowever, running costs for the intermediate transfer method are higher than the direct transfer method because an intermediate transfer medium must be used. ",
"Printing also takes longer. ",
"Furthermore, depending on the design of the card, even if the entire front surface is required for printing, often times the back side only is used to print precautions for card use, thus there are fewer cases requiring printing over the entire surface, so there are merits and demerits for both methods of printing. ",
"Furthermore, according to the technology disclosed in Japanese Patent Publication (KOKAI) No. ",
"H8-58125, a plurality of thermal heads and ink films are disposed so the printing apparatus becomes very large in size thereby increasing associated costs. ",
"Still further, in the event that a coating film is used to protect the ink transferred to the back side of the recording paper in the transferred layer using the aforementioned different thermal head, or to prevent falsification, a separate apparatus such as an over-coating apparatus would be required, thereby increasing the overall size of the apparatus and its associated costs.",
"\nTherefore, to handle information relating to printing, such as the surface shape and characteristics of the recording medium including the type of material of the recording medium such as whether it is PVC or PET, embossed or whether or not it includes IC elements and whether or not it is necessary to print to the entire surface of the recording medium, a printing apparatus can switch printing methods between the direct transfer method and the indirect transfer method to enable printing with the method most appropriate to the recording medium, and to reduce running costs associated with printing. ",
"Furthermore, members required for printing in the direct transfer method and the indirect transfer method are intensively arranged and if part of the members can be unified, the overall size of the printing apparatus can be made more compact and a lower cost printing apparatus can be attained. ",
"Furthermore, an over-coating apparatus is built-in to cover the surface of recording medium thereupon directly printed by the printing apparatus and if the member is shared, it is possible to conserve space and to promote the reduction of cost so such printing apparatus could be widely used.",
"\nAn object of the present invention is to provide a low cost printing apparatus that can switch between the direct transfer method and the indirect transfer method for printing and is not large in overall size.",
"\nAnother object of the present invention is to provide a printing apparatus that can print to a recording medium with the most appropriate printing method and that reduces the running costs associated with printing.",
"\nStill another object of the present invention is to provide a printing apparatus can form high quality images with both the direct transfer method and the indirect transfer method.",
"\nIn order to attain the aforementioned objectives, the print apparatus according to the present invention is equipped with a first printing means for forming images on a recording medium and a second printing means for forming images on an intermediate transfer medium that temporarily retains the image, a transfer means for transferring the image on the aforementioned intermediate transfer medium to the aforementioned recording medium, the aforementioned first printing means and the aforementioned second printing means rearranged at the same position.",
"\nThe aforementioned first printing means and the aforementioned second printing means are composed of the same printing elements. ",
"A platen is opposingly arranged to the aforementioned printing elements that support the aforementioned recording medium when forming images thereto by the aforementioned first printing means and that supports the aforementioned intermediate transfer medium when forming images thereto by the aforementioned second printing means.",
"\nFurther provided is a thermal energy control means for controlling the aforementioned printing elements to vary the thermal energy for printing images when forming images on a recording medium with the aforementioned first printing means and when forming images on a recording medium with the aforementioned second printing means. ",
"The aforementioned thermal energy control means controls so that the thermal energy applied when forming images on a recording medium using the aforementioned first printing means is greater than that applied when forming images on the intermediate transfer medium by the aforementioned second printing means.",
"\nThe aforementioned transfer means can be a heat roller comprising a heating element.",
"\nStill further comprised are a recording medium transport means for transporting the aforementioned recording medium, a recording medium transport drive means for driving the aforementioned recording medium transport means, an intermediate transfer medium transport means for transporting the aforementioned intermediate transfer medium and an intermediate transfer medium transport drive means for driving the aforementioned intermediate transfer medium transport means, wherein the aforementioned recording medium transport drive means and the aforementioned intermediate transfer medium transport drive means are driven so that the transport direction of the aforementioned recording medium when forming images thereto by the aforementioned first printing means and the transport direction of the aforementioned intermediate transfer medium when forming images thereto by the aforementioned second printing means are the same.",
"\nStill further comprised are a recording medium transport means for transporting the aforementioned recording medium, a recording medium transport drive means for driving the aforementioned recording medium transport means, an intermediate transfer medium transport means for transporting the aforementioned intermediate transfer medium and an intermediate transfer medium transport drive means for driving the aforementioned intermediate transfer medium transport means, wherein the aforementioned recording medium transport drive means and the aforementioned intermediate transfer medium transport drive means are driven so that the transport speed of the aforementioned recording medium when forming images thereto by the aforementioned first printing means and the transport speed of the aforementioned intermediate transfer medium when forming images thereto by the aforementioned second printing means are the different. ",
"At this time, it is preferable that the transport speed of the intermediate transfer medium by the aforementioned intermediate transfer medium transport means is higher than the transport speed of the recording medium by the aforementioned recording medium transport means.",
"\nStill further comprised are the first thermal transfer sheet comprising a plurality of colored inks that is applied by the aforementioned first printing means, and the second thermal transfer sheet comprising a plurality of colored inks that is applied by the aforementioned second printing means, wherein the aforementioned first and the aforementioned second thermal transfer sheets are composed of the same sheet. ",
"The aforementioned first and second thermal transfer sheets are arranged with the layer region of a plurality of inks and either a layer region of a single adhesive or a protective layer region in order.",
"\nAlso comprised are the thermal transfer sheet transport means for transporting the aforementioned first and second thermal transfer sheets, the aforementioned thermal transfer sheet transport means being driven so that the transport speed of the aforementioned first thermal transfer sheet when forming images to a recording medium by the aforementioned first printing means and the transport speed of the aforementioned second thermal transfer sheet when forming images to the aforementioned intermediate transfer medium by the aforementioned second printing means are different. ",
"At this time, the transport speed of the aforementioned second thermal transfer sheet when forming images to the aforementioned intermediate transfer medium by the aforementioned second printing means is preferred to be higher than the transport speed of the first thermal transfer sheet when forming images to the aforementioned recording medium by the aforementioned first printing means.",
"\nAlso provided is a thermal energy control means for controlling the first and second printing means to form images by varying the thermal energy the aforementioned first printing means applies to the aforementioned first thermal transfer sheet when forming images to the aforementioned recording medium and the thermal energy the aforementioned second printing means applies to the aforementioned second thermal transfer sheet when forming images to the aforementioned recording medium. ",
"At this time, it is preferred that the aforementioned thermal energy control means controls so that the thermal energy applied to the first thermal transfer sheet by the aforementioned first printing means is greater than that applied to the aforementioned second thermal transfer sheet by the aforementioned second printing means.",
"\nThe print apparatus according to the present invention is equipped with at least one printing means for selectively forming images to a recording medium and to an intermediate transfer medium that temporarily retains images, an over-coating means to cover the surface of the aforementioned recording medium formed thereupon with images with a coating film and a transfer means for transferring the image on the aforementioned intermediate transfer medium to the aforementioned recording medium, the aforementioned over-coating means and the aforementioned transfer means arranged at the same position.",
"\nThe aforementioned over-coating means and the aforementioned transfer means arranged at the same position are composed of the same heating elements. ",
"The aforementioned heating elements can be a heat roller comprising exothermic body.",
"\nHere, further comprised are the supply spool shaft that is capable of mounting the first supply spool for supplying the aforementioned intermediate transfer medium and the second supply spool for supplying the aforementioned coating film and the take-up spool shaft that is capable of mounting the first take-up spool for taking up the aforementioned intermediate transfer medium and the second take-up spool for taking up the aforementioned coating film, at least one of the aforementioned supply spool shaft and the aforementioned take-up spool shaft is a single spool shaft.",
"\nA platen is opposingly arranged to the aforementioned heating elements and supports the aforementioned recording medium when covering by the aforementioned over-coating means and when transferring images by the aforementioned transfer means.",
"\nFurther equipped is the first drive means that rotatingly drives the aforementioned take-up spool shaft, wherein this first drive means rotatingly drives the aforementioned first supply spool and/or the aforementioned second supply spool. ",
"At this time, it is preferred that the aforementioned first drive means is a reversible rotating drive motor.",
"\nThe intermediate transfer medium transport means for transporting the aforementioned intermediate transfer medium is equipped in the intermediate transfer medium transport path between the aforementioned first supply spool and the aforementioned first take-up spool and further equipped is the second drive means for rotatingly driving the aforementioned intermediate transfer medium transport means. ",
"At this time, the second drive means is a reversible drive motor, and further equipped with a measuring means for measuring the feeding and returning amount of the aforementioned intermediate transfer medium disposed in the aforementioned intermediate transfer medium transport path.",
"\nOther objectives and features of the present invention shall be clearly explained in a detailed description of the preferred embodiment below based upon the drawings provided."
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"Why does everybody in porn movies have that eyes-closed, SHOW ME YOUR WAR FACE expression? ",
"What? ",
"Is porn boot camp held on Paris Island?",
"\n\nI’m a guy who hates porn. ",
"And I don’t mean I hate the idea of porn or the political implications of porn. ",
"It’s not like I hate the concept of porn. ",
"Hell, I’m fine with that. ",
"I literally hate the actual experience of watching porn. ",
"I’ve tried. ",
"Believe me. ",
"I mean, as an American man, I’m obligated to try, right? ",
"But, it’s been unpleasant to say the least.",
"\n\nI know there’s a big socio-political brouhaha about porn. ",
"You can’t really raise the issue of filming people humping without getting into a discussion of the impact it has in and out of the bedroom. ",
"When I have some distance from the experience of actually watching porn, say, when I’m shaking hands with the minister after Sunday services, I can think objectively about it. ",
"I can ponder its implications from numberous intellectual angles.",
"\n\nBut if I sit down and hit “play” on a porn movie, all my intellectual considerations go right out the window and horrified panic sets in.",
"\n\nI think we can all agree that, society wide, porn is encouraging a rather less lofty approach to the romantic arts. ",
"Recently, the Good Men Project posted an article titled Unsolicited Penis Pics.",
"\n\nOzy Frantz notes, “Seriously. ",
"There is a (small, but evident) group of men who think the single most attractive thing they can do is send a woman they barely know a picture of their erect penis, to the point that nearly all my female and female-assigned friends who do online dating have received a dick pic.”",
"\n\nMe, I’m thinking these somewhat overzealous lads have been staring at a parade of extra close-up body parts for so long that they now consider emailing a jpeg of their dick to a girl as the modern day equivalent of a jaunty tip of the hat.",
"\n\nDon’t like ads? ",
"Become a supporter and enjoy The Good Men Project ad free\n\n♦◊♦\n\nAnd even though, thanks to the internet, porn has diversified across an infinite range of erotic interests, the plot structures of these videos remain pretty straight forward. ",
"Based, no doubt, on the age old formula that can be summed up as follows:\n\n1) Pizza man comes to door.",
"\n\n2) Housewife invites him in.",
"\n\n3) They both raise their eyebrows.",
"\n\n4) Clothes off.",
"\n\n5) Pizza discarded.",
"\n\n6) Begin humping.",
"\n\nAnd its the “begin humping” part where I lurch forward, stabbing frantically at the off button.",
"\n\nBecause here’s where the erect, swollen, wagging up and down, lookie at what I got here, erections enter the story and take over not only the plot, but the entire screen. ",
"The penis enters the mouth or the vagina and we get to see things up close and personal. ",
"At which point, it freaks me out. ",
"In part, because I feel like I’m WAY too close to some people I don’t know all that well. ",
"AND because I know what’s coming next. ",
"Good old part two. ",
"Just a sure as the sun comes up tomorrow some very sticky body fluids end up on some nice lady’s face. ",
"That freaks me the fuck out. ",
"And then comes that weird hyper fast humping that goes on for hours. ",
"That also freaks me the fuck out.",
"\n\nThe simple fact is I really don’t want to watch unfamiliar erections lurching around the screen like a Godzilla movie for dicks. ",
"I don’t want to watch 20 minutes of fornication that mimics that frantic high speed horseback riding in a 1920’s silent western. ",
"And please. ",
"Why does everybody in porn movies have that eyes-closed, SHOW ME YOUR WAR FACE expression? ",
"What? ",
"Is porn boot camp held on Paris Island? ",
"And don’t even get me started on the hissing breathing thing.",
"\n\nIt’s not the erections that bother me per se. ",
"I don’t mind an erection or two from a respectful distance. ",
"Like, how about far enough away to see the actual people attached to the erections? ",
"It’s the vantage point. ",
"It’s the grinding movement of frantic genitalia shot from six inches away and going on for HOURS.",
"\n\nAnd then there’s the final thing that hits me when I even IMAGINE watching your typical porn film. ",
"Immediately, I start conjuring up the smell. ",
"Yes, that’s right. ",
"The smell. ",
"Like, here I am SIX INCHES AWAY from this…activity. ",
"Did these people wash their asses today? ",
"Did they bathe? ",
"Have they worked out this week or is that sweat they’re dripping kind of bitter and sour? ",
"Do they have hangover breath? ",
"Did they do too much cocaine last night?"
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"\n\n\"She saw a head in the bin?\" ",
"he said.",
"\n\n\"That makes me think twice.\"",
"\n\nMr Hussen said he had no idea what had happened to his daughter for he had not heard from her \"for quite a long time\".",
"\n\nBut he said hearing Shamima Begum's story gave him hope.",
"\n\nImage:Kadiza Sultana (L) married an American, Shamima Begum (C) a Bosnian and Amira Abase an Australian\n\nHe said he would \"give her a hug\" if he was ever reunited with her.",
"\n\nShamima Begum said she had seen two of her friends a fortnight ago, but it is not clear whether Amira Abase was one of them.",
"\n\n:: A nationally representative sample of 1,001 Sky customers were interviewed by SMS on 14 February 2019 about Shamima Begum.",
"\n\nData are weighted to the profile of the population. ",
"Sky Data is a member of the British Polling Council and abides by its rules. ",
"The results of the survey can be found here here."
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"There is an urgent need for a new microbicide that may be used as a vaginal application under female control, to halt the spread of sexually transmitted diseases (STD's). ",
"Of greatest concern is the rapid spread of HIV into the heterosexual population, in which females appear to be more susceptible to the infection. ",
"Vaginal barrier creams, which are under female control contain Nonoxynol 9 (N-9), a nonionic surfactant that is the most frequently used spermicide both nationally and internationally. ",
"Indeed, N-9 is the only FDA-approved spermicide available in the U.S.A. Studies with N-9 over the past two decades have shown that it is bacteriocidal for Neisseria gonorrhea, Trepenoma pallidum and Chlamydia trachomatis. ",
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"Thus, there is an urgent need for microbicides that do not disrupt the delicate epithelia of the reproductive tract and colon. ",
"C31G is a compound with broad spectrum antibacterial, antiviral and antifungal activity with potential to provide protection against STDs. ",
"Interestingly, C31G displays differential toxicity. ",
"Effects on microbes and yeasts are detected at a MIC lesser 0.001% (minimum concentration of drug that inhibits bacterial growth) while effects on mammalian spermatozoa are seen at least one order of magnitude higher (0.01%), and it is considerably les toxic to human somatic cells as compared with N-9. ",
"In project #6, we will evaluate new formulae and formulations of C31G for cytotoxicity against human epithelial somatic cells and spermatozoa. ",
"This will be done using conventional cytotoxicity assays, at two pH levels (5.5 and 7.0) to reflect the environment of the vagina before and after sexual intercourse, and in the presence of cervical mucus and spermatozoa. ",
"Once potential microbicidal formulations have been identified, the assays will be refined by the use of microfabricated channels in 'chips'. ",
"Using these chips in conjunction with cells labelled with fluorescent probes, the viability of epithelial and sperm cells will be evaluated by means of fluorescent microscopy as well as evaluating the effects on two pathogens, Neisseria gonorrheae and Chlamydia trachomatis int he presence of cervical mucus and seminal plasma. ",
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"The bathroom is the only room in your house that you can guarantee everyone is going to visit sooner or later. ",
"It's not a luxury it's a necessity, everyone has to go. ",
"It's the only room in your house that your guests will ask directions to.",
"\nIt makes a lot of sense then, when you are making improvements to your home, to consider the bathroom as a very important target on your list because potentially it can make a very big difference.",
"\n\nTo my surprise it seems that many people don't put the bathroom top of their list when planning home improvements. ",
"This could be because they think that it's too big a job or their bathroom is too small to do anything with. ",
"This isn't necessarily the case.",
"\nRemember that improving a small bathroom doesn't have to be about its physical size but more about it's apparent size and how you give the illusion of space to your visitors. ",
"Choosing light colours, adding lighting around the edges of the bathroom and carefully placing a mirror or two are all inexpensive and relatively simple things you can do that can make a lot of difference in a small bathroom.",
"Reasons for improving your home\nThe main reasons that most people undertake home improvements fall mostly into the categories below:\n\nRepairs\n\nImproving your living standards\n\nIncrease the value of your property\n\nEnergy efficiency\n\nJust because you can\n\nLets take each of these and see how they apply to your small bathroom.",
"\n\nSmall Bathroom Repairs\nRepairing leaky faucets, broken mirrors and cracked bathtubs are all things that you should be doing no matter what the size of your bathroom. ",
"The fact that the room is small might mean that there is less to go wrong but it also means that it could be more awkward to fix. ",
"There is no doubt that making repairs in the bathroom will improve your home to the benefit of your family and increase the value of your property.",
"Improving your living standards\nAdding and improving the features in the most used room in the house can make a big difference to your living standards. ",
"Make the bathroom a place that you are happy to spend time in.",
"Increase the value of your property\nThis is a very important reason for creating the best small bathroom design that you can. ",
"When it comes to selling your property an impressive bathroom can make a very real difference. ",
"If you are planning to sell up soon then you should pay particular attention to your bathroom.",
"Energy efficiency\nWith a little thought with your small bathroom design you can make some energy savings and do your part for the good of the planet. ",
"By installing an on-demand water heater in the shower and taking showers instead of baths you can reduce your electricity and water usage. ",
"Replacing your toilet for a dual-flush type can also save water.",
"Just because you can\nSome people just like a change and there isn't anything wrong with that providing you have the money and the time.",
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"1. ",
"Field of the Invention\nThe present invention relates to an electronic component that includes a capacitor provided on a substrate, for example formed by semiconductor processing technology.",
"\n2. ",
"Description of the Related Art\nIn a radio frequency (hereinafter, RF) system such as a mobile phone or a wireless LAN, signals have to be subjected to phase-matching for satisfactory transmission among functional devices constituting the system. ",
"Accordingly, the input/output terminal of each device is generally provided with a passive component such as an inductor or a capacitor, and that acts as a phase shifter for controlling the phase of the signals.",
"\nIn the RF system in general, a SAW filter is employed for use as a narrow-band frequency filter. ",
"The SAW filter, which includes a piezoelectric element, produces a difference in potential between piezoelectric element electrodes because of a piezoelectric effect, when a physical impact or a thermal effect is applied to the SAW filter or the piezoelectric element thereof during the manufacturing process of the apparatus in which the SAW filter is incorporated. ",
"In this case, a predetermined voltage is applied to an electronic component electrically connected to the SAW filter. ",
"The capacitor included in the passive element (phase shifter) is usually electrically connected to the SAW filter, and hence the capacitor has to have a high withstand voltage (150 V or higher, for instance), to thereby prevent a dielectric breakdown between the capacitor electrodes, which may take place upon application of a voltage accidentally generated by the SAW filter or the piezoelectric element thereof.",
"\nThere has been a constant demand for reduction in dimensions of various parts composing the RF system, driven by the increase in number of parts for achieving a higher performance. ",
"For making the system smaller in dimensions, an integrated passive device (hereinafter, IPD) manufactured based on a semiconductor processing technology, which includes a plurality of predetermined passive components such as an inductor, a capacitor, a resistance and a filter densely integrated on a substrate, may be employed as the passive element (phase shifter). ",
"When employing the IPD, the capacitor included therein still has to have a high withstand voltage, for preventing a dielectric breakdown between the capacitor electrodes, as stated above. ",
"Techniques related to the IPD are found, for example, in JP-A-H04-61264 and JP-A-2002-33239.",
"\nThe capacitor included in the IPD generally has a laminate structure consisting of a lower electrode layer provided on a substrate, an upper electrode layer opposed to the lower electrode layer, and a dielectric layer disposed between the electrode layers. ",
"The lower electrode layer and the upper electrode layer are both expected to have low resistance and to achieve sufficient adhesion to the dielectric layer. ",
"Insufficient adhesion between the layers provokes deterioration with time in adhesion status between those layers (for example, expansion of a gap between the layers with time), thus causing variation in static capacitance characteristic of the capacitor, which is undesirable.",
"\nConventionally, the lower electrode layer of the capacitor included in the IPD is often constituted of a multilayer structure including Ti/Au/Ni/Au layers. ",
"Specifically, such multilayer structure includes a Ti layer (for instance, 50 nm in thickness) provided on a substrate, a first Au layer (for instance, 500 nm in thickness) provided on the Ti layer, a Ni layer (for instance, 50 nm in thickness) provided on the first Au layer, and a second Au layer (for instance, 500 nm in thickness) provided on the Ni layer, such that a minute amount of Ni originating from the Ni layer reaches the surface of the second Au layer on the side of the dielectric layer, because of thermal diffusion. ",
"Such multilayer structure is known to have low resistance, and to achieve sufficient adhesion especially to a SiO2 dielectric layer, because of the presence of Ni on the surface of the second Au layer on the side of the dielectric layer.",
"\nEmploying the Ti/Au/Ni/Au multilayer structure as the lower electrode layer, however, may not always assure the required adhesion performance between the lower electrode layer and the dielectric layer. ",
"Also, employing the Ti/Au/Ni/Au multilayer structure as the lower electrode layer may lead to failure in attaining the withstand voltage of a required level in the capacitor. ",
"Increasing the thickness of the dielectric layer may help in improving the withstand voltage of the capacitor, however the increase in thickness of the dielectric layer requires as much increase in area of the upper electrode layer, in order to secure the required static capacitance of the capacitor. ",
"Therefore, increasing the thickness of the dielectric layer is not a desirable solution, from the view point of suppressing an increase in dimensions of the capacitor, hence the IPD including the capacitor as a component."
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"AgileBits shows off what Android O’s Autofill Framework will look like\n\nWe may earn a commission for purchases made using our links.",
"\n\nAgileBits, the developers behind 1Password, are showing off what Android O’s new password autofill framework will look like once implemented. ",
"For those of you who aren’t familiar, the Android O was recently announced earlier this week and one of the changes outlined in the Developer Preview is the new Autofill Framework. ",
"Since Android O is still in its infancy, we had no way of knowing exactly how this Autofill Framework would work in practice for the end user, until now.",
"\n\nAs you can see in the screen capture above, published on AgileBits’ Vimeo channel, when the user navigates to a login page (eg. ",
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"The Autofill Service tells the Autofill Framework that 1Password recognized the field as a valid username/password input field, but that 1Password needed to be unlocked first before entry. ",
"After unlocking 1Password with biometrics, the user’s credentials were displayed in a dropdown menu which, after selected, are automatically filled in.",
"\n\nGiven the explosion of popularity in password managers in recent years thanks to an increasing number of data breaches, it makes sense for Google to officially support password managers as their own unique category of application in Android. ",
"Users will now spend less time filling in password input fields, as they will no longer have to switch apps or input methods in order to access their password. ",
"Plus, it should be more secure than the copy/paste method of password entry, since Android’s clipboard is accessible by any app on your device.",
"\n\nOnce you’re on Android O, a new autofill service menu will be accessible under Settings –> Apps & Notifications –> Default apps –> Autofill app. ",
"Much like Android’s Accessibility Services or Notification Listeners, you will have to go to this menu to manually grant your password manager app the permission to start its Autofill Service. ",
"Developers can learn how to do so on the Android Developers documentation page for the Autofill Framework.",
"\n\nThis move is a great step forward in making mundane tasks easier to perform. ",
"I’m a big fan of password autofill frameworks, having used several on my desktop browsers, although I prefer to use open source password managers such as Keepass for my password management. ",
"In any case, Android O is still in its early stages, so it will take some time before every password manager service gets updated to support this new feature in Android O."
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"Gov. Mike Pence has confirmed that Donald Trump would remove the Obama administration’s guidance on transgender students. ",
"Among other things, it urged school districts across the country not to discriminate against trans students.",
"\n\nSpeaking on Dr James Dobson’s Family Talk radio show, Pence said that should he and Trump be elected, they would remove the administration’s guidance so that “the transgender bathroom issue can be resolved with common sense at the local level”.",
"\n\n“There’s no area of our lives too small for [the administration] to want to regulate, no aspect of our constitution too large for them to ignore,” he continued. “",
"Donald Trump and I both believe these questions can be resolved with common sense at the local level.”",
"\n\nPence then said that such issues were “resolved in the state of Indiana whenever they come up, and they should be resolved, for the safety and well-being of our children first and foremost, their privacy and rights, and with common sense.”",
"\n\n“Washington has no business intruding on the operation of our local schools. ",
"It’s just one more example of the heavy hand of this administration,” he said, adding: “Washington DC has no business imposing its bill and its values on communities around the nation.”",
"\n\nOf course, Pence is no stranger to imposing values on a community. ",
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"\n\nAfter pressure from businesses and outrage from activists, Indiana was forced to “fix” the law, clarifying that it could not be used to discriminate against LGBT people.",
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"Q:\n\nCisco 3548XL VLANs, no router\n\nI am working on a project currently in our lab. ",
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" Is it possible with the 3548 to have each of my nodes in a different VLAN and still get out to the Internet via our uplink? ",
" I cannot run dot1q for our uplink. ",
" An engineer told me this wasn't possible without router on a stick or an L3 switch. ",
" \nAny advice here is appreciated, for the sake of learning, if the answer is \"no\", could you explain why?",
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"Please advice me what needs to be done. ",
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"Then simply search for your old url, and replace with the new. ",
"This will do this for every post type, post data and if your theme has settings it will also replace in the settings. ",
"Regards TTech \nSecond thing you could do is this method and start your move from scratch\nhttps://wordpress.org/plugins/duplicator/ Download and install this plugin on server 1, active the plugin select it from the menu, run through the steps. ",
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"upload both to server 2. ",
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"\n\nBut what may have started out as an innocent experimentation – a sip here, a gulp there – seems to have developed into an addiction.",
"\n\nBefore Grisham got hooked on Trump she worked for a long time within Arizona politics, most notably for former Attorney General Tom Horne, former House Speaker David Gowan and for the Republican majority of the Arizona House.",
"\n\nAfter the election she was named a special adviser for operations and served on Trump's transition team and eventually became press secretary for first lady Melania Trump.",
"\n\nHer work and history in Arizona were laid out in depth in an article by The Arizona Republic’s Yvonne Wingett Sanchez and Ronald J. Hansen.",
"\n\nShe was known in Arizona as a fierce defender of her employers. ",
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"\n\nApparently, the stuff is addictive.",
"\n\nShe seems now to be pumping it into her veins through an IV infuser.",
"\n\nThere’s no other explanation for Grisham saying of former Trump chief of staff John Kelly, \"I worked with John Kelly, and he was totally unequipped to handle the genius of our great President.\"",
"\n\nThis came after Kelly, a retired Marine Corps general, said at a summit that he might have prevented Trump’s current impeachment troubles if he’d stayed in the job.",
"\n\n\"I said, whatever you do — and we were still in the process of trying to find someone to take my place — I said whatever you do, don't hire a 'yes man,' someone who won't tell you the truth — don't do that,\" Kelly said. \"",
"Because if you do, I believe you will be impeached.\"",
"\n\nThe president snapped back with statement – one of the many, many times he’s attacked former staffers – saying, \"John Kelly never said that, he never said anything like that. ",
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"He just wants to come back into the action like everybody else does.\"",
"\n\nFour-star general versus 'genius'\n\nThen the normally silent Grisham added, \"I worked with John Kelly, and he was totally unequipped to handle the genius of our great President.\"",
"\n\nSeriously?",
"\n\nWhile Trump was taking bone spur deferments during the Vietnam War, Kelly joined the Marine Corps.",
"\n\nHe rose through the ranks, having had his promotions approved again and again by Congress, retiring in 2016 as a four-start general in command of United States Southern Command. ",
"This after 45 years of service.",
"\n\nHis two sons followed him into the Marine Corp, and in 2010 one of them, 29-year-old Robert, was killed in Afghanistan.",
"\n\nTo suggest that a man like Kelly was “unequipped to handle the genius” of Trump is not just proof that Grisham is hooked on the president’s Kool-Aid.",
"\n\nIt’s proof that she’s ODed.",
"\n\nReach Montini at ed.montini@arizonarepublic.com."
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"A nonbleachable rhodopsin analogue with a slow photocycle.",
"\nArchaeal rhodopsins, e.g. bacteriorhodopsin, all have cyclic photoreactions. ",
"Such cycles are achieved by a light-induced isomerization step of their retinal chromophores, which thermally re-isomerize in the dark. ",
"Visual pigment rhodopsins, which contain in the dark state an 11-cis retinal Schiff base, do not share such a mechanism, and following light absorption, they experience a bleaching process and a subsequent release of the photo-isomerized all-trans chromophore from the binding pocket. ",
"The pigment is eventually regenerated by the rebinding of a new 11-cis retinal. ",
"In the artificial visual pigment, Rh(6.10), in which the retinal chromophore is locked in an 11-cis geometry by the introduction of a six-member ring structure, an activated receptor may be formed by light-induced isomerization around other double bonds. ",
"We have examined this activation of Rh(6.10) by UV-visible and FTIR spectroscopy and have revealed that Rh(6.10) is a nonbleachable pigment. ",
"We could further show that the activated receptor consists of two different subspecies corresponding to 9-trans and 9-cis isomers of the chromophore. ",
"Both subspecies relax in the dark via separate pathways back to their respective inactive states by thermal isomerization presumably around the C(13)=C(14) double bond. ",
"This nonbleachable pigment can be repeatedly photolyzed to undergo identical activation-relaxation cycles. ",
"The rate constants of these photocycles are pH-dependent, and the half-times vary between several hours at acidic pH and about 1.5 min at neutral to alkaline pH, which is several orders of magnitude longer than for bacteriorhodopsin."
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"Mycobacterium confluentis\n\nMycobacterium confluentis is a non-pathogenic bacterium of the oral cavity.",
"\n\nDescription\nGram-positive, nonmotile, acid-fast coccobacillus (0.5-0.8 µm x 0.7-1.7 µm), does not form spores, capsules or aerial hyphae.",
"\n\nPhysiology\nRapid growth within 2 to 4 days on Löwenstein-Jensen media at 22 °C, 31 °C, 37 °C and 41 °C (optimum growth between 31 °C and 37 °C).",
"\nIn vitro susceptibility to isoniazid, ethambutol and streptomycin.",
"\n\nDifferential characteristics\nDifferentiation from other thermotolerant mycobacteria by its inability to grow at temperatures of more than 41 °C.",
"\nSeparation from other rapidly growing mycobacteria by its susceptibility to antituberculotic drugs.",
"\nDifferentiated from the phenotypic closely related M. thermoresistibile by its inability to grow at 52 °C.",
"\n\nPathogenesis\nNot associated with disease. ",
" Biosafety level 1.",
"\n\nType strain\nFirst isolated from sputum, Koblenz, Germany.",
"\nstrain 1389/90 = ATCC 49920 = CIP 105510 = DSM 44017 = JCM 13671.",
"\n\nReferences\n\nKirschner et al. ",
"1992. ",
"Mycobacterium confluentis sp. ",
"nov. ",
"Int. ",
"J. Syst. ",
"Bacteriol., ",
"42, 257-262.",
"\n\nExternal links\nType strain of Mycobacterium confluentis at BacDive - the Bacterial Diversity Metadatabase\n\nCategory:Acid-fast bacilli\nconfluentis\nCategory:Bacteria described in 1992"
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"Esta tarde, familiares y amigos de víctimas de las fuerzas de seguridad, organismos de derechos humanos, organizaciones sociales y partidos políticos participaron de la 5° Marcha Nacional contra el Gatillo Fácil.",
"\n\nLa misma partió desde el Congreso de la Nación a las 15 hasta llegar un rato más tarde a la Plaza de Mayo: la movilización tuvo réplicas en otras ciudades importantes del país como Córdoba, Mendoza y Mar del Plata.",
"\n\nMirta Baravalle, madre y abuela de Plaza de Mayo se acerca a la marcha nacional contra el gatillo fácil y es abrazada por el pueblo. ",
"pic.twitter.com/tr94mtGtcW — Revista Cítrica (@revistacitrica) August 27, 2019\n\n“Si bien todos los gobiernos desde la vuelta a la democracia han sostenido y profundizado el gatillo fácil, ‘Cambiemos’ es el más represivo desde entonces“, aseguraron desde CORREPI.",
"\n\n“Un gobierno que ajusta y profundiza la pobreza, necesita de la mano dura para hacerlo y es, en ese sentido, que desde hace casi 4 años, las muertes en manos del aparato represivo no paran de aumentar, dejando unx pibx asesinadx en manos del aparato represivo estatal cada 21 horas“, denunciaron.",
"\n\nVanesa Orieta, hermana de Luciano Arruga, habló durante la marcha: “Necesitamos que el Estado deje de matar a nuestros pibes y pibas. ",
"La única propuesta del Estado para los pibes es el paco o una bala“.",
"\n\n“Basta de estigmatización, basta de matarnos. ",
"Ni una bala más, ni un pibe menos. ",
"El estado es siempre responsable“, agregó Emilia Vassallo, madre de “Paly Alcorta”, asesinado en 2013 por un policía bonaerense de un tiro en la cabeza.",
"\n\n✊? “",
"No son casos aislados. ",
"El gatillo fácil es una política de Estado. ",
"Bullrich y su doctrina Chocobar buscan justificar el poder que le dan a la policía”\n\n? ",
"Foto: lavacatuitera\n\n? ",
"Las cifras de CORREPI ➖ Desde 1983 hasta febrero de este año se registraron 6.564 muertes a manos de las fuerzas represivas ➖ De los 6.564 casos registrados desde 1983, 1.303 ocurrieron entre el 10 de diciembre de 2015 y el 12 de febrero de 2019\n\nComentarios\n\ncomentarios"
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"– ESPN2 and ESPNU to Televise Draft Live from Mohegan Sun Arena in Connecticut –\n\n– Storm Owns Top Pick for Second Straight Year; Sun to Select Third and Fourth –\n\nNEW YORK, Feb. 22, 2016 – WNBA Draft 2016 presented by State Farm will be held on Thursday, April 14 at Mohegan Sun Arena in Uncasville, Conn. ESPN2 will provide coverage and analysis of the first round beginning at 7 p.m. ET, and ESPNU will air coverage of the second and third rounds starting at 8 p.m. ET. ",
"The draft comes one month before tip-off of the WNBA’s historic 20th season, which opens on Saturday, May 14.",
"\n\n“We are thrilled that the WNBA Draft 2016 presented by State Farm will once again be held in front of a great crowd at the Mohegan Sun Arena and televised live on ESPN2,” said WNBA President Lisa Borders. “",
"Through the network’s in-depth coverage our fans around the country will have the opportunity to see these players as they embark on their professional careers and take the first step toward making their mark on the WNBA.”",
"\n\n“We are looking forward to continuing ESPN’s 20-year collaboration with the WNBA,” said Julie Sobieski, ESPN Vice President, League Sports Programming. “",
"The WNBA Draft is a key opportunity for us to welcome the next generation of players who will become integral to ESPN’s coverage and storytelling of this landmark season.”",
"\n\nThe draft will also be available through WatchESPN, accessible on computers, smartphones, tablets and connected devices to fans who receive their video subscription from an affiliated provider. ",
"In addition, WNBA.com will provide complete draft-day coverage and serve as the web destination for fans who want to track the top college seniors in advance of the draft. ",
"In addition, WNBA.com will provide complete draft-day coverage and serve as the web destination for fans who want to track the top college seniors in advance of the draft.",
"\n\nThe Seattle Storm holds the top pick in the draft for the second consecutive year and the fourth time in franchise history after winning the WNBA Draft Lottery presented by State Farm last Sept. 24. ",
"The San Antonio Stars will select second, followed by two selections for the Connecticut Sun, which has its own pick at No. ",
"3 and a pick acquired from the Atlanta Dream at No. ",
"4. ",
"The fifth pick belongs to the Los Angeles Sparks.",
"\n\nLast year, the Storm used the No. ",
"1 overall pick to select Jewell Loyd, who was named WNBA Rookie of the Year presented by Samsung and headlined the 2015 WNBA All-Rookie Team. ",
"The All-Rookie Team also featured the New York Liberty’s Brittany Boyd and Kiah Stokes, the Nos. ",
"9 and 11 overall selections, respectively, in last year’s draft.",
"\n\nMohegan Sun Arena has hosted the WNBA Draft twice before (2014 and 2015) and the WNBA All-Star Game four times (2005, 2009, 2013, and 2015).",
"\n\n“The draft is a perfect event for a live audience that is passionate and knowledgeable about the women’s game, and that is the description of the fans in our area,” said Sun CEO Mitchell Etess. “",
"The building should be particularly electric this year given the talent at the top of the draft class, so we very much look forward to having Mohegan Sun Arena once again serve as the home of the WNBA Draft.”",
"\n\nThe event is open to the public. ",
"Sun season-ticket holders will be admitted free of charge and have access to priority seating as well as a special opportunity to meet Connecticut’s draft picks in attendance. ",
"Fans who are not season-ticket holders will be admitted with the donation of a canned food item at the door, which will benefit the New London Community Meal Center.",
"\n\nThe current order for WNBA Draft 2016 presented by State Farm is as follows:\n\n2016 ORDER OF SELECTION\n\nFirst Round\n\n1) Seattle (10-24)\n\n2) San Antonio (8-26)\n\n3) Connecticut (15-9)\n\n4) Connecticut from Atlanta (15-19) (E. Williams, 2/3/16)\n\n5) Dallas (18-16) (R. Williams, Phillips, 3/1/16)\n\n6) Los Angeles (14-20) (R. Williams, Phillips, 3/1/16)\n\n7) Washington (18-16)\n\n8) Phoenix (20-14)\n\n9) Indiana (20-14)\n\n10) Chicago (21-13)\n\n11) Atlanta from Minnesota (22-12) (S. Fowles, E. DeSouza, D. Dantas, R. Gray, 7/26/15)\n\n12) New York (23-11)\n\nSecond Round\n\n1) Atlanta from San Antonio (8-26) (S. Logic, 7/5/15)\n\n2) Minnesota from Seattle (10-24) (M. Wright, R. Montgomery, 7/20/15)\n\n3) Connecticut (15-19)\n\n4) Atlanta (15-19)\n\n5) Los Angeles (14-20)\n\n6) Dallas (18-16)\n\n7) Washington (18-16)\n\n8) Phoenix (20-14)\n\n9) Indiana (20-14)\n\n10) Minnesota from Chicago (21-13) (S. Fowles, E. DeSouza, D. Dantas, R. Gray, 7/26/15)\n\n11) Connecticut from Minnesota (22-12) (A. Jones, 5/13/15)\n\n12) New York (23-11)\n\nThird Round\n\n1) San Antonio (8-26)\n\n2) Seattle (10-24)\n\n3) Connecticut (15-19)\n\n4) Atlanta (15-19)\n\n5) Los Angeles (14-20)\n\n6) Dallas (18-16)\n\n7) Washington (18-16)\n\n8) Phoenix (20-14)\n\n9) Indiana (20-14)\n\n10) Chicago (21-13)\n\n11) Minnesota (22-12)\n\n12) New York (23-11)"
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[
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"\n\nThe MFi Program is intended for hardware developers who wish to develop electronic accessories specifically for iPhone, iPad or iPod*. ",
"Companies, organizations, government entities and educational institutions are all eligible to apply. ",
"Your organization must have a registered legal entity name to apply."
] | {
"pile_set_name": "OpenWebText2"
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"Both works great. ",
"\nNow what I want to do is find the time offset between the clocks, based on seconds, and add it to the local system clock. ",
"\nFor example: my system clock is: 10:00:00 and the server clock is 12:15:00 at the same date.",
"\nthen the offset will be: 02:15:00 (of course it will be in seconds but just for the example I wrote it that way). ",
"And then add it to (browser)local time so I eventually get to show the server time. ",
"12:15:00. ",
" \nThis is what I'm doing here:\nvar interval = self.setInterval(function(){\n clock();\n},1000);\n\nfunction clock()\n{ \n //Get local server time\n <?",
"php $today = getdate(); ?",
">;\n var ser = <?",
"php echo $today[0]; ?",
">;\n\n //Local client time\n var seconds = Date.now();\n var offset = seconds-ser*1000;\n parseInt(offset/1000);\n\n var d = new Date();\n d.setTime(Date.now()-offset);\n var h = d.getHours();\n var m = d.getMinutes();\n var s = d.getSeconds();\n\n if(s < 10)\n s = \"0\" + s;\n if(m < 10)\n m = \"0\" + m;\n if(h < 10)\n h = \"0\" + h;\n\n var tm = h+\":\"+m+\":\"+s;\n document.getElementById(\"clock\").value = tm;\n} \n\nBut as soon as I put the variable \noffset\n\nin this line: d.setTime(Date.now()-offset);\nThe clock doesn't updates anymore. ",
"I guess there is an issue with PHP compatibility.",
"\nAny idea how to solve it?",
"\nThanks \n\nA:\n\nThe offset calculation has to be outside of the repeadly called function:\n//Get local server time\n<?",
"php $today = getdate(); ?",
">;\nvar ser = <?",
"php echo $today[0]; ?",
">;\n\n//Local client time\nvar seconds = Date.now();\nvar offset = seconds-ser*1000;\nparseInt(offset/1000); // BY THE WAY: As the returnval of parseInt isn't stored anywhere, this line does nothing\n\nvar interval = self.setInterval(function(){\n clock();\n},1000);\n\nfunction clock()\n{ \n\n var d = new Date();\n d.setTime(Date.now()-offset);\n var h = d.getHours();\n var m = d.getMinutes();\n var s = d.getSeconds();\n\n if(s < 10)\n s = \"0\" + s;\n if(m < 10)\n m = \"0\" + m;\n if(h < 10)\n h = \"0\" + h;\n\n var tm = h+\":\"+m+\":\"+s;\n document.getElementById(\"clock\").value = tm;\n}\n\n"
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"The Goodnight Show with Michael Essany\n\nThe Goodnight Show with Michael Essany was an American television talk show hosted by Michael Essany. ",
"The show's three episodes began streaming on Amazon Video in August 2017.",
"\n\nReferences\n\nCategory:2010s American television talk shows\nCategory:2017 American television series debuts\nCategory:2010s American late-night television series\nCategory:English-language television programs"
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"CD133 and CD44 cell surface markers do not identify cancer stem cells in primary human gastric tumors.",
"\nEmerging evidence suggests that tumors contain and are driven by a cellular component that displays stem cell properties, the so-called cancer stem cells (CSCs). ",
"CSCs have been identified in several solid human cancers; however, there are no data about CSCs in primary human gastric cancer (GC). ",
"By using CD133 and CD44 cell surface markers we investigated whether primary human GCs contain a cell subset expressing stem-like properties and whether this subpopulation has tumor-initiating properties in xenograft transplantation experiments. ",
"We examined tissues from 44 patients who underwent gastrectomy for primary GC. ",
"The tumorigenicity of the cells separated by flow cytometry using CD133 and CD44 surface markers was tested by subcutaneous or intraperitoneum injection in NOD/SCID and nude mice. ",
"GCs included in the study were intestinal in 34 cases and diffuse in 10 cases. ",
"All samples contained surface marker-positive cells: CD133(+) mean percentage 10.6% and CD133(+)/CD44(+) mean percentage 27.7%, irrespective of cancer phenotype or grade of differentiation. ",
"Purified CD133(+) and CD133(+)/CD44(+) cells, obtained in sufficient number only in 12 intestinal type GC cases, failed to reproduce cancer in two mice models. ",
"However, the unseparated cells produced glandular-like structures in 70% of the mice inoculated. ",
"In conclusion, although CD133(+) and CD133(+)/CD44(+) were detectable in human primary GCs, they neither expressed stem-like properties nor exhibited tumor-initiating properties in xenograft transplantation experiments."
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"Q:\n\nrestore SQL 2008 DB R2 to SQL2008 (no r2)\n\non my developper pc is installed SQL 2008 R2 \non the internal server is installed SQL 2008 R2 (some applications are hosted here)\non the external 3.rd party hosting company uses SQL 2008 (no r2).",
"\nso when I created DB on my developper pc I need to restore on external hosting server which is SQL 2008 (w/o r2).... but I get an build version error... it says SQL2008 r2 has higher build number so I can't restore on the w/o r2 server.",
"\nI thought creating the DB on w/o R2 server and restore on my localhost and make changes and restore back to w/o r2 server, but it says the same error... Build number is changed.",
"\nI thought I can delete r2 version on my developper pc and use SQL 2008 w/o r2, but the issue remains I can't restore the DB from internal server to my developper pc...:(\nso in short:\nIf I want to restore/backup the DB between SQL2008 R2 and SQL2008, how to handle this (I als need the data of database ? ",
"Any property to assign to the DB or whatever?",
"\nIs there a procedure that I can use SQL2008 R2 DB as SQL2008 DB? ",
"\nI can't touch the SQL 2008 versions on the server...\nplease advice?",
"\n\nA:\n\nYou have to export/import using the wizard in SSMS. ",
"Or use some 3rd party tool (eg Red Gate)\nThere is NO downgrade option using attach/detach or backup/restore. ",
"And no magic setting.",
"\n\nA:\n\nThere is no simple property that you can switch to be able to restore to older versions.",
"\nYou might try this, in Management Studio:\n\nSelect your source Database \nSelect Tasks>Generate Scripts. ",
"\nSelect 'Script entire database and all database objects', press 'Next' \nSelect 'Save to File' and click on the 'Advanced' button \nSelect 'Script for Server Version' and select the version you want: 2000/2005/2008\nSelect 'Type of data to Script' and select Schema/Data/both \nClick 'OK',Next and do it! ",
"\nCopy the resulting file to the target machine.",
"\nLog onto your SQL Management Studio and open the copied .sql file... \n\nIt's likely to work if you have a small database. ",
"For a larger one you will run into limitations.",
"\n\n"
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"In vitro and in vivo hepatoprotective effects of the aqueous extract from Taraxacum officinale (dandelion) root against alcohol-induced oxidative stress.",
"\nThe protective effects of Taraxacum officinale (dandelion) root against alcoholic liver damage were investigated in HepG2/2E1 cells and ICR mice. ",
"When an increase in the production of reactive oxygen species was induced by 300 mM ethanol in vitro, cell viability was drastically decreased by 39%. ",
"However, in the presence of hot water extract (TOH) from T. officinale root, no hepatocytic damage was observed in the cells treated with ethanol, while ethanol-extract (TOE) did not show potent hepatoprotective activity. ",
"Mice, which received TOH (1 g/kg bw/day) with ethanol revealed complete prevention of alcohol-induced hepatotoxicity as evidenced by the significant reductions of serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities compared to ethanol-alone administered mice. ",
"When compared to the ethanol-alone treated group, the mice receiving ethanol plus TOH exhibited significant increases in hepatic antioxidant activities, including catalase, glutathione-S-transferase, glutathione peroxidase, glutathione reductase, and glutathione. ",
"Furthermore, the amelioration of malondialdehyde levels indicated TOH's protective effects against liver damage mediated by alcohol in vivo. ",
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"\nif you really MUST have it as a List then put () around the whole \"From a in.... to select new xxx {};) and call ToList() on the result first.",
"\nOtherwise do \"var searchresult = ....\" and you can foreach on your \"searchresult\" variable still.",
"\n\nA:\n\nYou may just need to wrap your linq with some parentheses and call .ToList on the result:\nList<BALHotelList> searchresult= (from a in bh\n join b in hr on a.HotelCode equals b.hotelCode\n orderby a.HotelName\n select new BALHotelList\n {\n HotelCode= a.HotelCode,\n ImageURL_Text = a.ImageURL_Text,\n HotelName = a.HotelName,\n StarRating = a.StarRating,\n HotelAddress = a.HotelAddress,\n Destination = a.Destination,\n Country = a.Country,\n HotelInfo = a.HotelInfo,\n Latitude = a.Latitude,\n Longitude = a.Longitude,\n totalPrice = b.totalPrice,\n totalPriceSpecified = b.totalPriceSpecified,\n totalSalePrice = b.totalSalePrice,\n totalSalePriceSpecified = b.totalSalePriceSpecified,\n rooms = b.rooms\n\n }).Tolist();\n\n"
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[
"Surgical management of large adrenal tumours: the University of Miami experience using liver transplantation techniques.",
"\nTo report our experience in the surgical management of patients with large adrenal masses and describe the key steps in performing radical resections, which are especially demanding where thrombi extend into the inferior vena cava (IVC). ",
"From 2003 to 2007, 14 patients presented with large adrenal mass, and underwent surgical extirpation. ",
"In five patients thrombi extended into the IVC, causing Budd-Chiari syndrome in one. ",
"The median (range) patient age was 48 (40-58) years. ",
"The excision was radical with negative tumour margins in all cases. ",
"Cardiopulmonary bypass (CPB) was required in one case with adherent intra-atrial thrombus. ",
"The mean blood loss was 500 (250-1500) mL except in the patient who required CPB. ",
"Morbidity included pleural effusion (three patients) and postoperative pneumonia (two), which responded to conservative management. ",
"All patients were alive and free of disease at a median follow-up of 12 (5-42) months. ",
"Surgical extirpation of large adrenal masses requires technical experience to optimize outcome. ",
"Total tumour excision is the only therapeutic option in such cases and provides acceptable results in survival and quality of life."
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[
"13, c: 2, y: 3}. ",
"What is prob of picking 1 x and 1 c?",
"\n26/153\nTwo letters picked without replacement from {x: 3, i: 2, k: 10}. ",
"What is prob of picking 1 x and 1 i?",
"\n2/35\nTwo letters picked without replacement from cgcwcwwwgwgc. ",
"What is prob of picking 2 w?",
"\n5/33\nThree letters picked without replacement from {x: 9}. ",
"Give prob of picking 3 x.\n1\nThree letters picked without replacement from {a: 12, g: 7}. ",
"Give prob of picking 3 a.\n220/969\nWhat is prob of picking 2 r and 1 y when three letters picked without replacement from orryryrryyroor?",
"\n3/13\nThree letters picked without replacement from {k: 3, s: 1, n: 1, z: 5, q: 6, o: 1}. ",
"Give prob of picking 1 n, 1 z, and 1 s.\n1/136\nFour letters picked without replacement from udduuzuxuuuxubbuuudu. ",
"What is prob of picking 1 u, 2 b, and 1 x?",
"\n8/1615\nWhat is prob of picking 1 l and 1 g when two letters picked without replacement from gfgsaglrgggssrgaall?",
"\n7/57\nThree letters picked without replacement from sdsssdsssddsd. ",
"What is prob of picking 3 d?",
"\n5/143\nFour letters picked without replacement from {l: 1, u: 2, r: 3, f: 8, b: 1, e: 3}. ",
"Give prob of picking 1 l, 1 u, 1 b, and 1 f.\n4/765\nThree letters picked without replacement from idmmirnud. ",
"What is prob of picking 1 u, 1 m, and 1 r?",
"\n1/42\nCalculate prob of picking 4 k when four letters picked without replacement from {k: 8, g: 2}.",
"\n1/3\nCalculate prob of picking 2 r and 1 e when three letters picked without replacement from {r: 4, z: 1, o: 1, e: 2}.",
"\n3/14\nCalculate prob of picking 3 a when three letters picked without replacement from {u: 2, t: 1, a: 3, x: 1, w: 6}.",
"\n1/286\nTwo letters picked without replacement from fkfkkpf. ",
"What is prob of picking 1 f and 1 k?",
"\n3/7\nCalculate prob of picking 2 s and 1 v when three letters picked without replacement from {q: 3, v: 5, f: 5, s: 2}.",
"\n1/91\nTwo letters picked without replacement from {x: 4, f: 2, v: 1, p: 8, y: 4}. ",
"What is prob of picking 1 f and 1 y?",
"\n8/171\nFour letters picked without replacement from aosfjtasffstfjs. ",
"Give prob of picking 2 s, 1 t, and 1 a.\n8/455\nThree letters picked without replacement from qmmqqmm. ",
"Give prob of picking 3 m.\n4/35\nThree letters picked without replacement from {s: 1, p: 11, f: 1, y: 1, v: 2, m: 4}. ",
"Give prob of picking 2 m and 1 y.\n1/190\nWhat is prob of picking 2 l and 1 g when three letters picked without replacement from ggggglgglggggglgllgg?",
"\n5/38\nThree letters picked without replacement from {u: 1, x: 1, i: 1, h: 1, f: 1}. ",
"Give prob of picking 1 h, 1 x, and 1 i.\n1/10\nCalculate prob of picking 1 b and 1 v when two letters picked without replacement from {o: 1, b: 2, v: 1, p: 2}.",
"\n2/15\nTwo letters picked without replacement from aayxrrrr. ",
"What is prob of picking 1 x and 1 a?",
"\n1/14\nThree letters picked without replacement from {e: 4, j: 8, b: 7, l: 1}. ",
"What is prob of picking 2 e and 1 l?",
"\n1/190\nTwo letters picked without replacement from {m: 10, x: 4, o: 1, i: 5}. ",
"Give prob of picking 1 x and 1 m.\n4/19\nWhat is prob of picking 1 b and 1 l when two letters picked without replacement from lllbllllllllllblbl?",
"\n5/17\nTwo letters picked without replacement from {f: 6}. ",
"What is prob of picking 2 f?",
"\n1\nTwo letters picked without replacement from uuuuuujuju. ",
"Give prob of picking 1 j and 1 u.\n16/45\nWhat is prob of picking 1 d, 2 c, and 1 m when four letters picked without replacement from dcdmjddcdicicdcd?",
"\n1/26\nCalculate prob of picking 2 u, 1 q, and 1 l when four letters picked without replacement from {t: 4, q: 2, w: 3, u: 8, l: 2}.",
"\n28/969\nWhat is prob of picking 2 f, 1 p, and 1 u when four letters picked without replacement from {f: 6, q: 5, p: 1, u: 1, h: 1}?",
"\n15/1001\nThree letters picked without replacement from gdyddydg. ",
"Give prob of picking 2 g and 1 d.\n1/14\nFour letters picked without replacement from {g: 9}. ",
"Give prob of picking 4 g.\n1\nFour letters picked without replacement from {k: 11, h: 5}. ",
"What is prob of picking 4 h?",
"\n1/364\nWhat is prob of picking 1 j, 1 z, 1 b, and 1 c when four letters picked without replacement from {z: 2, b: 2, h: 3, c: 4, j: 1}?",
"\n16/495\nCalculate prob of picking 2 a when two letters picked without replacement from saaasssaaasas.",
"\n7/26\nWhat is prob of picking 2 o and 2 m when four letters picked without replacement from {m: 2, o: 9}?",
"\n6/55\nFour letters picked without replacement from mpmmkwmwmmmw. ",
"Give prob of picking 1 w, 2 m, and 1 k.\n7/55\nThree letters picked without replacement from beeeeeeeeeweebb. ",
"Give prob of picking 1 w and 2 e.\n11/91\nCalculate prob of picking 3 a when three letters picked without replacement from aaaaraaaaaaraaraara.",
"\n455/969\nWhat is prob of picking 2 r and 1 t when three letters picked without replacement from {r: 4, t: 3}?",
"\n18/35\nCalculate prob of picking 2 r when two letters picked without replacement from {r: 2, b: 10}.",
"\n1/66\nFour letters picked without replacement from {e: 4, l: 4, c: 6}. ",
"What is prob of picking 1 e and 3 l?",
"\n16/1001\nWhat is prob of picking 2 m when two letters picked without replacement from {o: 2, x: 2, m: 5, p: 1, l: 2, a: 2}?",
"\n10/91\nWhat is prob of picking 1 m and 1 e when two letters picked without replacement from {v: 2, e: 3, a: 3, m: 8}?",
"\n1/5\nFour letters picked without replacement from {c: 4, u: 10}. ",
"What is prob of picking 4 u?",
"\n30/143\nCalculate prob of picking 3 k and 1 a when four letters picked without replacement from {k: 3, a: 11}.",
"\n1/91\nWhat is prob of picking 1 g, 1 t, and 1 f when three letters picked without replacement from {f: 2, m: 2, t: 1, g: 1}?",
"\n1/10\nWhat is prob of picking 2 z, 1 p, and 1 k when four letters picked without replacement from {k: 1, p: 3, z: 3}?",
"\n9/35\nCalculate prob of picking 1 l and 1 e when two letters picked without replacement from {l: 2, e: 1}.",
"\n2/3\nWhat is prob of picking 3 q when three letters picked without replacement from qqqxxqxxqqxqq?",
"\n28/143\nCalculate prob of picking 2 x when two letters picked without replacement from xxzzz.",
"\n1/10\nWhat is prob of picking 2 e when two letters picked without replacement from {e: 5}?",
"\n1\nCalculate prob of picking 2 q when two letters picked without replacement from qjqajqaazj.",
"\n1/15\nCalculate prob of picking 1 n and 1 m when two letters picked without replacement from mngmmmndmmdngmmn.",
"\n4/15\nWhat is prob of picking 2 d when two letters picked without replacement from {d: 4, a: 2, q: 2, x: 2}?",
"\n2/15\nThree letters picked without replacement from rehrttrdhr. ",
"What is prob of picking 1 r, 1 h, and 1 d?",
"\n1/15\nWhat is prob of picking 1 l and 2 f when three letters picked without replacement from llflllfllf?",
"\n7/40\nTwo letters picked without replacement from ttmmtm. ",
"Give prob of picking 2 t.\n1/5\nWhat is prob of picking 1 m and 1 b when two letters picked without replacement from emmmbcb?",
"\n2/7\nCalculate prob of picking 1 z and 1 s when two letters picked without replacement from vsmdzzr.",
"\n2/21\nWhat is prob of picking 1 y and 1 g when two letters picked without replacement from ggsxgtetyxtysy?",
"\n9/91\nCalculate prob of picking 2 g when two letters picked without replacement from {o: 3, f: 1, g: 1, j: 5}.",
"\n0\nTwo letters picked without replacement from rjrod. ",
"What is prob of picking 1 j and 1 o?",
"\n1/10\nWhat is prob of picking 2 w when two letters picked without replacement from {o: 1, w: 3, k: 5, y: 1, a: 4, r: 4}?",
"\n1/51\nWhat is prob of picking 1 u, 1 q, 1 b, and 1 p when four letters picked without replacement from {q: 3, b: 1, p: 6, u: 2, s: 5}?",
"\n9/595\nWhat is prob of picking 2 i when two letters picked without replacement from {e: 2, i: 5}?",
"\n10/21\nTwo letters picked without replacement from {g: 1, u: 1, z: 1}. ",
"Give prob of picking 1 z and 1 u.\n1/3\nWhat is prob of picking 2 o when two letters picked without replacement from oorroo?",
"\n2/5\nTwo letters picked without replacement from cczcczzczcc. ",
"Give prob of picking 1 c and 1 z.\n28/55\nCalculate prob of picking 1 b and 1 o when two letters picked without replacement from {j: 2, y: 2, c: 1, b: 1, o: 1}.",
"\n1/21\nTwo letters picked without replacement from zenenezeuzssuunu. ",
"What is prob of picking 1 e and 1 n?",
"\n1/10\nWhat is prob of picking 1 u and 1 a when two letters picked without replacement from {a: 6, u: 1, r: 1, y: 1, m: 3}?",
"\n1/11\nThree letters picked without replacement from qdqdddqqddqhdq. ",
"What is prob of picking 1 q, 1 h, and 1 d?",
"\n3/26\nTwo letters picked without replacement from csyiwis. ",
"What is prob of picking 2 i?",
"\n1/21\nWhat is prob of"
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"The present subject matter relates generally to systems and methods for securely validating and protecting firmware software while maintaining authorized reprogrammability of the firmware software. ",
"More specifically, the present subject matter provides systems and methods in which a secure logic device is inserted between a firmware device and a microprocessor-based system, wherein the secure logic device is responsible for validating the firmware in hardware logic before the microprocessor is allowed to start executing the firmware code.",
"\nThere are many computer systems in which one or more firmware devices control various systems within the computer system. ",
"While there are nearly limitless variations of such systems and environments in which they are used, the disclosure provided herein discussed the subject matter in the context of gambling machines. ",
"While described in the gambling machine context, it is understood that the teachings provided herein are applicable to any system which incorporate one or more firmware devices with one or more processing devices.",
"\nComputer systems for use in gaming and gambling machines are often referred to as “slot machines.” ",
"It is usually necessary for slot machines to comply with certain standards defined by government, state, or other regulatory bodies relating to the security of the slot machines, as they handle significant revenue streams. ",
"It is usual for there to be security requirements to ensure the machines are not tampered with, for example, to prevent manipulation of payouts to users or prevent tampering with the recording of transactions for the purpose of collecting government gaming taxes from machine operators. ",
"Of course, in other contexts, there may be additional or alternative regulatory security requirements.",
"\nSlot machine manufacturers also have a strong interest in security in order to protect their intellectual property and prevent cloning of their systems or designs and/or the use of legitimate machines outside of the agreed terms, for example installation of a newer game on a machine without payment. ",
"Again, in other contexts, there may be additional or alternative commercial security requirements.",
"\nAs part of these security requirements (whether commercial or regulatory), it is usually necessary to be able to validate the various software modules associated with a slot machine in order to detect any attempt at tampering or unauthorized change and to prevent the machine from operating when any alteration is detected.",
"\nPresently implemented slot machine security is usually complex in nature and comprises many layers to increase the overall strength of the security measures. ",
"Virtually all modern slot machines are controlled by some form of computer system internal to the machine. ",
"Typically, these computer systems are architecturally compatible with the IBM PC standard.",
"\nIn electronic systems using microprocessors, there is normally an initial piece of software that is responsible for configuring the hardware and setting up the basic functioning of the system when power is turned on. ",
"This form of software is generally referred to as “firmware” as it is generally not changed during system use and is usually stored in non-volatile memory devices so that it is present and available to be used as soon as a system is powered up. ",
"A given computer system (or peripheral device) may contain one or more processing devices, so there may be more than one set of firmware and one or more memory devices containing the firmware.",
"\nIn slot machine based on PC architecture, the firmware for the main processor is referred to as a BIOS (Basic Input-Output System). ",
"When a computer system having a BIOS is powered on, the BIOS first configures the hardware and environment. ",
"Then, once the BIOS completes its configuration of the hardware and environment, the system “boots” a computer operating system (OS). ",
"Finally, the OS executes the game program, which will be responsible for the behavior of the slot machine.",
"\nSlot machine manufacturers often incorporate security features inside their game programs. ",
"However, these can be reverse-engineered or defeated if not supplemented by additional security measures. ",
"For example, it is common for the game program to be located on a different storage device to the OS. ",
"The OS is then configured such that it performs a verification of the game storage media before it executes any program contained on it. ",
"If this verification fails, then the system halts. ",
"This security feature prevents alteration of the media containing the game and potential modification or insertion of malicious software. ",
"However, this can be defeated if an attacker is able to modify the OS media and either remove or modify the software responsible for verifying the game media. ",
"Therefore, it is necessary to also verify the integrity of the OS media before it is booted. ",
"To do this, it is usual for the BIOS to verify the OS media before it attempts to boot the OS contained on it. ",
"Again, if a change is detected the system halts, preventing any unauthorized use.",
"\nFinally, it is further necessary to verify that the BIOS itself has not been altered in any way, for example to remove the verification of the OS media to allow the booting of altered software. ",
"As the BIOS is the first piece of software to be executed after the system is started up, there has been no alternative other than to modify the BIOS so that it performs a check on itself. ",
"There are several drawbacks to this approach.",
"\nFirst, any program that is responsible for validating itself is open to attack. ",
"If an attacker can identify the code that performs the self-validation, it is possible to alter or eliminate it and allow the execution of further unauthorized code, namely modified OS software and/or game software. ",
"Second, modifying a BIOS to add the code to verify itself is often a complex procedure, as BIOS software requires expert knowledge of computer hardware and low-level programming.",
"\nAs can be understood from the explanation above, providing strong security to the computer system within a slot machine is a complex process and can be defeated by an attack on the lowest piece of software in the chain—the BIOS. ",
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"Search the Internet and you can find tons of homebrew recipes that will let you clone well-known craft beers, from Pliny the Elder to Hopslam.",
"\n\nBut what about recipes for beers from Memphis craft breweries?",
"\n\nWith that in mind, Memphis homebrew shop Bernoulli Brew Werks has announced the Clone Wars homebrew competition, aimed at recreating four Memphis brews: Ghost River Riverbank Red, Wiseacre Ananda IPA, High Cotton ESB and Memphis Made Reverberation Belgian Coffee Stout.",
"\n\nOn Sunday, Bernoulli’s Brooks Sease said a fifth beer, from Boscos, is likely being added, though the beer has not been selected.",
"\n\n“There is no guide, no suggested ingredients, no BJCP manual, no limits to your imagination…” according to Bernoulli’s website.",
"\n\n“So get out on the town and hit your taprooms, bars and stores to pick up these great beers so you can begin your research.”",
"\n\nThe contest, which is based on a point system, starts in May and continues through September. ",
"The brewer with the most points at the end of the competition will be named the “Master of the Memphis Homebrew Galaxy” and will win a 15-gallon stainless steel SS Brewtech conical fermenter valued at $595.",
"\n\nWhat’s really cool about this competition is that brewers from each Memphis brewery will be judging the entries for their clones. ",
"The fee is $20 for the whole series or $8 for one beer entry.",
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"Q:\n\nHow to install zotero in ubuntu?",
"\n\nI download the tar.bz file from the home page of zotero, extract it and run the file 'run-zotero.sh', but it open zotero rather than install it. ",
"How to install it? ",
"Any help or suggestion will be appreciated!",
"\n\nA:\n\nI suggest you add a ppa so that the program gets updated regularly:\nsudo apt-add-repository ppa:smathot/cogscinl \n\nSay yes/press enter to accept any requests.",
"\nsudo apt-get update\n\nwait for it to complete, then:\nsudo apt-get install zotero-standalone\n\nThis will install the program.",
"\n\nA:\n\nAs of 2019, the preferred way of installing Zotero is by using Emiliano Heyns' packages.",
"\nRun the following instructions on your terminal:\nwget -qO- https://github.com/retorquere/zotero-deb/releases/download/apt-get/install.sh | sudo bash\nsudo apt update\nsudo apt install zotero\n\nFor additional information about the provided packages, see the README file.",
"\nOther answers should be considered obsolete, Sebastiaan Mathot's packages being no longer maintained.",
"\n\nA:\n\nThis project is designed to automate installation. ",
"It worked for me with 13.04. ",
"To install it, run the following in your terminal: \nwget https://raw.github.com/smathot/zotero_installer/master/zotero_installer.sh -O /tmp/zotero_installer.sh\nchmod +x /tmp/zotero_installer.sh\n/tmp/zotero_installer.sh\n\nand answer the questions. ",
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"Top Clicks\n\nThe Crazy\n\nSearch CLAF\n\nMeta\n\nGetting loose.",
"\n\nDid Swings, Windmills and Turkish Get Ups today. ",
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"Then I hit Goblet Squats and Hammer Curls. ",
"I opened and closed with Indian clubs. ",
"This was far more work than expected, but I feel nicely loosened up after sitting in the truck all day. ",
"In addition, everything on my body is tired now, especially my core.",
"\n\nThe T-handle worked well, but I need to cover the threads on the handles.",
"\n\nHere are some videos that are a far better explanation of what I did than I can offer. ",
"I used a dumbbell and T-handle but the idea is the same."
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"This album featured his 1939 Decca recording of the song, not the 1931 recording he made for Brunswick.",
"\n\nOriginal track listing\nThese previously issued songs were featured on a 6-disc, 78 rpm album set, Decca Album No. ",
"181.",
"\n\nRe-issue track listing\nIn 1950, a set of the same name but slightly different selections was released with a darker cover. ",
"These reissued songs were featured on a 4-disc, 78 rpm album set, Decca Album No. ",
"A-678.",
"\n\nDisc 1 (25365): \"Star Dust\" / \"Deep Purple\"\nDisc 2 (25366): \"I Cried for You\" / \"My Melancholy Baby\"\nDisc 3 (25367): \"The One Rose\" / \"Moonlight and Shadows\"\nDisc 4 (25368): \"A Blues Serenade\" / \"S'posin'\"\n\nThe one new song to the collection was \"Moonlight and Shadows\", written by Leo Robin and Frederick Hollander and recorded by Bing with Victor Young and his Orchestra on March 5, 1937 (running time: 3:15).",
"\n\nLP track listing\nThe 1950 10\" LP album issue Decca DL 5126 consisted entirely of Decca A-678 on a 10\" LP. ",
" All were reissues of earlier recordings:\n\nSide 1\n\nSide 2\n\nOther releases\nIn 1949, the same selections as Decca DL 5126 were released on a set of three 45s on Decca 9-25.",
"\n\nIn 1957, the same set was released on two 45 rpm EP records on a set titled Decca ED 581.",
"\n\nReferences\n\nCategory:Bing Crosby compilation albums\nCategory:1940 compilation albums\nCategory:Decca Records compilation albums"
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"editAreaLoader.load_syntax[\"js\"] = {\n\t'DISPLAY_NAME' : 'Javascript'\n\t,'COMMENT_SINGLE' : {1 : '//'}\n\t,'COMMENT_MULTI' : {'/*' : '*/'}\n\t,'QUOTEMARKS' : {1: \"'\", 2: '\"'}\n\t,'KEYWORD_CASE_SENSITIVE' : false\n\t,'KEYWORDS' : {\n\t\t'statements' : [\n\t\t\t'as', 'break', 'case', 'catch', 'continue', 'decodeURI', 'delete', 'do',\n\t\t\t'else', 'encodeURI', 'eval', 'finally', 'for', 'if', 'in', 'is', 'item',\n\t\t\t'instanceof', 'return', 'switch', 'this', 'throw', 'try', 'typeof', 'void',\n\t\t\t'while', 'write', 'with'\n\t\t]\n \t\t,'keywords' : [\n\t\t\t'class', 'const', 'default', 'debugger', 'export', 'extends', 'false',\n\t\t\t'function', 'import', 'namespace', 'new', 'null', 'package', 'private',\n\t\t\t'protected', 'public', 'super', 'true', 'use', 'var', 'window', 'document',\t\t\n\t\t\t// the list below must be sorted and checked (if it is a keywords or a function and if it is not present twice\n\t\t\t'Link ', 'outerHeight ', 'Anchor', 'FileUpload', \n\t\t\t'location', 'outerWidth', 'Select', 'Area', 'find', 'Location', 'Packages', 'self', \n\t\t\t'arguments', 'locationbar', 'pageXoffset', 'Form', \n\t\t\t'Math', 'pageYoffset', 'setTimeout', 'assign', 'Frame', 'menubar', 'parent', 'status', \n\t\t\t'blur', 'frames', 'MimeType', 'parseFloat', 'statusbar', 'Boolean', 'Function', 'moveBy', \n\t\t\t'parseInt', 'stop', 'Button', 'getClass', 'moveTo', 'Password', 'String', 'callee', 'Hidden', \n\t\t\t'name', 'personalbar', 'Submit', 'caller', 'history', 'NaN', 'Plugin', 'sun', 'captureEvents', \n\t\t\t'History', 'navigate', 'print', 'taint', 'Checkbox', 'home', 'navigator', 'prompt', 'Text', \n\t\t\t'Image', 'Navigator', 'prototype', 'Textarea', 'clearTimeout', 'Infinity', \n\t\t\t'netscape', 'Radio', 'toolbar', 'close', 'innerHeight', 'Number', 'ref', 'top', 'closed', \n\t\t\t'innerWidth', 'Object', 'RegExp', 'toString', 'confirm', 'isFinite', 'onBlur', 'releaseEvents', \n\t\t\t'unescape', 'constructor', 'isNan', 'onError', 'Reset', 'untaint', 'Date', 'java', 'onFocus', \n\t\t\t'resizeBy', 'unwatch', 'defaultStatus', 'JavaArray', 'onLoad', 'resizeTo', 'valueOf', 'document', \n\t\t\t'JavaClass', 'onUnload', 'routeEvent', 'watch', 'Document', 'JavaObject', 'open', 'scroll', 'window', \n\t\t\t'Element', 'JavaPackage', 'opener', 'scrollbars', 'Window', 'escape', 'length', 'Option', 'scrollBy'\t\t\t\n\t\t]\n \t,'functions' : [\n\t\t\t// common functions for Window object\n\t\t\t'alert', 'Array', 'back', 'blur', 'clearInterval', 'close', 'confirm', 'eval ', 'focus', 'forward', 'home',\n\t\t\t'name', 'navigate', 'onblur', 'onerror', 'onfocus', 'onload', 'onmove',\n\t\t\t'onresize', 'onunload', 'open', 'print', 'prompt', 'scroll', 'scrollTo', 'setInterval', 'status',\n\t\t\t'stop' \n\t\t]\n\t}\n\t,'OPERATORS' :[\n\t\t'+', '-', '/', '*', '=', '<', '>', '%', '!'",
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"SpruceupyourphotoswithtextanddesignsinUponPixels\n\nUponPixels ($0.99) by taprrific, LLC is a fun app that allows users to add text and design elements to their images for sharing with others. ",
"With the holidays just around the corner, apps like this are a great addition to your collection. ",
"It is similar to apps we’ve already covered, such as Hipstify, Over, and Rhonna Designs.",
"\n\nPersonally, I’m not too into the whole text-on-photos thing, but it is a popular trend on social networks like Instagram. ",
"With the holidays upon us, it’s a fun way to spruce up your family photos, so I get the appeal. ",
"With UponPixels, it’s never been easier to make something great with your photos.",
"\n\nThe design of UponPixels is fairly simple, so it’s intuitive from the get-go, especially if you’ve used other apps like this one. ",
"The home screen of UponPixels is beautiful and elegant, only showing users the basics and nothing else, so it’s not cluttered. ",
"The rest of the app has a flat aesthetic that fits in with iOS, and the editing tools are clearly labeled and recognizable, so anyone can understand how to use the app.",
"\n\nThere are two ways to get an image in to UponPixels: Photo Library import or a new camera capture. ",
"There is also the Lightbox, which is where all of your edits in UponPixels go automatically, and you can further edit them if you choose to.",
"\n\nOnce you have an image, the fun begins. ",
"To add text, just double-tap on the starting text and write whatever you want. ",
"To save it, just tap outside of the text box. ",
"You can select the text again to move it, resize it, and change the font and color. ",
"There are a lot of fonts to choose from, so there will always be something to fit every occassion, without the need for in-app purchases. ",
"More refinements to the text can be made when it’s selected and you tap on “Adjust,” including kerning, leading, rotation, and more.",
"\n\nTo make your image even more spiffy, there is a plethora of various design elements that can be added, which you can resize or move just like text, as well as change the color. ",
"There’s no limit to how much text or design components you can add to a single image, so feel free to let loose.",
"\n\nIn addition to the text and designs, you have basic editing tools for cropping and adjusting the overall tint of the photo. ",
"While the tinting feature is a bit limiting, there are a lot of crop ratios, so you are bound to find one that best suits your photo.",
"\n\nWhen you tap on Done, the image gets saved to the Lightbox automatically, so you can pick up where you left off later. ",
"There are also other options for the image, including saving it to the Camera Roll, sending it through email, sharing on Twitter, Facebook, Instagram, Flickr, or opening it in another app.",
"\n\nFor the price, UponPixels has a lot of variety for users who are into decorating their images with text and fancy designs. ",
"It’s fast and simple to use, so there’s no learning curve. ",
"The design is also pretty slick, making it an enjoyable experience, and the Lightbox is a handy feature. ",
"It still feels a little rough around the edges with some things, but I’m sure that it will be improved over time."
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"// Copyright 2015 go-swagger maintainers\n//\n// Licensed under the Apache License, Version 2.0 (the \"License\");\n// you may not use this file except in compliance with the License.",
"\n// You may obtain a copy of the License at\n//\n// http://www.apache.org/licenses/LICENSE-2.0\n//\n// Unless required by applicable law or agreed to in writing, software\n// distributed under the License is distributed on an \"AS IS\" BASIS,\n// WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.",
"\n// See the License for the specific language governing permissions and\n// limitations under the License.",
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[
"Lithuanian–Polish–Ukrainian Brigade\n\nLithuanian–Polish–Ukrainian Brigade (LITPOLUKRBRIG; ; ; ) is a multinational brigade consisting of units from the Lithuanian, Polish and Ukrainian armies. ",
"Other countries are free to join the trilateral agreement. ",
"An agreement on its creation was signed on November 16, 2009. ",
"The brigade was to reach operational status in autumn 2011, but it was delayed; a January 2012 estimate put that date at some time in 2013. ",
"The unit was finally formed on September 19, 2014. ",
"In July 2015 the defense ministers of the three countries signed an agreement on the operation of the unit.",
"\n\nThe LITPOLUKRBRIG headquarters was opened in Lublin (Poland) on 25 January 2016.",
"\n\nLithuania and Poland are NATO members, while Ukraine is not. ",
"Ukraine asked to join the NATO Membership Action Plan in January 2008 (see Ukraine–NATO relations) but shelved these plans early June 2010, however, Ukraine's co-operation with NATO continued.",
"\n\nThe brigade participated in the training exercise \"Brave Band\" in February 2016.",
"\n\nName\n2017-10 named after Konstanty Ostrogski.",
"\n\nHistory\n\nOn June 14, 2007, during an EU Defence Ministers' meeting, Lithuanian, Polish and Ukrainian ministers agreed to create a multinational unit. ",
"In fall of 2008 the proposed unit type was specified as a brigade. ",
"The three countries did have experience in past joint military operations, most notably, through the Lithuanian-Polish Peace Force Battalion and the Polish–Ukrainian Peace Force Battalion. ",
"Lithuania and Poland are NATO members, Ukraine is currently not but requested to join the NATO Membership Action Plan in January 2008. ",
"On November 2009 a \"Protocol of Intent\" covering formation of a joint Lithuanian, Polish and Ukrainian brigade (\"LITPOLUKRBRIG\") was signed by Defense Minister of Lithuania, Rasa Jukneviciene, Deputy Secretary of the Polish Ministry of Defense Stanisław Komorowski (representing the indisposed Defense Minister of Poland, Bogdan Klich) and acting Defense Minister of Ukraine Valeriy Ivashchenko.",
"\n\nOn March 17, 2014, The Daily Telegraph (online edition) reported, as part of its live coverage of the 2014 Crimean crisis, that Poland’s defence ministry had announced it was re-launching plans to establish a joint Polish, Ukrainian and Lithuanian military brigade.",
"\n\nThe ministry said \"defence ministers would meet later that week to discuss the formation of the brigade that would straddle Nato’s eastern border and bring Ukraine’s armed forces closer to the Western fold\".",
"\n\nIn February 2016, the brigade participated in the training exercise \"Brave Band\".",
"\n\nOrganization\n\nThe brigade has its headquarters and staff in Lublin, Poland, with the national components stationed in their respective countries and actually gathering together only for exercises and foreign missions. ",
"Only its staff officers are supposed to cooperate on a regular basis. ",
"The unit is intended to be used to fulfill tasks given to it by NATO, European Union (EU) and the United Nations. ",
"The operating language of the brigade is agreed to be English. ",
" The unit was formed on 19 September 2014. ",
"Headquarters was officially opened in Lublin on 25 January 2016, in a ceremony attended by defence ministers of the three countries.",
"\n\nPolitical ramifications\n\nThe agreement between Lithuania, Poland and Ukraine was signed two days before an EU summit with Russia aimed at increasing cooperation between the two. ",
"Analysts expected the formation of the brigade could anger Russia, because Russia is against Ukraine joining NATO. ",
"A NATO spokesman welcomed the Polish-Lithuanian plan, stating that cooperation may increase trust and capabilities.",
"\n\nAccording to Poland's Deputy Defence Minister Stanisław Komorowski \"This move reflects our support for Ukraine. ",
"We want to tie Ukraine closer to Western structures, including military ones\".",
"\n\nIn November 2009 Polish newspaper Gazeta Wyborcza predicted the chances that the brigade would become a reality were larger if Yulia Tymoshenko would win the 2010 Ukrainian presidential election, and smaller if Viktor Yanukovych would win them. ",
"Yanukovych won the elections, but preparations for the brigade continued. ",
"Yanukovych stated on May 27, 2010 that Ukraine considered Ukraine's relations with NATO as a partnership, \"And Ukraine can't live without this [partnership], because Ukraine is a large country\".",
"\n\nSee also\nMultinational Engineer Battalion Tisa\nMilitary of the European Union\nMultinational Corps Northeast - NATO formation grouping units from Denmark, Germany and Poland\nPolish–Lithuanian Commonwealth (historical)\n\nReferences\n\nExternal links\n List intencyjny w sprawie LITPOLUKRBRIG podpisany Polish Ministry of Defense official announcement (November 16, 2009)\n\nCategory:Brigades of Lithuania\nCategory:Army brigades of Poland\nCategory:Brigades of Ukraine\nCategory:Military units and formations established in 2009\nCategory:Multinational army units and formations\nCategory:Lithuania–Ukraine military relations\nCategory:Lithuania–Poland military relations\nCategory:Poland–Ukraine military relations"
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"On Saturday the Tigers succeeded in defending their home court against regional rival Ole Miss. The Rebels were no slouches and hit 12 of 27 threes while Memphis’ only triples came by way of Tyler Harris, who hit three shots from deep.",
"\n\nMemphis forward Precious Achiuwa stepped up in a big way for the Tigers with a 25 point, 11 rebound performance with 10 of 16 shooting from the field. ",
"This was the first game where Precious truly stepped up in the paint and took care of business, showing flashes of why he is a projected NBA draft lottery pick.",
"\n\nAlex Lomax and Tyler Harris, both local Memphis sophomore guards, played huge roles off the bench for Penny Hardaway. ",
"They each put up double digit scoring. ",
"Lomax added 7 rebounds and 7 assists in what was hopefully his breakout performance of 2019-20.",
"\n\nWith the help of DJ Jeffries, the Tigers bench outscored the starters 52-37. ",
"Jeffries contributed 23 points and several highlight reel dunks, much to the pleasure of the home crowd.",
"\n\nOn a sour note, guard Lester Quinones – who had been the most consistent Tiger this season – was injured in the first half and only amassed 9 minutes. ",
"The diagnosis is a broken hand and he will be out a minimum of 3 weeks, with some reports saying between 4-6. ",
"This is a huge blow for the Tigers, who will also be without star center James Wiseman until January 12th.",
"\n\nIsaiah Maurice drew the start on Saturday in the place of Wiseman, but had a very lackluster performance. ",
"During a press conference this week, Hardaway said that he will likely stick with Maurice in the starting lineup instead of inserting Lance Thomas, who had 5 rebounds and 3 blocks off the bench on Saturday.",
"\n\nThe easy move for Hardaway would be to move DJ Jeffries to the starting lineup, but if he does that then he loses significant fire power off the bench. ",
"Jeffries led the team in minutes against Ole Miss despite coming off the bench. ",
"I think that if he is content in playing that role, the Tigers have a significant advantage over many of their opponents.",
"\n\nWith Alex Lomax’s impressive performance last week, I would move him to the starting lineup to suit up alongside fellow guards Boogie Ellis and Damion Baugh, who have decent height and length for their positions.",
"\n\n\n\nLooking Ahead to NC State\n\nOn Thanksgiving day at three o’clock, you can push back the Turkey and tune in to watch the Tigers face off against NC State at the Barclays Center.",
"\n\nThe Wolfpack will present a compelling matchup to the shorthanded Tigers. ",
"NC State is returning 6 of their 7 leading scorers from a year ago. ",
"They are a group that takes care of the ball and forces their opponents to turn the ball over.",
"\n\nMemphis will need to be alert and quick on defense as the Wolfpack are shooting 33% from three and also 54% from two. ",
"Similar to Memphis, they like to push the pace and get a shot off within the first 16 seconds of the shot clock on average.",
"\n\nTheir high powered offense averages 84.5 points per game to Memphis’ 86.7. ",
"Coach Kevin Keatts’ squad is experienced with the average player having over two years of playing time under their belt.",
"\n\nFor the most part, Keatt’s utilizes an 8 man rotation that is ripe with shooting talent.",
"\n\nSenior guard Markell Johnson is the main distributor, dishing out 6.8 assists – his assists rate is top 50 in the country – in addition to scoring 10 points of his own. ",
"Right now, he is not one of their more efficient scorers, but has the potential to punish teams based on his history. ",
"Johnson is shooting 10 percentage points lower than his career average and we can only expect that he will break out of this early-season slump soon.",
"\n\nThe biggest offensive threat for NC State is CJ Bryce, a 6’5” senior who is the most efficient scorer on the Wolfpack roster and is averaging 17.7p/7.7r/2.7a.",
"\n\nGuard Devon Daniels averages almost 2 steals per game and takes 24% of NC State’s shots on his way to averaging 14.2p/3.7r/2.3a.",
"\n\nDown low, the best offensive rebounder for NC State is Jericole Hellems, who averages 9.7p/4.3r/1a.",
"\n\nWith Wiseman out, Manny Bates will be the tallest player on the court at 6’11”. ",
"The redshirt freshman averages almost 4 blocks per game and is close to tops in the nation in block percentage.",
"\n\nA threat from the outside, stretch forward Pat Andree is shooting 41.9% from three this year. ",
"He is a graduate transfer from Lehigh. ",
"Braxton Beverly is another three point threat for the Wolfpack who averages 9.8p/3.7r/2.7a. ",
"Rounding out the bench mob is DJ Funderburk, a 6’10” forward who is contributing 11.5 points and 5.5 rebounds per game.",
"\n\nTo help get an insider’s perspective, I reached out to Steven Muma of BackingThePack.com with some questions to help shed some light what folks on the NC State side of things are feeling about this matchup.",
"\n\nWho has been NC State’s top newcomer so far?",
"\n\nThere are only two to choose from, and while both have been good, I’ll give the nod to grad transfer Pat Andree, who came in from Lehigh. ",
"NC State recruited him to give the Wolfpack more perimeter scoring depth and he’s been as advertised so far, hitting 13-27 of his three-point attempts this season. ",
"He’s definitely more of a role player, but definitely the sort capable of changing the trajectory of a game by hitting a handful of threes.",
"\n\nWho has been the most consistent player on the roster and what can you expect from him night in and night out?",
"\n\nThis season that’s been senior wing C.J. Bryce, who came with Kevin Keatts from UNC-Wilmington. ",
"Bryce isn’t a great jump shooter and doesn’t rely heavily on threes, which is fine since he’s always been a capable scorer from 15 feet and in. ",
"He’s scored at least 16 points in five of NC State’s first six games. ",
"He’s a pretty good rebounder for his size and a decent passer as well, so he’s able to do a bit of everything.",
"\n\nBut Markell Johnson is the best player on this team, without question. ",
"He just hasn’t found the range on his jumper yet, and when that happens, I expect him to be the consistent leader that State needs him to be in order to reach its full potential as a team. ",
"Johnson has great quickness and is excellent around the rim, and those things will create problems whether or not he’s making jumpers.",
"\n\nWhat personnel matchup you are most looking forward to?",
"\n\nBefore the season, I would have simply said “James Wiseman doing things against whoever” but since the NCAA rudely has taken that off the table (seriously, as a fan of basketball in general, I hate seeing NCAA shenanigans sideline a big-time talent like this) I’m looking forward to seeing how these teams’ guards stack up against each other.",
"\n\nWhat are some ways that Memphis can beat NC State and ways that NC State can beat Memphis?",
"\n\nThe turnover column will be one to watch on both sides, since both of these teams have been good at creating turnovers. ",
"NC State likes to press more often than most teams and if that’s effective, it’s going to make winning a lot easier for the Wolfpack. ",
"Does Memphis’ youth become a problem for the Tigers there? ",
"We’ll see.",
"\n\nMemphis has been excellent on the offensive glass this season, while State has been only so-so on the defensive boards, and that’s always a key for the Wolfpack defensively. ",
"If the Tigers end up controlling the glass at that end of the floor, I could see that costing NC State the game. ",
"This becomes more critical if NC State isn’t forcing turnovers.",
"\n\nKeys to the game\n\nContain CJ Bryce. ",
"The Tigers are going to need Damion Baugh to step up and play tough defense if he draws this assignment.",
"\n\nThe Memphis frontcourt is only as good as Precious Achiuwa. ",
"He will need another big game for Memphis to come out on top.",
"\n\nKeep NC State off the offensive boards. ",
"No easy putbacks.",
"\n\nForce turnovers. ",
"Memphis has done this all season and will need to keep this as part of their core.",
"\n\nHit a three or five. ",
"If NC State plays zone, like most teams have against Memphis, someone will need to break it. ",
"I’m looking at you, Tyler.",
"\n\nMore College Hoops Content\n\nZak (@BarnBurnerBro) is a native Memphian who covers the Memphis Grizzlies, Tigers, and St. Louis Cardinals for The Barn. ",
"He spends his free time exploring breweries, restaurants, and leading the Ivan Rabb stan club.",
"\n\nFollow us on Twitter HERE. ",
"For more Tigers content check out the rest of The BarnBurner HERE.",
"\n\nShare this: Twitter\n\nFacebook\n\nReddit\n\n"
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" TEXAS COURT OF APPEALS, THIRD DISTRICT, AT AUSTIN\n\n\n JUDGMENT RENDERED JULY 18, 2018\n\n\n\n NO. ",
"03-18-00227-CV\n\n\n Sattar Investments, Inc. and Adnan Sattar, Appellants\n\n v.\n\n Ingrid Radkey, Appellee\n\n\n\n\n APPEAL FROM COUNTY COURT AT LAW NO. ",
"1 OF TRAVIS COUNTY\n BEFORE CHIEF JUSTICE ROSE, JUSTICES PEMBERTON AND FIELD\n DISMISSED ON APPELLANTS’ MOTION -- OPINION BY JUSTICE FIELD\n\n\n\n\nThis is an appeal from the judgment signed by the trial court on September 14, 2017. ",
"Appellants\n\nhave filed a motion to dismiss the appeal, and having considered the motion, the Court agrees\n\nthat the motion should be granted. ",
"Therefore, the Court grants the motion and dismisses the\n\nappeal. ",
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"Interview by Roberta Ilaria Rossi\n\n\n\n\n\nAfter so many years of silence, Xandria comes back in the metal scene with a masterpiece album, “Neverworld’s End”, showing the power and the new direction the band is going through. ",
"I had the chance to talk with the new singer, Manuela Kraller, which brought me into a magic world, explaining what is this new album for the band and for helself as well.",
"\n\nHi Manuela, welcome to Femme Metal! ",
"New Xandria’s album, “Neverworld’s End” was released a few days ago, would you like to share something with us?",
"\n\nI was very excited before the release and about the reaction of the people. ",
"But all went well and until now we got a lot of good feedback from the fans, what shows us that we are on the right path 😉\n\nThe record was released by Napalm Records and I know that it took long time to produce it and to create it. ",
"What can you tell about it? ",
"How long did the recording last?",
"\n\nThe recording itself took a few months all in all. ",
"The recording has taken less time than creating and producing the album of course: The production and songwriting from beginning till the end took a few years… ….it was a lot of work, but it was worth the passion and time we put in it.",
"\n\nLast Xandria album, “Salomé – The Seventh Veil”, has been released in 2007. ",
"What prompted you to “delay” the release and the creation of this new album? ",
"I know that some changes have been made: Lisa left the band, then Kerstin left as well… What can you tell us about it?",
"\n\nOf course there has been a delay because of the front woman changes and the searching for a new singer. ",
"For the Xandria boys it was hard to find a new singer after Kerstin has left, but finally they found me 😉\n\nYou have a sort of opera singing and listening to the album, I’ve found so many references to Tarja Turunen. ",
"Some fans that had the chance to listen to “Valentine” have thought the same thing. ",
"Do you agree with this statement? ",
"Do you see yourself like the heir of the great Tarja?",
"\n\nNo, I don’t see myself as a heir of Tarja and I don´t want to be a second Tarja. ",
"I am Manuela and I am an individual woman with my own voice. ",
"Of course people compare us, because we both sing classical and have a dark timbre, but everything else is different. ",
"And everybody who listens closely will recognize this. ",
"Some people also think I want to sound like Tarja, but that´s not correct. ",
"My voice sounded like this already before I have ever listened to Tarja. ",
"My voice is like this, not because of Tarja, but because of myself. ",
"Well, don´t understand me wrong: It is not a bad thing being compared with Tarja, but I really hope that once people will stop this comparison and say: “This is Manuela‘s voice” and not saying “She sounds like Tarja“. ",
"That´s my aim, to develop my voice more and more and get my own unique voice.",
"\n\nI think that this album will finally make the history for Xandria and it will bring you lots of great surprises. ",
"Now Xandria is a symphonic band, to all intents and purposes. ",
"What do you expect from yourself and from the band?",
"\n\nWith “Neverworld´s End” we laid down the basis for a new beginning. ",
"And now it is time to go forward and upwards, step by step. ",
"I expect a lot from Xandria and from myself. ",
"I am a kind of perfectionist concerning singing, so I will always try to make my voice grow and to give my best on stage. ",
"My wish for Xandria is that we will make music that enthuses people, give as many concerts as possible and perhaps once make a world tour, I think this must be amazing! ",
"😉\n\nListening to the record, I’ve found similarities that recall albums like “Once”, “Century Child” and, why not, “Wishmaster” by Nightwish as well. ",
"What is your thought about this? ",
"Have you ever thought of proposing yourself as the new Nightwish singer?",
"\n\nMany don’t know it, but I really applied in 2006 as new Nightwish singer!;) ",
"But at this time I didn´t have any possibilities to make a demo, so I just send some live recordings of me when I sang in church, not a very good way to make an application 😉 But I tried and that´s the most important thing for me, even if they didn´t take me as new singer. ",
"But Xandria did and now I can make real symphonic metal, yeahh! ",
"Many people compare us with Nightwish, we expected this, because we make symphonic metal with opera voice and if you do this it is normal that people make this comparison, because Nightwish is the most known band in this genre and people always compare with something that they know. ",
"The comparison is ok for me, but I think that Xandria nevertheless has its own style! ",
"For example do we have much more progressive style in our music than Nightwish had in further times, we have our own catchy melodies and I use my voice in a much more different way than Tarja does. ",
"I also use rock voice sometimes (f.e. ",
"in “Soulcrusher”) or a very fragile not very classical voice in the verses of “A 1000 letters…”\n\nPersonally, I think that now Xandria can consider itself as “Old Nightwish at the Age of Tarja“. ",
"Many similitaries have been found and I think that you’ve “stolen” something from Nightwish, in order to explore some new “lands”. ",
"Do you agree with this statement?",
"\n\nWe surely wanted to explore new lands, but don’t want to “steal” anything from anyone, though I know you don’t mean this in a way of plagiarism but of spirit in the music. ",
"Yes, we share a lot of this spirit with Nightwish, I think we have some similar visions and it’s great to realize that people enjoy our music because of this vision. ",
"But we would not reduce this to a certain era of another band, we surely want to originate much of a similar spirit but create our own music with it.",
"\n\nTalking about the sound, a change is so evident, a sort of an evolution, as if the band wanted to experiment a new sound. ",
"You are more metal-oriented, more symphonic metal and you’ve “left” the gothic genre, as experienced in the first albums. ",
"What did cause such choice?",
"\n\nWith “Salome” you can say the music of Xandria hasn’t had a real development anymore, they went in a kind of blind alley in my opinion. ",
"It was time to decide in which direction Xandria wanted to go and Marco and the others found their consent in focus on the symphonic and metal elements. ",
"Marco also wanted a coherent sound for Xandria and the music and this was the way for a new beginning.",
"\n\nWe can say that Xandria has been brought to life again: after a possible split in the years, Xandria found a new singer, worthy of this role, a new sound, a metal-oriented one. ",
"It will be a successful year for you. ",
"What are you expectations for this news adventure?",
"\n\nAs I said before: We expect that our way leads now upwards step by step and we are working for this with passion. ",
"What the future will bring for us nobody can tell, but hopefully it will bring only good things to us 😉\n\nHow do you see yourself in 10 years?",
"\n\nI’ll see myself in my red wooden house on a lake, with a golden record on my wall 🙂 and as someone that made a living from singing (it´s not about the money, but about the opportunity making music everyday and everytime ;), someone who still tours around the world and gives concerts…\n\nWhat does it represent “Neverworld’s End” for you?",
"\n\nIt’s my fantasy world. ",
"The world that I loved as a child and when I sing the songs, I have the feeling I am reviving my childish dreams again…\n\nWhat is Xandria for you,for your personal and artistic growth?",
"\n\nSince I am in Xandria I learned a lot, also personally. ",
"I grow with every step on our way and I have the feeling I find more and more myself as a person. ",
"Artistically it gives me the possibility to develop my voice and to make the music I always wanted to make…\n\nWe’ve talked about bands, I know that you’ve worked with Haggard. ",
"What is the most beautiful memory related to this experience?",
"\n\nWe had a concert in front of 100.000 people in Colombia, that was quite amazing! ",
"I also made wonderful experiences on tour, got to know many great people and countries and learned a lot. ",
"But the most beautiful memory stays the very first concert with Haggard. ",
"It was the first time that I sang in front of a few thousand people at the Masters of Rock festival. ",
"It was an amazing feeling to stand there on stage, because in this moment I knew that I want to be a singer and that this is the right profession for me.",
"\n\nHad you worked with some other bands before?",
"\n\nBefore Haggard I have never worked with any band before. ",
"Haggard was my first band, second band was Nagor Mar (now Forty Shades) of switzerland.",
"\n\nNow you’ve joined Xandria and you’re the female singer, replacing that role that once was Lisa’s. ",
"how do you feel to be in her shoes, now? ",
"I know that you and Lisa have a beautiful friendship. ",
"Will we ever see the both of you in a duet, someday?",
"\n\nWell, I think I brought my own shoes with me 😉 I don´t want to step in somebody’s footsteps, I want to leave my own on Xandria’s way. ",
"To be honest, I don´t know Lisa very much, we’ve met only twice in life…I don´t know if there’ll be a duet one day, we’ll see 😉\n\nRitual question: what do you think was the impact of the fans when they heard about your entrance in Xandria?",
"\n\nFrom the first moment on the reaction of the fans was very positive. ",
"They supported me from the very beginning. ",
"Of course some fans will always say: “We want Lisa back!”, ",
"but that´s ok. ",
"Everybody has its own opinion and own taste concerning voices. ",
"I try to concentrate on the positive critics and feedback, that´s what counts for me 🙂\n\nAt the first public event, Classic Meets Pop, where the band officially introduced you to fans, you’ve performed live the song called “Ravenheart”, as you have sung several famous songs at Out of the Dark Fest, like “Now and forever”, “India”, “Save My Life”. ",
"In my opinion, your voice makes perfectly what the song wants to convey to the listener. ",
"How did you prepare yourself to sing these songs?",
"\n\nI tried not to copy Lisa, but do give in my own voice into the songs. ",
"I thought a lot about the meaning of the lyrics and tried to express the content of the songs with my voice. ",
"It wasn’t very hard to sing the songs. ",
"For the new songs I had to practise a lot more, cause they are much more complex.",
"\n\nIs there a song, among the ones I’ve named, or among the most famous Xandria songs, that you like the most or you feel more connected to? ",
"If so, why?",
"\n\nI can almost not choose just one song of the new album, every song fascinates me and I love to sing everyone of them! ",
"Of the older songs I like “India” and “End of Every Story” a lot…\n\nA videoclip for “Valentine” will be out very soon, in particular it will be released for St Valentine’s Day. ",
"Would you like to share something with us? ",
"From a small taste, I was under the impression that it seems a very particular videoclip…\n\nWell, it is not about love 😉 It´s about an artist that sells his soul and heart to a higher instance. ",
"Outside he laughs, but inside he is very sad. ",
"The harlequin represents the artist….",
"\n\nTalkin’ about live experience: after a long time, Xandria embarked on a short tour in Europe, and as I was saying earlier, you’ve been the long- awaited protagonist for Out of the Dark Fest, along with Serenity, Amberian Dawn, Van Canto and Tristania. ",
"What was it like for you to scale back on stage with your new band, feeling the chills down your spine given by fans that were there, all the emotions, giving the people what they wanted to convey? ",
"I guess it was a truly remarkable experience for you…\n\nIt was a great feeling to stand finally with Xandria on stage and sing a full set with them! ",
"The fans were amazing and we really had a great time on tour also with the other bands! ",
"It was a wonderful time!",
"\n\nThe audience has witnessed the power of your voice and how much drama, energy and versatility you will be able to give. ",
"How do you train your voice? ",
"How do you prepare yourself before a show or a particular event?",
"\n\nI make some voice practices every day, 2 times a week I go into a rehearsal room near my home, where I practice the Xandria songs and sing to the instrumentals. ",
"Because it is not possible to practice every week with Xandria: We are living about 800 kilometers away from each other, so I have to practice also on my own. ",
"Next to that I do sports: Swimming, jogging and I also go to fitness (Pilates, Zumba). ",
"My body is my instrument so I try to take care of it as much as I can 😉\n\nAccording to what you wrote in your “biography”, you’ve been introduced in the music scene at 23. ",
"What could you tell about it? ",
"What has been your Art Education?",
"\n\nThat’s right, I started singing very late. ",
"In my family no one made music, so it lasted a long time until I found music on my own. ",
"In a choir in Finland I discovered classical singing for me and back home I started to take singing lessons. ",
"I have never studied singing, I had 6 years of private classical singing lessons. ",
"Now I practise on my own….",
"\n\nHow did you discover your own passion for metal music? ",
"Is there any band that has inspired your way of singing or that you like to listen to/to sing of?",
"\n\nWhen I started taking singing lessons, I haven’t been inspired by female fronted metal bands or Tarja. ",
"After two years of singing I started to listen to Nightwish’s “Once” and that was the point when I recognized by myself in which direction I wanted to go as a singer. ",
"Tarja was for sure an inspiration when I started singing.",
"\n\n2012, as I was saying, will be very rich and full of surprises. ",
"We’ve seen you around Europe last year. ",
"What will happen this year? ",
"Are you going to plan a new tour? ",
"I know that you will support Epica for a few dates…\n\nYes, we’ll support Epica in March and in April! ",
"I am really looking forward to this! ",
"And we want to play as many festivals as possible. ",
"There is not another tour planned yet, but there’ll be one for sure this year…\n\nWhich is the most beautiful memory related to the band and to the music itself? ",
"Maybe I realize that it’s too early to ask for this question…\n\nThat’s difficult, because there have been so many wonderful moments. ",
"For example at concerts. ",
"But when I saw our CD “Neverworld’s End” in a record store between all the other Metal CD´s, I was very proud:) It was like a kind of present for all the hard work we’ve done. ",
"It was a wonderful feeling…and of course every single concert, when I see in the people’s face that they love our music and that we bring joy to them with what we do. ",
"That´s the biggest present of all 🙂\n\nThanks so much Manuela for having allowed us this interview. ",
"Waiting for the release of new Xandria album, the editorial staff wishes you lots of happiness and we wish you all the best. ",
"Is there something you would like to tell Xandria’s fans and to our readers as well?",
"\n\nThank you! ",
"It was a pleasure for me:) To all the fans: Thank you sooooo much for the support and for the positive reactions and comments related to our new CD!! ",
"It makes me very happy to see that you love our music…Love you!! ",
"Kisses, Manuela.",
"\n\nLinks\n\nMySpace * Facebook * Twitter * Site\n\nLatest Multimedia"
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[
"Analyzing nanoparticles in complex matrices reveals challenging {#Sec1}\n===============================================================\n\nThe recent recommendation of the European Commission on the definition of nanomaterials is emphasizing the determination of the non-bound particles as a number size distribution from 1 to 100 nm (EU Commission [@CR8]). ",
"While this definition is precise from a legal point of view, it causes substantial constraints as there are very few or no easy analytical methods to measure this variable without any conversions. ",
"An additional limitation is due to the fact that currently only a few already existing analytical techniques can reach far down to 1 nm as required by the definition. ",
"Thus, the detailed analytical characterization of the basic particle inherent properties like size, shape and surface area should stand at the very beginning of any further considerations. ",
"A thorough characterization of the nanoparticles especially in complex matrices is still the biggest challenge in this research area and could potentially become a pitfall for further innovation in the field.",
"\n\nAnalytical methods, limitations and repository materials {#Sec2}\n--------------------------------------------------------\n\nDouglas Gilliland (Joint Research Center JRC---Institute for Health and Consumer Protection IHCP, Italy) discussed the currently available analytical methods. ",
"Electron microscopy (EM) enables visualizing of the nanoparticles itself (Linsinger et al. [",
"@CR37]). ",
"Although this technique is usually regarded as the standard method for particle size determination, this is only unrestrictedly true for very ideal samples. ",
"If the composition of the analyzed sample becomes more complex, for example, due to the formation of aggregates, the determination of the particle size distribution by EM is rather challenging.",
"\n\nOther commonly used techniques are light scattering methods with dynamic light scattering (DLS) being the principal one. ",
"For monodisperse samples, DLS can be used to obtain quite precise size measurements, but for the analysis of complex mixtures of \"real-life samples,\" this technique has some severe limitations. ",
"In particular, in the presence of larger particles, a heavy weighting toward the larger particle sizes occurs.",
"\n\nOne scientifically accepted alternative overcoming this difficulty is using a whole suite of appropriate techniques in a tiered order. ",
"The JRC/IHCP recommends a multi-technique approach integrating optical methods, direct imaging and precise separation methods. ",
"One preferred way of analyzing a composition of nanoparticles is the detachment of size separation from the actual size measurement in order to determine the relative quantities in conjunction with the relative particle size. ",
"For example, techniques like asymmetric flow field-flow fractionation (AF^4^) or centrifugal particle sedimentation (CPS) are used to fractionate particles into different portion sizes. ",
"The purpose of these comparatively gentle separation techniques is the full recovery of particles in their separated state. ",
"At this point, a wide variety of different detectors can be used for a more precise nanoparticle characterization. ",
"Examples for such detectors, which can be combined with AF^4^, are the refractive index, DLS and the ultraviolet/visible (UV/Vis) detector. ",
"To achieve ultimate sensitivity in case of inorganic nanoparticles such as silver, AF^4^ can be connected online to the inductively coupled plasma mass spectrometry (ICP-MS).",
"\n\nAt JRC, the following techniques are used for in-depth analyses of the properties of nanoparticles at the molecular level: X-ray photoelectron spectroscopy (XPS) to characterize the surface chemistry of the nanoparticles; synchrotron radiation circular dichroism (CD) to study the various alterations of the protein corona that would occur during interaction of the particles (Laera et al. [",
"@CR111]) and nuclear magnetic resonance (NMR) spectroscopy to monitor any changes which can occur in the conformation of ligands.",
"\n\nBesides instrumentation, the absolute quantification of nanoparticles, the validation of the analytical method of choice and the calibration of the analytical equipment require the availability of appropriately characterized reference materials. ",
"In the absence of certified reference materials, which are so far restricted to gold and silica nanomaterials, the creation of a repository of well-characterized representative nanomaterials is essential for the implementation of any analytical test methods. ",
"The nanosilver repository material NM300 K provided by the JRC is well characterized, monodispersed, highly concentrated (10 % w/w) with more than 90 % of the material being below 20 nm in size (maxima 10--15 nm). ",
"This has been achieved by applying a mixture of two different surfactants as stabilizing agents, that is, 4 % w/w of each polyoxyethylene glycerol trioleate and Tween 20^®^.\n\nAs nanoparticles normally interact very quickly with their surrounding media, thereby altering their physico-chemical properties, measurement of the changes in particle size distribution in different media is essential for the understanding of the toxicological effects that may occur. ",
"The following results from studies carried out by the JRC may illustrate such alterations. ",
"In the presence of a high ionic content solution, the nanosilver particle dispersion becomes unstable. ",
"After 30 min in such an environment, the material reveals hardly detectable, and after 60 min, no nanoparticles could be observed anymore either due to aggregation or complete dissolution in the sample. ",
"Conversely, when the nanoparticles are kept in a protein-rich environment, like cell culture media, even after 12 h, there is a significant amount of material left in the mere monodispersed state and only after 48 h most of the material begins to disappear from the nanorange. ",
"In addition, silver nanoparticles may also remain relatively stable even after 24 h in water possessing low ionic strength. ",
"Increasing the ionic content by using water of ascending degrees of hardness, the dissolution or aggregation level of nanosilver particles is simultaneously rising until particles are no more detectable after 24 h. The addition of humic acid revealed as very powerful stabilizing agent, even when applied in very small quantities such as 10 μg per ml. ",
"Under such conditions, 50 % of the originally monodispersed nanoparticles remain preserved over 24 h. Studying the dissolution rate of silver particles stabilized with maltose in relation to particle size, it was found that the particles dissolve only between 5 and 10 % in 24 h, and even after around 7 days in solution only between 20 and 50 % of the silver particles had been dissolved. ",
"Although the larger particles had the lowest dissolution rate, it is assumed that this effect is only due to the changed surface-to-volume ratio, because the difference between larger and smaller particles was not nearly as significant as expected.",
"\n\nExperimental challenges analyzing complex matrices {#Sec3}\n--------------------------------------------------\n\nIn his talk, Stefan Weigel (RIKILT, The Dutch Institute for Food Safety, The Netherlands) was focusing on the analysis of silver nanoparticles in complex matrices. ",
"Recent exposure assessments are hampered by the limited availability of specific methods to determine size and elemental composition of complex matrices as exemplified by consumer products and food. ",
"Consequently, there is hardly any validated data on the presence of silver nanoparticles in such products.",
"\n\nA promising technique might be the single particle inductively coupled plasma--mass spectrometry (sp ICP-MS) as it represents a tool for the determination of both the number and mass concentration of silver nanoparticles. ",
"Instrument settings and nanoparticle concentration in the sample will be adjusted in a way that individual nanoparticles are being recorded. ",
"While the number of peaks corresponds to the particle number concentration, the intensity of the signal is proportional to the mass of the particles (Pace et al. [",
"@CR42]). ",
"Under the assumption of spherical non-porous particles, which are not composed of different materials, it is possible to calculate the original size of the particles. ",
"The method has successfully been applied to, for example, environmental, biological and food samples. ",
"Hyphenated separation and detection techniques have proven to be suited for the quantitative determination of silver nanoparticles in complex media. ",
"In particular, AF^4^ is commonly used for the separation of nanoparticles according to their sizes and can be coupled online to a variety of different detectors such as UV, light scattering and ICP-MS (von der Kammer et al. [",
"@CR54]). ",
"Screening methods are a cost-efficient alternative to the aforementioned techniques and recently a biosensor method for the detection of silver nanoparticles has been reported (Rebe et al. [",
"@CR45]). ",
"This surface plasmon resonance-based assay uses a human metallothionein as a recognition element on the sensor chip surface.",
"\n\nCharacterization of nanoparticles is often carried out in pure suspensions with sizing techniques that are not element specific (e.g., light scattering, particle tracking analysis or EM) and/or with element-specific methods (e.g., AAS, ICP-MS, ICP-OES) that are not size specific (determination of bulk concentration). ",
"In application media and even more in vivo, the nanoparticles may change considerably. ",
"Agglomeration, aggregation, dissolution and attachment to proteins have been described. ",
"Therefore, it is essential to characterize nanoparticles in cell culture media or under in vivo conditions by using size and element-specific methods or a combination of methods to achieve a meaningful answer to the experimental question addressed.",
"\n\nA further specific issue is the existence of different solid forms of silver species that via dissolution can be partly transformed into other species. ",
"Thus, elemental silver (Ag^0^) slowly dissolves and depending on the chemical environment, the resulting Ag^+^ ions may form soluble complexes such as AgCl~2~^−^, AgCl~3~^2−^, \\[Ag(NH~3~)~2~\\]^+^, covalent adducts with thiol group containing compounds (e.g., glutathione, cysteine, proteins) or insoluble salts (AgCl, Ag~2~S) which may precipitate as particulates (Liu et al. [",
"@CR38]). ",
"Furthermore, Ag^+^ can be easily reduced to Ag^0^, for example, by glucose, thus leading to *de novo* formation of Ag^0^ nanoparticles. ",
"It therefore becomes crucial to determine the identity of the chemical species in which silver nanoparticles are present in the test tube.",
"\n\nIn summary, despite the already-mentioned difficulties, a number of different approaches for the detection and characterization of nanoparticles in complex matrices have yet been developed or are currently under development. ",
"However, sample preparation is one critical issue for such samples and the formation of artifacts and matrix effects is a common problem (Dudkiewicz et al. [",
"@CR11]). ",
"Furthermore, the validation of methods for the analysis of silver nanoparticle's size, distribution and overall presence is currently severely hampered by the absence of any certified reference materials, both for pure dispersions as well as in various matrices.",
"\n\nConsumer exposure scenarios are only starting to be developed {#Sec4}\n=============================================================\n\nIrrespective of the claimed benefit of nanomaterials, their utilization must be safe. ",
"As part of the overall risk assessment exposure characterization comprises the systematic identification of potential exposure scenarios and the estimation of exposure levels via oral, dermal and inhalative routes. ",
"Direct exposure to pristine manufactured nanomaterials is most likely for workers in industrial settings when handling nanomaterials without protection measures or by accidental release from enclosed automatic production systems. ",
"Consumers are mostly intentionally or unavoidably exposed to nanomaterials when using the increasing variety of products meanwhile containing these materials, such as lotions, antiperspirants, shoe sprays and food package materials. ",
"Next to the content, an assessment of the resulting exposure will have to take into account the material humans come into contact with. ",
"The four talks in this session covered current results of research on textile functionalization, nanoparticle abrasion from surface coatings and content, release and uptake assessments for silver and nanomaterials from food, dietary supplements and consumer products. ",
"For the purpose of this review, their contents have been sorted according to exposure routes.",
"\n\nInhalative exposure {#Sec5}\n-------------------\n\nAmong other applications, silver is used as a biocidal agent in sprays to treat shoes and feet, and to act as antiperspirant which can result in exposure via the respiratory tract. ",
"Natalie von Götz (ETH Zürich, Switzerland) reported the levels of 6--9 ppm silver and below the detection limit in the solutions of sprays investigated at the ETH Zürich and EMPA (Lorenz et al. [",
"@CR39]). ",
"Subsequent TEM analysis of the corresponding aerosols indicated no silver particles. ",
"It was argued that this finding might be due to the silver having been a mixture of silver salts and nanosilver particles, and would need to be elucidated further. ",
"A recent US study for comparison detected up to 56 ng nanosilver per spray action in aerosols (Quadros and Marr [@CR44]). ",
"A remarkable finding reported by von Götz was that the investigated pump spray did not generate particles in aerosols measurable with a scanning particle mobility sizer after thermodesorption in 80-cm distance to the spraying nozzle. ",
"The emitted droplets dropped down by gravity before they reached the detector. ",
"However, the propellant gas driven sprays produced many inhalable nanoparticles or nanoscaled droplets irrespective of the original nanoparticle content in the dispersion.",
"\n\nIn tiered release experiments, Michael Stintz and co-workers (Technical University of Dresden, Germany) applied increasingly stressing surface treatments to coated parquet. ",
"In a first tier, abrasers with sand stone wheels achieved a low-velocity scratching treatment used to simulate an abrasion process comparable to walking on the parquet with sandy shoes. ",
"Parquet coatings contained zinc oxide in nanoform (clear coat) and/or titanium dioxide as whitening pigment. ",
"In this setting, the treated surfaces released negligible amounts of nanoparticles because of the low velocity and the elasticity of the clear coat (Vorbau et al. [",
"@CR56]). ",
"In the second tier, a high-speed rotating sander was used. ",
"As a major result, it was impossible to distinguish between the generated aerosols from several surface coatings with nanoparticles (zinc oxide and iron oxide) and from those without (Göhler et al. [",
"@CR13]). ",
"In a third step, furniture, parquet and architectural coatings were artificially aged by UV radiation in a dry atmosphere (2,000 h at 50 °C; European Standard for indoor aging) prior to a fully encapsulated sanding procedure. ",
"In essence, no free nanoparticle additives (e.g., ZnO) were observed by applying extensive analytical procedures (scanning/transmission electron microscopy and energy disperse X-ray spectroscopy, SEM, TEM, EDX), despite considerable sanding-induced release of particles in the nanoscale. ",
"The TEM images revealed that the nanoparticle additives remained firmly embedded in the surrounding matrix material of larger particles, hence the nanoscaled particles observed originated solely from the pure matrix material. ",
"Irrespective of the kind of surface coating, additional nanoparticle additives did not have any impact on particle size distribution patterns. ",
"However, the patterns and generated amounts were significantly altered by aging. ",
"In these cases, more particles were detected and a broader particle size distribution was noted. ",
"Stintz estimated that up to 150.000 respirable particles per cm^3^ can be produced through sanding procedures. ",
"Reasoning that comparably high particle concentrations are reached in heavy traffic roads during rush hour, he considered it remarkable that special breath masks are recommended especially for long-time exposure of professional sanding workers (Hillemann et al. [",
"@CR19]). ",
"Besides standardized procedures for the mechanical treatment of surfaces exist, the workshop did not address a harmonized strategy to determine number concentrations at the workplace (Kuhlbusch et al. [",
"@CR33]).",
"\n\nDermal exposure {#Sec6}\n---------------\n\nThe intact skin has been shown to be an effective barrier for nanoparticles. ",
"For silver nanoparticles, skin penetration rates less than 0.01 % have been published (Larese et al. [",
"@CR35]). ",
"Despite such low rates, the internal exposure resulting from high external burden may still be considerable. ",
"Lorenz and co-workers have recently published an assessment of potential exposure via cosmetics and personal care products taking into account the behavior patterns of German consumers (Lorenz et al. [",
"@CR40]). ",
"However, the authors did not include creams in their reflections on silver. ",
"Based on a reported common application of 0.8 g each on hands and face trice a day and a content of 0.1 % silver, von Götz calculated an external exposure of 4.500 μg silver/day. ",
"While internal exposures can be assessed from external burden on the basis of uptake factors, von Götz emphasized that up to date, irrespective of the route regarded, these factors have been determined in only a few studies, if any. ",
"Furthermore, these have usually been conducted with a specific nanoparticle material and intact skin. ",
"This should be taken into account when employing the factors as they are prone to be influenced by changes of characteristics, such as size, surface coating and form of nanoparticles. ",
"In addition, conditions with reduced skin barrier function may enlarge the taken up fraction of particles.",
"\n\nNina Keusgen (RWTH Aachen Institute for Interactive Materials Research, Germany) presented the results on nanosilver functionalization of textiles for medical purposes. ",
"The investigated functionalization techniques are based on the 2--10 nm nanosilver being alternatively: (1) incorporated into polyvinyl alcohol fibers, (2) deposited on organic or inorganic nanocarriers which are fixed to the textile surface via ionic interaction and/or polymers and (3) incorporated in microgel containers to form nanogels for textile finishing. ",
"0.75 % w/w of 2--8 nm nanosilver bound to polyvinyl alcohol fibers was found to inhibit bacterial growth in the fiber efficiently. ",
"Fastness and efficiency of the functionalization have been shown to depend on the employed carriers and binding technology. ",
"A polycationic finishing prevented elution best. ",
"All developed techniques showed superior performance in comparison to a cotton sample finished with a commercial silver salt-based product.",
"\n\nOral exposure {#Sec7}\n-------------\n\nRichard Winterhalter (Bavarian Institute for Health and Food Safety, Germany) elucidated sources of nanoscaled materials in food and food supplements. ",
"In essence, nanoscaled silver could occur due to unintended contamination during production processes, migration from food contact materials (FCM) or from deliberate inclusion. ",
"In regard to the last two sources, he explained that within the European Union, silver as food additive is only authorized for the specific use to make food surfaces more shiny (sweets), which cannot be achieved by nanosilver. ",
"Furthermore, up-to-date employment of nanosilver in FCM and in preparations marketed as food supplements is not assessed in the European Union. ",
"However, products containing them can be obtained via the Internet. ",
"The increasing application of nanotechnology and synthetic nanomaterials or nanoparticles in the production of food and FCM presents a challenge for food safety authorities. ",
"The Bavarian Health and Food Safety Authority and the Fraunhofer Institute for Process Engineering and Packaging have therefore set up a project which aims to measure nanoparticle migration from food packages into food, to characterize nanoparticles in food and food supplements and to develop the required sensitive and specific analytics for these tasks. ",
"An asymmetric flow field-flow fractionation (AF^4^) in combination with UV and multi-angle light scattering (MALS) detection has been developed for concentration measurement and characterization of silica and silver nanoparticles. ",
"While further method development will be needed for refinement of cross-flow rates, solvents and sample preparation, its first application to colloidal silver preparations measured concentrations generally falling significantly short of labeled contents. ",
"Additional information given during the following discussions was that migration experiments for titanium from plastic bottles did not lead to levels in the food stimulants exceeding the reference value. ",
"However, reasoning that there are studies revealing globally marketed FCM may release up to a few percent of silver, such results should not be generalized.",
"\n\nVon Goetz et al. ([",
"@CR55]) also presented results on silver release from FCM. ",
"Using ICP-MS and TEM, her group examined four food containers bought in the United States and Germany claiming to contain silver in their material or rubber sealing. ",
"With a detection limit of 0.1 μg/g material, this claim could only be verified for two products (18.7 and 37.1 μg/g plastic). ",
"Both were subsequently subjected to release experiments. ",
"Employing water, ethanol and acetic acid as food stimulants, silver release was observed for one box. ",
"Acetic conditions resulted in the highest yield (30 ng/cm^2^). ",
"Remarkably, using MD-ICP-MS, an estimated amount of 10--20 % of the silver detected in the simulant was shown to be particulate. ",
"To explore the impact of multiple utilization, the food simulant was removed and the box stored for some days before repeating the measurement. ",
"In this experimental setup, the silver release dropped markedly. ",
"A worst-case assessment was thus based on the assumption of an initial use of the box for storage of acetic food. ",
"An easily consumable amount of 100 ml would result in an acute oral exposure to 4.2 μg of silver. ",
"While this seems low in comparison to reported silver concentrations in US drinking water in the 60s and 70s of the last century, von Götz reasoned that a comparison to apparently safe water levels could be foiled by the circumstance that a small fraction of the released silver might consist of nanoparticles.",
"\n\nThe current knowledge on the human health hazard of nanosilver is growing but yet limited {#Sec8}\n=========================================================================================\n\nChallenges and pitfalls {#Sec9}\n-----------------------\n\nThe presentations in this session provided both reviews on the existing database and insights into ongoing research aiming at a better understanding and estimation of the human health hazard potential of nanosilver for regulatory purposes. ",
"Particular challenges of nanospecific toxicological testing were also addressed. ",
"The subsequent plenary discussion stressed the importance of reliable and comprehensive toxicological information for manufactured nanosilver, which in turn requires standardization and harmonization of test materials and methods.",
"\n\nIn terms of testing requirements, Helinor Johnston (Heriot-Watt University Edinburgh, UK) emphasized the necessity for extensive characterization of the nanomaterial in a given test medium, since physiochemical properties that drive toxicity may vary dramatically depending on the test system applied. ",
"Likewise, dispersion protocols need to be properly documented and justified. ",
"Furthermore, the interaction with biological molecules as well as interference with chemical compounds and reagents of the assay system has to be addressed. ",
"Identification of crossover challenges in human and environmental studies may also be helpful (e.g., how to cope with agglomeration of nanoparticles). ",
"In this context, cross-species comparisons have also been encouraged (Gaiser et al. [",
"@CR12]). ",
"Exposure information is relevant not only for risk assessment, but also for interpreting existing hazard information and for adjusting the dosing regimen when designing toxicological studies. ",
"Further investigation on the relationship between exposure to a nanomaterial, its effects and its physico-chemical properties, may provide insight into structure--activity relationships and clues on the most appropriate dose metric prompting to describe toxicity. ",
"In consideration of the large variety of different nanoforms of the same chemical identity as well as the limitations in resources and access to sophisticated analytical instrumentation, testing and analysis will necessarily face constraints. ",
"These may be overcome by intelligent testing approaches. ",
"In vitro testing was identified as one important step in this direction since the results might support to generate a solid database for grouping of nanomaterials according to the toxicological potency and, ultimately, fostering the development of high throughput systems. ",
"However, currently used in vitro models or those that are under development need to be validated and their predictive values for in vivo toxicity yet to be determined (Kermanizadeh et al. [",
"@CR28]). ",
"It was also emphasized that there is a need to identify those physico-chemical properties which trigger mode of action and specific adverse responses, in order to develop structure--activity relationships that are able to predict nanomaterial toxicity. ",
"Until this process becomes viable, the present methodological limitations have to be considered carefully in risk assessment.",
"\n\nThe current toxicological database {#Sec10}\n----------------------------------\n\nSusan Wijnhoven (National Institute for Public Health and the Environment, The Netherlands) presented an overview on the available toxicological data for nanosilver (Wijnhoven et al. [",
"@CR57]). ",
"Various knowledge gaps precluding meaningful hazard assessment were identified. ",
"One of the most important knowledge gaps---the role of ion release in distribution and toxic responses to nanosilver---was addressed by intravenous injection of nanosilver of different particles sizes into rats. ",
"Because of distinct distribution patterns observed for each particle size, it was concluded that the nanoparticles could not have degraded immediately (Lankveld et al. [",
"@CR34]). ",
"However, ion release behavior may have varied itself with particle size and available surface. ",
"With respect to toxicity studies, the database could be improved in recent years, in particular by a number of repeated dose toxicity studies in rodents investigating different routes of exposure (Ji et al. [",
"@CR23]; Kim et al. [",
"@CR29], [@CR30]; Sung et al. [",
"@CR51]; [@CR52]). ",
"In addition, a recent dermal toxicity study in guinea pigs reported local as well as systemic effects (Korani et al. [",
"@CR32]). ",
"The repeated dose studies may give valuable input for risk assessment but require thorough evaluation.",
"\n\nBased on these data, preliminary risk assessments have been published for nanosilver (Christensen et al. [",
"@CR7]; Pronk et al. [",
"@CR43]). ",
"Since being afflicted with uncertainty, they do not support waiving of further testing of systemic effects. ",
"For a more robust risk assessment, more valid data have to be generated both on the exposure and on hazard. ",
"For the latter, toxicokinetic investigation of different types of adequately characterized nanosilver materials was encouraged. ",
"Other major gaps identified to be investigated with priority include repeated dose toxicity, potential target organs (liver, lung, immune system), genotoxicity, reproductive toxicity, as well as oral, dermal and inhalative studies relevant and designed according to relevant occupational and consumer settings.",
"\n\nNew toxicological data {#Sec11}\n----------------------\n\nWim de Jong (National Institute for Public Health and the Environment, The Netherlands) presented data from a 17-day toxicokinetic study and a 28-day repeated dose study using nanosilver of different sizes (all from nanoComposix). ",
"Nanoparticles were administered to rats by daily intravenous injection in order to analyze the systemic distribution and to identify organs at risk of adverse effects by these nanoparticles. ",
"The silver content in blood and organs was measured by inductively coupled plasma mass spectrometry (ICP-MS). ",
"Early target organs were liver and spleen, while after 5 days, particles had accumulated most in spleen, and also in liver and lungs. ",
"The silver content was highest in spleen, liver and lungs for particles of 80 and 110 nm, while 20-nm particles were most prevalent in kidneys. ",
"The low recovery of the latter might be attributable to a higher rate of degradation due to a high surface-to-volume ratio. ",
"The concentration of silver in blood fell rapidly within minutes after intravenous administration, reaching a plateau at one-third of the initial concentration. ",
"After intravenous treatment for 28 days, relative body weight gains were lower in both sexes of rats in the high dose groups (2 and 6 mg/kg bw). ",
"In both particle size ranges of 20 and 100 nm, liver weights remained unaffected while spleen weights in the 6-mg/kg bw dose group were increased. ",
"Organs as well as lymph nodes showed pigmentation in treated groups. ",
"The overall spleen, B and T cell numbers were significantly increased, while natural killer (NK) cells were only slightly increased. ",
"By contrast, spleen NK cell activity was decreased at 2 and 6 mg/kg bw for the 20-nm nanosilver particles and greatly diminished at 6 mg/kg bw for the 100-nm particle size (only dose level tested). ",
"Mitogenic responses of spleen B and T cells to concanavalin A remained unaffected. ",
"In the blood, the mean corpuscular volume and mean corpuscular hemoglobin of erythrocytes were decreased as were relative lymphocyte numbers (from 90 to 78 %), while IgM, IgE, absolute and relative granulocyte numbers were increased. ",
"Overall, the intravenous study indicated that nanosilver may have an immunotoxic potential.",
"\n\nMary Boudreau (Federal Drug Administration, USA) summarized results from studies of the US National Toxicology Program (NTP) on well-characterized silver nanoparticles of discrete sizes in rats. ",
"A toxicokinetic study investigated citrate-stabilized particles of 10, 75 and 110 nm and of silver acetate. ",
"Administration was oral (10 mg/kg) or intravenous (3 mg/kg), and silver mass was determined in blood by ICP-MS. ",
"In the intravenous study, blood silver concentrations decreased rapidly for nanoscaled silver and less so for the salt. ",
"This was followed by re-appearance of silver in the circulation and a subsequent plateau with similar blood silver content for all tested forms on days 2 and 3. ",
"In the oral study, *t*~max~ (12 h), *t*~1/2~ (4--5 h) and elimination time (24 h) were similar among silver particles. ",
"The area under the curve (AUC) and *c*~max~ increased with decreasing particle size, but did not reach the levels observed with silver acetate. ",
"The ADME study investigated the fate of a single oral administration of 20 mg/kg and discovered minimal absorption from this regimen with 0.002--0.006 % of the dose absorbed for nanosilver and approximately 0.016 % for silver acetate at a recovery of 90--120 %. ",
"Traces accumulated in the blood, excretory organs and urine. ",
"The major route of elimination was via feces within 48 h. In the 90-day subchronic study, 9, 18 or 36 mg/kg of 10-, 75- or 110-nm silver particles with properties comparable to the particles evaluated in the ADME study, or 100, 200 or 400 mg/kg of silver acetate were administered by gavage. ",
"Characterization of all materials by transmission electron microscopy (TEM), dynamic light scattering (DLS) and ICP-MS confirmed test article and dose certifications deviating less ±10 % of target values. ",
"One preliminary finding was a reduced weight gain and an increase in morbidity in rats with silver acetate doses ≥200 mg/kg, but not in animals treated with nanosilver particles. ",
"Gastroenteritis was identified as the cause of death from silver acetate. ",
"Renal disease was noted in the case of three rats treated with nanoparticles but a dose-response relationship was not yet established. ",
"Further analysis including effects on gut microflora, gross pathology and histopathology, clinical chemistry and hematology as well as TEM of selected tissues was not completed.",
"\n\nIn a further presentation, Saber Hussain (Air Force Research Laboratory, USA) presented data on the effects of size, shape, surface coating and charge on silver particle toxicity. ",
"He pointed out that a comprehensive mechanistic understanding of how physical parameters of nanosilver particles are linked to biological effects is still lacking. ",
"In vitro observations on rat hepatocytes, alveolar macrophages and keratinocytes suggested that silver nanomaterials exhibit size-dependent toxicity (primary particle size and agglomerate size) and elevated reactive oxygen species (ROS) generation (Carlson et al. [",
"@CR6]; Hussain et al. [",
"@CR21]). ",
"Interestingly, there was no linear size-response relationship. ",
"Among primary particle sizes of 20, 40 and 80 nm, the agglomerates from medium-sized primary particles showed the highest activity. ",
"A comparison of 4- and 20-μm silver nanowires in a human alveolar lung co-culture model did not provide evidence for a major influence on epithelial cell viability---possibly due to effective particle scavenging by co-cultured macrophages---but showed alterations in cytokine expression and matrix metalloproteases turnover. ",
"Quantitative differences in IL-6 responses indicated a possible influence of shape on effect size. ",
"Furthermore, differences in cytotoxicity toward germline stem cells were demonstrated between hydrocarbon-coated and polysaccharide-coated nanosilver with different sizes between 10 and 30 nm (Braydich-Stolle et al. [",
"@CR3]). ",
"It was also noted, however, that over time the coating may degrade in the cellular environment, as analyzed by X-ray photoelectron spectroscopy (XPS). ",
"Finally, interference of silver and nanosilver with the epidermal growth factor (EGF) signaling pathway was proposed as the underlying mechanism for ROS generation and, ultimately, loss of cell viability. ",
"Silver nanoparticles were observed to reduce EGF-dependent phosphorylation of Akt (protein kinase B) and Erk (extracellular regulated kinase), regulators of cell metabolism, survival and proliferation.",
"\n\nThe extensive application of nanosilver might contribute to the spread of silver resistance mechanisms {#Sec12}\n======================================================================================================\n\nSilver resistance mechanisms {#Sec13}\n----------------------------\n\nIn this session, it was initially discussed whether the putative spread of silver resistance mechanisms, due to the extensive application of nanosilver, may be of major concern. ",
"Silver is an effective, broad-spectrum antimicrobial agent commonly used in many medical applications, for instance, as topical antimicrobial agent in bandages for burn wounds, trauma and diabetic wounds or tonsillitis but also in silver-coated catheters and medical devices, dental silver amalgams and was historically used as an agent for treatment of syphilis (e.g., silver arsphenamine). ",
"In addition to these essential medical benefits, there is an increasing application of nanosilver in consumer products as coating of clothing (e.g., sports fabrics, sleeping bags, socks), in household products and electric devices (refrigerators, boards, PC boards), as an agent to disinfect water, as growth promoter in agriculture or as coating of food packaging materials.",
"\n\nA brief introduction recalled the mode of action of silver toxicity in microorganisms. ",
"Despite its use as antimicrobial agent over decades, our current understanding on the mechanism of silver toxicity in microorganisms is still limited. ",
"The main cytotoxic effect results from interaction of silver ions with thiol (sulfhydryl) groups and other functional groups in enzymes and proteins, disrupting essential cellular processes such as respiration and the establishment of proton motive force (Jung et al. [",
"@CR25]). ",
"Silver treatment also results in the release of potassium ions from bacterial cells, suggesting that the cytoplasmic membrane is compromised upon silver exposure (Schreurs and Rosenberg [@CR48]). ",
"An additional impact might come from its interactions with nucleic acids, though the contribution of this target molecule to toxicity remains ambiguous unclear (Yakabe et al. [",
"@CR58]).",
"\n\nSilver resistance has been reported as early as the 1970s in various clinical relevant species including *Escherichia coli*, *Salmonellatyphimurium*, *Enterobacter cloacae*, *Pseudomonas stutzeri* and *Acinetobacter baumannii* (McHugh et al. [",
"@CR41]; Annear et al. [",
"@CR1]; Bridges et al. [",
"@CR4]; Hendry and Stewart [@CR18]; Haefeli et al. [",
"@CR17]; Kaur et al. [",
"@CR27]; Deshpande and Chopade [@CR10]). ",
"Resistance mechanisms include efflux mechanisms (e.g., encoded by *sil* genes) and extracellular or periplasmic silver binding peptides (*silE*). ",
"In addition, mechanisms capable to reduce silver ions into less reactive metallic particles which are subsequently deposited periplasmatically are also assumed to contribute to silver resistance, as described mainly for *P. stutzeri* (Klaus et al. [",
"@CR31]). ",
"The resistance determinants may be located on chromosomes and on genetic transmissible elements. ",
"The as yet best known resistance mechanism is encoded on a 180-kb IncH1 plasmid called pMG101 (Silver [@CR49]). ",
"This conjugative plasmid also confers resistance to mercury, tellurite and several antibiotics and is transferable to a wide spectrum of host bacteria (Gupta et al. [",
"@CR14], [@CR15], [@CR16]). ",
"It is likely that more resistance mechanisms will emerge in the future as more and more bacteria genomes are getting sequenced and characterized.",
"\n\nPrevalence of silver resistance {#Sec14}\n-------------------------------\n\nThe good news from the conference was that at present prevalence of silver resistance is low (Ip et al. [",
"@CR22]; Jakobsen et al. ",
"2011). ",
"Yet, although resistance rates among clinical isolates have remained low despite long-term use, silver resistance determinants may be located on mobile genetic elements that confer resistance to multiple other antibiotics. ",
"Lotte Jakobsen (Statens Serum Institut, Copenhagen, Denmark) described the IncHI2 plasmid from an extraintestinal pathogenic *E. coli* isolate which conferred resistance to sulfonamides, streptomycin, gentamicin, tetracycline, potassium tellurite, copper sulfate and benzalkonium chloride besides silver nitrate (Johnson et al. [",
"@CR24]). ",
"Another cited study reported a major nosocomial outbreak associated with the multi-resistant highly pathogenic *E. coli* ST131 lineage with evidence of multiple cases of transfer of a multi-resistant silver resistant plasmid to patients' intestinal flora (Sandegren et al. [",
"@CR47]). ",
"The finding of co-resistance demonstrates that selection of silver resistance by other antimicrobials is likely. ",
"A further case of concern, which was addressed, lies in the development of cross-resistance (Li et al. [",
"@CR36]). ",
"Of particular concern is the cross-resistance toward carbapenems which are now the antibiotics of choice to treat one of the fastest growing resistance problems with both community and hospital acquired infections emerging worldwide, that is, the extended-spectrum β-lactamase (ESBL) producing *Enterobacteriaceae* (Sütterlin et al. [",
"@CR53]). ",
"Taken together, silver resistance may be co-selected by the use of many antimicrobial agents just like silver use may co-select or cross-select for resistance toward critically important antimicrobials for human medicine. ",
"This may occur in a clinical setting as well as in animal production where growth promoters (e.g., copper) are intensively used since the ban of antimicrobials (Johnson et al. [",
"@CR24]). ",
"Thus, monitoring of resistance (and consumption) in patients and in the environment is needed to avoid future spread of silver resistance.",
"\n\nImpact on the composition of the human skin microbiome {#Sec15}\n------------------------------------------------------\n\nDirk Höfer (Hohenstein Institute, Germany) discussed the putative adverse impact on the composition of the human skin microflora due to the extensive application of silver or nanosilver especially as coating of clothing (e.g., sports fabrics, sleeping bags, socks). ",
"It is well known that the normal skin microflora acts as a barrier against colonization of potentially pathogenic microorganisms and against overgrowth of already present opportunistic microorganisms (Sullivan et al. [",
"@CR50]). ",
"This kind of control of growth of opportunistic microorganisms is termed colonization resistance. ",
"Consequently, one might expect that the release of antimicrobial silver or nanosilver from textiles might affect the microbiome on the human skin. ",
"During the conference, results from a study on the short- and long-term effects of antimicrobial active clothes on the ecological balance of the healthy human skin microflora were reported. ",
"The wear trials with 60 volunteers carrying silver-coated textile samples releasing 1.9 or 2.5 ppm of silver showed no significant impact on their skin microflora (Hoefer and Hammer [@CR20]).",
"\n\nImpact on the wastewater treatment {#Sec16}\n----------------------------------\n\nBesides the putative spread of resistance mechanisms toward silver and antibiotics, silver and nanosilver in wastewater are highlighted as a concern due to the potential impact on the biological treatment processes and its poorly known elimination efficiency in wastewater treatment plants (WWTP). ",
"Of particularly concern is the discharge of nanosilver in the form of individual particles thereby receiving waters and effects on non-target organisms by released silver ions. ",
"Knowledge on the occurrence of silver particles in wastewater and WWTP is still scarce. ",
"Michael Burkhardt (HSR University of Applied Sciences Rapperswil, Switzerland) presented a study on the influence of nanosilver on the treatment performance of a real WWTP (60,000 inhabitants equivalent) and a pilot scale WWTP (70 inhabitants equivalent), and on how nanosilver is distributed in the system, particularly in the excess sludge and treated effluent waters (Burkhardt et al. [",
"@CR5]; Kaegi et al. [",
"@CR26]). ",
"The effect of four different silver additives (AgCl 20--500 nm; nano-AgA 5--50 nm; OECD reference material NM-300 K; nano-AgB 5--50 nm) on the nitrification (ammonia oxidation) in activated sludge has been studied in batch reactors. ",
"The concentrations of silver were measured by ICP-OES, particulate silver was investigated using analytical electron microscopy in combination with energy disperse X-ray spectroscopy (SEM-EDX, TEM-EDX), and the speciation was assessed using X-ray absorption spectroscopy (XAS). ",
"On real scale, concentrations \\<20 μg/l silver even under worst-case conditions of industrial silver discharge were determined in the influent of the real WWTP. ",
"Silver was shown to be eliminated with an efficiency of 95--99 %, efficiently transformed within less than 30 min to insoluble silver sulfide (Ag~2~S) which was mostly attached to sludge flocs enabling further filtration in the pilot scale and full scale WWTP. ",
"Individual nanosilver, not associated with sludge flocs, was observed occasionally only. ",
"The elimination of silver revealed very high compared to organic micropollutants omnipresent in wastewater. ",
"All XAS measurements from the full scale WWTP, including samples of the influent, effluent and the digested sludge, confirmed that silver exists as Ag~2~S. The investigated nanosilver additives are readily converted into Ag~2~S in the real-life wastewater matrix. ",
"Silver concentrations \\<0.5 μg/l in effluent waters of municipal WWTP are measured. ",
"Ag~2~S is nearly insoluble with a benign ecotoxicity profile compared to free silver ions. ",
"Effects on the nitrification process (microbial activity) were not detected even after the addition of 1 mg/l silver corresponding to 250 mg silver in dried sludge. ",
"Since the vast majority of nanosilver was found: (1) to be attached to the activated sludge flocs, (2) eliminated by more than 95 % with excess sludge and (3) fully transformed to Ag~2~S with apparently no release of silver ions; Burkhardt concluded that there is no need for action to take special measures for nanosilver removal in the area of WWTP. ",
"However, it was argued in the subsequent discussion that a number of published results only refer to tests under artificial laboratory conditions (matrix, concentration, coating) which give only limited insight into environmental behavior in real wastewater.",
"\n\nNanosilver containing products are or will be regulated by different legislations around the globe {#Sec17}\n==================================================================================================\n\nDepending on their actual use and functionality claims, nanosilver as the active substance and/or nanosilver containing products are or will be regulated by different legislations around the globe. ",
"Examples are the European Cosmetics Regulation (Regulation (EC) No 1223/2009), the European Biocidal Product Regulation (BPR, Regulation (EU) No 528/2012) or the US Federal Insecticide, Fungicide and Rodenticide Act (FIFRA).",
"\n\nAssessment and regulation of nanomaterials under the European Biocides Regulation {#Sec18}\n---------------------------------------------------------------------------------\n\nIsabel Günther (BfR, Germany) provided the details on the new Regulation (EU) No 528/2012, which replaces the older Biocidal Product Directive (BPD, 98/8/EC) from September 2013 on. ",
"For the first time in Europe, the BPR explicitly makes provisions not only for labeling, but also for the assessment of products containing nanomaterials. ",
"Like the preceding Biocidal Product Directive, the new BPR foresees a two-step procedure for the final authorization of a biocidal product. ",
"In the first step leading to approval (previously: Annex I listing), the active substances undergo a rigorous hazard characterization with peer review by all member state competent authorities, and at least one safe use has to be demonstrated for a respective example product. ",
"Considering the uncertainty about the risk-related properties of nanomaterials, the new regulation clarifies that any approval for a biocidal active substance will not include its nanoform unless specified, and a separate dossier will usually need to be submitted. ",
"Applicability and reliability of the methods used for testing of nanoscaled active substances are to be justified by the applicant, and adaptations to existing test protocols have to be made, if required. ",
"In addition, new test methods specific for nanomaterials will have to be developed. ",
"It becomes readily apparent that the risk assessment of nanomaterials to be performed under this regulation may become challenging, and for harmonized evaluation specific guidance has to be developed. ",
"Any biocidal products authorized in the second step of the assessment according to the BPR will have to be labeled as \"nano\" next to any nanoscaled ingredient.",
"\n\nEPA's approach to nanosilver risk assessment and regulation {#Sec19}\n-----------------------------------------------------------\n\nJed Costanza (Environmental Protection Agency, United States; Costanza et al. [",
"@CR9]) illustrated key elements with respect to human health risks of a US EPA decision about the first registration for an explicitly nanosilver pesticide to be used as textile preservative (EPA-HQ-OPP-2009-1012-0064). ",
"The material was described as 1--10-nm silver particles with some particles in the 50-nm range sintered onto amorphous silica. ",
"The risk assessment of the pesticide considered occupational as well as consumer exposure to the material, as well as silver nanoparticles, and ionic silver released by degradation. ",
"It was based on the currently available data, making conservative assumptions to compensate for knowledge gaps. ",
"The toxicity information submitted by the applicant included animal data on acute oral, dermal and inhalation toxicity as well as eye irritation with the product. ",
"This was complemented by a characterization of the potential occupational exposure from handling nanosilver powder via the inhalation and the dermal route. ",
"For consumer exposure, a scenario in which a 3-year-old toddler is exposed daily to a fresh nanosilver-coated jumpsuit was considered worst case and formed the basis for risk characterization. ",
"The US EPA found that the nanosilver risk assessment presented unique challenges with regard to not only the experimental database, but also the methodology of assessment, thus prompting the installation of an external advisory panel. ",
"The panel concluded that hazard information for ionic and metallic silver cannot be read across to the nanomaterial. ",
"Only a minority of the panel supported bridging to silver materials of similar size and essentially identical physicochemistry. ",
"On this basis, risk was assessed using the NOAEL from a 90-day rat inhalation study on uncoated nanosilver of 6--55 (mean 18) nm (Sung et al., [",
"@CR51]) and a 28-day mouse oral (presumably gavage) study with silver particles measuring on average 42 nm (Park et al. [",
"@CR112]). ",
"Interestingly, the immunological effects reported in the oral study on mice provided an endpoint that was by a factor of 60 more sensitive than an oral 90-day study in rats with 56-nm silver particles (Kim et al. [",
"@CR30]) performed according to OECD test guideline 408. ",
"A dermal repeated-dose toxicity study with nanosilver was not available. ",
"The US EPA also identified concerns and data gaps for neurotoxicity, developmental and reproductive toxicity, as well as deficiencies in the database on mutagenicity of nanosilver. ",
"An additional uncertainty factor of 10 was applied to account for these deficiencies in risk characterization, resulting in a \"no risk\" statement for consumer as well as for textile manufacturing workers (taking into account appropriate risk mitigation measures).",
"\n\nEPA's finding that the proposed use of the pesticide would not cause unreasonable adverse effects on the environment that did not require consideration of the benefits from the use of the pesticide because no risk concern was identified. ",
"However, EPA did consider some benefits from the use of the pesticide in determining that granting a conditional registration pending development of additional data would be in the public interest. ",
"For example, one public interest benefit identified was an up to 200-fold reduction in silver released into the environment due to the replacement of registered conventional forms of silver by the nanosilver material.",
"\n\nThis conditional registration requires the manufacturer to close gaps in the data set for the product in a tiered 4-year testing program. ",
"Tier 1 includes endpoints such as particle size distribution and surface area, degradation kinetics, leaching and dermal/inhalation/laundry exposure estimation, as well as a 90-day inhalation and dermal toxicity assay, a reproductive/developmental toxicity screening test and an in vitro micronucleus assay. ",
"Tier 2 may require similar testing for any nanoscaled silver released from the composite product.",
"\n\nThe Swedish chemicals agency's (Kemikalieinspektionen KEMI, Sweden) approach to nanosilver risk assessment and regulation {#Sec20}\n-------------------------------------------------------------------------------------------------------------------------\n\nUlrike Frank pointed out the fact that in consumer goods silver is used with the aim to employ a biocidal effect. ",
"This effect can be reached by the release of silver ions from different silver compounds or silver forms in contact with water. ",
"The application of nanoscaled silver or nanosilver composites is only one possibility besides the use of silver salts, silver ion exchangers, silver composites and elemental silver.",
"\n\nSilver is a broad-spectrum microbiocide and has the advantage that the technical handling is comparatively easy. ",
"Moreover, so far silver has a better reputation than organic biocides. ",
"This makes it feasible to add silver to a great variety of consumer goods, either via incorporation into the polymer material, or via a silver containing coating.",
"\n\nThe selling point of silver-treated articles is the demand for \"hygienic\" goods, or the general fear of bacteria. ",
"This fear is differently strong in different cultures. ",
"The demand for such products is generally higher in the United States and in East Asia than in Europe.",
"\n\nThe majority of silver containing biocidal products contain silver in microscale rather than in nanoscale. ",
"The aim of nanoscaled silver as well as of microscaled silver is to release silver ions, as the ions cause the biocidal effect. ",
"Consumers are in the first place exposed to silver ions. ",
"In the environment, silver ions are rapidly complexed with inorganic sulfides and organo-sulfur compounds. ",
"Whether consumers and the environment are exposed to nanoscaled silver has to be shown during the evaluation. ",
"Generally, the modeling of exposure is very demanding due to the great variety of consumer articles and their different uses.",
"\n\nAustria's approach to nanosilver risk assessment and regulation {#Sec21}\n---------------------------------------------------------------\n\nAlexander Zilberszac (Austrian Federal Ministry of Health, Austria) talked about the Austrian approach to risk governance for nanosilver. ",
"Risk governance is based on the process of risk assessment and includes policy-driven risk management as well as communication of risk management decisions. ",
"It also involves the dialog with or between stakeholders. ",
"Whenever the scientific basis of risk assessment is limited by methodological or data constraints, risk management and communication measures will dominate the governance process. ",
"In the case of nanosilver-based consumer products, a study commissioned by the Federal Ministry of Health concluded that \"... an extensive use of nanosilver at low concentrations in consumer products might promote the development of allergies and multi-resistant bacteria.\" ",
"This conclusion was supported by the opinion of the BfR concerning this matter (BfR [@CR2]). ",
"Considering that silver and nanosilver have a high value for certain medical applications, notably treatment of burn victims, the situation of scientific uncertainty prompted a policy response. ",
"On July 8, 2011, the Austrian Parliament unanimously adopted a resolution requesting the government \"to take all necessary measures to ensure the therapeutic efficacy of nanosilver in human medicine.\" ",
"The government is now following parallel approaches to implement the Parliament resolution, namely enforcement of existing regulation, communication with consumers as well as supporting relevant research activities and voluntary/private initiatives. ",
"With regard to law enforcement, the provisions of the Regulation on the Provision of Food Information to Consumers with respect to labeling of technical nanomaterials (Regulation (EU) No 1169/2011) in addition to the Cosmetics Regulation (1223/2009) and the Biocidal Products Regulation (528/2012) were emphasized. ",
"The Federal Ministry of Health further took lead in the installation of the nanoinformation platform (NIP), which is intended to provide an information portal for the interested general public to facilitate opinion making. ",
"A NANO Environment, Health and Safety Program (NANO EHS) was set up based on the Austrian Nanotechnology Action Plan. ",
"It is the strategic objective of this program to fill knowledge gaps that limit the environmental, occupational and consumer risk assessment for applications of nanomaterials including nanosilver. ",
"Last but not least, measures have been installed to ensure that administrations purchase goods and services taking into account potential risks from nanosilver. ",
"In particular, the city of Vienna must \"...make sure to avoid buying cutting boards or packaging materials with antimicrobial nanosilver coatings,\" and may \"...not allow antimicrobial paint additives (e.g., nanosilver) for routine applications.\" ",
"Similar provisions apply for nanosilver coatings in textiles and household appliances. ",
"It is also intended to include respective text passages in all sets of criteria for the Austrian eco-label \"Öko-Kauf Wien.\"",
"\n\nConclusions {#Sec22}\n===========\n\nIdentity and analytics {#Sec23}\n----------------------\n\nThe enormous number of possible variants of silver nanoparticles is the result of the simplicity of silver nanoparticle syntheses. ",
"This huge variety of different silver nanoparticle entities may also be the reason for the absence of certified reference materials for silver. ",
"Thus, any real generalizations on what sort of behavior would be expected from any particular material are very difficult to make. ",
"A careful characterization on a case-by-case basis is needed to avoid errors coming from the apparently different behavior of nanoparticles due to the use of unknown stabilizing agents. ",
"Additionally, the knowledge about the dissolution rates of silver is likely to be extremely critical as variations in the dissolution behavior are strongly related to the physico-chemical properties of the examined nanoparticles.",
"\n\nThe biggest challenge so far is to gain a better understanding of the reciprocal effects of nanoparticles when in contact with biological media. ",
"Single particle ICP-MS has made a promising progress to overcome some of these hurdles and is able to detect inorganic, non-porous nanoparticles which are composed of one material in complex media. ",
"With the completion of current ongoing EU projects, the first finalized validation studies combined with standard operation procedures are expected to become available. ",
"However, there are still major gaps related to commonly agreed guidelines for sample preparation and central analytical techniques like electron microscopy.",
"\n\nHuman exposure {#Sec24}\n--------------\n\nSilver nanoparticles are released from a growing number of commercially available products. ",
"Skin and respiratory tract were identified as relevant routes for exposure. ",
"In this context, the barrier function of the skin, in particular of damaged skin, has to be taken into account in any exposure assessment. ",
"Likewise, the inhalative route will have to be addressed in more detail in order to model exposure levels. ",
"Next to production techniques, multiple usage and product aging were identified as impact factors for nanoparticle release. ",
"These observations indicate a need for case-by-case exposure assessments. ",
"Further research has to consider aging processes as a basis for scientific establishment of worst-case assumptions and refinements to more realistic exposure levels. ",
"Respirable particles may occur due to spraying or abrasion processes. ",
"Sanding procedures of macroscopic surface coatings revealed no generation of free engineered nanoparticles (additives or pigments), previous aging lead to coarser particle size distributions irrespective of the original nanoparticle content. ",
"Workplace measurement techniques for aerosols and dry powders are already part of tiered approaches to quantify exposure levels. ",
"However, consumer exposure scenarios are only starting to be developed and exposure measurement data are still rare.",
"\n\nToxicological aspects {#Sec25}\n---------------------\n\nClearly, the availability of valid toxicological data and information on toxicokinetics has been improved in recent years thus reducing the degree of uncertainty in hazard and risk assessment for nanoforms of silver. ",
"Comparability of studies requires thorough characterization of test materials as well as further adjustments and developments in testing design, methodology and analysis. ",
"The toxic principle of nanosilver, that is, whether toxicity is ion or particle driven, yet has to be elucidated and analysis of the toxicological profile has to be adjusted accordingly. ",
"With regard to particles characteristics, it was noted that physical parameters are directly linked to its biological and toxicological effects. ",
"Particularly, the size of primary particles and their most prevalent agglomerates, the size distribution, shape and coating may alter the strength of an effect by orders of magnitude. ",
"Silver nanoparticles accumulate in liver and spleen and may affect immunogenic factors after having become systemically available. ",
"Key aspects to be addressed in the future are the unequivocal detection of nanosilver particles, their absorption, fate and toxic response. ",
"This includes addressing issues such as secondary particle formation, \"Trojan horse\" effects and interaction of silver particles with biological structures. ",
"One has to intensify particle toxicology and learn to understand the differences to soluble chemicals toxicology. ",
"This is most striking in terms of barrier penetration, unusual exposure routes (e.g., the olfactory bulb) and accumulation in the body. ",
"As existing information showed distribution of silver to brain and testis, testing should also address potential neuro- and reproductive toxicity of nanosilver. ",
"The appropriate investigations include kinetics, long-term toxicity testing, standardized, harmonized and predictive in vitro models and their correlation with in vivo data.",
"\n\nMicrobiological aspects {#Sec26}\n-----------------------\n\nVarious clinical relevant species use either efflux mechanisms, extracellular or periplasmic silver-binding peptides or mechanisms capable of reducing silver ions into less reactive metallic particles. ",
"It is likely that more resistance mechanisms will emerge in the future as more and more bacteria genomes are getting sequenced. ",
"It was common sense on the workshop that the use of silver may lead to the selection of silver resistant bacteria. ",
"Since conjugative silver resistance plasmids also confer resistance to several antibiotics and are transferable to a wide spectrum of host bacteria, the selection of silver resistant bacteria may coincide with the selection of antibiotic resistant bacteria. ",
"Yet, resistance rates among clinical isolates have remained low despite long-term use. ",
"A further issue of concern, which was addressed, lies in the development of cross-resistance. ",
"Especially worrisome is the cross-resistance toward carbapenems. ",
"Thus, monitoring of resistance (and consumption) in patients and in the environment is needed to avoid future spread of silver resistance.",
"\n\nWith respect to environmental behavior of silver, it was proposed that there is no need for action to take special measures for nanosilver removal in the area of WWTP, since the vast majority of nanosilver is converted into insoluble Ag~2~S, found to be attached to biological particles and more than 95 % of silver is eliminated by activated sludge during the wastewater treatment process. ",
"Based on these results, it was suggested that nanosilver released to wastewater may have negligible ecotoxicological effects in the aquatic environment. ",
"However, in the subsequent discussion, it was argued that a number of published results only refer to tests under artificial laboratory conditions which do not reflect the process conditions from real life and, therefore, may present misleading results to relevant mechanisms.",
"\n\nRisk assessment and regulation of nanosilver {#Sec27}\n--------------------------------------------\n\nThe presentations and discussion on risk assessment and regulation of nanosilver applications showed that different approaches can be assumed in a data deficient situation. ",
"Taking a more \"precautionary approach\" law enforcement and communication measures were chosen in Austria to limit the use of nanosilver while supporting further research in the frame of a Nanotechnology Action Plan. ",
"In the United States, registration of a nanosilver textile preservative was granted weighing uncertainties arising from knowledge gaps against benefits, namely potential reductions in the overall use quantity of silver as a biocide, and---at the same time---linking this registration with the implementation of a testing program to be conducted by the manufacturer. ",
"In Europe, the regulation of biocides has been enhanced to specifically address definition, assessment and labeling of nanobiocides such as nanosilver in the near future.",
"\n\nWe would like to thank all lecturers and participants of the BfR Nanosilver Conference held in February 8--9, 2012 at BfR in Berlin, Germany. ",
"We greatly appreciate their valuable contribution and presentation that helped to make this conference a real success.",
"\n"
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"Q:\n\nForce.com IDE Winter '16 unit test feature not working?",
"\n\nI just upgraded when I saw the opportunity to do Apex Unit Test configurations (to make testing as easy as clicking the \"Play\" button). ",
"What I've found, though, is that when the tests run, they run on the server-side version of the code, which defeats the purpose since I can't make changes locally and test them.",
"\nHere's some evidence:\n1) I put System.",
"AsssertEquals(1, 2); and it's still passing\n2) I created a new test method locally and chose it as an option for \"Test method\" in the \"Run Configurations\" popup, but when I run it, it gives the warning \"Method asdfadfasd does not exist in the the apex class with Id :01po0000004o54e\"\nAm I missing something obvious here to be able to test local unit tests? ",
"I'm trying to find a rapid way to do unit tests without having to deploy to the server (which requires running all my unit tests and thus takes forever).",
"\nAny help is appreciated!",
"\n\nA:\n\nThat feature simply creates a preset list of tests to run (along with defined logging levels) for a given configuration. ",
"It still runs them on the server. ",
"It just makes it easier to run a group of tests that you may need to run to test things frequently\nmaybe you are thinking of Apex Debugger? ",
"That is a paid feature..\nCurrently there is no \"Local\" version of Salesforce to run anything against.",
"\n\n"
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"13 August 2009\n\nCierra At The Vet\n\nCierra visited the vaccine clinic today. ",
"She was really good (as if she would be anything less). ",
"She visited a lot of dogs, got to sniff a cat, and visit with a lot of people who said how cute and perfect and well behaved she is. ",
"She's an even 56 pounds.",
"So much to see, dogs to the left.",
"\n\nDogs to the right.",
"\n\nWhat's behind door number 1?",
"\n\nWhat's behind door #2? ",
"I hear dogs barking back there.",
"\n\n*sniff* *sniff* *sniff*\n\nWhile we were waiting in the lobby, one of the vet tech's came and asked everyone to move so that the owner of two Great Dane's could bring her dogs out, adding that they are dog aggressive. ",
"They were pretty dogs, white and black, and MUZZLED. ",
"What a shame. ",
"I know of a dog whisperer who could help them.",
"\n\nHundewanderer\n\nLittle Heart K9\n\nHelicopters\n\nColumbus\n\nI dream of Columbus With my maps and my beautiful charts I dream of Columbus And there's peace in a traveling heart~Mary Black, \"Columbus\"\n\nDreams\n\n\"Everyone has oceans to fly, as long as you have the heart to do it.",
"\n\nIs it reckless? ",
"Maybe.",
"\n\nBut what do dreams know of boundaries?\"",
"\n\n-closing lines from the movie \"Amelia\"\n\nMy First German Shepherd Dog, Cierra\n\nShe is your friend, your partner, your defender, your dog / You are her life, her love, her leader / She will be yours, faithful and true, to the last beat of her heart.",
"\n\nHiking with Cierra\n\nSunrise Mountain, Peoria, Arizona\n\nHiking with Zane\n\nScottsdale's McDowell Sonoran Preserve, Arizona\n\nWater Dog\n\nWhiteriver, Arizona\n\nBoca Bear\n\nI will always love you, my Bear.",
"\n\n.",
"\n\nMother of Wolves\n\nI LOVE YOU JESSICA\n\nMine\n\nJohn and Jessica 1996\n\nPrayer of Saint Francis Assisi\n\nLord, make me an instrument of your peace.",
"Where there is hatred, let me sow love.",
"Where there is injury, pardon.",
"Where there is doubt, faith.",
"Where there is despair, hope.",
"Where there is darkness, light.",
"Where there is sadness, joy.",
"\n\nO Divine Master,grant that I may not so much seek to be consoled, as to console;to be understood, as to understand;to be loved, as to love.",
"For it is in giving that we receive.",
"It is in pardoning that we are pardoned,and it is in dying that we are born to Eternal Life."
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"Padilla\n\nPadilla may refer to:\n\nPlaces\n Padilla Municipality, Tamaulipas, in the Mexican state of Tamaulipas\n Padilla, Cauca, in Colombia\n Padilla, Bolivia\n Moises Padilla, Negros Occidental, in the Philippines\n Padilla Bay, in the U.S. state of Washington\n Padilla de Abajo, in Spain\n Padilla de Arriba, in Spain\n\nOther uses\n Padilla (surname)\n Padilla v. Kentucky, a United States Supreme Court case pertaining to the immigration consequences faced by lawful permanent residents who are convicted of crimes, and their rights to be warned of those consequences\n Rumsfeld v. Padilla, a United States Supreme Court case pertaining to the War on Terror and defendant José Padilla\n Padilla (cigar brand), a brand of cigars launched in 2003 by Ernesto Padilla\n Padilla (spider), a genus of jumping spiders\n Almirante Padilla-class frigate, a class of four ships of the Colombian Navy"
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"At least, that’s how it seems with a peculiar group of restaurants. ",
"Diverging from celebrity chef hopefuls, the people behind these restaurants don’t advertise, seek media attention, or even hang a sign. ",
"They remain conundrums to the outside world, with only a select few joining the inner circle of diners privy to their culinary secrets.",
"\n\nSome of these \"secret\" restaurants are simply humble. ",
"Others are fiercely exclusive, demanding passwords, intermediaries, and unspecified proofs of loyalty to land a seat at the table. ",
"Then, there are those that use secrecy as its own form of publicity. ",
"During the past decade, an increasing number of restaurants and bars have tried this approach. ",
"Clever at first, it's now gotten to the point that \"clandestine\" places with \"secret\" names are putting signs up outside that say things like, \"Speakeasy.\" ",
"Why not a 10-foot tall, flashing neon sign outside proclaiming, \"SECRET BAR AND RESTAURANT HERE!\" ",
"But there are places that go beyond the gimmick, or do it better than others.",
"\n\nComing up with a list of the most secret or hidden restaurants isn't easy. ",
"After all, someone's been, right? ",
"These are restaurants that we're talking about. ",
"But it's not hard to strike off the most obvious ones — restaurants that are much less hidden and much more known than others. ",
"So no, New York City's La Esquina and PDT (it's really a bar anyway) don't count. ",
"Neither do supper clubs. ",
"And to be included on this list, the restaurant has to be more than some dude in his basement making lobster rolls or grilled cheese sandwiches.",
"\n\nSo why keep yourself hidden with all of the competition out there in the restaurant world? ",
"Vernon Hidden Steakhouse’s general manager, Jamie Monske, explains, “We want to do something no one else does. ",
"With the current economy, we had to stand out, and [our speakeasy theme] has really helped us to stay afloat. ",
"Not only are we afloat, but we are growing.” ",
"A manager from Sidecar in Washington D.C. elaborates on the advantages of privacy, “Sidecar has a positive effect on restaurant business in the sense that it offers a nice contrast to the slightly more casual environment of [sister restaurant] PJ Clarke’s on the upper level.”",
"\n\nAfter all, who doesn’t want to feel like the member of a club, a “chosen one” of a selective circle? ",
"Indeed, many of these restaurants promise such pampering. ",
"Says Kimi Watanabe of Bohemian New York, “What we try to offer is a space where customers can have a quality time with their friends and loved ones. ",
"We try to establish and maintain close relationships with each one of our customers.” ",
"Eating in a secret restaurant can make you feel like you are being paid attention to, and that you belong.",
"\n\nWhether it's a gimmick, indifference, or a defense mechanism, the secrecy of a restaurant only makes a reservation there that much more desirable. ",
"Ultimately, we can’t help but want what we can’t have."
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"Barno\n\nBarno is a surname. ",
"Notable people with the surname include:\n\nDavid Barno (born 1954), American lieutenant general\nElisha Barno, Kenyan marathon runner\nEsther Barno (born 1968), Kenyan volleyball player"
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"Pages\n\nMonday, 29 February 2016\n\nI love painting my nails and would actually admit to staying up an hour or two later just to wait for them to dry, then go to bed when I need too. ",
"Since I developed a love for painting my nails I now find it tranquil and relaxing plus if you do it correctly it can last days before you have to reapply. ",
"I went through a phase of going to get them done at a professional nail salon. ",
"As lovely as it was, I came to the realisation that I can do it in the comfort of my own home and save money as well. ",
"However they may not always look as good; but practise makes perfect!",
"\n\nInstead of painting my nails all the same colour, I have recently loved painting four of my nails one colour than the ring finger white. ",
"As I don't wear rings or a lot of make up on a day to day basis, I love painting my nails as I find when they are well groomed, you can look much more put-together throughout the day. ",
"So this odd white nail look is my way of adding a quirky effect to a well known basic colour.",
"\n\nSunday, 28 February 2016\n\nIn today's day and age, we can get caught of being a shopaholic without even knowing we are. ",
"With more and more gadgets and more and more of the latest things, no wonder we are eager to keep up to date with society and enjoy new things. ",
"There is nothing wrong with that at all, but sometimes it may be a little pricey or a little cluttering. ",
"Therefore I have put together a few ideas to help you save money or stop buying things that you may not necessarily need. ",
"Obviously these are only techniques and tips for you if you wish to spend less money or are maybe thinking of becoming more minimalistic.",
"\n\nTip 1\n\nThis may seem obvious but keep a handful of bags with you whilst shopping. ",
"In the UK bags are now 5p from any store that has over 200 members of staff working for them as a whole. ",
"5p isn't that much however as all proceeds should go to a selected charity from that organisation. ",
"But if you are doing your weekly or monthly household shop you may find that you are adding roughly 30p on top of your bill already. ",
"Shockingly the 5p's add up, so if you get one bag and use it as much as possible before it breaks you have got the most use out of that 5p as possible, also you are saving the planet too.",
"\n\nTip 2\n\nThink long and hard before making a big purchase. ",
"So you've seen a pair of shoes that you love and you are thinking of buying them. ",
"I mean they're even on sale! ",
"However don't get mislead like most of the population by buying something because it's on sale. ",
"Ask yourself a few questions before you buy them like: Have you got some like these already? ",
"Would you get good use out of them? ",
"Are they good quality? ",
"Would you buy them normally if they were not on sale? ",
"After thinking about it, you still like them... get them! ",
"If you are unsure it may be best to leave them behind and save the money and space for something else.",
"\n\nTip 3\n\nThis is something that has really helped me recently. ",
"I never really thought about how much this can affect your decision but it does. ",
"Say again there is something your really like or want to buy. ",
"Instead of using you card to pay for it, go to a cash machine and withdraw the money you need for the purchase. ",
"Then go back into the shop and pay for it using only the cash. ",
"This may sound silly, but you are more aware of the money you are giving away. ",
"If you go to give over the money and feel guilty it is most likely you don't want to spend your money on that particular item. ",
"If however handing the money over doesn't bother you it is more likely that the item you are buying is worth while.",
"\n\nTip 4\n\nCheck how much money you have in your account before you go shopping. ",
"This way you will know how much money you have actually got and whether you can actually afford it. ",
"Most of the time we shop not knowing actually how much money we have. ",
"I work in retail and there has been multiple times that people have gone to buy something for me to then have to tell them they can't. ",
"So it is much safer overall to be aware about how much money you have got and how to budget it correctly.",
"\n\nI would love to wear them, if I could apply them. ",
"Unfortunately I have tried many times and keep failing.",
"\n\nDid you know that you are supposed to change your mascara every 3 months?",
"\n\nYes, which reminds me - I need to go through my make up.",
"\n\nWhat brand of mascara do you use?",
"\n\nI don’t use just one brand but at the moment I'm loving Maybelline’s mascara.",
"\n\nWhat make up tools do you use in make up application?",
"\n\nIn my everyday make routine I only use an eyelash curler as when I’m in a hurry I tend to just use my fingers to apply my makeup as it is very minimalistic. ",
"However if I'm going out I tend to use a kabuki brush.",
"\n\nDo you use make-up base/primer for the eyes?",
"\n\nNope, I'm not to skilled with make up yet so I tend to be as minimalistic as possible.",
"\n\nWhat is your favourite eye shadow (colour or shade)?",
"\n\nI don’t have specific favourite brand but I do enjoy to wear brown shades when I go out. ",
"If I feel a little more adventurous I may go for a silver eye shadow.",
"\n\nDo you use pencil or liquid eye liner?",
"\n\nI use pencil eye liner, I can never get on with liquid eye liner – it normally ends up everywhere. ",
"So if you can, you have some serious skills!",
"\n\nHow often do you poke your eyes with an eye liner pencil?",
"\n\nAlmost every other day. ",
"It is a regular thing.",
"\n\nWhat is your favourite lipstick?",
"\n\nThe one I tend to use whether I'm going out or going to work is by UNE. ",
"However it is running out of date so I may need to find another red shade. ",
"I don’t think I could get away with wearing any fancy pink shades.",
"\n\nHow about lip-gloss?",
"\n\nI hardly where lip-gloss, I used to when I was little but as I’m growing up I wear it less and less. ",
"If I do it’s normally to create a more glossy effect on a lipstick which I will then wear a clear lip-gloss.",
"\n\nWhat is your favourite blush to use?",
"\n\nWhen I was younger I used to apply so much blush to the cheeks and people used to laugh at me so since then I stopped wearing any. ",
"If I want colour in my cheeks I either pinch them or slap them a little bit to create a natural blush.",
"\n\nDo you buy your make up on eBay?Nope, I rarely shop online. ",
"But I guess I would if there was a product that I brought before and know it well enough in order to buy a new one.",
"Do you like drug store make up?For me personally it doesn't really matter if it’s high end or drug store make up, if I like it I am going to buy it.",
"Do you go to cosmetic company outlets?I've never been to one but I would love to at some point, it looks like you could get some good bargains.",
"Did you ever consider taking make-up classes?I haven’t ever thought about it, I've always loved the idea of hairdressing but as for make-up classes not really. ",
"But I do think it might be beneficial for me.",
"Are you clumsy in putting on make up?If I'm tired and it’s the first thing in the morning then yes definitely if it’s getting ready to go on a night out, no I'm really careful about every detail as I try to make more of an effort.",
"Name a make up crime that you hate?Not curling your eyelashes before applying mascara. ",
"It makes your eyelashes so much better. ",
"Also another pet peeve is when people pour foundation on to them hand then slather it onto their face. ",
"Foundation is expensive! ",
"Plus the finish is not as smooth it looks more caked on.",
"\n\nSaturday, 20 February 2016\n\nDo you know you skin's undertone? ",
"Not many people do, I didn't until about a year ago. ",
"I never even thought there was such thing. ",
"But after knowing what my undertone is, it helps a lot when picking out what colours you are going to wear whether that's clothes or make up.",
"\n\nThere are three types of skin undertones: they are cool, neutral and warm. ",
"You may now be thinking how do I know which one I am? ",
"Is it based on my skin tone? ",
"Surprisingly it is easier than you may think and you find out what your skins undertone is by using the colour of your veins. ",
"The same principle applies whether your skins tone is fair or dark. ",
"The easiest and most well known way of looking at your veins is by using your wrist as in the pictures. ",
"But without rambling too much, let's begin.",
"\n\nCool\n\nYou have a cool undertone if your veins appear with a blue and/or purple colour. ",
"You may find that your skin may also appear to have either a pink, red or blue tint. ",
"It is common that silver jewellery appears to be more at home on your skin. ",
"You can also rock a blue eye shadow and rose or purple lips.",
"\n\nNeutral\n\nYour veins will appear more blue/green. ",
"If you look at your skin under sunlight you may find that it appears to have a green tint to it. ",
"Luckily for you both gold and silver jewellery flatters your skin tone. ",
"You can also get away with a darker or lighter look with red lip colours and burgundy blush.",
"\n\nWarm\n\nYour veins will be either green or olive colour. ",
"You may find that your skin has a more yellow, gold or peach tint. ",
"Gold jewellery tends to flatter your skin more than silver. ",
"More earthy colour shades suit you better, maybe enhance you lips with a orange based red or brown colour.",
"\n\nTuesday, 16 February 2016\n\nSome are round and some are thin, some are hard, some are soft and some are complex and some not as much.",
"\n\nEach chocolate is like a chapter of your life, once it has gone it's gone. ",
"It's only when the chocolate melts on your tongue and the flavours spreads like confetti. ",
"You truly cherish the moment you're in. ",
"But when it is gone it will forever be just another memory.\"",
"\n\nI thought I'd try something a little different today and show a metaphorical piece of writing that I have made recently. ",
"I actually wrote this on a bus in the notepad section of my phone, but equally I wanted to share it on here to see what you thought of it?",
"\n\nI've had this book sitting on my bookshelf for about three years. ",
"As I finished another book I decided to give it ago, despite how bright neon pink it is. ",
"As I read the first chapter I didn't think to much of it but as I progress throughout the book I am becoming hooked I am literally obsessed with every chapter and find it hard to put the book down.",
"\n\nI got this for Christmas off of a family friend. ",
"At first I wasn't too keen on the product as I didn't quite know what calendula cream was. ",
"So it took to the Internet to do some research about this product. ",
"I decided to give it a try and fell in love. ",
"It's also 100% natural, 45% organic and hand made. ",
"I use it every night on my hands at the moment and it has really helped them become less painful. ",
"But you can use it all over your body as healing cream for sensitive skin.",
"\n\nBarry M is becoming my all time favourite brand for nail polish as they are affordable as well as being great quality. ",
"I've used multiple whites in the pass and they haven't given good coverage until now. ",
"With this white you just need to do one basic coat followed by a strong second and you have a perfect white nail. ",
"I have developed a bad habit of not applying nail polish unless I have a base coat and top coat after as I find it gives a much better finish.",
"\n\nBoy | Anne-Marie\n\nThis was harder than I thought, to pick just one song as I'm a bigger lover of music from all genres. ",
"But it finally came down to this song, which I have had on repeat throughout the month as I find it's really catchy and can pick up your mood.",
"\n\nWednesday, 3 February 2016\n\nWhat a month you have been!? ",
"It has been a rather unique and eventful beginning to 2016. ",
"It started with lots of hope and encouragement. ",
"I am very happy where I am at the moment and already it looks like 2016 is going to be full with more ups than downs.",
"\n\nThis month has reminded me of the common phrase \"quality over quantity\". ",
"January you have shown me who my family and friends are once again. ",
"I began January by entering my house at a frosty 3am after spending a wonderful evening with friends.",
"\n\nI am 16 chapters into my current book \"What I Saw and How I Lied\". ",
"I have also made some life changing decisions for the future, which is something I never thought I'd do. ",
"But have developed a strong love and dedication for it and it is something I want to pursue.",
"\n\nJanuary you have done well and have created a lot of excitement for 2016."
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"Electronic circuits are typically constructed in the form of a printed circuit board (PCB) that includes a plurality of electronic components soldered to a circuit board substrate having conductive traces interconnecting various device terminals to form an electrical circuit. ",
"As PCBs and the implemented electrical circuits thereof are often complex, board testing at manufacture has become increasingly automated. ",
"In this respect, board testing apparatuses have evolved from simple I/O functional testers that connect to I/O connectors of a populated PCB for high level automated functional testing, to test fixtures that include probe pins for making electrical contact with all or some of the circuit nodes of a tested board for performance of high level and lower level testing, to integrated testing devices that provide for automated testing of a PCB without the need to externally probe individual circuit nodes of the tested board.",
"\nThe testing of electronic circuits in boards and devices is typically controlled by Testing Automation Tools, which support the steps needed to proceed from a definition of the test algorithm to the actual testing operation. ",
"In order to facilitate testing automation, testing resources often are embedded inside the boards and devices, and can be accessed using a standardized interface, usually called a Test Access Port (TAP). ",
"This has the effect of limiting the pin count and rationalizing resource access and management. ",
"In general, most of the existing standards offer one or more languages that can be used to describe the resources inside the system under test (SUT), and which can be used as inputs to Testing Automation Tools. ",
"These Testing Automation Tools can apply their own algorithms in order to generate testing sequences exploiting the TAP. ",
"These testing sequences can then be used by a Test Control Unit (TCU) to command the TAP and execute the testing operations. ",
"The features and performance of the testing operations depend on each of these elements, namely, the access standard, the data format, and the TCU implementation.",
"\nThe Joint Test Action Group (JTAG) has developed a circuit board testing standard, denoted as IEEE 1149.1. ",
"IEEE 1149.1 specifies a Test Access Port (TAP) for testing circuit boards. ",
"IEEE 1149.1 supports Boundary Scan (BS) testing of hardware via test devices included on the tested circuit boards. ",
"Boundary Scan testing involves controlling and monitoring boundary pins of a JTAG-compatible device under the control of software to provide test coverage beyond that which might otherwise be available. ",
"Further, Instruction JTAG (IJTAG) is being standardized (denoted as P1687) to overcome existing JTAG limitations associated with moving from board-level JTAG to chip-level JTAG.",
"\nJTAG and IJTAG may be used by Automated Test Generation (ATG) tools to test chips and electronic devices. ",
"JTAG presents a simple 5-wire TAP that allows serially access, with minimal overhead, to resources implemented inside a chip. ",
"The access infrastructure can then be described into a specific language such as the Boundary Scan Description Language (BSDL), which can be used by many commercial TGTs to generate testing vectors. ",
"These testing vectors are typically saved in a format called Serial Vector Format (SVF), which enables a high-level description of the basic operations of the 1149.1 TAP. ",
"A more complex alternative to SVF is STAPL, which extends the vector operations of SVF to allow for basic flow control (if-then-else) and arithmetic operations on the test vectors. ",
"A JTAG-compliant TAP receives commands from a SVF or STAPL player, and generates simple Go/NoGo results which can later be interpreted offline.",
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"A first limitation is in the data format, because the test player does not have any knowledge of the system under test and, therefore, can perform only very basic operations. ",
"A second limitation is that interactive testing (local or remote) cannot be supported; rather, any testing results must be examined offline. ",
"Further, these existing approaches are implementation-dependent and are typically proprietary."
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"Understanding Yin Yang Theory\n\nYin and Yang may be the most important theory in Chinese Medicine and Martial Arts. ",
"The concept of Yin and Yang is simple and at the same time vast in nature. ",
"The relationship of Yin and Yang can be represented in the famous Tai Ji symbol. ",
"This symbol is called “Supreme Ultimate”, describing the profoundness of Yin and Yang. ",
"Although Yin and Yang are opposite stages, they form unity and are complementary. ",
"Yin contains a seed of Yang, and Yang contains a seed of Yin which is represented by the dots within each color. ",
"The symbol is showing that nothing can be totally Yin or totally Yang in nature. ",
"Yin is constantly changing into Yang as Yang is constantly merging in to Yin. ",
"Calligraphy Master Jin Huai Wang once explained to me these concepts of Yin and Yang. ",
"He said, “The mountain has a Yin side (shaded) and a Yang side (sun drenched), and each of those sides contain Yin qualities and Yang qualities, just as the river, just as life (translation).” ",
"The most beautiful part was how he described Yin and Yang, from the tone of his voice to physical movement he was just as he performs his calligraphy a true expression of Yin and Yang.",
"\n\nCyclical Motion\n\nThe earliest origin of Yin and Yang must have come from the observation of day turning into night and night turning into day. ",
"Since the day time is the time of activity it is attributed to Yang. ",
"At night or yin time, involves a time of rest and inactivity. ",
"The Yin Yang symbol below relate to the first correspondences of Yin and Yang.",
"\n\nTransformation\n\nAn example of transformation of Yin and Yang: Yang relates to creation and activity, which can transform into expansion that rises. ",
"Yin relates to condensation and materialization which can create contraction which descends.",
"\n\nFour Aspects\n\nThe Opposition of Yin and Yang: Yin and Yang are opposite stages of a cycle. ",
"However opposition is relative, not absolute.",
"\n\nThe Interdependence of Yin and Yang: Yin and Yang are interdependent of each other. ",
"Yin can not survive without Yang and vice versa. “",
"There cannot be activity without rest”.",
"\n\nMutual Consumption of Yin and Yang\n\nThe Inter-transformation of Yin and Yang\n\nYin and Yang transform into each other. ",
"Yin can change into Yang and vice versa. ",
"Summer changes into winter, day turns into night and life turns into death.",
"\n\nBody Structure\n\nEvery part of the Human body can be labeled as either Yin or Yang.",
"\n\nOpposition\n\nThe opposition of Yin and Yang can be seen in the opposing Yin-Yang structures of the human body, the opposing Yin-Yang characterization if the organs, and in the opposing symptomatology of Yin and Yang."
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[
"Sulfated hyaluronan containing collagen matrices enhance cell-matrix-interaction, endocytosis, and osteogenic differentiation of human mesenchymal stromal cells.",
"\nInorganic-organic composite implant materials mimicking the environment of bone are promising applications to meet the increasing demands on biomaterials for bone regeneration caused by extended life spans and the concomitant increase of bone treatments. ",
"Besides collagen type I (Col-I) glycosaminoglycans (GAG), such as hyaluronan, are important components of the bone extracellular matrix (ECM). ",
"Sulfated GAGs are potential stimulators of bone anabolic activity, as they are involved in the recruitment of mesenchymal stromal cells (MSCs) to the site of bone formation and support differentiation to osteoblasts. ",
"Nevertheless, no consecutive data is currently available about the interaction of hyaluronan or sulfated hyaluronan derivatives with hMSCs and the molecular processes being consequently regulated. ",
"We applied quantitative proteomics to investigate the influence of artificial ECM composed of Col-I and hyaluronan (Hya) or sulfated hyaluronan (HyaS3) on the molecular adaptation of osteogenic-differentiated human MSCs (hMSCs). ",
"Of the 1,370 quantified proteins, the expression of 4-11% was altered due to both aECM-combinations. ",
"Our results indicate that HyaS3 enhanced multiple cell functions, including cell-matrix-interaction, cell-signaling, endocytosis, and differentiation. ",
"In conclusion, this study provides fundamental insights into regulative cellular responses associated with HyaS3 and Hya as components of aECM and underlines the potential of HyaS3 as a promising implant-coating-material."
] | {
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".",
"\n990\nSuppose -18*j + 1044 + 252 = 0. ",
"What is the lowest common multiple of 270 and j?",
"\n1080\nLet q = 10 - 8. ",
"Suppose 5*z + 2*t - 26 = 0, -2*z - 18 = -5*z - q*t. ",
"Calculate the lowest common multiple of 1 and z.\n4\nLet z(i) = i**2 + 3*i - 5. ",
"Let n be z(2). ",
"Suppose 2*b - 4*p - 31 = p, 13 = b - n*p. ",
"What is the least common multiple of 18 and b?",
"\n18\nLet s = -19011/79 - 2484221/632. ",
"Let v be 1*7*(-2 + 599). ",
"Let f = v + s. Find the common denominator of -57/4 and f.\n8\nSuppose -3*k = -2*d - 3*d + 150, 30 = d + 4*k. ",
"Let t be (-1 - 6)*d/(-35). ",
"Suppose -t = -3*m + 18. ",
"What is the smallest common multiple of m and 8?",
"\n8\nLet p be -24 - (-12)/(-3 + -1). ",
"Let o = 33 + p. What is the least common multiple of o and 2?",
"\n6\nFind the common denominator of 2 + -12 + 6104/651 and -31/5.",
"\n465\nSuppose 3*w - 2*l + 19 = -0*l, -7 = -w - 2*l. ",
"Let f(g) = -8*g - 8. ",
"What is the least common multiple of f(w) and 18?",
"\n144\nLet z = -1/22540 + 250759/33810. ",
"What is the common denominator of z and -133/12?",
"\n12\nFind the common denominator of (-580)/(-36)*-6*2/(-152) and -17/24.",
"\n456\nLet s = 15902 + -556632/35. ",
"Find the common denominator of -36/25 and s.\n175\nSuppose 57*a - 44281 = -10195. ",
"Calculate the lowest common multiple of a and 16.",
"\n4784\nSuppose -2*u + 111 = -o, -o + 4 = 3*u - 155. ",
"What is the smallest common multiple of 16 and u?",
"\n432\nLet j = 89867/2334 + -4/1167. ",
"What is the common denominator of j and 43/136?",
"\n136\nWhat is the lowest common multiple of 3 + -1 - (-5 + -2 + 4) and 25?",
"\n25\nFind the common denominator of 3/2 - 3 - 202/(-198) and 51/8.",
"\n792\nLet i(o) = 85*o + 7. ",
"Let t be i(9). ",
"Let w = 12373/16 - t. Calculate the common denominator of w and 103/34.",
"\n272\nSuppose q - 47 = 3*x + 2*x, 0 = -2*x + 4*q - 26. ",
"Let z(f) = f**2 + 8*f - 5. ",
"Let m = -87 - -91. ",
"What is the least common multiple of m and z(x)?",
"\n4\nLet w(o) = o**2 + 7*o + 2. ",
"Let s be w(-7). ",
"Suppose 0*r - f = -3*r + 44, -f + 26 = s*r. ",
"Calculate the least common multiple of (9/(-6))/(8/(-416)) and r.\n546\nSuppose -4*f = -641 - 159. ",
"Suppose 13*k - f = 3*k. ",
"What is the smallest common multiple of k and 4?",
"\n20\nSuppose -5*l - 19 + 49 = 0. ",
"What is the lowest common multiple of 6 and l?",
"\n6\nLet w(a) = 3*a**2 + 4*a + 3. ",
"Suppose 2*t = -4*i - 3*t + 15, 5*i = 4*t + 70. ",
"What is the least common multiple of w(-2) and i?",
"\n70\nLet v = -209909/792 - -2384/9. ",
"Find the common denominator of v and -9/32.",
"\n352\nLet i = 49 - 25. ",
"Calculate the common denominator of 48/512*-130 - 6/(-1) and 0/3 - (-226)/i.",
"\n48\nLet u(l) = 2*l**3 + 14*l**2 - 2*l + 5. ",
"Let x be u(-7). ",
"Suppose 4*z - x = 1. ",
"Calculate the smallest common multiple of z and 1.",
"\n5\nSuppose 78 = 27*j - 111. ",
"Let d(f) = 3*f + f**3 + f**2 - 8 + 4*f + 9*f**2. ",
"Calculate the lowest common multiple of d(-9) and j.\n70\nSuppose 4*x = w - 26, -x = 5*w - 2*w. ",
"Let j(b) = 12*b**2 - 2*b + 1. ",
"Let n = 0 - -1. ",
"What is the lowest common multiple of j(n) and w?",
"\n22\nLet n(h) = -143*h - 2. ",
"Let o = -2 + 1. ",
"Let l be n(o). ",
"What is the common denominator of 11/18 and l/(-16) + 8 + -5?",
"\n144\nLet n = 76704131/550 + -139462. ",
"What is the common denominator of -31/2 and n?",
"\n550\nSuppose -9*s + 28560 = 76*s. ",
"Calculate the least common multiple of 144 and s.\n1008\nSuppose -7*p + 3*p = 3*x - 40, -4*x = -p - 47. ",
"Let a(b) = -b + 26. ",
"What is the least common multiple of a(x) and 3?",
"\n42\nSuppose 0 = -5*s + 2*c - 3, s = 2*c - 0*c - 7. ",
"Suppose 0*g = -q - 2*g - s, -5*g + 2 = 4*q. ",
"Calculate the lowest common multiple of 54 and q.\n54\nLet y be ((-114)/95)/((-6)/(-20)). ",
"Let n(b) = b**3 + 3*b**2 - 5*b - 1. ",
"Calculate the smallest common multiple of 8 and n(y).",
"\n24\nSuppose 3*j = 3*u - 285, -5*u + 7*u = 4*j + 194. ",
"Calculate the common denominator of 41/12 and (12 - 15)/(-1 + u).",
"\n276\nLet b be (16/(-4) + 54)/1. ",
"Find the common denominator of 1 + b/18 - (1 - 2) and 43/3.",
"\n9\nSuppose -116 = -26*b + 118. ",
"What is the lowest common multiple of 21/1 + 2 + 1 and b?",
"\n72\nLet p be ((-906)/42)/(2/377). ",
"Let i = p - -4070. ",
"What is the common denominator of 51/14 and i?",
"\n14\nLet d(z) = z + 1. ",
"Let c be d(0). ",
"Let g = -1105157/42 + 26312. ",
"What is the common denominator of -19*2/16*c and g?",
"\n168\nLet b = 23 - 15. ",
"Suppose 2*p - 10 = -3*z, -2*p = -0*p - z - 18. ",
"Let o = p - 1. ",
"What is the lowest common multiple of b and o?",
"\n56\nLet d be (-2 - -256)*(0 - 1). ",
"Calculate the common denominator of -113/6 and (d/(-60))/(66/55).",
"\n36\nLet w = -604 - -1154. ",
"What is the smallest common multiple of w and 150?",
"\n1650\nLet m = 41/6 + -151/30. ",
"Calculate the common denominator of -77/8 and m.\n40\nLet c be (-52 + 3 + 1)/(-1). ",
"Let x = -32 + c. Calculate the smallest common multiple of x and 50.",
"\n400\nFind the common denominator of 2 + (-18)/12 - (-253)/198 and -43/1140.",
"\n3420\nLet s = -156623/16 + 9793. ",
"Let c = -7779293/308 + 275362/11. ",
"Let l = c + 1486/7. ",
"Calculate the common denominator of s and l.\n16\nLet m be (6/(-4))/((-21)/11310). ",
"Let v = m + 6871/28. ",
"Let h = 10497/10 - v. What is the common denominator of h and 101/8?",
"\n40\nSuppose -q = 2*i + 2, 4*q + 8 = 5*i - 13. ",
"What is the common denominator of (23/(-20))/(1/q) and 2145/(-22)*(-4)/18?",
"\n15\nSuppose 364 = -3*q + 400. ",
"What is the lowest common multiple of q and 36?",
"\n36\nWhat is the common denominator of (-81)/135 + -1 + (-141)/(-30) and (118/4)/((-5)/2)?",
"\n10\nSuppose 0 = -4*z + 17 + 3. ",
"Suppose j = z - 2. ",
"Calculate the common denominator of 133/18 and (j - 1)*325/60.",
"\n18\nLet g(v) = 4*v + 1. ",
"Let h be g(1). ",
"Let w(a) = 10*a - 36. ",
"Calculate the smallest common multiple of w(h) and 12.",
"\n84\nLet v(c) = -8*c**3 + 3*c**2 + 5*c + 6. ",
"Let t be v(-5). ",
"Let w = -4157/4 + t. Find the common denominator of 157/30 and w.\n60\nLet h = -18475265/788676 - 139/9389. ",
"Let r = h + 263/21. ",
"Let l = 1975/318 + -7/159. ",
"Find the common denominator of l and r.\n12\nWhat is the common denominator of (-343)/(-240) - 77/385 and ((-22)/(-72))/(2/(-20))?",
"\n144\nLet b = 3 + -1. ",
"Suppose u = -b*u - 48. ",
"Calculate the least common multiple of 8 and (8/u)/((-1)/14).",
"\n56\nLet s = 3625/7 + -518. ",
"Calculate the common denominator of 49/164 and s.\n1148\nSuppose -197*z = -181*z - 96. ",
"Let q(h) = -h**3 - 3*h**2 - 7*h + 1. ",
"Calculate the smallest common multiple of q(-5) and z.\n258\nSuppose 4*k - 5 = -3*d + 2, 2*k = 4*d - 46. ",
"Let v be 6/(-8) - 201/(-12). ",
"Let o = v - 13. ",
"What is the lowest common multiple of d and o?",
"\n9\nLet v = -18 - -15. ",
"Let b be v/6*(-9 - -1). ",
"Calculate the common denominator of 109/10 and 30/(-2)*b/8.",
"\n10\nCalculate the common denominator of (-11)/88 - 132/16 and 37/20.",
"\n40\nLet v = -9733 + 233669/24. ",
"What is the common denominator of (-51)/54 - 8/(-16) and v?",
"\n72\nWhat is the common denominator of (-13)/14 - (-3)/30 and 111/50?",
"\n350\nSuppose -2*b = 3*j - 115, 0 = -5*b - j + 308 - 27. ",
"What is the lowest common multiple of b and 42?",
"\n168\nWhat is the common denominator of (2/147)/((-12)/(-45)) and -19/56?",
"\n392\nLet h = 4547/6 - 761. ",
"Let j(u) = 4*u**2 - 2. ",
"Let q be j(3). ",
"Find the common denominator of q/153 + 47/(-90) and h.\n30\nSuppose -3*q - 6 + 18 = 0. ",
"Let b be (1 - 1)*(-4 - (-1 - 4)). ",
"Suppose b*d = -4*d + 4. ",
"What is the least common multiple of q and d?",
"\n4\nLet w = 1231902143/503588 - -1/251794. ",
"Let p = w - 2470. ",
"Let n = -2503 + 60107/24. ",
"What is the common denominator of p and n?",
"\n24\nLet o(l) = -7*l + 1. ",
"Suppose -5*j + 16 + 19 = 0. ",
"Let d = j + -8. ",
"Calculate the lowest common multiple of o(d) and 8.",
"\n8\nLet g be 9/(-18) + (-10)/(-4). ",
"Suppose 7*p = g*p - 2025. ",
"Calculate the common denominator of 40 and 2/(-8) + p/204.",
"\n17\nSuppose -15 = 3*i, 2*b + 490 = 3*b - 5*i. ",
"Let z = -71452 + 431591/6. ",
"Let d = z - b. What is the common denominator of -64/3 and d?",
"\n6\nCalculate the least common multiple of 3/((-9)/(-12)*1) and 7.",
"\n28\nLet d = -108487/18620 + -22/931. ",
"Let h be 86 - 0*(-1)/(-4). ",
"Calculate the common denominator of d and (h/(-4))/(1*2).",
"\n20\nSuppose -5*r + 25 = -0*r, 1 = -2*z + r. Calculate the common denominator of 1*-1 - (-1271)/(-451) and 222/27*2/z.\n99\nLet b = -4428165804977/21764412393724 - 21/268683181. ",
"Let z = b + -2/1841. ",
"What is the common denominator of -45/11 and z?",
"\n44\nLet d(l) = -2011*l - 15. ",
"Let c be d(3). ",
"Calculate the common denominator of 39/8 and 6/(c/3124) - (-2)/(-9).",
"\n56\nLet u(l) = -6*l + 2. ",
"Let v be u(-6). ",
"What is the common denominator of ((-22)/4)/(v/(-14)) and -71/12?",
"\n228\nLet j(n) = n**3 - 15*n**2 - 16*n - 9. ",
"Let c be j(16). ",
"Let z be 1191/c*(-78)/(-4384). ",
"Let b = 40/137 + z. What is the common denominator of 81/14 and "
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"\n\nFuture of Retail: Why It Won’t Be Empty Windows - wretched\nhttp://iamvictorio.us/post/13356312465/future-of-retail-why-it-wont-be-empty-windows\n\n======\ntoddh\nIf a retailer has to provide the lowest cost and the highest experience,\ndoesn't that sound like predicting empty windows? ",
"And if those rents go down\nthe malls collapse and all the windows will be empty. ",
"Plus, with electric self\ndriving cars we are going to see delivery costs plummet. ",
"It doesn't look good.",
"\n\n"
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"A wide variety of containers are used to transport bulk materials. ",
"Typically, containers for transporting bulk materials are constructed of sheet metal either fashioned into a tank or an open container such as a fixed truck box, pivoting dump truck box, or roll-off container. ",
"As used in connection with the present invention, \"containers\" includes open containers such as pivoting dump truck boxes, fixed truck boxes, roll-off containers detachable from a truck, intermodal containers designed to be transported by ship, train or truck, substantially enclosed tanks for use in transporting bulk liquids, and any other container assembly for transporting bulk materials that is adapted to be attached to a truck, truck-like vehicle, or trailer. ",
"Containers within the meaning of that term as used in connection with the present invention are designed to transport bulk materials in loads ranging from one-half ton or more. ",
"The materials can include soil, rocks, grains, foods, liquids, etc.",
"\nThe containers are typically manufactured using sheet metal (typically steel) attached to a framework of structural members. ",
"Sheet metal is used to manufacture the boxes because of its strength and resistance to wear--both properties that are required during typical use of the trucks. ",
"In spite of the durability and toughness provided by the sheet metal boxes, there are drawbacks associated with metal truck boxes and other containers.",
"\nOne problem is that the truck boxes and other containers manufactured with sheet metals are themselves typically relatively heavy which limits the loads that can be transported by the trucks. ",
"Furthermore, the sheet metal used to manufacture the truck boxes and containers typically corrodes easily, reducing the useful life of the containers. ",
"In addition, it may not be desirable or allowable to allow some materials to come into contact with the sheet metal, thereby requiring the use of expensive liners or other methods to prevent contact between the materials and the sheet metal.",
"\nFurthermore, the sheet metal can make unloading difficult in some situations. ",
"For example, in colder climates moisture in the materials may cause them to freeze to the interior of the container, typically requiring hand labor to dislodge the material. ",
"In some situations, the entire container may need to be heated to facilitate unloading and/or pressurized water may be required to completely unload the container. ",
"All of these actions raise the cost of transporting materials using conventional containers manufactured from sheet metal.",
"\nIn addition to freezing, friction between the materials and the sheet metals used in the containers can also make unloading difficult, requiring the operator, in some situations, to rapidly accelerate and decelerate the containers (which may be mounted to pivot about the end of the truck) in an attempt to jar the materials loose. ",
"Such actions add unnecessary stress and wear to the containers as well as the hydraulic lifts used to pivot them, adding the cost to repair any damage and potentially reducing the useful life of the containers and/or hydraulic lifts.",
"\nIn addition to causing difficulty in unloading when the load remains in the container, such situations may also result in personal injury or damage to the truck because the probability of, for example, a dump truck tipping over is greatly increased when its box is raised to dump a load of material. ",
"The probability of tipping is increased because the load typically stays in the front end of the box (which is raised the highest). ",
"The raised load may raise the center of gravity of the truck above a point at which the truck is stable, particularly in locations, such as construction sites, where the ground is uneven or unstable.",
"\nTo address the issue of friction between the load and truck box, some users may coat the interior of the truck box with a release agent, such as diesel fuel, that assist in removal of the load during dumping. ",
"That practice can cause undesirable environmental contamination as the materials unloaded from the container invariably carry with them some of the diesel fuel or other release agent."
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"The side shields are formed integral with the write shield, and are positioned in the cross-track direction of the main pole. ",
"The side shields are magnetized in one direction in the cross-track direction. ",
"For this reason, in the write head, an easy direction of magnetization in which the magnetic flux of the recording magnetic field can easily flow, and a hard direction of magnetization in which the magnetic flux of the recording magnetic field can hardly flow exist in the cross-track direction."
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