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[ "Mighty Future Queen By Lopoddity Watch\n\n4K Favourites 467 Comments 146K Views\n\n\"Oh my goodness!\" ", "Princess Celestia gawked at the newly hatched grub, fresh from the remains of her dripping egg. ", "The baby babbled quietly and dribbled a little, and the drool hissed and burned as it pooled on the carpet.", "\n\n\n\n\"She's so cute!\"", "\n\n\n\n\"Indeed.\" ", "Chrysalis lifted her chin proudly. \"", "You are lucky, Celestia-our union has produced a very handsome heir. ", "For a moment I worried about producing a cross-breed, but she is healthy, and her acid glands are already salivating, as is typical of a changeling infant. ", "Although Princess Iridescence is but a grub, I know that one day she'll be a fine Queen, and rule the kingdom with a iron hoof-\"\n\n\n\n\"I'm gonna call you 'Bugaboo!\" ", "Celestia cooed, ignoring Chrysalis's monologue entirely to nuzzle her snout against her baby's tummy. ", "The little grub squealed with laughter, kicking with her not-yet-developed hind legs. \"", "Who's the cutest little princess in the world? ", "You are, yes you are!\" ", "Under the affection, the newborn giggled and happily spat a gob of poisonous green acid at her mother, which Celestia nonchalantly dodged. \"...", "Nice try, Junior, but you'd better work on your aim.\" ", "The Sun Princess teased. \"", "My little princess bugaboo.\" ", "She snuggled her baby close.", "\n\n\n\n\"Iridescence.\" ", "Chrysalis corrected.", "\n\n\n\n\"Bug-a-boo.\" ", "Celestia corrected back with a pleasant smile, emphasizing each syllable.", "\n\n\n\n\"Princess Iridescence.\" ", "Chrysalis repeated, frowning.", "\n\n\n\n\"Irie-dearie.\" ", "Celestia lilted back.", "\n\n\n\n\"...You're going to ruin our daughter with your horrible coddling.\" ", "Chrysalis groused.", "\n\n\n\n\"Yes. ", "Yes I am. ", "I'm going to spoil her rotten and snuggle her all day and night. ", "And there isn't a thing you can do to stop me.\"", "\n\n\n\n\"And...and then she'll become your little accomplice of...of awful pony love.\" ", "Chrysalis said, with growing horror. \"", "And someday you and her will both serve to annoy me.\"", "\n\n\n\n\"That's the plan, dear.\" ", "Celestia kissed her wife's cheek. \"", "Starting right now. ", "By royal decree, I command you to curl up with me and Bugaboo for double mommy snuggle time. ", "Look at this little face, Chryssy.\" ", "Celestia held up their baby in her hooves, imploring Chrysalis to look at their daughter's pleading eyes and chubby cheeks. \"", "I know you can't resist it.\" ", "Celestia fluttered her own eyelashes, to maximize the charm.", "\n\n\n\n\"...I can't.\" ", "Chrysalis admitted quietly. ", "Glancing around to make sure nopony else was in the room, she heaved a weary sigh, and bravely resigned herself to her fate, snuggling under Celestia's wing, close to her daughter.", "\n\n\n\n\"Hehee.\" ", "Celestia smiled. \"", "I love you.\"", "\n\n\n\n\"Hnng.\" ", "Chrysalis shut her eyes, powerless against the Sun Princess' never ending assault of ruthless warmth, love, and tolerance. \"", "I...ahem. ", "I...love you too. ", "I suppose.\" ", "Chrysalis mumbled back, hoping Celestia wouldn't hear, but of course the Princess' sharp ears caught it, and Chrysalis found herself (and tiny Princess Iridescence) suddenly under attack by a barrage of alicorn kisses.", "\n\n\n\n~~~~~~~~~~~~~~~~~~~~~~~~~~~\n\n\n\nsuper quickie doodle before i go home\n\n\n\ntheir daughter Iridescence is in her larval stage, she doesn't really resemble her adult form yet, still just a grub babbu\n\nIMAGE DETAILS Image size 2588x2550px 1.8 MB Show More\n\nPublished : Mar 13, 2016" ]

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[ "GSGS: a computational approach to reconstruct signaling pathway structures from gene sets.", "\nReconstruction of signaling pathway structures is essential to decipher complex regulatory relationships in living cells. ", "Existing approaches often rely on unrealistic biological assumptions and do not explicitly consider signal transduction mechanisms. ", "Signal transduction events refer to linear cascades of reactions from cell surface to nucleus and characterize a signaling pathway. ", "We propose a novel approach, Gene Set Gibbs Sampling, to reverse engineer signaling pathway structures from gene sets related to pathways. ", "We hypothesize that signaling pathways are structurally an ensemble of overlapping linear signal transduction events which we encode as Information Flows (IFs). ", "We infer signaling pathway structures from gene sets, referred to as Information Flow Gene Sets (IFGSs), corresponding to these events. ", "Thus, an IFGS only reflects which genes appear in the underlying IF but not their ordering. ", "GSGS offers a Gibbs sampling procedure to reconstruct the underlying signaling pathway structure by sequentially inferring IFs from the overlapping IFGSs related to the pathway. ", "In the proof-of-concept studies, our approach is shown to outperform existing network inference approaches using data generated from benchmark networks in DREAM. ", "We perform a sensitivity analysis to assess the robustness of our approach. ", "Finally, we implement GSGS to reconstruct signaling mechanisms in breast cancer cells." ]

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[ "Since the late 1990s, a broad reform movement has swept Latin America, aimed at granting independence to central banks and freeing them from government pressure to print money to finance government spending. ", "Laws have been passed and constitutions changed to allow independent central banks to focus on the fight against inflation.", "\n\nA more complicated case has been Brazil, where the central bank is still technically under the authority of the government, and where inflation has fluctuated according to the relative autonomy of the institution. ", "There the debate over the need for a fully autonomous central bank has never quite disappeared. ", "It played large in the presidential campaigns of 2014, and it may return as a topic of controversy in the upcoming elections, with some candidates against and others in favor of central bank independence.", "\n\nIn light of these discussions, I have worked with colleagues to analyze the high inflation period of Brazil before 1994 and the relationship of this time of inflation to the independence of the central bank. ", "Our conclusions are clear. ", "Periods in which there was not a clear separation between fiscal and monetary authorities were also those in which the government used its monopoly over the printing of money to finance its spending. ", "Inflation rates, correspondingly, were high.", "\n\nFigure 1 illustrates this phenomena, showing the relationship between inflation rates and the rates of money growth (the monetary base) before 1994 for Brazil.", "\n\nWhy did the Central Bank of Brazil (CBB), created as a separate institution, lack the necessary autonomy? ", "The institutional framework in which the CBB was created gives us some clues.", "\n\nA history of limited autonomy\n\nIn 1964, when the CBB was established during the first years of military dictatorship, the government also created the National Monetary Council (CMN), which had regulatory powers over the bank. ", "This council had nine members, six of whom had fixed mandates of six years each. ", "Four of those six members sat on the board of the bank, one of them being its governor. ", "These fixed mandates provided the bank with some independence, as the bank’s board members could not be removed until their terms were completed. ", "But this arrangement did not last long. ", "In 1967, during the first transition of power, the new military government decided it wanted full control over economic policy and forced the board of the CBB to resign. ", "It also stopped respecting the fixed mandates, removing board members whenever it saw fit.", "\n\nThe result was that the government, using the National Monetary Council as its instrument, began to print large amounts of money, over which it had direct control, with congress having no say.", "\n\nOver the next three decades, the Council expanded to include 26 members, as different interest groups, including unions, began demanding a piece of the pie. ", "This made things even worse, as the Council was now dedicated more to satisfying the interest groups than to fighting inflation, as it had been originally conceived to do.", "\n\nFigure 2 shows this relationship between of the growth of the council and inflation.", "\n\nCentral Bank independence, macroeconomic stability\n\nIt was only in 1994, eight years after the end of military rule, that the democratic government under Itamar Franco put forth a successful anti-inflationary package, known as the Real Plan, which increased the autonomy of the central bank to levels it had never experienced before and prevented the Council from interfering with central bank decisions. ", "The Council, now consisting of only three members (the president of CBB, the Minister of Finance, and the Minister of Planning), instead dedicated itself to other issues, including economic development.", "\n\nThe result has been a dramatic reduction in inflation rates over the last 24 years and greater macroeconomic stability. ", "Central Bank independence, as shown both in Brazil and in other countries of the region, is an essential component of healthy economies.", "\n\nIn September, the IDB together with the Becker Friedman Institute of the University of Chicago will host a conference on the Fiscal and Monetary History of Latin America, which will discuss, among other issues, this history in more detail. ", "Watch this space for updates on the event.", "\n\nThe views expressed in this blog are those of the authors and do not necessarily reflect the views of The Latin American and Caribbean Economic Association (LACEA), its Board of Executive Directors or its member Governments." ]

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[ "This invention relates to the art of weather barriers and, more particularly, to an installable and removable external weather barrier for an opening through a wall of a building and comprising thin plastic film adhesively mounted on external mounting surfaces surrounding the opening.", "\nIt is of course well known to provide weather barriers across openings such as those for doors and windows in homes or other buildings for purposes of eliminating drafts and conserving energy in connection with the internal heating of the building. ", "Such weather barriers have included exteriorly mounted glass or plastic storm doors and windows which are convertible to provide screens to facilitate opening the interior of the building to outside air when desired. ", "While such devices serve their intended purpose, they are expensive, cumbersome to use if they are the type which requires removal and replacement of glass panels and screens and, if of the self-storing type, often become difficult to operate with ease after a period of use and weathering which results in oxidation and/or scoring of the metal which impairs relative sliding movement therebetween.", "\nAs an alternative to such exterior weather barrier arrangements, or as a supplement thereto, a variety of internally mountable weather barriers have been proposed. ", "One of the more recent of such interior arrangements is provided by mounting a double faced adhesive tape on a supporting surface such as the frame and sill of a window, adhering a heat shrinkable plastic film to the adhesive tape, and heating the film such as by use of a hair blow-dryer to shrink the film to a taut, wrinkle free condition. ", "The shear strength of the adhesive tape is sufficient for the bond to be maintained between the film and tape and between the tape and mounting surface under the tensile force of the shrunk film and, at the end of the period of use of the barrier, the film and adhesive tape are pulled away from the mounting surface and discarded. ", "Such an internal weather barrier is relatively inexpensive and easy to install and, because of relatively stable temperature and humidity conditions within a building, remains stable in its mounted condition throughout its period of use. ", "Moreover, because of the internal mounting relative to window or door glass and the mounting of the adhesive tape on surfaces which most often are not exposed to direct sunlight, the plastic film and adhesive tape remain stable against the effects of ultraviolet light during the period of installation of the weather barrier.", "\nWhile plastic film barriers of the foregoing character serve their intended weatherproofing purposes, the interior mounting of the film is considered by many to be unattractive and, while the adhesive tape is intended to be separable from the mounting surface after use without staining the latter or leaving any adhesive thereon, there is apprehension in this respect on the part of potential users. ", "Other concerns of potential users include the fact that hardware for curtains, drapes, window shades or the like may have to be removed to facilitate mounting of the tape and plastic film and/or that such window or door accessories themselves would have to be removed or would not be accessible for opening and closing displacements thereof relative to a window or door in that they would be behind the plastic film.", "\nSome homeowners, as an alternative to the foregoing weather barrier arrangements, have attempted to provide exterior weather barriers for doors and windows by positioning sheets of plastic material across the opening and suitably securing the plastic in place such as through the use of masking tape, staples, nails, tacks and the like. ", "Such effort most often are basically unacceptable and ineffective for a number or reasons, including the damaging or marring of the mounting surfaces through the use of staples, nails and the like, and the inability of masking or other tapes or adhesives to maintain the plastic in place for an extended period of time when exposed to rain, wind, snow and gusting winds and variations in temperature from below freezing to as high as 100.degree. ", "F. Moreover the plastic materials used in connection with such efforts often are hazy, cannot be maintained with any degree of tautness under the varying weather conditions to which they are exposed, and often crack or tear in a relatively short period of time as a result of such exposure.", "\nWhile it might appear obvious to at least attempt to avoid the foregoing disadvantages of exterior weather barriers and of an interior tape and heat shrink film type weather barrier by installing the latter on the exterior side of a building window or door, the tape and film materials will not perform satisfactorily under the weather conditions encountered, and the working conditions under which such an exterior system would have to be installed make it potentially dangerous for the person doing the installation and thus undesirable. ", "More particularly in this respect, the heat shrink film, when installed and distended such as by the impact of rain and gusty winds thereon, will not over an extended period of such exposure return to its undistended taut condition. ", "Thus, the film becomes unattractive in appearance and, through looseness, more subject to tearing or separation from the mounting surfaces in that winds whip the plastic and thus severely impact load the adhesive. ", "Further, the shrink film and tape provided for interior barriers are adversely affected if used exteriorly by ultraviolet light and varying temperature and humidity conditions and, for these reasons too, subject the exterior installation to failure.", "\nWith respect to installing such a heat shrink system exteriorly, the exterior installation would require, at least in a majority of instances, the use of an ungrounded hair blow-dryer with an extension cod which would subject the installer to potentially dangerous electrical shock. ", "Furthermore, the use of a blow-dryer in connection with an installation requiring the use of a ladder would necessitate the installer carrying the blow-dryer up the ladder together with the weather barrier materials to be installed, or would PG,5 require the installer to undergo the inconvenience of installing the weather barrier materials and then descending and again ascending the ladder with the blow-dryer to shrink the film. ", "Accordingly, considerable inconvenience as well as potential injury would accompany efforts to externally install such a shrink film system." ]

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[ "2012 Arab Handball Championship of Champions\n\nThe 2012 Arab Handball Championship of Champions Club officially named Prince Faisal bin Fahd Handball Championship for Arab Club Champions was the 29th edition of Arab world's premier club handball tournament held in Berkane, Morocco. ", "Al Ahly SC is the defending champion.", "\n\nGroup stage\n\nGroup A\n\nGroup B\n\nGroup C\n\nGroup D\n\nKnockout stage\n\nQuarterfinals\n\nSemifinals\n\nFinal\n\nReferences\n\n2012\nCategory:2012 in handball" ]

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[ "Kentucky's state Senate has approved a bill that creates different marriage license forms for gay and straight couples, with one Republican senator saying a form that does not include the words \"bride\" and \"groom\" is offensive to traditional families.", "\n\nThe Senate voted 30-8 on the bill that also removes the names of county clerks from marriage license forms. ", "The bill is in response to Rowan County Clerk Kim Davis' refusal to issue marriage licenses to same-sex couples because the licenses contained her name. ", "Davis spent five days in jail for refusing to obey a federal court order.", "\n\nDemocratic Sen. Morgan McGarvey attempted to amend the bill so the state would only have one form. ", "He said having just one form would save money and would treat everyone equally." ]

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[ "\n575 F.Supp. ", "159 (1983)\nUNITED STATES of America\nv.\nDonna G. WARD, Defendant.", "\nNo. ", "82-79-01-CR-5.", "\nUnited States District Court, E.D. North Carolina.", "\nNovember 15, 1983.", "\n*160 *161 Samuel T. Currin, U.S. Atty. ", "by Gary H. Clemmons, Asst. ", "U.S. Atty., ", "Raleigh, N.C., for plaintiff.", "\nHenry W. Jones, Jr. of Jordan, Brown, Price & Wall, Raleigh, N.C., for defendant.", "\n\nORDER\nLARKINS, Senior District Judge:\nThis matter is on appeal from the defendant's conviction of a violation of 7 U.S.C. § 2024(b). ", "Defendant, Donna G. Ward, was charged in a two count Criminal Information of having knowingly made false statements which did not accurately reflect income on applications for acquisition of food stamps valued under $100, on June 12, 1980 and July 14, 1980. ", "Count one, relating to the application of June 12, 1980, was dismissed prior to trial. ", "Defendant appeared before the Honorable Charles K. McCotter, Jr., United States Magistrate and entered a plea of not guilty. ", "She was tried by jury and convicted of count two of the Criminal Information for violating 7 U.S.C. § 2024(b).", "\nFollowing her conviction, defendant received a sentencing hearing before Magistrate McCotter at which time she received a sentence of imprisonment for a period of one year, which was suspended and the defendant was placed on probation for a period of five years. ", "Defendant was fined $125 and was also ordered, as conditions of probation, to make restitution in the amount of $716 and to make reimbursement of the amount of compensation approved for her court-appointed attorney. ", "The defendant gave notice of appeal to the undersigned.", "\nDefendant assigns five errors on appeal:\n(1) Whether the trial court committed error in allowing the food stamp application and face sheet into evidence?", "\n(2) Whether the trial court abused its discretion in allowing certain Government documents into evidence over the defendant's objection that the Government did not make the discoverable materials available in the discovery process?", "\n(3) Whether the testimony provided by a Government witness was so tainted with prejudice as to warrant reversal and a new trial?", "\n(4) Whether there was insufficient evidence to sustain the conviction?", "\n(5) Whether the trial court erred in failing to grant the defendant's Motion for Judgment of Acquittal?", "\nOral arguments were held before the undersigned on October 24, 1983. ", "After a thorough examination of the record including the briefs filed by both parties, the transcript of the trial proceeding, and the appropriate case law, this Court concludes that none of defendant's errors raised on appeal warrant a remand for a new trial or a reversal of the judgment. ", "Accordingly, this Court affirms the defendant's judgment of conviction.", "\n\nI.\nOn July 14, 1980, the defendant went to the Department of Social Services in Raleigh, North Carolina to make application for food stamp coupons. ", "During her interview, in which she was asked a series of questions, the defendant stated that she had worked only at the City of Raleigh Police Department prior to July 14, 1980; that at the time of the application she had no other earned income; and, that she understood the penalties for making false statements on the food stamp application form. ", "Defendant signed the application form signifying that she understood all questions asked as well as the penalty warning.", "\nDefendant's application was processed and she was certified to receive food stamps. ", "During the period of July 1980 through January 1981, the defendant was issued $1212 in food stamps. ", "Upon subsequent investigation it was learned that defendant had failed to report at the time of *162 her application that she had been working for Manpower Temporary Services, Inc. on temporary assignments. ", "It appears that defendant had worked for Manpower, Inc. all but two weeks during the period of March 1980 through August 1980. ", "Had defendant reported her income from Manpower, Inc., the monetary value of the food stamps she should have received would have been $496. ", "The overissuance amounted to $716. ", "In essence, the Government maintains that the defendant received food stamps illegally because she failed to report her proper income from Manpower, Inc. in 1980 on her food stamp application.", "\nDuring her testimony, the defendant acknowledged that she did indeed receive temporary assignments through Manpower, Inc.; however, it was her understanding that she was not employed by Manpower Temporary Services, but she only received temporary assignments for an indefinite period of time. ", "Thus, at the time she made application for food stamps, defendant asserted that she was unemployed.", "\n\nII.", "\nDefendant's first three assignments of error on appeal can be disposed of with brief comment.", "\nDefendant argues that it was error for the trial court to allow the food stamp application and face sheet—which were completed by the interviewer as a result of a series of questions asked of her and the application then signed by the defendant—to be admitted into evidence. ", "This Court believes that the magistrate was correct in allowing the interviewer to testify as to the contents of the documents which were admissions of a party opponent and were clearly admissible under Rule 801(d)(2)(B) of the Federal Rules of Evidence. ", "A statement which is reduced to writing by one other than the accused is generally admissible where the accused reads it over and signs it. ", "United States v. Johnson, 529 F.2d 581, 584 (8th Cir.), ", "cert. ", "denied, 426 U.S. 909, 96 S.Ct. ", "2233, 48 L.Ed.2d 835 (1976); see, United States v. Evans, 320 F.2d 482, 486 (6th Cir.1963); United States v. Del Porte, 357 F.Supp. ", "969, 976 (S.D.N.Y.), aff'd 483 F.2d 1399 (2nd Cir.1973). ", "Such a statement is not hearsay. ", "Federal Rules of Evidence 801(d)(2)(B). ", "Furthermore, it is clear that the documents could be admitted under the business record exception to the hearsay rule. ", "Federal Rules of Evidence 803(6).", "\nDefendant also argues that the trial court erred in allowing the face sheet and the Manpower, Inc. checks into evidence over her objection that the Government did not make the materials available during the discovery process. ", "Clearly, the documents were admitted to supplement already existing evidence and testimony and defendant was not prejudiced by their admission into evidence. ", "The face sheet was admitted to supplement and clarify defendant's food stamp application. ", "The checks were admitted along with other evidence and testimony to show that the defendant was employed with Manpower, Inc. while applying for food stamps. ", "Accordingly, the admission of these documents were not prejudicial to defendant's substantial rights and the trial court did not err in admitting the face sheet and the checks into evidence. ", "Federal Rules of Evidence 103(a), Rule 52(a) of the Federal Rules of Criminal Procedure.", "\nNext, defendant argues that certain testimony from Julie Dean, a receptionist at Manpower, Inc., was prejudicial because it was hearsay. ", "On re-direct examination, Ms. Dean testified that she received information from another source, who acquired it from Manpower, Inc. microfilm, that defendant worked July 14-20, 1980. ", "Defendant promptly objected to her testimony as hearsay and the magistrate instructed the jury to disregard that portion of her testimony whereby the witness received any information from the microfilm that defendant worked the week of July 14, 1980. ", "This Court believes that the magistrate's proper instruction cured any prejudicial damage that may have been rendered by the witness's testimony. ", "In addition, it should be noted that there was a substantial *163 amount of evidence, independent of the microfilm testimony, that the defendant was employed with Manpower, Inc., when she applied for food stamps, such that the jury's exposure to the excluded testimony after proper instruction was not prejudicial error.", "\nAccordingly, defendant's first three assignments of error are without merit.", "\n\nIII.", "\nDefendant's final two assignments of error will be considered collectively. ", "Defendant argues that there was insufficient evidence to sustain a conviction; therefore, the magistrate erred by not granting defendant's Motion for Judgment of Acquittal at the conclusion of the Government's case and after discharge of the jury. ", "The sole point raised by defendant is that the Government failed to produce any evidence that the defendant ever received or benefited from a single food stamp coupon during the period of time she was certified for food stamp coupons subsequent to the filing of her application on July 14, 1980. ", "Consequently, having failed to prove the possessory or custodial element of the offense described in 7 U.S.C. § 2024(b), the Government has failed to produce sufficient evidence for the matter to be presented to the jury. ", "It follows, therefore, that the defendant's Motion for Judgment of Acquittal should have been allowed, as a matter of law, at the close of the Government's case in chief. ", "The question for inquiry before this Court is whether the magistrate correctly denied defendant's Motion for Judgment of Acquittal and this in turn depends upon the sufficiency of the government's proof.", "\nSection 2024(b) of Title 7 of the United States Code, in pertinent part provides:\n[W]hoever knowingly uses, ... acquires, ... or possesses [food] coupons or authorization cards in any manner not authorized by this chapter or the regulations issued by this chapter ... if such coupons or authorization cards are of a value of less than $100, shall be guilty of a misdemeanor ...\nDefendant argues that the government has not presented any evidence as to how the food stamp coupons, once issued, were conveyed or transmitted to a participant in the food stamp program. ", "There is no evidence in the record to show what actions are taken by a participant in the food stamp program to utilize the food stamps; nor is there evidence indicating how the food stamps are traced by the Department of Social Services back to the food stamp recipient.[1] In brief, it would be highly illogical to conclude that the defendant received or acquired the coupons merely because they were \"issued\" without showing a chain of possession or custody.", "\nThe Government maintains that 7 U.S.C. § 2024(b) does not mandate possession only; the statute also states that a person will be guilty of this crime if he \"acquires\" food coupons illegally. ", "The Government argues that \"acquire\" is synonymous with \"receive\"; that once the Government has presented evidence that a participant has submitted fraudulent information which results in an overissuance of food stamp coupons, then upon a showing of overissuance of food stamp coupons, there exists a reasonable inference that the participant acquired the food stamps illegally. ", "In addition, the Government asserts that the record is replete with evidence proving beyond a reasonable doubt that the defendant did in fact receive food stamps subsequent to her filing a food stamp application on July 14, 1980.", "\nNeither side has cited any appellate decision on point, and the undersigned, likewise, has found none. ", "Therefore, this Court approaches the issue anew.", "\n\n\n*164 A.\nAs a starting point, this Court looks to the legislative history of § 2024(b). ", "A 1977 House Committee Report which described the then-current rules and practice on penalties and sanctions under the Food Stamp Act of 1964, as amended, 7 U.S.C. § 2011 et seq., ", "stated:\nThe Food Stamp Act of 1964, as amended and as implemented by Federal rules, provides for three groups of offenders and penalties, the first for recipients (and other persons) who knowingly use, transfer, acquire, alter, or possess food stamps or authorization to purchase documents illegally, or who use food stamps knowing that they have been used illegally; the second for retail food stores, wholesale food concerns, and meal services that violate rules governing the use and redemption of food stamps; and the third for state agencies that do not comply with program rules or administer the program in a manner deemed to be grossly negligent or fraudulent.", "\nH.R.Rep. ", "No. ", "95-464, 95th Cong., ", "1st Sess. ", "376 (1977), reprinted in 1977 U.S.Code Cong. & ", "Ad.", "News 1704, 2305 (emphasis added). ", "The emphasized portion of this statement corresponds to § 2024(b) and when compared, the meaning is clear: The Food Stamp Act provides sanctions for an individual recipient \"who knowingly ... acquires ... or possesses ... food stamps ... illegally.\" ", "United States v. Marvin, 687 F.2d 1221, 1224 (8th Cir.1982), cert. ", "denied, ___ U.S. ___, 103 S.Ct. ", "1768, 76 L.Ed.2d 342 (1983).", "\nThe illegal nature of the transaction involves the acquisition and possession of food stamps as a \"consequence of fraudulent concealment.\" ", "United States v. Barrington, 662 F.2d 1046, 1052 (4th Cir.1981). ", "It is this willful concealment of pertinent information which triggers the application of the statute. ", "In other words, when an individual applies for food stamps and willfully makes false statements upon application, that individual may be subject to criminal prosecution under the Act. ", "Accordingly, the crux of the Government's burden of proof is to show knowledge of the illegal nature of the transaction. ", "United States v. Marvin, supra.", "\nDefendant argues, however, that the Government must additionally show that defendant \"acquired\" or exercised some degree of dominion, custody or control over the coupons or authorization cards in order to complete the offense; and lacking evidence of this essential element of the offense, the Government has not sustained its burden of proof. ", "This Court believes that defendant's interpretation of the statute is too strictly construed.", "\nThe 1977 House Committee Report, referred to earlier in this opinion, discusses penalties and sanctions to be imposed upon individual recipients who knowingly make fraudulent or deliberate misrepresentations upon application of food stamps and there is an \"overissuance\" of coupons to the recipient. ", "Nowhere in the Report does it refer to corrective action being undertaken whenever it has been determined that the individual actually received or acquired coupons illegally; instead, it purports to impose criminal liability upon an individual recipient whereby there has been a determination of overissuance of coupons as a result of fraud or deliberate misrepresentation of facts by the recipient. ", "See, H.R. Rep. No. ", "95-464, supra., ", "at 376-383, reprinted in 1977 U.S.Code Cong. & ", "Ad. ", "News, supra., ", "at 2305-2312.", "\nFurthermore, the Report makes a distinction between an individual recipient and a retailer or wholesaler. ", "Retailers and wholesalers and their agents are usually found to have violated provisions of the Food Stamp Act by such activities as accepting food stamps for ineligible items, giving cash as change, accepting food stamps for cash (usually, at a discount), or accepting known counterfeit food stamps or knowingly accepting food stamps from ineligible persons. ", "See, H.R.Rep. ", "No. ", "95-464, id. at 384, reprinted in 1977 U.S.Code Cong. & ", "Ad.", "News, id. at 2313. ", "Here the element of acquisition or possession of food stamps can be readily seen. ", "However, *165 where an individual recipient who applies for food stamps is involved, this Court thinks that Congress intended the element of possession to be shown by issuance of coupons to the recipient.", "\nBlack's Law Dictionary defines \"issue\" as \"to send forth\". ", "Black's Law Dictionary 964 Rev. 4th Ed. (", "1968). ", "Food stamp coupons or authorization cards are usually issued through the mail.[2] Logically, if the Government can show that the food stamps or authorization cards were issued through the mail to the individual recipient, then it follows that the coupons or cards were received by the recipient. ", "See, Elmore v. United States, 465 F.2d 1232 (4th Cir.1972) (the regularity of the mails is such that proof of mailing is prima facie proof of receipt by the addressee). ", "To require the Government to show that the recipient actually exercised dominion or some degree of control over the food stamps or authorization cards in addition to showing that the coupons or cards were issued imposes a greater burden of proof on the part of the Government than the statute calls for. ", "This Court thinks that such was not the intent of Congress. ", "So long as the Government shows that the participant intentionally makes knowingly false statements on the application which results in an overissuance of coupons to the recipient, then the Government has sustained its burden of proof under § 2024(b).", "\n\nB.\nWith this in mind, this Court must now determine whether the evidence was sufficient to support the jury's determination that the defendant knowingly acquired food stamps illegally. ", "The relevant question in this inquiry \"is whether, after viewing the evidence in the light most favorable to the prosecution, any rational trier of fact could have found the essential elements of the crime beyond a reasonable doubt.\" ", "Jackson v. Virginia, 443 U.S. 307, 319, 99 S.Ct. ", "2781, 2789, 61 L.Ed.2d 560 (1979).", "\nThe Government presented evidence to the effect that at the time defendant applied for food stamps at the Department of Social Services in Raleigh, North Carolina, she failed to report that she had been working for Manpower Temporary Services, Inc. on temporary assignments. ", "The Government's Exhibit # 1 was the food stamp application form which reflects defendant's signature on the form signifying that defendant understood all questions asked as well as the penalty warning. ", "Evidence of the checks that defendant received while working for Manpower, Inc. were also introduced into evidence. (", "Government's Exhibit # 3).", "\nMrs. Bonnie Bell, an investigator of food stamp fraud for the Department of Social Services described in detail the Government's Exhibit # 8, admitted into evidence. ", "She pointed out that the document evidenced the monetary value of food stamps actually received by the defendant and what she was entitled to receive. (", "Transcript of trial, pgs. ", "182-186). ", "Government's Exhibit # 8 reveals that during the period of the investigation (July 1980 through January 1981), the defendant was issued food stamps valued at $1212, when she was entitled to be issued only $496 worth of food coupons during this period. ", "The amount of overissuance equalled $716. ", "Moreover, Ms. Bell testified that the defendant was issued food stamps through the mail. (", "Transcript, pg. ", "184). ", "Clearly, the evidence shows that the defendant received more food stamps than she was legally entitled to. ", "It is also clear that the defendant was working for Manpower, Inc. before, during, and after the time she made application for food stamps on July 14, 1980. ", "Whether she knowingly misrepresented information on her application is a question of fact for the jury, not this Court, to decide.", "\nCertainly, the evidence in this case is not overwhelming. ", "And it is not for this Court to determine whether it believes the evidence *166 established guilt beyond a reasonable doubt. ", "Jackson v. Virginia, id. at 318-319, 99 S.Ct. ", "at 2788-2789. ", "This Court simply finds that the evidence in this case is sufficient to take it to the jury, and the jury could quite properly conclude that the defendant knowingly acquired food stamps or authorization cards in an unauthorized manner in contravention of § 2024(b). ", "Because the evidence is sufficient, the magistrate did not err in denying defendant's Motion for Judgment of Acquittal. ", "Defendant's last two assignments of error are without merit.", "\nFinding no error, the judgment is hereby AFFIRMED.", "\nNOTES\n[1] Defendant's argument that the Government should produce records indicating that defendant actually cashed the coupons or purchased goods thereto is without merit. ", "A defendant's use of food stamps or his transfer of them for money need not be shown in prosecution for a violation of § 2024(b). ", "United States v. French, 683 F.2d 1189 (8th Cir.), ", "cert. ", "denied, ___ U.S. ___, 103 S.Ct. ", "304, 74 L.Ed.2d 284 (1982).", "\n[2] Food stamp coupons are generally not issued by special delivery or registered mail unless there are repeated reports of nondelivery to the recipient. ", "See H.R.Rep. ", "No. ", "95-464, supra. ", "at 313, reprinted in 1977 U.S.Code Cong. & ", "Ad. ", "News, supra. ", "at 2249.", "\n" ]

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[ "\nIs there anything Google can do to solve the problem of slow Android updates? - ", "evo_9\nhttp://www.extremetech.com/computing/131749-is-there-anything-google-can-do-to-solve-the-problem-of-slow-android-updates\n======\nvibrunazo\nThe best they could do, they're already doing. ", "Which is decouple functionality\nfrom the core into updatable apps. ", "And develop the backward compatibility\nlibraries for developers. ", "In other OSes you usually have to wait for a whole\nsystem update to get small new features. ", "But google is often pushing updates\nto important apps. ", "iOS users have to wait for the new iOS to get the new maps\napp. ", "While android users are getting new updates even if they have old 2.x\ndevices. ", "So at the end of the day, how does it matter if the version number on\nyour device is low, if you're getting the latest features? ", "Of course, there's\nstill a lot to improve in this area. ", "More apps to decouple. ", "With ICS they\ndecoupled the browser for the first time by launching Chrome Beta. ", "This is\nhuge for future versions since the browser is the most important app on the\nphone. ", "And developing websites for android 2.x suck. ", "So they get the idea,\nhopefully they'll keep improving in that direction.", "\n\nThat said, can't google offer a service for OEMs to update their device\ndrivers using google's own engineers? ", "Say google charges X to have it's\nengineers drop not only the newest version source code on github at realease.", "\nBut also your device's updated drivers at your company's repository, by the\nrelease of a new android update. ", "Would that work?", "\n\n~~~\njonhendry\nPerhaps Google could pay the all or part of the wages of one or more engineers\nat each sizable OEM, with them dedicated to getting new versions running and\nshipped.", "\n\nGive them special training and support, maybe require the OEM to provide\nadditional engineers who would work with and be mentored by the Google-paid\nengineer(s).", "\n\nIt'd probably be worth the expense in the end.", "\n\n------\nkephra\n> This brings things full circle to the original question of what Google can\n> do to solve the problem of slow Android rollouts, and the answer might be\n> “nothing.”", "\n\nThere is one simple thing Google could do. ", "Disallow hardware vendors to lock\nthe kernel, and provide an Debian/apt-get like infrastructure that allows end\nusers to upgrade their phones themself.", "\n\nGoogle should start with Motorola, who is one of the most evil cases, where\nits impossible to install an own kernel. ", "E.g. all Motorola Defy+ ship with\ninsecure kernels. ", "They are ready for the trashcan at the date of delivery from\nsecurity standpoint.", "\n\n~~~\nphilwelch\nThis is a great solution for individual hackers to get upgradeable phones.", "\nThis is a shitty solution for fixing the platform fragmentation problem. ", "As an\nAndroid developer, less than 1% of your potential customer base are going to\nknow what to do with a solution that looks even remotely like apt-get.", "\n\nThe correct answer is to close down the platform with a stricter licensing\nagreement and provide over-the-air system updates from a central source.", "\n\n------\nkogir\nThe elephant in the room that nobody ever talks about is the linux kernel's\nlack of a stable ABI. ", "Windows and OS X drivers don't need to be recompiled\nevery time the kernel is updated, whereas in linux it's nearly always\nrequired.", "\n\nIf the same drivers would continue to work, Google could just update the\nsoftware like happens regularly on Windows and OS X.\n\nOh, and to head it off: Yes, it would be magical if all the device drivers\nwere open source and contributed back to the kernel proper. ", "But that's not\nhappening now, and likely never will. ", "Linux is under no obligation to provide\na stable ABI, but Google's choice to use it now has consequences.", "\n\n------\nGroxx\n> _What they reveal are cold, hard facts — such as, just 7.1% of active\n> Android users are currently sinking their teeth into ICS..._\n\ns/users/carriers/\n\nSeriously, carriers have _zero_ incentive to upgrade their users, unless they\nwish to define themselves as \"the carrier that upgrades Android devices\" (I\ndon't know of any). ", "Every software upgrade is a potential lost sale of a new,\nvery expensive, device + 2 year contract. _", "That_ is the cause of the\nextremely-high OS fragmentation, and it won't change until Google starts\nstrong-arming carriers into fixing it.", "\n\n~~~\nnradov\nSprint upgraded the Samsung Epic 2.1 → 2.2 → 2.3 (including multiple\nmaintenance releases)\n\n------\npieter\nIt would probably help a lot if they would develop Android in the open instead\nof dumping all changes once they release the OS.", "\n\n~~~\nwmf\nUgh, now I'm imagining phones that were built off a random git checkout\ninstead of an actual release.", "\n\n------\nrfolstad\nEventually consumers will figure out what most of this crowd probably knows\nalready. ", "If you want the best android phone experience with the cleanest\nimplementation and the most updates buy the phones produced / branded google.", "\n\n------\nk3n\nAlthough I'm having trouble locating it atm, I remember seeing an article a\nfew weeks ago saying that Google was going to become more active in the\nselling of phones, so as to circumvent this very problem.", "\n\nThey, too, are frustrated at the big providers not only taking their sweet\ntime, but also that they add in all of the bloatware seeing as both of these\npractices hurt Android, and ultimately, Google as well.", "\n\n------\ntrimbo\nHonestly, we'll probably find out in an hour or so. ", "I kind of doubt that\nGoogle will leave this issue alone at Google I/O. It's a huge one.", "\n\n~~~\nrogerbinns\nAt last years event they announced the update alliance. ", "That didn't work out\n<http://www.pcmag.com/article2/0,2817,2397729,00.asp>\n\n------\ngreedo\nShort of making it a requirement in the licensing to the carriers/vendors, I\ndon't see any way for Google to improve the situation. ", "The carriers have no\nincentive to provide or enable updates.", "\n\n------\nTwoBit\nI don't think most users care about this nearly as much as the tech community\nthinks. ", "All I care about is that my phone is reliable for the 2 or 3 years I\nhave it.", "\n\n------\ngte910h\nSure there is: Google could pay for updates out of store revenues.", "\n\n------\nwissler\nCarriers could pay Google a maintenance fee to port Android instead of trying\nto do it themselves.", "\n\n~~~\nwmf\nThen they would just not pay and not get any updates.", "\n\n~~~\nMiguelHudnandez\nRight -- Carriers might even resist _free_ updates from Google. ", "It's in\ncarriers' interests to have their users get frustrated with their old devices\nright around the two-year mark.", "\n\n" ]

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[ "No one ever told me about this. ", "My previous machine worked just fine with the long paralell cable (a PIII running first WIN98SE, then Ubuntu, then Debian).", "\n\nIts probably not a very commonly known failure area, if only because most people don't use very long parallel cables. ", "It will also vary depending on the way individual machines are designed. ", "In general, modern machines with more components packed into a relatively small space will probably be more susceptible because there is less space for heat to escape, not to mention higher heat output from CPUs and other components.", "\n\nQuote\n\nWhat diagnostics are available to me under VL? ", "If my parallel port is toasted, because of the cable or because of something else, is there a PCI card I can use to drive the printer? (", "I understand that Laserjet 4's can also run from Ethernet, though that takes extra hardware). ", "I really don't want to replace the whole motherboard. ", "I may as well just junk the computer.", "\n\nSorry, I have no idea what, if any diagnostics for this sort of problem would be available under Linux. ", "I use an (expensive) commercial test suite, and would probably have to build a loopback plug to test for this sort of problem.", "\n\nFinding a PCI card parallel card may be possible, but what may be a better (and cheaper) alternative might be to get a USB to parallel converter. ", "I picked one up for a customer a short while ago - he has an oldish Epson, but his nice new Dell doesn't have any parallel ports. ", "Cost about £5, and seems to work quite well.", "\n\nBefore you go and spend money, it would be useful to make sure that the problem is really hardware. ", "Maybe a local computer shop that could test the port for you? ", "Or maybe someone can suggest some hardware diagnostics that you can get to do the testing yourself?", "\n\nBut that point's moot. ", "Now every time I try to print something, I get no output at all, and an \"error\" message in the job viewer in the control center. ", "And I'm pretty sure that's because I mis-adjusted something, I know not what, and I don't know how to put things right again.", "\n\nCan you try some hardware diagnostics on the machine? ", "From the errors you are seeing, I would be worried about a hardware failure.", "\n\npaul.", "\n\nWhat diagnostics are available to me under VL? ", "If my parallel port is toasted, because of the cable or because of something else, is there a PCI card I can use to drive the printer? (", "I understand that Laserjet 4's can also run from Ethernet, though that takes extra hardware). ", "I really don't want to replace the whole motherboard. ", "I may as well just junk the computer.", "\n\nYou should be able to find so-called multifunction boards at a decent computer shop that have parallel ports on them. ", "If you get one of these boards, you may want to disable the onboard parallel port via the BIOS.", "\n\nAlso, I noticed that when I tried to make a test print from the CUPS GUI, I got a message: \"Permission denied\". ", "Obviously I need to reset a permission. ", "How do I do that?", "\n\nI just had a thought. ", "My old PIII had a nice, beefy 350-watt power supply. ", "Most reeady-made PC's like Dells have fairly wimpy power supplies (150 watts or something equally absurd in my Optiplex). ", "Dollars to doughnuts that's part of the problem.", "\n\nYou need to add yourself to the lp group so that you can access the printer, if you're not already in it. ", "Open a terminal and type groups at the prompt. ", "Here is a sample of the output for me on my box:\n\nYou need to add yourself to the lp group so that you can access the printer, if you're not already in it. ", "Open a terminal and type groups at the prompt. ", "Here is a sample of the output for me on my box:\n\nIf you don't see lp in the output for you, then you'll need to add yourself via the usermod command as root.", "\n\nHTH a bit,John\n\nI'm in the lp group, as far as I can see. ", "Here's what I got:\n\nusername lp floppy audio video cdrom games scanner users\n\nWhen logged in as root, the lp group does not appear in the output.", "\n\nWhat should I do? ", "And what is the proper syntax for the usermod command in this type of instance?", "\n\nAs for the USB to parallel interface, which brand do you recommend? ", "Would something like this device work? ", "I assume that for going over any real distance, I'd have to connect to the printer via a USB hub.", "\n\nThank you for the help you've given me thus far. ", "Just a couple of questions:\n\nWouldn't the presence in the computer-printer connection chain of a USB interface confuse the driver or the printer (to say nothing of the user! )? ", "Have you or anyone else here had any experience using a legacy parallel-port printer like the Laserjet 4 with a USB-to-parallel adapter?", "\n\nI tried printing a test page using the \"localhost\" method described here. ", "When I did, I got the following error screen, even though there were no jobs in the queue:\n\nWhen I tried performing a task which required a login, when I used the very same username and password which I use to log into my system every day, I got an authentication failure. (", "Logging in as root worked just fine, though I still couldn't fix things).", "\n\nOn other occasions, I got a \"permission denied\" screen. ", "There's obviously something funny going on here with permissions or software or both.", "\n\nI SO don't want to have to burn off all my data onto DVD's, wipe my hard drive clean and re-install VL from scratch. ", "But it seems to me like something, SOMEWHERE, I know not what or where has become corrupt, which I'll NEVER be able to pin down otherwise.", "\n\nI should also tell you that before I tried printing tonight, I switched my Dell's parallel port mode from PS/2 to EPP. ", "I did that after doing a little research on the web, thinking that it might solve my problem, but no such luck.", "\n\nThe machine apparently thinks that CUPS isn't installed, even though it seems to be, according to GSLAPT. ", "There are some unchecked entries in GSLAPT for CUPS. ", "Right-clicking on them pulls up only a \"downgrade\" option. ", "This whole thing just gets weirder and weirder!", "\n\nThat is one of the reasons I really don't much like Gslapt. ", "If it is offering you a downgrade, it means that there is a more recent version installed. ", "It just doesn't make it very clear in its display, and shows all versions in the repos, which I find most confusing..." ]

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[ "A Historic New Jersey Cemetery Sits Neglected and Blighted\n\nImage\n\nWoodland Cemetery, which opened in 1855. “", "The cemetery has been failing our community for decades,” a resident says.", "CreditChristopher Occhicone for The New York Times\n\nBy Noah Remnick\n\nMarch 19, 2017\n\nNEWARK — Every Mother’s Day, Ann Jeffress and her two sisters have come to Woodland Cemetery here to lay a rose at the grave of their mother, Lucy. ", "The visits were never easy, but now they have become traumatic in ways they never imagined. ", "When the women enter the cemetery, they walk hand in hand, clutching sticks to fend off dogs or potential attackers. ", "They poke cautiously through mounds of rubble in search of the spot where their mother was laid to rest.", "\n\nA once illustrious cemetery where over 80,000 people have been buried, and with a history dating to Newark’s heyday in the 19th century, Woodland has fallen into a bleak state of disrepair. ", "These days, the cemetery is a blight on a neighborhood striving for renewal, a magnet for crime and garbage.", "\n\nWoodland’s 37 sloping acres are choked with chest-high weeds. ", "Its gatehouse is crumbling, much of its fence is broken and many headstones have been toppled or vandalized. ", "Lucy Jeffress struggled to raise her family on a housekeeper’s salary — now her gravestone lies cracked on the ground.", "\n\nAnn Jeffress said that she had called the cemetery’s management repeatedly, but that her entreaties, like those of many other relatives of those buried there, had gone unanswered or unheeded.", "\n\n“I feel like we were cheated,” Ms. Jeffress, 73, said. “", "We put our mother there to rest in peace, but instead she was desecrated.”", "\n\nThere have been many calls to revive Woodland, but they have all sputtered. ", "The board that runs Woodland says the privately operated cemetery is grappling with unavoidable financial challenges. ", "But many of those who have grown concerned about Woodland believe otherwise and have filed a formal complaint with a state agency accusing the board of financial mismanagement. ", "They also argue that a board made up entirely of white people from out of town has fallen out of touch with the community it was meant to serve.", "\n\nImage\n\nCreditChristopher Occhicone for The New York Times\n\nSome elected officials blame the State of New Jersey, which, unlike many other states, does not provide financial help for decrepit graveyards.", "\n\n“It’s not a direct city responsibility. ", "It’s not a direct county responsibility; it’s not a direct state responsibility, so everyone lets themselves off the hook,” said State Senator Ronald L. Rice, a Democrat whose district includes Woodland. “", "And, meanwhile, the cemetery is a wreck that runs down the entire neighborhood.”", "\n\nJudy Welshons, the executive director of the nonprofit New Jersey Cemetery Association, estimated that there were as many as 100 financially or physically distressed cemeteries in the state. “", "But none are quite as big or as legendary as Woodland,” she said. “", "This is a disturbing and unusual case.”", "\n\nThe trajectory of Woodland largely mirrors the history of Newark itself. ", "The city was in the midst of an industrial boom when the cemetery opened in 1855, drawing throngs of European immigrants. ", "Woodland was designed as a garden-style cemetery with rolling hills, winding dirt pathways and a Gothic Revival gatehouse that made the cemetery an unofficial city landmark. ", "In its early years, many of those buried were Germans; over time came immigrants from Ireland, Greece, Italy and Eastern Europe.", "\n\nAfrican-Americans were also admitted to Woodland, but, as in many cemeteries, their interments were commonly held in a separate section until the 1960s. ", "Woodland’s broader integration coincided with a wave of white flight from Newark, and the cemetery soon catered predominantly to black residents.", "\n\nAmong those buried there is Ike Abrams Quebec, a renowned African-American jazz saxophonist. ", "Woodland also became the final resting place for hundreds of veterans of conflicts stretching from the War of 1812 through the Vietnam War.", "\n\nBut as the social fabric of the city began to fray in the middle of the last century — a combination of deindustrialization, discriminatory lending and racial unrest that culminated in the 1967 riots — Woodland deteriorated as well.", "\n\nImage\n\nThe board that runs Woodland says it is facing financial challenges.", "CreditChristopher Occhicone for The New York Times\n\n“It became a tough area, and the burials just started dwindling,” said Mary Lish, 65, a retired court clerk who has studied the cemetery’s history. “", "Soon enough, everyone began to turn a blind eye to the place.”", "\n\nBy the 1980s, Woodland had degenerated into squalor. ", "Amid the fallen headstones and mounds of trash, drug dealers sold their wares, prostitutes solicited clients, homeless people set up camp and stray dogs ran wild.", "\n\nMurders occur within the cemetery and in the surrounding blocks, a mostly African-American and low-income section of the city’s West Side dotted with modest clapboard houses, not far from the commercial strip of Springfield Avenue. (", "Only a few weeks ago, a man was found shot to death just outside the cemetery.)", "\n\n“This is supposed to be a sacred place, and instead it’s one of the worst parts of the city,” said John S. James, a member of the city council.", "\n\nOfficials have long implored the city to help. ", "As early as 1988, records show, the council described “deplorable conditions” at Woodland and sought financing from the mayor, Sharpe James. ", "When those appeals failed, they turned to the state, repeatedly asking the New Jersey Cemetery Board, which regulates cemeteries, to help Woodland.", "\n\n“It’s in a crisis situation,” Donald Bradley, the council president, wrote in 1997. ", "In 2003, the council even urged the city to sue the state cemetery board for failure to maintain Woodland.", "\n\nA spokesman for the State Division of Consumer Affairs, which oversees the board, said that the board “cannot comment on the reasons why Woodland has been in disrepair,” and that it did not have the authority to provide aid to cemeteries.", "\n\nImage\n\nDespite volunteer cleanup efforts, trash is often found in the 37-acre cemetery.", "CreditChristopher Occhicone for The New York Times\n\nWhile many states require cemeteries to contribute to a fund for distressed or abandoned graveyards, New Jersey does not. ", "Efforts to establish such a fund have languished in the State Senate.", "\n\nWithout help, the Woodland board says it is trapped in a vicious financial cycle.", "\n\n“We’re caught in a Catch-22,” said Rosemary Hilbert, the board president. “", "We can’t tend to the cemetery until we get more money, and we can’t get more money until we tend to the cemetery.”", "\n\nBut some critics claim that Woodland’s problems are more insidious. ", "Last year, Karima Jackson, a graduate student at Rutgers University and a lifelong Newark resident, filed a complaint against the cemetery’s board with the Division of Consumer Affairs claiming financial mismanagement, regulatory violations and a lack of transparency.", "\n\n“The cemetery has been failing our community for decades, and no one has held them accountable,” said Ms. Jackson, 38, whose great-grandfather is buried in Woodland.", "\n\nMs. Hilbert denied Ms. Jackson’s assertions, calling her “an agitator with an agenda.” ", "She said the cemetery was steadily moving forward with its own restoration plan.", "\n\nCity officials say there is little they can do since Woodland is run privately.", "\n\nMs. Jackson has led a group of local volunteers called Organize Change on weekly cleanups of the cemetery. ", "Ms. Hilbert initially seemed receptive to the effort, but the relationship soured after Ms. Jackson began questioning management of the cemetery and lobbied to become a board member.", "\n\nThe board has not held an annual meeting, as required by the state, since January 2015, and Ms. Jackson said it had refused to consider new members since she and several other community activists submitted applications last year. (", "The board has scheduled a meeting for late April.)", "\n\nImage\n\nMany of the cemetery’s headstones have been toppled or vandalized.", "CreditChristopher Occhicone for The New York Times\n\nThe activists, all of whom are black residents of Newark, also question why the current six-person Woodland board is made up of white people who do not live in the city. ", "They see their stymied membership efforts as part of a longer history of black exclusion from the Woodland board.", "\n\n“Any time a black person spoke out, we got the boot,” said Keith Bush, a Newark resident who said he had been kicked off the board after filing a complaint against it. “", "I hate the race card, but it is what it is.”", "\n\nMs. Hilbert acknowledged that there used to be several black people on the board, but rejected any suggestion that there was a racial problem. ", "She said the board intended to add African-American members soon.", "\n\n“The race card is the last card they play, but it’s not an issue with us,” she said.", "\n\nAfter Ms. Jackson submitted her complaint to the state, the situation became more heated, culminating in a fistfight in the cemetery between Warren Vincentz, a Woodland board member, and Horatio Joines, an Organize Change member and Ms. Jackson’s fiancé. ", "Ms. Hilbert stopped allowing the group into the cemetery, though Ms. Jackson has still managed to lead several cleanups.", "\n\nThough Ms. Jackson filed her initial complaint in February 2016, her claim remains unresolved. ", "The spokesman for the Division of Consumer Affairs would not comment on the complaint.", "\n\nWith no resolution in sight, the families of those buried at Woodland are left frustrated at how a problem they consider so egregious is allowed to fester.", "\n\nOne afternoon last fall, Vera Jones, a bookkeeper from Newark, tried to visit the cemetery to lay flowers at her mother’s grave. ", "The sight of fractured headstones and overgrown weeds was so dismaying that she turned around and drove back home.", "\n\n“The city? ", "The state?’’ ", "asked Ms. Jones, 52. “", "No one can do anything?”", "\n\nA version of this article appears in print on , on Page A21 of the New York edition with the headline: A Final Resting Place, and a Haven for Crime. ", "Order Reprints | Today’s Paper | Subscribe\n\nSign up for the New York Today Newsletter\n\nEach morning, get the latest on New York businesses, arts, sports, dining, style and more." ]

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[ "Share 31 Shares\n\nThis analysis on Aragon (ANT) was first published in our FB Group called, “Master The Crypto: Advanced Cryptocurrency Knowledge” on the 23rd of August 2017. ", "At the time of publication, it was trading near USD $2.50, and is currently trading at USD $3.", "\n\nThis represents the writer’s personal opinions and does not – in any way- constitute a recommendation of an investment or financial advice. ", "Please assume caution when investing in cryptocurrencies and do so at your own risk, as it is extremely volatile and you can lose your money.", "\n\nWhat is Aragon?", "\n\nAragon is a decentralized management platform built on Ethereum that allows anyone to create and manage organisations. ", "More specifically, you can build Decentralised Autonomous Organisations (DAOs) complete with basic features of an organization like a cap table management, token transfers, voting, role assignments, payroll, fundraising, and accounting. ", "Basically, Aragon wants to dis-intermediate (remove intermediaries within the traditional organizational setting). ", "And the best part is that their platform aims to be extremely easy to use for non-coders. (", "See also: A Guide To Fundamental Analysis For Cryptocurrencies)\n\nUnique Differentiator\n\nDecentralized arbitration The platform will feature a decentralized court mechanism to settle disputes, which aims to solve human-related problems which arise during DAO governance.(i.e. ", "disputes between 2 parties). ", "ANT token holders get to vote on basic rules the arbitration system will adhere to, thereby leveraging on its network effects. ", "Upgradeability A central concept to upgradeability in blockchain is modularity. ", "Aragon recognizes that different organization may have different needs, and in order to cater to custom-requirements, they’ve built Aragon as a modular system that allows additional functionalities to be developed on top of Aragon platform. ", "Simplicity More importantly, Aragon’s platform will not require technical coding skills for anyone to create smart contracts for their DAOS, thereby simplifying the entire process. ", "This simplification is what’s powerful; it has the potential to precipitate mass adoption of the tech.", "\n\nUtility of ANT Tokens\n\nUnlike many projects that leverages blockchain as a secondary component, Aragon uses blockchain to actualize a potentially game-changing idea; decentralizing how organisations, at a micro level (say trade between me and you), function by breaking down the intermediary elements. ", "Not only does it bring a greater level of efficiency, transparency and reduction of costs, but at a deeper level, it’s an ideological goal. (", "Read also: Beginner’s Guide to ICO Investing: How to Participate in ICOs)\n\nThe ANT token will be used to govern each aspect of its functioning of the Aragon Network by allowing token holders to have voting rights & access rights.", "\n\nIt's circulating supply is at 33,605,167 ANT while its total supply will stand at 39,609,523. ", "Aragon employs a Continuous Token Model, whereby ANT tokens will continue to be minted by the AN following ICO and network deployment sometimes in 2018. ", "The total supply will be constant only until the AN (Aragon Network) is deployed. ", "From then on, ANG (AN governance) will decide the monetary policy and inflation rate going forward. (", "See more: Coins, Tokens & Altcoins: What’s the Difference?)", "\n\nTeam\n\nThe Aragon team is headed by Luis Cuende and Jorge Izquierdo. ", "Luis was listed in Forbes 30 Under 30 and MIT Tech review, which represents a great accolade. ", "He founded Stampery, a time-stamping project in the Blockchain ecosystem. ", "His has experience working with the likes of the Estonian government, Microsoft and Telefonica. ", "Jorge on the other hand is also a tech prodigy. ", "Having created various popular applications, with accolades ranging from receiving a Thiel fellowship and a WWDC scholarship by Apple at a tender age of 15 as one of the most promising young app developers. (", "Read also: Guide on Identifying Scam Coins)\n\nAragon has a high degree of professionalism, with timely developer updates, adherence to their timeline and communicating relevant information through their official slack channel.", "\n\nAdvisors\n\nThe advisors are well-known blockchain world entrepreneurs, which include Jake Brukhman, co-founder of CoinFund, Kenny Rowe, COO of Dai Foundation, Brayton Williams, founding partner at Boost VC. ", "It's quite an impressive list.", "\n\nTraction\n\nAragon’s Token Sale raised $25 Million in 15 Minutes, which is a testament to the potential of their vision. ", "Since February, the number of Aragon organizations deployed to their testnet has grown from 130 to more than 770! ", "In addition, the Aragon Slack channel now comprises over 500 community members and the platform is available for Linux, MacOS, Windows and web browsers.", "\n\nCompetitors\n\nOtonomos: The Otonomos project incorporates legal entities online in a given number of jurisdictions. ", "Aragon is “legal-entity agnostic” as the team puts it; It's not linked to any specific jurisdictions and is to be used by organizations regardless of their legal status.", "\n\nBoardroom: Aragon is a product-focused company that offers corporate governance solutions, while Boardroom is researching governance solutions with a broader focus\n\nRoad-Map\n\n1) Initial Release: Released the private Alpha (MAC OS) on Feb before their ICO on May, with great reviews on user experience. ", "Covers basic functionalities for organisations\n\n2) Public Alpha: Released to the public on the following month in March, with a focus on user interface styling\n\n3) Governance Release: Released in April and focuses on the interoperability with other ERC-20 tokens within the ANT ecosystem (See also: Guide to Cryptocurrency Wallets: Opening a MyEtherWallet (MEW)\n\n4) Money Release: Expected to be released on Nov-Dec. A major developmental upgrade since the first Mainnet Aragon organizations to be deployed will use this version of the contracts at the end of the year\n\n5) Modular Release: Expected release by Dec as well, with a focus on enhancing its modularity and second layer protocol for APIs\n\n6) Upgradeable Release: Expected release on Feb 2018, with a focus on upgradeability within Ethereum blockchain (See also: What's the Difference Between Ethereum and Ethereum Classic?)", "\n\n7) Network Release: Expected release on May 2018 with a focus on Basic network-wide governance, ANT token minting and Integrate upgradeability\n\n8) The Court Release: Deployment to the main net on Q4 2018 with a focus on the establishment of the Aragon jurisdiction\n\n9) Unknown Release: UNKNOWN\n\nPossible Issue\n\nTechnical implementation for some future components still needs to be found (e.g. for a decentralized arbitrage system), and the full source code is not published yet. (", "See also: Dangers in Cryptocurrency Investing)\n\nTechnical Analysis\n\nAragon’s price hasn’t been performing very well, currently testing the support at 0.0006. ", "It has been consolidating at that resistance line for weeks, and is poised to break out towards the upside after the resistance trendline is broken. ", "MACD looks like ins venturing into the positive side, while the RSI looks to be neutral. ", "An increase in volume could potentially shoot Aragon’s price upwards, and after months of consolidation, the next push can be big.", "\n\nSummary\n\nA young team with a great vision of not only what they’re building, but also the direction of the ecosystem. ", "Their pragmatic vision and foresight is substantiated by Aragon’s core components of integrating an arbitration jurisdiction, as well as building a modular platform. ", "If they live up to their development plans, there is great potential for them to shape the DAO ecosystem in the future.", "\n\nVerdict: Great Project\n\nYou might also be interested in Cryptocurrency Review: Analysis on Factom\n\nThis represents the writer’s personal opinions and does not – in any way- constitute a recommendation of an investment or financial advice. ", "Please assume caution when investing in cryptocurrencies and do so at your own risk, as it is extremely volatile and you can lose your money.", "\n\nEnroll in our Free Cryptocurrency Webinar now to learn everything you need to know about crypto investing.", "\n\nGet our exclusive e-book which will guide you on the step-by-step process to get started with making money via Cryptocurrency investments!", "\n\nYou can also join our Facebook group at Master The Crypto: Advanced Cryptocurrency Knowledge to ask any questions regarding cryptos!", "\n\nReferences\n\nAragon’s White Paper\n\nAragon’s Development Roadmap" ]

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[ "This video stitches together nine separate videos about energy sources (hydro, coal, geothermal, nuclear, wind, biofuels, solar, natural gas, and oil) from the Switch Energy site. ", "Videos can be viewed as a group, or separately, each under their own title.", "\n\nThis video is one of a series from the Switch Energy project. ", "It presents pros and cons of hydraulic fracturing, or fracking. ", "In this video, new fracking technologies are presented as more economical and environmentally safe.", "\n\nThis video is one of a series from the Switch Energy project. ", "It reviews the environmental impacts of various energy resources including fossil fuels, nuclear, and renewables. ", "CO2 emissions as a specific environmental impact are discussed.", "\n\nThis video from the U.S. National Academies summarizes the energy challenges the United States faces, the technological challenges, and the need for behavior and policy changes required to meet the challenge.", "\n\nThis Energy Flow Charts website is a set of energy Sankey diagrams or flow charts for 136 countries constructed from data maintained by the International Energy Agency (IEA) and reflects the energy use patterns for 2007." ]

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[ "TAAN launches technology division of TBI\n\nDUBAI, January 21, 2016\n\nTAAN Worldwide, a leading network of carefully selected independent advertising and communications agencies, has launched 'Accelerate,' the technology division of The Big Idea (TBI).", "\n\nIt seeks to combine creativity with technology and bring about a revolution in the world experiences socio-digital platforms, said a statement.", "\n\nPeter Gerritsen, president, TAAN Network, said: “In the last decade, web, mobile and cloud technologies have transformed the way we communicate and influence consumer behavior. ", "TAAN worldwide network is built on the concept that shared knowledge, technology and intelligence creates powerful insight in addressing the goals of agencies and marketers throughout the world.", "\n\n\"It is a well-known fact that the UAE and other Gulf countries are early adopters of any new technology and I am confident that TBI’s Accelerate will help marketers connect the dots.”", "\n\nTBI’s latest prodigy 'Accelerate' will have an innovation lab and will develop its own tech products that will include enterprise mobility solutions, mobile apps, and gamification and e-commerce platforms.", "\n\nHoshi Siganporia, chief executive officer, TBI, said: “The convergence of creativity and technology have resulted in creating richer and more impactful experiences. ", "We are now living in a more intelligent world and run of the mill print, TV and radio ads are going to be less effective.", "\n\n\"Accelerate will use technology to bridge the gap between the creative big idea and the always-on social and digital channels.”", "\n\nAccelerate’s service offerings will include customised solutions for small and mid-size enterprises, said the statement.", "\n\nThe focus will be to create technology solutions to enhance customer experiences and improve collaboration and productivity within an enterprise, it added. - ", "TradeArabia News Service" ]

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[ 0.012048192771084338, 0, 0.0111731843575419, 0, 0.005405405405405406, 0.004830917874396135, 0.011976047904191617, 0, 0, 0, 0, 0.041666666666666664 ]

[ { "analysis_explanation": null, "end": 47, "entity_type": "LOCATION", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 42 }, { "analysis_explanation": null, "end": 65, "entity_type": "DATE_TIME", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 49 }, { "analysis_explanation": null, "end": 409, "entity_type": "PERSON", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 394 }, { "analysis_explanation": null, "end": 461, "entity_type": "DATE_TIME", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 446 }, { "analysis_explanation": null, "end": 803, "entity_type": "LOCATION", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 800 }, { "analysis_explanation": null, "end": 818, "entity_type": "LOCATION", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 814 }, { "analysis_explanation": null, "end": 1172, "entity_type": "PERSON", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 1156 } ]

[ "Borsodi RC Modell Fórum event 2017\n\nIn 2017 Borsodi RC Modell Fórum has organized few events with different title, car, boat, FPV, airplane and helicopter in May, June and December. ", "Thanks Attila Krajcz provide a lot of photos of the events." ]

{ "pile_set_name": "Pile-CC" }

[ 0.02197802197802198, 0.01694915254237288 ]

[ { "analysis_explanation": null, "end": 34, "entity_type": "DATE_TIME", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 30 }, { "analysis_explanation": null, "end": 43, "entity_type": "DATE_TIME", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 39 }, { "analysis_explanation": null, "end": 167, "entity_type": "DATE_TIME", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 158 }, { "analysis_explanation": null, "end": 180, "entity_type": "DATE_TIME", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 172 }, { "analysis_explanation": null, "end": 202, "entity_type": "PERSON", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 189 } ]

[ "// Copyright 2013 The Go Authors. ", "All rights reserved.", "\n// Use of this source code is governed by a BSD-style\n// license that can be found in the LICENSE file.", "\n\npackage language\n\nimport (\n\t\"bytes\"\n\t\"errors\"\n\t\"fmt\"\n\t\"sort\"\n\t\"strconv\"\n\t\"strings\"\n\n\t\"golang.org/x/text/internal/tag\"\n)\n\n// isAlpha returns true if the byte is not a digit.", "\n// b must be an ASCII letter or digit.", "\nfunc isAlpha(b byte) bool {\n\treturn b > '9'\n}\n\n// isAlphaNum returns true if the string contains only ASCII letters or digits.", "\nfunc isAlphaNum(s []byte) bool {\n\tfor _, c := range s {\n\t\tif !('", "a' <= c && c <= 'z' || 'A' <= c && c <= 'Z' || '0' <= c && c <= '9') {\n\t\t\treturn false\n\t\t}\n\t}\n\treturn true\n}\n\n// errSyntax is returned by any of the parsing functions when the\n// input is not well-formed, according to BCP 47.", "\n// TODO: return the position at which the syntax error occurred?", "\nvar errSyntax = errors.", "New(\"language: tag is not well-formed\")\n\n// ValueError is returned by any of the parsing functions when the\n// input is well-formed but the respective subtag is not recognized\n// as a valid value.", "\ntype ValueError struct {\n\tv [8]byte\n}\n\nfunc mkErrInvalid(s []byte) error {\n\tvar e ValueError\n\tcopy(e.v[:], s)\n\treturn e\n}\n\nfunc (e ValueError) tag() []byte {\n\tn := bytes.", "IndexByte(e.v[:], 0)\n\tif n == -1 {\n\t\tn = 8\n\t}\n\treturn e.v[:n]\n}\n\n// Error implements the error interface.", "\nfunc (e ValueError) Error() string {\n\treturn fmt.", "Sprintf(\"language: subtag %q is well-formed but unknown\", e.tag())\n}\n\n// Subtag returns the subtag for which the error occurred.", "\nfunc (e ValueError) Subtag() string {\n\treturn string(e.tag())\n}\n\n// scanner is used to scan BCP 47 tokens, which are separated by _ or -.", "\ntype scanner struct {\n\tb []byte\n\tbytes [max99thPercentileSize]byte\n\ttoken []byte\n\tstart int // start position of the current token\n\tend int // end position of the current token\n\tnext int // next point for scan\n\terr error\n\tdone bool\n}\n\nfunc makeScannerString(s string) scanner {\n\tscan := scanner{}\n\tif len(s) <= len(scan.bytes) {\n\t\tscan.b = scan.bytes[:copy(scan.bytes[:], s)]\n\t} else {\n\t\tscan.b = []byte(s)\n\t}\n\tscan.init()\n\treturn scan\n}\n\n// makeScanner returns a scanner using b as the input buffer.", "\n// b is not copied and may be modified by the scanner routines.", "\nfunc makeScanner(b []byte) scanner {\n\tscan := scanner{b: b}\n\tscan.init()\n\treturn scan\n}\n\nfunc (s *scanner) init() {\n\tfor i, c := range s.b {\n\t\tif c == '_' {\n\t\t\ts.b[i] = '-'\n\t\t}\n\t}\n\ts.scan()\n}\n\n// restToLower converts the string between start and end to lower case.", "\nfunc (s *scanner) toLower(start, end int) {\n\tfor i := start; i < end; i++ {\n\t\tc := s.b[i]\n\t\tif 'A' <= c && c <= 'Z' {\n\t\t\ts.b[i] += 'a' - 'A'\n\t\t}\n\t}\n}\n\nfunc (s *scanner) setError(e error) {\n\tif s.err == nil || (e == errSyntax && s.err !", "= errSyntax) {\n\t\ts.err = e\n\t}\n}\n\n// resizeRange shrinks or grows the array at position oldStart such that\n// a new string of size newSize can fit between oldStart and oldEnd.", "\n// Sets the scan point to after the resized range.", "\nfunc (s *scanner) resizeRange(oldStart, oldEnd, newSize int) {\n\ts.start = oldStart\n\tif end := oldStart + newSize; end !", "= oldEnd {\n\t\tdiff := end - oldEnd\n\t\tif end < cap(s.b) {\n\t\t\tb := make([]byte, len(s.b)+diff)\n\t\t\tcopy(b, s.b[:oldStart])\n\t\t\tcopy(b[end:], s.b[oldEnd:])\n\t\t\ts.b = b\n\t\t} else {\n\t\t\ts.b = append(s.b[end:], s.b[oldEnd:]...)\n\t\t}\n\t\ts.next = end + (s.next - s.end)\n\t\ts.end = end\n\t}\n}\n\n// replace replaces the current token with repl.", "\nfunc (s *scanner) replace(repl string) {\n\ts.resizeRange(s.start, s.end, len(repl))\n\tcopy(s.b[s.start:], repl)\n}\n\n// gobble removes the current token from the input.", "\n// Caller must call scan after calling gobble.", "\nfunc (s *scanner) gobble(e error) {\n\ts.setError(e)\n\tif s.start == 0 {\n\t\ts.b = s.b[:+copy(s.b, s.b[s.next:])]\n\t\ts.end = 0\n\t} else {\n\t\ts.b = s.b[:s.start-1+copy(s.b[s.start-1:], s.b[s.end:])]\n\t\ts.end = s.start - 1\n\t}\n\ts.next = s.start\n}\n\n// deleteRange removes the given range from s.b before the current token.", "\nfunc (s *scanner) deleteRange(start, end int) {\n\ts.setError(errSyntax)\n\ts.b = s.b[:start+copy(s.b[start:], s.b[end:])]\n\tdiff := end - start\n\ts.next -= diff\n\ts.start -= diff\n\ts.end -= diff\n}\n\n// scan parses the next token of a BCP 47 string. ", " Tokens that are larger\n// than 8 characters or include non-alphanumeric characters result in an error\n// and are gobbled and removed from the output.", "\n// It returns the end position of the last token consumed.", "\nfunc (s *scanner) scan() (end int) {\n\tend = s.end\n\ts.token = nil\n\tfor s.start = s.next; s.next < len(s.b); {\n\t\ti := bytes.", "IndexByte(s.b[s.next:], '-')\n\t\tif i == -1 {\n\t\t\ts.end = len(s.b)\n\t\t\ts.next = len(s.b)\n\t\t\ti = s.end - s.start\n\t\t} else {\n\t\t\ts.end = s.next + i\n\t\t\ts.next = s.end + 1\n\t\t}\n\t\ttoken := s.b[s.start:s.end]\n\t\tif i < 1 || i > 8 || !", "isAlphaNum(token) {\n\t\t\ts.gobble(errSyntax)\n\t\t\tcontinue\n\t\t}\n\t\ts.token = token\n\t\treturn end\n\t}\n\tif n := len(s.b); n > 0 && s.b[n-1] == '-' {\n\t\ts.setError(errSyntax)\n\t\ts.b = s.b[:len(s.b)-1]\n\t}\n\ts.done = true\n\treturn end\n}\n\n// acceptMinSize parses multiple tokens of the given size or greater.", "\n// It returns the end position of the last token consumed.", "\nfunc (s *scanner) acceptMinSize(min int) (end int) {\n\tend = s.end\n\ts.scan()\n\tfor ; len(s.token) >= min; s.scan() {\n\t\tend = s.end\n\t}\n\treturn end\n}\n\n// Parse parses the given BCP 47 string and returns a valid Tag. ", "If parsing\n// failed it returns an error and any part of the tag that could be parsed.", "\n// If parsing succeeded but an unknown value was found, it returns\n// ValueError. ", "The Tag returned in this case is just stripped of the unknown\n// value. ", "All other values are preserved. ", "It accepts tags in the BCP 47 format\n// and extensions to this standard defined in\n// http://www.unicode.org/reports/tr35/#Unicode_Language_and_Locale_Identifiers.", "\n// The resulting tag is canonicalized using the default canonicalization type.", "\nfunc Parse(s string) (t Tag, err error) {\n\treturn Default.", "Parse(s)\n}\n\n// Parse parses the given BCP 47 string and returns a valid Tag. ", "If parsing\n// failed it returns an error and any part of the tag that could be parsed.", "\n// If parsing succeeded but an unknown value was found, it returns\n// ValueError. ", "The Tag returned in this case is just stripped of the unknown\n// value. ", "All other values are preserved. ", "It accepts tags in the BCP 47 format\n// and extensions to this standard defined in\n// http://www.unicode.org/reports/tr35/#Unicode_Language_and_Locale_Identifiers.", "\n// The resulting tag is canonicalized using the the canonicalization type c.\nfunc (c CanonType) Parse(s string) (t Tag, err error) {\n\t// TODO: consider supporting old-style locale key-value pairs.", "\n\tif s == \"\" {\n\t\treturn und, errSyntax\n\t}\n\tif len(s) <= maxAltTaglen {\n\t\tb := [maxAltTaglen]byte{}\n\t\tfor i, c := range s {\n\t\t\t// Generating invalid UTF-8 is okay as it won't match.", "\n\t\t\tif 'A' <= c && c <= 'Z' {\n\t\t\t\tc += 'a' - 'A'\n\t\t\t} else if c == '_' {\n\t\t\t\tc = '-'\n\t\t\t}\n\t\t\tb[i] = byte(c)\n\t\t}\n\t\tif t, ok := grandfathered(b); ok {\n\t\t\treturn t, nil\n\t\t}\n\t}\n\tscan := makeScannerString(s)\n\tt, err = parse(&scan, s)\n\tt, changed := t.canonicalize(c)\n\tif changed {\n\t\tt.remakeString()\n\t}\n\treturn t, err\n}\n\nfunc parse(scan *scanner, s string) (t Tag, err error) {\n\tt = und\n\tvar end int\n\tif n := len(scan.token); n <= 1 {\n\t\tscan.toLower(0, len(scan.b))\n\t\tif n == 0 || scan.token[0] !", "= 'x' {\n\t\t\treturn t, errSyntax\n\t\t}\n\t\tend = parseExtensions(scan)\n\t} else if n >= 4 {\n\t\treturn und, errSyntax\n\t} else { // the usual case\n\t\tt, end = parseTag(scan)\n\t\tif n := len(scan.token); n == 1 {\n\t\t\tt.pExt = uint16(end)\n\t\t\tend = parseExtensions(scan)\n\t\t} else if end < len(scan.b) {\n\t\t\tscan.setError(errSyntax)\n\t\t\tscan.b = scan.b[:end]\n\t\t}\n\t}\n\tif int(t.pVariant) < len(scan.b) {\n\t\tif end < len(s) {\n\t\t\ts = s[:end]\n\t\t}\n\t\tif len(s) > 0 && tag.", "Compare(s, scan.b) == 0 {\n\t\t\tt.str = s\n\t\t} else {\n\t\t\tt.str = string(scan.b)\n\t\t}\n\t} else {\n\t\tt.pVariant, t.pExt = 0, 0\n\t}\n\treturn t, scan.err\n}\n\n// parseTag parses language, script, region and variants.", "\n// It returns a Tag and the end position in the input that was parsed.", "\nfunc parseTag(scan *scanner) (t Tag, end int) {\n\tvar e error\n\t// TODO: set an error if an unknown lang, script or region is encountered.", "\n\tt.lang, e = getLangID(scan.token)\n\tscan.setError(e)\n\tscan.replace(t.lang.", "String())\n\tlangStart := scan.start\n\tend = scan.scan()\n\tfor len(scan.token) == 3 && isAlpha(scan.token[0]) {\n\t\t// From http://tools.ietf.org/html/bcp47, <lang>-<extlang> tags are equivalent\n\t\t// to a tag of the form <extlang>.", "\n\t\tlang, e := getLangID(scan.token)\n\t\tif lang !", "= 0 {\n\t\t\tt.lang = lang\n\t\t\tcopy(scan.b[langStart:], lang.", "String())\n\t\t\tscan.b[langStart+3] = '-'\n\t\t\tscan.start = langStart + 4\n\t\t}\n\t\tscan.gobble(e)\n\t\tend = scan.scan()\n\t}\n\tif len(scan.token) == 4 && isAlpha(scan.token[0]) {\n\t\tt.script, e = getScriptID(script, scan.token)\n\t\tif t.script == 0 {\n\t\t\tscan.gobble(e)\n\t\t}\n\t\tend = scan.scan()\n\t}\n\tif n := len(scan.token); n >= 2 && n <= 3 {\n\t\tt.region, e = getRegionID(scan.token)\n\t\tif t.region == 0 {\n\t\t\tscan.gobble(e)\n\t\t} else {\n\t\t\tscan.replace(t.region.", "String())\n\t\t}\n\t\tend = scan.scan()\n\t}\n\tscan.toLower(scan.start, len(scan.b))\n\tt.pVariant = byte(end)\n\tend = parseVariants(scan, end, t)\n\tt.pExt = uint16(end)\n\treturn t, end\n}\n\nvar separator = []byte{'-'}\n\n// parseVariants scans tokens as long as each token is a valid variant string.", "\n// Duplicate variants are removed.", "\nfunc parseVariants(scan *scanner, end int, t Tag) int {\n\tstart := scan.start\n\tvarIDBuf := [4]uint8{}\n\tvariantBuf := [4][]byte{}\n\tvarID := varIDBuf[:0]\n\tvariant := variantBuf[:0]\n\tlast := -1\n\tneedSort := false\n\tfor ; len(scan.token) >= 4; scan.scan() {\n\t\t// TODO: measure the impact of needing this conversion and redesign\n\t\t// the data structure if there is an issue.", "\n\t\tv, ok := variantIndex[string(scan.token)]\n\t\tif !", "ok {\n\t\t\t// unknown variant\n\t\t\t// TODO: allow user-defined variants?", "\n\t\t\tscan.gobble(mkErrInvalid(scan.token))\n\t\t\tcontinue\n\t\t}\n\t\tvarID = append(varID, v)\n\t\tvariant = append(variant, scan.token)\n\t\tif !", "needSort {\n\t\t\tif last < int(v) {\n\t\t\t\tlast = int(v)\n\t\t\t} else {\n\t\t\t\tneedSort = true\n\t\t\t\t// There is no legal combinations of more than 7 variants\n\t\t\t\t// (and this is by no means a useful sequence).", "\n\t\t\t\tconst maxVariants = 8\n\t\t\t\tif len(varID) > maxVariants {\n\t\t\t\t\tbreak\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\t\tend = scan.end\n\t}\n\tif needSort {\n\t\tsort.", "Sort(variantsSort{varID, variant})\n\t\tk, l := 0, -1\n\t\tfor i, v := range varID {\n\t\t\tw := int(v)\n\t\t\tif l == w {\n\t\t\t\t// Remove duplicates.", "\n\t\t\t\tcontinue\n\t\t\t}\n\t\t\tvarID[k] = varID[i]\n\t\t\tvariant[k] = variant[i]\n\t\t\tk++\n\t\t\tl = w\n\t\t}\n\t\tif str := bytes.", "Join(variant[:k], separator); len(str) == 0 {\n\t\t\tend = start - 1\n\t\t} else {\n\t\t\tscan.resizeRange(start, end, len(str))\n\t\t\tcopy(scan.b[scan.start:], str)\n\t\t\tend = scan.end\n\t\t}\n\t}\n\treturn end\n}\n\ntype variantsSort struct {\n\ti []uint8\n\tv [][]byte\n}\n\nfunc (s variantsSort) Len() int {\n\treturn len(s.i)\n}\n\nfunc (s variantsSort) Swap(i, j int) {\n\ts.i[i], s.i[j] = s.i[j], s.i[i]\n\ts.v[i], s.v[j] = s.v[j], s.v[i]\n}\n\nfunc (s variantsSort) Less(i, j int) bool {\n\treturn s.i[i] < s.i[j]\n}\n\ntype bytesSort [][]byte\n\nfunc (b bytesSort) Len() int {\n\treturn len(b)\n}\n\nfunc (b bytesSort) Swap(i, j int) {\n\tb[i], b[j] = b[j], b[i]\n}\n\nfunc (b bytesSort) Less(i, j int) bool {\n\treturn bytes.", "Compare(b[i], b[j]) == -1\n}\n\n// parseExtensions parses and normalizes the extensions in the buffer.", "\n// It returns the last position of scan.b that is part of any extension.", "\n// It also trims scan.b to remove excess parts accordingly.", "\nfunc parseExtensions(scan *scanner) int {\n\tstart := scan.start\n\texts := [][]byte{}\n\tprivate := []byte{}\n\tend := scan.end\n\tfor len(scan.token) == 1 {\n\t\textStart := scan.start\n\t\text := scan.token[0]\n\t\tend = parseExtension(scan)\n\t\textension := scan.b[extStart:end]\n\t\tif len(extension) < 3 || (ext !", "= 'x' && len(extension) < 4) {\n\t\t\tscan.setError(errSyntax)\n\t\t\tend = extStart\n\t\t\tcontinue\n\t\t} else if start == extStart && (ext == 'x' || scan.start == len(scan.b)) {\n\t\t\tscan.b = scan.b[:end]\n\t\t\treturn end\n\t\t} else if ext == 'x' {\n\t\t\tprivate = extension\n\t\t\tbreak\n\t\t}\n\t\texts = append(exts, extension)\n\t}\n\tsort.", "Sort(bytesSort(exts))\n\tif len(private) > 0 {\n\t\texts = append(exts, private)\n\t}\n\tscan.b = scan.b[:start]\n\tif len(exts) > 0 {\n\t\tscan.b = append(scan.b, bytes.", "Join(exts, separator)...)\n\t} else if start > 0 {\n\t\t// Strip trailing '-'.", "\n\t\tscan.b = scan.b[:start-1]\n\t}\n\treturn end\n}\n\n// parseExtension parses a single extension and returns the position of\n// the extension end.", "\nfunc parseExtension(scan *scanner) int {\n\tstart, end := scan.start, scan.end\n\tswitch scan.token[0] {\n\tcase 'u':\n\t\tattrStart := end\n\t\tscan.scan()\n\t\tfor last := []byte{}; len(scan.token) > 2; scan.scan() {\n\t\t\tif bytes.", "Compare(scan.token, last) !", "= -1 {\n\t\t\t\t// Attributes are unsorted. ", "Start over from scratch.", "\n\t\t\t\tp := attrStart + 1\n\t\t\t\tscan.next = p\n\t\t\t\tattrs := [][]byte{}\n\t\t\t\tfor scan.scan(); len(scan.token) > 2; scan.scan() {\n\t\t\t\t\tattrs = append(attrs, scan.token)\n\t\t\t\t\tend = scan.end\n\t\t\t\t}\n\t\t\t\tsort.", "Sort(bytesSort(attrs))\n\t\t\t\tcopy(scan.b[p:], bytes.", "Join(attrs, separator))\n\t\t\t\tbreak\n\t\t\t}\n\t\t\tlast = scan.token\n\t\t\tend = scan.end\n\t\t}\n\t\tvar last, key []byte\n\t\tfor attrEnd := end; len(scan.token) == 2; last = key {\n\t\t\tkey = scan.token\n\t\t\tkeyEnd := scan.end\n\t\t\tend = scan.acceptMinSize(3)\n\t\t\t// TODO: check key value validity\n\t\t\tif keyEnd == end || bytes.", "Compare(key, last) !", "= 1 {\n\t\t\t\t// We have an invalid key or the keys are not sorted.", "\n\t\t\t\t// Start scanning keys from scratch and reorder.", "\n\t\t\t\tp := attrEnd + 1\n\t\t\t\tscan.next = p\n\t\t\t\tkeys := [][]byte{}\n\t\t\t\tfor scan.scan(); len(scan.token) == 2; {\n\t\t\t\t\tkeyStart, keyEnd := scan.start, scan.end\n\t\t\t\t\tend = scan.acceptMinSize(3)\n\t\t\t\t\tif keyEnd !", "= end {\n\t\t\t\t\t\tkeys = append(keys, scan.b[keyStart:end])\n\t\t\t\t\t} else {\n\t\t\t\t\t\tscan.setError(errSyntax)\n\t\t\t\t\t\tend = keyStart\n\t\t\t\t\t}\n\t\t\t\t}\n\t\t\t\tsort.", "Sort(bytesSort(keys))\n\t\t\t\treordered := bytes.", "Join(keys, separator)\n\t\t\t\tif e := p + len(reordered); e < end {\n\t\t\t\t\tscan.deleteRange(e, end)\n\t\t\t\t\tend = e\n\t\t\t\t}\n\t\t\t\tcopy(scan.b[p:], bytes.", "Join(keys, separator))\n\t\t\t\tbreak\n\t\t\t}\n\t\t}\n\tcase 't':\n\t\tscan.scan()\n\t\tif n := len(scan.token); n >= 2 && n <= 3 && isAlpha(scan.token[1]) {\n\t\t\t_, end = parseTag(scan)\n\t\t\tscan.toLower(start, end)\n\t\t}\n\t\tfor len(scan.token) == 2 && !", "isAlpha(scan.token[1]) {\n\t\t\tend = scan.acceptMinSize(3)\n\t\t}\n\tcase 'x':\n\t\tend = scan.acceptMinSize(1)\n\tdefault:\n\t\tend = scan.acceptMinSize(2)\n\t}\n\treturn end\n}\n\n// Compose creates a Tag from individual parts, which may be of type Tag, Base,\n// Script, Region, Variant, []Variant, Extension, []Extension or error. ", "If a\n// Base, Script or Region or slice of type Variant or Extension is passed more\n// than once, the latter will overwrite the former. ", "Variants and Extensions are\n// accumulated, but if two extensions of the same type are passed, the latter\n// will replace the former. ", "A Tag overwrites all former values and typically\n// only makes sense as the first argument. ", "The resulting tag is returned after\n// canonicalizing using the Default CanonType. ", "If one or more errors are\n// encountered, one of the errors is returned.", "\nfunc Compose(part ...interface{}) (t Tag, err error) {\n\treturn Default.", "Compose(part...)\n}\n\n// Compose creates a Tag from individual parts, which may be of type Tag, Base,\n// Script, Region, Variant, []Variant, Extension, []Extension or error. ", "If a\n// Base, Script or Region or slice of type Variant or Extension is passed more\n// than once, the latter will overwrite the former. ", "Variants and Extensions are\n// accumulated, but if two extensions of the same type are passed, the latter\n// will replace the former. ", "A Tag overwrites all former values and typically\n// only makes sense as the first argument. ", "The resulting tag is returned after\n// canonicalizing using CanonType c. If one or more errors are encountered,\n// one of the errors is returned.", "\nfunc (c CanonType) Compose(part ...interface{}) (t Tag, err error) {\n\tvar b builder\n\tif err = b.update(part...); err !", "= nil {\n\t\treturn und, err\n\t}\n\tt, _ = b.tag.canonicalize(c)\n\n\tif len(b.ext) > 0 || len(b.variant) > 0 {\n\t\tsort.", "Sort(sortVariant(b.variant))\n\t\tsort.", "Strings(b.ext)\n\t\tif b.private !", "= \"\" {\n\t\t\tb.ext = append(b.ext, b.private)\n\t\t}\n\t\tn := maxCoreSize + tokenLen(b.variant...) + tokenLen(b.ext...)\n\t\tbuf := make([]byte, n)\n\t\tp := t.genCoreBytes(buf)\n\t\tt.pVariant = byte(p)\n\t\tp += appendTokens(buf[p:], b.variant...)\n\t\tt.pExt = uint16(p)\n\t\tp += appendTokens(buf[p:], b.ext...)\n\t\tt.str = string(buf[:p])\n\t} else if b.private !", "= \"\" {\n\t\tt.str = b.private\n\t\tt.remakeString()\n\t}\n\treturn\n}\n\ntype builder struct {\n\ttag Tag\n\n\tprivate string // the x extension\n\text []string\n\tvariant []string\n\n\terr error\n}\n\nfunc (b *builder) addExt(e string) {\n\tif e == \"\" {\n\t} else if e[0] == 'x' {\n\t\tb.private = e\n\t} else {\n\t\tb.ext = append(b.ext, e)\n\t}\n}\n\nvar errInvalidArgument = errors.", "New(\"invalid Extension or Variant\")\n\nfunc (b *builder) update(part ...interface{}) (err error) {\n\treplace := func(l *[]string, s string, eq func(a, b string) bool) bool {\n\t\tif s == \"\" {\n\t\t\tb.err = errInvalidArgument\n\t\t\treturn true\n\t\t}\n\t\tfor i, v := range *l {\n\t\t\tif eq(v, s) {\n\t\t\t\t(*l)[i] = s\n\t\t\t\treturn true\n\t\t\t}\n\t\t}\n\t\treturn false\n\t}\n\tfor _, x := range part {\n\t\tswitch v := x.(type) {\n\t\tcase Tag:\n\t\t\tb.tag.lang = v.lang\n\t\t\tb.tag.region = v.region\n\t\t\tb.tag.script = v.script\n\t\t\tif v.str !", "= \"\" {\n\t\t\t\tb.variant = nil\n\t\t\t\tfor x, s := \"\", v.str[v.pVariant:v.pExt]; s !", "= \"\"; {\n\t\t\t\t\tx, s = nextToken(s)\n\t\t\t\t\tb.variant = append(b.variant, x)\n\t\t\t\t}\n\t\t\t\tb.ext, b.private = nil, \"\"\n\t\t\t\tfor i, e := int(v.pExt), \"\"; i < len(v.str); {\n\t\t\t\t\ti, e = getExtension(v.str, i)\n\t\t\t\t\tb.addExt(e)\n\t\t\t\t}\n\t\t\t}\n\t\tcase Base:\n\t\t\tb.tag.lang = v.langID\n\t\tcase Script:\n\t\t\tb.tag.script = v.scriptID\n\t\tcase Region:\n\t\t\tb.tag.region = v.regionID\n\t\tcase Variant:\n\t\t\tif !", "replace(&b.variant, v.variant, func(a, b string) bool { return a == b }) {\n\t\t\t\tb.variant = append(b.variant, v.variant)\n\t\t\t}\n\t\tcase Extension:\n\t\t\tif !", "replace(&b.ext, v.s, func(a, b string) bool { return a[0] == b[0] }) {\n\t\t\t\tb.addExt(v.s)\n\t\t\t}\n\t\tcase []Variant:\n\t\t\tb.variant = nil\n\t\t\tfor _, x := range v {\n\t\t\t\tb.update(x)\n\t\t\t}\n\t\tcase []Extension:\n\t\t\tb.ext, b.private = nil, \"\"\n\t\t\tfor _, e := range v {\n\t\t\t\tb.update(e)\n\t\t\t}\n\t\t// TODO: support parsing of raw strings based on morphology or just extensions?", "\n\t\tcase error:\n\t\t\terr = v\n\t\t}\n\t}\n\treturn\n}\n\nfunc tokenLen(token ...string) (n int) {\n\tfor _, t := range token {\n\t\tn += len(t) + 1\n\t}\n\treturn\n}\n\nfunc appendTokens(b []byte, token ...string) int {\n\tp := 0\n\tfor _, t := range token {\n\t\tb[p] = '-'\n\t\tcopy(b[p+1:], t)\n\t\tp += 1 + len(t)\n\t}\n\treturn p\n}\n\ntype sortVariant []string\n\nfunc (s sortVariant) Len() int {\n\treturn len(s)\n}\n\nfunc (s sortVariant) Swap(i, j int) {\n\ts[j], s[i] = s[i], s[j]\n}\n\nfunc (s sortVariant) Less(i, j int) bool {\n\treturn variantIndex[s[i]] < variantIndex[s[j]]\n}\n\nfunc findExt(list []string, x byte) int {\n\tfor i, e := range list {\n\t\tif e[0] == x {\n\t\t\treturn i\n\t\t}\n\t}\n\treturn -1\n}\n\n// getExtension returns the name, body and end position of the extension.", "\nfunc getExtension(s string, p int) (end int, ext string) {\n\tif s[p] == '-' {\n\t\tp++\n\t}\n\tif s[p] == 'x' {\n\t\treturn len(s), s[p:]\n\t}\n\tend = nextExtension(s, p)\n\treturn end, s[p:end]\n}\n\n// nextExtension finds the next extension within the string, searching\n// for the -<char>- pattern from position p.\n// In the fast majority of cases, language tags will have at most\n// one extension and extensions tend to be small.", "\nfunc nextExtension(s string, p int) int {\n\tfor n := len(s) - 3; p < n; {\n\t\tif s[p] == '-' {\n\t\t\tif s[p+2] == '-' {\n\t\t\t\treturn p\n\t\t\t}\n\t\t\tp += 3\n\t\t} else {\n\t\t\tp++\n\t\t}\n\t}\n\treturn len(s)\n}\n\nvar errInvalidWeight = errors.", "New(\"ParseAcceptLanguage: invalid weight\")\n\n// ParseAcceptLanguage parses the contents of an Accept-Language header as\n// defined in http://www.ietf.org/rfc/rfc2616.txt and returns a list of Tags and\n// a list of corresponding quality weights. ", "It is more permissive than RFC 2616\n// and may return non-nil slices even if the input is not valid.", "\n// The Tags will be sorted by highest weight first and then by first occurrence.", "\n// Tags with a weight of zero will be dropped. ", "An error will be returned if the\n// input could not be parsed.", "\nfunc ParseAcceptLanguage(s string) (tag []Tag, q []float32, err error) {\n\tvar entry string\n\tfor s !", "= \"\" {\n\t\tif entry, s = split(s, ','); entry == \"\" {\n\t\t\tcontinue\n\t\t}\n\n\t\tentry, weight := split(entry, ';')\n\n\t\t// Scan the language.", "\n\t\tt, err := Parse(entry)\n\t\tif err !", "= nil {\n\t\t\tid, ok := acceptFallback[entry]\n\t\t\tif !", "ok {\n\t\t\t\treturn nil, nil, err\n\t\t\t}\n\t\t\tt = Tag{lang: id}\n\t\t}\n\n\t\t// Scan the optional weight.", "\n\t\tw := 1.0\n\t\tif weight !", "= \"\" {\n\t\t\tweight = consume(weight, 'q')\n\t\t\tweight = consume(weight, '=')\n\t\t\t// consume returns the empty string when a token could not be\n\t\t\t// consumed, resulting in an error for ParseFloat.", "\n\t\t\tif w, err = strconv.", "ParseFloat(weight, 32); err !", "= nil {\n\t\t\t\treturn nil, nil, errInvalidWeight\n\t\t\t}\n\t\t\t// Drop tags with a quality weight of 0.", "\n\t\t\tif w <= 0 {\n\t\t\t\tcontinue\n\t\t\t}\n\t\t}\n\n\t\ttag = append(tag, t)\n\t\tq = append(q, float32(w))\n\t}\n\tsortStable(&tagSort{tag, q})\n\treturn tag, q, nil\n}\n\n// consume removes a leading token c from s and returns the result or the empty\n// string if there is no such token.", "\nfunc consume(s string, c byte) string {\n\tif s == \"\" || s[0] !", "= c {\n\t\treturn \"\"\n\t}\n\treturn strings.", "TrimSpace(s[1:])\n}\n\nfunc split(s string, c byte) (head, tail string) {\n\tif i := strings.", "IndexByte(s, c); i >= 0 {\n\t\treturn strings.", "TrimSpace(s[:i]), strings.", "TrimSpace(s[i+1:])\n\t}\n\treturn strings.", "TrimSpace(s), \"\"\n}\n\n// Add hack mapping to deal with a small number of cases that that occur\n// in Accept-Language (with reasonable frequency).", "\nvar acceptFallback = map[string]langID{\n\t\"english\": _en,\n\t\"deutsch\": _de,\n\t\"italian\": _it,\n\t\"french\": _fr,\n\t\"*\": _mul, // defined in the spec to match all languages.", "\n}\n\ntype tagSort struct {\n\ttag []Tag\n\tq []float32\n}\n\nfunc (s *tagSort) Len() int {\n\treturn len(s.q)\n}\n\nfunc (s *tagSort) Less(i, j int) bool {\n\treturn s.q[i] > s.q[j]\n}\n\nfunc (s *tagSort) Swap(i, j int) {\n\ts.tag[i], s.tag[j] = s.tag[j], s.tag[i]\n\ts.q[i], s.q[j] = s.q[j], s.q[i]\n}\n" ]

{ "pile_set_name": "Github" }

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[ "Wednesday, March 27, 2013\n\nSo I recently upgraded PostgreSQL from 8.3 to 8.4 and more or less at the same time upgraded Bacula to 5.2.14 from some earlier version, I don't remember what can I say.", "\n\nAnyway in the process I ran into this error when opening bconsole:\n\nJobId 0: Fatal error: Pool Default not in database. ", "sql_create.c:189 pool record Default already existsI couldn't for the life of me figure this out.", "So I eventually got into pgsql as bacula and did a select statement\n\nI had an issue where several users that no longer work here still had active sync devices in AD for whatever reason so I needed to get rid of them.", "Quick Google Search found this Technet threadThe long and short of it are these two lines that gather all the active sync devices that haven't checked in within the past 30 days and then removes them.", "For my purposes I changed it 90 days the first time through, however I now run this script once monthly.-- Powershell Start --$DevicesToRemove = Get-ActiveSyncDevice -result unlimited | Get-ActiveSyncDeviceStatistics | where {$_.LastSuccessSync -le (Get-Date).AddDays(\"-30\")}$DevicesToRemove | foreach-object {Remove-ActiveSyncDevice ([string]$_.Guid) -confirm:$false}\n-- Powershell End --Now let's say the user doesn't have a mailbox on Exchange anymore.", "You first have to temporarily recreate the mailbox-- Powershell Start --Enable-Mailbox -Identity:'OU/User'-- Powershell End --Then rerun the above script.", "If you don't create the mailbox you get a can't find recipient error.", "Then after the active sync devices are gone simply run-- Powershell Start --Remove-Mailbox -Identity:'OU/User'-- Powershell End --If for some reason you still can't remove the Active Sync devices you can open ADSI Edit and look forCN=ExchangeActiveSyncDevices container under the user objectThen simply remove that." ]

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[ "The most important objectives of wireless communications, broadcasting, telemetry, infrared and in general “radio” systems as well as “wired” systems include: power and bandwidth or spectrum efficiency combined with robust Bit Error Rate (BER) performance in a noisy and/or strong interference environment. ", "These system objectives are specified in numerous systems including wireless communications and cellular systems, satellite systems, mobile and telemetry systems, broadcasting systems, cable, fiber optics and practically all communication transmission systems. ", "A partial list of publications, references, and patents are provided separately below. ", "The cited publications, references [1-23] and patents [P1-P8], and the references within the aforementioned publications contain definitions and descriptions of many terms used in this new patent disclosure and for this reason these conventional terms and definitions will be described only briefly, and highlighted on a case by case basis.", "\nRobust or high performance Bit Error Rate (BER) specifications and/or objectives are frequently expressed in terms of the required BER as a function of Energy per Bit (Eb) divided by Noise Density or simply noise (No), that is, by the BER=f(Eb/No) expression. ", "Low cost, reduced size, and compatibility and/or interoperability with other conventional or previously standardized systems, also known as “legacy systems,” are highly desired. ", "Several standardization organizations have adopted modulation techniques such as conventional Binary Phase Shift Keying (BPSK), Quadrature Phase Shift Keying (QPSK), Offset Quadrature Phase Shift Keying (OQPSK) also designated as Staggered Quadrature Phase Shift Keying (SQPSK), and pi/4-QPSK (or π/4-QPSK) techniques including differential encoding variations of the same. ", "See publications [1-23] and referenced patents [P1-P8] for examples and further description. ", "For spectrally or spectrum efficient signaling (such as band-limited signaling), these conventional methods exhibit a large envelope fluctuation of the modulated signal, and thus have a large increase in peak radiated power relative to the average radiated power. ", "For these reasons such systems are not suitable for BRA, robust BER performance NLA operated RF power efficient systems.", "\nWithin the present state of the technology, for numerous BRA Transceiver applications, it is not practical to introduce band-pass filtering after the NLA power efficient Radio Frequency (RF) final amplifier stage. ", "Here we are using the term “Radio Frequency” (RF) in its broadest sense, implying that we are dealing with a modulated signal. ", "The RF could be, for example, as high as the frequency of infrared or fiber optic transmitters; it could be in the GHz range, for example, between 1 GHz and 300 GHz or more, or it could be in the MHz range, for example, between about 1 MHz and 999 MHz, or just in the kHz range. ", "The term RF could even apply to Quadrature Modulated (abbreviated “QM” or “QMOD”) Base-Band (BB) signals or to Intermediate Frequency (IF) signals.", "\nIn conventional BPSK, QPSK, OQPSK or SQPSK, and differentially-encoded phase-shift keying systems variants of these systems, such as DBPSK and DQPSK, as well as in pi/4-DQPSK and trellis coded QPSK and DQPSK, large envelope fluctuations require linearized (LIN) or highly linear transmitters including frequency up-converters and RF power amplifiers and may require expensive linear receivers having linear Automatic Gain Control (AGC) circuits. ", "A transmitter NLA reduces the time domain envelope fluctuation of conventional QPSK type of band-limited signals and this reduction of the envelope fluctuation, being a signal distortion, is the cause of spectral restoration or spectral regrowth and the cause of unacceptably high levels of out-of-band spectral energy transmission, also known as out-of-band interference. ", "Additionally, for conventional BPSK, QPSK, and also Quadrature Amplitude Modulation number (QAM) signals, undesired in-phase channel (I) to quadrature channel (Q) crosstalk is generated. ", "This crosstalk degrades the BER=f(Eb/N0) performance of the modulated radio transmitter.", "\nExperimental work, computer simulation, and theory documented in many recent publications indicates that for band-limited and standardized BPSK, QPSK, OQPSK or SQPSK or pi/4-QPSK, and QAM system specifications, very linear amplifiers are required to avoid the pitfalls of spectral restoration and of BER degradation. ", "Linearized or linear amplifiers are less RF power efficient (during the power “on” state, power efficiency being defined as the transmit RF power divided by DC power), are considerably more expensive and/or having less transmit RF power capability, are larger in size, and are not as readily available as NLA amplifiers. ", "The advantages of NLA over LIN amplifiers are even more dramatic at higher RF frequencies, such as frequencies above about 1 GHz for applications requiring low dc voltage, for example applications or systems operating on size “AA” batteries having only 1.5 Volt dc and for high RF modulated power requirements, for example transmit RF power in the 0.5 Watt to 100 Watt range.", "\nPublished references [P1 to P8] and [1 to 23] include additional background information. ", "These references include descriptions of binary-state and multiple-state Transmitter/Receiver (Transceiver) or for short (“TR”) systems that are suitable for NLA. ", "In the aforementioned references Processors, Modems, Transmitters, Receivers and Transceivers, suitable for NLA, have been described, defined and designated as first generation of Feher patented Quadrature Shift Keying (FQPSK). ", "For example, in reference [22] published on May 15, 1999 the authors Drs. ", "M. K. Simon and T. Y. Yan of JPL/NASA-Caltech present a detailed study of Unfiltered Feher-Patented Quadrature Phase Shift Keying (FQPSK). ", "In references [1-22] and patents #[P1-P8] numerous first generation FQPSK technology based terms, and terms other than the FQPSK abbreviation/acronym have been used. ", "In addition to FQPSK Transceivers, these first generation of systems have been also described and/or defined as: Feher's Minimum Shift Keying (FMSK), Feher's Frequency Shift Keying (FFSK), Feher's Gaussian Minimum Shift Keying (FGMSK), Feher's Quadrature Amplitude Modulation (FQAM) and/or Feher's (F) Modulation/Amplification (FMOD). ", "Additionally terms such as Superposed Quadrature Amplitude Modulation (SQAM), Intersymbol Interference and Jitter Free (IJF) and/or IJF-OQPSK have been also described in Feher et al.", "'s prior patents and publications, each of which is incorporated by reference.", "\nIn the cited patents and other references, among the aforementioned abbreviations, acronyms, designation, terms and descriptions the “FQPSK” abbreviation/term has been most frequently used to describe in most generic terms one or more of these afore described Feher or Feher et al. ", "first generation of Non-Linearly Amplified (NLA) inventions and technologies. ", "The 1st generation of FQPSK systems have significantly increased spectral efficiency and enhanced end-to-end performance as compared to other NLA systems. ", "RF power advantages, robust BER performance, and NLA narrow spectrum without the pitfalls of conventional BPSK and DBPSK, QPSK and OQPSK have been attained with these 1st generation FQPSK systems and methods. ", "The generic 1st generation terms such as FQPSK, as well as other previously mentioned terms/acronyms are retained and used in this description to describe the new BRA, Code Selectable (CS), Modem Format Selectable (MFS) and modulation-demodulation Mis-Matched (MM) filtered architectures and embodiments of “2nd generation” FQPSK Transceivers.", "\nWhile these earlier issued patents and publications describe material of a background nature, they do not disclose the original new enhanced performance bit rate agile and modulation agile/selectable technologies disclosed in this new invention." ]

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[ "1997 Limerick Senior Hurling Championship\n\nThe 1997 Limerick Senior Hurling Championship was the 103rd staging of the Limerick Senior Hurling Championship since its establishment by the Limerick County Board.", "\n\nPatrickswell were the defending champions.", "\n\nOn 21 September 1997, Patrickswell won the championship after a 1-12 to 0-09 defeat of Garryspillane in the final. ", "It was their third title in succession and their 16th title overall which allowed them to draw level with Ahane at the top of the all-time toll of honour.", "\n\nResults\n\nFinal\n\nReferences\n\nLimerick Senior Hurling Championship\nCategory:Limerick Senior Hurling Championship" ]

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[ { "analysis_explanation": null, "end": 4, "entity_type": "DATE_TIME", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 0 }, { "analysis_explanation": null, "end": 13, "entity_type": "LOCATION", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 5 }, { "analysis_explanation": null, "end": 51, "entity_type": "DATE_TIME", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 47 }, { "analysis_explanation": null, "end": 60, "entity_type": "LOCATION", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 52 }, { "analysis_explanation": null, "end": 221, "entity_type": "PERSON", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 209 }, { "analysis_explanation": null, "end": 272, "entity_type": "DATE_TIME", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 255 }, { "analysis_explanation": null, "end": 286, "entity_type": "PERSON", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 274 }, { "analysis_explanation": null, "end": 328, "entity_type": "DATE_TIME", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 324 }, { "analysis_explanation": null, "end": 478, "entity_type": "PERSON", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 473 }, { "analysis_explanation": null, "end": 604, "entity_type": "LOCATION", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 596 } ]

[ "/*!The Treasure Box Library\n *\n * Licensed under the Apache License, Version 2.0 (the \"License\");\n * you may not use this file except in compliance with the License.", "\n * You may obtain a copy of the License at\n *\n * http://www.apache.org/licenses/LICENSE-2.0\n *\n * Unless required by applicable law or agreed to in writing, software\n * distributed under the License is distributed on an \"AS IS\" BASIS,\n * WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.", "\n * See the License for the specific language governing permissions and\n * limitations under the License.", "\n * \n * Copyright (C) 2009-2020, TBOOX Open Source Group.", "\n *\n * @author ruki\n * @file option.c\n * @ingroup utils\n *\n */\n\n/* //////////////////////////////////////////////////////////////////////////////////////\n * trace\n */\n#define TB_TRACE_MODULE_NAME \"option\"\n#define TB_TRACE_MODULE_DEBUG (0)\n\n/* //////////////////////////////////////////////////////////////////////////////////////\n * includes\n */\n#include \"option.h\"\n#include \"../libc/libc.h\"\n#include \"../object/object.h\"\n\n/* //////////////////////////////////////////////////////////////////////////////////////\n * types\n */\n\n// the option impl type\ntypedef struct tb_option_impl_t\n{\n // the command name\n tb_char_t name[64];\n\n // the command help\n tb_string_t help;\n\n // the options\n tb_option_item_t const* opts;\n\n // the option list\n tb_object_ref_t list;\n\n}tb_option_impl_t;\n\n/* //////////////////////////////////////////////////////////////////////////////////////\n * helper\n */\nstatic __tb_inline__ tb_bool_t tb_option_is_bool(tb_char_t const* data)\n{\n // check\n tb_assert_and_check_return_val(data, tb_false);\n return (!", "tb_stricmp(data, \"y\") || !", "tb_stricmp(data, \"n\"))? ", "tb_true : tb_false;\n}\nstatic __tb_inline__ tb_bool_t tb_option_is_integer(tb_char_t const* data)\n{\n // check\n tb_assert_and_check_return_val(data, tb_false);\n \n // init\n tb_char_t const* p = data;\n\n // skip '-' & '+'\n if (*p == '-' || *p == '+') p++;\n\n // walk\n for (; *p && tb_isdigit(*p); p++);\n\n // ok?", "\n return *p? ", "tb_false : tb_true;\n}\n#ifdef TB_CONFIG_TYPE_HAVE_FLOAT\nstatic __tb_inline__ tb_bool_t tb_option_is_float(tb_char_t const* data)\n{\n // check\n tb_assert_and_check_return_val(data, tb_false);\n \n // init\n tb_char_t const* p = data;\n\n // walk\n for (; *p && (tb_isdigit10(*p) || *p == '.'); ", "p++);\n\n // ok?", "\n return *p? ", "tb_false : tb_true;\n}\n#endif\nstatic __tb_inline__ tb_option_item_t const* tb_option_item_find(tb_option_item_t const* opts, tb_char_t const* lname, tb_char_t sname)\n{\n // check\n tb_assert_and_check_return_val(opts, tb_null);\n\n // walk\n tb_bool_t ok = tb_false;\n tb_option_item_t const* item = opts;\n while (item && !", "ok)\n {\n switch (item->mode)\n {\n case TB_OPTION_MODE_KEY:\n case TB_OPTION_MODE_KEY_VAL:\n {\n // find lname\n if (item->lname && lname && !", "tb_strcmp(lname, item->lname)) \n {\n ok = tb_true;\n break;\n }\n\n // find sname\n if (item->sname && sname && (sname == item->sname) && (sname !", "= '-')) \n {\n ok = tb_true;\n break;\n }\n\n // next\n item++;\n }\n break;\n case TB_OPTION_MODE_VAL:\n item++;\n break;\n case TB_OPTION_MODE_MORE:\n case TB_OPTION_MODE_END:\n default:\n item = tb_null;\n break;\n }\n }\n\n // ok?", "\n return ok? ", "item : tb_null;\n}\n#if 0\nstatic __tb_inline__ tb_bool_t tb_option_check(tb_option_impl_t* impl)\n{\n // check\n tb_assert_and_check_return_val(impl && impl->list && impl->opts, tb_false);\n\n // walk\n tb_bool_t ok = tb_true;\n tb_option_item_t* item = impl->opts;\n while (item && ok)\n {\n switch (item->mode)\n {\n case TB_OPTION_MODE_KEY:\n case TB_OPTION_MODE_KEY_VAL:\n item++;\n break;\n case TB_OPTION_MODE_VAL:\n {\n if (item->lname && !", "tb_option_find(impl, item->lname)) ok = tb_false;\n item++;\n }\n break;\n case TB_OPTION_MODE_MORE:\n case TB_OPTION_MODE_END:\n default:\n item = tb_null;\n break;\n }\n }\n\n // ok?", "\n return ok;\n}\n#endif\n\n/* //////////////////////////////////////////////////////////////////////////////////////\n * implementation\n */\ntb_option_ref_t tb_option_init(tb_char_t const* name, tb_char_t const* help, tb_option_item_t const* opts)\n{\n // check\n tb_assert_and_check_return_val(name && opts, tb_null);\n\n // done\n tb_bool_t ok = tb_false;\n tb_option_impl_t* impl = tb_null;\n do\n {\n // make option\n impl = tb_malloc0_type(tb_option_impl_t);\n tb_assert_and_check_break(impl);\n\n // init option\n impl->opts = opts;\n impl->list = tb_oc_dictionary_init(TB_OC_DICTIONARY_SIZE_MICRO, tb_false);\n tb_assert_and_check_break(impl->list);\n\n // init name\n tb_strlcpy(impl->name, name, sizeof(impl->name));\n\n // init help\n if (!", "tb_string_init(&impl->help)) break;\n if (help) tb_string_cstrcpy(&impl->help, help);\n\n // ok\n ok = tb_true;\n\n } while (0);\n\n // failed?", "\n if (!", "ok)\n {\n // exit it\n if (impl) tb_option_exit((tb_option_ref_t)impl);\n impl = tb_null;\n }\n\n // ok?", "\n return (tb_option_ref_t)impl;\n}\ntb_void_t tb_option_exit(tb_option_ref_t option)\n{\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n if (impl)\n {\n // exit help\n tb_string_exit(&impl->help);\n\n // exit list\n if (impl->list) tb_object_exit(impl->list);\n impl->list = tb_null;\n\n // exit option\n tb_free(impl);\n }\n}\ntb_bool_t tb_option_find(tb_option_ref_t option, tb_char_t const* name)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return_val(impl && impl->list && name, tb_false);\n\n // find it\n return tb_oc_dictionary_value(impl->list, name)? ", "tb_true : tb_false;\n}\ntb_bool_t tb_option_done(tb_option_ref_t option, tb_size_t argc, tb_char_t** argv)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return_val(impl && impl->list && impl->opts, tb_false);\n\n // walk arguments\n tb_size_t i = 0;\n tb_size_t more = 0;\n tb_option_item_t const* item = impl->opts;\n tb_option_item_t const* last = tb_null;\n for (i = 0; i < argc; i++)\n {\n // the argument\n tb_char_t* p = argv[i];\n tb_char_t* e = p + tb_strlen(p);\n tb_assert_and_check_return_val(p && p < e, tb_false);\n\n // is long key?", "\n if (p + 2 < e && p[0] == '-' && p[1] == '-' && tb_isalpha(p[2]))\n {\n // the key\n tb_char_t key[512] = {0};\n {\n tb_char_t* k = key;\n tb_char_t* e = key + 511;\n for (p += 2; *p && *p !", "= '=' && k < e; p++, k++) *k = *p; \n }\n\n // the val\n tb_char_t* val = (*p == '=')? (", "p + 1) : tb_null;\n\n // trace\n tb_trace_d(\"[lname]: %s => %s\", key, val);\n\n // find the item\n tb_option_item_t const* find = tb_option_item_find(impl->opts, key, '\\0');\n if (find)\n {\n // check key & val\n if (!", "val == !(", "find->mode == TB_OPTION_MODE_KEY_VAL))\n {\n // has value?", "\n tb_object_ref_t object = tb_null;\n if (val)\n {\n // init the value object\n switch (find->type)\n {\n case TB_OPTION_TYPE_CSTR:\n object = tb_oc_string_init_from_cstr(val);\n break;\n case TB_OPTION_TYPE_INTEGER:\n tb_assert_and_check_return_val(tb_option_is_integer(val), tb_false);\n object = tb_oc_number_init_from_sint64(tb_atoll(val));\n break;\n case TB_OPTION_TYPE_BOOL:\n tb_assert_and_check_return_val(tb_option_is_bool(val), tb_false);\n object = tb_oc_boolean_init(!tb_stricmp(val, \"y\")? ", "tb_true : tb_false);\n break;\n#ifdef TB_CONFIG_TYPE_HAVE_FLOAT\n case TB_OPTION_TYPE_FLOAT:\n tb_assert_and_check_return_val(tb_option_is_float(val), tb_false);\n object = tb_oc_number_init_from_double(tb_atof(val));\n break;\n#endif\n default:\n tb_assert_and_check_return_val(0, tb_false);\n break;\n }\n }\n else\n {\n // check\n tb_assert_and_check_return_val(find->type == TB_OPTION_TYPE_BOOL, tb_false);\n\n // key => true\n object = tb_oc_boolean_init(tb_true);\n }\n\n // add the value object\n if (object)\n {\n tb_oc_dictionary_insert(impl->list, key, object);\n if (tb_isalpha(find->sname)) \n {\n tb_char_t ch[2] = {0};\n ch[0] = find->sname;\n tb_oc_dictionary_insert(impl->list, ch, object);\n tb_object_retain(object);\n }\n }\n }\n else if (val)\n {\n // print\n tb_trace_e(\"%s: unrecognized option value '--%s=%s'\", impl->name, key, val);\n\n // next\n continue ;\n }\n else\n {\n // print\n tb_trace_e(\"%s: no option value '--%s='\", impl->name, key);\n\n // next\n continue ;\n }\n }\n else\n {\n // print\n tb_trace_e(\"%s: unrecognized option '--%s'\", impl->name, key);\n\n // next\n continue ;\n }\n }\n // is short key?", "\n else if (p + 1 < e && p[0] == '-' && tb_isalpha(p[1]))\n {\n // the key\n tb_char_t key[512] = {0};\n {\n tb_char_t* k = key;\n tb_char_t* e = key + 511;\n for (p += 1; *p && *p !", "= '=' && k < e; p++, k++) *k = *p; \n }\n\n // the val\n tb_char_t const* val = (*p == '=')? (", "p + 1) : tb_null;\n\n // trace\n tb_trace_d(\"[sname]: %s => %s\", key, val);\n\n // is short name?", "\n if (tb_strlen(key) !", "= 1)\n {\n // print\n tb_trace_e(\"%s: unrecognized option '-%s'\", impl->name, key);\n\n // next\n continue ;\n }\n\n // find the item\n tb_option_item_t const* find = tb_option_item_find(impl->opts, tb_null, key[0]);\n if (find)\n {\n // check key & val\n if (!", "val == !(", "find->mode == TB_OPTION_MODE_KEY_VAL))\n {\n // has value?", "\n tb_object_ref_t object = tb_null;\n if (val)\n {\n // add value\n switch (find->type)\n {\n case TB_OPTION_TYPE_CSTR:\n object = tb_oc_string_init_from_cstr(val);\n break;\n case TB_OPTION_TYPE_INTEGER:\n tb_assert_and_check_return_val(tb_option_is_integer(val), tb_false);\n object = tb_oc_number_init_from_sint64(tb_atoll(val));\n break;\n case TB_OPTION_TYPE_BOOL:\n tb_assert_and_check_return_val(tb_option_is_bool(val), tb_false);\n object = tb_oc_boolean_init(!tb_stricmp(val, \"y\")? ", "tb_true : tb_false);\n break;\n#ifdef TB_CONFIG_TYPE_HAVE_FLOAT\n case TB_OPTION_TYPE_FLOAT:\n tb_assert_and_check_return_val(tb_option_is_float(val), tb_false);\n object = tb_oc_number_init_from_double(tb_atof(val));\n break;\n#endif\n default:\n tb_assert_and_check_return_val(0, tb_false);\n break;\n }\n }\n else\n {\n // check\n tb_assert_and_check_return_val(find->type == TB_OPTION_TYPE_BOOL, tb_false);\n\n // key => true\n object = tb_oc_boolean_init(tb_true);\n }\n\n // add the value object \n if (object)\n {\n tb_oc_dictionary_insert(impl->list, key, object);\n if (find->lname)\n {\n tb_oc_dictionary_insert(impl->list, find->lname, object);\n tb_object_retain(object);\n }\n }\n }\n else if (val)\n {\n // print\n tb_trace_e(\"%s: unrecognized option value '--%s=%s'\", impl->name, key, val);\n\n // next\n continue ;\n }\n else\n {\n // print\n tb_trace_e(\"%s: no option value '--%s='\", impl->name, key);\n\n // next\n continue ;\n }\n }\n else\n {\n // print\n tb_trace_e(\"%s: unrecognized option '-%s'\", impl->name, key);\n\n // next\n continue ;\n }\n }\n // is value?", "\n else\n {\n // trace\n tb_trace_d(\"[val]: %s\", p);\n\n // find the value item \n while (item && item->mode !", "= TB_OPTION_MODE_VAL && item->mode !", "= TB_OPTION_MODE_END && item->mode !", "= TB_OPTION_MODE_MORE)\n item++;\n\n // has value item?", "\n if (item->mode == TB_OPTION_MODE_VAL)\n {\n // check\n tb_assert_and_check_return_val(item->lname, tb_false);\n\n // add value\n switch (item->type)\n {\n case TB_OPTION_TYPE_CSTR:\n tb_oc_dictionary_insert(impl->list, item->lname, tb_oc_string_init_from_cstr(p));\n break;\n case TB_OPTION_TYPE_INTEGER:\n tb_assert_and_check_return_val(tb_option_is_integer(p), tb_false);\n tb_oc_dictionary_insert(impl->list, item->lname, tb_oc_number_init_from_sint64(tb_atoll(p)));\n break;\n case TB_OPTION_TYPE_BOOL:\n tb_assert_and_check_return_val(tb_option_is_bool(p), tb_false);\n tb_oc_dictionary_insert(impl->list, item->lname, tb_oc_boolean_init(!tb_stricmp(p, \"y\")? ", "tb_true : tb_false));\n break;\n#ifdef TB_CONFIG_TYPE_HAVE_FLOAT\n case TB_OPTION_TYPE_FLOAT:\n tb_assert_and_check_return_val(tb_option_is_float(p), tb_false);\n tb_oc_dictionary_insert(impl->list, item->lname, tb_oc_number_init_from_double(tb_atof(p)));\n break;\n#endif\n default:\n tb_assert_and_check_return_val(0, tb_false);\n break;\n }\n\n // save last\n last = item;\n\n // next item\n item++;\n }\n // has more item?", "\n else if (item->mode == TB_OPTION_MODE_MORE && last)\n {\n // the more name\n tb_char_t name[64] = {0};\n tb_snprintf(name, 63, \"more%lu\", more);\n\n // add value\n switch (last->type)\n {\n case TB_OPTION_TYPE_CSTR:\n tb_oc_dictionary_insert(impl->list, name, tb_oc_string_init_from_cstr(p));\n break;\n case TB_OPTION_TYPE_INTEGER:\n tb_assert_and_check_return_val(tb_option_is_integer(p), tb_false);\n tb_oc_dictionary_insert(impl->list, name, tb_oc_number_init_from_sint64(tb_atoll(p)));\n break;\n case TB_OPTION_TYPE_BOOL:\n tb_assert_and_check_return_val(tb_option_is_bool(p), tb_false);\n tb_oc_dictionary_insert(impl->list, name, tb_oc_boolean_init(!tb_stricmp(p, \"y\")? ", "tb_true : tb_false));\n break;\n#ifdef TB_CONFIG_TYPE_HAVE_FLOAT\n case TB_OPTION_TYPE_FLOAT:\n tb_assert_and_check_return_val(tb_option_is_float(p), tb_false);\n tb_oc_dictionary_insert(impl->list, name, tb_oc_number_init_from_double(tb_atof(p)));\n break;\n#endif\n default:\n tb_assert_and_check_return_val(0, tb_false);\n break;\n }\n\n // next more\n more++;\n }\n }\n }\n\n // ok\n return tb_true;//tb_option_check(impl);\n}\ntb_void_t tb_option_dump(tb_option_ref_t option)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return(impl && impl->list);\n\n // dump \n tb_object_dump(impl->list, TB_OBJECT_FORMAT_JSON);\n}\ntb_void_t tb_option_help(tb_option_ref_t option)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return(impl && impl->opts);\n\n // dump usage head\n tb_printf(\"======================================================================\\n\");\n tb_printf(\"[usage]: %s\", impl->name);\n\n // dump usage item\n tb_bool_t bopt = tb_false;\n tb_option_item_t const* item = impl->opts;\n while (item)\n {\n // dump options\n if (bopt && item->mode !", "= TB_OPTION_MODE_KEY && item->mode !", "= TB_OPTION_MODE_KEY_VAL)\n {\n tb_printf(\" [options]\");\n bopt = tb_false;\n }\n\n // dump item\n switch (item->mode)\n {\n case TB_OPTION_MODE_KEY:\n case TB_OPTION_MODE_KEY_VAL:\n {\n bopt = tb_true;\n item++;\n }\n break;\n case TB_OPTION_MODE_VAL:\n {\n tb_printf(\" %s\", item->lname);\n item++;\n }\n break;\n case TB_OPTION_MODE_MORE:\n tb_printf(\" ...\");\n case TB_OPTION_MODE_END:\n default:\n item = tb_null;\n break;\n }\n }\n\n // dump usage tail\n tb_printf(\"\\n\\n\");\n\n // dump help\n if (tb_string_size(&impl->help)) \n tb_printf(\"[help]: %s\\n\\n\", tb_string_cstr(&impl->help));\n\n // dump options head\n tb_printf(\"[options]: \\n\");\n for (item = impl->opts; item; )\n {\n // dump item\n tb_size_t spaces = 32;\n switch (item->mode)\n {\n case TB_OPTION_MODE_KEY:\n case TB_OPTION_MODE_KEY_VAL:\n {\n // dump spaces\n tb_printf(\" \"); spaces -= 3;\n\n // has short name?", "\n if (tb_isalpha(item->sname))\n {\n // dump short name\n tb_printf(\"-%c\", item->sname);\n spaces -= 2;\n\n // dump long name\n if (item->lname) \n {\n tb_printf(\", --%s\", item->lname);\n spaces -= 4;\n if (tb_strlen(item->lname) <= spaces) spaces -= tb_strlen(item->lname);\n }\n }\n // dump long name\n else if (item->lname) \n {\n tb_printf(\" --%s\", item->lname);\n spaces -= 6;\n if (tb_strlen(item->lname) <= spaces) spaces -= tb_strlen(item->lname);\n }\n\n // dump value\n if (item->mode == TB_OPTION_MODE_KEY_VAL)\n {\n switch (item->type)\n {\n case TB_OPTION_TYPE_BOOL:\n tb_printf(\"=BOOL\"); spaces -= 5;\n break;\n case TB_OPTION_TYPE_CSTR:\n tb_printf(\"=STRING\"); spaces -= 7;\n break;\n case TB_OPTION_TYPE_INTEGER:\n tb_printf(\"=INTEGER\"); spaces -= 8;\n break;\n case TB_OPTION_TYPE_FLOAT:\n tb_printf(\"=FLOAT\"); spaces -= 6;\n break;\n default:\n break;\n }\n }\n\n // dump help\n if (item->help) \n {\n tb_char_t line[8192] = {0};\n tb_char_t const* pb = item->help;\n tb_char_t* qb = line;\n tb_char_t* qe = line + 8192;\n while (qb < qe)\n {\n if (*pb !", "= '\\n' && *pb) *qb++ = *pb++;\n else\n {\n // strip line and next\n *qb = '\\0'; qb = line;\n\n // dump spaces\n while (spaces--) tb_printf(\" \");\n\n // dump help line\n tb_printf(\"%s\", line);\n\n // reset spaces\n spaces = 32;\n\n // next or end?", "\n if (*pb) \n {\n // dump new line\n tb_printf(\"\\n\");\n pb++;\n }\n else break;\n }\n }\n }\n\n // dump newline\n tb_printf(\"\\n\");\n\n // next\n item++;\n }\n break;\n case TB_OPTION_MODE_VAL:\n item++;\n break;\n case TB_OPTION_MODE_MORE:\n case TB_OPTION_MODE_END:\n default:\n item = tb_null;\n break;\n }\n }\n\n // dump options tail\n tb_printf(\"\\n\\n\");\n\n // dump values head\n tb_printf(\"[values]: \\n\");\n for (item = impl->opts; item; )\n {\n // dump item\n tb_size_t spaces = 32;\n switch (item->mode)\n {\n case TB_OPTION_MODE_KEY:\n case TB_OPTION_MODE_KEY_VAL:\n item++;\n break;\n case TB_OPTION_MODE_VAL:\n {\n // dump spaces\n tb_printf(\" \"); spaces -= 3;\n\n // dump long name\n if (item->lname) \n {\n tb_printf(\"%s\", item->lname);\n if (tb_strlen(item->lname) <= spaces) spaces -= tb_strlen(item->lname);\n }\n\n // dump help\n if (item->help) \n {\n tb_char_t line[8192] = {0};\n tb_char_t const* pb = item->help;\n tb_char_t* qb = line;\n tb_char_t* qe = line + 8192;\n while (qb < qe)\n {\n if (*pb !", "= '\\n' && *pb) *qb++ = *pb++;\n else\n {\n // strip line and next\n *qb = '\\0'; qb = line;\n\n // dump spaces\n while (spaces--) tb_printf(\" \");\n\n // dump help line\n tb_printf(\"%s\", line);\n\n // reset spaces\n spaces = 32;\n\n // next or end?", "\n if (*pb) \n {\n // dump new line\n tb_printf(\"\\n\");\n pb++;\n }\n else break;\n }\n }\n }\n\n // dump newline\n tb_printf(\"\\n\");\n\n // next\n item++;\n }\n break;\n case TB_OPTION_MODE_MORE:\n tb_printf(\" ...\\n\");\n case TB_OPTION_MODE_END:\n default:\n item = tb_null;\n break;\n }\n }\n\n // dump values tail\n tb_printf(\"\\n\");\n}\ntb_char_t const* tb_option_item_cstr(tb_option_ref_t option, tb_char_t const* name)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return_val(impl && impl->list && name, tb_null);\n\n // the option item\n tb_object_ref_t item = tb_oc_dictionary_value(impl->list, name);\n tb_check_return_val(item, tb_null);\n tb_assert_and_check_return_val(tb_object_type(item) == TB_OBJECT_TYPE_STRING, tb_null);\n\n // the option item value\n return tb_oc_string_size(item)? ", "tb_oc_string_cstr(item) : tb_null;\n}\ntb_bool_t tb_option_item_bool(tb_option_ref_t option, tb_char_t const* name)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return_val(impl && impl->list && name, tb_false);\n\n // the option item\n tb_object_ref_t item = tb_oc_dictionary_value(impl->list, name);\n tb_check_return_val(item, tb_false);\n tb_assert_and_check_return_val(tb_object_type(item) == TB_OBJECT_TYPE_BOOLEAN, tb_false);\n\n // the option item value\n return tb_oc_boolean_bool(item);\n}\ntb_uint8_t tb_option_item_uint8(tb_option_ref_t option, tb_char_t const* name)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return_val(impl && impl->list && name, 0);\n\n // the option item\n tb_object_ref_t item = tb_oc_dictionary_value(impl->list, name);\n tb_check_return_val(item, 0);\n tb_assert_and_check_return_val(tb_object_type(item) == TB_OBJECT_TYPE_NUMBER, 0);\n\n // the option item value\n return tb_oc_number_uint8(item);\n}\ntb_sint8_t tb_option_item_sint8(tb_option_ref_t option, tb_char_t const* name)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return_val(impl && impl->list && name, 0);\n\n // the option item\n tb_object_ref_t item = tb_oc_dictionary_value(impl->list, name);\n tb_check_return_val(item, 0);\n tb_assert_and_check_return_val(tb_object_type(item) == TB_OBJECT_TYPE_NUMBER, 0);\n\n // the option item value\n return tb_oc_number_sint8(item);\n}\ntb_uint16_t tb_option_item_uint16(tb_option_ref_t option, tb_char_t const* name)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return_val(impl && impl->list && name, 0);\n\n // the option item\n tb_object_ref_t item = tb_oc_dictionary_value(impl->list, name);\n tb_check_return_val(item, 0);\n tb_assert_and_check_return_val(tb_object_type(item) == TB_OBJECT_TYPE_NUMBER, 0);\n\n // the option item value\n return tb_oc_number_uint16(item);\n}\ntb_sint16_t tb_option_item_sint16(tb_option_ref_t option, tb_char_t const* name)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return_val(impl && impl->list && name, 0);\n\n // the option item\n tb_object_ref_t item = tb_oc_dictionary_value(impl->list, name);\n tb_check_return_val(item, 0);\n tb_assert_and_check_return_val(tb_object_type(item) == TB_OBJECT_TYPE_NUMBER, 0);\n\n // the option item value\n return tb_oc_number_sint16(item);\n}\ntb_uint32_t tb_option_item_uint32(tb_option_ref_t option, tb_char_t const* name)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return_val(impl && impl->list && name, 0);\n\n // the option item\n tb_object_ref_t item = tb_oc_dictionary_value(impl->list, name);\n tb_check_return_val(item, 0);\n tb_assert_and_check_return_val(tb_object_type(item) == TB_OBJECT_TYPE_NUMBER, 0);\n\n // the option item value\n return tb_oc_number_uint32(item);\n}\ntb_sint32_t tb_option_item_sint32(tb_option_ref_t option, tb_char_t const* name)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return_val(impl && impl->list && name, 0);\n\n // the option item\n tb_object_ref_t item = tb_oc_dictionary_value(impl->list, name);\n tb_check_return_val(item, 0);\n tb_assert_and_check_return_val(tb_object_type(item) == TB_OBJECT_TYPE_NUMBER, 0);\n\n // the option item value\n return tb_oc_number_sint32(item);\n}\ntb_uint64_t tb_option_item_uint64(tb_option_ref_t option, tb_char_t const* name)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return_val(impl && impl->list && name, 0);\n\n // the option item\n tb_object_ref_t item = tb_oc_dictionary_value(impl->list, name);\n tb_check_return_val(item, 0);\n tb_assert_and_check_return_val(tb_object_type(item) == TB_OBJECT_TYPE_NUMBER, 0);\n\n // the option item value\n return tb_oc_number_uint64(item);\n}\ntb_sint64_t tb_option_item_sint64(tb_option_ref_t option, tb_char_t const* name)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return_val(impl && impl->list && name, 0);\n\n // the option item\n tb_object_ref_t item = tb_oc_dictionary_value(impl->list, name);\n tb_check_return_val(item, 0);\n tb_assert_and_check_return_val(tb_object_type(item) == TB_OBJECT_TYPE_NUMBER, 0);\n\n // the option item value\n return tb_oc_number_sint64(item);\n}\n#ifdef TB_CONFIG_TYPE_HAVE_FLOAT\ntb_float_t tb_option_item_float(tb_option_ref_t option, tb_char_t const* name)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return_val(impl && impl->list && name, 0);\n\n // the option item\n tb_object_ref_t item = tb_oc_dictionary_value(impl->list, name);\n tb_check_return_val(item, 0);\n tb_assert_and_check_return_val(tb_object_type(item) == TB_OBJECT_TYPE_NUMBER, 0);\n\n // the option item value\n return tb_oc_number_float(item);\n}\ntb_double_t tb_option_item_double(tb_option_ref_t option, tb_char_t const* name)\n{\n // check\n tb_option_impl_t* impl = (tb_option_impl_t*)option;\n tb_assert_and_check_return_val(impl && impl->list && name, 0);\n\n // the option item\n tb_object_ref_t item = tb_oc_dictionary_value(impl->list, name);\n tb_check_return_val(item, 0);\n tb_assert_and_check_return_val(tb_object_type(item) == TB_OBJECT_TYPE_NUMBER, 0);\n\n // the option item value\n return tb_oc_number_double(item);\n}\n#endif\n" ]

{ "pile_set_name": "Github" }

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[ "hat is the square root of 4837 to the nearest integer?", "\n70\nWhat is the cube root of 86278 to the nearest integer?", "\n44\nWhat is 316 to the power of 1/2, to the nearest integer?", "\n18\nWhat is the third root of 1578 to the nearest integer?", "\n12\nWhat is the tenth root of 700 to the nearest integer?", "\n2\nWhat is the seventh root of 129901 to the nearest integer?", "\n5\nWhat is the eighth root of 2660 to the nearest integer?", "\n3\nWhat is 4342 to the power of 1/6, to the nearest integer?", "\n4\nWhat is the eighth root of 509 to the nearest integer?", "\n2\nWhat is the ninth root of 21420 to the nearest integer?", "\n3\nWhat is the third root of 21500 to the nearest integer?", "\n28\nWhat is the square root of 806 to the nearest integer?", "\n28\nWhat is the third root of 6734 to the nearest integer?", "\n19\nWhat is the square root of 8969 to the nearest integer?", "\n95\nWhat is the cube root of 3649 to the nearest integer?", "\n15\nWhat is the tenth root of 2359 to the nearest integer?", "\n2\nWhat is 22947 to the power of 1/2, to the nearest integer?", "\n151\nWhat is the square root of 8518 to the nearest integer?", "\n92\nWhat is 4857 to the power of 1/7, to the nearest integer?", "\n3\nWhat is 46864 to the power of 1/2, to the nearest integer?", "\n216\nWhat is the sixth root of 5132 to the nearest integer?", "\n4\nWhat is the cube root of 14693 to the nearest integer?", "\n24\nWhat is the square root of 2038 to the nearest integer?", "\n45\nWhat is the fifth root of 5028 to the nearest integer?", "\n5\nWhat is the ninth root of 4278 to the nearest integer?", "\n3\nWhat is 16384 to the power of 1/6, to the nearest integer?", "\n5\nWhat is the fifth root of 11 to the nearest integer?", "\n2\nWhat is the third root of 60067 to the nearest integer?", "\n39\nWhat is 7759 to the power of 1/10, to the nearest integer?", "\n2\nWhat is 44020 to the power of 1/3, to the nearest integer?", "\n35\nWhat is 3708 to the power of 1/10, to the nearest integer?", "\n2\nWhat is 21418 to the power of 1/3, to the nearest integer?", "\n28\nWhat is 1216 to the power of 1/8, to the nearest integer?", "\n2\nWhat is 1227 to the power of 1/3, to the nearest integer?", "\n11\nWhat is 919 to the power of 1/3, to the nearest integer?", "\n10\nWhat is 31250 to the power of 1/2, to the nearest integer?", "\n177\nWhat is 4771 to the power of 1/4, to the nearest integer?", "\n8\nWhat is 655 to the power of 1/2, to the nearest integer?", "\n26\nWhat is the square root of 37263 to the nearest integer?", "\n193\nWhat is the ninth root of 617 to the nearest integer?", "\n2\nWhat is the square root of 21602 to the nearest integer?", "\n147\nWhat is the sixth root of 21289 to the nearest integer?", "\n5\nWhat is the square root of 872 to the nearest integer?", "\n30\nWhat is the seventh root of 528 to the nearest integer?", "\n2\nWhat is the square root of 62482 to the nearest integer?", "\n250\nWhat is the third root of 1093 to the nearest integer?", "\n10\nWhat is 1924 to the power of 1/3, to the nearest integer?", "\n12\nWhat is the cube root of 18464 to the nearest integer?", "\n26\nWhat is 65640 to the power of 1/2, to the nearest integer?", "\n256\nWhat is 2560 to the power of 1/3, to the nearest integer?", "\n14\nWhat is the square root of 4510 to the nearest integer?", "\n67\nWhat is 3677 to the power of 1/5, to the nearest integer?", "\n5\nWhat is 20578 to the power of 1/5, to the nearest integer?", "\n7\nWhat is the third root of 91223 to the nearest integer?", "\n45\nWhat is 3996 to the power of 1/2, to the nearest integer?", "\n63\nWhat is 30063 to the power of 1/4, to the nearest integer?", "\n13\nWhat is the cube root of 22487 to the nearest integer?", "\n28\nWhat is the fourth root of 12830 to the nearest integer?", "\n11\nWhat is the seventh root of 6129 to the nearest integer?", "\n3\nWhat is the square root of 1248 to the nearest integer?", "\n35\nWhat is the square root of 574 to the nearest integer?", "\n24\nWhat is the square root of 34873 to the nearest integer?", "\n187\nWhat is 2914 to the power of 1/2, to the nearest integer?", "\n54\nWhat is the cube root of 5659 to the nearest integer?", "\n18\nWhat is the fourth root of 29226 to the nearest integer?", "\n13\nWhat is the square root of 77780 to the nearest integer?", "\n279\nWhat is the seventh root of 15206 to the nearest integer?", "\n4\nWhat is 32083 to the power of 1/2, to the nearest integer?", "\n179\nWhat is the third root of 1464 to the nearest integer?", "\n11\nWhat is 43468 to the power of 1/3, to the nearest integer?", "\n35\nWhat is the square root of 4 to the nearest integer?", "\n2\nWhat is the square root of 13516 to the nearest integer?", "\n116\nWhat is the third root of 3135 to the nearest integer?", "\n15\nWhat is 1654 to the power of 1/3, to the nearest integer?", "\n12\nWhat is the cube root of 8069 to the nearest integer?", "\n20\nWhat is 7154 to the power of 1/9, to the nearest integer?", "\n3\nWhat is the ninth root of 4629 to the nearest integer?", "\n3\nWhat is the cube root of 12200 to the nearest integer?", "\n23\nWhat is 49271 to the power of 1/7, to the nearest integer?", "\n5\nWhat is the cube root of 1354 to the nearest integer?", "\n11\nWhat is 593 to the power of 1/2, to the nearest integer?", "\n24\nWhat is the square root of 46453 to the nearest integer?", "\n216\nWhat is the ninth root of 341 to the nearest integer?", "\n2\nWhat is 94435 to the power of 1/2, to the nearest integer?", "\n307\nWhat is the cube root of 876 to the nearest integer?", "\n10\nWhat is 1247 to the power of 1/4, to the nearest integer?", "\n6\nWhat is 1354 to the power of 1/3, to the nearest integer?", "\n11\nWhat is the seventh root of 130356 to the nearest integer?", "\n5\nWhat is 6842 to the power of 1/3, to the nearest integer?", "\n19\nWhat is 854 to the power of 1/2, to the nearest integer?", "\n29\nWhat is the square root of 7376 to the nearest integer?", "\n86\nWhat is 492 to the power of 1/8, to the nearest integer?", "\n2\nWhat is 680 to the power of 1/7, to the nearest integer?", "\n3\nWhat is 156438 to the power of 1/2, to the nearest integer?", "\n396\nWhat is the square root of 151253 to the nearest integer?", "\n389\nWhat is the square root of 4103 to the nearest integer?", "\n64\nWhat is the fourth root of 79620 to the nearest integer?", "\n17\nWhat is the cube root of 36175 to the nearest integer?", "\n33\nWhat is the cube root of 1096 to the nearest integer?", "\n10\nWhat is 60229 to the power of 1/6, to the nearest integer?", "\n6\nWhat is the cube root of 164 to the nearest integer?", "\n5\nWhat is the fourth root of 1363 to the nearest integer?", "\n6\nWhat is 406 to the power of 1/4, to the nearest integer?", "\n4\nWhat is the eighth root of 3087 to the nearest integer?", "\n3\nWhat is the third root of 24982 to the nearest integer?", "\n29\nWhat is the square root of 39399 to the nearest integer?", "\n198\nWhat is the third root of 21359 to the nearest integer?", "\n28\nWhat is the cube root of 457 to the nearest integer?", "\n8\nWhat is 8457 to the power of 1/5, to the nearest integer?", "\n6\nWhat is the seventh root of 25730 to the nearest integer?", "\n4\nWhat is the eighth root of 1284 to the nearest integer?", "\n2\nWhat is the cube root of 11386 to the nearest integer?", "\n22\nWhat is the seventh root of 14267 to the nearest integer?", "\n4\nWhat is the sixth root of 16037 to the nearest integer?", "\n5\nWhat is 17352 to the power of 1/7, to the nearest integer?", "\n4\nWhat is the tenth root of 1304 to the nearest integer?", "\n2\nWhat is the third root of 7523 to the nearest integer?", "\n20\nWhat is the third root of 35363 to the nearest integer?", "\n33\nWhat is 17625 to the power of 1/6, to the nearest integer?", "\n5\nWhat is the third root of 4051 to the nearest integer?", "\n16\nWhat is the square root of 1054 to the nearest integer?", "\n32\nWhat is the cube root of 2937 to the nearest integer?", "\n14\nWhat is 5629 to the power of 1/2, to the nearest integer?", "\n75\nWhat is 40591 to the power of 1/3, to the nearest integer?", "\n34\nWhat is 1057 to the power of 1/8, to the nearest integer?", "\n2\nWhat is the square root of 1076 to the nearest integer?", "\n33\nWhat is the seventh root of 1529 to the nearest integer?", "\n3\nWhat is the third root of 170479 to the nearest integer?", "\n55\nWhat is 15489 to the power of 1/3, to the nearest integer?", "\n25\nWhat is the third root of 1310 to the nearest integer?", "\n11\nWhat is 14330 to the power of 1/10, to the nearest integer?", "\n3\nWhat is the square root of 16483 to the nearest integer?", "\n128\nWhat is 97 to the power of 1/2, to the nearest integer?", "\n10\nWhat is 25058 to the power of 1/3, to the nearest integer?", "\n29\nWhat is the square root of 2747 to the nearest integer?", "\n52\nWhat is 0 to the power of 1/2, to the nearest integer?", "\n0\nWhat is the seventh root of 76807 to the nearest integer?", "\n5\nWhat is the eighth root of 555 to the nearest integer?", "\n2\nWha" ]

{ "pile_set_name": "DM Mathematics" }

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[ "Q:\n\nHow to make a secure key distribution scheme/protocol?", "\n\nWe are building a data processing platform on Amazon AWS. ", "We are going to store sensitive data in the S3 (encrypted) and then the Amazon EC2 node is going to be utilized to process this data. ", "We are planning to use hybrid encryption for the S3 data i.e. using symmetric Data Encryption Keys (DEK) & asymmetric Key Encryption Keys (KEK) & it will be done on client side before uploading the data to S3. ", "The encrypted DEK will be stored with S3 object in metadata The are going to be group of datasets & the keys will be different for these datasets. ", "\nWe are planning to build a small KMS system which can distribute keys to the EC2 nodes when they are going to process the data to decrypt it. ", "The KMS will be hosted on our premises and the transfer of the keys will be on VPN.", "\nThe question we are having is regarding the most suitable Key Distribution Protocol to build to distribute the keys to EC2 nodes. ", "We are considering building a webservice using REST/SSL to distribute the keys however since there are no WS-Security spec available for REST, we feel only REST/SSL will not suffice. ", "\n\nWhat can be additional implementation to tighten security?", "\nWhat are ways to authenticate/provision the EC2 node when it calls the REST webservice that it is spawned by us?", "\nWhat is most suitable - passing encrypted DEK to webservice & getting decrypted DEK vs simply getting KEK from the webservice & using it to decrypt DEK to decrypt the data?", "\nAny additional points to consider?", "\n\nA:\n\nFirst, you cannot securely move data over an untrusted network between two untrusted endpoints. ", "To securely distribute anything, whether it's keys or 100 GB Blu-Ray images, you're going to need one of two things set up on each endpoint to establish initial mutual trust between the two:\n\nA shared secret (i.e. a password or a shared key)\nOne half of an asymmetric keypair (i.e. a trusted certificate)\n\nSecond, you say you're using a VPN. ", "The whole point of a VPN is to transform an untrusted network into a trusted network between two now-trusted endpoints. ", "If your hosts automatically authenticate and join the VPN, they already have either a shared secret or a trusted certificate.", "\nAssuming your VPN is encrypted, your data will already be encrypted in transit between your network and the EC2 network. ", "If your EC2 hosts can join the VPN on startup, they already have enough information to identify themselves as one of your hosts. ", "If they can't, you can establish trust when the hosts are manually connected to the VPN by an administrator.", "\nOnce the endpoints are authenticated to join your trusted network, your EC2 hosts can exchange certificates, establishing a trusted link all the way through. ", "This is (sorta) how Kerberos works.", "\nNote that this won't protect your data against:\n\nA malicious insider - say, one of your own system or network admins\nPrograms that retain key material on the EC2 hosts longer than they need it\n\nThird, at an absolute minimum, for your own protection, your company will want to be able to audit all access to key materials in a way that's secured against an attacker with root access. ", "You may also need to audit all access to encrypted materials in the database. ", "Think hard about what it would take to implement that.", "\nFourth, protecting your keys at rest (against an attacker who wants to gain root on your KMS or any of your EC2 hosts) is an entirely different problem, and it's even harder to solve than protecting keys in transit between two mutually trusted hosts. ", "I've been involved in implementing a \"PCI-DSS network island\" in the past, and it's a giant pain.", "\nI strongly recommend that your company hire a security consultant with experience setting up distributed key management systems. ", "The problem here isn't only the known risks - the things you know you need to defend yourself against - but what Rumsfeld famously called the \"unknown unknowns\" - risks you don't even know you have. ", "\nAs a developer myself, I wouldn't trust my abilities to design and implement a full crypto-system without outside advice from an expert.", "\n\n" ]

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[ "Exploring a benzyloxyaniline linker utilizing ceric ammonium nitrate (CAN) as a cleavage reagent: solid-phase synthesis of N-unsubstituted beta-lactams and secondary amides.", "\n[figure: see text] A novel benzyloxyaniline linker that uses ceric ammonium nitrate (CAN) as a cleavage reagent is described. ", "Its application in the solid-phase synthesis of N-unsubstituted beta-lactams and secondary amides furnishes compounds in moderate to excellent yield (45-91%) and high purity (93-99%)." ]

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[ "\n109 Ariz. 427 (1973)\n510 P.2d 743\nSTATE of Arizona, Appellee,\nv.\nElgin BENTON, Appellant.", "\nNo. ", "2470.", "\nSupreme Court of Arizona, In Banc.", "\nJune 12, 1973.", "\nGary K. Nelson, Atty. ", "Gen., Thomas A. Jacobs, Asst. ", "Atty. ", "Gen., Phoenix, for appellee.", "\nRoss P. Lee, Public Defender, Maricopa County, James H. Kemper, Deputy Public Defender, Phoenix, for appellant.", "\nLOCKWOOD, Justice:\nThe defendant Elgin Benton appeals from a judgment based upon a jury verdict finding him guilty of robbery in violation of A.R.S. § 13-641 and from a sentence of not less than six nor more than eight years.", "\nIt was alleged in the information that Benton robbed Victor Garcia on August 3, 1971. ", "The defendant pleaded not guilty. ", "The facts pertaining to the robbery are as follows: As Garcia approached a phone booth, he noticed two boys near the New Valley Market. ", "They approached him and asked him how long he was going to use the phone. ", "When he turned to dial, one of the boys (later identified by him as the defendant) *428 unsuccessfully reached for his wallet. ", "Garcia ran the two boys off, completed his call, and started to return to his truck parked nearby. ", "As he reached it, he was attacked by four or five boys who began to beat him. ", "A fight ensued and after this the man identified by Garcia as Benton ran away and the others followed. ", "Garcia did not actually see anyone take his wallet, but he testified that prior to the struggle he had his wallet in his pocket containing $80.00 and several credit cards and that after the struggle the wallet was gone.", "\nElizabeth Graves, a cashier at the market, knew the defendant by name and recalled seeing him at the market just prior to the time of the incident. ", "She also testified that she saw Benton running toward the housing project after what was apparently a tussle on the other side of the truck.", "\nDuring the course of its instructions to the jury, the court gave one on flight. ", "In addition, at trial the prosecutor, during cross-examination, asked the defendant if he had told anyone besides the arresting officer of his innocence.", "\nThe defendant claims the court erred in giving an instruction on flight as evidence of guilt. ", "Defendant further contends that his right to refrain from self-incrimination under the fifth and fourteenth amendments of the federal constitution was violated by the question relating to whether he had told anyone beside the arresting officer of his innocence.", "\nThe test for whether an instruction on flight is warranted by the evidence was pronounced in State v. Owen, 94 Ariz. 404, 411, 385 P.2d 700, 704 (1963), reversed on other grounds, 378 U.S. 574, 84 S.Ct. ", "1932, 12 L.Ed.2d 1041 (1964).", "\nWe said:\n\"Certainly a mere leaving of the scene of a crime is not a fact sufficient to constitute flight under all circumstances * * *. ", "Ordinarily, unless the flight or attempted flight be open, as upon immediate pursuit, the element of concealment is considered a necessary component.\"", "\nThe state in Owen, supra, as in the present case, did not introduce specific evidence that the defendant was pursued or that he had later hidden or concealed himself. ", "Nevertheless, in Owen there was evidence that after the event, the defendant \"took off down the road\".", "\nWe do not feel that the flight instruction in the present case constitutes error. ", "From the testimony elicited at trial, there was substantial evidence showing that the defendant ran away from the parking lot for no apparent reason.", "\nElizabeth Graves, a cashier at the New Valley Market on whose property this crime took place, testified on direct examination as follows:\n\"Q. Okay. ", "Now, when you say Elgie, are you talking about this fellow right here?", "\n\"A. Yes.", "\n\"Q. Are you sure that he was one of them that was running away?", "\n\"A. Right.\"", "\nOn cross-examination she stated:\n\"A. Well, all I said is that I did see three guys running, and Elgie Benton was one of them.\"", "\nFrom the foregoing we feel that the flight instruction was justified as was any reasonable inference drawn therefrom and did not constitute error.", "\nThe defendant also claims that certain questions asked him during cross-examination and several statements made by the prosecutor during closing argument constituted reversible error, even though not objected to at the time.", "\nThe arresting officers testified that they merely served the warrant upon the defendant telling him it was for robbery and he said he was not involved in any robbery. ", "The prosecutor asked him if he had told this to anyone else and he replied that he had not. ", "No objection was made to this line of questioning and we cannot *429 see that it raises any question of fundamental error. ", "State v. Belcher, 108 Ariz. 290, 496 P.2d 590 (1972); State v. Jackson, 201 Kan. 795, 443 P.2d 279 (1968), cert. ", "denied, 394 U.S. 908, 89 S.Ct. ", "1019, 22 L.Ed.2d 219 (1969).", "\nAffirmed.", "\nHAYS, C.J., CAMERON, V.C.J., and STRUCKMEYER and HOLOHAN, JJ., ", "concur.", "\n" ]

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[ "A lethal neonatal phenotype of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency.", "\nShort-chain enoyl-CoA hydratase (SCEH) is a mitochondrial enzyme involved in the oxidation of fatty acids and the catabolic pathway of valine and, to a lesser extent, isoleucine. ", "Deficiency of this enzyme was recently shown to cause an early childhood Leigh syndrome phenotype. ", "The few reported patients were compound heterozygotes for two missense or missense with truncating variants in ECHS1 that encodes SCEH. ", "We describe two siblings with severe refractory lactic acidosis and death within the first 2 days of life. ", "Following negative clinical whole-exome and whole-genome sequencing, we resorted to autozygome/exome analysis on research basis and identified a homozygous splice site mutation (c.88+5G>A) in the two cases. ", "Analysis of cDNA confirmed complete replacement of the normal transcript with an aberrant transcript (r.88_89ins 88+1_88+11) predicting premature truncation of the protein [p.(Ala31Glufs*23)]. ", "Furthermore, quantitative reverse transcriptase polymerase chain reaction (RTPCR) showed marked reduction in ECHS1, most likely nonsense-mediated decay (NMD)-mediated. ", "This is the first report of homozygosity for a truncating mutation in ECHS1, which may explain the severe phenotype. ", "Our report highlights the need to consider SCEH deficiency in patients with lethal neonatal lactic acidosis, and the potentially limited sensitivity of untargeted genomic sequencing towards non-canonical splicing mutations, which may explain at least some of the 'negative' cases on clinical exome/genome sequencing." ]

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[ "Mining Ether on a Mac\n\nIs there an alpha mining client for mac? ", "I've downloaded the \"Proof of Concept client #3 for mac and I've got it running but I don't see anything connecting or working. ", "And there are no \"mining\" options that I can see. ", "And I don't see a link or info about the test mining clients.", "\n\nCould someone please point me in the right direction or explain the current status of test mining with a mac.", "\n\ni've got Console 1: geth --rpc and Console 2: ethminer -G running and this is a sample of the output i'm getting. ", "I'm also getting the memory frag warning as you can see but i do think i'm getting a higher hash so it must be working somewhat. ", "any ideas?", "\n\nUPDATE: So i have been able to see my through the geth console my hashrate and ether balanceI think i mined 1 block, ether balance = 1.5 hashrate states 384(sounds pretty poor)still would be good to get my dual gpus mining\n\nI have not been able to mine on my Macbook Pro. ", "I have set one other rig with multiple cards, but getting it to work in my Mac is a real pain... if anyone has a formula for Macbook Pro mining. ", "Please can u share every step?", "\n\nHow to get it all going. ", "For those like me who are getting their feet wet in this Ethereum mining ... pool, as with Bitcoin mining, there are lots and lots of people who say \"Dont' bother. ", "Run away. ", "You will never make any money.\" ", "Well \"yaa, boo, sux\" to them. ", "I'm investigating this because it's interesting, and will be as big as the Internet in a day or so. ", "And things change. ", "Things change daily. ", "And there is money to be made. ", "Not much admittedly, but some.", "\n\nSo after much head scratching - because yes, there are no DOCs, and what there is is often out of date by days, or even years at worst. ", "So this is what I have finally managed.", "I have the Mist, Ethereum-Wallet installed on my Mac Mini. ", "16Gb RAM, 2TB Storage. ", "A built up Late 2012 model. ", "Not the fastest kid on the block, but what I can afford.", "That unpacks into it's own directory, that you can put anywhere you like. ", "In that directory is two programs. ", "One is called Ethereum-Wallet - with a Diamond as the icon. ", "That's the GUI. ", "Don't run that first actually, although you can if you want to have a look at it. ", "It starts up in Test mode anyway. ", "That's fine. ", "Create your valid account later. ", "But the big secret is. ", "Nothing will happen usefully until the whole thing synchronises the blocks. ", "And there are millions ... it can take days. ", "So here's what you do. ", "You use the other program that comes with it called 'geth' to start the synchronising. ", "It's command line, so you need to be in a Terminal window. ", "First: Start Ethereum-Wallet to create the required system storage directories, then stop it.", "Now. ", "cd to the directory where you put your unpacked program bundle, and type this in../geth --fast --ipcpath /Users/robert/Library/Ethereum/geth.ipcPress enter.", "Note the --ipcpath option. ", "Replace my name - robert - with your user account name on your mac. ", "It's your home directory. ", "ok.", "\n\nNow, go away for a few days. ", "Go 5,000 miles away. ", "Change your name. ", "Begin a new life. ... ", "because synchronising will take like - forever.", "\n\nOnce it settles down, and starts pulling in blocks. ", "You can watch the count by starting Ethereum-Wallet. ", "Point Finder at it and double click. ", "Once it starts, It will show you a running count of what is done, and what is left to do.", "You can't mine until it's finished.....When you come back in a few days, months, years...\n\nThe next thing is Mining. ", "Ahhh, show me the money. ", "For this I will be using AlethZero. ", "And guess what. ", "A really nice package is available that contains AlethZero - a nice Ether mining app that runs ONLY on ElCaptain, and Yosemite. ", "If you are pre that, forget it. ", "Roll your own with that sodding Homebrew thing. ", "Which I hate. ", "Upgrade dude.", "So these are pre-built DMG packages that jstt install right out of the bag. ", "Nice. ", "You also get Mix-ide. ", "Forget that for now. ", "What's so nice about AlethZero, is that it's Ether mining for the GPU, as well as the CPU, and I think mining rigs, although I haven't investigated that yet. ", "Like everything else to do with Ethereum and Bitcoin - There are NO instructions. ", "One rubbish Video clip on Youtube that is like two years old. ", "Shees. ", "You see, that's what happens when everyone starts saying \"No point now, the Chinese made all the money, don't bother.", "\"But having said that, it's actually pretty easy to figure out, and a nice GUI interface to go with it.", "Again - don't bother until your blocks are synchronised.", "\n\nYou will note that so far - I haven't installed anything with Homebrew. ", "That is so last year. ", "If this is the technology that is taking over the world - then someone had better get off their butt, and create some decent software to run it all, and Instruction manuals.", "\n\nThe bottom line is. ", "Yes, mining is slow, even for Bitcoin and Ethereum. ", "But given the prices for both now, even small grains are becoming expensive. ", "Look at it this way. ", "No one throws out the gold dust in the bottom of the pan, just because its not a 5oz nugget do they...\n\nI installed geth and cpp-ethereum both using homebrew because I already use that for other things. ", "I also downloaded mist from github. ", "I started trying to sync with mist and that was a serious mistake. ", "It was taking forever, and was constantly hanging. ", "I tried running geth and cpp-ethereum to see which was faster, but it seemed to be about equal. ", "I have also upgraded both geth and cpp-ethereum several times with hombrew and not had any issues. ", "I am running geth 1.4.5-stable-a269a713.", "\n\nTo make sure that I had a clean blockchain DB I deleted the existing DB (geth removedb), then ran geth --fast (taking the default DB location so there would be no issues later) and let it go. ", "The sync took maybe 25-30 minutes and now I usually leave geth running in it's own terminal window to keep the blockchain DB up to date.", "\n\nWhen I run mist now, it determines that I already have geth running and automatically uses it. ", "I have conducted a number of transactions and voted on a number of TheDAO proposals with no problems.", "\n\nFor mining I am using a separate GPU mining rig with a single MSI R7 370 Gaming 4G GPU. ", "It runs ethOS which is a tweaked version of ubuntu 14.04. ", "The mining rig points directly to the pool and is earning me a bit over 1 ETH per week. ", "I see the deposits from the mining pool in my mist mining account with a dedicated wallet so I can see the transactions.", "\n\nI installed geth and cpp-ethereum both using homebrew because I already use that for other things. ", "I also downloaded mist from github. ", "I started trying to sync with mist and that was a serious mistake. ", "It was taking forever, and was constantly hanging. ", "I tried running geth and cpp-ethereum to see which was faster, but it seemed to be about equal. ", "I have also upgraded both geth and cpp-ethereum several times with hombrew and not had any issues. ", "I am running geth 1.4.5-stable-a269a713.", "\n\nTo make sure that I had a clean blockchain DB I deleted the existing DB (geth removedb), then ran geth --fast (taking the default DB location so there would be no issues later) and let it go. ", "The sync took maybe 25-30 minutes and now I usually leave geth running in it's own terminal window to keep the blockchain DB up to date.", "\n\nWhen I run mist now, it determines that I already have geth running and automatically uses it. ", "I have conducted a number of transactions and voted on a number of TheDAO proposals with no problems.", "\n\nFor mining I am using a separate GPU mining rig with a single MSI R7 370 Gaming 4G GPU. ", "It runs ethOS which is a tweaked version of ubuntu 14.04. ", "The mining rig points directly to the pool and is earning me a bit over 1 ETH per week. ", "I see the deposits from the mining pool in my mist mining account with a dedicated wallet so I can see the transactions.", "\n\nCheers,\n\n- zed\n\nThis is really useful stuff. ", "So it looks like I'm going to be better off buying a good PC, one of these cards, and setting up the same way.", "Clean and straight forward.", "Thanks.", "\n\nMeantime, I'm still struggling with trying to get cpp-ethereum built on the Mac.", "\n\n@ShanghaiTimes if you want to set up a rig, try working with gpushack.com. ", "They have some nice MOBO bundles that includes everything you need to mine except GPU and PSU. ", "If you can source PC stuff cheaper/easier do yourself a favor and order the download version of ethOS from gpushack.com and write it to an SSD (16GB is enough). ", "I purchased this MOBO bundle http://gpushack.com/collections/gpushack/products/mobo-cpu-ram-ssd-bundle-for-4-gpus and with the GPU and PSU I bought elsewhere, was up and running very quickly. ", "The miner has been up almost 3 weeks non-stop. ", "It would have been longer except we lost power here. ", "Here is a link to some info about the miner: http://d9c53b.ethosdistro.com\n\nRegarding the home-brew error, try running brew update, then brew doctor and see if anything is not quite right. ", "If all is well, try to install cpp-ethereum again. ", "I installed the latest cpp-ethereum a few minutes ago with no problems at all.", "\n\n@zedzednova Thanks, that's invaluable advice. ", "Much appreciated. ", "The Homebrew error was because - probably just at that time - the git hub repo had been moved to webthree-umbrella from cpp-ethereum on git. ", "I eventually got it installed by pulling down the webthree-umbrella repo and just building that by hand. ", "If the Homebrew maintainers havent fixed it already, I'm sure they will soon.", "I am definately going to have to go the way you did, explained above.", "Meantime I struggle on to understand this lot. :", "-)Thanks." ]

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[ "What are your thoughts in using a 3rd party batteries for GoPro Hero 7?", "\n\nhello! ", "Been reading on the net about this and it is a mixed reaction. ", "Some say that they deplete faster than the original GoPro battery and some have fantastic result. ", "I'm also concerned that it might damage the unit? ", "or perhaps when goPro update their firmware, it will not detect the battery?", "\n\nRe: What are your thoughts in using a 3rd party batteries for GoPro Hero 7?", "\n\nI don't think it's worth saving a few bucks to have a non-offical battery, especially if GoPro ever decides to kill our ability to use 3rd-party with a firmware update (They have done that in the past)." ]

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[ "using System;\nusing System.", "Threading.", "Tasks;\nusing CloudStructures.", "Internals;\nusing StackExchange.", "Redis;\n\n\n\nnamespace CloudStructures.", "Structures\n{\n /// <summary>\n /// Provides string related commands.", "\n /// </summary>\n /// <typeparam name=\"T\">Data type</typeparam>\n public readonly struct RedisString<T> : IRedisStructureWithExpiry\n {\n #region IRedisStructureWithExpiry implementations\n /// <summary>\n /// Gets connection.", "\n /// </summary>\n public RedisConnection Connection { get; }\n\n\n /// <summary>\n /// Gets key.", "\n /// </summary>\n public RedisKey Key { get; }\n\n\n /// <summary>\n /// Gets default expiration time.", "\n /// </summary>\n public TimeSpan? ", "DefaultExpiry { get; }\n #endregion\n\n\n #region Constructors\n /// <summary>\n /// Creates instance.", "\n /// </summary>\n /// <param name=\"connection\"></param>\n /// <param name=\"key\"></param>\n /// <param name=\"defaultExpiry\"></param>\n public RedisString(RedisConnection connection, RedisKey key, TimeSpan? ", "defaultExpiry)\n {\n this.", "Connection = connection ?? ", "throw new ArgumentNullException(nameof(connection));\n this.", "Key = key;\n this.", "DefaultExpiry = defaultExpiry;\n }\n #endregion\n\n\n #region Commands\n //- [] StringAppendAsync\n //- [x] StringDecrementAsync\n //- [x] StringGetAsync\n //- [] StringGetRangeAsync\n //- [x] StringGetSetAsync\n //- [x] StringGetWithExpiryAsync\n //- [x] StringIncrementAsync\n //- [x] StringLengthAsync\n //- [x] StringSetAsync\n //- [] StringSetRangeAsync\n\n\n /// <summary>\n /// DECRBY : http://redis.io/commands/decrby\n /// </summary>\n public Task<long> DecrementAsync(long value = 1, TimeSpan? ", "expiry = null, CommandFlags flags = CommandFlags.", "None)\n {\n expiry ??", "= this.", "DefaultExpiry;\n return this.", "ExecuteWithExpiryAsync\n (\n (db, a) => db.", "StringDecrementAsync(a.key, a.value, a.flags),\n (key: this.", "Key, value, flags),\n expiry,\n flags\n );\n }\n\n\n /// <summary>\n /// INCRBYFLOAT : http://redis.io/commands/incrbyfloat\n /// </summary>\n public Task<double> DecrementAsync(double value, TimeSpan? ", "expiry = null, CommandFlags flags = CommandFlags.", "None)\n {\n expiry ??", "= this.", "DefaultExpiry;\n return this.", "ExecuteWithExpiryAsync\n (\n (db, a) => db.", "StringDecrementAsync(a.key, a.value, a.flags),\n (key: this.", "Key, value, flags),\n expiry,\n flags\n );\n }\n\n \n /// <summary>\n /// GET : http://redis.io/commands/get\n /// </summary>\n public async Task<RedisResult<T>> GetAsync(CommandFlags flags = CommandFlags.", "None)\n {\n var value = await this.", "Connection.", "Database.", "StringGetAsync(Key, flags).ConfigureAwait(false);\n return value.", "ToResult<T>(this.", "Connection.", "Converter);\n }\n\n\n /// <summary>\n /// GETSET : http://redis.io/commands/getset\n /// </summary>\n public async Task<RedisResult<T>> GetSetAsync(T value, TimeSpan? ", "expiry = null, CommandFlags flags = CommandFlags.", "None)\n {\n expiry ??", "= this.", "DefaultExpiry;\n var serialized = this.", "Connection.", "Converter.", "Serialize(value);\n var result\n = await this.", "ExecuteWithExpiryAsync\n (\n (db, a) => db.", "StringGetSetAsync(a.key, a.serialized, a.flags),\n (key: this.", "Key, serialized, flags),\n expiry,\n flags\n )\n .ConfigureAwait(false);\n return result.", "ToResult<T>(this.", "Connection.", "Converter);\n }\n\n\n /// <summary>\n /// GET : http://redis.io/commands/get\n /// </summary>\n public async Task<RedisResultWithExpiry<T>> GetWithExpiryAsync(CommandFlags flags = CommandFlags.", "None)\n {\n var value = await this.", "Connection.", "Database.", "StringGetWithExpiryAsync(this.", "Key, flags).ConfigureAwait(false);\n return value.", "ToResult<T>(this.", "Connection.", "Converter);\n }\n\n\n /// <summary>\n /// INCRBY : http://redis.io/commands/incrby\n /// </summary>\n public Task<long> IncrementAsync(long value = 1, TimeSpan? ", "expiry = null, CommandFlags flags = CommandFlags.", "None)\n {\n expiry ??", "= this.", "DefaultExpiry;\n return this.", "ExecuteWithExpiryAsync\n (\n (db, a) => db.", "StringIncrementAsync(a.key, a.value, a.flags),\n (key: this.", "Key, value, flags),\n expiry,\n flags\n );\n }\n\n\n /// <summary>\n /// INCRBYFLOAT : http://redis.io/commands/incrbyfloat\n /// </summary>\n public Task<double> IncrementAsync(double value, TimeSpan? ", "expiry = null, CommandFlags flags = CommandFlags.", "None)\n {\n expiry ??", "= this.", "DefaultExpiry;\n return this.", "ExecuteWithExpiryAsync\n (\n (db, a) => db.", "StringIncrementAsync(a.key, a.value, a.flags),\n (key: this.", "Key, value, flags),\n expiry,\n flags\n );\n }\n\n\n /// <summary>\n /// STRLEN : https://redis.io/commands/strlen\n /// </summary>\n public Task<long> LengthAsync(CommandFlags flags = CommandFlags.", "None)\n => this.", "Connection.", "Database.", "StringLengthAsync(this.", "Key, flags);\n\n\n /// <summary>\n /// SET : http://redis.io/commands/set\n /// </summary>\n public Task<bool> SetAsync(T value, TimeSpan? ", "expiry = null, When when = When.", "Always, CommandFlags flags = CommandFlags.", "None)\n {\n expiry ??", "= this.", "DefaultExpiry;\n var serialized = this.", "Connection.", "Converter.", "Serialize(value);\n return this.", "Connection.", "Database.", "StringSetAsync(this.", "Key, serialized, expiry, when, flags);\n }\n #endregion\n\n\n #region Custom Commands\n /// <summary>\n /// GET : http://redis.io/commands/get\n /// SET : http://redis.io/commands/set\n /// </summary>\n public async Task<T> GetOrSetAsync(Func<T> valueFactory, TimeSpan? ", "expiry = null, CommandFlags flags = CommandFlags.", "None)\n {\n expiry ??", "= this.", "DefaultExpiry;\n var result = await this.", "GetAsync(flags).ConfigureAwait(false);\n if (result.", "HasValue)\n {\n return result.", "Value;\n }\n else\n {\n var value = valueFactory();\n await this.", "SetAsync(value, expiry, When.", "Always, flags).ConfigureAwait(false);\n return value;\n }\n }\n\n\n /// <summary>\n /// GET : http://redis.io/commands/get\n /// SET : http://redis.io/commands/set\n /// </summary>\n public async Task<T> GetOrSetAsync(Func<Task<T>> valueFactory, TimeSpan? ", "expiry = null, CommandFlags flags = CommandFlags.", "None)\n {\n expiry ??", "= this.", "DefaultExpiry;\n var result = await this.", "GetAsync(flags).ConfigureAwait(false);\n if (result.", "HasValue)\n {\n return result.", "Value;\n }\n else\n {\n var value = await valueFactory().ConfigureAwait(false);\n await this.", "SetAsync(value, expiry, When.", "Always, flags).ConfigureAwait(false);\n return value;\n }\n }\n\n\n /// <summary>\n /// GET : http://redis.io/commands/get\n /// DEL : http://redis.io/commands/del\n /// </summary>\n /// <param name=\"flags\"></param>\n /// <returns></returns>\n public async Task<RedisResult<T>> GetAndDeleteAsync(CommandFlags flags = CommandFlags.", "None)\n {\n var result = await this.", "GetAsync(flags).ConfigureAwait(false);\n if (result.", "HasValue)\n await this.", "DeleteAsync(flags).ConfigureAwait(false);\n return result;\n }\n\n\n /// <summary>\n /// LUA Script including incrby, set\n /// </summary>\n public async Task<long> IncrementLimitByMaxAsync(long value, long max, TimeSpan? ", "expiry = null, CommandFlags flags = CommandFlags.", "None)\n {\n expiry ??", "= this.", "DefaultExpiry;\n var script =\n@\"local inc = tonumber(ARGV[1])\nlocal max = tonumber(ARGV[2])\nlocal x = redis.call('incrby', KEYS[1], inc)\nif(x > max) then\n redis.call('set', KEYS[1], max)\n x = max\nend\nreturn x\";\n var keys = new[] { this.", "Key };\n var values = new RedisValue[] { value, max };\n var result\n = await this.", "ExecuteWithExpiryAsync\n (\n (db, a) => db.", "ScriptEvaluateAsync(a.script, a.keys, a.values, a.flags),\n (script, keys, values, flags),\n expiry,\n flags\n )\n .ConfigureAwait(false);\n return (long)result;\n }\n\n\n /// <summary>\n /// LUA Script including incrbyfloat, set\n /// </summary>\n public async Task<double> IncrementLimitByMaxAsync(double value, double max, TimeSpan? ", "expiry = null, CommandFlags flags = CommandFlags.", "None)\n {\n expiry ??", "= this.", "DefaultExpiry;\n var script =\n@\"local inc = tonumber(ARGV[1])\nlocal max = tonumber(ARGV[2])\nlocal x = tonumber(redis.call('incrbyfloat', KEYS[1], inc))\nif(x > max) then\n redis.call('set', KEYS[1], max)\n x = max\nend\nreturn tostring(x)\";\n var keys = new[] { this.", "Key };\n var values = new RedisValue[] { value, max };\n var result\n = await this.", "ExecuteWithExpiryAsync\n (\n (db, a) => db.", "ScriptEvaluateAsync(a.script, a.keys, a.values, a.flags),\n (script, keys, values, flags),\n expiry,\n flags\n )\n .ConfigureAwait(false);\n return double.", "Parse((string)result);\n }\n\n\n /// <summary>\n /// LUA Script including incrby, set\n /// </summary>\n public async Task<long> IncrementLimitByMinAsync(long value, long min, TimeSpan? ", "expiry = null, CommandFlags flags = CommandFlags.", "None)\n {\n expiry ??", "= this.", "DefaultExpiry;\n var script =\n@\"local inc = tonumber(ARGV[1])\nlocal min = tonumber(ARGV[2])\nlocal x = redis.call('incrby', KEYS[1], inc)\nif(x < min) then\n redis.call('set', KEYS[1], min)\n x = min\nend\nreturn x\";\n var keys = new[] { this.", "Key };\n var values = new RedisValue[] { value, min };\n var result\n = await this.", "ExecuteWithExpiryAsync\n (\n (db, a) => db.", "ScriptEvaluateAsync(a.script, a.keys, a.values, a.flags),\n (script, keys, values, flags),\n expiry,\n flags\n )\n .ConfigureAwait(false);\n return (long)result;\n }\n\n\n /// <summary>\n /// LUA Script including incrbyfloat, set\n /// </summary>\n public async Task<double> IncrementLimitByMinAsync(double value, double min, TimeSpan? ", "expiry = null, CommandFlags flags = CommandFlags.", "None)\n {\n expiry ??", "= this.", "DefaultExpiry;\n var script =\n@\"local inc = tonumber(ARGV[1])\nlocal min = tonumber(ARGV[2])\nlocal x = tonumber(redis.call('incrbyfloat', KEYS[1], inc))\nif(x < min) then\n redis.call('set', KEYS[1], min)\n x = min\nend\nreturn tostring(x)\";\n var keys = new[] { this.", "Key };\n var values = new RedisValue[] { value, min };\n var result\n = await this.", "ExecuteWithExpiryAsync\n (\n (db, a) => db.", "ScriptEvaluateAsync(a.script, a.keys, a.values, a.flags),\n (script, keys, values, flags),\n expiry,\n flags\n )\n .ConfigureAwait(false);\n return double.", "Parse((string)result);\n }\n #endregion\n }\n}\n" ]

{ "pile_set_name": "Github" }

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[ "The environmental activist group Greenpeace wanted to be prepared to counter President Bush's visit last week to Pennsylvania to promote his nuclear energy policy.", "\n\n\"This volatile and dangerous source of energy\" is no answer to the country's energy needs, shouted a Greenpeace fact sheet, decrying the \"threat\" posed by the reactors Bush visited in Limerick.", "\n\nBut after that assertion, the Greenpeace authors were apparently stumped while searching for the ideal menacing metaphor.", "\n\n\"In the twenty years since the Chernobyl tragedy, the world's worst nuclear accident, there have been nearly [FILL IN ALARMIST AND ARMAGEDDONIST FACTOID HERE],\" the sheet said.", "\n\nThe Greenpeace spokesman who issued the memo, Steve Smith, told the Web site that a colleague was making a joke in a draft that was then mistakenly released.", "\n\nThe final version did not mention Armageddon; instead it warned of plane crashes and reactor meltdowns.", "\n\n-- Philly.com" ]

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[ "Design of a high-foot high-adiabat ICF capsule for the national ignition facility.", "\nThe National Ignition Campaign's [M. J. Edwards et al., ", "Phys. ", "Plasmas 20, 070501 (2013)] point design implosion has achieved DT neutron yields of 7.5×10(14) neutrons, inferred stagnation pressures of 103 Gbar, and inferred areal densities (ρR) of 0.90 g/cm2 (shot N111215), values that are lower than 1D expectations by factors of 10×, 3.3×, and 1.5×, respectively. ", "In this Letter, we present the design basis for an inertial confinement fusion capsule using an alternate indirect-drive pulse shape that is less sensitive to issues that may be responsible for this lower than expected performance. ", "This new implosion features a higher radiation temperature in the \"foot\" of the pulse, three-shock pulse shape resulting in an implosion that has less sensitivity to the predicted ionization state of carbon, modestly lower convergence ratio, and significantly lower ablation Rayleigh-Taylor instability growth than that of the NIC point design capsule. ", "The trade-off with this new design is a higher fuel adiabat that limits both fuel compression and theoretical capsule yield. ", "The purpose of designing this capsule is to recover a more ideal one-dimensional implosion that is in closer agreement to simulation predictions. ", "Early experimental results support our assertions since as of this Letter, a high-foot implosion has obtained a record DT yield of 2.4×10(15) neutrons (within ∼70% of 1D simulation) with fuel ρR=0.84 g/cm2 and an estimated ∼1/3 of the yield coming from α-particle self-heating." ]

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[ "Prognostic value of Doppler transmitral flow patterns in patients with congestive heart failure.", "\nThis study was designed to determine whether Doppler echocardiographic transmitral flow patterns can predict cardiac mortality in patients with congestive heart failure. ", "Previous studies have indicated that Doppler transmitral flow patterns are related to New York Heart Association functional class and exercise capacity in patients with congestive heart failure. ", "However, the prognostic significance of these flow patterns is not known. ", "We analyzed the relation of transmitral flow patterns and cardiac mortality in 100 consecutive patients (76 men, 24 women; mean [+/- SD] age 60 +/- 11 years) with congestive heart failure symptoms and left ventricular ejection fraction < 40%. ", "At the time of entry into the study, functional class and ejection fraction by radionuclide angiography were determined, and Doppler echocardiography was performed in all patients. ", "Transmitral flow was obtained from the apical four-chamber view at the mitral annulus level. ", "Measurements included early (E) and atrial (A) filling velocities, E/A ratio and deceleration time of the E wave. ", "The patients were assigned to two groups according to E/A ratio or deceleration time of transmitral flow patterns, or both: a non-restrictive group (42 patients) with E/A < or = 1 or E/A = 1 to 2 and deceleration time > 140 ms, and a restrictive group (58 patients) with E/A > or = 2 or E/A = 1 to 2 and deceleration time < or = 140 ms. ", "Of 100 patients, 26 died during a mean follow-up period of 16 +/- 8 months. ", "The cumulative cardiac mortality rate determined by the Kaplan-Meier method was 14% at 1 year and 35% at 2 years. ", "Cox proportional hazards model analysis revealed that transmitral flow (restrictive vs. nonrestrictive, chi-square 6.99, p = 0.008), patient gender (female vs. male, chi-square 4.59, p = 0.03) and New York Heart Association functional class (IV vs. II, chi-square 3.95, p = 0.05) were significantly related to cardiac mortality in patients with congestive heart failure. ", "Mortality rate in the restrictive group was markedly higher than that in the nonrestrictive group at 1 year (19% vs. 5%, respectively, p < 0.05) and at 2 years (51% vs. 5%, respectively, p < 0.01) by log-rank test. ", "Relative risk for cardiac death was estimated as 4.1 at 1 year and 8.6 at 2 years in the restrictive group compared with the nonrestrictive group. ", "In patients with congestive heart failure, a restrictive transmitral flow pattern, female gender and advanced functional class are predictive of higher cardiac mortality. ", "The restrictive transmitral flow pattern by Doppler echocardiography is the single best clinical predictor for cardiac death in patients with congestive heart failure." ]

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[ "\n590 F.Supp. ", "643 (1984)\nPACIFIC INDEMNITY COMPANY\nv.\nRobert LINN, D.O., Stephen D. Moses, D.O., Robert Linn Medical Associates, David H. Smith, Individually and as Administrator of the Estate of Patricia Smith, Deceased, Jack Silberlicht, Executor of the Estate of Judith Silberlicht, Deceased, Aetna Insurance Company, William K. Myrletus, Director, Pennsylvania Professional Liability Catastrophe Loss Fund, Chicago Insurance Company, and Interstate Fire & Casualty Company\nv.\nNATIONWIDE MUTUAL FIRE INSURANCE COMPANY, Pennsylvania Professional Liability Joint Underwriting Association.", "\nCiv. ", "A. No. ", "79-699.", "\nUnited States District Court, E.D. Pennsylvania.", "\nJune 25, 1984.", "\n*644 *645 Henry H. Janssen, Rawle & Henderson, Philadelphia, Pa., for plaintiff.", "\nWalter W. Rabin, Philadelphia, Pa., for Robert Linn, D.O., Stephen D. Moses, D.O. and Robert Linn Medical Associates.", "\nJay J. Lambert, Philadelphia, Pa., for Pennsylvania Professional Liability Joint Underwriting Ass'n.", "\nJohn A. Guernsey, Philadelphia, Pa., for Interstate Fire & Cas. ", "Co.\nKevin Canavah, Philadelphia, Pa., for Nationwide Mut. ", "Fire Ins. ", "Co.\nThomas C. DeLorenzo, Philadelphia, Pa., for Aetna Ins. ", "Co.\nDavid M. Donaldson, Philadelphia, Pa., for Pennsylvania Professional Liability Catastrophe Loss Fund.", "\n\nMEMORANDUM AND ORDER\nSHAPIRO, District Judge.", "\nThis is a declaratory judgment action by Pacific Indemnity Company (\"Pacific\") to determine which insurance company, if any, must defend and indemnify claims against Robert Linn, D.O. (\"Dr. Linn\") which have been or may be asserted on behalf of persons who read Dr. Linn's book, The Last Chance Diet, followed the diet program it recommended, and consequently suffered personal injury or death. ", "Liability was asserted for malpractice, professional negligence, breach of warranty and/or products liability arising out of the purchase of Dr. Linn's book and/or a dieting protein product called \"Prolinn.\" ", "As notice of each of these \"bookreader\" claims was given to the insured, Pacific agreed to defend Dr. Linn under a reservation of rights in cases falling within its policy period. ", "The other insurers refused to defend Dr. Linn against any of the claims. ", "By Memorandum and Order dated July 24, *646 1981, and by Opinion filed December 1, 1982, the court determined obligations to defend Dr. Linn against these underlying claims and now disposes of remaining indemnity issues and motions for reimbursement filed by the parties.", "\nThe matter first came before the court on cross-motions for summary judgment by all insurance companies that were defendants to the amended complaint. ", "Nationwide Mutual Fire Insurance Company (\"Nationwide\"), a third-party defendant, did not move for summary judgment. ", "The Joint Underwriting Association (\"JUA\") was then a defendant; it challenged the jurisdiction of the court because JUA is an unincorporated association with some corporate members in the state of citizenship of plaintiff. ", "The court determined that JUA was a legal entity separate from its members and a citizen only of Pennsylvania but then reconsidered. ", "By Memorandum of September 14, 1981, the court dismissed JUA as a party defendant with leave to join JUA as a third-party defendant; JUA was subsequently so joined by agreement of the parties.", "\nIn a Memorandum and Order of July 24, 1981 on the motions, the court: denied certification of a nationwide defendant class of claimants who had not yet asserted claims against Dr. Linn; held the issues of insurance coverage were determined by Pennsylvania law; dismissed defendant Chicago Insurance Company (\"Chicago\") because it did not provide coverage either at the time the alleged torts occurred or at the time the claims were made; and decided issues as to the duty of the insurance companies to defend to the extent there were no material issues of fact. ", "The complaint in each underlying case of record was analyzed in regard to each insurance policy then before the court.", "\nBut in deciding the cross-motions for summary judgment, the court limited its decision to the duty to defend and declined to determine each insurer's duty to indemnify Dr. Linn for judgments that might be entered against him. ", "The duty to defend is distinct from the duty to indemnify; an insurance company must defend the action if the factual allegations of the underlying complaint on their face state a claim against the insured to which the policy potentially applies. ", "C.H. Heist Caribe Corp. v. American Home Assurance Company, 640 F.2d 479, 483 (3d Cir.1981). ", "Because factual findings not yet made in the underlying actions would affect the insurers' obligations to indemnify, this court was of the opinion that decision on the obligation to indemnify was premature and must await further developments.", "\nBy agreement of Dr. Linn and all insurance companies other than Nationwide, and in accordance with an order entered by this court on October 2, 1981, Aetna Insurance Company (\"Aetna\") and Interstate Fire & Casualty Company (\"Interstate\") each contributed the sum of $20,000 and JUA contributed $5,000 to a fund to be disbursed by counsel for Dr. Linn in payment of costs and counsel fees expended in defense of the lawsuits pending against him.", "\nOn December 14, 1981, following trial on December 7-11, 1981 of the issues remaining as to the duty to defend, in consideration of the parties' request for a prompt decision and with the agreement of all parties hereto, the court filed a Memorandum of Decision that stated its opinion of the parties' duty to defend defendants Robert Linn, D.O., Stephen D. Moses, D.O. and Robert Linn Medical Associates. ", "Attorneys' fees, costs and expenses incurred to that date were to be awarded accordingly. ", "Attorneys' fees, costs and expenses in the action for declaratory judgment were not awarded to that date but the court informed the parties that it might award such fees and costs from that time forward.", "\nWith the encouragement of the court considerable discussion ensued among the parties as to a modus vivendi prior to a final, appealable order. ", "On December 4, 1981, a stipulation of procedure was filed that provided that in the event one or more of the parties was held liable to reimburse reasonable defense and investigation fees, costs and expenses incurred either in the *647 defense of the underlying claims or the declaratory judgment itself, any dispute on the reasonableness of the amounts would be referred to final, binding Defense Research Institute Arbitration. ", "However, all parties continued to seek final determination not only of the obligation to defend but also of the obligation to indemnify. ", "The court granted leave to the parties to move to amend the complaints, cross-claims and third-party complaints to assert claims only as to the obligation to defend and to delete claims as to indemnification without prejudice to their reassertion in a subsequent action or actions for indemnification, but only defendant Linn so moved and his motion was opposed by others.", "\nIn accordance with and pursuant to the court's December 14, 1981 Memorandum, and following a pretrial conference, Aetna undertook to defend and settle the James, Bass, Lehman, Silberlicht, Cochran, Hudgens, Harmon, and Hunton,[1] cases without prejudice to its right to seek reimbursement and without question, objection or contest regarding the necessity or reasonableness of the sums paid by Aetna in defense or settlement; Aetna did undertake the defense of those cases, reimbursed Pacific for Aetna's proportionate shares of defense costs in the James and Bass cases, and expended certain sums in settlement of the Lehman and Silberlicht cases and in defense of the Lehman, Silberlicht, Cochran, Hudgens, Harmon, and Hunton cases.", "\nUpon due notice to and refusal by Nationwide to advance 50% of those settlement and defense expenditures, Aetna paid and was assigned the claims of Dr. Linn against Nationwide for costs in defense of the lawsuits brought against him. ", "Aetna filed its first motion for reimbursement in November, 1982; it was opposed by Nationwide in part on the ground that there had been no judgment filed by the court.", "\nThereafter, on December 1, 1982, the court filed Findings of Fact and Conclusions of Law as to the parties' duty to defend only. ", "The court reconsidered whether it should decide the duty to indemnify because subsequent to decision on the summary judgment motions, the Court of Appeals, in ACandS Casualty and Surety Co. v. The Travelers Indemnity Co., 666 F.2d 819 (3d Cir.1981), had reversed a district court's determination of non-justiciability in a declaratory judgment action to determine which of two insurance companies had the obligation to defend and indemnify asbestos lawsuits. ", "It held an actual case or controversy present with respect to that indemnity obligation notwithstanding uncertainty as to the amount of the insured's liability; determining the insurers' respective liabilities would permit settlement of the underlying lawsuits and avoid unnecessary costs and the risk of litigation. ", "Id. at 823.", "\nIn ACandS, the insurance dispute was \"real and concrete,\" because \"the factors that will determine the relative duties and benefits under the insurance contracts are independent of the underlying claims.\" ", "Id. at 822-23. ", "But here not only the amount of potential liability but the factual predicate for determining coverage itself was missing; the insurers' obligations to indemnify Dr. Linn were not independent of the underlying claims. ", "The underlying complaints stated claims for personal and professional negligence, strict products liability, breach of warranty, and misrepresentation; if a particular suit were to result in a judgment for that plaintiff against Dr. Linn, the indemnity obligation of his insurers could depend on which theory or theories might prevail at trial. ", "ACandS was inapposite because each insurer's contractual duty to indemnify Dr. Linn was dependent on development of factual records in the underlying cases.", "\nAs in Heist, supra, which was neither referred to nor overruled by the panel in ACandS, \"[the] obligation to indemnify ... cannot be determined merely on the basis of whether the factual allegations of [each] complaint potentially state a claim against *648 the insured. ", "Actual indemnification depends upon the existence or nonexistence of facts not yet established.\" ", "Id. at 483. ", "Therefore, the court held the obligation of Pacific, Aetna, JUA and Nationwide to indemnify Dr. Linn, Dr. Moses and Linn Associates could not yet be determined. ", "In the view of the court, there was no actual controversy under the Declaratory Judgment Act because the question of indemnification as to the policies in suit was not ripe for decision. ", "But this holding was clearly without prejudice to later determination of the right of indemnification upon final disposition of the underlying claims, whether by settlement or judgment. ", "Cf., ", "Sandoz, Inc. v. Employer's Liability Assurance Corp., 554 F.Supp. ", "257 (D.N.J. 1983) (plaintiff, having incurred costs in settlement in underlying cases, presented issue as to indemnification sufficiently concrete, immediate and adverse to defendant insurance companies to constitute a justiciable controversy on partial summary judgment; factual disputes as to date of onset and manifestation of injuries precluded allocation of liability among the defendants prior to trial).", "\nAetna and Pacific moved for reimbursement but Nationwide moved for amendment of the judgment or in the alternative for new trial. ", "Then Nationwide withdrew its motion and appealed the judgment, as did Aetna and Pacific.", "\nOn February 22, 1983, the Court of Appeals dismissed the interlocutory appeals for lack of jurisdiction without prejudice to certification by the district court under Fed.", "R.Civ.", "P. 54(b); Aetna and Nationwide moved for certification to the appellate court. ", "But while the interlocutory appeals were pending, all the underlying cases except for Harmon had been terminated. ", "All underlying actions except for Harmon[2] having been determined, the indemnification issues had become ripe for decision by this court. ", "Therefore, by Memorandum and Order dated November 9, 1983, this court denied the motions for certification of appeal as not in the interest of sound judicial administration. ", "But the motions for reimbursement were denied until presented in a manner enabling resolution consistent with the court's determination of the legal issues.", "\nThe court held argument on all remaining issues, particularly with regard to certain recent cases decided by the Third Circuit subsequent to the court's Opinion filed December 1, 1982.[3]\n\nI. DUTY TO DEFEND\nThe court determined the various obligations to defend Dr. Linn against the underlying complaints by Memorandum and Order of July 24, 1981 and an Opinion filed December 1, 1982, incorporated by reference herein. ", "Since then, two cases, Selected Risks, supra, and Standard Venetian Blind Co. v. American Empire Insurance Co., 469 A.2d 563 (Pa.1983), have limited the insurer's obligation to explicitly inform a prospective insured of policy exclusions. ", "In Hionis v. Northern Mutual Insurance Co., 230 Pa.Super. ", "511, 327 A.2d 363 (1974), the Pennsylvania Superior Court had held that \"where a policy is written in unambiguous terms, the burden of establishing the applicability of the exclusion or limitation involves proof that the insured was aware of the exclusion or limitation and that the effect thereof was explained to him.\" ", "230 Pa.Super. ", "at 517, 327 A.2d at 365. ", "The Third Circuit subsequently held in Selected Risks that Hionis protected only reasonable expectations, so that an exclusion, even if not explained to the insured, is effective against the insured's unreasonable expectations. ", "But Standard Venetian Blind, a later decision of the Pennsylvania *649 Supreme Court, rejected Hionis entirely so long as the exclusion clause is clear, unambiguous, and prominently displayed, whether or not the insured had reasonable expectations of coverage; to the extent that Selected Risks is inconsistent, it is Standard Venetian Blind that now provides the basis for decision:\n\nHionis, which would permit an insured to avoid the application of a clear and unambiguous limitation clause in an insurance contract, is not to be followed. ... ", "We hold only that where, as here, the policy limitation relied upon by the insurer to deny coverage is clearly worded and conspicuously displayed, the insured may not avoid the consequences of that limitation by proof that he failed to read the limitation or that he did not understand it.", "\n469 A.2d at 567 (emphasis added). ", "However, neither Selected Risks nor Standard Venetian Blind alters the court's prior rulings as to duty to defend.", "\nThe relevant exclusion in the JUA professional liability policy states that the policy does not cover liability arising out of \"ownership, operation or supervision by the Insured ... of ... any business enterprise.\" ", "The court has previously decided that the meaning of \"business enterprise,\" not defined in the policy, and the intent of the parties as to the scope of the exclusion were unclear and were therefore strictly construed against the insurer. (", "Memorandum and Order of July 24, 1981 at 28). ", "The insured physician could have reasonably expected that a professional liability policy would provide coverage for lawsuits alleging medical malpractice or professional negligence even though they arise from the publication and sale of a book. ", "Because the exclusion is not clear and unambiguous, this court's decision does not deviate from the plain language of the insurance contract in disregard of Standard Venetian Blind.", "\nAetna's commercial insurance policy contains a \"products hazard\" exclusion which denies coverage for \"[b]odily injury ... arising out of the named insured's products.", "\"[4] The \"named insured's product\" is defined as \"goods or products manufactured, sold, handled or distributed by the named insured, ... including any container thereof.\" ", "The court has held this exclusion ineffective because the insured was unaware of it, and even if he \"[h]ad ... read the 140-page Aetna commercial package policy and been made aware of the products hazard exclusion clause prior to writing the book, [he] would not have understood that manufacture or distribution of a product referred to writing a book.... The ordinary person does not consider that an author `manufacturers' a book in writing it.\" (", "Opinion filed December 1, 1982 at 7, 14).", "\nStandard Venetian Blind does not change the inapplicability of this exclusion. ", "While Aetna may in fact have intended the clause to exclude the instant occurrences from coverage, that intent is certainly not clearly worded nor prominently displayed in the 140-page policy. ", "The clause is ambiguous; it cannot be ascertained from its undefined terms whether or not writing a book is manufacturing a product within the meaning of the exclusion. ", "Even if Dr. Linn were fully aware of the products hazards exclusion, he would not necessarily have understood that manufacture or distribution of a product referred to and included writing a book. ", "Neither would most people. ", "It is not unreasonable to expect that a commercial insurance policy will cover liability incurred by writing a book.", "\nFinally, Nationwide's \"personal negligence\" policy excludes liability arising from \"any errors or omissions in the rendering of a professional service, ... [and] activities in connection with a business *650 solely owned by an Insured or owned by a partnership of which an Insured is a partner.\" ", "The court previously held that even if these exclusionary clauses were not rendered inapplicable by Hionis, they did not exclude coverage for the bookreader claims. (", "See, Opinion filed December 1, 1982 at 16-17). ", "The former exclusion applied only to professional acts; Nationwide was not required to defend Dr. Linn against complaints alleging negligent professional rather than personal acts. ", "The latter exclusion applied only to \"activities in connection with a business solely owned by an Insured or owned by a partnership of which the Insured is a partner,\" and not to income-producing endeavors which are not part of a business operating with assets of the insured. ", "Because Hionis had no material effect on Nationwide's exclusions, its subsequent limitation is not relevant to the applicability of its exclusions.", "\nThe only other exclusion the applicability of which might be affected by the Standard Venetian Blind and Selected Risks cases is the \"business or business products\" exclusion in Interstate's professional and personal liability excess policy. ", "But it is now clear that the excess coverage of the Interstate policy will not be called upon by any of the bookreader cases with the possible (although highly unlikely) exception of Harmon. ", "The exclusion would affect Interstate's obligation to indemnify and not its obligation to defend; the court has not yet determined whether the exclusion precludes coverage although Hionis would have made the clause inapplicable. ", "There is no need to determine now whether Standard Venetian Blind or Selected Risks have affected the applicability of the Interstate exclusion. ", "Should the Interstate policy in fact be implicated by Harmon, the court will then deal with the exclusionary clause.", "\n\nII. ", "DUTY TO INDEMNIFY\nThe underlying bookreader claims, excepting Harmon, have all now been terminated by settlement or final judgment in favor of Dr. Linn. ", "The obligation to indemnify in each case (except Harmon) is now ripe for decision.[5] Unlike the duty to defend, the duty to indemnify \"cannot be determined merely on the basis of whether the factual allegations of [the underlying] complaint potentially state a claim against the insured.\" ", "Heist, supra at 483. ", "Rather, there must be a determination that the insurer's policy actually covers the claimed incident.", "\nHere, the various insurers were obligated to defend Dr. Linn because the underlying complaints stated causes of action on which there was potential liability. ", "The court deferred deciding which insurers were obligated to indemnify Dr. Linn until the final disposition of each underlying case presented a factual basis for determining which insurers had indemnity obligations. ", "However, because those cases implicating the duty to indemnify were terminated by settlement rather than final judgment,[6] it is now impossible to determine on what theories of liability, if any, the underlying plaintiffs would have prevailed. ", "There are no factual findings to consider in determining which insurers are obligated to indemnify Dr. Linn. ", "As a result, the duty to indemnify must follow the duty to defend.", "\nWhere a complaint alleges facts supporting more than one theory of recovery from an insured, including a claim potentially covered by the insured's policy, \"it [is] the duty of the [insurer] to undertake the defence, until it [can] confine the claim to a recovery that the policy [does] not cover.\" ", "Lee v. Aetna Casualty & Surety *651 Co., 178 F.2d 750, 753 (2d Cir.1949). ", "See also, Pittsburgh Plate Glass Co. v. Fidelity and Casualty Co. of N.Y., 281 F.2d 538 (3d Cir.1960) (insurer obligated to defend must do so until claim is narrowed to one outside policy coverage); Cadwallader v. New Amsterdam Casualty Co., 396 Pa. 582, 152 A.2d 484 (1959) (same). ", "Thus, the duty to defend in effect carries with it the conditional obligation to indemnify until such time as it becomes clear that there can be no recovery within the insuring clause. ", "See, Cadwallader, supra. ", "Since all the relevant underlying cases (except Harmon) have been settled and there are no factual findings establishing those claims, if any, on which the bookreader plaintiffs would have prevailed, the insurers cannot confine potential claims to those clearly outside the scope of coverage.[7] Those insurers found obligated to defend Dr. Linn are therefore also responsible for any payments made in settling the bookreader cases. ", "See, Ripepi v. American Insurance Companies, 349 F.2d 300 (3d Cir.1969); Cadwallader, supra.[8]\nAccordingly, the following carriers are initially obligated to indemnify the insured up to the amounts of their respective policy limits:\nJames: Pacific, JUA, Aetna\nSmith: Pacific, JUA, Aetna, Nationwide\nLehman: Aetna, Nationwide\nSilberlicht: Aetna, Nationwide\nBass: Pacific, JUA, Aetna\nIf the Harmon case is terminated in favor of Dr. Linn or settles prior to a determination that any claims therein do not fall within the scope of a particular policy, the duty to indemnify will follow that in the Silberlicht case (Aetna and Nationwide sharing the primary obligation to indemnify Dr. Linn).[9] The court will retain jurisdiction and determine the duty to indemnify in Harmon following final disposition of that case.", "\nThis discussion of indemnification applies to the primary insurers. ", "The excess policies are not implicated by the results in the underlying cases to date. ", "It is now unnecessary to determine which excess insurers would have had indemnification obligations. ", "In the unlikely event that Harmon results in a settlement or judgment in excess of the primary policy limits, that issue remains for subsequent determination.", "\n\nIII. ", "APPORTIONMENT AND CONTRIBUTIONS\nVarious policies contain \"other insurance\" clauses limiting the extent of liability where the insured carries another policy or policies applicable to the claimed loss.[10] Under Pennsylvania law, \"other or *652 double insurance exists only where there are two or more insurance policies covering the same interest, the same subject matter and against the same risk.\" ", "Blue Anchor Overall Co. v. Pennsylvania Lumbermens Mutual Insurance Co., 385 Pa. 394, 400, 123 A.2d 413, 415 (1956). ", "For example, in Blue Anchor, plaintiff had suffered damage due to leakage from a fire sprinkler system. ", "Although plaintiff carried three fire insurance policies, including defendant's, only defendant's policy afforded protection against loss from leakage from fire protective equipment. ", "The court held defendant's \"other insurance\" clause, which required apportionment of liability in the event of other insurance, inapplicable because the other fire policies did not cover the same risk and therefore did not constitute other insurance. ", "See also, United National Insurance Co. v. Philadelphia Gas Works, 221 Pa.Super. ", "161, 289 A.2d 179 (1972) (certificate of self-insurance covering vehicles owned by and registered in the name of insured not \"other insurance\" with respect to insured's policy covering rented car).", "\nHere, some but not all the policies would be considered \"other insurance.\" ", "Pacific and JUA provide coverage for professional liability, i.e., liability for professional services rendered or which should have been rendered by the insured in the practice of the insured's profession. ", "Therefore, they are \"other insurance\" as to each other. ", "However, Aetna's primary policy provided commercial general liability coverage for occurrences resulting in bodily injury or property damage and insured against a risk distinct from the professional liability risk covered under the Pacific and JUA policies. ", "The Nationwide policy, the homeowner's policy protecting Dr. Linn against loss from negligent personal acts, insured against a risk different from that intended to be covered by either the Aetna commercial general liability policy or the professional liability policies of Pacific and JUA. ", "Neither the Aetna policy nor the Nationwide policy would be \"other insurance\" with respect to each other or to the Pacific and JUA policies.", "\nMore than one policy has been deemed applicable to each bookreader case because the underlying complaints alleged several theories of liability that implicate different insurers. ", "But had a bookreader case resulted in monetary judgment against Dr. Linn, only one insurer might have been liable for the judgment. ", "For example, the plaintiff in Lehman alleged both strict liability and negligence; therefore, Aetna and Nationwide were obligated to defend Dr. Linn. ", "Had the case not settled, it is possible that the plaintiff would have prevailed on one claim but not the other. ", "In that case, only one of the insurers would have been obligated to indemnify Dr. Linn. ", "Aetna and Nationwide cannot be \"other insurance\" as to each other because they did not insure against the same risk of liability.", "\nOnly JUA and Pacific insure the same interest, the same subject matter and the same risk, and may be deemed \"other insurance\" as to each other. ", "The Pacific policy provides that if the insured has other insurance covering the occurrence, any loss shall be distributed on a \"pro rata\" basis, i.e., each insurer shall be liable for that portion of the loss which the applicable limit of the single policy bears to the total applicable limits of all valid and collectible insurance. ", "JUA's policy contains an \"excess\" other insurance clause which states, \"[i]f the Insured carries a policy of another insurer against any loss covered by this policy, the Association shall not be liable for any payment hereunder until all payments under such other insurance are exhausted.\" ", "JUA's \"other insurance\" clause also states that \"the limits of liability under this policy shall be reduced by the extent of payments made by such other insurer.\" ", "This additional language could operate as an \"escape\" clause if the other insurers have policy limits equal to or in excess of JUA's policy limits.[11] Where *653 one policy containing an \"excess\" clause and another policy containing a \"pro rata\" clause are concurrently effective, the \"excess\" clause will be given full effect and the \"pro rata\" clause will be disregarded. ", "Walters v. Dunlap, 250 F.Supp. ", "76 (W.D. Pa.) aff'd 368 F.2d 118 (3rd Cir.1966). ", "Therefore, unless and until the Pacific policy limits have been reached, JUA is not obligated to pay.", "\nThere is no bookreader case in which only these two insurers have been found liable for defense and indemnity costs. ", "Two cases, James and Bass, implicate JUA, Pacific and Aetna. ", "One case, Smith, implicates those three insurers and also Nationwide. ", "While the JUA \"other insurance\" clause affects the amount payable under the Pacific policy, the JUA policy is not excess to either Aetna's policy (in James, Bass and Smith) or Nationwide's policy (in Smith) because neither of those policies insures against the same risk as the JUA policy. ", "For the same reason, the Pacific \"pro rata\" clause does not affect amounts payable under the Aetna or Nationwide policies.", "\nAs a result, in the James and Bass cases, JUA, Pacific, and Aetna would initially be equally liable for the amount paid in settlement and in the Smith case, JUA, Pacific, Aetna and Nationwide would be liable. ", "However, because JUA's \"other insurance\" clause is effective as to Pacific's policy, Pacific is also liable for JUA's share of settlement costs.[12] Therefore, in James and Bass, Pacific is obligated to indemnify Dr. Linn for two-thirds of each settlement payment (its own one-third liability and JUA's one-third liability) and Aetna is liable for one-third. ", "In Smith, Pacific must indemnify Dr. Linn for one-half of the settlement payment (its own one-quarter liability plus JUA's one-quarter liability); Aetna and Nationwide are each obligated for one-quarter of the settlement payment. ", "In the remaining cases, Lehman and Silberlicht, Aetna and Nationwide are each liable for one-half the settlement.", "\nEach insurer has the following policy limits: Aetna — $500,000 each occurrence, $500,000 yearly aggregate; Pacific—$200,000/$600,000; JUA — $100,000/$300,000; Nationwide — $100,000 each occurrence with no aggregate. ", "The James case was settled for $1,500, Smith for $100,000, Lehman for $40,000, Silberlicht for $115,000, and Bass for $35,000. ", "Therefore, the liability of each insurer is:\nJames: Aetna is liable for $500;\n Pacific is liable for $1,000;\n JUA is not liable for any amount\n because no payment in excess of\n the Pacific policy was required.", "\nSmith: Aetna is liable for $25,000;\n Pacific is liable for $50,000;\n Nationwide is liable for $25,000;\n JUA is not liable for any amount\n because no payment in excess of\n the Pacific policy was required.", "\nLehman: Aetna and Nationwide are each\n liable for $20,000.", "\nSilberlicht: Aetna and Nationwide are each\n liable for $67,500.", "\nBass: Aetna is liable for $11,666.67;\n Pacific is liable for $23,333.33;\n JUA is not liable for any amount\n because no payment in excess of\n the Pacific policy was required.", "\nNo case disposition to date implicates the excess policies. ", "It is possible that Harmon may result in a settlement or judgment which would require payments from one or more of the excess policies, but the plaintiff in Harmon would have to recover more than $475,333.33 (the $375,333.33 remaining from Aetna's $500,000/$500,000 policy limit plus the $100,000 per occurrence limit of Nationwide's policy). ", "That figure is more than four times higher than the highest recovery in a bookreader case to date. *", "654 Of course, if the case proceeds to judgment, the basis for recovery against Dr. Linn could render either Aetna's or Nationwide's policy, or both, inapplicable, in which case an insurer excess on the coverage implicated by the ground for recovery against the insured (e.g., CAT Fund, Interstate, or Aetna) might be liable. ", "The court has determined to await the outcome of Harmon to decide if any excess insurer has an indemnity obligation.", "\n\nIV. ", "REIMBURSEMENT\nThe insurers seek reimbursement for money expended in the defense and settlement of various bookreader cases. ", "These claims for reimbursement had been denied without prejudice until all underlying cases had been terminated. ", "The court has now determined the obligations regarding the defense and indemnification of Dr. Linn in the underlying bookreader cases except for Harmon. ", "The reimbursement petitions are ripe for determination except that reimbursement for money spent in regard to the Harmon case must await its termination.", "\nPacific, Aetna, JUA and Interstate have all filed petitions for reimbursement. ", "Pacific seeks reimbursement from Aetna, or, in the alternative, Interstate, for funds expended in the defense and/or settlement of the James, Bass, Smith, Lehman, Cochran and Silberlicht cases.[13] Aetna claims reimbursement from Nationwide for money expended in defense and/or settlement of the Lehman, Silberlicht, Cochran, Hudgens and Hunton cases,[14] and from Pacific for settlement payments made in the James and Bass cases. ", "JUA seeks reimbursement from Aetna and Nationwide for funds expended in defense of the Hunton case. ", "Interstate seeks reimbursement from Aetna and Nationwide for funds advanced in defense of Hunton.", "\nReimbursement will be awarded in accordance with the duties to defend and indemnify. ", "Since the duty to defend is independent of liability and any limitations thereon, see, Liberty Mutual, supra at 988; Brunner, supra at 499, each insurer owing Dr. Linn a defense is required to contribute to costs of defense in equal shares with any other insurer also obligated to defend Dr. Linn. ", "See, e.g., First Insurance Co. of Hawaii v. Continental Casualty Co., 466 F.2d 807, 811 (9th Cir. ", "1972).[15] Each carrier required to indemnify Dr. Linn for settlement costs must do so in the amount previously specified.[16] Therefore, each party's claim for reimbursement is granted to the extent the claim reflects payment in excess of the defense and indemnity obligations determined above. ", "Any question as to the reasonableness of the amounts claimed (including, for example, Aetna's claim that certain defense sums were not expended on the Hunton case) is to be submitted to arbitration *655 in accordance with the agreement of the parties.[17]\n\nV. DECLARATORY JUDGMENT EXPENSES\nThe court may award attorneys' fees and costs in bringing an action to establish the duties to defend and indemnify where an insurer's refusal to defend an insured in an underlying action has been unreasonable and in bad faith. ", "Montgomery Ward & Co. v. Pacific Indemnity Co., 557 F.2d 51 (3d Cir.1977); Kelmo Enterprises v. Commercial Union Ins. ", "Co., 285 Pa.Super. ", "13, 426 A.2d 680 (1981). ", "The court determined in its prior opinion, filed December 1, 1982, that the conduct of the insurers did not then warrant an award of attorneys' fees and costs because the complex and unusual factual and legal situation prevented clear determination of the duties to defend and indemnify to that time. ", "But that opinion also clearly determined the various obligations to defend. ", "Since then, only Nationwide has refused to contribute in any way to the defense of Dr. Linn in the bookreader cases. ", "Such refusal in light of the court's opinion on Nationwide's duty to defend can only be characterized as unreasonable and lacking in the good faith required of an insurer with respect to its insured. ", "Therefore, the court will award the other parties attorneys' fees and costs in maintaining this declaratory judgment action from the date of the court's prior opinion, December 1, 1982.", "\nThe court recognizes that part of the fees and costs incurred by the remaining carriers since the court's prior opinion were spent in briefing the duty to indemnify and would have been incurred in spite of Nationwide's obstinate behavior. ", "But the court is not required to allocate fees and costs where allocation would be exceedingly difficult. ", "See generally, Hensley v. Eckerhart, 461 U.S. 424, 103 S.Ct. ", "1933, 76 L.Ed.2d 40 (1983). ", "Moreover, Nationwide's refusal to supply any defense at all to Dr. Linn made settlement of both the underlying cases and the instant declaratory judgment action more difficult and extended the time needed to dispose of the matter. ", "The court awards attorneys' fees and costs without reduction for time spent on the indemnity issue. ", "Any question of reasonableness of the fees and costs will be determined through arbitration in accordance with the agreement of the parties.", "\n\nVI. ", "INTEREST\nThose carriers entitled to reimbursement for defense and indemnity costs are also entitled to prejudgment interest on the reimbursed funds. ", "In an ordinary suit for contract damages, prejudgment interest is limited to the six percent legal rate. ", "Peterson v. Crown Financial Corp., 661 F.2d 287, 292 (3d Cir.1981). ", "Where a claim calls for a court's broader equitable powers, e.g., claims involving unjust enrichment, the court may award prejudgment interest in an amount greater than six percent. ", "Id. at 292-93. ", "Although the actual duties to defend and indemnify are contractual in nature, see, e.g., Gedeon v. State Farm Mutual Automobile Ins. ", "Co., 261 F.Supp. ", "122, 123 (W.D.Pa.1966), aff'd in part, rev'd in part, 386 F.2d 600 (3d Cir. ", "1967), the right of contribution from others sharing a common burden is grounded in equity and does not arise from contract. ", "Massachusetts Bonding & Ins. ", "Co. v. Car & General Ins. ", "Co., 152 F.Supp. ", "477, 482 (E.D.Pa.1957); Embrey v. Borough of West Mifflin, 257 Pa.Super. ", "168, 390 A.2d 765 (1978). ", "Therefore, the court is not limited to an award of prejudgment interest at the statutory rate but may in its *656 discretion increase or decrease the applicable interest rate. ", "See, Peterson, supra.", "\nSince 1982, the Clerk of this court has awarded interest on judgments at the prevailing three-month Treasury Bill rate, as provided by the Federal Courts Improvement Act of 1982. ", "According to the Federal Reserve Bank figures during the pendency of this action, the average three-month Treasury Bill rate fluctuated between 8.63% and 14.08%. ", "The court considers ten percent (10%) a fair average figure and awards prejudgment interest at that rate for all reimbursable funds from the date expended.[18]\n\nVII. ", "FED.R.CIV.P. 54(b) CERTIFICATION\nIn this declaratory judgment action to determine duties of defense and indemnification with regard to certain claims against the insured, one of the underlying claims remains pending; the duty to indemnify therein cannot yet be determined. ", "The court cannot render a final judgment so the Court of Appeals would still lack jurisdiction over an interlocutory appeal unless certified under Fed.", "R.Civ.", "P. 54(b).", "\nThis court previously denied certification of the duty to defend issues to prevent the necessity of duplicative and piecemeal review by the Court of Appeals and to determine the obligation to indemnify issues that were then ripe for decision. ", "See, Memorandum and Order dated November 9, 1983. ", "The trial court has now determined all the defense obligations and the indemnity obligations for all the underlying actions except Harmon. ", "Because the indemnity obligation in Harmon, if terminated prior to preclusion of any claims now made, will follow the obligation in Silberlicht, the risk of duplicative and piecemeal review is no longer significant. ", "It is unlikely the disposition of Harmon will implicate the excess policies, but if it does, the issue is severable from those finally disposed of by the trial court herein. ", "There now being no just reason for delay, pursuant to Fed.", "R.Civ.", "P. 54(b) the court will expressly direct the entry of judgment on defense and indemnification as to all the bookreader cases except for Harmon to permit consideration by the Court of Appeals now.", "\n\nJUDGMENT\n\nFor the parties referred to herein, see Appendix \"A.\"\n\nFor the Complaints referred to herein, see Appendix \"B.\"\n\nFor the Insurance Policies referred to herein, see Appendix \"C.\"\nAND NOW, this 25th day of June, 1984, upon consideration of the plaintiff's claim for declaratory relief, counterclaims, cross-claims and third-party claims, and for the reasons stated in the foregoing Memorandum, it is ORDERED that each party has the following obligations:\n\n\nA. Obligation to Defend:\n James - Pacific, Aetna, JUA\n Smith - Pacific, Aetna, JUA,\n Nationwide\n Lehman - Aetna, Nationwide\n Silberlicht - Aetna, Nationwide\n Cochran - Aetna, Nationwide\n Hudgens - Aetna, Nationwide\n Bass - Pacific, Aetna, JUA\n Harmon - Aetna, Nationwide\n Hunton - Aetna, Nationwide\n\nThe above obligations and corresponding costs are to be shared equally.", "\n\n\nB. Obligation to Indemnify:\n James - Pacific, two-thirds of recovery;\n Aetna, one-third of recovery\n Smith - Pacific, one-half of recovery;\n Aetna, one-quarter of\n recovery; Nationwide,\n one-quarter of recovery\n Lehman - Aetna, one-half of recovery;\n Nationwide, one-half of\n recovery\n Silberlicht - Aetna, one-half of recovery;\n Nationwide, one-half of\n recovery\n Cochran - Judgment for defendant\n Hudgens - Judgment for defendant\n Bass - Pacific, two-thirds of recovery;\n Aetna, one-third of recovery\n\n\n\n*657\n Harmon - Not ripe for decision\n Hunton - Judgment for defendant\n\nWHEREFORE,\n1. ", "On Pacific's claim against all defendants, Pacific is GRANTED declaratory relief as to the obligation to defend in the Lehman, Silberlicht, Cochran, Hudgens, Harmon and Hunton cases and DENIED declaratory relief as to the obligation to defend in the James, Smith and Bass cases, but it is adjudged that Aetna is also obligated to defend in James, Bass and Smith. ", "Pacific is GRANTED declaratory relief as to the obligation to indemnify in the Lehman and Silberlicht cases and DENIED declaratory relief as to the obligation to indemnify in the James, Smith and Bass cases. ", "Pacific is GRANTED declaratory relief as to the obligation to indemnify in the Lehman and Silberlicht cases and DENIED declaratory relief as to the obligation to indemnify in the James, Smith and Bass cases, but it is adjudged that Aetna is also obligated to indemnify in the James, Smith and Bass cases.", "\nPacific's motion for reimbursement from Aetna for funds expended in the defense and/or settlement of the James, Bass, Smith, Lehman, Cochran and Silberlicht cases is GRANTED to the extent that the funds requested exceed Pacific's defense and indemnity obligations therein. ", "Aetna shall reimburse Pacific for funds expended by Pacific which should have been expended by Aetna. ", "Nationwide shall reimburse Pacific for funds expended by Pacific in the defense and/or settlement of those cases which should have been expended by Nationwide. ", "Pacific's alternative claim for reimbursement from Interstate is DENIED without prejudice to renewal if the underlying insurance is uncollectible.", "\n2. ", "On Linn, Moses and Linn Associates' cross-claim against Interstate, Linn, Moses and Linn Associates are DENIED declaratory relief and judgment is entered in favor of Interstate. ", "On Linn, Moses and Linn Associates' third-party claim against JUA, Linn, Moses and Linn Associates' are GRANTED declaratory relief as to the obligation to defend in the James, Smith and Bass cases and DENIED declaratory relief as to the obligation to defend in the Lehman, Silberlicht, Cochran, Hudgens, Harmon and Hunton cases. ", "Linn, Moses and Linn Associates are DENIED declaratory relief and judgment is entered in favor of JUA as to the obligation to indemnify. ", "On Linn, Moses and Linn Associates' cross-claim against Aetna and third-party claim against Nationwide, Linn, Moses and Linn Associates are GRANTED declaratory relief.", "\n3. ", "On Aetna's counterclaim against Pacific and third-party claim against JUA, Aetna is DENIED declaratory relief as to the obligation to defend, but it is adjudged that Pacific and JUA are also obligated to defend the James, Smith and Bass cases. ", "Aetna is DENIED declaratory relief as to the obligation to indemnify, but it is adjudged that Pacific is also obligated to indemnify in the James, Bass and Smith cases. ", "On Aetna's cross-claim against Interstate, Aetna is DENIED declaratory relief and judgment is entered in favor of Interstate. ", "On Aetna's third-party claim against Nationwide, Aetna is DENIED declaratory relief, but it adjudged that Nationwide is also obligated to defend in the Lehman, Silberlicht, Cochran, Hudgens, Harmon and Hunton cases, and indemnify in the Smith, Lehman and Silberlicht cases.", "\nAetna's motion for reimbursement from Nationwide for funds expended in defense and/or settlement of the Lehman, Silberlicht, Cochran, Hudgens and Hunton cases, and from Pacific for settlement payments made in the James and Bass cases is GRANTED to the extent that the funds requested exceed Aetna's defense and indemnity obligations therein.", "\n4. ", "On Interstate's cross-claim against Aetna and third-party claims against JUA and Nationwide, Interstate is GRANTED declaratory relief and judgment is entered in favor of Interstate. ", "Interstate's motion for reimbursement from Aetna and Nationwide for funds expended in defense of the Hunton case is GRANTED; Aetna and Nationwide shall each reimburse Interstate *658 for one-half of the funds expended by Interstate therein.", "\n5. ", "On JUA's counterclaim against Aetna, JUA is GRANTED declaratory relief that Aetna is obligated to share the defense of the James and Bass cases with Pacific and JUA. ", "JUA is GRANTED declaratory relief as to the obligation to indemnify and it is adjudged that JUA has no indemnity obligation in any of the underlying cases. ", "On JUA's counterclaim against Linn, Moses and Linn Associates, JUA is GRANTED declaratory relief as to the obligation to indemnify and it is hereby adjudged that JUA has no indemnity obligation in any of the underlying cases. ", "On JUA's counterclaim against Linn, Moses and Linn Associates, JUA is GRANTED declaratory relief as to the obligation to defend in the Lehman, Silberlicht, Cochran, Hudgens, Harmon and Hunton cases, and DENIED declaratory relief as to the obligation to defend the James, Smith, and Bass cases. ", "JUA is GRANTED declaratory relief as to the obligation to indemnify and it is adjudged that JUA has no obligation to indemnify in any of the underlying cases. ", "On JUA's counterclaim against Interstate, JUA is DENIED declaratory relief and judgment is entered in favor of Interstate.", "\nJUA's motion for reimbursement from Aetna and Nationwide for funds expended in defense of the Hunton case is GRANTED; Aetna and Nationwide shall each reimburse Interstate for one-half of the funds expended by JUA therein.", "\n6. ", "Nationwide shall reimburse the other parties for attorneys' fees and costs incurred in maintaining this declaratory judgment action from December 1, 1982 to the date of this judgment.", "\n7. ", "In accordance with the parties' stipulation of procedure, any dispute as to the amount of fees, costs and expenses is referred to final and binding Defense Research Institute arbitration.", "\n8. ", "Prejudgment interest at a rate of ten percent (10%) from the date of expenditure is awarded on all reimbursed funds, but not on fees and costs incurred in maintaining this declaratory action.", "\n9. ", "All claims for indemnity and/or reimbursement in the Harmon case are DENIED without prejudice to later determination when ripe for decision under the Declaratory Judgment Act.", "\n10. ", "The court expressly determines that there is no just reason for delay and that this Judgment (except as to the Harmon case) is entered as final pursuant to Fed.", "R. Civ.", "P. 54(b).", "\n\nAPPENDIX \"A\"\nIn this Judgment Order, the parties will be referred to as follows:\n\n\n Pacific Indemnity Company .......................................... \"Pacific\"\n Robert Linn, D.O. ................................................. \"Dr. Linn\"\n Stephen D. Moses, D.O. ........................................... \"Dr. Moses\"\n Robert Linn Medical Associates ............................. \"Linn Associates\"\n David H. Smith, Individually and as Administrator of\n the Estate of Patricia Smith, Deceased ..................... \"Smith Estate\"\n Jack Silberlicht, Executor of the Estate of\n Judith Silberlicht, Deceased .......................... \"Silberlicht Estate\"\n Aetna Insurance Company .............................................. \"Aetna\"\n [*]William K. Myrletus, Director, Pennsylvania\n Professional Liability Catastrophe Loss Fund .................... \"CATFUND\"\n Interstate Fire & Casualty Company .............................. \"Interstate\"\n Nationwide Mutual Fire Insurance Company ....................... \"Nationwide\"\n Pennsylvania Professional Liability Joint\n Underwriting Association ............................................ \"JUA\"\n [**]Chicago Insurance Company ......................................... \"Chicago\"\n\n\n\n*659 APPENDIX \"B\"\n\n\n Williard D. James, Administrator of the Estate of Marilyn\n Verna James v. Robert Linn, D.O., et al., ", "Civil Action\n No. ", "C77-873V (W.D.Wash., ", "filed December 2, 1977) ......................... \"James\"\n David H. Smith, Individually and as Administrator for the\n Estate of Patricia Smith v. Robert Linn, D.O., et al.,", "\n No. ", "78-11694 (Pa.Ct. ", "Common Pleas, Montg. ", "Co.,\n filed July 12, 1978) ..................................................... \"Smith\"\n John H. Lehman, et al. ", "v. Superior Health Vitamins & Health\n Foods, Inc., et al., ", "No. ", "NEC 24600 (Cal.", "Super.", "Ct. ", "L.A. Co.,\n filed July 17, 1978) .................................................... \"Lehman\"\n Jack Silberlicht, Executor of the Estate of Judith Silberlicht v.\n Robert Linn, et al., ", "No. ", "3214, Aug. Term, 1978 (Pa.Ct.", "\n Common Pleas, Phila. ", "Co., filed August 22, 1978) ................... \"Silberlicht\"\n John Calvin Cochran, et al. ", "v. Superior Health Vitamins &\n Health Foods, Inc., et al., ", "No. ", "C259486 (Cal.", "Super.", "Ct.,", "\n L.A. Co., filed October 25, 1978) ...................................... \"Cochran\"\n Anna Shaw Hudgens v. Twin Laboratories, et al., ", "No. ", "C259693\n (Cal.", "Super.", "Ct. ", "L.A. Co., filed October 26, 1978) ....................... \"Hudgens\"\n Linda Mae Bass v. Controlled Drugs, et al., ", "No. ", "C240163 (Cal.", "\n Super.", "Ct., ", "L.A. Co., filed December 1, 1978) .............................. \"Bass\"\n Lawrence J. Harmon, Administrator of the Estate of Charlene\n Harmon v. Wayne M. Kassel, et al., ", "No. ", "79L5097 (Ill.Cir.", "Ct.,", "\n Cook Co., Law Div., ", "filed on or about March 12, 1979) ................... \"Harmon\"\n Della Berry Hunton, Executrix of the Estate of Johnie Eugene\n Berry v. Deane L. Crow, M.D., et al., ", "Civil No. ", "C79-146B\n (D.Wyo., ", "filed May 22, 1979) ............................................ \"Hunton\"\n *************************************\n [*]Theresa Weiss and Bert William Steinberg, Executors of the\n Estate of Herbert Weiss, deceased and Theresa Weiss v.\n Robert Linn, D.O., No. _____ (", "N.Y.Sup.", "Ct.", "N.Y.\n filed April 13, 1978) .................................................. \"Weiss I\"\n [*]Theresa Weiss and Bert William Steinberg, Executors of the\n Estate of Herbert Weiss, deceased and Theresa Weiss v.\n Ambix Laboratories, et al., ", "No. _____ (", "N.Y.Sup.", "Ct.", "\n N.Y.Cty., ", "filed September 15, 1978) ................................... \"Weiss II\"\n\n\nAPPENDIX \"C\"\nThe coverage provided by the various insurance companies is as follows:\n\nI. Professional liability policies—\nA. Primary Coverage\n\n1. ", "Pacific Indemnity Company (\"Pacific\") — # LOP 95117537 — professional services rendered or which should have been rendered during policy period: May 31, 1975 — May 31, 1977; limits of liability of $100,000 per occurrence and $300,000 per annual aggregate.", "\n\n*660 2. ", "Pennsylvania Professional Liability Joint Underwriting Association (\"JUA\") — # D0308201 — professional services rendered or which should have been rendered from June 1, 1977 to the present; limits of liability of $100,000 per occurrence and $300,000 per annual aggregate.", "\nB. Excess Coverage\n\n\n[*]3. ", "Pennsylvania Professional Liability Catastrophe Loss Fund (\"CATFUND\") — a contingency fund to which Dr. Linn is required to contribute by statute and which in turn affords him excess professional liability limited to $1,000,000 for each occurrence and $3,000,000 per annual aggregate; effective date of statute was October 15, 1975.", "\n\n[**]4. ", "Chicago Insurance Company (\"Chicago\") — Professional Comprehensive Personal Catastrophe Liability Policy No. ", "256-6578 with respect to any occurrence not covered by underlying policies for the policy period June 30, 1973 — June 30, 1976; policy limits of $5,000,000.", "\n5. ", "Interstate Fire & Casualty Insurance Company (\"Interstate\") — Professional Comprehensive Personal Catastrophe Liability Policy No. ", "155-017143, with respect to any occurrence not covered by the underlying policies for the period June 30, 1976 — June 30, 1977; policy limits of $1,000,000.", "\n\nII. ", "General Liability Policies\n\nA. Primary\n\n\n[***]1. ", "Pacific — Office Premises Endorsement to professional liability policy # LOP 95117537 covering liability for personal injuries arising out of hazards connected with the ownership, maintenance or use of the physicians' office premises and all operations necessary or incidental thereto and having limits of $100,000 per person and $300,000 per accident; policy period: May 31, 1975 — May 31, 1977.", "\n2. ", "Aetna Insurance Company (\"Aetna\") — Commercial Package Policies Nos. ", "CPP385400 and 397474 covering occurrences which result in bodily injury and having limits of liability of $500,000 per occurrence and $500,000 per aggregate; policy period: January 1, 1976 — January 1, 1981.", "\nB. Excess\n\n3. ", "Aetna — Umbrella Liability Policies Nos. ", "759436, 760346, 760228 and 760285 covering ultimate net loss for damages owed because of personal injuries caused by an occurrence; and having limits of $2,000,000 per occurrence and $2,000,000 per aggregate; policy period: January 1, 1976 — January 1, 1980.", "\n\nIII. ", "Personal Liability Policies\n\nA. Primary\n\n1. ", "Nationwide Insurance Company (\"Nationwide\") — Homeowner Policy No. ", "58MP 602-749 effective August 1, 1976 — July 31, 1978; Bodily Injury and Property Damage: $100,000 each occurrence; coverage was originally issued to Dr. Linn and his wife on July 1, 1961 and remains effective to the date of this action.", "\nB. Excess\n\n\n[†]2. ", "Chicago — Chicago's policy has a $5,000,000 limit for personal liability; policy period: June 30, 1973 — June 30, 1976.", "\n3. ", "Interstate — Interstate has a $1,000,000 limit for personal liability; *661 policy period: June 30, 1976 — June 30, 1977.", "\nNOTES\n[*] Aetna also undertook to defend and settle the Kerr case. ", "However, at a hearing held on November 30, 1983, the parties all agreed that the Kerr case was not involved in this action.", "\n[**] The Harmon case remains pending in an Illinois state court with no likelihood of disposition in the foreseeable future. ", "The court now deems it unnecessary to postpone an appeal in this action until the termination of Harmon.", "\n[*] Aetna also undertook to defend and settle the Kerr case. ", "However, at a hearing held on November 30, 1983, the parties all agreed that the Kerr case was not involved in this action.", "\n[*] Aetna also undertook to defend and settle the Kerr case. ", "However, at a hearing held on November 30, 1983, the parties all agreed that the Kerr case was not involved in this action.", "\n[**] The Harmon case remains pending in an Illinois state court with no likelihood of disposition in the foreseeable future. ", "The court now deems it unnecessary to postpone an appeal in this action until the termination of Harmon.", "\n[***] The relevant decisions were Selected Risks Ins. ", "Co. v. Bruno, 718 F.2d 67 (3d Cir.1983); McDowell-Wellman Engineering Co. v. Hartford Accident and Indemnity Co., 711 F.2d 521 (3d Cir. ", "1983); Viger v. Commercial Ins. ", "Co. of Newark, N.J., 707 F.2d 769 (3d Cir.1983). ", "Only Selected Risks is of any import here.", "\n[†] The exclusion applies \"only if the bodily injury ... occurs away from premises owned by or rented to the named insured and after physical possession of such products has been relinquished to others.\"", "\n\nAetna's policy also contained three other exclusions which on their face are inapplicable to the bookreader claims. ", "See, Memorandum and Order dated July 24, 1981, at pp. ", "29-34.", "\n[5] Final determination of the pending Harmon case must await its final outcome. ", "If Harmon settles or ends in favor of Dr. Linn, the duty to indemnify will be the same as determined in Silberlicht. ", "Should the case be decided against Dr. Linn, special interrogatories would help determine which insurer had to indemnify Dr. Linn. ", "The court will retain jurisdiction and await the disposition of Harmon before finally determining the indemnity obligations therein.", "\n[6] The Cochran, Hudgens and Hunton cases were terminated by final judgment in favor of Dr. Linn and do not implicate a duty to indemnify.", "\n[7] The court is not obligated, nor indeed able, to make the evidentiary findings necessary to determine on what claims, if any, the underlying plaintiffs would have recovered had the cases been fully litigated. ", "See, Ripepi v. American Insurance Companies, 349 F.2d 300, 303 (3d Cir.1965) (\"Appellant wishes us, by the use of hindsight, to speculate what evidence might have been presented in the Common Pleas action and determine whether, on the basis of such evidence, a compulsory nonsuit would have been required. ", "This is well beyond our present competence and the requirements of the law.\").", "\n[8] An insurer who refuses to defend a claim potentially within the scope of the policy does so at its own peril. ", "Ripepi, supra at 302; Cadwallader, supra at 152 A.2d 488. ", "Therefore, Nationwide, which has refused to provide any defense for Dr. Linn, may not now protest that it was deprived of an opportunity to litigate and establish that the underlying claims fell outside its policy coverage. ", "Those insurers that did contribute to Dr. Linn's defense are also precluded from arguing that the underlying claims fell outside their policies since they had the opportunity and declined to litigate the claims to conclusion.", "\n[9] The Cochran, Hudgens and Hunton cases all were terminated in favor of Dr. Linn and do not implicate the duty to indemnify. ", "See, note 5, supra.", "\n[10] This discussion of \"other insurance\" applies not to the duty to defend but only to the duty to indemnify since, in general, an \"other insurance\" clause is invoked only when the insured has made some payment in discharge of liability. ", "See, Green v. Benson, 271 F.Supp. ", "90, 96 (E.D.Pa.1967). ", "The duty to defend is unaffected by an \"other insurance\" clause because, unless stated otherwise, that obligation is independent of liability and any limitations thereon. ", "See, Liberty Mutual Insurance Co. v. Pacific Indemnity Co., 557 F.Supp. ", "986, 988 (W.D.Pa.1983); Brunner v. McCullough, 216 F.Supp. ", "496, 499 (E.D.Pa.1963).", "\n[11] An \"escape\" clause generally provides that the company invoking it is relieved of any obligation to the insured if other coverage is available. \"", "Escape\" clauses are disfavored in the law and will ordinarily not be given effect. ", "See, Maryland Casualty Co. v. Horace Mann Insurance Co., 551 F.Supp. ", "907 (W.D.Pa.1982). ", "Because the JUA policy does not attempt to escape liability in its entirety where other insurance is applicable, the JUA \"other insurance\" clause is deemed an \"excess\" clause rather than an \"escape\" clause.", "\n[12] Pacific is liable only to the extent of its policy limits. ", "However, none of the relevant bookreader cases involve payments exceeding Pacific's policy limits.", "\n[13] Pacific also seeks reimbursement for defense costs in the Harmon case, but any reimbursement claim relating to Harmon must await its termination.", "\n[14] Aetna also seeks reimbursement for funds advanced in defense and settlement of the Kerr case, but that case is not involved in this action.", "\n[15] It has not been determined under Pennsylvania law how defense costs are to be distributed between insurers. ", "This distribution seems the most equitable in view of the unique facts involved herein, and the most likely result were the Pennsylvania courts to rule on this issue. ", "See, McKenna v. Ortho Pharmaceutical Corp., 622 F.2d 657 (3d Cir.), ", "cert. ", "denied, 449 U.S. 976, 101 S.Ct. ", "387, 66 L.Ed.2d 237 (1980).", "\n[16] Each insurer is jointly and severally liable for the entire cost of a defense and/or liability (to the extent the court has imposed liability), regardless of the liability of other insurers. ", "Sandoz, supra at 266-267. ", "Pacific would ordinarily be entitled to recover its entire claim for reimbursement in excess of its own obligations from Aetna (and Aetna could thereafter recover its excess payments from Nationwide) and is not limited to seeking only half from Aetna and half from Nationwide. ", "However, because this is a declaratory judgment action, and since all the relevant parties are concurrently before the court, the court will only award reimbursement from each carrier as described above, i.e., each party must pay only its required percentage of defense and settlement costs.", "\n[17] Pacific's claim for reimbursement from Interstate is premature. ", "Pacific claims that since Interstate's coverage is \"collapsible,\" i.e., if the underlying insurance is not \"collectible by the Insured,\" Interstate's coverage will \"collapse\" to become primary, Pacific should be entitled to judgment against Interstate directly for all defense and settlement payments made in excess of its obligations. ", "pacific cannot yet show that the underlying insurance as to the Interstate policy is in fact not collectible. ", "But Aetna is now being ordered to reimburse Pacific for defense and settlement costs. ", "There is no justiciable issue at this time regarding Interstate's potential obligations to Pacific.", "\n[18] Interstate submitted an affidavit establishing a somewhat higher rate of return for its commercial paper and negotiable certificates of deposit from January 1, 1981 to September 30, 1983. ", "The court finds such a rate less appropriate to these parties on these facts.", "\n[*] The motion of William K. Myrletus, Director, Pennsylvania Professional Liability Catastrophe Loss Fund (\"CATFUND\") for summary judgment was granted with respect to its duty to defend Dr. Linn. ", "CATFUND's obligation of indemnification was not determined.", "\n[**] The motion of Chicago Insurance Company for summary judgment was granted on July 24, 1981.", "\n[] The motions for summary judgment which were decided on July 24, 1981 did not relate to this coverage. ", "Aetna amended its answer to assert a counterclaim against Pacific by reason of this coverage on November 20, 1981.", "\n[] The motion of Chicago Insurance Company for summary judgment was granted on July 24, 1981.", "\n" ]

{ "pile_set_name": "FreeLaw" }

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"recognizer_name": "UrlRecognizer" }, "score": 0.5, "start": 59348 }, { "analysis_explanation": null, "end": 52914, "entity_type": "US_DRIVER_LICENSE", "recognition_metadata": { "recognizer_identifier": "UsLicenseRecognizer_140094861023792", "recognizer_name": "UsLicenseRecognizer" }, "score": 0.4, "start": 52908 }, { "analysis_explanation": null, "end": 53199, "entity_type": "US_DRIVER_LICENSE", "recognition_metadata": { "recognizer_identifier": "UsLicenseRecognizer_140094861023792", "recognizer_name": "UsLicenseRecognizer" }, "score": 0.4, "start": 53191 }, { "analysis_explanation": null, "end": 53603, "entity_type": "PHONE_NUMBER", "recognition_metadata": { "recognizer_identifier": "PhoneRecognizer_140094861343232", "recognizer_name": "PhoneRecognizer" }, "score": 0.4, "start": 53597 }, { "analysis_explanation": null, "end": 53603, "entity_type": "US_DRIVER_LICENSE", "recognition_metadata": { "recognizer_identifier": "UsLicenseRecognizer_140094861023792", "recognizer_name": 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[ "The present invention relates to an image encoding method and apparatus thereof. ", "Specifically with relation to an image encoding apparatus comprising of a code amount control circuit which makes both an orthogonal transformation and a variable-length encoding of the entered image signals.", "\nIn general, the conventional image encoding apparatus utilizes an orthogonal transformation and variable-length encoding process. ", "The image encoding apparatus makes an orthogonal transformation of the entered image signals, causing a polarization of the transformed coefficients. ", "It then assigns short code words to the transformed coefficients with high occurrence probabilities, and long code words to those with low occurrence probabilities, compressing the entire code amount. ", "This enables high efficient encoding. ", "The image encoding apparatus needs a code amount control circuit to encode the entered image with different information contents and different characteristics, using a given amount of codes.", "\nCode amount control circuits utilizing conventional technologies need to control the code amount within a given time, when it encodes dynamic images in real time. ", "Thus, it makes use of a method with the combination of a feedforward and feedback control approaches.", "\nIt is well-known that with the feedforward control approach through both quantizing and variable-length encoding DCT coefficients in advance, control of the code amount can be most accurately made to analyze the characteristics of both the entered images and the variable-length code words to be utilized for encoding. ", "However, it is difficult, to develop small-sized apparatus due to the large scale circuits to a variable-length encode. ", "Thus, the control is made utilizing a correlation of neighboring pixels in the entered image and/or the sum of the absolute values of the DCT coefficients, realizing smaller-sized circuits with lower predictive accuracy. ", "Such control with the sum of the absolute values of DCT coefficients accords the variable-length encoding operation in which a short code word will be assigned to a low transformed coefficient with a high occurrence frequency, while a long code word will be assigned to a high transformed coefficient with a low occurrence frequency.", "\nWith the feedback control approach, a quantization step value is decreased for the image encoded with less than a given code amount reference so as also to decrease corresponding quantization step size, allowing for reducing the number of quantization coefficients to be discarded. ", "Conversely, the quantization step value is increased for the image encoded with not less than the code amount reference so as also to increase the quantization step size, allowing to increase the number of quantization coefficients to be discarded.", "\nHowever, with the aforementioned conventional feedforward approach, prediction of the referential quantization step value, which will be used to encode the entered image in a vicinity of the code amount reference, is hard to be made. ", "Moreover, the occurrence of a local image quality degrading may be easily recognized when the image is processed with several quantization step values; thus it is necessary to take into consideration the characteristics of the image. ", "This kind of problem occurs due to the fact that the relation between the sum of the absolute values of DCT coefficients and the generated code amount is not linear. ", "The relation also largely depends on the characteristics of the image.", "\nAs described earlier, the image encoding apparatus, which controls the entire code amount, in accordance with both the sum of the absolute values of DCT coefficients calculated with a conventional approach, and a cumulative code amount output from the variable-length encoding unit, has difficulty in making a prediction of the referential quantization step value in the vicinity of a code amount reference. ", "In addition, the occurrence of degrading image quality may be seen as a defect in the beginning period of the image encoding process. ", "Particularly, for an entered image with different characteristics, a partial degradation of the image quality may be easily be recognized in a level image block but a complex image block, when quantization operation is performed with a same quantization step value for both the level and complex image blocks. ", "This may cause for missing information in the low frequency bands of transformed coefficients, this can be attributed to the fact that the human eye is not good at visually recognizing a degrading image easily within complex image portions, while good at doing so within level image portions.", "\nAccordingly, the objective of the present invention is to provide an image encoding method and apparatus thereof which will effectively encode an image at a low price. ", "Particularly, a prospective greatly compressed (encoded) image region where degrading image quality may be easily recognized, into an encoded image in not more than a given code amount reference, and also generating a reproduced image of high quality.", "\nAccording to an aspect of the present invention, the foregoing objectives are attained by generating a quantization step value for the spatial frequency-domain coefficients in each macroblock in an image frame, dependent upon at least a code amount reference, a macroblock absolute values sum, and a frame absolute values sum; quantizing the spatial frequency-domain coefficients for a macroblock in accordance with at least the quantization step value; and variable-length encoding the quantized spatial frequency-domain coefficients into encoded data. ", "An example processing structure to realize the previous operation will be shown as a feedforward control system in FIGS. ", "1 and 2.", "\nAccording to another aspect of the present invention, the foregoing objectives are attained by generating a quantization step value for the spacial frequency-domain coefficients in each macroblock in an image frame, dependent upon at least a code amount reference, a slice absolute values sum, and a frame absolute values sum; quantizing the spatial frequency-domain coefficients for a macroblock in accordance with at least the quantization step value; and variable-length encoding the quantized spacial frequency-domain coefficients into encoded data. ", "An example processing structure to realize the previous operation will be shown as a feedforward control system in FIGS. ", "1 and 7.", "\nAccording to yet another aspect of the present invention, the foregoing objectives are attained by generating a quantization step value for the spatial frequency-domain coefficients in each macroblock in an image frame, dependent upon at least a code amount reference, a macroblock absolute values sum, a slice absolute values sum, and a frame absolute values sum; quantizing the spatial frequency-domain coefficients for a macroblock in accordance with at least the quantization step value; and variable-length encoding the quantized spacial frequency-domain coefficients into encoded data. ", "An example processing structure to realize the previous operation will be shown as a feedforward control system in FIGS. ", "1 and 8.", "\nAccording to yet another aspect of the present invention, the foregoing objectives are attained by generating a quantization step value for the spatial frequency-domain coefficients in each macroblock in an image frame, dependent upon at least a code amount reference, a macroblock absolute values sum, a frame absolute values sum, and the latest code amount; quantizing the spatial frequency-domain coefficients for a macroblock in accordance with at least the quantization step value; and variable-length encoding the quantized spacial frequency-domain coefficients into encoded data, and accumulates an amount of the encoded data into the latest code amount. ", "An example processing structure to realize the previous operation will be shown as a feedforward and feedback control systems in FIGS. ", "1 and 2.", "\nAccording to yet another aspect of the present invention, the foregoing objectives are attained by generating a quantization step value for the spatial frequency-domain coefficients in each macroblock in an image frame, dependent upon at least a code amount reference, a slice absolute values sum, a frame absolute values sum, and the latest code amount output from a variable-length encoding means; quantizing the spatial frequency-domain coefficients for a macroblock in accordance with at least the quantization step value; and variable-length encoding the quantized spacial frequency-domain coefficients into encoded data, and accumulates an amount of the encoded data into the latest code amount. ", "An example processing structure to realize the previous operation will be shown as a feedforward and feedback control systems in FIGS. ", "1 and 7.", "\nAccording to yet another aspect of the present invention, the foregoing objectives are attained by generating a quantization step value for the spatial frequency-domain in each macroblock in an image frame, dependent upon at least a code amount reference, a macroblock absolute values sum, a slice absolute values sum, a frame absolute values sum, and the latest code amount; quantizing the spatial frequency-domain coefficients for a macroblock in accordance with at least the quantization step value; and variable-length encoding the quantized spacial frequency-domain coefficients into encoded data, and accumulates an amount of the encoded data into the latest code amount. ", "An example processing structure to realize the previous operation will be shown as a feedforward and feedback control systems in FIGS. ", "1 and 8.", "\nAccording to yet another aspect of the present invention, the foregoing objectives are attained by: block partitioning means (1) for partitioning entered image signals (100) into small blocks, each made up of a plurality of pixels; orthogonal transformation means (2) for making an orthogonal transformation of each of the small blocks; quantization means (5) for quantizing orthogonally transformed coefficients (102); code amount control means for calculating a quantization step value (105) for each macroblock made up of a plurality of blocks, which will be used by the quantization means (5); variable-length encoding means (6) for variable-length encoding the quantized, transformed coefficients (108), utilizing the run-length coding method or the Huffman coding method; and then outputting them as encoded data (109) corresponding to the image signals (100). ", "An example processing structure to realize the previous operation will be shown as a feedforward and feedback control systems in FIG. ", "1." ]

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[ "Q:\n\nconfigatron a singleton? ", "Why can't I access the configatron in my class\n\nI'm using configatron to store my config values. ", " I can access the config values without a problem, except when the scope is within a class's method. ", "\nI'm using configatron 3.0.0-rc1 with ruby 2.0.0\nHere is the source I'm using in a single file called 'tc_tron.rb'\nrequire 'configatron'\n\nclass TcTron \n def simple(url)\n puts \"-------entering simple-------\"\n p url\n p configatron\n p configatron.url\n p configatron.database.server\n puts \"-------finishing simple-------\"\n end\nend\n\n# setup the configatron. ", " I assume this is a singleton\nconfigatron.url = \"this is a url string\"\nconfigatron.database.server = \"this is a database server name\"\n\n# this should print out all the stuff in the configatron\np configatron\np configatron.url\np configatron.database.server\n\n# create the object and call the simple method.", "\na = TcTron.new\na.simple(\"called URL\")\n\n# this should print out all the stuff in the configatron\np configatron\np configatron.url\np configatron.database.server\n\nWhen I run the code, I get\n{:url=>\"this is a url string\", :database=>{:server=>\"this is a database server name\"}}\n\"this is a url string\"\n\"this is a database server name\"\n-------entering simple-------\n\"called URL\"\n{}\n{}\n{}\n-------finishing simple-------\n{:url=>\"this is a url string\", :database=>{:server=>\"this is a database server name\"}}\n\"this is a url string\"\n\"this is a database server name\"\n\nBetween the 'entering simple' and 'finishing simple' output I don't know why I'm not getting the configatron singleton.", "\nWhat am I missing?", "\n\nA:\n\nThe current implementation of configatron is\nmodule Kernel\n def configatron\n @__configatron ||= Configatron::Store.new\n end\nend\n\nfrom here\nSince Kernel is included in Object that makes the method available in every object. ", "However, b/c the method simply sets an instance variable, that store will only be available to each instance. ", "Weird choice for a gem whose whole job is providing a globally accessible store.", "\nIn v2.4 they used a similar method to access a singleton, which probably worked much better\nmodule Kernel\n # Provides access to the Configatron storage system.", "\n def configatron\n Configatron.instance\n end\nend\n\nfrom here\nLooks like you could solve this yourself using require 'configatron/core' instead to avoid the monkey-patch, and provide your own singleton wrapper.", "\n\n" ]

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[ "Big Sky, Montana\n\nBig Sky is a census-designated place (CDP) in Gallatin and Madison counties in southwestern Montana. ", "As of the 2010 census it had a population of 2,308. ", "It is southwest of Bozeman. ", "This unincorporated community straddles both counties, is not considered a town, and does not have a town government. ", "The primary industry of the area is tourism.", "\n\nGeography\nBig Sky is located at (45.269940, -111.299725), approximately midway between West Yellowstone and Bozeman on U.S. Highway 191 and just from the northwestern border of Yellowstone National Park.", "\n\nThe \"Meadow\" area of Big Sky lies in an alpine valley formed during the Cretaceous period. ", "Initially called the \"Gallatin Canyon Basin\", the Meadow is braided with small rivers that channel mountain snow run-off. ", "Fishing is permitted on all of these Gallatin feeders. ", "Two ponds are found on the Middle Fork of the Gallatin River that bisects the Meadow, and fishing there is permitted for those 16 and younger. ", "Since 1993, an innovative sewer system has protected the water in the area from sewage discharge. ", "Several agencies, such as the Gallatin River Task Force, monitor the health of the rivers.", "\n\nThe community had two large ski resorts that are sited in the \"Mountain\" area: Big Sky Resort and Moonlight Basin. ", "In October 2013, these resorts merged: both are now managed by Big Sky Resort, and both are alpine ski and golf resorts. ", "The combined terrain of the two resorts allows them to market themselves as the \"Biggest Skiing in America.\" ", "The Spanish Peaks Mountain Club is an exclusive ski and golf resort that has three chairlifts and 13 ski runs connecting it to Big Sky Resort at the base of Big Sky's Southern Comfort lift. ", "Spanish Peaks is also now owned by Big Sky Resort, in collaboration with the Yellowstone Club. ", "Another resort, Lone Mountain Ranch, is a Nordic ski and summer resort that professionally grooms over 75 kilometers of cross-country ski trails. ", "Yellowstone Club, a private resort, is located to the south and adjacent to Big Sky Resort.", "\n\nThe \"Canyon\" area of Big Sky lies in the Gallatin Canyon, along the Gallatin River, a favorite for white water rafters and kayakers. ", "The Gallatin River, named after Albert Gallatin who was the Secretary of the Treasury during the Lewis and Clark Expedition, is a Blue Ribbon trout stream that attracts fly-fishers from around the world. ", "Several dude ranches (320 Guest Ranch, Elkhorn Ranch, Cinnamon Lodge and 9 Quarter Circle) operate in the Gallatin Canyon.", "\n\nAccording to the United States Census Bureau, the CDP has a total area of , of which is land and , or 0.18%, is water. ", "Most of the CDP drains to the east into the Gallatin River, while the westernmost portions drain west via Cedar Creek and Jack Creek to the Madison River. ", "The Gallatin and the Madison both drain north to the Missouri River.", "\n\nClimate\nThis climatic region is typified by large seasonal temperature differences, with warm to hot summers and cold (sometimes severely cold) winters. ", " According to the Köppen Climate Classification system, Big Sky has a borderline humid continental (Dfb)/alpine subarctic climate (Dfc). ", "for most of the area, but the lower elevations may be closer to a dry continental climate.", "\n\nDemographics\nAt the 2010 census, there were 2,308 people living in the CDP. ", "The population density was 10.1 per square mile.", "\n\nActivities\nHiking trails thread throughout the landscape and into neighboring national forests. ", "Camping sites are available throughout the Spanish Peaks and the Gallatin National Forest. ", "Elk, deer, black bears, grizzlies, upland birds, waterfowl, and wolves call this area home. ", "Hunting is prohibited in Big Sky proper, but it is permitted throughout the National Forests that surround the area. ", "Recreational snowmobiling is also not permitted within the Meadow or Mountain terrain, but is permitted in the Gallatin Canyon and in areas to the south of Big Sky.", "\n\nBig Sky offers a variety of recreational venues. ", "In addition to outdoor activities, the Lone Peak Cinema movie theater shows current blockbuster films. ", "The Warren Miller Performing Arts Center, a community and school-based facility, is located at the school on US Highway 191. ", "The venue attracts local, national, and international artists in every genre (music, drama, dance, visual arts, and creative composition). ", "Known to locals as the WMPAC, the center is home to the Big Sky Community Chorus, the Big Sky Community Theater, and Big Sky Broadway, a children's musical theater company. ", "During the summer, the Arts Council of Big Sky presents weekly free music concerts with musicians from across the nation at Center Stage in Town Center Park. ", "Each August, the Arts Council holds a four-day classical music festival. ", "A wide variety of music can be heard year-round at the resorts and local restaurants and bars. ", "Several art galleries feature local and regional photography and other visual media.", "\n\nIn mid-summer, Big Sky hosts the Big Sky PBR (Professional Bull Riders) event. ", "The Big Sky Farmers Market features live music, children's activities, and over 90 vendors selling fresh, locally grown food, and crafts each Wednesday during the summer months in Town Center's Fire Pit Park. ", "In the winter months, Town Center Park hosts Big Sky's hockey and ice skating rink that is operated by the Big Sky Skating and Hockey Association.", "\n\nEducation\nThe area is served by a K-12 public school district, called the Big Sky School District #72, and a preK-6 non-profit private school, Big Sky Discovery Academy. ", "There are three public schools: Ophir Elementary School, Ophir Middle School and Lone Peak High School. ", "The district educates approximately 275 students.", "\n\nMedia\n\nBig Sky has two local newspapers, Explore Big Sky, and \"Lone Peak Lookout,\" in addition to the regional publication, Bozeman Chronicle.", "\n\nThe local radio station is KBZM. ", "Other regional radio stations can be received from Bozeman.", "\n\nThree television stations are available: KTVM (6) NBC, KBZK (7) CBS, and KUSM (9) PBS.", "\n\nExploreBigSky.com is a regional daily news website.", "\n\nNotable residents\nThere are numerous year-round and part-time residents who are world-renowned athletes, politicians, physicians, and business/industry leaders, including:\n Jessica Biel, actress, and her husband, pop star Justin Timberlake, have a home at the Yellowstone Club\n Robert Peter Gale, noted cancer researcher\n Chet Huntley, pioneering newscaster, retired to Big Sky and put together corporate resources for the financing of the Big Sky Resort; however, he died several years later, March, 1974, after the ski area opened for its first season of skiing. ", " The Golf Course and other meeting facilities opened the prior year.", "\n Warren Miller, ski-film industry icon, lived in Big Sky during the winter\n Matt Morris, former Major League Baseball pitcher with the St. Louis Cardinals, San Francisco Giants, and Pittsburgh Pirates\n Marty Pavelich, National Hockey League Hall of Famer, year-round resident\n Jamie Pierre, professional skier, snowboarder\n\nSee also\n Soldiers Chapel\n\nReferences\n\nExternal links\n Visit Big Sky\n Biggest Skiing in America\n Big Sky Chamber of Commerce\n Big Sky Community Organization\n\nCategory:Census-designated places in Gallatin County, Montana\nCategory:Census-designated places in Madison County, Montana" ]

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[ "Introduction {#Sec1}\n============\n\nKeyhole limpet hemocyanin (KLH) is a high-molecular-weight glycoprotein, purified from a marine snail species called *Megathura crenulata*, that induces both cell-mediated and humoral responses in animals and humans. ", "Because of its high immunogenicity and low toxicity, KLH is used for a variety of basic research and clinical applications \\[[@CR1]\\]. ", "KLH was introduced into the clinic in 1967 to assess immunocompetence of individuals \\[[@CR2]\\]. ", "Later, KLH became a standard carrier for the production of antibodies (Abs) to small molecule haptens such as peptides and oligosaccharides \\[[@CR1]\\]. ", "Besides this, KLH is used as a local treatment for patients with bladder cancer \\[[@CR3]\\]. ", "Finally, KLH has progressed into clinical trials as either adjuvant- or immunomonitoring tool in a variety of vaccines directed against cancer \\[[@CR4], [@CR5]\\] or infectious diseases \\[[@CR6]\\].", "\n\nDendritic cells (DCs) are potent antigen presenting cells and play a central role in the induction and maintenance of antigen-specific immunity. ", "Antigen-specific immune responses in cancer patients can be induced by exploiting autologous DCs \\[[@CR7]\\]. ", "In our institute, autologous DCs are activated ex vivo and loaded with tumor antigens. ", "KLH is added to the vaccine both as a nonspecific T helper cell stimulus and to facilitate monitoring of the vaccine-induced immune responses \\[[@CR8]--[@CR10]\\]. ", "After DC injection, the cells migrate toward the lymph nodes where they present their processed antigens to the adaptive arm of the immune system, inducing antigen-specific T and B cell responses \\[[@CR11]\\].", "\n\nIn the last decade, several parameters of DC-based therapy have been optimized to improve vaccine-induced immunological responses, particularly in melanoma patients \\[[@CR12]\\]. ", "For example, it is well-accepted that the use of mature DC is superior to immature DC \\[[@CR13]\\] and pretreatment with anti-CD25 antibodies does not improve immunological responses \\[[@CR14]\\]. ", "The route of administration largely dictates the failure or success of the induced immunological responses \\[[@CR15], [@CR16]\\]. ", "Similarly, evidence is accumulating that the use of nonspecific helper epitopes, such as KLH, is critical to the induction of effective antitumor responses \\[[@CR17]\\]. ", "In these clinical trials, much effort has been put in the detection of tumor-antigen-specific immune responses, for example ELIspots \\[[@CR18], [@CR19]\\], T cell receptor (TCR) frequency assessment \\[[@CR20]\\] and analyses of skin test biopsies \\[[@CR21], [@CR22]\\]. ", "These assays have multiple disadvantages; the assays are laborious, have limited sensitivity, often lack association with clinical outcome and are difficult to standardize \\[[@CR23], [@CR24]\\]. ", "Strikingly, not much attention has been paid to the dynamics, levels and patterns of the vaccine-induced anti-KLH humoral responses in clinical trials, which could provide a simple and direct method for evaluation of vaccine-induced immune responses.", "\n\nAssays to monitor cellular \\[[@CR25], [@CR26]\\] and humoral \\[[@CR27]--[@CR29]\\] immune responses against KLH have been developed to facilitate optimal use of biomedical KLH applications. ", "The enzyme-linked immunosorbent assay (ELISA) proved a simple and sensitive assay to measure serological Abs, and in 1979, the first quantitative assay to detect KLH-specific Ab in mice was published \\[[@CR27]\\]. ", "Five years later, the first ELISA was developed to detect KLH-specific Ab in human serum \\[[@CR28]\\]. ", "Currently, all published human anti-KLH ELISA's report Ab responses in arbitrary units based on optical density values, which yields relative units/values only.", "\n\nBecause of the lack of a quantitative human anti-KLH assay, so far it has not been possible to monitor the dynamics of KLH-specific Ab responses after in vivo KLH exposure. ", "It was neither possible to link the concentration of induced KLH Abs either to the immunocompetence of an individual or to the immunogenicity of KLH-containing vaccines.", "\n\nIn this study, we present the first quantitative ELISA to measure KLH-specific Abs in human serum, measuring both IgG, IgA, IgM and all IgG-subclasses. ", "We demonstrate that it is now possible to monitor the dynamics of both KLH-specific Ab levels and Ab class-switching in individuals who are repeatedly exposed to KLH. ", "Furthermore, we retrospectively analyzed the humoral anti-KLH responses of melanoma patients enrolled in our clinical trials investigating dendritic cell-based vaccinations. ", "Our data confirm that individuals exposed to KLH react to it as a primary immunogen, inducing a characteristic primary immune response. ", "Moreover, analyses of our clinical DC-based vaccination protocols demonstrated that variations in the vaccination parameters dramatically influence both the quantity and the quality of the induced humoral response.", "\n\nMaterials and methods {#Sec2}\n=====================\n\nPreparation of serum pool containing anti-KLH antibodies {#Sec3}\n--------------------------------------------------------\n\nSerum was pooled from HLA-A\\*02:01 melanoma patients and colorectal cancer patients who were previously vaccinated with KLH-pulsed dendritic cells (DCs). ", "To generate a serum pool with a broad spectrum of KLH-specific Abs, sera were obtained from 28 patients enrolled in different clinical trials within our institute in which the maturation status of the DCs and the route of vaccine administration varied per clinical trial \\[[@CR13]--[@CR15], [@CR30], [@CR31]\\]. ", "For the exact details regarding the vaccination protocols and the patient inclusion, we refer to these individual studies. ", "In all studies, KLH was added at day 3 of the DC culture at a concentration of 10 μg/ml and patients received maximum three vaccination cycles of 3 bi-weekly vaccinations at a 6-month interval. ", "Informed consent was obtained from all patients, and the study was approved by our Institutional Review Board.", "\n\nPurification of KLH-specific antibodies {#Sec4}\n---------------------------------------\n\nUsing a KLH-coated column (Alpha Diagnostic International, San Antonio, TX, USA), 18 ml starting serum pool of KLH-specific Abs was isolated from the above-mentioned trials. ", "Prior to use, the column was extensively washed with elution buffer (0.1 M glycine HCl pH 2.5) to dissociate multimeric KLH and remove monomers that were not covalently linked to the Sepharose bed. ", "Subsequently, the column was equilibrated with PBS, followed by application of the pooled serum, washed with PBS and elution of the KLH-specific Abs with elution buffer and neutralized with Tris/HCL pH 9.0. ", "The KLH-specific IgM-, IgA- and IgG-Abs in the eluate with a volume of 1,380 μl were quantified using nephelometry on an Immage apparatus (Beckman Coulter, Brea, CA, USA), IgG subclasses were measured on a BNII (Siemens, Münich, Germany) using reagents of The Binding Site (Birmingham, UK) all according to the manufacturers protocol. ", "Following this approach, a 1.4 ml polyclonal anti-KLH stock was obtained in which all major immunoglobulin isotypes and IgG subclasses were represented (Supplementary Table 1, available online). ", "This stock of purified and quantified KLH-specific Abs was stored at −80 °C and used to generate standard curves for the quantitative ELISA. ", "All experiments in this manuscript were performed with one single calibrated work standard of 34 ml created from 28 different patients.", "\n\nQuantitative anti-KLH ELISA {#Sec5}\n---------------------------\n\nNinety-six-well plates were coated for 18 h at 4 °C with 5 μg/mL KLH (Biosyn, Carlsbad, CA, USA) in PBS in a total volume of 120 μL per well, and wells were subsequently blocked with skimmed milk powder. ", "After washing the plates, different concentrations of patient serum were added for 1 h at room temperature. ", "To prepare suitable standard curves for the anti-KLH ELISA's, the work standard was serially diluted to establish a 7-point standard curve for each Ab isotype (Supplementary Figure 1, available online). ", "For analysis of individual patient samples, a standard curve was added to each plate. ", "After washing, specific Abs against human IgM or IgA or total IgG or IgG1 or IgG2 or IgG3 or IgG4 labeled with horseradish peroxidase (Invitrogen, San Diego, CA, USA) at 1:500 were added to the wells as 100 μL aliquots. ", "The isotype-specific secondary Abs allow quantification of both human IgM, IgA, total IgG, IgG1, IgG2, IgG3 and IgG4 KLH-specific Abs. ", "After a further incubation for 1 h at room temperature and a final washing with buffer, peroxidase activity was revealed using 3,3′ 5,5-tetramethyl-benzide as substrate. ", "The reaction was stopped with sulfuric acid, and samples were measured in a microtiter plate reader at 450 nm. ", "A uniform detection limit of the anti-KLH ELISA's was arbitrarily determined at 20 μg/ml. ", "This detection limit falls within the lower linear part of all anti-KLH calibration curves. ", "Precision and linearity were determined according to the Clinical and Laboratory Standards Institute protocols EP5 and EP6, respectively.", "\n\nStatistical analysis {#Sec6}\n--------------------\n\nPrecision and linearity were analyzed using EP Evaluator 9 software, and all other statistical analyses were performed by Graphpad Prism 5.0. ", "For the comparison of different vaccination protocols, patients were grouped based on similar protocol characteristics, such as stage of disease on entry, route of administration, pretreatment with anti-CD25 antibodies, additional treatment with interleukin-2 (IL-2) or the method of tumor antigen loading. ", "For the comparison of 2 groups, all the above-mentioned protocol characteristics should be similar, except for the single parameter under investigation. ", "Maximum KLH-specific Ab responses, out of at least 3 samples obtained at standard time points during the first cycle, were compared, as this reflects the individual's competence to generate a humoral response. ", "Nonparametric Mann--Whitney test was performed to compare the KLH-specific Ab responses of similar isotypes in two groups of melanoma patients exposed to KLH. ", "A two-tailed *p* value \\<0.05 was considered significant.", "\n\nResults {#Sec7}\n=======\n\nAssay performance and validation {#Sec8}\n--------------------------------\n\nTo evaluate the precision of the assay, pooled serum samples were measured in 2 replicates per run, 1 run per day for a minimum of 20 runs. ", "The resulting anti-KLH ELISA's have an intra-assay imprecision, denoted by the coefficient of variation (CV), that ranged from 4.3 to 6.7 %. ", "The inter-assay CV varied from 6.4 to 9.9 % (Table [1](#Tab1){ref-type=\"table\"}). ", "To test for assay-linearity, we serially diluted 2 individual patient serum samples per KLH assay isotype at a minimum of 5 levels, assayed in quadruplicate. ", "The results yielded slopes ranging from 0.918 to 1.036, and the coefficients of determination (R^2^) ranged from 0.991 to 0.998 (Fig.", " [1](#Fig1){ref-type=\"fig\"}). ", "A method-comparison analysis was not possible, as there is no golden standard quantitative human anti-KLH available.", "Table 1Performance assessment of the anti-KLH ELISA assaysIgG~total~IgG~1~IgG~2~IgG~3~IgG~4~IgA~total~IgM~total~Mean (mg/L)478.0282.080.45.076.322.8719.7VariationIntraInterIntraInterIntraInterIntraInterIntraInterIntraInterIntraInterSD22.130.513.625.15.47.10.220.404.15.11.12.244.471.6CV (%)4.66.44.88.96.77.14.37.95.46.75.09.76.29.9CV, coefficient of variation; intra, intra-assay imprecision; inter, inter-assay imprecisionFig.", " 1Serial dilution linearity of the anti-KLH ELISA*.* ", "Serum samples of patients exposed to KLH were serially diluted with assay buffer and measured in quadruplicate. ", "The results for linearity of the ELISA for the anti-KLH isotypes IgG (**a**) IgA (**b**) and IgM (**c**) are shown. ", "Calculated concentrations are based on stock-concentration and dilution factor. ", "Slopes and coefficients of determination (R^2^) are indicated in each panel. ", "The *line* of identity is indicated by the *dashed line*\n\nMonitoring the dynamics of humoral anti-KLH responses in individual patients {#Sec9}\n----------------------------------------------------------------------------\n\nRepetitive serum sampling of individual patients enrolled in clinical trials on dendritic cell-based vaccinations allows in-depth monitoring of the kinetics of the KLH-specific Ab responses during therapy. ", "In the majority of patients, we detected the first KLH-specific Abs after the 2nd or 3rd vaccination. ", "We show one representative melanoma patient who had detectable levels of KLH-specific IgM Abs after the second vaccination (Fig.", " [2](#Fig2){ref-type=\"fig\"}a). ", "The IgM response was followed by KLH-specific IgG Abs and after four vaccinations also by IgA Abs. ", "Ab titers were drastically decreased between vaccination cycles and after the last vaccination.", "Fig.", " 2A detailed characterization of KLH-specific antibody responses in individual patients, two examples. ", "Two patients who received 9 vaccinations of KLH-loaded dendritic cells over a period of 18 months are characterized in detail for KLH-specific antibody responses. ", "Each vaccination is indicated by a *black arrow*. ", "One patient had a robust humoral response, the kinetics of the KLH-specific IgG, IgA and IgM responses are shown in (**a**). ", "In **b,** the IgG immune response is subdivided into the four IgG subclasses, demonstrating that IgG1 predominantly contributes to the KLH-specific immune response in this patient. ", "The second patient received vaccinations with DC not loaded with KLH. ", "In this patient, KLH-specific antibody responses were completely absent (**c**, **d**)\n\nIgG subclass analysis showed that IgG1 predominantly contributed to the KLH-specific IgG response in this patient (Fig.", " [2](#Fig2){ref-type=\"fig\"}b). ", "This example demonstrates that the KLH Ab response strongly depends on the schedule of KLH exposure and the time point of serum sampling. ", "One vaccinated patient received 9 vaccinations that did not contain KLH, because of a severe shellfish allergy. ", "We detected no KLH-specific Abs in this specific patient (Fig.", " [2](#Fig2){ref-type=\"fig\"}c, d), demonstrating that KLH-specific Ab responses are caused specifically by the KLH added to the vaccine and not by the vaccine itself. ", "The high specificity of the anti-KLH ELISA is further illustrated by the fact that none of the 57 tested patients had detectable KLH-specific Abs prior to vaccination (Fig.", " [3](#Fig3){ref-type=\"fig\"}a, bars indicated by 'before').Fig.", " 3Variations in vaccination parameters induce different humoral anti-KLH responses*.* ", "In total, 128 melanoma patients were exposed to KLH by 3 bi-weekly vaccinations containing KLH-loaded DC. ", "None of the 35 patients tested (protocols 4 and 5) had KLH-specific antibodies prior to vaccination (**a**). ", "KLH-specific Ab responses compared between **a** patients treated with or without daclizumab prior to the KLH exposure; **b** patients vaccinated with immature or mature KLH-loaded DC; **c** peptide-loaded or mRNA-transfected KLH-loaded DC; **d** intranodal or intravenous/intradermal routes of administration and **e** patients with locoregional metastatic disease or distant metastatic disease at inclusion. ", "Mean levels of KLH-specific IgG (*white bars*), IgA (*gray bars*) and IgM (*black bars*) antibodies are shown in mg/L. *Error bars* indicate standard error of the mean; *Nd* not detected\n\nVariations in vaccination parameters have major influence on the levels and patterns of humoral anti-KLH responses {#Sec10}\n------------------------------------------------------------------------------------------------------------------\n\nAnother application of this novel assay is that it allows the comparison of the humoral immunogenicity of different KLH-containing interventions. ", "To demonstrate this, we performed subgroup analyses in a total of 118 melanoma patients, 43 stage III and 85 stage IV, who received dendritic cell-based vaccinations according to different protocols (Table [2](#Tab2){ref-type=\"table\"}).Table 2Patients and protocol characteristicsProtocol nr.", "StageNr of patientsMaturation statusRoute of administrationAnti-CD25 pretreatmentMethod of Ag-loading1IV9Immaturei.v./i.d.", "NoPeptide pulsing2IV17Maturei.n.", "NomRNA electroporation3IV24Maturei.n.", "NoPeptide pulsing4IV13Maturei.v./i.d.", "YesPeptide pulsing5IV22Maturei.v./i.d.", "NoPeptide pulsingTotal856III43Maturei.n.", "NoPeptide pulsing or mRNA electroporationTotal43\n\nPretreatment with a single dose of intravenous humanized monoclonal anti-CD25 antibody (Daclizumab) significantly reduced the overall anti-KLH Ig responses (Fig.", " [3](#Fig3){ref-type=\"fig\"}a). ", "The mean level of anti-KLH IgG without pretreatment (protocol 5, *n* = 22) was 142 mg/L compared to 18 mg/L after pretreatment (protocol 4, *n* = 13, *p* = 0.0267). ", "With regard to anti-KLH IgA, the mean levels were 5 mg/L with no pretreatment and 2 mg/L with pretreatment; for anti-KLH IgM, this was 157 mg/L compared to 7 mg/L, respectively (*p* = 0.0275).", "\n\nVaccination with immature DC (protocol 1, *n* = 9) barely induced anti-KLH antibodies compared to vaccination with mature DC (protocol 5, *n* = 22) (Fig.", " [3](#Fig3){ref-type=\"fig\"}b). ", "Anti-KLH IgG antibodies were detected in 2/9 patients upon immature DC vaccination and in 12/22 patients after vaccination with mature DC, mean 9 mg/L and 142 mg/L, respectively (*p* = 0.0600). ", "Anti-KLH IgM antibodies were induced in the same patients, 2/9 patients after immature DC vaccination and 9/22 patients after mature DC vaccination, to similar extend, 147 mean mg/L and 157 mg/L, respectively (*p* = 0.4157).", "\n\nAs expected, the method of loading the tumor antigens onto the dendritic cells, either pulsing with defined peptides (protocol 3, *n* = 24) or electroporation with mRNA encoding the tumor antigens (protocol 2, *n* = 17), did not affect the concentration or the pattern of vaccine-induced anti-KLH humoral responses (Fig.", " [3](#Fig3){ref-type=\"fig\"}c).", "\n\nCombined intravenous/intradermal vaccination (protocol 5, *n* = 22) induced significantly more anti-KLH IgM antibodies as compared to intranodal vaccination (protocol 2 and 3, *n* = 41), mean 157 mg/L and 27 mg/L, respectively (*p* = 0.0222), but no differences in IgG or IgA levels were noted (Fig.", " [3](#Fig3){ref-type=\"fig\"}d).", "\n\nWe observed significantly higher anti-KLH IgG titers in melanoma patients who were vaccinated adjuvant to radical lymph node dissection (stage III) compared to melanoma patients with irresectable locoregional disease or distant metastatic disease (stage IV). ", "Mean concentrations of all isotypes were at least two times higher in stage III patients compared to stage IV melanoma patients (Fig.", " [3](#Fig3){ref-type=\"fig\"}e). ", "However, the most prominent was anti-KLH IgG, mean 310 mg/L in stage III patients (protocol 6, *n* = 43) compared to 94 mg/L in stage IV patients (protocol 2 and 3, *n* = 41), *p* = 0.0002.", "\n\nDiscussion {#Sec11}\n==========\n\nKLH is widely used for biomedical applications because of its remarkable immunogenic properties. ", "In the current study, we describe a novel, highly sensitive and quantitative, sandwich ELISA standardized to measure IgM, IgA and IgG Abs specific for KLH. ", "We demonstrate that it is now possible to monitor the dynamics and concentrations of humoral KLH-specific immune responses in individuals exposed to KLH and in clinical trials. ", "Importantly, we show that vaccine-induced KLH-specific humoral responses largely depend on variations in vaccination parameters in DC-based clinical trials.", "\n\nUsing our novel anti-KLH ELISA, we found that melanoma patients exposed to KLH-loaded DCs often initially develop KLH-specific IgM Abs, which is associated with a primary immune response as was expected from the literature \\[[@CR32]\\]. ", "After subsequent vaccinations in our patients, this is usually followed by class-switching and the production of KLH-specific IgG Abs, suggestive for a secondary immune response. ", "This secondary immune response is accompanied by KLH-specific IgA Abs in a minority of patients. ", "In general, Ab-isotype switching and the identity of the immunoglobulin subclasses is regulated by cytokines and B cell activators \\[[@CR33]\\]. ", "In this respect, Ab responses in terms of isotype and subclass will be influenced by the route and conditions under which KLH is administered. ", "In our studies, in which all individuals were exposed to KLH-loaded cytokine-matured DCs, IgG1 was the predominant subclass produced. ", "We hypothesize that the method of KLH exposure and/or individual patient characteristics can result in significant skewing of the IgG subclass response.", "\n\nWe further demonstrate that, using this novel assay, it is now possible to link the concentration of induced KLH-specific Abs to the humoral immunogenicity of the KLH-containing DC-based vaccines used in our institute. ", "In our cohort of patients with metastatic melanoma, we have found that adjustments in the vaccination protocol can significantly affect the humoral responses against KLH. ", "We show for example that a single dose of daclizumab, a humanized monoclonal anti-CD25 Ab, prior to the injection of KLH-loaded DCs almost completely abolishes the KLH-specific humoral response. ", "Blocking CD25 on activated T cells and regulatory T cells greatly reduces the capacity of the immune system to respond to de novo antigens. ", "The in vivo effects of daclizumab on T cells are well documented \\[[@CR34]\\], but the effects of daclizumab on humoral immune responses were largely unexplored. ", "Although injected prior to vaccination, circulating daclizumab may bind to CD25-expressing vaccinated DC, providing yet another possible explanation for the strongly reduced vaccine-induced humoral responses to KLH. ", "The maturation status of the DCs is another parameter that strongly affects humoral immunogenicity of the vaccine. ", "We previously demonstrated that more effective cellular immune responses are induced with mature DCs compared to immature DCs \\[[@CR13]\\]. ", "Now we demonstrate that mature DC also generate stronger humoral immune responses and are essential for efficient immunoglobulin class-switching. ", "In addition, we show that there is no significant difference in the KLH-specific IgG and IgA responses when the KLH-vaccine is administered intravenously/intradermally or intranodally in melanoma patients. ", "However, intravenous/intradermal injections tend to result in increased KLH-specific IgM responses compared to intranodal injection. ", "In case of differential tumor antigen loading onto the DC, we would not expect different KLH responses since in all protocols, the DC are pulsed with KLH at day 3 after isolation, and loading with tumor antigen occurs just before administration. ", "Indeed, with regard to different methods of tumor antigen loading, we did not detect differences in levels or specificity of anti-KLH humoral responses.", "\n\nSeveral lines of evidence demonstrate that tumor cells actively create a local and systemic immune suppressive environment \\[[@CR35]--[@CR37]\\]. ", "The level of tumorload may therefore negatively correlate with the competence of a patients' immune system to respond to antigens such as KLH \\[[@CR38]\\]. ", "We investigated the humoral KLH responses in patients treated with DC-based vaccinations adjuvant to radical lymph node dissection, and thus without macroscopic disease (stage III), and in patients with distant metastatic and measurable disease, stage IV melanoma. ", "We indeed confirm that anti-KLH Ab production was higher in stage III patients compared to patients with stage IV melanoma, which argues in favor of applying immunotherapy at earlier stages of disease.", "\n\nFurther analysis is warranted to investigate whether the KLH-specific Ab response in the context of anti-cancer vaccines can be used as a surrogate biomarker for tumor-specific immune responses. ", "The standardized ELISA presented here can facilitate in this effort as it allows inter-institutional comparisons of the humoral immunogenicity of KLH-containing vaccines.", "\n\nAlthough we initially developed the quantitative anti-KLH ELISA to monitor vaccine-induced immune responses, the assay allows quantification of humoral responsiveness as a measure of immunocompetence in individuals exposed to KLH. ", "Since KLH elicits a primary immune response, intramuscular injection of KLH is the method of choice to investigate the capacity of an individual to respond to novel antigens, overcoming the confounding influence of previous exposure history \\[[@CR39]\\].", "\n\nFinally, because of its capacity as a nonspecific immune stimulator, KLH has been investigated as an intravesical agent to treat superficial bladder cancer \\[[@CR3]\\]. ", "Previously, it has been reported that the presence of anti-KLH antibodies was associated with treatment response \\[[@CR40]\\]. ", "In this respect, it is interesting to investigate whether in-depth analysis of the KLH-specific Ab responses in these patients can be an early predictor of therapy outcome.", "\n\nIn conclusion, we here present a sensitive and specific quantitative assay to measure KLH-specific Abs in human serum. ", "We demonstrate that with this assay, it is now possible to monitor both the dynamics and absolute concentrations of KLH-specific humoral responses in individuals exposed to KLH, for example to evaluate humoral immune competence. ", "In addition, it may provide a valuable biomarker for the immunogenicity and clinical effectiveness of KLH-containing vaccines and therapies.", "\n\nElectronic supplementary material {#AppESM1}\n=================================\n\n {#SecESM1}\n\nSupplementary material 1 (PDF 45 kb)\n\nThis work was supported by grants from the Dutch Cancer Society (KUN2006-3699, KUN2009-4402), The Netherlands Organization for Scientific Research (NWO-Vidi-917.76.363, AGIKO-2008-2-4) and the Nijmeegs Offensief Tegen Kanker (NOTK) foundation.", "\n\nConflict of interests {#d29e1200}\n=====================\n\nThe authors declare that they have no conflict of interest.", "\n\nOpen Access {#d29e1205}\n===========\n\nThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "From RationalWiki\n\n“ ” I live like a capitalist every single day, I live like a capitalist every single day, Cenk ! ", "I live as a capitalist, okay? ", "I live what I believe! —", "Charlie Kirk, losing his temper in a debate with The Young Turks' Cenk Uygur, attempting to physically attack the latter.[1]\n\nIf you don’t like this RationalWiki article, why don’t you move to Venezuela\n\nCharlie \"Chuckles\" Kirk (1993–)[2] is an American right-wing grifter, professional meme maker, and diaper enthusiast. ", "He is the founder and spiritual leader of Toilet Paper USA Turning Point USA (TPUSA), which organizes bizarre conservative stunts on college campuses and (according to an exposé at the conservative leaning Washington Examiner) has a long history of teen underage drinking and rape at its student conventions.[3] Kirk is also known for cameoing as the spokesperson for the fictional restaurant Li'l Bits in an episode of Rick and Morty.[4]\n\nTPUSA claim that they're a \"youth organization that promotes the principles of fiscal responsibility, free markets, and limited government,\" when in reality, they're just a right-wing echo chamber for dying boomers and edgy white boys that takes any chance they can get to insult socialists and anyone left of Henry Kissinger. ", "Most of their Twitter feed consists of calling out socialists for being \"hypocrites\"[5] (because apparently using an iPhone and buying things to survive instead of living in a cavemen commune invalidates all your left-leaning arguments), complaining about leftist propaganda in the curriculum,[6] making antisemitic and/or rape jokes,[7] preying on naive first year college students instead of debating professionals, pundits and experts, sharing terrible memes, et cetera.", "\n\nKirk really thinks that making \"vagina hands\" à la Donald Trump[8] makes him look badass.[9][10]\n\nBiography [ edit ]\n\nCharlie Kirk was born into a wealthy Illinois family. ", "His father, Robert W. Kirk, was the project architect manager for Trump Tower in New York. ", "Charlie became politically active after Barack Obama became President. ", "In 2010, he joined the Tea Party and volunteered for the US Senate campaign of Illinois Republican Mark Kirk (no relation). ", "In 2012, he wrote his first piece for Breitbart complaining about \"liberal bias\" in high school economics textbooks.[11] Despite being promoted as \"Trump's man on campus\",[12] Kirk actually dropped out of community college; he was allegedly rejected from Vienna's Academy of Fine Arts West Point, and blamed it (without any evidence)[13] on affirmative action.[14] Because of course.", "\n\nOn religion [ edit ]\n\n“ ” [A]s the world adds more the more atheists there are in the world, the bigger government will grow[.] ", "Atheism must be defeated[.] [", "A]s the world adds more atheists the moral fiber of our civilization will continue to decay. ", "And[.][.] —", "Charlie Kirk[15]\n\nKirk, who is an evangelical Christian, believes that atheism leads to socialism, as men attempt to fashion themselves into Gods:\n\nIn short, Kirk blames much moral failure in communist countries on atheism. ", "Of course, he excludes the highly-irreligious countries like Japan, Sweden, and the UK that do not appear to have collapsed amidst their own immorality. ", "He also seems to have missed that former communist countries which have embraced religion (particularly Russia) haven't become more moral as a result. ", "Elsewhere, Kirk has separated \"secular\" from \"Western democracies\":\n\nThere are four competing global philosophies that will determine the 21st century: 1) Western centered, pro-capitalist constitutional democracies 2) Islamic Theocratic Fascism 3) Chinese Communist Totalitarianism 4) European-style secular socialism The West must win[16]\n\nThis is deeply ironic, given the history of increasing secularism within the West for almost half a millennium, usually by pro-democracy advocates – a history that Kirk himself acknowledges:\n\nGiven his love for tired talking points, it is unsurprising that Kirk also really likes the \"not enough faith\" line of thought, probably because it sounds clever:\n\nI don't have enough faith to be an atheist[15]\n\nI don't have enough faith to be an Atheist [sic] [18]\n\nOf all the religions, the hardest one for me to believe that people believe is atheism[19]\n\nThe amount of blind faith it takes to be an Atheist [sic] never ceases to amaze me.[20]\n\nJudging by his speech above, Kirk appears not to understand how atheists can \"have faith\" in a non-God origin of the universe, a non-God creation of life, a non-God origin of human life, or a non-God origin of morality. ", "Fortunately for the rest of us, science and philosophy have moved past the 1500s.", "\n\nLike most Christian conservatives, Kirk understands how essential it is for us as a society to understand and accept science. ", "Except when it comes to climate change and religion.[21]\n\nEditorial note: Don't capitalize atheism. ", "You also don't capitalize theism. ", "These aren't proper nouns, Charlie.", "\n\nConservative deceit [ edit ]\n\nCharlie Kirk made fallacious claims about the family of Candace Owens. ", "Kirk claimed that \"both\" of Owens' parents were alcoholics and also claimed that \"her sisters\" were on welfare.[22] Owens later debunked his claims about her family on Twitter.[23] However, instead of calling out Charlie Kirk for his racially charged lies, Owens decided to denounce the \"sadistic\" journalism that pointed out his blatant dishonesty (so basically she attacked journalists for doing their jobs).[24]\n\nIn addition, Kirk claimed that Roseanne Barr isn't racist[25] for tweeting about Obama aide Valerie Jarrett: \"muslim brotherhood & planet of the apes had a baby=vj\". ", "Definitely no racism there.", "\n\nKirk praised Kanye West for becoming an incoherent Trump fanboy politically active, but later he criticized Taylor Swift for endorsing Tennessee Democrats Phil Bredesen and Jim Cooper, and told her to stay away from politics.[26]\n\nAlso, Kirk praised Trump for signing a pardon for someone sentenced for doing drugs, but he attacked Barack Obama for pardoning 330 federal inmates convicted of drug charges.[27]\n\nIn a further display of hypocrisy, he criticized Obama for visiting Cuba and not pointing out their corruption, but praised Trump for making peace with North Korea (without pointing out their corruption.)[28]\n\nOn January 21st, 2019, former Turning Point USA Director of High School Outreach Kyle Kashuv announced that Charlie had thrown out his back and a had a potential blood clot, and that the hospital made Charlie lay on a bench outside the hospital as they had run out of beds.[29] Ironically, despite getting screwed over by the American healthcare system, Charlie Kirk firmly believes the United States has the best healthcare system in the world[30] and that healthcare isn't a right.[31] Later, Charlie stated that he had visited a chiropractor who he claimed had made \"my spine go back into line\" by doing \"some very targeted treatment right behind my ear with his hands\".[32]\n\nHilariously, YAF blacklisted Charlie Kirk & Turning Point USA in a conservative group feud.[33]\n\nOh, and he also can't spell \"socialism\" correctly.[34][35] That's what happens when you don't graduate from college![36]\n\nCharlie Kirk has basically lost all credibility at this point.[37]\n\nGreatest hits [ edit ]\n\nIn June of 2018, Kirk expressed his support for Trump's criminal justice reform that released some non-violent drug offenders. ", "A mere four days earlier, he was complaining about how irresponsible it was for Obama to have done basically the same thing, illustrating just how high his level of partisanship is. [", "38]\n\nCharlie complaining about how intolerant \"the left\" really is for companies not wanting to advertise on Fox while threatening to boycott the NFL if players didn't stand for the anthem. [", "39]\n\nCharlie pretending to care about due process as it pertains to Brett Kavanaugh despite the fact that he claimed Hillary Clinton should have been sent to prison even if the FBI and Justice Department didn't think there was enough evidence. [", "40] [41]\n\nCharlie in 2014 bitching about how Obama was an open borders Marxist who was perfectly content with letting millions of illegals flood over the border. ", "Then, Charlie in 2018 defending child separation policy by saying that Obama did the exact same thing as Trump. ", "So, apparently Obama was letting a lot of illegals in while kicking them all out. [", "42] [43] [44]\n\nCharlie shredding Obama for the Dow-Jones Industrial Average dropping 500 points while remaining awkwardly silent when the same thing happened recently. [", "45]\n\nCharlie complaining that taxation is theft while complaining that Amazon didn't pay any. [", "46]\n\nCharlie trying to criticize Alexandria Ocasio-Cortez for losing 25,000 jobs because of Amazon pulling out of NYC while simultaneously claiming that Amazon pulling out was the right decision. [", "47] [48]\n\nCharlie claims that open borders are a sign of a weak and inhumane country while denouncing the Berlin Wall. [", "49]\n\nCharlie can't decide if taxes are a good thing. [", "50] [51]\n\nCharlie can't decide if Europe is a socialist wasteland. [", "52]\n\nCharlie claims that undocumented immigrants don't have rights because they aren't citizens. ", "About a month earlier, while delivering a speech, he said that rights don't come from governments. [", "53]\n\nCharlie can't decide if more laws is a good thing. [", "54]\n\nCharlie can't decide if he accepts basic biology. [", "55]\n\nCharlie can't decide if tragedies should be politicized. [", "56] [57]\n\nCharlie can't decide if the Democratic party is the party of the KKK or the party of MS-13. [", "58] [59]\n\nCharlie thinks homes and countries are the same things. [", "60]\n\nCharlie thinks that Trump deserves credit for Botswana legalizing same-sex marriage. [", "61]\n\nCharlie isn't sure if world leaders were ever attacked before Trump's presidency. [", "62]\n\nCharlie thinks California, the world's fifth largest economy, is a third world nation. [", "63]\n\nCharlie isn't sure about the lowest ever black unemployment rate. [", "64]\n\nCharlie can't decide if victimhood is a cancer. [", "65]\n\nCharlie using Mother's Day as an opportunity to own the libs. [", "66]\n\nCharlie doing a complete 180 in regards to Trump being the most moral president ever. [", "67]\n\nCharlie confused about majority rule [68]\n\nStopped clock [ edit ]\n\nKirk (most likely accidentally) stated that it was an injustice for Mack Beggs (a FTM trans boy) to be prevented from competing in the boys' wrestling league because of his birth sex (he was assigned female at birth but underwent gender confirmation surgery to become a man).[69] Charlie Kirk has a definite stopped clock moment in his opposition to the death penalty. ", "He says it is more expensive than life in prison and says innocent people are executed. [", "70][71]\n\nCharlie and the Bullshit Factory: Turning Point USA [ edit ]\n\nObvious Photoshop, his face looks bigger than it actually is\n\nTurning Point USA,[72] Charlie's pet project, is an astroturf nonprofit funded by the Koch brothers in order to make boring old conservatism look cool and appealing to millennials by sharing/posting/reposting cringeworthy memes and image macros. ", "These images consist mostly of inspirational quotes by great conservative thinkers, such as Ronald Reagan, Ben Shapiro, Tomato Larynx, and, obviously, Chairman Kirk himself, but also by filthy commies such as George Orwell and Nelson Mandela (taken wildly out of context, of course). ", "Their other favorite template is Top Panel: Liberal Quote (i.e. \"Capitalism is bad.\" —", "Bernie Sanders), Bottom Panel: TPUSA's Response (\"Then why don't you move to North Korea? ", "Also, socialism has killed 100 billion iPhones\"), accompanied by a picture of Charlie Kirk or a smug/confused-looking stock photo model wearing lensless glasses (because that's what dem youngsters wear these days). ", "Along with hashtags such as #BigGovSucks, #SocialismSucks, #iHeartCapitalism, and #iHeartFossilFuels.", "\n\nTurning Point's attempted launch in the UK (Turning Point UK) has not gotten off to a smooth start, as an immediate influx of parody accounts attributing ludicrous ancap ideas to the organization popped up almost instantly and were often indistinguishable from the real thing. [", "73]\n\nBill Montgomery, TPUSA's cofounder and Kirk's mentor, died in July 2020 of COVID-19 after months of downplaying it.[74]\n\nOf diapers and watchlists [ edit ]\n\n“ ” As of right now, I am in disbelief at how I went from being so upbeat, enthusiastic, and passionate about this organisation to being disgusted, frustrated, and embarrassed to have invested my entire senior year into an organisation founded by a college dropout who hires some of the most incompetent, lazy, and downright dishonest people I have ever encountered. —", "Kaitlin Bennett, former president and campus coordinator for Turning Point USA at Kent State University, reacting to the diaper shitshow.[75]\n\nCharlie Kirk loves freedom of speech so much, he came up with the idea of a so-called \"free speech ball,\" an oversized beach ball for grade school college students to write whatever the hell they want to. ", "With hilarious results.[76]\n\nAnother totally mature TPUSA stunt was their infamous 2017 \"diaper protest,\" in which they dressed and acted as toddlers in order to protest against safe spaces,[77] at Kent State of all places. ", "Not only did they lose funding and members after the incident,[78] but they also have been relentlessly mocked ever since.[79] Kirk himself, in a desperate attempt of damage control, disavowed the now defunct Kent State chapter of TPUSA.[80]\n\nOf course, Charlie Kirk also believes that free speech should not apply to the left, so he started a very McCarthyist project called Professor Watchlist, whose stated mission is \"to expose and document college professors who discriminate against conservative students and advance leftist propaganda in the classroom.", "\"[81] In reality, Professor Watchlist has resulted in over 100 cases of harassment (including death threats) against \"leftist\" professors.[82]\n\nFeud with Nick Fuentes [ edit ]\n\nOn October 2019, Kirk and Donald Trump, Jr. went to UCLA to promote Junior's latest piece of shit book titled — wait for it: Triggered: How the Left Thrives on Hate and Wants to Silence Us. ", "Expecting to epicly own some easily triggered, blue-haired, antifa SJW communist snowflakes who hate freedom of speech, Don Jr. and Kirk were hilariously heckled off the stage... by a group of Trump supporters.[83] More specifically, by fans of the far-right YouTuber Nick Fuentes (known as \"groypers\", a reference to a grotesque version of Pepe the Frog). ", "Fuentes, a white nationalist and Holocaust denier, has claimed that TPUSA, Dan Crenshaw, Ben Shapiro and other right-wing individuals and organizations are fake conservatives because they aren't fascist enough for his taste (maybe not, but damn, they're trying).", "\n\nTroll farm USA [ edit ]\n\nTurning Point Action, an affiliate of TPUSA, has been directing teenagers (including minors) to spread disinformation about COVID and mail-in ballots on Twitter and Facebook in an attempt to disrupt the 2020 election in favor of Trump. ", "The campaign has been likened to a 'troll farm'.[84]\n\nBibliography [ edit ]\n\nOur boy Charlie has also published some ridiculously out-of-touch[85][86] love letters to Trump \"books\":\n\nTime for a Turning Point: Setting a Course Toward Free Markets and Limited Government for Future Generations (2016)\n\n(2016) Campus Battlefield: How Conservatives Can WIN the Battle on Campus and Why It Matters – Foreword by Donald Trump, Jr. (2018)\n\n(2018) The MAGA Doctrine: The Only Ideas That Will Ruin Win the Future (2020)\n\nSee also [ edit ]" ]

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[ "INTRODUCTION\n============\n\nThe ability of a cell to respond rapidly and specifically to changes in the surrounding environment is controlled by protein--protein interactions at the plasma membrane and along the signaling cascade. ", "While much is known about the biochemical events that govern signaling pathways, this information has mostly been derived from population-based measurements that average over millions of cells and/or proteins. ", "However, there is growing evidence that system heterogeneity at both the cellular and molecular levels contribute to cellular information processing ([@B35]; [@B9]; [@B6]; [@B57]). ", "The epidermal growth factor receptor (EGFR/ErbB1/HER1) has 20 cytoplasmic tyrosines, at least six of which (Y992, Y1045, Y1068, Y1086, Y1148, and Y1173) are capable of recruiting signaling proteins when phosphorylated ([@B24]; [@B50]; [@B16]). ", "The potential for multisite phosphorylation on individual receptors provides a mechanism to control signaling output that is dependent on complex factors such as steric hindrance, relative abundance of receptors and adaptors, cooperative interactions, and lifetimes of complexes ([@B13]; [@B6]; [@B48]; [@B37]; [@B59]). ", "Signal propagation is opposed by cellular phosphatases ([@B30]), whose activity is proposed to be blocked when phosphotyrosine substrates are engaged with binding partners ([@B47]; [@B2]; [@B21]). ", "To better understand the contributions of these factors on the differential phosphorylation of EGFR, we have combined quantitative single-molecule measurements with rule-based modeling of EGFR signaling.", "\n\nLimitations of existing techniques, such as Western blot analysis and those of quantitative mass spectrometry-based proteomics, preclude the detection or accurate quantification of receptor phosphorylation in intact, individual signaling proteins. ", "Single-molecule pull down (SiMPull) is a powerful technique that allows for interrogation of macromolecular complexes at the individual protein level. ", "This technique captures macromolecular complexes on glass coverslips, combining the power of immunoprecipitation with high-resolution imaging for single-molecule quantitative analysis ([@B22]). ", "We made a number of critical improvements to SiMPull that allowed us to directly detect and rigorously quantify the phosphorylation state of thousands of individual membrane receptors. ", "This represents a significant improvement over traditional, semiquantitative methods, which report only trends in phosphorylation state changes over the entire population. ", "Our improvements to SiMPull protocols include pretreatment to reduce autofluorescence and corrections for receptor surface expression. ", "We employed a simplified imaging chamber that accommodates up to 20 samples, each with sample volumes of only 10 μl. ", "We also demonstrate the critical importance of optimizing antibody labeling and fixation conditions. ", "To quantify receptor phosphorylation, we have used two- and three-color imaging to identify individual proteins and their corresponding phosphorylation status. ", "These multiplex SiMPull measurements provide a new level of detail in the status of receptor phosphorylation that was previously inaccessible with traditional biochemical techniques.", "\n\nThe unique data provided by SiMPull were used to parameterize a mathematical model for site-specific phosphorylation kinetics of EGFR and to test model predictions. ", "Particularly, we explored two traits of relevance for signaling processes: 1) the influence of adaptor protein abundances on the phosphorylation levels of the EGFR residues to which these proteins bind; and 2) the frequency of multisite phosphorylation across individual EGFRs in the population. ", "We specifically explore how the phosphorylation status of individual receptors reflects the opposing contributions of adaptor binding versus phosphatase activity. ", "For example, simulations predicted that overexpression of the adaptor protein Grb2 would lead to increased phosphorylation at the EGFR tyrosine residue where Grb2 binds (Y1068). ", "This prediction was confirmed experimentally using SiMPull and compared with phosphorylation at the EGFR tyrosine residue where Shc1 binds (Y1173), which was found to be significantly less affected by Grb2 overexpression. ", "Additionally, our model predicts that differences in adaptor protein abundances across cell lines should result in differences in phosphorylation patterns. ", "We used our model to evaluate observed phosphorylation kinetics of mutant versus wild-type EGFR, as well as EGFR engaged by the low-affinity ligand epigen versus the high-affinity ligand EGF. ", "Simulation results suggest that the ligand-specific differences we observed in phosphorylation can be explained by differences in receptor dimer lifetimes. ", "These new insights into the extent of phosphorylation at individual tyrosines, along with the existence of multisite phosphorylation, have implications for how EGFR translates extracellular cues into downstream signaling outcomes.", "\n\nRESULTS\n=======\n\nAssessing receptor phosphorylation at the single-molecule level\n---------------------------------------------------------------\n\nOur principal method to interrogate the phosphorylation status of individual EGFRs after different treatments is single-molecule immunoprecipitation via SiMPull. ", "SiMPull samples are prepared in a manner similar to SDS--PAGE/Western blot protocols, but the sample is evaluated using single-molecule microscopy to dramatically improve quantification. [", "Figure 1A](#F1){ref-type=\"fig\"} illustrates the basic principles of our assay. ", "Briefly, cells expressing GFP-tagged EGFR are lysed before or after treatments (as specified in the figure legends). ", "Clarified lysates are diluted and dispensed onto coverslips precoated with anti-EGFR antibodies. ", "Following incubation and washes, individual EGFR-GFPs are imaged by total internal reflection fluorescence (TIRF) microscopy. ", "In the raw images, receptors appear as diffraction-limited fluorescent spots that may represent more than one molecule ([Figure 1B](#F1){ref-type=\"fig\"}, top left). ", "Single molecules are selected by fitting each emission profile to a point spread function model and rejecting fluorescent spots that do not fit to a single-emitter model ([Figure 1B](#F1){ref-type=\"fig\"}, bottom left). ", "To evaluate the overall phosphorylation state of individual receptors, coverslips are incubated with pan-reactive, anti-phosphotyrosine (anti-PY) antibodies bearing fluorescent tags with spectral emission distinct from GFP ([Figure 1B](#F1){ref-type=\"fig\"}, center). ", "Colocalization between EGFR-GFP and anti-PY identifies phosphorylated receptors. ", "In this example, the overlay image shows that 34.4% of EGFR-GFPs are phosphorylated on at least one tyrosine site ([Figure 1B](#F1){ref-type=\"fig\"}, right). ", "Phosphorylation at specific tyrosines in the EGFR cytoplasmic tail is evaluated by substituting a site-specific phosphotyrosine antibody (anti-pY1068 or anti-pY1173) for the pan-PY antibodies.", "\n\n{#F1}\n\nOver the course of this study, we implemented a series of improvements in the experimental process and image analysis to achieve efficient and accurate quantification. ", "These are described briefly here and more detail is found in the *Materials and Methods* section and in legends to Supplemental Figures S1--S3. ", "As has been previously noted ([@B23]), autofluorescence background was observed in our green spectral channel (503--548 nm) that was identified as single-GFP molecules in the absence of cell lysate. ", "We found that incubating the PEG-coated coverglass with sodium borohydride (10 mg/ml NaBH~4~ for 4 min) significantly reduced the number of background fluorescent molecules (Supplemental Figure S1, A and B). ", "To increase our throughput, we generated a simple sample chamber by using a hydrophobic barrier pen to create an array of up to 20 independent regions on a coverglass that requires as little as 10 µl of sample (Supplemental Figure S1C). ", "Because antibodies are used to quantify protein phosphorylation, it is critical to optimize the antibody labeling conditions, including time and concentration (Supplemental Figure S1, D--F). ", "We found that on the time scale of our image acquisition the antibody could dissociate from EGFR (Supplemental Figure S1E), which would lead to an underestimation of receptor phosphorylation. ", "Post--antibody labeling fixation with 4% paraformaldehyde/0.1% glutaraldehyde (PFA/GA) for 10 min stabilized the antibody levels for at least 1 h (Supplemental Figure S1E, PFA/GA). ", "Because binding affinity will vary for each antibody and fluorescent conjugation may also alter antibody affinity, it is necessary to perform a binding curve for each antibody (Supplemental Figure S1F) to ensure optimal labeling conditions. ", "Therefore, in the SiMPull assays reported here, we used antibody doses yielding saturated labeling and chemical cross-linking to permanently couple antibodies to surface-captured receptors, removing potential artifacts from antibody affinities or dissociation. ", "The phosphotyrosines probed in EGFR are located in an intrinsically disordered region of the C-terminal tail; therefore these sites are likely to be more accessible to antibodies than if they were located in folded regions. ", "If a phosphorylation site of interest is found in a folded region of a protein, a denaturation step may be used ([@B27]).", "\n\nCorrecting for EGFR surface expression in SiMPull data analysis\n---------------------------------------------------------------\n\nLike all immunoprecipitation methods that rely on detergent permeabilization of cells as a first step, SiMPull does not distinguish between EGFR trafficking through different intracellular compartments. ", "We observed intracellularly localized EGFR-GFP ([Figure 1C](#F1){ref-type=\"fig\"}, left) that would be inaccessible to ligand. ", "To determine the fraction of EGFR at the plasma membrane, we labeled all surface proteins on the CHO-EGFR-GFP cells with membrane-impermeable AF647-NHS ester ([Figure 1C](#F1){ref-type=\"fig\"}, right) and used SiMPull to visualize the amount of EGFR-GFP colocalized with AF647. ", "By increasing the concentration of AF647-NHS until saturation is achieved, we estimated that ∼65% of the receptors are located at the plasma membrane ([Figure 1D](#F1){ref-type=\"fig\"}). ", "With this information, we corrected our measurements to account for only those receptors available to bind ligand (see *Materials and Methods*). ", "For example, application of this correction shows that ∼14% of the receptors are phosphorylated at Y1068 after 1 min stimulation with 50 nM EGF ([Figure 1E](#F1){ref-type=\"fig\"}). ", "We note that while surface labeling of receptors with AF647-NHS ester allows for identification of surface proteins, we found that prelabeling of EGFR in this way reduced EGF binding (unpublished data). ", "Therefore, we did not use global NHS labeling of receptors for the study of EGFR activation. ", "To validate our correction method, we analyzed the phosphorylation levels of receptors from CHO cells expressing ACP-tagged EGFR. ", "We directly labeled the plasma membrane--­localized EGFR using membrane-impermeable CoA-Atto488 as described previously ([@B69]; [@B62]). ", "Cells were then exposed to EGF and probed for EGFR phosphorylation with SiMPull, this time using Atto488 as the marker for plasma membrane EGFR. ", "The percentages of phosphorylated EGFR were similar when comparing the membrane-localized ACP-EGFR and the membrane-corrected EGFR-GFP samples ([Figure 1E](#F1){ref-type=\"fig\"}). ", "Therefore, the effects of EGF binding to EGFR on the plasma membrane can be accurately determined from whole cell lysates and we apply this correction for the remainder of the results.", "\n\nExtent of phosphorylation varies by tyrosine residue\n----------------------------------------------------\n\nResults of the use of SiMPull to characterize phosphorylation of EGFR in CHO-EGFR-GFP cells over a range of EGF doses are shown in [Figure 2A](#F2){ref-type=\"fig\"}. ", "The multiwell hydrophobic array format made it possible to efficiently examine a full dose response of activation in a single imaging session. ", "We quantified total EGFR tyrosine phosphorylation (PY) and compared it with the phosphorylation patterns for two specific tyrosine sites (Y1068 and Y1173). ", "Cells stimulated for 5 min ([Figure 2A](#F2){ref-type=\"fig\"}) with increasing concentrations of EGF showed the expected increase in total phosphorylation with ligand dose ([Figure 2A](#F2){ref-type=\"fig\"}, PY, blue bars). ", "This fraction reached 40.8 ± 1.3% with 50 nM EGF, a dose that is considered saturating. ", "While the extent of phosphorylation on specific tyrosines is lower than total PY values across the dose response curve, the fraction of EGFR with phosphorylation at Y1173 was consistently higher than at Y1068 ([Figure 2A](#F2){ref-type=\"fig\"}).", "\n\n![", "The extent of phosphorylation varies by tyrosine residue. (", "A) Dose response curve determined by SiMPull measurements for CHO-EGFR-GFP cells after 5 min of EGF addition at 37°C. ", "Number of receptors analyzed per condition, *N* \\> 1500. \\*, *", "P* ≤ 0.05; \\*\\*, *P* ≤ 0.01; \\*\\*\\*, *P* ≤ 0.001. (", "B) Schematic of EGFR tyrosine site-specific model, represented as an extended contact map ([@B5]). (", "C) The model is capable of generating dose-response behaviors similar to those observed experimentally (A). (", "D) Phosphorylation time course for CHO-EGFR-GFP cells stimulated with 25 nM EGF at 37°C. *", "N* \\> 1800. ", "Symbols are the SiMPull data and error bars are SE of measured phosphorylation percentages. ", "The series of experiments reported in A and D were each performed on the same day, but the two series of experiments were performed on different days. ", "For this reason, results at the final time point in D are not combined with the results shown in A. Solid lines in D are derived from simulations using best-fit parameter values. ", "As described in *Materials and Methods*, dose-response data in A and all times-series data in D were considered in curve fitting, that is, the parameter estimates are based on a global fit. ", "Shaded areas in D indicate prediction uncertainties, determined by sampling parameter values from the multidimensional posterior established via Bayesian parameter estimation.](mbc-31-695-g002){#F2}\n\nThese results provide important observations. ", "First, phosphorylation detection by SiMPull is sensitive, capable of detecting receptor phosphorylation at low ligand dose. ", "Second, even under saturating ligand conditions, only a fraction of receptors is found to be phosphorylated, reaching a maximum of approximately 41% with 5 min stimulation. ", "Third, the extent of phosphorylation varies by tyrosine residue. ", "The detected phosphorylation levels are not restricted due to limitations in antibody labeling, because Western blot results show similar trends in tyrosine phosphorylation (Supplemental Figure S2, A--C) and cells stimulated in the presence of phosphatase inhibitors showed increased receptor phosphorylation (Supplemental Figure S2, D and E) for all three antibodies. ", "The addition of high salt (500 mM NaCl) in the buffer for the immunoprecipitation protocol, which interferes with electrostatic protein--protein interactions, did not change the detected phosphorylation (Supplemental Figure S2F). ", "This control suggests that, under our conditions, adaptor proteins that might interfere with antibody recognition in the SiMPull protocol are not coprecipitating.", "\n\nComputational model suggests biased phosphorylation is explained by variations in adaptor protein abundances\n------------------------------------------------------------------------------------------------------------\n\nTo interpret the SiMPull data, we built a mathematical model based on our understanding of EGFR signaling mechanisms. ", "We defined the model in terms of formal rules for interactions using the BioNetGen language (BNGL; [@B8]). ", "Supplemental Table S1 summarizes key references and measurements that provide estimates of model parameters, including our own estimates of receptor expression levels in the cell lines utilized in the study. ", "Our model explicitly incorporates the asymmetric orientation of the EGFR kinase domains during dimerization, which assumes one monomer is active while the other monomer serves as an allosteric activator over the lifetime of that dimer pair ([@B68]; [@B43]). ", "We also incorporated the observation that structural accessibility limits the efficiency of self-phosphorylation (i.e., within an active monomer's own tail) by about 30% ([@B32]). ", "An electronic version of the model is provided in the form of a BNGL file in the online Supplemental Material (Supplemental File S1). ", "Included with the BNGL file are all of the files necessary to perform the fitting and Bayesian uncertainty quantification procedures (Supplemental File S2). ", "These files are also available online at the RuleHub repository (<https://github.com/RuleWorld/RuleHub/tree/2019Jun18/Published/Salazar-Cavazos2019>).", "\n\n[Figure 2B](#F2){ref-type=\"fig\"} illustrates the structure of our model. ", "Our first goal for computational modeling was to explore the possible mechanisms giving rise to the observed biased phosphorylation in EGFR at Y1173 compared with Y1068. ", "As depicted in [Figure 2B](#F2){ref-type=\"fig\"}, and described in detail in *Materials and Methods*, our model includes site-specific phosphorylation of Y1068 and Y1173, and the recruitment of adaptor proteins Grb2 and Shc1 to these sites, respectively. ", "We considered a range of parameter values in the model that might be adjusted to reproduce the biased phosphorylation (Supplemental Table S2). ", "First, we considered the possibility that the phosphorylation and/or dephosphorylation rates are not equivalent for each tyrosine. ", "It is possible for the model to fit our SiMPull data by allowing phosphorylation and dephosphorylation rate constants for Y1068 and Y1173 to be different, but earlier work suggests that these rate constants have similar values for the two sites ([@B30]; [@B28]). ", "Thus, our data do not allow site-­specific differences in phosphorylation and dephosphorylation at Y1068 and Y1173 to be ruled out, but such differences are dissonant with results from earlier studies.", "\n\nAn alternative possibility is that the binding of adaptor proteins (i.e., Grb2 and Shc1) physically serves as a barrier to protect specific phosphorylated tyrosines from phosphatase activity. ", "This hypothesis is supported by in vitro and cellular studies showing the ability of SH2 domains to protect phosphosites from dephosphorylation ([@B47]; [@B2]; [@B21]). ", "To test whether variation in protein abundances alone could explain our observations, we allowed the concentration of Grb2 and Shc1 to independently vary during the fitting process, while all other parameters were held constant. ", "As a simplification, we took binding parameters (forward and reverse rate constants) for Grb2 interaction with pY1068 (via Grb2's SH2 domain) and Shc1 interaction with pY1173 (via Shc1's phosphotyrosine binding \\[PTB\\] domain) to be identical. ", "The equilibrium dissociation constants measured* *in vitro by fluorescence polarization for these two interactions are comparable (2.6 µM for Grb2 SH2-pY1068 and 1.4 µM for Shc1 PTB-pY1173; [@B16]). ", "By allowing Grb2 and Shc1 to have different abundances, it became possible to parameterize the model (through curve fitting, as described in *Materials and Methods*) such that the model generates dose-response behaviors ([Figure 2C](#F2){ref-type=\"fig\"}) as well as dynamic behaviors at the saturating dose of 25 nM EGF ([Figure 2D](#F2){ref-type=\"fig\"}) similar to those observed with SiMPull. ", "The results of uncertainty quantification, illustrated in [Figure 2D](#F2){ref-type=\"fig\"}, show that there is model discrepancy (i.e., variability in experiments not captured by the model). ", "Nevertheless, we regard simulations to adequately reproduce the data, at least qualitatively. ", "The similarity between simulations and observed behaviors suggests that different abundances of phosphotyrosine site-specific binding partners are a plausible explanation for the observed differences in phosphorylation at Y1068 and Y1173.", "\n\nPredicted influence of Grb2 overexpression in phosphorylation levels is observed experimentally\n-----------------------------------------------------------------------------------------------\n\nOur next goal was to experimentally validate the model prediction that biased phosphorylation is best explained by having different expression levels of Grb2 and Shc1. ", "To set up conditions for these experiments, we ran simulations over a range of Grb2 overexpression values (two-, four-, and eightfold). ", "Results in [Figure 3A](#F3){ref-type=\"fig\"} predict that Grb2 overexpression will lead to increased phosphorylation at Y1068, where Grb2 binds. ", "Notably, no change is predicted for phosphorylated Y1173, where Grb2 is not expected to bind ([Figure 3B](#F3){ref-type=\"fig\"}). ", "To test these predictions, we created CHO-EGFR-GFP cells overexpressing Grb2-mCherry and evaluated the influence on EGFR phosphorylation using SiMPull ([Figure 3, C and D](#F3){ref-type=\"fig\"}). ", "Consistent with trends in the simulation results, overexpression of Grb2 led to a significant (approximately threefold) increase in phosphorylation of Y1068 ([Figure 3C](#F3){ref-type=\"fig\"}) and a much less pronounced increase in phosphorylation of Y1173 ([Figure 3D](#F3){ref-type=\"fig\"}). ", "The relatively small change in phosphorylation at Y1173 ([Figure 3D](#F3){ref-type=\"fig\"}) is consistent with reports that high expression of Grb2 can enhance phosphorylation at sites beyond the canonical Grb2 binding sites in EGFR ([@B21]).", "\n\n{#F3}\n\nModel predicts cell-specific phosphorylation patterns based on differences in adaptor protein abundances\n--------------------------------------------------------------------------------------------------------\n\nOn the basis of these results, we hypothesized that cell types naturally expressing different levels of these adaptor proteins would display different phosphorylation patterns. ", "Protein copy numbers have been assayed using both global and targeted mass spectrometry-based proteomics in various cell lines ([@B33]; [@B54]). ", "These estimates include the protein copy numbers (per cell) for EGFR, Grb2, and Shc1 in the nontumorigenic mammary epithelial HMEC and MCF10A cells, as well as in HeLa cervical cancer cells (see Supplemental Table S1). ", "As described in *Materials and Methods*, we performed simulations using these measured cell-­specific protein copy numbers (Supplemental Table S1) and obtained model predictions for the phosphorylation patterns and kinetics in each of the three cell lines ([Figure 4, A--C](#F4){ref-type=\"fig\"}). ", "In HMEC cells, where the estimated abundances of both adaptor proteins are relatively low, the model predicts similar levels of phosphorylation at both tyrosine residues ([Figure 4A](#F4){ref-type=\"fig\"}). ", "For MCF10A cells, the model predicts slightly higher phosphorylation at Y1173 given that its binding partner, Shc1, is expressed at a higher level than Grb2 ([Figure 4B](#F4){ref-type=\"fig\"}). ", "The most striking difference in expression levels between the two adaptor proteins is found in HeLa S3 cells, where it is estimated that there are ∼600,000 copies of Grb2 per cell compared with ∼100,000 copies of Shc1 per cell (Supplemental Table S1). ", "Accordingly, for these cells, the model predicts that phosphorylation at Y1068 should be higher than at Y1173 ([Figure 4C](#F4){ref-type=\"fig\"}), the reverse of what is predicted by the version of the model parameterized for consistency with our CHO-cell data. ", "Experimental results using SiMPull are shown in [Figure 4D](#F4){ref-type=\"fig\"}. ", "These results confirm that HeLa S3 cells exhibit the expected reversal in biased phosphorylation. ", "The difference in phosphorylation is less pronounced than predicted, with phosphorylation at Y1068 only slightly higher than phosphorylation at Y1173, but there is qualitative consistency between the predicted and observed phosphorylation levels at the two sites.", "\n\n![", "Predicted phosphorylation patterns in cell lines with varying adaptor protein expression. (", "A--C) Predictions of phosphorylation kinetics for HMEC (A), MCF10A (B), and HeLa S3 (C) cell lines. ", "HMEC cells express low levels of both Grb2 and Shc1; MCF10A cells have slightly higher levels of Shc1 than Grb2; HeLa S3 cells express approximately seven times more Grb2 than Shc1 ([@B33]; [@B54]; see Supplemental Table S1). (", "D) Phosphorylation pattern in HeLa S3 cells obtained by SiMPull measurements. *", "N* \\> 1550. \\*\\*, *", "P* ≤ 0.01. ", "Error bars represent mean ± SEM.](mbc-31-695-g004){#F4}\n\nThree-color SiMPull reveals frequency of multisite phosphorylation on individual EGFR\n-------------------------------------------------------------------------------------\n\nOur results above suggest that EGF-treated cells bear subpopulations of receptors with differing phosphorylation patterns. ", "SiMPull offers unique advantages over traditional methods, because individual molecules can be probed with more than one antibody providing each has a spectrally distinct fluorescent tag. ", "We utilized the capability for simultaneous three-color SiMPull imaging to determine the frequency of multisite phosphorylation on individual EGFRs. [", "Figure 5A](#F5){ref-type=\"fig\"} illustrates the basic protocol used to evaluate the incidence of multisite phosphorylation at the single-receptor level. ", "The image in [Figure 5B](#F5){ref-type=\"fig\"} shows a typical result, where each receptor is resolved based on GFP emission (dark green), and then overlaid with detection of anti--PY1068-CF555 (light green) and detection of anti--PY-AF647 (purple). ", "Circled, white spots indicate the presence of EGFRs that are positive for both antibodies and, therefore, phosphorylated on PY1068 as well as at least one other tyrosine in the cytoplasmic tail.", "\n\n{#F5}\n\nWhen labeling a single protein with two or more antibodies, the potential for steric hindrance must be considered. ", "We first tested whether colabeling of receptors with pairwise combinations of antibodies to PY1068, PY1173, and/or pan-PY was technically feasible. ", "Results in Supplemental Figure S3 confirm the feasibility of a method that employs sequential, pairwise antibody labeling and also provides for correction of steric blocking during our labeling procedures (see also *Materials and Methods*). ", "We also performed step-photobleaching analysis to assure that the doubly labeled receptors were associated with a single EGFR-GFP molecule and not two or more EGFRs in a diffraction-limited spot (Supplemental Figure S4A). ", "Step photobleaching confirmed that at our pull-down density the majority of double-labeled receptors are indeed monomers (∼98%).", "\n\nBy combining anti--pan-PY labeling with each of the two specific sites (pY1173 or pY1068), we were able to quantify the frequency of multisite phosphorylation on individual receptors. ", "First, we examined to what extent a receptor phosphorylated at Y1068 or Y1173 might also be phosphorylated at another tyrosine (pan-PY). [", "Figure 5C](#F5){ref-type=\"fig\"} reports the percentage of all receptors exhibiting multisite phosphorylation, found to reach 13.0 ± 1.8% as a function of EGF dose for each of the two tyrosines examined here. ", "From this data, we can also interrogate the behavior of specific phosphorylation events with respect to a particular receptor pool. ", "For example, [Figure 5D](#F5){ref-type=\"fig\"} shows the probability of a receptor being phosphorylated (PY) within three distinct subpopulations. ", "As expected, the total percentage of phosphorylated EGFR increased with dose ([Figure 5D](#F5){ref-type=\"fig\"}, PY in total EGFR, dark blue). ", "In the fraction of receptors phosphorylated at Y1068, there is a high probability of that same receptor being colabeled for pan-PY, reaching 80.3 ± 4.9% after 5 min of 50 nM EGF stimulation ([Figure 5D](#F5){ref-type=\"fig\"}, PY in pY1068+ EGFR, medium blue). ", "Additionally, we found that pY1173+ receptors were frequently colabeled for pan-PY ([Figure 5D](#F5){ref-type=\"fig\"}, PY in pY1173+, light blue) at a high frequency, albeit lower than for pY1068+ EGFR. ", "These data suggest that, at least in CHO cells, there is a slight increase in multisite phosphorylation in combination with pY1068 over pY1173. ", "We also analyzed the data in a manner to determine the fraction of pY1068 within the total receptor (pY1068 in total EGFR) or phosphoreceptor (pY1068 in PY+ EGFR) populations. [", "Figure 5E](#F5){ref-type=\"fig\"} shows that the total fraction of EGFR phosphorylated at Y1068 increases with ligand dose (red), while the fraction of pY1068 within the PY+ EGFR population remains relatively constant (pink). ", "Simulations corresponding to experiments in [Figures 5, D and E](#F5){ref-type=\"fig\"}, are qualitatively consistent with the observed results (Supplemental Figure S4, B and C), and predict that even at subnanomolar EGF concentrations the levels of pY1068 in PY+ EGFR remain at comparable levels as when EGF concentrations are high (Supplemental Figure S4C). ", "This supports the idea that, at least for tyrosine sites with fast phosphorylation kinetics such as Y1068, the phosphorylation levels within a signaling unit (activated receptor) remain relatively constant and the influence of ligand dose is in the number of activated receptors. ", "Together, these results directly demonstrate that it is common for individual EGFRs to acquire phosphorylation on multiple sites.", "\n\nDual phosphorylation at Y1068-Y1173 is predicted by the model and supported by SiMPull measurements\n---------------------------------------------------------------------------------------------------\n\nWe next explored the mechanistic basis for multisite phosphorylation in our computational model, which was initially trained using only single-site phosphorylation data. ", "Simulation results in [Figure 5F](#F5){ref-type=\"fig\"} predict that approximately 3% of receptors will become dually phosphorylated at Y1068 and Y1173 (pYpY) within 1 min of saturating ligand dose, reaching a steady-state value sustained for at least 5 min. ", "To test this prediction experimentally, we performed three-color analysis by treating cells for 5 min with EGF, followed by lysis and SiMPull isolation. ", "Samples were colabeled with anti-pY1068 and anti-pY1173 antibodies and corrected for reduced labeling efficiency due to steric blocking (see Supplemental Figure S3, B--D, and *Materials and Methods*). ", "As shown in [Figure 5G](#F5){ref-type=\"fig\"}, we found that 6.9 ± 1.3% of total receptors have dual phosphorylation at Y1068 and Y1173 (pYpY). ", "As a control, we treated cells with EGF in the presence of phosphatase inhibitors and found a corresponding increase in the percentage of dually phosphorylated EGFR (Supplemental Figure S3E). ", "Therefore, both our computational model and quantitative SiMPull experiments indicate that a fraction of EGFR is dually phosphorylated at Y1068 and Y1173 in response to ligand stimulation.", "\n\nDimerization efficiency and lifetime are key factors in multisite phosphorylation\n---------------------------------------------------------------------------------\n\nWe performed a sensitivity analysis to determine how dual phosphorylation depends on parameter values (Supplemental Figure S5). ", "Changes in phosphorylation and dephosphorylation rate constants had the greatest effect on the percentage of dual phosphorylation. ", "Changes in parameters that govern adaptor protein recruitment had the next largest effects on dual phosphorylation.", "\n\nTo validate the impact of changes in kinase activity, we turned to our prior work with activating EGFR mutations common in non--small cell lung cancer ([@B62]). ", "The oncogenic properties of the L858R EGFR mutant have been attributed in part to increased kinase activity ([@B68]), as well as structural changes that enhance dimerization potential in the absence of ligand ([@B62]). ", "Using the mathematical model, we simulated the mono- and dual-site phosphorylation in response to increased kinase activity (reflected by the pseudo first-order rate constant used in the model to characterize autophosphorylation) for L858R EGFR dimers over wild-type (WT) EGFR dimers. ", "The model predictions in [Figure 6A](#F6){ref-type=\"fig\"} show that enhanced kinase activity will lead to increases in phosphorylation at both Y1068 and Y1173, as well as in dual phosphorylation. ", "Experimentally, we compared single and multisite phosphorylation in CHO cells expressing WT or L858R EGFR under saturating EGF conditions, where our prior work showed that ligand-bound WT and mutant EGFR have the same dimer lifetime ([@B62]). ", "In qualitative agreement with modeling predictions, we found that L858R EGFR exhibits an increase in phosphorylation at each individual tyrosine as well as in dual phosphorylation at both Y1068 and Y1173 ([Figure 6B](#F6){ref-type=\"fig\"}). ", "To obtain a quantitative estimate of the increased kinase activity, we fitted our model to the data of [Figure 6B](#F6){ref-type=\"fig\"}. ", "In the fitting procedure, we allowed the rate constant for autophosphorylation to vary, but held all other parameters fixed at their previously estimated values. ", "The one-parameter fit indicates that the intrinsic kinase activity of L858R EGFR is 3.6-fold higher than WT EGFR. ", "Simulation results based on the best fit are shown in [Figure 6A](#F6){ref-type=\"fig\"}. ", "Our estimate is consistent with previous in vitro measurements, in which the kinase activity for the L858R kinase domain was determined to be approximately 3.5-fold higher ([@B68]).", "\n\n{#F6}\n\nWe were particularly interested in exploring the interdependent relationships between ligand affinity, dimerization off-rates, and multisite phosphorylation. ", "To explore this experimentally, we focused on comparing multisite EGFR phosphorylation in cells stimulated with either (high affinity) EGF or another natural EGFR ligand, (low affinity) epigen. ", "We chose this system because shorter dimer lifetimes were recently proposed to be a key feature that explains altered cellular outcomes of epigen-mediated signaling ([@B11]). ", "We used the mathematical model to predict the outcome of shorter dimer lifetimes on EGFR phosphorylation and found that receptor phosphorylation at pY1068 is expected to be reduced ([Figure 6C](#F6){ref-type=\"fig\"}), in qualitative agreement with Western blot results reported by [@B11]. ", "The model also predicted that phosphorylation at Y1173 and dual phosphorylation should be reduced. ", "We used three-color SiMPull to evaluate the differential levels of multisite phosphorylation for EGFR after stimulation with either EGF or epigen, using saturating levels of both ligands to ensure equivalent occupancy ([Figure 6D](#F6){ref-type=\"fig\"}). ", "We found that both tyrosines were phosphorylated to a lesser extent by epigen than in EGF-stimulated cells. ", "The number of receptors achieving dual phosphorylation was also reduced with epigen activation. ", "To determine what dimer lifetime best explains these results, we fitted our model to the data of [Figure 6D](#F6){ref-type=\"fig\"}. ", "In the fitting procedure, we allowed the rate constant for EGFR dimer dissociation to vary, but held all other parameters fixed at their previously estimated values. ", "The one-parameter fit indicates that epigen-induced dimers have 4.8-fold shorter lifetime than EGF-induced dimers. ", "Simulation results based on the best fit are shown in [Figure 6C](#F6){ref-type=\"fig\"}. ", "These results strengthen the argument that altered epigen signaling is a result of shorter-lived dimer interactions.", "\n\nDISCUSSION\n==========\n\nMathematical modeling of cellular signaling, including EGFR signaling, has historically relied on population-based measurements ([@B25]; [@B17]). ", "Parameterization of mathematical models has improved over time, incorporating more accurate measurements such as quantitative mass spectrometry techniques to profile overall protein abundance patterns for the EGFR--MAPK pathway ([@B53]), as well as ligand-induced changes in the phosphoproteome ([@B67]). ", "Concomitantly, the systems biology field has increasingly recognized the influence of heterogeneity at the single-cell scale in determining signaling output ([@B31]). ", "Recent advances in quantitative imaging now provide powerful new methods to interrogate single-cell and single-molecule dynamics, which are providing new insights on how cells encode and interpret information ([@B14]; [@B64]; [@B45]). ", "In prior work, we have built spatial stochastic models of EGFR/ErbB signaling ([@B43], [@B44]) that incorporate single-molecule measurements, including experimentally derived values for receptor diffusion and ligand-dependent changes in dimer off-rates ([@B40]; [@B58]). ", "These properties of EGFR continue to be key features of our current phosphorylation site-specific, rule-based model.", "\n\nWollman and colleagues have proposed that a deeper understanding of signaling networks requires richer data sets collected at the single-cell level, coupled closely with computational modeling in an iterative process of prediction, experimental confirmation, and manipulation ([@B15]). ", "In this work, we set out to purposely pair simulations with novel single-molecule quantitative data, capturing the dose-dependent heterogeneity in phosphorylation of thousands of single receptors. ", "Improvements in the single-molecule technique, SiMPull, allowed us to obtain robust, quantitative information about EGFR multisite phosphorylation patterns and to identify the frequency of subpopulations. ", "We found that there are distinct populations of receptors with varying phosphorylation patterns, indicating an early diversification of downstream signaling. ", "These data were used to train a rule-based model of site-specific EGFR phosphorylation and adaptor recruitment (i.e., to estimate unknown model parameter values via a curve-fitting procedure).", "\n\nOur rule-based model for EGFR signaling, illustrated in [Figure 2B](#F2){ref-type=\"fig\"} as an extended contact map ([@B5]), has a structure consistent, to a first-order approximation, with known and well-established mechanisms of ligand--receptor binding, ligand-dependent receptor-mediated receptor dimerization, autophosphorylation, and phosphotyrosine-dependent recruitment of adaptor proteins. ", "However, the model should be viewed as an idealization, because as a simplification, we purposely excluded a number of potentially relevant complicating factors, such as inside-out effects of signaling on ligand binding ([@B41]), competition among the cellular milieu of SH2/PTB domain-containing signaling proteins for phosphotyrosine docking sites in EGFR ([@B59]), and cooperative recruitment of adaptor proteins ([@B55]). ", "These and other aspects of EGFR signaling are not yet fully understood. ", "Another reason to view the model as an idealization is the outcome of our Bayesian analysis of prediction uncertainty, described in *Materials and Methods*. ", "Results from this analysis, which are illustrated in [Figure 2D](#F2){ref-type=\"fig\"}, indicate that the parameterized model is not able to fully capture variability in the training data. ", "Despite this model discrepancy issue, we deemed the parameterized model to adequately reproduce the training data and to be useful for guiding further experiments, for the following reasons. ", "Simulations are similar to and qualitatively consistent with observed dose-response behaviors (cf. [", "Figure 2, A and C](#F2){ref-type=\"fig\"}) and observed dynamic behaviors (cf. ", "the curves and data points in [Figure 2D](#F2){ref-type=\"fig\"}). ", "It should be noted that SiMPull assays are destructive. ", "Thus, any training data spanning multiple conditions would necessarily need to be generated from multiple independent experiments performed in parallel. ", "This requirement very likely introduces uncontrolled variability, which is not accounted for in the model.", "\n\nWe directly tested the widely held assumption that SH2 domain binding transiently protects specific phosphotyrosines from cellular phosphatases, as suggested by prior work using semiquantitative, population-based Western blot techniques ([@B47]; [@B2]; [@B55]; [@B21]). ", "As our model predicted, overexpression of Grb2 led to a pronounced increase in phosphorylation at Y1068 in EGFR, the principal site where Grb2 binds, but largely left phosphorylation at Y1173, where Shc1 binds, unchanged. ", "This behavior may be important for understanding EGFR signaling in cancer cells, where expression levels of signaling proteins are commonly altered ([@B63]; [@B49]). ", "In particular, we predicted and observed biased phosphorylation of Y1068 and Y1173 that shifts across cell lines having different adaptor protein abundances (cf. [", "Figures 2](#F2){ref-type=\"fig\"} and [4](#F4){ref-type=\"fig\"}).", "\n\nIt should be acknowledged that the observed reversal in biased phosphorylation of Y1068 and Y1173 for HeLa S3 cells (vs. CHO cells) was less pronounced than predicted (cf. [", "Figure 3, C and D](#F3){ref-type=\"fig\"}). ", "There are at least two potential explanations for this discrepancy of degree. ", "First, there could be errors in the copy number measurements that were used to obtain the cell-specific models. ", "In a recent study, concerns were raised about the accuracy of available data sets ([@B7]), including the data set that we used to set abundances of EGFR, Grb2, and Shc1 for the HeLa cell--specific model. ", "Second, as a simplification, we held rate constants for receptor phosphorylation and dephosphorylation fixed across the different cell-specific versions of the model. ", "However, these rate constants are potentially cell specific. ", "Phosphatase abundances are known to vary across cell type ([@B54]), giving rise to the possibility that effective dephosphorylation rates may be cell specific. ", "Furthermore, membrane properties are known to vary across cell type ([@B36]), with potential impacts on EGFR localization and dimerization, which could affect autophosphorylation. ", "Finally, it should be recalled that our model is an idealization, and as such, it cannot be expected to match observations with fine-grained resolution. ", "The model provides a plausible explanation for our findings about the interplay between adaptor protein abundances and site-specific EGFR phosphorylation patterns, but there may be other explanations, such as cell-specific kinase and phosphatase activities, which cannot be ruled out. ", "Although we focused on two prototypical examples of binding partners, Grb2 and Shc1 ([@B26]), the principles we describe likely apply to the broader interactome map of ∼89 SH2-bearing proteins that interact with ErbB receptors with varying degrees in affinity, abundance, and tissue-specific expression ([@B16]). ", "Of course, some SH2-bearing proteins, such as Grb2, may be somewhat promiscuous and bind with weaker affinity to more than one phosphosite in the receptor cytoplasmic tail ([@B21]). ", "Binding of adaptors at one or more sites may partially block the accessibility of other SH2 proteins or phosphatases at nearby sites or even serve as scaffolds to build larger macromolecular complexes ([@B20]; [@B60]). ", "Addressing the combinatorial complexity of these signaling interactions is a strength of rule-based approaches ([@B4]), particularly when combined with single-molecule quantification.", "\n\nWe demonstrate the advantages of SiMPull for determining the fraction of receptors that simultaneously bear more than one posttranslational modification. ", "This ability required considerable optimization of SiMPull protocols, representing a step forward over previous protocols that failed to detect an EGF-dependent increase in multisite EGFR phosphorylation ([@B27], [@B29]). ", "Notably, our modeling and experimental results indicating that individual copies of EGFR are phosphorylated at multiple sites are consistent with previous work indicating that multisite phosphorylation is important for recruitment of certain combinations of signaling proteins to activated EGFR ([@B55]; [@B10]). ", "Interestingly, our results demonstrate that not all receptors are phosphorylated identically. ", "Differential phosphorylation patterns may allow individual receptors to connect to distinct pathways for biased signaling. ", "It is particularly important to understand biased signaling in the context of different ligand types and doses, as well as cell variables such as the expression levels of receptors and their signaling partners ([@B66]; [@B3]; [@B65]; [@B11]).", "\n\nOur combination of modeling and experiments has provided a connection between receptor dimer lifetimes and phosphorylation outcomes. ", "Recent work from the Lemmon group has explored differential phosphorylation patterns and signaling outcomes after EGFR stimulation with high- and low-affinity ligands ([@B11]). ", "Our contributions to that study supported the conclusion that low-affinity ligands, such as epigen, induce distinct dimer structures that are less stable than dimers induced by EGF. ", "By allowing the dissociation rate constant for ligand-induced EGFR dimers to vary in a one-parameter fit, our model became capable of closely reproducing the SiMPull data from experiments with epigen-treated cells. ", "The adjusted value for this rate constant corresponds to a reduced dimer lifetime, suggesting that shorter-lived epigen-induced EGFR dimers is a sufficient explanation for the observed differences in epigen- versus EGF-induced EGFR phosphorylation kinetics. ", "Taken together with our results from EGFR mutants, the data indicate that dimer lifetime and kinase efficiency act together to dictate rates of multisite phosphorylation. ", "We showed previously that EGF-bound WT and L858R EGFR dimers have similar lifetimes ([@B62]), while our new SiMPull results show that EGF treatment leads to significant increases in single- and dual-site phosphorylation for the mutant. ", "Simulations reported in [Figure 6](#F6){ref-type=\"fig\"} indicate that this can be explained by the 3.6-fold increase in intrinsic kinase activity, a result that is reasonably consistent with biochemical measurements using recombinant kinase domains ([@B68]). ", "On the other hand, L858R receptors also favor ligand-independent signaling, attributed to \"inside-out\" signaling that promotes extension of the extracellular domain and exposure of the dimer arm in the absence of ligand ([@B62]) and/or more favorable orientation of cytoplasmic kinase domains ([@B52]; [@B46]). ", "So, the oncogenic properties of the L858R mutation can be attributed to both the increase in catalytic activity and enhanced dimerization in the absence of ligand.", "\n\nIn summary, we have integrated the unique data sets provided by SiMPull with mathematical modeling to better understand the combinatorial aspects of EGFR signaling. ", "We have shown that there are distinct populations of receptors with varying degrees of phosphorylation that can connect individual receptors to distinct pathways for biased signaling. ", "Our results provide novel insight into the regulation of EGFR phosphorylation, demonstrating critical roles for adaptor protein abundance and receptor dimerization lifetimes. ", "The abundances of adaptor proteins vary across cell types ([@B54]) and it has been proposed that these variations explain cell-specific functions of EGFR and other receptor tyrosine kinases (RTKs). ", "Here, we have seen that there is an interplay between single-molecule patterns of phosphorylation and adaptor protein abundances. ", "Thus, SiMPull assays complement measurements of these abundances. ", "We have also shown that these types of data can be analyzed in an integrated manner using a mechanistic model. ", "Finally, we have demonstrated that multisite phosphorylation is quite prevalent and needs to be considered in modeling of EGFR signaling. ", "Further work along these lines will help us to better understand the context-dependent functions of RTKs in the future.", "\n\nMATERIALS AND METHODS\n=====================\n\nCell lines and reagents\n-----------------------\n\nCHO cells expressing GFP-tagged ([@B1]; [@B39]) or ACP-tagged EGFR (provided by Donna Arndt-Jovin, Max Planck Institute for Biophysical Chemistry) were cultured in DMEM supplemented with 10% fetal bovine serum, penicillin--streptomycin, and 2 mM [l]{.smallcaps}-glutamine (Thermo Fisher Scientific). ", "ACP-tagged EGFR was as described in [@B69] and [@B62] with the exception that a shortened 16 aa sequence was introduced at the EGFR N-terminus ([@B12]). ", "EGF, protease and phosphatase inhibitor cocktail, Alexa Fluor 647 NHS ester, and NeutrAvidin were purchased from Thermo Fisher Scientific. ", "CoA 488 and ACP synthase were purchased from New England Biolabs. *", "N*-(2-aminoethyl)-3-aminopropyltrimethoxysilane was purchased from United Chemical Technologies (\\#A0700). ", "Sodium bicarbonate and sodium borohydride were purchased from EMD Millipore (\\#SX0320-1, \\#SX0380-3). ", "mPEG-succinimidyl valerate (MPEG-SVA-5000-5g) and biotin-PEG-succinimidyl valerate (Biotin-PEG-SVA-5000-500 mg) were from Laysan Bio. ", "Biotinylated anti-EGFR antibody (E101) was obtained from Leinco Technologies. ", "Antibodies in carrier-free buffer were purchased from Cell Signaling Technologies: EGFR pY1068 (clone 1H12, 2236BF) and EGFR pY1173 (clone 53A5, 4407BF). ", "Monoclonal antibody prelabeled with AF647 to detect pan-tyrosine phosphorylation (PY99 antibody, sc-7020 AF647) was purchased from Santa Cruz Biotechnology. ", "Mix-n-Stain CF555 and CF640R antibody labeling kits were purchased from Biotium. ", "PFA and GA were purchased from Electron Microscopy Sciences. ", "Each of the three commercial antibodies used to detect phosphotyrosines in EGFR (1H12, 53A5, and PY99) is vendor-recommended for Western blotting. ", "Recognition of epitopes is likely insensitive to whether surface-captured receptor is in a denatured or folded state, because the epitopes of PY99 lie mostly within the intrinsically disordered C-terminal region of the receptor and the epitopes of 1H12 and 53A5 (peptides encompassing pY1068 and pY1173) lie entirely within this region. [", "@B27] evaluated and confirmed the site specificity of 1H12 and 53A5 using immunoblotting and mutant forms of EGFR (Y1068F and Y1173F).", "\n\nLabeling of antibodies\n----------------------\n\nCarrier-free antibodies (50 μg at 0.5--1 mg/ml per reaction) were labeled using Mix-n-Stain antibody labeling kits following the manufacturer's instructions. ", "Briefly, the labeling reaction was carried out for 30 min at room temperature and antibodies were centrifuged using the ultrafiltration vial provided to remove the unconjugated dye. ", "Antibodies were resuspended in phosphate-buffered saline (PBS) and stored at 4°C. ", "The labeling efficiency achieved was between 2.7 and 4.4 dyes/antibody.", "\n\nCell treatment and lysate preparation\n-------------------------------------\n\nCHO-EGFR-GFP cells were plated overnight in 60-mm tissue culture dishes at 800,000 cells/dish and CHO-ACP-EGFR cells in 24-well plates at 50,000 cells/well. ", "For ACP labeling, CHO-ACP-EGFR cells were washed with serum-free DMEM medium (SFM), incubated with ACP labeling solution (SFM; 10 mM MgCl~2~, 4 μM CoA 488, and 1 μM ACP) for 20 min at 37°C and washed three times with SFM before stimulation. ", "Cells were washed in Tyrode's solution (135 mM NaCl, 10 mM KCl, 0.4 mM MgCl~2~, 1 mM CaCl~2~, 10 mM HEPES, 20 mM glucose, 0.1% bovine serum albumin \\[BSA\\], pH 7.2) and treated with ligand or Tyrode's solution alone (resting cells) at 37°C. ", "At the indicated time points, cells were placed on ice, washed once with cold PBS followed by the addition of lysis buffer (1% IGEPAL CA-630, 150 mM NaCl, 50 mM Tris, pH 7.2) containing protease and phosphatase inhibitors. ", "Cell lysates were collected using cell scrapers (Greiner Bio-One North America; \\#541070), transferred to fresh tubes on ice, and gently vortexed every 5 min for a total of 20 min. ", "Lysates were centrifuged at 16,000 × *g* for 20 min at 4°C and the supernatant was transferred to a new tube and stored at −80°C. ", "For experiments involving treatment of cells with phosphatase inhibitors a stock solution of 30 mM pervanadate (PV) was prepared before each experiment by mixing equimolar concentrations of hydrogen peroxide and activated sodium orthovanadate incubated in the dark for at least 15 min before use. ", "Cells were pre-treated for 15 min with a Tyrode's solution containing 1 mM PV followed by incubation for 5 min in a solution with 50 nM EGF and 1 mM PV.", "\n\nFabrication of hydrophobic arrays and surface functionalization\n---------------------------------------------------------------\n\nCoverglasses (24 × 60 mm, \\#1.5; Electron Microscopy Sciences; \\#63793) were Piranha-cleaned ([@B34]) and placed in a coverglass holder (Fisher Scientific; \\#08-817). ", "Coverglasses were sequentially sonicated in methanol and acetone for 10 min each, and in 1 M KOH for 20 min using a bath sonicator (Branson Ultrasonics; B1200R-1). ", "These solutions were stored in polypropylene 50 ml tubes (VWR; \\#89401-564) and reused up to five times. ", "Coverglasses were rinsed with Milli-Q water two times, dried by quickly passing them multiple times over the flame of a Bunsen burner using metal tweezers, and placed in a dry coverglass holder. ", "A solution containing 95% methanol, 5% acetic acid, and 1% aminosilane (*N*-(2-aminoethyl)-3-aminopropyltrimethoxysilane) was prepared in an Erlenmeyer flask, immediately poured into the coverglass holder, and incubated at room temperature for 10 min in the dark, followed by 2 min sonication, and another 10 min incubation in the dark. ", "Coverglasses were next washed with methanol for 2 min, rinsed and washed for 2 min with water, and dried in the dark. ", "Treated coverglasses were placed on top of a parafilm-covered coverglass containing a guide pattern, which was used as reference to draw the sample array (Supplemental Figure S1C) with a hydrophobic barrier pen (Vector Laboratories; \\#H-4000). ", "Ink was allowed to dry for at least 5 min before coverglasses were placed in a humidified chamber. ", "For surface functionalization, 50 mg of mPEG-succinimidyl valerate, 1.3 mg of biotin-PEG-succinimidyl valerate, and 200 µl of freshly prepared 10 mM sodium bicarbonate were mixed thoroughly by pipetting up and down, centrifuged for 1 min at 10,000 × *g* at room temperature, and immediately applied to the SiMPull array (10--13 µl per region). ", "After incubating for 3--4 h in the dark inside the humidified boxes, arrays were washed by sequential 30 s submersions into three water-filled 250-ml glass beakers. ", "Coverglasses were dried with nitrogen gas, and stored in pairs (back to back) inside 50-ml tubes, which were filled with nitrogen gas before being closed and sealed with parafilm. ", "Coverglasses were stored in the dark at −20°C for up to a week before use.", "\n\nLabeling and quantification of surface receptors\n------------------------------------------------\n\nCHO-EGFR-GFP cells grown in 24-well plates were placed on ice and washed three times with cold PBS. ", "AF647-NHS ester was dissolved at the indicated concentrations in PBS. ", "Cells were incubated with this solution for 30 min at 4°C with gentle agitation, washed three times with cold PBS, and subjected to cell lysis. ", "The percentage of receptors labeled with AF647 across different dye concentrations was assessed with SiMPull (see also [Figure 1D](#F1){ref-type=\"fig\"}). ", "To estimate the percentage of receptors at the cell surface the AF647-labeling curve was fitted to a biexponential decay curve in its increasing form using the \"fit\" function in MATLAB: *y* = *C*1 (1-e^-^*^ax^*) + *C*2 (1-e^-^*^bx^*), where *y* is the percentage of AF647-labeled receptors, *x* is the concentration of reactive AF647-NHS ester used, and *a* \\> 0, *b* \\> 0, *C*1, and *C*2 are coefficients to be fitted. ", "The sum of the coefficients *C*1 and *C*2 represent the asymptote of the curve and an approximation of the fraction of receptors at the cell surface.", "\n\nSingle-molecule pull down and phosphosite labeling\n--------------------------------------------------\n\nT50 (10 mM Tris, pH 8.0, 50 mM NaCl) and T50-BSA (T50 with 0.1 mg/ml BSA) solutions were prepared and stored for up to a month at room temperature. ", "SiMPull arrays were equilibrated at room temperature and placed on a TC100 plate lined with parafilm. ", "Each region of the SiMPull array was treated with 10--15 µl of a 10 mg/ml sodium borohydride (NaBH~4~)/PBS solution for 4 min at room temperature to reduce background fluorescence (Supplemental Figure S1, A and B) and washed three times with PBS. ", "SiMPull regions were then incubated with a 0.2 mg/ml NeutrAvidin/T50 solution for 5 min and washed three times with T50, followed by incubation with a 2 µg/ml biotinylated anti-EGFR/T50-BSA solution for 10 min and washed three times with T50-BSA.", "\n\nThe plate containing the SiMPull array(s) was kept on ice during sample preparation. ", "Lysates were diluted in cold T50-BSA with protease and phosphatase inhibitors (T50-BSA/PPI), gently vortexed, and added to the SiMPull array. ", "After 10 min incubation, the lysates were removed and the SiMPull regions washed four times with cold T50-BSA/PPI. ", "To determine the appropriate dilution factor, the density of pull-down receptors as a function of lysate concentration was first assessed to achieve a pull-down density 0.04--0.08/μm^2^ (see also Supplemental Figure S4). ", "Antibodies were diluted in cold T50-BSA/PPI, incubated for 1 h, washed six times with cold T50-BSA, and washed twice with cold PBS. ", "Immediately after, antibodies were fixed for 10 min with a 4% PFA/0.1% GA solution and washed twice with 10 mM Tris (pH 7.4)/PBS for a total of 10 min to inactivate fixatives. ", "See also Supplemental Figure S1 for discussion on the need for incubation with saturating antibody concentration and subsequent fixation. ", "For three-color SiMPull experiments the same antibody incubation and fixation procedure was performed for the second antibody. ", "Tris solution was replaced by T50-BSA and the SiMPull array was equilibrated to room temperature before proceeding to imaging.", "\n\nSiMPull imaging\n---------------\n\nImaging of SiMPull samples was performed using an inverted microscope (Olympus America; model IX71) equipped with a 150×/1.45 NA oil-immersion objective for TIRF microscopy (Olympus America; UAPON 150XOTIRF) and a three-dimensional piezo stage (Mad City Labs; Nano-LPS100). ", "Excitation of CF640R- or AF647-labeled antibodies was done using a 642-nm laser (Thorlabs; HL63133DG), CF555-labeled antibodies using a 561-nm laser (Coherent; sapphire 561-100 CW CDRH), and of GFP- and CoA 488--tagged receptors using a 488-nm laser (Spectra Physics; cyan 100 mW). ", "All lasers were set in total internal reflection configuration, and laser powers were adjusted to prevent photobleaching of the sample at the time scale of the image exposure time (300 ms). ", "Sample illumination and emission were filtered using a quad-band dichroic and emission filter set (Semrock; LF405/488/561/635-A-000). ", "Emission light was separated into four channels using a quad-view multichannel imaging system (Photometrics; model QV2) equipped with the appropriate dichroics (Chroma; 495 DCLP, 565 DCLP, 660 DCLP) and emission filters (Semrock; 685/40 nm, 600/37 nm, 525/45 nm). ", "Emission light was collected with an electron-multiplying charge-coupled device camera (Andor Technology; DU-897E-C50-\\#BV) with EM gain set to 200. ", "Each channel was 256 × 256 pixels, with a pixel size of 106.7 nm. ", "Photobleaching and bleed through were prevented by controlling the laser shutters and microscope stage through a MATLAB script to sequentially excite and acquire the different fluorophores (642-nm laser first, 488-nm laser last). ", "A minimum of 20 regions of interest were acquired per condition. ", "For quantification of step photobleaching of EGFR-GFP molecules, a 100-frame time series (300 ms exposure time) was acquired after imaging of the other two channels.", "\n\nQuantification of receptor phosphorylation\n------------------------------------------\n\nAll image processing was performed using MATLAB together with the MATLAB toolbox for image-processing DIPImage (Delft University of Technology; [@B18]) and all software is available upon request. ", "The location of emitters in each channel was calculated using graphics processor unit computing as previously described ([@B56]). ", "Fits in the GFP channel were filtered based on the quality of the fit to the point spread function to reduce the chances of detecting multiple receptors in close proximity as a single molecule. ", "Image registration was performed as previously described ([@B51]). ", "In our studies, the root mean square error for image registration was \\<10 nm. ", "For visualization purposes, Gaussian blob representations of the fluorophore localizations were generated. ", "A receptor was considered to be phosphorylated when the localization centers of the receptor and labeled antibody were at a distance \\<106.7 nm (within 1 pixel).", "\n\nPhosphorylation percentages were calculated as 100\\*(*N*~Phos~)/(*N*~GFP~), where *N*~Phos~ is the number of receptors identified as phosphorylated and *N*~GFP~ is the corrected number of single molecules in the GFP channel. ", "The number of GFP localizations was calculated by subtracting background spots and accounting only for surface receptors as follows: *N*~GFP~ = (*N*~LOC~-*N*~BG~)\\**SR*, where *N*~LOC~ is the total number of emitters localized, *N*~BG~ is the expected number of background emitters in the area imaged, and *SR* (surface ratio) is the fraction of receptors located at the cell surface. ", "The density of background emitters was quantified for each SiMPull array and used for background correction of samples in that array. ", "For three-color SiMPull experiments where steric hindrance between sequentially incubated antibodies was observed (i.e., pY1068-pY1173 detection), estimations of dual phosphorylation were corrected to account for this hindrance as explained in Supplemental Figure S3. ", "Note that use of a three-color imaging scheme to correlate phosphoantibody labeling directly with GFP-tagged receptors was critical, due to the relatively high nonspecific binding of the antibodies (Supplemental Figure S6). ", "In the absence of the GFP channel to remove the nonspecific binding, the values for dual labeling are underestimated (Supplemental Figure S6).", "\n\nStatistical analysis\n--------------------\n\nBased on the consideration that the phosphorylation state of each receptor analyzed has the properties of a Bernoulli trial, SEs of phosphorylation measurements were calculated as for sample proportions in a binomial distribution: SE = *p*(1−*p*)/*n*, where *p* is the fraction of receptors phosphorylated and *n* is the total number of receptors. ", "The condition *np* \\> 10 (with the exception of [Figure 6E](#F6){ref-type=\"fig\"}, *np* \\> 5) and *np*(1−*p*) \\> 10 was ensured to be met to allow this approximation to be adequate. ", "Two-sample Z test (two-tailed) was used to estimate *p* values ([@B38]).", "\n\nStep-photobleaching analysis\n----------------------------\n\nFor step-photobleaching analysis of multiphosphorylated receptors, the average fluorescence intensity of the area (200 × 200 nm) surrounding each of these EGFR-GFP molecules was quantified and plotted for the duration of the time series. ", "Intensity plots were manually analyzed and the number of photobleaching steps was quantified.", "\n\nMathematical modeling\n---------------------\n\nThe model was formulated using BNGL ([@B8]). ", "The BioNetGen input file that defines the model is available as Supplemental File S1. ", "This file is a plain-text file. ", "The model accounts for the proteins, sites, and interactions depicted in [Figure 2B](#F2){ref-type=\"fig\"}. ", "The model implicitly accounts for three compartments, which are each taken to be well mixed: the extracellular fluid, the plasma membrane, and the cytosol. ", "In the model, EGFR dimer-dependent autophosphorylation is taken to be asymmetric, as discussed in the main text. ", "In addition to Y1068 and Y1173, the model accounts for other tyrosines in EGFR, which are lumped together and labeled YN in the BNGL-formatted model-definition file. ", "The model structure was optimized using model restructuration (reviewed in the supplementary tutorial of [@B7]).", "\n\nIn the one-parameter fits carried out to characterize the increased kinase activity of L858R EGFR and the lifetime of epigen-induced EGFR dimers, we used simple grid search as the fitting method, meaning that we systematically varied the free parameter over a specified range, calculating the quality of fit at each parameter value. ", "When the free parameter was the rate constant for autophosphorylation, we considered a range 0.1× below and 100× above the estimated value for WT EGFR. ", "We considered a step size of 0.1 in the grid search. ", "When the free parameter was the rate constant for EGFR dimer dissociation, we similarly considered a range 0.1× below and 100× above the estimated value for EGF-induced dimers. ", "We again considered a step size of 0.1 in the grid search.", "\n\nSimulations were performed as follows. ", "In a preprocessing step, rules were interpreted by BioNetGen to obtain the rule-implied reaction network and the corresponding ordinary differential equations (ODEs) for mass-action chemical kinetics. ", "Simulations of the dynamics of responses to ligand stimulation were performed by numerically integrating the BioNetGen-derived ODEs using CVODE with BioNetGen's default CVODE settings. ", "CVODE (<https://computation.llnl.gov/projects/sundials>; [@B19]) is a dependency of BioNetGen.", "\n\nModel parameters were estimated via curve fitting, which was performed using the differential evolution (DE) algorithm implemented in PyBioNetFit ([@B42]), a software package for parameterization of biological models that supersedes BioNetFit ([@B61]). ", "An important parameter of the DE algorithm is population size: this algorithmic parameter was set to 200. ", "Fitting runs were allowed to continue until apparent convergence, that is, until the value of the objective function in the optimization problem stopped decreasing. ", "PyBioNetFit takes as input three file types: a BioNetGen input file (i.e., a BNGL-formatted model definition), a configuration file, and one or more EXP files with experimental data. ", "These files are packaged together in a ZIP archive as Supplemental File S2. ", "The parameters listed in Supplemental Table S1 were held fixed in fitting. ", "These parameters were estimated on the basis of prior knowledge, referenced in the table, or measured/determined in this study as indicated. ", "The parameters listed in Supplemental Table S2 were taken to be the free parameters to be adjusted by PyBioNetFit during fitting within the indicated intervals. ", "The data used in fitting included the dose-response data in [Figure 2A](#F2){ref-type=\"fig\"} (for EGF doses eliciting a significant change in phosphorylation, 0.5, 5, and 50 nM) and the time-series data in [Figure 2D](#F2){ref-type=\"fig\"}. ", "Parameter estimates are based on a global fit to all of these data.", "\n\nAll parameter estimates were originally made for CHO cells. ", "Additional cell-specific models were obtained by modifying CHO-cell protein copy numbers, as follows. ", "As indicated in Supplemental Table S1, the EGFR abundance that we estimated for CHO cells via direct measurement (flow cytometry) and the Grb2 and Shc1 abundances that we estimated for CHO cells via fitting to data in [Figure 2, A and D](#F2){ref-type=\"fig\"}, were replaced with direct measurements of EGFR, Grb2, and Shc1 abundances made in earlier studies for HMEC, MCF10A, and HeLa S3 cells ([@B33]; [@B54]). ", "As a simplification, other parameter values were taken to be the same across cell types.", "\n\nConfidence intervals for best-fit parameter values were estimated using PyBioNetFit's bootstrapping procedure. ", "A total of 1000 bootstrap replicates of fitting were performed, and the reported 90% confidence intervals give the range from the 5th percentile to the 95th percentile of the replicate results (Supplemental Table S3). ", "The bootstrapping procedure used the same BioNetGen and EXP files as before and the configuration file fit_bootstrap.conf provided in Supplemental File S2.", "\n\nBayesian uncertainty quantification (UQ) was performed using the parallel tempering (PT) algorithm implemented in PyBioNetFit, which is a parallelized Markov chain Monte Carlo method. ", "We used PT to find 90% credible intervals for each parameter listed in Supplemental Table S2. ", "The prior distribution considered for each parameter was a log-uniform distribution over the range indicated for the parameter in Supplemental Table S2. ", "Ten independent runs were performed, each consisting of 200,000 iterations (36 simulations per iteration), with samples recorded after a burn-in period of 50,000 iterations. ", "Reported 90% credible intervals (Supplemental Table S3) for each parameter give the range from the 5th to 95th percentile of the sampled parameter sets. (", "Note that credible intervals are not identical to bootstrap confidence intervals.) ", "Prediction uncertainties ([Figure 2D](#F2){ref-type=\"fig\"}, shaded areas; [Figure 6, A and C](#F6){ref-type=\"fig\"}, error bars) were calculated by running simulations with sampled parameter sets and finding the 2.5th and 97.5th percentile pEGFR percentage at each time point. ", "UQ jobs used the same BioNetGen and EXP files as before and the configuration file fit_pt.conf provided in Supplemental File S2. ", "Distributions of parameter values in sampled parameter sets and the correlation between each pair of parameters (Supplemental Figure S7) were plotted using the function plotmatrix from MATLAB.", "\n\nFitting was performed on a laptop. ", "Bootstrapping was performed using 7000 core hours on a multicore workstation. ", "PT was performed using 40,000 core hours on a computer cluster.", "\n\nSupplementary Material\n======================\n\n###### \n\nClick here for additional data file.", "\n\n###### \n\nClick here for additional data file.", "\n\n###### \n\nClick here for additional data file.", "\n\nThis article was published online ahead of print in MBoC in Press (<http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E19-09-0548>) on January 8, 2020.", "\n\nWe thank Donna Arndt-Jovin and Mark Lemmon for helpful discussions. ", "We also thank Donna Arndt-Jovin for the CHO-ACP-EGFR cell line and suggesting the ACP-EGFR comparison experiment. ", "We thank Richard Pepermans for generating the Grb2-mCherry construct, Hannah Johnson for generation of the CHO-EGFR-GFP Grb2-mCherry cell line, Shayna Lucero for assistance with cell culture, and Aubrey Gibson for assistance with Western blots. ", "This work was supported by the New Mexico Spatiotemporal Modeling Center (National Institutes of Health \\[NIH\\] P50GM-085273), Mexican Secretariat of Public Education SEP (E.S.-C.), National Science Foundation CAREER MCB-0845062 (D.S.L.), NIH R35GM-126934 (D.S.L.), and the UNM Comprehensive Cancer Center (NIH P30CA118100). ", "We gratefully acknowledge use of the University of New Mexico Comprehensive Cancer Center fluorescence microscopy and flow cytometry facilities, as well as the NIH P30CA118100 support for these cores. ", "We acknowledge use of computing resources provided by the Los Alamos National Laboratory Institutional Computing program, which is operated for the National Nuclear Security Administration of the Department of Energy under contract.", "\n\nACP\n\n: acyl carrier protein\n\nBNGL\n\n: BioNetGen language\n\nEGFR\n\n: epidermal growth factor receptor\n\nGA\n\n: glutaraldehyde\n\nGFP\n\n: green fluorescent protein\n\nNHS\n\n: N-hydroxysuccinimide\n\nPEG\n\n: polyethylene glycol\n\nPFA\n\n: paraformaldehyde\n\nPTB\n\n: phosphotyrosine binding\n\nPV\n\n: pervanadate\n\nPY\n\n: phosphotyrosine\n\nRTK\n\n: receptor tyrosine kinase\n\nSH2\n\n: Src homology 2\n\nSiMPull\n\n: single-molecule pull down\n\nTIRF\n\n: total internal reflection fluorescence\n\nWT\n\n: wild type\n\n[^1]: The authors declare no conflict of interest.", "\n\n[^2]: Author contributions: E.S.-C. performed all single-molecule experiments and data analysis. ", "E.S.-C. and K.A.L. developed analysis methods and algorithms. ", "E.S.-C. formulated the mathematical model, estimated model parameter values, and performed simulations and sensitivity analysis with guidance from W.S.H. C.F.N. performed biochemistry experiments. ", "E.D.M. performed bootstrapping and parallel tempering to quantify parameter uncertainty. ", "D.S.L. directed the project. ", "D.S.L., E.S.-C., K.A.L, and B.S.W. designed and interpreted experiments. ", "D.S.L., E.S.-C., W.S.H., and B.S.W. wrote the manuscript with input from all authors.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "\n672 F.3d 832 (2012)\nUNITED STATES of America, Plaintiff-Appellee,\nv.\nGlenn J. DAMATO, Defendant-Appellant.", "\nNo. ", "10-3191.", "\nUnited States Court of Appeals, Tenth Circuit.", "\nFebruary 22, 2012.", "\n*835 Melanie Susan Morgan, Morgan Pilate LLC, Olathe, KS, for the Defendant-Appellant.", "\nLeon Patton, Assistant United States Attorney, (Barry R. Grissom, United States Attorney, with him on the briefs), Office of the United States Attorney, District of Kansas, Kansas City, KS, for the Plaintiff-Appellee.", "\nBefore LUCERO, SEYMOUR, and EBEL, Circuit Judges.", "\nLUCERO, Circuit Judge.", "\nGlenn Damato appeals his 96-month sentence for conspiracy to distribute marijuana. ", "He argues that the district court erred in calculating drug quantity by including as relevant conduct a drug transaction that occurred more than thirteen years prior to the offense of conviction. ", "The government argues only that this transaction was part of the \"same course of conduct\" as the offense of conviction. ", "See U.S.S.G. § 1B1.3(a)(2). ", "We cannot agree with the government's contention. ", "The thirteen-year interval at issue far exceeds the gap between relevant conduct and the charged offense in the case law of any circuit including our own. ", "Further, that extreme lack of temporal proximity was not mitigated by strong evidence of regularity or similarity. ", "To the contrary, the government presented no evidence of regularity for an eight-year block of time between the putatively relevant conduct and the charged offense. ", "And the government's evidence with respect to similarity, while substantial, was not so powerful as to compensate for the weight we must accord the temporal proximity and regularity factors given their extraordinary status in this case.", "\nWe nevertheless exercise our discretion to consider an alternative basis to affirm, and conclude that the prior transaction qualifies as relevant conduct because it and the offense of conviction were part of a \"common scheme or plan.\" ", "See id. The earlier conduct was substantially connected to the offense of conviction; both featured common co-conspirators who worked together to procure a distribution quantity of marijuana from a source in Southern California. ", "Because of this substantial connection, the prior transaction qualifies as relevant conduct.", "\nWe reject Damato's remaining contentions that that the district court should not have sentenced him as a leader or organizer of the charged conspiracy, and that his below-Guidelines sentence was substantively unreasonable. ", "Exercising jurisdiction under 28 U.S.C. § 1291, we affirm.", "\n\nI\n\nA\nIn August of 2004, a drug dog alerted to a package sent from Mark McPherson in Olathe, Kansas to Leon Livingston in San Diego, California. ", "The package contained $30,000 in cash. ", "When Livingston attempted to retrieve the package, he was arrested. ", "An ensuing investigation revealed a cross-country, marijuana-distribution conspiracy involving Damato, McPherson, Livingston, Harold Michael Bower, Neal Limtiaco, Thomas Starr, and others.", "\nMcPherson, Bower, and Starr were indicted in April of 2006. ", "All three eventually pled guilty to federal drug charges and provided statements detailing their involvement in drug trafficking. ", "In April of 2008, Damato was charged with conspiracy to distribute 100 kilograms or more of *836 marijuana along with Livingston and Limtiaco. ", "The indictment alleged a conspiracy beginning in or about December 2003, and continuing to approximately March 30, 2006. ", "All three defendants pled guilty. ", "As with the previously indicted co-conspirators, Livingston and Limtiaco cooperated with law enforcement.", "\n\nB\nDamato pled guilty without the benefit of a plea agreement. ", "The United States Probation Office prepared a Presentence Investigation Report (\"PSR\") for Damato. ", "Based on interviews of McPherson, Starr, Livingston, and Bower, along with information provided by law enforcement, the PSR attributed 782 kilograms of marijuana to Damato. ", "This total included four transactions in which marijuana was seized from co-conspirators by police, and an estimate based on the amount of marijuana that could be purchased with the $30,000 seized in August 2004.", "\nAlthough some of the drugs attributed to Damato had been physically seized by police, most of the drug quantity calculation derived from statements of co-conspirators. ", "McPherson described two loads of marijuana delivered to Damato and Starr in 2003 or 2004, which he estimated contained 120 pounds each. ", "Livingston stated that he received four or five packages of $30,000 from McPherson prior to his arrest (other than the package that had been seized), which the PSR estimated would purchase 68 kilograms of marijuana. ", "Finally, Starr indicated that he helped to transport four loads of marijuana between October 2004 and August 2005, each of which contained 150 to 200 pounds. ", "All of the transactions included in the PSR— both those for which drugs were recovered, and those in which no drugs were recovered—occurred between 2003 and 2006 during the charged conspiracy.", "\nThe PSR also included background information obtained from interviews with McPherson, Starr, and Bower. ", "According to McPherson, he and Damato met in 1981. ", "Damato was engaged in marijuana distribution at that time, with his suppliers located in Florida. ", "McPherson was also engaged in marijuana distribution, and was using Starr to transport loads across the country. ", "Sometime in the mid to late 1980s, Damato switched to a pair of marijuana suppliers located in California, one of whom was Livingston. ", "However, McPherson stated that he and Damato were not \"partners\" then.", "\nAround the same time, McPherson introduced Bower to Damato. ", "McPherson had been using Bower as a driver to distribute marijuana, and Bower began working for Damato as well. ", "Bower stated that he delivered marijuana five or six times for Damato in the 1990s, until he was arrested in 1995. ", "Bower was incarcerated from 1995 to 2003.", "\nMcPherson also served time in prison in the 1990s. ", "After he was released, McPherson reunited with Damato, who said he was still in the marijuana business and was still working with Starr. ", "Damato and McPherson began purchasing marijuana from Livingston in 2003, and continued to do so until August 2004 when Livingston was arrested. ", "Following Livingston's arrest, they began buying marijuana from Limtiaco. ", "Starr, Bower, and others were paid to drive marijuana from California to various points in the Midwest during this time period. ", "These delivery trips formed the basis of the PSR's drug quantity calculation.", "\nUsing a drug quantity estimate of 782 kilograms, the PSR recommended a base offense level of 30. ", "It added four levels under U.S.S.G. § 3B1.1(a) because Damato was a leader or organizer of an extensive *837 drug operation and subtracted three levels for acceptance of responsibility, yielding a total offense level of 31. ", "Combined with a criminal history category of I, Damato's advisory Guidelines range was calculated at 108 to 135 months.", "\n\nC\nDamato objected to both the drug quantity calculation and to the leader or organizer enhancement. ", "Specifically, Damato argued that he was not involved in a transaction in which three pounds of marijuana were seized, with the transaction which led to the seizure of $30,000 in cash, or with one of the transactions from which drugs were not recovered. ", "He also objected to the \"paragraphs within the [PSR] based on cooperator Mark McPherson's statement that [Damato] was involved.\"", "\nThe government also objected to the PSR's drug quantity estimate. ", "It submitted a spreadsheet listing nineteen total transactions which the government claimed involved Damato. ", "The spreadsheet indicates that the factual bases for the transactions were statements from McPherson and Bower, along with \"hotel records, GPS tracking information, and law enforcement reports.\" ", "The spreadsheet attributed 2298 pounds (1042.4 kilograms) of marijuana to Damato from seventeen transactions alleged to have occurred during the charged conspiracy. ", "It also included two additional transactions as relevant conduct: A 1995 occurrence in which Bower was arrested with 62.5 pounds (28.35 kilograms) of marijuana, and a January 1990 incident in which McPherson and Livingston were arrested for attempting to purchase 1200 pounds (544.32 kilograms) of marijuana from an undercover Drug Enforcement Agency (\"DEA\") agent. ", "The government thus argued that Damato was responsible for a total of 3560.5 pounds (1615 kilograms).", "\nThe district court held a sentencing hearing to consider these objections. ", "Robert Hawkins, a financial investigator for the DEA, was the only witness to testify. ", "Hawkins provided hearsay testimony relayed from co-conspirators McPherson, Bower, Livingston, and Limtiaco, along with information contained in various law enforcement reports. ", "He claimed that \"for a period [of] probably 25 years,\" Damato, McPherson, Bower, Livingston, \"and others were for the most part trafficking marijuana, one or more of them all the time.\"", "\nHawkins discussed the support behind the nineteen entries in the government's spreadsheet. ", "He provided a detailed description of the first fifteen transactions, all of which occurred between 2003 and 2006. ", "Many of these transactions were supported by hotel records and GPS tracking data that had been obtained by law enforcement.", "\nIn addition, Hawkins provided testimony on the two claimed relevant conduct transactions. ", "He stated that McPherson and Livingston had been arrested, and eventually served time, for attempting to purchase 1200 pounds of marijuana from an undercover DEA agent in January of 1990. ", "Based on statements from Bower, McPherson, and Livingston, Hawkins testified that Damato had been involved in the transaction, and was at Livingston's home waiting for McPherson and Livingston to return with the drugs. ", "Damato left the house with a bag of cash when he learned of the arrest and was never apprehended. ", "Hawkins further testified about statements made by Bower regarding a 1995 transaction. ", "As the PSR indicated, Bower delivered five or six loads of marijuana for Damato in the 1990s. ", "In 1995, Bower was arrested while transporting 62.5 pounds of marijuana.", "\n*838 At the close of the sentencing hearing, the district court sustained both Damato's and the government's drug quantity objections. ", "It removed the three specific transactions to which Damato objected, but added the additional drug quantity listed on the government's spreadsheet—including the two relevant conduct transactions. ", "With these adjustments, the district court attributed 1515.8 kilograms of marijuana to Damato, for a base offense level of 32. ", "Damato objected to the court's consideration of \"alleged conduct that took place back in 1990\" as relevant to \"the conspiracy that was charged from 2003 to 2006,\" but the court was not persuaded. ", "It also rejected Damato's objection to the leader or organizer enhancement. ", "Adding four levels for that enhancement, and subtracting three levels for acceptance of responsibility, the court adopted a total offense level of 33 and a criminal history category of I. Damato's Guidelines range was 135 to 168 months. ", "However, the court settled on a below-Guidelines sentence of 96 months.", "\nDamato timely appealed the sentence imposed.", "\n\nII\nOn appeal, Damato contends the district court erred in calculating drug quantity and in applying the leader or organizer enhancement. ", "A claim that a district court improperly calculated an advisory Guidelines range implicates procedural reasonableness. ", "See United States v. Huckins, 529 F.3d 1312, 1317 (10th Cir. ", "2008). ", "In considering such a claim, \"[w]e review the district court's factual finding supporting a determination of relevant conduct for clear error but review the ultimate determination of relevant conduct de novo.\" ", "United States v. Tran, 285 F.3d 934, 938 (10th Cir.2002); See also United States v. Egbert, 562 F.3d 1092, 1096-97 (10th Cir.2009).", "\nDamato also argues that his sentence is substantively unreasonable. \"[", "S]ubstantive reasonableness addresses whether the length of the sentence is reasonable given all the circumstances of the case in light of the factors set forth in 18 U.S.C. § 3553(a).\" ", "United States v. Huckins, 529 F.3d 1312, 1317 (10th Cir.2008) (quotation omitted). ", "We review substantive reasonableness claims for abuse of discretion. ", "United States v. Lewis, 594 F.3d 1270, 1277 (10th Cir.2010). \"", "A district court abuses its discretion when it renders a judgment that is arbitrary, capricious, whimsical, or manifestly unreasonable.\" ", "Id.\n\nIII\nThe parties have helpfully narrowed for us the scope of Damato's drug quantity claim. ", "Damato admits that he is responsible for 683.8 kilograms of the marijuana listed in the PSR. ", "And he further admits that he is responsible for 45.36 kilograms that were not contained in the PSR but considered at the sentencing hearing. ", "Thus, there is no dispute that Damato was responsible for at least 729.16 kilograms of marijuana.", "\nThat stipulated quantity would place Damato at a base offense level of 30, which applies when 700 to 1000 kilograms of marijuana are attributed to a defendant. ", "U.S.S.G. § 2D1.1(c)(5). ", "Damato was sentenced under U.S.S.G. § 2D1.1(c)(4), which provides for a base offense level of 32 when a defendant is responsible for 1000 to 3000 kilograms of marijuana. ", "Accordingly, the question before us is whether Damato should have been sentenced under U.S.S.G. § 2D1.1(c)(5) or (c)(4). ", "And that question turns on the propriety of counting a single transaction: the 1990 incident in which McPherson and Livingston were arrested *839 while attempting to purchase 1200 pounds of marijuana. ", "Regardless of the other alleged incidents, Damato should be sentenced under U.S.S.G. § 2D1.1(c)(5) if this transaction qualifies but subsection (c)(4) if it does not. ", "Cf. ", "United States v. Wilken, 498 F.3d 1160, 1170 (10th Cir. ", "2007) (erroneous Guidelines calculation is harmless if it has no effect on a defendant's Guidelines range).", "\nUnder U.S.S.G. § 1B1.3, a defendant's base offense level is based on \"relevant conduct.\" ", "Relevant conduct is defined to include:\n(1) (A) all acts and omissions committed, aided, abetted, counseled, commanded, induced, procured, or willfully caused by the defendant; and\n(B) in the case of a jointly undertaken criminal activity ... all reasonably foreseeable acts and omissions of others in furtherance of the jointly undertaken criminal activity, that occurred during the commission of the offense of conviction, in preparation for that offense, or in the course of attempting to avoid detection or responsibility for that offense; [and]\n(1) solely with respect to offenses of a character for which § 3D1.2(d) would require grouping of multiple counts, all acts and omissions described in subdivisions (1)(A) and (1)(B) above that were part of the same course of conduct or common scheme or plan as the offense of conviction....\nU.S.S.G. § 1B1.3(a).", "\nIt is a given that the 1990 transaction does not qualify under subsection (1). ", "The offense of conviction was a conspiracy beginning around December, 2003—more than a decade after the 1990 occurrence— and there is no evidence suggesting that the earlier transaction was conducted \"in preparation for\" the later conspiracy. ", "U.S.S.G. § 1B1.3(a)(1). ", "If the 1990 transaction is to be counted, it must qualify as \"part of the same course of conduct or common scheme or plan as the offense of conviction.\" ", "U.S.S.G. § 1B1.3(a)(2).[1]\nOur circuit has distinguished between the phrases \"same course of conduct\" and \"common scheme or plan.\" ", "See United States v. Svacina, 137 F.3d 1179, 1182 (10th Cir.1998); See also U.S.S.G. § 1B1.3 app. ", "n. 9(B) (\"Offenses that do not qualify as part of a common scheme or plan may nonetheless qualify as part of the same course of conduct....\"). ", "At sentencing, the district court did not indicate which prong it applied. ", "The government relies exclusively upon the \"same course of conduct\" prong on appeal.", "\n\nA\nTwo offenses qualify as part of the \"same course of conduct\" if \"they are sufficiently connected or related to each other as to warrant the conclusion that they are part of a single episode, spree, or ongoing series of offenses.\" ", "U.S.S.G. § 1B1.3 app. ", "n. 9(B). ", "We consider \"the degree of similarity of the offenses, the regularity (repetitions) of the offenses, and the time interval between the offenses.\" ", "Id.; see also United States v. Roederer, 11 F.3d 973, 979 (10th Cir.1993) (\"Similarity, regularity, and temporal proximity are the significant elements to be evaluated.\" (", "citation omitted)). ", "In weighing these factors, we utilize the \"sliding scale\" approach mandated by *840 U.S.S.G. § 1B1.3. ", "See United States v. Hill, 79 F.3d 1477, 1484 (6th Cir.1996). ", "As an application note provides:\nWhen one of the above factors is absent, a stronger presence of at least one of the other factors is required. ", "For example, where the conduct alleged to be relevant is relatively remote to the offense of conviction, a stronger showing of similarity or regularity is necessary to compensate for the absence of temporal proximity.", "\nU.S.S.G. § 1B1.3 app. ", "n. 9(B). ", "Although we have construed relevant conduct to cover a broad range of activities, See United States v. Garcia, 411 F.3d 1173, 1177 (10th Cir.2005), we are mindful that \"[o]ffenses of the same kind, but not encompassed in the same course of conduct or plan, are excluded,\" United States v. White, 888 F.2d 490, 500 (7th Cir.1989).", "\n\n1\nWe begin our analysis with temporal proximity. ", "Damato was convicted of engaging in a conspiracy that began in or about December 2003. ", "McPherson and Livingston attempted to purchase 1200 pounds of marijuana in January 1990, more than thirteen years prior to the offense of conviction. ", "As the government acknowledged at oral argument, treating conduct separated by that length of time as part of the same course of conduct would be unprecedented. ", "None of the cases cited by the government contain such a lengthy gap between potentially relevant conduct and the crime of conviction, nor have we discovered any in our independent research. ", "In fact, we have been unable to uncover a case holding that conduct even half as temporally distant qualifies as relevant conduct. ", "The largest time difference we have observed in the case law is the five-year interval at issue in Roederer, 11 F.3d 973.", "\nFurther, the five-year delay in Roederer appears to be an outlier.[2] We have described a \"fifteen month interval\" as \"temporally distant.\" ", "United States v. Clark, 415 F.3d 1234, 1242 (10th Cir.2005). ", "Other circuits have held that temporal gaps as brief as five months cut against a finding that an activity was part of the same course of conduct as the offense of conviction. ", "See United States v. Hahn, 960 F.2d 903, 910-11 (9th Cir.1992) (five-month gap is \"relatively remote\"); See also United States v. McGowan, 478 F.3d 800, 802 (7th Cir.2007) (eight-month \"gap is long enough to cast doubt on the relevance of the earlier conduct\"); United States v. Ortiz, 431 F.3d 1035, 1041 (7th Cir.2005) (ten-month \"gap suggests the lack of a common plan or course of conduct\"); United States v. Mullins, 971 F.2d 1138, 1144 (4th Cir.1992) (temporal proximity factor \"extremely weak ... if present at all, as the uncharged conduct took place over six months prior to the two phone calls underlying the offense of conviction\"). ", "And courts have repeatedly held that temporal proximity is lacking or that conduct is very remote when the interval exceeds one year. ", "See United States v. Kulick, 629 F.3d 165, 171, 172 (3d Cir.2010) (twenty-seven month interval is \"substantial\" and \"temporally remote\"); Hill, 79 F.3d at *841 1484 (\"[W]e find that temporal proximity is extremely weak in that nineteen months is an exceedingly long lapse between offenses.\"); ", "United States v. Sykes, 7 F.3d 1331, 1337 (7th Cir.1993) (temporal gap of fourteen months \"tends to indicate conduct that can easily be separated into discrete, identifiable units rather than behavior that is part of the same course of conduct\" (quotation omitted)).", "\nThe Fifth Circuit accurately summarized the bulk of the case law in stating: \"Various courts have found that a period of separation of over one year negated or weighed against [a finding of] temporal proximity.\" ", "United States v. Wall, 180 F.3d 641, 646 (5th Cir.1999). ", "With this consensus in mind, it clearly follows that the thirteen-year interval between the 1990 transaction and Damato's offense of conviction is extraordinary. ", "Given this extreme lack of temporal proximity, the 1990 transaction may not be treated as relevant conduct unless one of the other factors—regularity or similarity—is \"authoritatively present.\" ", "United States v. Miller, 179 F.3d 961, 967 n. 10 (5th Cir.1999); See U.S.S.G. § 1B1.3 app. ", "n. 9(B) (\"When one of the above factors is absent, a stronger presence of at least one of the other factors is required.\").", "\n\n2\nThe government has not made such a showing with respect to regularity. \"", "To determine whether `regularity' is present, we inquire whether there is evidence of a regular, i.e., repeated, pattern of similar unlawful conduct\" between \"the purported relevant conduct and the offense of conviction.\" ", "United States v. Rhine, 583 F.3d 878, 889-90 (5th Cir.2009). ", "The government presented a great deal of regularity evidence for the time period during the charged conspiracy. ", "Its spreadsheet contains seventeen transactions between \"late 2003\" and November 2006. ", "Fourteen of these transactions occurred between February 2004 and November 2006. ", "Each of the transactions included between 100 and 200 pounds of marijuana being driven across the country.", "\nHowever, evidence regarding Damato's activities between 1990 and 2003 is exceedingly sparse. ", "Bower claimed that he delivered marijuana on Damato's behalf five or six times between 1990 and 1995, when Bower was arrested transporting a load. ", "But the government presented no evidence of regularity for the 1995 to 2003 time frame. ", "When McPherson was released from prison in 2002 or 2003, he met up with Damato, who reported that he was \"still\" in the marijuana business and was using Starr as a driver. ", "Hawkins relayed this statement at the sentencing hearing, noting that Starr worked as a driver for Damato while McPherson was in prison. ", "The government presented no other evidence regarding the eight-year gap between Bower's arrest in 1995 and the beginning of the charged conspiracy in 2003.[3]\nAlthough the record supports an inference that Damato was somehow involved in marijuana distribution between 1995 and 2003, there is no evidence whatsoever regarding the regularity of such distribution. ", "The record does not tell us when or how often Damato used Starr as a driver during this time frame. ", "There is evidence, however, suggesting that Damato's drug distribution activities would have been dissimilar to those during the charged conspiracy. ", "See Rhine, 583 F.3d *842 at 890 (regularity inquiry looks for a \"pattern of similar unlawful conduct\"). ", "Three of Damato's primary coconspirators, McPherson, Livingston, and Bower, were incarcerated during this time period. ", "McPherson was in prison following his 1990 arrest until 2002 or 2003. ", "Livingston also served time following he and McPherson's attempted purchase of 1200 pounds of marijuana from a DEA agent. ", "And Bower was jailed from 1995 to 2003. ", "The PSR also notes that Damato was diagnosed with a relapse of lymphoma in 1995 and underwent chemotherapy and a stem cell transplant.", "\nIt was established that Damato engaged in five or six transactions between 1990 and 1995, and that Damato was somehow involved in marijuana distribution when McPherson was released from prison in 2002 or 2003. ", "But the government has not presented evidence of regularity for eight of the thirteen years between the 1990 transaction and the crime of conviction. ", "Given this eight-year dark period, we are compelled to conclude that regularity, like temporal proximity, is lacking. ", "See United States v. Clark, 415 F.3d 1234, 1241 (10th Cir.2005) (regularity absent when record does not show drug transactions over two-year period); See also United States v. Culverhouse, 507 F.3d 888, 897 (5th Cir.2007) (\"[F]ive offenses over the course of fifteen years, separated as they are by time and circumstances, cannot be considered repetitious or regular conduct to a degree significant enough to constitute sufficient connection under the [G]uidelines.\" (", "quotation omitted)).", "\n\n3\nWe turn to the similarity prong. ", "During the charged conspiracy, Damato and McPherson regularly had Livingston purchase between 100 and 200 pounds of marijuana from Limtiaco in San Diego. ", "The coconspirators then used a variety of drivers— frequently Starr and Bower—to transport the marijuana to locations in the Midwest. ", "The 1990 transaction shares several characteristics with the crime of conviction. ", "Both involved marijuana, the participants Damato, Livingston, and McPherson, and a location in Southern California. ", "See United States v. Caldwell, 585 F.3d 1347, 1352-53 (10th Cir.2009) (similarity established by showing conduct involving same drug, same accomplices, and occurring in same geographic area for relevant conduct separated from charged conduct by eighteen months).", "\nHowever, there are several important differences between the transactions included in the charged conspiracy and the 1990 transaction. ", "First, the amount McPherson and Livingston attempted to purchase in 1990 was much larger than the purchases that occurred during the charged conspiracy. ", "Most of the transactions included in the offense of conviction involved 100 to 120 pounds of marijuana, and none exceeded 200 pounds. ", "The 1990 transaction, in contrast, involved 1200 pounds—an order of magnitude greater than the usual amount involved in the charged conduct. ", "See Hill, 79 F.3d at 1484 (drug transactions dissimilar, in part because \"quantities involved in each deal differ substantially\").", "\nSecond, the 1990 transaction and the conspiracy transactions involved different sources. ", "Limtiaco was the drug source during the charged conspiracy. ", "Yet there is no suggestion that Limtiaco was involved in the 1990 transaction. ", "To the contrary, the putative source in that deal was an undercover DEA agent. ", "Although both transactions occurred in the same general geographic area, we must be careful not to consider similarity \"at such a level of generality as to eviscerate the evaluation of whether uncharged criminal *843 activity is part of the `same course of conduct or common scheme or plan' as the offense of conviction.\" ", "Mullins, 971 F.2d at 1145; See also Hill, 79 F.3d at 1483 (\"When considering the similarity factor, the conduct should not be considered at a level of generality that would render worthless the relevant conduct analysis.\"). ", "The fact that the drug suppliers were unrelated is significant.", "\nThird, the record is essentially devoid of evidence regarding Damato's role in the 1990 transaction. ", "Hawkins testified that Livingston was responsible for taking delivery of the marijuana, and that McPherson was in possession of the cash intended to cover the purchase price. ", "As to Damato, Hawkins testified only that \"Damato was at Leon Livingston's home waiting\" and that Damato \"ditched a bag of cash\" after fleeing. ", "It is thus difficult to compare Damato's role in the 1990 transaction to his role in the offense of conviction. ", "See United States v. Moore, 130 F.3d 1414, 1418 (10th Cir.1997) (\"In assessing a defendant's course of conduct, the court is to consider such factors as the nature of the defendant's acts, his role,? ", "and the number and frequency of repetitions of those acts.\" (", "quotation omitted)).", "\nFourth, the record does not establish whether the 1990 transaction shared a similar modus operandi with the transactions included in the charged conspiracy. ", "Given the quantity involved, we can infer that the 1200 pounds McPherson and Livingston attempted to purchase was destined for distribution. ", "However, the government did not present any evidence regarding the manner in which those drugs would have been distributed. ", "In contrast, the transactions included in the offense of conviction generally shared a similar transportation and distribution scheme.", "\n\n4\nWe conclude that the 1990 transaction was similar to the charged conduct to a moderate degree, but that this level of similarity falls short of compensating for the extreme lack of temporal proximity and the absence of evidence regarding regularity. ", "See U.S.S.G. § 1B1.3 app. ", "n. 9(B) (\"When one of the above factors is absent, a stronger presence of at least one of the other factors is required.\"). ", "We stress that the level of similarity at issue here would qualify the 1990 transaction as part of the same course of conduct in many cases, but the extraordinary—indeed unprecedented—temporal remoteness coupled with the absence of regularity evidence in this case is unique. ", "In Caldwell, for example, the level of similarity between the relevant conduct and offense of conviction was reasonably close to the level of similarity here. ", "See 585 F.3d at 1352-53. ", "But the conduct in that case was separated from the offense conduct by approximately eighteen months, id. at 1351, and the government established that the defendant \"regularly engaged in conduct that was similar to the conduct of conviction,\" id. at 1352.", "\nAs noted above, we apply a \"sliding scale\" analysis to determine whether a transaction qualifies as part of the \"same course of conduct.\" ", "See Hill, 79 F.3d at 1484. ", "That scale is tipped decidedly against the government in this case as a result of the thirteen-year gap between the claimed relevant conduct and the charged offense. ", "In addition to this strongly mitigating factor, the government failed to establish regularity over an eight-year period. ", "With these two factors weighing so strongly against a finding of relevant conduct, the government's substantial similarity evidence is simply not enough to qualify the 1990 transaction.", "\n*844 Although the temporal element factors very heavily into this decision, we emphasize that all three factors must be considered in determining whether an offense qualifies as part of the \"same course of conduct,\" and that \"each case depends largely on its own facts.\" ", "Roederer, 11 F.3d at 979 (quotation omitted). ", "Further, we do not purport to establish a bright-line cutoff for temporal proximity beyond which conduct will never qualify. ", "In Roederer, for example, we excused a five-year gap—much longer than the typical relevant conduct interval—based on the strength of the other two factors: The government showed that the defendant had engaged in nearly identical transactions \"on a continuous basis\" for the vast majority of the five-year period. ", "See 11 F.3d at 980. ", "In this case, however, we cannot accept the government's claim that conduct thirteen years prior to the offense of conviction qualified as part of a same course of conduct.", "\n\nB\nThe government does not argue that the 1990 transaction qualifies under the \"common scheme or plan\" prong, which provides an independent basis for holding a prior act to be relevant conduct. ", "See Svacina, 137 F.3d at 1182 (\"This court has agreed with the Second Circuit distinction between the terms `same course of conduct' and `common scheme or plan.'\"). ", "And although we generally \"will not craft a party's arguments for him,\" Perry v. Woodward, 199 F.3d 1126, 1141 n. 13 (10th Cir.1999), we do have \"discretion to affirm on any ground adequately supported by the record.\" ", "Davis v. Roberts, 425 F.3d 830, 834 (10th Cir.2005) (quotation omitted); See also United States v. Lott, 310 F.3d 1231, 1242 n. 7 (10th Cir.2002) (\"This court is not limited to the particular legal theories advanced by the parties, but rather retains the independent power to identify and apply the proper construction of governing law.\" (", "quotation omitted)).", "\nWe exercise our discretion to consider an alternative theory only when \"the appellant has had a fair opportunity to address that ground.\" ", "Alpine Bank v. Hubbell, 555 F.3d 1097, 1108 (10th Cir. ", "2009) (quotation omitted). ", "Damato was provided such an opportunity in this appeal. ", "He acknowledged in the Opening Brief that \"relevant conduct can be conduct that is part of the same course of conduct or common scheme or plan as the offense of conviction\" and that the district court \"failed to state under which theory it was proceeding.\" ", "Despite his recognition that the 1990 transaction might qualify as relevant conduct under the common scheme or plan prong, Damato did not discuss this prong. ", "He did, however, have a fair opportunity to do so.[4]\nWe have identified several guiding factors in determining whether to consider an alternative theory: \"[1] whether the ground was fully briefed and argued here and below; [2] whether the parties have had a fair opportunity to develop the factual record; and [3] whether, in light of factual findings to which we defer or uncontested facts, our decision would involve only questions of law.\" ", "Elkins v. Comfort, 392 F.3d 1159, 1162 (10th Cir.2004) (citations omitted). ", "In the case at bar, the first of these factors has not been met. ", "Neither party argued the common scheme or plan prong before the district court or this court.", "\n*845 Both the second and third Elkins factors, however, weigh in favor of considering the alternative ground. ", "The government argued below that the 1990 transaction constituted relevant conduct without limiting itself to either of the available prongs. ", "Specifically, it presented evidence regarding the 1990 transaction from Hawkins, but did not focus on one prong of the relevant conduct inquiry to the exclusion of the other. ", "See United States v. Hinojosa, 484 F.3d 337, 340 (5th Cir.2007) (noting the two relevant conduct prongs \"are closely related concepts\"). ", "Although Damato's counsel elected not to cross examine Hawkins about the 1990 transaction, Damato was afforded \"a fair opportunity to develop the factual record.\" ", "Elkins, 392 F.3d at 1162. ", "He was on notice that the government sought to include the 1990 transaction as relevant conduct and was free to present evidence at the sentencing hearing.", "\nThe third Elkins factor, whether the issue is one of law \"in light of factual findings to which we defer or uncontested facts,\" id., also supports an analysis of the common scheme or plan prong. ", "In reviewing a district court's sentencing determination, we defer to its factual findings unless clearly erroneous and \"view the evidence and inferences therefrom in the light most favorable to the district court's determination.\" ", "United States v. Beltran, 571 F.3d 1013, 1020 (10th Cir.2009). ", "But \"the ultimate determination of relevant conduct\" is a legal question we review under a de novo standard. ", "Tran, 285 F.3d at 938.", "\nBecause we reject the government's theory on appeal, and because Damato had a fair opportunity to argue whether the 1990 transaction qualifies under the common scheme or plan prong, we exercise our discretion to consider this legal question. ", "We caution the government in future cases, however, that consideration of an unargued issue is committed to our discretion.", "\n\nC\nA prior offense may qualify as relevant conduct under the common scheme or plan prong if it is \"substantially connected to [the offense of conviction] by at least one common factor, such as common victims, common accomplices, common purpose, or similar modus operandi.\" ", "U.S.S.G. § 1B1.3 app. ", "n. 9(A). ", "A Guidelines application note provides the following example of a common scheme or plan:\nthe conduct of five defendants who together defrauded a group of investors by computer manipulations that unlawfully transferred funds over an eighteen-month period would qualify as a common scheme or plan on the basis of any of the above listed factors; i.e., the commonality of victims (the same investors were defrauded on an ongoing basis), commonality of offenders (the conduct constituted an ongoing conspiracy), commonality of purpose (to defraud the group of investors), or similarity of modus operandi (the same or similar computer manipulations were used to execute the scheme).", "\nId.\nWe have repeatedly noted the distinction between the two relevant conduct prongs. ", "Although \"a common scheme or plan may require some connection between the acts by common participants, purpose, or overall scheme, the analysis of same course of conduct focuses on whether there is a pattern of criminal conduct.\" ", "Svacina, 137 F.3d at 1182 (quotations omitted); See also Roederer, 11 F.3d at 979 (\"Common identity of coconspirators, which could be a key factor in identifying a common scheme or plan, ... may be unnecessary in *846 determining whether a defendant himself has engaged in a pattern of criminal behavior—the focus of the same course of conduct inquiry.\" (", "quotation and alteration omitted)). ", "As these quotations suggest, the common course of conduct prong usually covers a broader array of conduct than does the common scheme or plan prong. ", "See United States v. West, 643 F.3d 102, 111 (3d Cir.2011) (\"[A]lthough there is substantial overlap between the terms `common scheme' and `course of conduct,' the latter envelops a greater sphere of activity than the former.\" (", "citation omitted)).", "\nNevertheless, in certain circumstances, acts that do not qualify under the same course of conduct prong may be part of a common scheme or plan as the offense of conviction. ", "Course of conduct is therefore broader in the sense that it sometimes permits the inclusion of conduct less similar to the offense of conviction than does a common scheme or plan. ", "It provides greater latitude with respect to similarity because the government is constrained by the regularity and temporal proximity factors when proceeding under a course of conduct theory. ", "As explained in Section II.A, supra, even conduct that is fairly similar to the offense of conviction fails to qualify as part of the same course of conduct if it is temporally distant and the government does not establish regularity. ", "But such conduct, if it shares a substantial connection to the offense of conviction, may constitute part of a common scheme or plan. ", "See U.S.S.G. § 1B1.3 app. ", "n. 9(A) (acts are part of a common scheme or plan if they are \"substantially connected to each other by at least one common factor, such as common victims, common accomplices, common purpose, or similar modus operandi\").", "\nWe conclude that this case presents one of the rare instances in which acts that were not part of the same course of conduct as the offense of conviction nonetheless qualify as part of a common scheme or plan. ", "As discussed in Section II.A.3, supra, the 1990 transaction and the offense of conviction were similar in many respects. ", "Both involved the sale of large amounts of marijuana, and both involved Damato obtaining (or attempting to obtain) marijuana from a source located in Southern California. ", "And importantly, Damato conspired with the same individuals— McPherson and Livingston—in both instances. \"", "Common identity of participants and similar role in the activity are the key factors in identifying whether the uncharged drug activities were part of a common scheme or plan.\" ", "United States v. Rios, 22 F.3d 1024, 1028 (10th Cir.1994); See also Roederer, 11 F.3d at 979 (\"Common identity of coconspirators ... could be a key factor in identifying a common scheme or plan. ...\" (", "quotation omitted)).", "\nAlthough we are troubled by the evidentiary gaps in the record regarding Damato's role in the 1990 transaction and the modus operandi underlying it, we nevertheless conclude that it was part of a common scheme or plan with the offense of conviction. ", "According to Hawkins, Damato was \"involved in [the 1990] deal.\" ", "Specifically, Damato was waiting at Livingston's home while Livingston and McPherson carried out the transaction with the agent they believed to be a marijuana supplier. ", "After Livingston and McPherson were arrested, Damato was tipped off. ", "He \"ran out of the house, hid in some nearby bushes, took off his running suit, ditched a bag of cash that he had with him, and got away.\" ", "Hawkins learned this information from debriefings with McPherson, Livingston, and Bower.", "\nAlthough this evidence is somewhat thin with respect to Damato's involvement, viewed in the light most favorable to the government, see Beltran, 571 F.3d at 1020, *847 it shows that Damato conspired with McPherson and Livingston to obtain a distribution quantity of marijuana from a Southern California source. ", "Damato's decision to flee and his possession of a \"bag of cash\" further support such an interpretation of Hawkins' otherwise ambiguous statement that Damato was \"involved\" in the 1990 transaction. ", "And given that Damato's conduct involved the same coconspirators as the offense of conviction, the same drug, and the same source location, we hold that the 1990 transaction qualifies as relevant conduct under the common scheme or plan prong.", "\nDamato complains that Hawkins' testimony is too unreliable to carry the government's burden of proving relevant conduct by a preponderance of the evidence. ", "See United States v. Fortier, 180 F.3d 1217, 1225 (10th Cir.1999). ", "However, we have consistently held that \"hearsay statements may be considered at sentencing if they bear some minimal indicia of reliability.\" ", "United States v. Cook, 550 F.3d 1292, 1296 (10th Cir.2008) (quotation omitted). ", "Hawkins' testimony regarding the 1990 transaction clears this low hurdle. ", "There is no doubt that the 1990 transaction occurred; both McPherson and Livingston served time for their role in the attempted purchase. ", "And because both coconspirators had already been convicted for the 1990 transaction, neither had a strong incentive to shift blame to Damato. ", "We thus hold that Hawkins' statements regarding the 1990 transaction bore the minimal indicia of reliability necessary.", "\nIn sum, although we reject the government's argument that the 1990 transaction was part of the same course of conduct as the offense of conviction, we conclude that the transaction qualified as relevant conduct under the common scheme or plan prong. ", "Accordingly, we reject Damato's challenge to the district court's drug quantity calculation.", "\n\nIV\nIn addition to his drug quantity objection, Damato also argues that the district court erred in imposing a four-level enhancement for his role as \"an organizer or leader of a criminal activity that involved five or more participants or was otherwise extensive.\" ", "U.S.S.G. § 3B1.1. ", "Damato contends the evidence was insufficient to establish that he acted as a leader or organizer.", "\nTo determine whether a defendant qualifies as a leader or organizer, the Guidelines direct us to consider: the exercise of decision making authority, the nature of participation in the commission of the offense, the recruitment of accomplices, the claimed right to a larger share of the fruits of the crime, the degree of participation in planning or organizing the offense, the nature and scope of the illegal activity, and the degree of control and authority exercised over others. ", "There can, of course, be more than one person who qualifies as a leader or organizer of a criminal association or conspiracy.", "\nU.S.S.G. § 3B1.1(a) cmt. ", "n. 4. ", "Further, a defendant need not lead or organize at least five individuals. ", "Rather, the criminal activity must include five or more participants (or be otherwise extensive). ", "U.S.S.G. § 3B1.1. ", "A defendant may be eligible for the leader or organizer enhancement if he leads or organizes even one other participant. ", "See United States v. Hamilton, 587 F.3d 1199, 1222 (10th Cir.2009).", "\nWe uphold the district court's conclusion that Damato qualifies as a leader or organizer. ", "McPherson's statements contained in the PSR show that Damato *848 and McPherson flew out to See Livingston after he was arrested to \"figure out how they were going to operate the business.\" ", "At the sentencing hearing, Hawkins explained that most of the marijuana deliveries were taken to Damato, or split between Damato and McPherson. ", "When Livingston introduced other members of the conspiracy to the supplier Limtiaco, Damato met with Limtiaco first. ", "By monitoring conspirators' phone calls, the government was able to establish that Damato almost certainly made more calls to Limtiaco than other members of the conspiracy. ", "Limtiaco stated that it appeared that Damato was \"in charge.\" ", "In light of this evidence, we cannot say that the district court clearly erred in classifying Damato as a leader or organizer of the conspiracy.", "\nWe also reject Damato's argument that evidence supporting the enhancement was inherently unreliable. ", "As previously noted, \"hearsay statements may be considered at sentencing if they bear some minimal indicia of reliability.\" ", "Cook, 550 F.3d at 1296. ", "Hawkins, a member of the DEA investigative team, testified that the coconspirator statements he relayed at the sentencing hearing were corroborated by telephone records, hotel records, and GPS tracking data. ", "Hearsay statements relayed by various coconspirators were largely consistent with each other. ", "This corroboration provides the necessary indicia of reliability.", "\n\nV\nLastly, we consider the substantive reasonableness of Damato's sentence. ", "Damato was sentenced below his advisory Guidelines range. ", "As such, his sentence is presumed to be reasonable. ", "See United States v. Balbin-Mesa, 643 F.3d 783, 788 (10th Cir.2011). ", "In attempting to rebut this presumption, Damato offers a single argument: He contends that his sentence is disparate to that of his coconspirators.", "\nUnder 18 U.S.C. § 3553(a)(6), sentencing courts should \"avoid unwarranted disparities among defendants with similar records who have been found guilty of similar conduct.\" ", "Damato complains that his coconspirators received lesser sentences than his own. ", "But we have repeatedly explained that § 3553(a)(6) \"requires a judge to take into account only disparities nationwide among defendants with similar records and Guideline calculations. ", "It is not reversible error for a sentencing court to adhere to this interpretation in its exercise of sentencing discretion.\" ", "United States v. Verdin-Garcia, 516 F.3d 884, 899 (10th Cir.2008) (citations omitted). ", "Damato has not presented any evidence suggesting his sentence is problematic in this sense.", "\nFurther, because \"avoidance of unwarranted disparities was clearly considered by the Sentencing Commission when setting the Guidelines ranges,\" a district court that \"carefully reviewed the Guidelines range ... necessarily gave significant weight and consideration to the need to avoid unwarranted disparities.\" ", "Gall v. United States, 552 U.S. 38, 54, 128 S.Ct. ", "586, 169 L.Ed.2d 445 (2007). \"", "We have interpreted Gall to conclude that ... § 3553(a) does not require a consideration of codefendant disparity.\" ", "United States v. Martinez, 610 F.3d 1216, 1228 (10th Cir.2010) (citation omitted).", "\nIn any event, Damato has not shown that he was similarly situated to his codefendants. ", "Although counsel questioned Hawkins regarding the lengths of several coconspirators' sentences, the record does not actually establish the length of several of their sentences. ", "The record lacks information as to the manner in which all of the coconspirators' sentences were calculated. ", "Only McPherson's record is discussed in *849 detail, and the difference between his and Damato's sentence is explained by the substantial assistance McPherson rendered to the government. ", "A \"sentencing disparity produced by substantial assistance departures was intended by Congress.\" ", "United States v. Candia, 454 F.3d 468, 476 (5th Cir.2006) (quotation omitted). ", "Accordingly, such a sentencing difference does not constitute an \"unwarranted sentence disparit[y].\" ", "18 U.S.C. § 3553(a)(6).", "\n\nVI\nFor the foregoing reasons, we AFFIRM the district court's sentencing determination.", "\nNOTES\n[1] Section 3D1.2(d) requires the grouping of multiple counts \"[w]hen the offense level is determined largely on the basis of the total amount of harm or loss, the quantity of a substance involved, or some other measure of aggregate harm....\" Damato's crime qualifies as a crime in which the offense level is determined largely by the \"quantity of substance involved.\" ", "Id.\n[2] In considering transactions that occurred five years apart, other circuits have been reluctant to regard the prior transaction as relevant to a given conspiracy. ", "See, e.g., United States v. Mankiewicz, 122 F.3d 399, 405 (7th Cir. ", "1997) (remanding for further explanation because the record revealed \"nothing about the 5-year period between the transactions\"); United States v. Fermin, 32 F.3d 674, 681-82 (2d Cir.1994) (reversing sentence because district court included as relevant conduct an incident that occurred five years before offense of conviction), overruled on other grounds, Bailey v. United States, 516 U.S. 137, 116 S.Ct. ", "501, 133 L.Ed.2d 472 (1995).", "\n[3] Bower also stated that Damato continued to engage in marijuana distribution after McPherson was incarcerated. ", "However, this statement clearly refers to the 1990 to 1995 time period. ", "Immediately after the statement, Bower explains that he drove five or six loads of marijuana in the 1990s. ", "And Bower himself was incarcerated from 1995 to 2003.", "\n[4] Damato appears to complain that the district court did not specify which of the prongs it was applying. ", "Although identifying which of the relevant conduct prongs is being applied is the better practice, we have never held that a district court is required to announce the portion of U.S.S.G. § 1B1.3(a)(2) it concludes is relevant.", "\n" ]

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[ "Q:\n\nIs it legal to use True Polymorph to become a really old adult dragon so that you become ancient with time?", "\n\nA scenario popped up in my mind that seems legal but feels like cheating. ", "Say a level 20 wizard used True Polymorph to become an Adult Gold Dragon, at age 800 years and 364 days old. ", "As stated in another question, this puts him a day before he becomes an Ancient Gold Dragon. ", "So the wizard just waits for a day, and now he is permanently an Ancient Gold Dragon. ", "This seems to not be what the spell intended because they put the CR cap, but I can't see anything restricting it.", "\n\nA:\n\nAsk your DM\nUnfortunately, while you can True Polymorph (PHB, 283) into a new form that:\n\n... can be any kind you choose whose challenge rating is equal to or less than the target's...\n\nIt doesn't actually state that you can pick age, etc. ", "Nor is it clear that the age categories are exact for dragons. ", "Nor is it clear you can pick a specific age dragon. ", "A DM could very reasonably rule you pick Red Dragon and it uses your age to determine what age dragon you are.", "\nUltimately, you're just picking \"Red Dragon\", and that's it. ", "But it's up to your and DM to determine if picking an Age and 'aging' into an Ancient dragon is allowable at your table.", "\nHow would this DM approach it?", "\nI probably wouldn't allow it. ", "It feels too much like trying to game the system and the rules aren't clear enough for me to allow it. ", "And becoming an Adult dragon is still pretty darn cool.", "\n\nA:\n\nSort of\nYou can't necessarily pick any particular age when you turn into a dragon; even 'adult red dragon' might not be a 'kind' of creature in your DM's campaign. ", " Even if you can turn into specifically an Adult Red Dragon instead of just choosing Red Dragon, you don't necessarily have any control over the exact age of that dragon when you turn into it.", "\nRegardless, unless your DM rules that 'Red Dragon' isn't a kind of creature, which would definitely be a big stretch, you can certainly turn into some age of Red Dragon and wait (or force-age yourself) to be ancient.", "\nEven so, though, note that you will never actually be an ancient dragon. ", " Ancient dragons have legendary actions and the rules say:\n\nIf a creature assumes the form of a legendary creature, such as through a spell, it doesn’t gain that form’s legendary actions, lair actions, or regional effects.", "\n\nSo you will never get those off a Legendary Dragon by assuming its form as a character that is a creature.", "\nFurthermore, even a permanent True Polymorph can be dispelled. ", " Unless you are an elf or a druid or both, you may well then immediately die of old age.", "\n\n" ]

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[ "Brixton Key\n\nBrixton Key was born in Isleworth, England in the 1950s to a party-loving Mum and an errant Dad. ", "Expelled from boarding school, which he attended on a scholarship, Brixton landed a gig with the British music weekly Melody Maker, writing under the name of Mark Plummer. ", "He left for America to manage Chris Isaak in the 1980s, guiding the pop idol and actor’s career as MTV started ruling the airwaves. ", "In the 90's Brixton suffered a life-threatening brain aneurism. ", "After he recovered, on the advice of his stepson he began writing fiction. ", "Brixton lives with his girlfriend Josephine in a downtown San Francisco loft. ", "In the late night hours he reads his favorite authors under skyscraper shadows, and works on his sequel of the Charlie Six trilogy, There Ain't No God Here." ]

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[ "Abstract\n\nThis paper identifies how the different ideologies of patriarchy, technology, capitalism, race and feminism shape how we see breastfeeding and the breastfeeding mother with child. ", "Ultimately, while we can make good strong arguments for breastfeeding from the perspective of health, of outcome, of good scientific data, we need to appreciate that they are only rationalizations for a shared belief that the image of the breastfeeding woman with baby represents something precious and valuable. ", "So while it may be important to make arguments that draw on what is valued in society, we need to think hard about what it is that we value so that as we move forward with our efforts to make breastfeeding safe, we can use but not be used by, the various ideologies or claims.", "\n\nIntroduction\n\nBear with me for a moment, and fill in the blanks below:\n\nThe rival brand to Pepsi is ______.", "\n\nA little jab in the ribs is a _____.", "\n\nA puff on a joint is a _____.", "\n\nA short funny story with a punch line is a ______.", "\n\nThe white of an egg is the _______.", "\n\nJust about everybody answers that the white of an egg is the yolk. ", "And, just about everybody knows that is not true. ", "The point of this exercise is to drive home the idea that what we see/hear/think is very context-dependent.", "\n\nAnd now, another thought exercise: Picture a small room, with one comfortable chair in the center, and in that chair a woman with a baby at her breast. ", "Please hold that image in your mind through everything I now say. ", "That room has several doors leading into it. ", "Which door you are coming in – \"where you are coming from\" – will shape what you see in that room. ", "I am going to identify just a few of the many doors from which we may be entering, and consider how they shape what we see. ", "Each of these doors represents a shared way of thinking, what we call \"an ideology.\" ", "Ideologies are political; that is, they rest on a power base. ", "When people internalize ideologies, they become part of \"common sense,\" what \"everyone knows,\" and what needs no explanation. ", "The doors, or ideologies, I am going to examine include patriarchy, technology, capitalism and race.", "\n\nPatriarchy\n\nPatriarchy is one of the easiest to understand of the ideologies that shape motherhood and the understanding we bring when we open the door to that suckling woman. ", "More than half the world has someplace to stand, another reality – women's reality – to contradict this particular ideology. ", "But, women's reality is not the dominant ideology, and women's view of the world is overruled by men's view. ", "Motherhood in a patriarchal society becomes what mothers and babies signify to men. ", "The term \"patriarchy\" sounds almost quaint now, a relic of 1970s feminism. ", "But in anthropological work, the term technically means \"rule of fathers,\" not just rule of men. ", "And, when the subject is mothering, there is an important difference. ", "Patriarchal kinship systems rank paternity as the central social relationship: children are born to men, out of the bodies of women, and women, in this system, bear the children of men. ", "In such a system, because what is valued is the relationship of men to their sons, women are a vulnerability that men have: to beget these sons, men must pass their seed through the body of women.", "\n\nPerhaps even more important in shaping what we see when we open the door to a breastfeeding mother, in patriarchy it is the \"seed\" that is the essence, and nurturance is reduced to \"soil,\" to \"dirt,\" to meaningless background which can only take-away from, never add to, the intrinsic value of the grown being. ", "In pregnancy, and in their motherhood, women can only ruin, hurt, destroy, damage their babies, or allow them to flower to the fullness of the essence they had from their seed. ", "Mothering in patriarchy – and reflected so powerfully in medical care – is a risk, not an act of creation.", "\n\nTechnology\n\nOne definition of technology is that it is just a tool, not good and not bad, but just a neutral tool that can be used for whatever purpose. ", "Yet neutrality is not consistent with the other attribute we ascribe to technology: its practicality. ", "Technology is the application of science, supposedly pure science, applied to practical ends. ", "But as soon as one concedes that technology is for something, then it is no longer neutral. ", "The ideology of a technological society is not just a package of tools, gimmicks, know-how; it is a way of thinking about the world in mechanical, industrial terms. ", "The use of mechanical, industrial metaphors influences so many aspects of our lives: organizations working like \"clockwork,\" people \"programmed\" to think in certain ways, bodily \"plumbing.\" ", "With changing times, the prototypes for the machines change, and along with it our fears and fantasies, from the runaway conveyor belt of a Charlie Chaplin film to HAL taking over in 2001: A Space Odyssey.", "\n\nAnd all this shapes how we see ourselves and our children. ", "The world and all that it contains, including our own bodies, ourselves and our children, become potential resources, something to make something of. ", "We build our bodies, sharpen our wits, and work on our relationships – and on our children. ", "Efficiency is a crucial value in such a system, and we apply our ideas about machines to people, asking them too to be more efficient, productive, rational, and controlled. ", "When a doctor manages a woman's labor, controlling her body with drugs and surgery, it is precisely to make her labor more efficient, predictable and rational. ", "And so it follows that mothers push their babies onto a schedule – so that feeding the baby meshes into the \"nine-to-five\" day. ", "We organize our time, our days, our lives and our relationships. ", "We divide up tasks, and do them in the most efficient way possible: perhaps one woman expressing milk, another feeding it to the baby, in the interests of better \"time management\" for all.", "\n\nCapitalism\n\nThe ideology of technology dehumanizes people by encouraging a mechanical self-image: breasts, in this case, as machines for the production of milk – women's nipples and babies' lips as transport systems. ", "Capitalism adds that not only is the body a collection of parts, but these parts become commodities. ", "In the United States the essential fluids of life – blood, milk, and semen – are all for sale. ", "There is a price tag on everything. ", "Similarly, relationships become services, available for purchase or hire. ", "Need arms to hold a baby, need someone to wield an alternative transport system for breast milk? ", "Hire them. ", "And, given the patriarchal focus on the seed, now expanded to include the highly valued seeds of some (educated, upper class) women, the nurturance work that is being hired is cheap and devalued.", "\n\nCapitalism is an ideology as much as it is an economic system, and we see that in the deep ways it influences our thinking and language in such a wide variety of areas. \"", "Choice,\" the language of the marketplace, is the only acceptable language to use to demand individual respect and autonomy. ", "Second wave feminists saw that, and used it very effectively: feminism and self-determination for women became a \"choice,\" and it is very difficult to argue against anyone's \"choice\" in a system ruled by this ideology. ", "In such thinking, power is allowed to slip below our radar: people have to be truly free to \"choose,\" and the power that would give them genuine freedom – and thus meaningful choices – is not discussed.", "\n\nRace\n\nRace, and most assuredly racism, is itself an ideology, a way of thinking about and ordering the social world. ", "The American history of race is something we bring with us as we open that door to a suckling woman. ", "A 1993 Cultural Studies conference at the University of Michigan used an image, taken from an advertisement for \"United Colors of Benetton,\" of a black woman suckling a white baby. ", "The University's Women of Color Task Force objected. ", "Patricia Williams was one of the people who responded to the controversy. ", "What would it mean, she asked, if we were to reverse the image, placing a black baby at the white breast?", "\n\nIs there not something unseemly, in our society, about the spectacle of a white woman mothering a black child? ", "A white woman giving totally to a black child; a black child totally and demandingly dependent for everything, sustenance itself, from a white woman. ", "The image of a white woman suckling a black child; the image of a black child suckling for its life from the bosom of a white woman. ", "The utter interdependence of such an image, the merging it implies; the giving up of boundary; the encompassing of other within self; the unbounded generosity and interconnectedness of such an image[1].", "\n\nAs a white adoptive mother of a child of African American descent, I have spent many hours of my life staring at exactly that, my black baby suckling at my white breasts, and thinking about it. ", "What am I looking at in that reverse image? ", "Unbounded generosity? ", "Interconnectedness? ", "Some weird gendered version of white man's burden? ", "Genocide? ", "A better Benetton ad?", "\n\nI cannot, still, after all these years and all this thinking, quite disentangle that image. ", "But the image of the white baby at the black breast, now that is an image with a powerful American back story, the enslaved wet nurse, the woman whose own babies were allowed to hunger and even die, as they nursed their little white charges. ", "That is the image that many of us hold in our heads as we look at a black or brown woman carefully defrosting the precious white milk of her employer and feeding it – not at breast but with bottle – to the white child. ", "That image and that history shapes what we see when we see a suckling baby.", "\n\nFeminism\n\nFeminism itself is an ideology, a way of thinking about the world, and represented an attempt – more or less successful – to grapple with each of these ideologies. ", "Many would argue that it was most successful in dealing with patriarchy, and so simply moved more women into the position of fathers, exacerbating in many ways the problems brought to us by ideologies of capitalism, technology and most especially race.", "\n\nBut feminism must be seen as one of the doors we enter through. ", "Many of us at the symposium are very much the product of the feminism of the 1970s, and some of us – such as Judy Norsigian representing Our Bodies Ourselves – are themselves the causes and not just the products of that feminism. ", "That second wave feminism asked us to stand in all those places, more or less critically, and think about mothering, and about breastfeeding.", "\n\nMy oldest child was born in 1974. ", "I was strongly committed to a personally-empowered home birth. ", "But I very clearly remember reading \"The Womanly Art of Breastfeeding\" while I was pregnant, and thinking, \"Well, I want to breastfeed anyway\" – in spite of the good arguments of La Leche League. ", "It is, frankly, much the way I feel about the current public health arguments: I want women to breastfeed anyway, however troubling the arguments and propaganda being offered.", "\n\nConclusion: why care?", "\n\nThe woman in that room is threatened. ", "Breastfeeding rates are low, and getting lower among some groups. ", "If it is not the sanctity of motherhood and women's ultimate feminine roles that persuades me to try to keep her safe, and it is not the emphasis on \"healthy babies,\" that persuades me, what is it then that I value about that image of a woman with baby at breast? ", "We were asked to think about that in this meeting, and I have been thinking hard.", "\n\nI find myself thinking about it in terms that might seem quite unrelated. ", "I have become interested in food studies, and attended some meetings of late. ", "At one, I found myself listening to a panel of artisanal food makers, people who were treating the production of food as something of deep cultural and social worth. ", "They were a bit unclear about what specifically they were valuing: the individualized small production? ", "Not necessarily. ", "The classic, traditional techniques? ", "Not always. ", "As I listened to them try to decide what was the \"essence\" of artisanal food production, what made it meaningful, I was reminded of the ways that midwives talk about birth. ", "Some work in big impersonal hospitals, and yet still claim to be practicing something that should be called midwifery. ", "Some use newer technologies and interventions. ", "Some work in groups and find themselves attending women they never met before. ", "What is it that they are clinging to that marks the essence, the essential truth of midwifery?", "\n\nAnd that is the question I hear at this conference, and among the breastfeeding community in general – lactation consultants, La Leche League people – what are we clinging to? ", "If we lose breastfeeding, they are saying, something precious will be lost. ", "This is, I do believe, not all about rationality, though we cling to that, as do the artisanal food makers and the midwives. ", "We can make good strong arguments from the perspective of health, of outcome, of good scientific data. ", "And yet, if they perfected commercial industrial food products, if they perfected cesarean sections, if they perfected artificial breast milk supplements – if all of these were made just as safe and healthy as the \"natural\" alternatives – I would be left without some of the good arguments I use, but I would not be satisfied. ", "We can make claims to health and to choice: but they are rationalizations we are using because – at root, fundamentally – we believe that the woman in that room with the baby at her breast represents something precious and valuable. ", "We need to make what arguments we can; we need to draw on whatever works in our society; but I think we also need to be honest with ourselves. ", "We need to think hard about where are we coming from and what we are hanging on to, what we can use but not be used by as we move ahead, as we try to make that room a safe space.", "\n\nDeclarations\n\nCompeting interests\n\nThe author declares that she has no competing interests.", "\n\nAuthors’ Affiliations\n\n(1)\n\nDepartment of Sociology, Baruch College, City University of New York\n\nReferences\n\nCopyright\n\nThis article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited." ]

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[ "This invention is directed to a splattle paddle as set forth in a disclosure document filed May 11, 2001.", "\nThe device sets forth a paddle to which a stretchable cord is secured at one end and the opposite end of the cord is secured to a holding means to which a mouth end of a balloon is secured.", "\nHeretofore a paddle in combination with a rubber ball attached to a stretchable band has been available for use. ", "The band is secured at one end to a center point of the paddle with the opposite end of the band secured to the ball. ", "The ball is then hit by the paddle for as many times as possible before the ball is not hit by the paddle. ", "Also, U.S. Pat. ", "No. ", "4,212,460 relates to a water-filled game toy.", "\nIt is therefore an object of the invention to provide a paddle in combination with a balloon. ", "The balloon is filled with water or used without water therein, and the game, is to hit the balloon with the paddle as many times as possible before bursting the balloon.", "\nAnother object is to fill a balloon with water, or without water, and to see how high you can hit the balloon which is not attached to the paddle with a stretchable band.", "\nStill another object is to attach a water ball to the paddle with a stretchable band and see how many times one can hit the ball before the ball bursts.", "\nOther objects and advantages of the invention will become obvious to those skilled in the art upon a review of the drawings, specification and claims." ]

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[ "This invention relates in general to machine controllers and in particular to an improved automated control system for controlling multiple operations of a machine tool.", "\nMany different machine tools are known in the art for performing various operations on a workpiece. ", "Typically, a single machine tool includes a plurality of individual tools, each of which is capable of performing an operation on the workpiece. ", "In many instances, these operations are related to one another in the sense that one operation must be completed before another operation can begin. ", "Thus, the timing and sequence of the various individual operations must usually be regulated in some manner.", "\nTo accomplish this efficiently, it is known to provide a machine tool with an electronic controller. ", "Such electronic controllers are typically embodied as programmable controllers, microprocessors, or similar automated computing devices which are connected to the various individual tools provided on the machine tool. ", "The controllers are usually programmed with a series of instructions which define the particular individual tools to be used and the timing and sequence thereof. ", "Many such electronic controllers are known in the art. ", "However, it has been found that known electronic controllers of this type are typically quite complicated to program and operate. ", "Furthermore, known electronic controllers of this type do not readily provide diagnostic information to the operator of the machine tool when abnormal occurrences arise. ", "Thus, it would be desirable to provide an improved structure for an electronic controller for a machine tool which is simple to program and operate, and further which readily provides diagnostic information to the operator of the machine tool when abnormal occurrences arise." ]

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[ "Event-related potentials as a tool in the evaluation of cognitive functions in young subjects through the execution of a simple task.", "\nEvent-related potentials (ERPs) were recorded in 20 student volunteers. ", "Three recordings were performed using aural stimuli of 4,000 (rare tones) and 250 Hz. ", "In the target recording subjects were asked to count the rare tones. ", "Endogenous and exogenous components of ERP recordings were analyzed. ", "During the target recording N2 and P3 components were observed at 200 ms and approximately 300 ms, respectively, in addition to N1 (100 ms) and P2 (180 ms). ", "The N2 and P3 waves are indicative of analysis at a higher cognitive level and have been termed the 'response set'. ", "The P3 wave appeared to be stable in all subjects and may represent a useful electrophysiological method to explore mnemonic and cognitive functions in man." ]

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[ "Marlowe and the Popular Tradition turns away from popular stereotypes to consider Marlowe as a popular dramatist who inherited an audience with certain expectations and shared experiences. ", "This work explores Marlowe's engagement with the traditions of the popular stage in the 1580's and early 1590's. ", "It offers a new approach to his major plays in terms of staging and audience response, as well as providing a new account of the English drama in these important but largely neglected years." ]

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[ "---\nlayout: global\ntitle: Multilayer perceptron classifier\ndisplayTitle: Multilayer perceptron classifier\nlicense: |\n Licensed to the Apache Software Foundation (ASF) under one or more\n contributor license agreements. ", " See the NOTICE file distributed with\n this work for additional information regarding copyright ownership.", "\n The ASF licenses this file to You under the Apache License, Version 2.0\n (the \"License\"); you may not use this file except in compliance with\n the License. ", " You may obtain a copy of the License at\n \n http://www.apache.org/licenses/LICENSE-2.0\n \n Unless required by applicable law or agreed to in writing, software\n distributed under the License is distributed on an \"AS IS\" BASIS,\n WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.", "\n See the License for the specific language governing permissions and\n limitations under the License.", "\n---\n\n > This section has been moved into the\n [classification and regression section](ml-classification-regression.html#multilayer-perceptron-classifier).", "\n" ]

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[ "Ordos Museum / ///byn\n\nChinese calligraphy is mainly based in three characteristics: status of mind, line and color. ", "These tree concepts triggered ///byn original ideas for the Ordos Museum. ", "A primary impression of non-organization is quickly overcome by a self-organized logic. ", "Here, the museum volumes have found their own space in the park. ", "The logics of placement come from many different aspects: orientation, functionality, targeted visuals, public space, creating a unique orchestrated sequence of spaces. ", "More images and project description after the break.", "\n\nThe inhabiting/space populating logic in Inner Mongolia is grouping. ", "Local herds of camels and horses are being used to browse the steppe in search for comfort. ", "This comfort was only fulfilled when they would arrive to a decision to settle in the landscape. ", "In the same manner, the always present clouds populate the inner Mongolian sky: groups of rounded and cotton locking clouds spread at the intense blue sky. ", "Finally, the original nomads will settle their yurts following a constellation.", "\n\nWeather has a big impact on Inner Mongolia as it merges everything together. ", "Winds blurs nature and manmade aspects of the environemnt. ", "Grasslands wrap the landscape entirely both in rural and urban scapes. ", "Water erodes the land creating grooves in the soil and rocks and, more importantly; Architecture is tightly blend to the nature by being inspired in its morphologies. ", "T.C.A.O MUSEUM doesn’t block the river park but on the contrary it expands it and makes it more accessible: It works as a hinge between the urban axis on the west and the river park on the east. ", "It combines a south-oriented public space dedicated to the citizen’s social activities with a North nature-preserved park. ", "It allows the water and the views towards the water flow along a new slope\n\nT.C.A.O MUSEUM doesn’t dialogue with the landscape in a unique way. ", "There is a constant play between the background (river / park) and the figure (museum) Sometimes the museum rests on the park, some others it sinks within; it evens buries inside. ", "The consequence is that the architecture frames the landscape and transforms it, bringing it to this river front the status of a Landmark/destination in Ordos." ]

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[ "Subscribe to this blog\n\nFollow by Email\n\nFallen in Love with a Metal God, We Must Learn to Share\n\nI've fallen in love with so many metal legends and some unknown over the past year and a half: Mr. Lordi, Gene Simmons, Paul Stanley, Ace Frehley, Tommy Thayer, Mick Thomson and Andreas Deris. ", "I know there's more to the list but I decided to put in just a few. ", "Now most people would often see this particular thing more common among teenage girls ages 14 - 18 who are single, rather than it being common for younger women ages 20 - 30 or even higher in some cases who are either single or married with children. ", "But I can officially say that that is not true because I've met many women my age and older who are in love with rock stars as well be it someone I love too or not. ", "There are basic musicians who we ladies fall in love with at any age and then there are big metal legends out there that lots of metal chicks swoon over and now, here is the one metal god that I most recently melt over along with millions of other girls:\n\nYes it's Dave Mustaine, the super hot lead guitarist and vocalist of Megadeth. ", "Some things that make me attracted to him romantically, is his irresistable smile and beautiful flaming hair. ", "Also in his personality is that I love how he's determined to make Megadeth successful, he even wishes Metallica should fail, hahahahaha! ", "Some people would often label him as a bit of a jerk sometimes because they may have met him and got the brush-off treatment. ", "That's common for rock stars but that's just life to me. ", "Perhaps inside Dave is kind-hearted inside but we Megafans may not see it.", "\n\nHowever, the reason why I am writing about Dave is not because of the fact that I am now in love with him as I am with Mr. Lordi, Gene Simmons and all the others. ", "I can always make another entry dedicated to how hot I think Dave is later. ", "What this entry really is about is dealing with other metal chicks who are romantically attracted to Dave as well. ", "As far as I'm concerned, most of the metal chicks I've met who are in love with Dave, their ages are around 14 - 16 and most of them will often express their love for Dave like any normal person would. ", "That I don't have a problem with because well every metal chick that loves him has a right to do that, but when they start to say things like \"I am actually married to Dave, he is my husband!\" ", "and with these words they may make fake marriage certificates, and pictures using Photoshop or other picture editing tools claiming these are licenses giving \"proof\" that they are married to Dave, that I do have a problem with. ", "Not just that, they may also say disturbing things that they want to do with Dave, for example: suck his dick, have intercourse of any kind, etc. ", "Okay, maybe saying they want sexual intercourse with him is not completely inappropriate but it depends on the type of intercourse. ", "There are even some metal chicks who have seen Megadeth live and will sometimes go as far as to strip down in front of Dave when he is on stage. ", "That is a sign of complete uncontrolled obsession or drunk insanity. ", "If I see Megadeth live one day I will not strip down in front of Dave to show my love for him, instead I will just scream how much I love him just like I did with Gene when I saw KISS this year. ", "On top of that, some of these teenage girls may approach other metal chicks (younger or older) that are in love with Dave and wish they could be married to him and/or say that he is their husband too in their own heart/imagination, and they tell them to not steal Dave from them because they believe that Dave belongs to them and only them. ", "The truth is that in my case: I am in love with Dave Mustaine, I am married to him in my heart and imagination just like with Mr. L, Gene, and the others I love, when I imagine myself with him I imagine myself kissing him and being held in his arms and maybe making love but I have no desire to fantasize about sucking on his dick, anal sex/oral sex and I'm not afraid to tell people about it, but if other young metal chicks who love him think that I'm trying to steal Dave from them because they are so overly protective and make false claims that he is their husband, the reality is that none of us are married to Dave and even if we make false certificates and pictures to claim the marriage is real it will never be real. ", "It will only exist in our hearts, and none of us are stealing him from one another because he doesn't belong to just one of us. ", "He belongs to all metal chicks that love him and we must learn to share him and recognize that is not just one person who likes to imagine themselves married to him.", "\n\nAlso when we are in love with a rock star we need to recognize the boundaries. ", "The sad and unfortunate truth is that Dave has a family. ", "For young metal chicks that love him, that information may be hard to accept due to the level of obsession for him. ", "Why I remember back when I was first falling in love with Mr. Lordi it took me a couple of months to get over the fact that he was married but then I learned from a friend of mine that his wife is very kind to the fans so I quickly was able to accept the reality, and when I fell in love with Gene I was able to do the same thing with his wife Shannon. ", "We will always have the right to love a rock star even if they are married but we must recognize that and respect it. ", "It's okay to not particularly like a band member's love interest but it's not okay to try and split them apart as I said in an earlier entry about Mr. Lordi and Gene.", "\n\nI have befriended a few metal chicks who are in love with Mr. Lordi and Gene for example and instead of fighting over them, we accept that we both love them and we have conversations about how hot we think they are. ", "I wish that the same thing could happen with Dave but I don't know if this is ever going to happen unless these young teenage girls start to act a little more mature with their love for Dave.", "\n\nNow this entry is not meant in any way to hate on younger metal chicks who love this metal guitar God known as Dave because we are all allowed to love him. ", "There is nothing wrong with loving him in general and imagining he's your husband in your heart. ", "But there is something wrong with taking it over the top by saying he only belongs to you/giving proof for that, wanting to do something inappropriate with him, and disrespecting his wife.", "\n\nI hope that someday anyone who loves him and has these issues is able to wake up and face the facts that there are boundaries that need to be recognized in this and that they are not the only ones with feelings for him.", "\n\nI love Dave, he's one of the hottest musicians from the big 4 I have ever seen and I am hoping to see Megadeth live in the future.", "\n\nComments\n\nPost a Comment\n\nPopular posts from this blog\n\nAlright, so after spending a fine evening listening to The Last Stand, I have to say I was not disappointed from start to finish.", "\n\nIt's been a while since I've done an album review so I thought why not write one for Sabaton's new album?", "\n\nJust like previous reviews I have done, this one is just going to be based on the music. ", "I would have to do a ton of research if I wanted to go into detail about the story each of these songs tell, and frankly I don't feel motivated to do that for an album review when I like to talk about the music itself. ", "But, when the time comes to feature a song from this album for Metal Monday, then I'll go into depth about the story behind the song as well!", "\n\nI always believed they would come back, and they did. ", "Last summer Sabaton suddenly came back into my life when they announced a new album. ", "The first single was released and that was my jam from June to late August. ", "I don't know what it was, but somehow that was the summer I became a more devoted fan and eventually they entered deeper into my heart. ", "Thus, my love for power metal has been significantly high.", "\n\nSo, I told myself that one day they will return soon, and this time I would be ready. ", "Last night, I certainly was ready, and went to hell and back with no regrets.", "\n\nI felt like I was the only person who wore full Sabaton gear. ", "Nobody else at the venue seemed to be wearing the pants or the wristband. ", "But I got a few compliments that I looked like one of them!", "\nIt was raining hard when we arrived at the venue and stood behind the sound system again. ", "Due to it being a sold out show and late arrival, I had no interest in going to the floor. ", "Large crowds spell bad news if you're no…\n\nAt last, after five years of long waiting for an event I thought would never come, it has finally happened! ", "Last night was the most epic night of my life, the most epic of all the concerts I've been to. ", "Lordi was amazing beyond words and that makes the entire wait worth it. ", "At last I can check off the top item on my bucket list.", "\n\nSo, how was it? ", "I went out of my way to prepare for this concert, even if it meant getting ready and eating early so that nothing would come up to distract me, and that's what I always seem to do when I attend concerts that are general admission for everyone.", "\n\nWe arrived at The Opera House at a reasonable time and surprisingly there was no lineup except a few people hanging outside the doors, so we stood near them chatting for hours until it was time for all VIP attendees to go inside. ", "While most people went for the merchandise stand, I bolted straight for the stage, propped myself up in front center against the railing. ", "I did not budge for the rest of …\n\nI'm a passionate writer about all that I love and I like to be a different character from time to time. ", "I also have a vivid imagination and I do what makes me happy. ", "If other people like it, that's a plus." ]

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[ "Tuesday, September 4, 2012\n\nDaniele Lanzarotta is the author of YA paranormal novels, including the Imprinted Souls Series and Academy of the Fallen.", "\n\nShe has a bachelor's in business and finance and a MBA. ", "With only a few semesters left in school, Daniele started writing as a hobby, but it didn't take long for her to be consumed by her stories. ", "That is her passion, and she now has several projects under way.", "\n\nShe enjoys reading and writing young adult novels with just about any sort of paranormal or supernatural bent...vampires... ghosts... She also enjoys watching hockey, playing rock band, guitar hero and spending time with the family.", "\n\nMy first book was Imprinted Souls. ", "I started writing it in 2008, so I was 28/29… seems like yesterday. ", "I’m really not looking forward for this series to be over, but it is time…\n\nWhat genre are you most comfortable writing?", "\n\nDefinitely YA paranormal! ", "I just love how in this genre anything is possible. ", "I’ve actually tried to write a novel with no supernatural beings at all and next thing I knew… every single character ended up being something other than human.", "\n\nWhat would you say is your interesting writing quirk?", "\n\nI write out of order. ", "I usually write the last chapter first. *", "laughs * Even when I don’t know what is going to happen along the way, I always know how it will end.", "\n\nWhat does your family think of your writing?", "\n\nI guess it depends on whom you ask. *", "laughs * My daughter (8) loves it! ", "She tells everyone that I write books about vampires, ghosts, and angels.", "\n\nWhat were your feelings when your first novel was accepted/when you first saw the cover of the finished product?", "\n\nWell, everything happened so fast… but I was very excited about it. ", "I couldn’t wait until the moment when everyone would be able to read it! ", "The feeling when I saw the first book cover is the same as with every single one of my book covers. ", "I feel so anxious while waiting for that email attachment to open and then, I’m so in love with the cover that the first thing I want to do is to share it with everyone.", "\n\nWhy do you feel you had to tell this story?", "\n\nAcademy of the Fallen actually has a number of life lessons worked into the story… some that I relate to, being that I have quite a few things in common with Kayla. ", "I knew that I wanted to create a new world; a world in which a spoiled and materialistic girl would learn to value the things that should really matter. ", "Yes, there is a reason why Kayla is such a brat is Wide Awake. *", "winks*\n\nImprinted Souls is a complete different story. ", "I felt as if I had to tell this ‘fairy tale’ in which soul mates would be together no matter what, but things changed when the characters’ personalities took over and they decided to tell their own story.", "\n\nWhat was one of the most surprising things you learned in creating Academy of the Fallen?", "\n\nHmm I don’t think I can answer this question without giving something away. *", "laughs * Let’s just say that I was surprised to learn about one very unique type of fallen angel and what ‘he’ can do. ", "He will actually make an appearance in Nephilim, but you will truly know what he is and what he can do on the third book of the series.", "\n\nIf you could introduce Hunter to any character from another book, who would it be and why?", "\n\nI could actually answer this question about any of my characters, except for Hunter. ", "All he needs is Kayla…. ", "His entire world revolves around her. ", "Although, I guess he could benefit from meeting Daniel from the Fallen series. ", "I believe he could learn a thing or two from someone immortal who has been around for that long.", "\n\nDo you have plans for a new book? ", "Is this book part of a series?", "\n\nI have plans for lots of new books. ", "I’m always working on something new… sometimes, more than one at a time. ", "Right now I’m working on Shattered Souls, which is the final book in the Imprinted Souls series. ", "I also have plans for a spinoff series, the first book titled Venom… and then there is the Academy of the Fallen Series, which I’m still playing around with the outline, but there will be at least two more books… among other projects.", "\n\nWhich character was your favorite to write about? ", "What about the hardest to write about?", "\n\nAs much as I hate to pick favorites… *Sighs* That would be Imprinted Souls’ Nicholas. ", "He is such a fun character to play with… very sarcastic, unpredictable… The hardest is Imprinted Souls’ Lexi. ", "That character grew and changed so much throughout the series. ", "She is by far my most complex character. ", "Kayla from Academy of the Fallen is not that far behind. ", "Her being immature in Wide Awake was a big part of her personality and she does a lot of growing up in Nephilim.", "\n\nWhat chapter was the most memorable to write and why?", "\n\nWow. ", "In Academy of the Fallen, the most memorable was actually a chapter in Nephilim where Kayla learns the reason why Ethan (Hunter’s roommate) became one of the fallen. ", "That leads her to realize many things about this world that seem unfair. ", "Her mind is a lot more open after that and she becomes more willing to accept others. ", "My most memorable Imprinted Souls chapter is without a doubt, the one where you find out the truth about the real Nicholas Taylor.", "\n\nWhat question are you never asked in interviews but wish you were?", "\n\nIt would probably be whether I ever dream about my characters. *", "laughs* I have the weirdest dreams. ", "The first was when I started working on Academy of the Fallen… I had a dream with Imprinted Souls’ Nicholas and he was pissed off because I was spending too much time working on books that he was not a part of…\n\nIs there a song you could list as the theme song for your book or any of your characters?", "\n\nArms by Christina Perri – That is definitely Kayla and Hunter’s song! ", "Also by Christina Perri – Jars of Hearts is the perfect song for the Imprinted Souls series. ", "It actually fits various characters.", "\n\nWhich author would you love to co-author a book with?", "\n\nRichelle Mead. ", "I love her character development… her stories. ", "She is brilliant.", "\n\nThe Academy has always been the home of fallen angels and haunted humans, but that is about to change.", "\n\nHunter and Kayla, the immortal and the Nephilim, find themselves trapped in a place that they hate... with beings that they do not trust. ", "Inside the Academy they are surrounded by fallen ones... the screw-ups... Outside, the Academy is surrounded by demons and ghosts who are trying to get in, including an incubus who has a history of tormenting Kayla.", "\n\nAs Kayla is forced to learn about what she is... about what she was born to do, Hunter only has one thing in mind. ", "Hunter wants to get Kayla out of the Academy, but leaving the Academy's protection will put everything and everyone at risk... themselves included.", "\n\n\"In this world, there is a reason why the Fallen ones are getting a second chance. ", "They are all that is left to protect the human race!\"", "\n\nYou can purchaseNephilim at the following Retailers:\n\nAnd now, The Giveaways.", "\n\nThank you Dani for making this giveaway possible.", "\n\n3 Winners will receive one e-copy of Nephilim by Daniele Lanzarotta.4 Winners will received one Signed Bookmarks by Daniele Lanzarotta." ]

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[ "Q:\n\nHow to fix getActionBar method may produce java.lang.", "NullPointerException\n\nI am using a toolbar as my actionbar in an activity. ", " I am trying to add the method getActionBar().setDisplayHomeAsUpEnabled(true); to the Activity.java file for Up navigation for older devices.", "\nThe method produces the following error message in Android Studio:\n\nMethod invocation may produce java.lang.", "NullPointerException\n\nThe Up navigation on the toolbar works fine on newer devices...now I'm trying to figure out how to make sure it will work for older devices.", "\nPlease advise.", "\nFrom build.gradle:\ndependencies {\n compile \"com.android.support:appcompat-v7:22.1.0\"\n}\n\nFrom AndroidManifest.xml:\nandroid:theme=\"@style/Theme.", "AppCompat.", "NoActionBar.", "FullScreen\" \n\nFrom styles.xml\n<style name=\"Theme.", "AppCompat.", "NoActionBar.", "FullScreen\" parent=\"AppTheme\">\n<item name=\"android:windowNoTitle\">true</item>\n<item name=\"windowActionBar\">false</item>\n<item name=\"android:windowFullscreen\">true</item>\n\nfrom Activity.java\npublic class CardViewActivity extends AppCompatActivity {\n\n @Override\n protected void onCreate(Bundle savedInstanceState) {\n super.onCreate(savedInstanceState);\n setContentView(R.layout.cardviewinput);\n\n Toolbar toolbar = (Toolbar) findViewById(R.id.toolbar);\n\n if (toolbar !", "= null) {\n // Up navigation to the parent activity for 4.0 and earlier\n getActionBar().setDisplayHomeAsUpEnabled(true);\n toolbar.setNavigationIcon(R.drawable.ic_action_previous_item);\n toolbar.setNavigationOnClickListener(new View.", "OnClickListener() {\n @Override\n public void onClick(View v) {\n onBackPressed();\n }\n });\n }\n\n}\n\nA:\n\nActually Android Studio isn't showing you an \"error message\", it's just a warning.", "\nSome answers propose the use of an assertion, Dalvik runtime has assertion turned off by default, so you have to actually turn it on for it to actually do something. ", "In this case (assertion is turned off), what you're essentially doing is just tricking Android Studio to not show you the warning. ", "Also, I prefer not to use \"assert\" in production code.", "\nIn my opinion, what you should do is very simple.", "\nif(getActionBar() !", "= null){\n getActionBar().setDisplayHomeAsUpEnabled(true);\n}\n\nUpdate:\nIn case you're using the support library version of the Action Bar, you should replace getActionBar() with getSupportActionBar().", "\nif(getSupportActionBar() !", "= null){\n getSupportActionBar().setDisplayHomeAsUpEnabled(true);\n}\n\nA:\n\nFirst off, you need to set the toolbar as the support ActionBar.", "\nThen if you're certain it's going to be there all the time, just assert it as !", "= null. ", "This will tell the compiler it won't be null, so the null check passes.", "\n@Override\nprotected void onCreate(Bundle savedInstanceState)\n{\n super.onCreate(savedInstanceState);\n setContentView(R.layout.cardviewinput);\n\n Toolbar toolbar = (Toolbar) findViewById(R.id.toolbar);\n setSupportActionBar(toolbar);\n\n assert getSupportActionBar() !", "= null;\n getSupportActionBar().setDisplayHomeAsUpEnabled(true); // it's getSupportActionBar() if you're using AppCompatActivity, not getActionBar()\n}\n\nA:\n\nThank You Andrew for your answer.", "\nIf you have a Nav Drawer or something else that uses getSupportActionBar() you need to add assert getSupportActionBar() !", "= null;\nPeace,\nExample:\n@Override\npublic void setTitle(CharSequence title) {\n mTitle = title;\n assert getSupportActionBar() !", "= null;\n getSupportActionBar().setTitle(mTitle);\n}\n\n" ]

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[ "5-FACTOR MARKETING AUDIT (free)\n\nTag for\n\nChocolate Lovers If eight out of ten people love chocolate, what can we conclude? ", "That’s easy, two people out of ten didn’t hear the question! ", "When it comes to pleasing others on Valentines Day, a box of chocolates is a no brainer. “", "All you need is love. ", "But a little chocolate now and then doesn’t hurt” ~Charles M Schulz (www.brainyquote.com)…. ", "Continue Reading »\n\nUsually it is imagined that website development doesn’t require much skills and it is the simplest job on the earth, but blog/website development is an art and requires a lot of skill, techniques, quality of knowledge, passions, time to develop the website etc. ", "Professional website designers and blog developers not only help your readers/customers to stay on your website for longer but they also Continue Reading »\n\nThe word blog and its concept should no longer conjure images of the cyber geek; home alone on a Saturday night, the click-clack of keyboard rising to a raucous crescendo as rantings. ", "The blog has now evolved into an increasingly powerful online tool. ", "It has been known to propel contemporary writers, previously unknown, to new heights of fame, and spawn political geniuses, technological pioneers and even award-winning screenwriters. ", "And now, more and more, its power is being harnessed to promote online business; because it works. ", "Continue Reading »" ]

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[ "PEPTIDE 1 - IPAMORELIN\nIpamorelin is a growth hormone releasing peptide (GHRP) similar to GHRP2 and GHRP6 that was developed by Novo Nordisk. ", "It is a pentapeptide composed of 5 amino acids that causes a significant release of growth hormone ..\n\nPEPTIDE 1 - GHRP6\nGrowth Hormone Releasing Peptide (GHRP-6) is a peptide in the growth factor family. ", "It has strong effect on the release of Human Growth Hormone (HGH) in a specific and dose-related manner. ", "GHRP can be effectively used in the tr..\n\nBIOPEPTIDE FRAGMENT176-191\nLifetech-Labs is using the most refined technology in order to obtain the highest quality and purity FRAGMENT 176-191 Peptide.", "\nPEPTIDE FRAGMENT 176-191 SPECIFICATION DETAILS\nUni..\n\nBIOPEPTIDE IPAMORELIN\nLifetech-Labs is using the most refined technology in order to obtain the highest quality and purity Ipamorelin Peptide.", "\nPEPTIDE IPAMORELIN SPECIFICATION DETAILS\nUnit Size\n1.8 mg/vial.." ]

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[ "// Copyright 2012 The Go Authors. ", " All rights reserved.", "\n// Use of this source code is governed by a BSD-style\n// license that can be found in the LICENSE file.", "\n\npackage ipv4\n\nimport (\n\t\"net\"\n\t\"syscall\"\n\t\"time\"\n)\n\n// A Conn represents a network endpoint that uses the IPv4 transport.", "\n// It is used to control basic IP-level socket options such as TOS and\n// TTL.", "\ntype Conn struct {\n\tgenericOpt\n}\n\ntype genericOpt struct {\n\tnet.", "Conn\n}\n\nfunc (c *genericOpt) ok() bool { return c !", "= nil && c.Conn !", "= nil }\n\n// NewConn returns a new Conn.\nfunc NewConn(c net.", "Conn) *Conn {\n\treturn &Conn{\n\t\tgenericOpt: genericOpt{Conn: c},\n\t}\n}\n\n// A PacketConn represents a packet network endpoint that uses the\n// IPv4 transport. ", " It is used to control several IP-level socket\n// options including multicasting. ", " It also provides datagram based\n// network I/O methods specific to the IPv4 and higher layer protocols\n// such as UDP.", "\ntype PacketConn struct {\n\tgenericOpt\n\tdgramOpt\n\tpayloadHandler\n}\n\ntype dgramOpt struct {\n\tnet.", "PacketConn\n}\n\nfunc (c *dgramOpt) ok() bool { return c !", "= nil && c.PacketConn !", "= nil }\n\n// SetControlMessage sets the per packet IP-level socket options.", "\nfunc (c *PacketConn) SetControlMessage(cf ControlFlags, on bool) error {\n\tif !", "c.payloadHandler.ok() {\n\t\treturn syscall.", "EINVAL\n\t}\n\tfd, err := c.payloadHandler.sysfd()\n\tif err !", "= nil {\n\t\treturn err\n\t}\n\treturn setControlMessage(fd, &c.payloadHandler.rawOpt, cf, on)\n}\n\n// SetDeadline sets the read and write deadlines associated with the\n// endpoint.", "\nfunc (c *PacketConn) SetDeadline(t time.", "Time) error {\n\tif !", "c.payloadHandler.ok() {\n\t\treturn syscall.", "EINVAL\n\t}\n\treturn c.payloadHandler.", "PacketConn.", "SetDeadline(t)\n}\n\n// SetReadDeadline sets the read deadline associated with the\n// endpoint.", "\nfunc (c *PacketConn) SetReadDeadline(t time.", "Time) error {\n\tif !", "c.payloadHandler.ok() {\n\t\treturn syscall.", "EINVAL\n\t}\n\treturn c.payloadHandler.", "PacketConn.", "SetReadDeadline(t)\n}\n\n// SetWriteDeadline sets the write deadline associated with the\n// endpoint.", "\nfunc (c *PacketConn) SetWriteDeadline(t time.", "Time) error {\n\tif !", "c.payloadHandler.ok() {\n\t\treturn syscall.", "EINVAL\n\t}\n\treturn c.payloadHandler.", "PacketConn.", "SetWriteDeadline(t)\n}\n\n// Close closes the endpoint.", "\nfunc (c *PacketConn) Close() error {\n\tif !", "c.payloadHandler.ok() {\n\t\treturn syscall.", "EINVAL\n\t}\n\treturn c.payloadHandler.", "PacketConn.", "Close()\n}\n\n// NewPacketConn returns a new PacketConn using c as its underlying\n// transport.", "\nfunc NewPacketConn(c net.", "PacketConn) *PacketConn {\n\tp := &PacketConn{\n\t\tgenericOpt: genericOpt{Conn: c.(net.", "Conn)},\n\t\tdgramOpt: dgramOpt{PacketConn: c},\n\t\tpayloadHandler: payloadHandler{PacketConn: c},\n\t}\n\tif _, ok := c.(*net.", "IPConn); ok && sockOpts[ssoStripHeader].name > 0 {\n\t\tif fd, err := p.payloadHandler.sysfd(); err == nil {\n\t\t\tsetInt(fd, &sockOpts[ssoStripHeader], boolint(true))\n\t\t}\n\t}\n\treturn p\n}\n\n// A RawConn represents a packet network endpoint that uses the IPv4\n// transport. ", " It is used to control several IP-level socket options\n// including IPv4 header manipulation. ", " It also provides datagram\n// based network I/O methods specific to the IPv4 and higher layer\n// protocols that handle IPv4 datagram directly such as OSPF, GRE.", "\ntype RawConn struct {\n\tgenericOpt\n\tdgramOpt\n\tpacketHandler\n}\n\n// SetControlMessage sets the per packet IP-level socket options.", "\nfunc (c *RawConn) SetControlMessage(cf ControlFlags, on bool) error {\n\tif !", "c.packetHandler.ok() {\n\t\treturn syscall.", "EINVAL\n\t}\n\tfd, err := c.packetHandler.sysfd()\n\tif err !", "= nil {\n\t\treturn err\n\t}\n\treturn setControlMessage(fd, &c.packetHandler.rawOpt, cf, on)\n}\n\n// SetDeadline sets the read and write deadlines associated with the\n// endpoint.", "\nfunc (c *RawConn) SetDeadline(t time.", "Time) error {\n\tif !", "c.packetHandler.ok() {\n\t\treturn syscall.", "EINVAL\n\t}\n\treturn c.packetHandler.c.", "SetDeadline(t)\n}\n\n// SetReadDeadline sets the read deadline associated with the\n// endpoint.", "\nfunc (c *RawConn) SetReadDeadline(t time.", "Time) error {\n\tif !", "c.packetHandler.ok() {\n\t\treturn syscall.", "EINVAL\n\t}\n\treturn c.packetHandler.c.", "SetReadDeadline(t)\n}\n\n// SetWriteDeadline sets the write deadline associated with the\n// endpoint.", "\nfunc (c *RawConn) SetWriteDeadline(t time.", "Time) error {\n\tif !", "c.packetHandler.ok() {\n\t\treturn syscall.", "EINVAL\n\t}\n\treturn c.packetHandler.c.", "SetWriteDeadline(t)\n}\n\n// Close closes the endpoint.", "\nfunc (c *RawConn) Close() error {\n\tif !", "c.packetHandler.ok() {\n\t\treturn syscall.", "EINVAL\n\t}\n\treturn c.packetHandler.c.", "Close()\n}\n\n// NewRawConn returns a new RawConn using c as its underlying\n// transport.", "\nfunc NewRawConn(c net.", "PacketConn) (*RawConn, error) {\n\tr := &RawConn{\n\t\tgenericOpt: genericOpt{Conn: c.(net.", "Conn)},\n\t\tdgramOpt: dgramOpt{PacketConn: c},\n\t\tpacketHandler: packetHandler{c: c.(*net.", "IPConn)},\n\t}\n\tfd, err := r.packetHandler.sysfd()\n\tif err !", "= nil {\n\t\treturn nil, err\n\t}\n\tif err := setInt(fd, &sockOpts[ssoHeaderPrepend], boolint(true)); err !", "= nil {\n\t\treturn nil, err\n\t}\n\treturn r, nil\n}\n" ]

{ "pile_set_name": "Github" }

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[ " ___________\n\n No. ", "96-1566\n ___________\n\nRobert Rydell Williams, *\n *\n Plaintiff-Appellant, *\n * Appeal from the United States\n v. * District Court for the\n * District of Minnesota.", "\nUnited States of America, *\n *\n Defendant-Appellee. ", " *\n ___________\n\n Submitted: July 26, 1996\n\n Filed: October 22, 1996\n ___________\n\nBefore BOWMAN, BEAM, and LOKEN, Circuit Judges.", "\n ___________\n\n\nLOKEN, Circuit Judge.", "\n\n\n Federal inmate Robert Rydell Williams appeals the denial of his 28\nU.S.C. § 2255 motion for post-conviction relief. ", " Williams argues that his\n1988 conviction for violating 18 U.S.C. § 924(c)(1) must be set aside\nbecause jury instructions on the statutory phrase \"uses . . . ", "a firearm\"\nwere contrary to Bailey v. United States, 116 S. Ct. ", "501 (1995). ", " The\n 1\ndistrict court concluded that Williams cannot establish \"actual\nprejudice,\" as United States v. Frady, 456 U.S. 152, 170 (1982), requires.", "\nWe agree and therefore affirm.", "\n\n\n A defendant violates § 924(c)(1) if \"during and in relation to any\n. . . ", "drug trafficking crime . . . [", "he] uses or carries a firearm.\" ", " In\nBailey, the Supreme Court held that a conviction for\n\n\n\n\n 1\n The HONORABLE DAVID S. DOTY, United States District Judge for\nthe District of Minnesota.", "\n\f\"use\" of a firearm \"requires evidence sufficient to show an active\nemployment of the firearm by the defendant, a use that makes the firearm\nan operative factor in relation to the predicate offense.\" ", " \"Active\nemployment\" includes \"brandishing, displaying, bartering, striking with .", "\n. . ", "firing or attempting to fire, a firearm.\" ", " However, \"[a] defendant\ncannot be charged under 924(c)(1) merely for storing a weapon near drugs\nor drug proceeds.\" ", " 116 S. Ct. ", "at 505-08. ", " Bailey overruled our prior\ndecisions affirming § 924(c)(1) convictions of defendants who merely stored\nfirearms at their residences to protect drugs or proceeds. ", " See, e.g.,\nUnited States v. Harris, 10 F.3d 596, 597 (8th Cir. ", "1993), and cases cited.", "\n\n\n Williams's indictment charged him with two drug trafficking crimes\nand a § 924(c)(1) violation -- that he \"did knowingly and unlawfully use\nand carry a firearm, namely, a Smith & Wesson .38 caliber revolver . . .", "\nduring and in relation to a drug trafficking crime, namely, the knowing and\nintentional possession with intent to distribute of approximately ten grams\nof cocaine base.\" ", " A jury convicted Williams on all three counts, and we\naffirmed. ", " United States v. Williams, 895 F.2d 1202 (8th Cir. ", "1990).", "\nWilliams subsequently filed two unsuccessful § 2255 motions for post-\nconviction relief, one of which challenged the evidentiary sufficiency of\nhis § 924(c)(1) conviction.", "\n\n\n Williams's trial was conducted on the assumption that our pre-Bailey\ncases were the governing law of this circuit. ", " Therefore, Williams did not\nobject to the district court's jury instruction defining \"use\" of a firearm\nunder § 924(c)(1). ", " In other words, the jury instruction issue he now\nraises is procedurally defaulted.2\n\n\n\n\n 2\n This § 2255 motion is also both successive and abusive under\nMcCleskey v. Zant, 499 U.S. 467 (1991), but the government does not\ncontend that this affects our standard of review. ", "Likewise, we do\nnot consider whether Williams's claim is even cognizable under\n§ 2255 because the government has not raised the issue. ", " See\nAnderson v. United States, 25 F.3d 704 (8th Cir. ", "1994).", "\n\n -2-\n\fTo obtain post-conviction relief for an erroneous jury instruction to which\nno contemporaneous objection was made, Williams must show cause excusing\nhis procedural default and \"actual prejudice\" resulting from the alleged\nerror. ", " Frady, 456 U.S. at 168. ", " The actual prejudice standard is more\nrigorous than the showing required to establish plain error on direct\nappeal. ", " 456 U.S. at 166, quoting Henderson v. Kibbe, 431 U.S. 145, 154\n(1977); see Dalton v. United States, 862 F.2d 1307, 1309 (8th Cir. ", "1988).", "\nTo establish such prejudice, Williams must show that an erroneous jury\ninstruction \"worked to his actual and substantial disadvantage, infecting\nhis entire trial with error of constitutional dimensions.\" ", " 456 U.S. at 170\n(emphasis in original). ", " We conclude that he has failed to do so for the\nfollowing reasons.", "\n\n\n First, it is not clear to us that the district court's instruction\non \"use\" of a firearm was plain error under Bailey. ", " The court instructed\nthe jury:\n\n\n Two essential elements are required to be proved in order to\n establish an offense of using a firearm in relation to a drug\n trafficking crime. ", "They are as follows: First, that the defendant\n committed a drug trafficking crime for which he might be prosecuted\n in the United States Court; and second, that during the commission\n of the drug trafficking crime the defendant used a firearm.", "\n\n * * * * *\n\n The defendant is considered to have used a firearm if its presence\n in his possession in any manner facilitated carrying out the drug\n trafficking crime. ", "It is not necessary that the firearm be fired in\n order that it may be considered as having been used.", "\n\n\n The word \"facilitated\" in this instruction is more passive than the\nwords used in Bailey to describe the concept of \"active employment\" --\nbrandishing, displaying, bartering, striking with, firing. ", " But the\ninstruction is far more consistent with Bailey than the instruction that\ncaused us to reverse for plain error in\n\n\n\n\n -3-\n 3\n\fUnited States v. Webster, 84 F.3d 1056, 1066 (8th Cir. ", "1996). ", " An\ninstructional error must be of \"constitutional dimensions\" to warrant post-\nconviction relief under Frady. ", " That requires a showing that \"the ailing\ninstruction by itself so infected the entire trial that the resulting\nconviction violates due process, not merely [that] the instruction is\nundesirable, erroneous, or even universally condemned.\" ", " Henderson, 431\nU.S. at 154, quoting Cupp v. Naughten, 414 U.S. 141, 146-47 (1973). ", " While\nwe would not recommend using this instruction in a post-Bailey case, it\nprovides a very flimsy basis for post-conviction relief under Frady.", "\n\n\n Second, to establish actual prejudice from an instruction error,\nFrady requires that Williams show a \"substantial likelihood\" that a\nproperly instructed jury would have acquitted him of violating § 924(c)(1).", "\n456 U.S. at 172. ", " At trial, consistent with Williams's indictment, the\ndistrict court instructed the jury, \"[i]t is sufficient if the United\nStates proves either that firearms were used or carried. ", " Both do not have\nto be proved.\" ", " Thus, in considering prejudice under Frady, we must\nconsider whether the evidence was sufficient to convict Williams of a\n\"carry\" violation. ", " Williams argues that we should not assume the jury\nfound a \"carry\" violation because the instructions devoted more attention\nto defining \"use.\" ", " But the instructions, fairly read, explicitly and\nproperly gave the jury the option of finding a \"carry\" violation, so that\noption is part of the Frady analysis.", "\n\n\n Briefly summarized, the trial evidence was that, in January 1988,\npolice raided a fortified Minneapolis crack house by driving a front-end\nloader through an exterior wall and into the first floor apartment where\nWilliams resided. ", " In that apartment, they found personal items belonging\nto Williams, drug paraphernalia, an unloaded .38 caliber revolver under the\ncouch, and four .38 caliber bullets near the revolver. ", " Williams was\narrested after he broke a basement window, bent back the bars over that\nwindow, and attempted to escape. ", " Police later found forty \"chunks\" of\ncrack cocaine and\n\n\n\n\n -4-\n 4\n\f$1290 in the basement apartment from which Williams had fled. ", " His two\nconspirators were arrested in the building eight days later after resuming\nsales of crack cocaine.", "\n\n\n \"[T]o sustain a conviction for `carrying' a firearm in violation of\n§ 924(c)(1), the government must prove that [the accused] bore the firearm\non or about his person during and in relation to a drug trafficking\noffense.\" ", " United States v. White, 81 F.3d 80, 83 (8th Cir. ", "1996). ", " As the\nfacts in White make clear, a person who throws a gun down and flees the\nscene of a drug trafficking crime may be convicted of a \"carry\" violation.", "\nHere, the government presented evidence that Williams fled the scene of on-\ngoing crack cocaine distribution, leaving a firearm and bullets scattered\nin his apartment. ", " We agree with the district court that this evidence was\nsufficient to convict Williams of a § 924(c)(1) \"carry\" violation. ", " See\nUnited States v. Willis, 89 F.3d 1371, 1378-79 (8th Cir.), ", "cert. ", "denied,\n65 U.S.L.W. 3265 (U.S. Oct. 7, 1996). ", " Thus, Williams cannot prove actual\n 3\nprejudice under Frady.", "\n\n\n The district court order dated February 20, 1996, is affirmed.", "\n\n\n A true copy.", "\n\n\n Attest:\n\n\n CLERK, U. S. COURT OF APPEALS, EIGHTH CIRCUIT.", "\n\n\n\n\n 3\n We do not reach the question whether this evidence would also\nsupport a § 924(c)(1) \"use\" conviction. ", "Unlike this case, Bailey\ndid not involve a drug conspiracy. ", "But Williams's indictment did\nnot charge him with using the firearm during and in relation to his\nconspiracy offense. ", "Had it done so, we would face the question\nwhether Bailey leaves intact prior decisions such as United States\nv. Drew, 894 F.2d 965, 968 (8th Cir.), ", "cert. ", "denied, 494 U.S. 1089\n(1990), in which we affirmed a § 924(c)(1) \"use\" conviction because\nparticipants in a drug trafficking conspiracy regularly displayed\nguns to intimidate purchasers at a drug house.", "\n\n -5-\n 5\n\f" ]

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[ "##\n# This file is part of WhatWeb and may be subject to\n# redistribution and commercial restrictions. ", "Please see the WhatWeb\n# web site for more information on licensing and terms of use.", "\n# http://www.morningstarsecurity.com/research/whatweb\n##\n# Version 0.2 # 2011-03-06 #\n# Updated OS detection\n##\nPlugin.define \"Java\" do\nauthor \"Brendan Coles <bcoles@gmail.com>\" # 2011-01-28\nversion \"0.2\"\ndescription \"Java allows you to play online games, chat with people around the world, calculate your mortgage interest, and view images in 3D, just to name a few. ", "It's also integral to the intranet applications and other e-business solutions that are the foundation of corporate computing. - ", "homepage: http://www.java.com/\"\n\n# ShodanHQ results as at 2011-01-28 #\n#\t10,814 for X-Powered-By: JSP\n#\t153,488 for JSESSIONID\n#\t571 for java.vendor=Sun Microsystems Inc\n#\t47 for java.vendor=IBM Corporation\n#\t118 for \"x-powered-by\" JSP JRE\n#\t13950 for server JAVA\n\n\n\n# Passive #\ndef passive\n\tm=[]\n\n\t# JSESSIONID Cookie\n\tm << { :name=>\"JSESSIONID Cookie\" } if @headers[\"set-cookie\"] =~ /JSESSIONID=[^;]{0,32};[\\s]?path=\\//i\n\n\t# X-Powered-By # JSP Version Detection\n\tm << { :version=>@headers['x-powered-by'].scan(/JSP\\/([\\d\\.]+)/) } if @headers['x-powered-by'] =~ /JSP\\/([\\d\\.]+)/\n\t# X-Powered-By # Servlet Version Detection\n\tm << { :string=>@headers['x-powered-by'].scan(/(Servlet\\/[\\d\\.]+)/i) } if @headers['x-powered-by'] =~ /(Servlet\\/[\\d\\.]+)/i\n\t# X-Powered-By # JRE Version Detection\n\tm << { :string=>@headers['x-powered-by'].scan(/(JRE\\/[\\d\\.\\-\\_]+)/) } if @headers['x-powered-by'] =~ /(JRE\\/[\\d\\.\\-\\_]+)/\n\n\t# Server # Version Detection\n\tm << { :version=>@headers['server'].scan(/java\\/([\\d\\.\\-\\_]+)/) } if @headers['server'] =~ /java\\/([\\d\\.\\-\\_]+)/\n\t# Server # JDK Version Detection\n\tm << { :string=>@headers['server'].scan(/(JDK [\\d\\.\\-\\_]+)/) } if @headers['server'] =~ /(JDK [\\d\\.\\-\\_]+)/\n\n\t# Servlet-Engine\n\tif @headers['servlet-engine'] =~ /\\((.*?); (.*?); ", "Java (.*?); (.*?); ", "java.vendor=[^\\)]{0,50}\\)/\n\n\t\t# JSP Version Detection\n\t\tm << { :string=>@headers['servlet-engine'].scan(/\\((.*?); (.*?); ", "Java (.*?); (.*?); ", "java.vendor=[^\\)]{0,50}\\)/)[0][0] }\n\t\t# Servlet Version Detection\n\t\tm << { :string=>@headers['servlet-engine'].scan(/\\((.*?); (.*?); ", "Java (.*?); (.*?); ", "java.vendor=[^\\)]{0,50}\\)/)[0][1] }\n\t\t# Version Detection\n\t\tm << { :version=>@headers['servlet-engine'].scan(/\\((.*?); (.*?); ", "Java (.*?); (.*?); ", "java.vendor=[^\\)]{0,50}\\)/)[0][2] }\n\t\t# OS Detection\n\t\tm << { :os=>@headers['servlet-engine'].scan(/\\((.*?); (.*?); ", "Java (.*?); (.*?); ", "java.vendor=[^\\)]{0,50}\\)/)[0][3] }\n\n\tend\n\n\t# Return passive matches\n\tm\n\nend\n\nend\n\n" ]

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[ "Q:\n\nPython regex, searching for prefixes inside a target string\n\nI need to find a list of prefixes of words inside a target string (I would like to have the list of matching indexes in the target string handled as an array).", "\n\nI think using regex should be the cleanest way.", "\nGiven that I am looking for the pattern \"foo\", I would like to retrieve in the target string words like \"foo\", \"Foo\", \"fooing\", \"Fooing\"\nGiven that I am looking for the pattern \"foo bar\", I would like to retrieve in the target string patterns like \"foo bar\", \"Foo bar\", \"foo Bar\", \"foo baring\" (they are still all handled as prefixes, am I right?)", "\n\nAt the moment, after running it in different scenarios, my Python code still does not work.", "\n\nI am assuming I have to use ^ to match the beginning of a word in a target string (i.e. a prefix).", "\nI am assuming I have to use something like ^[fF] to be case insensitive with the first letter of my prefix.", "\nI am assuming I should use something like \".*\" ", "to let the regexp behave like a prefix.", "\nI am assuming I should use the \\prefix1|prefix2|prefix3** to put in **logic OR many different prefixes in the pattern to search.", "\n\nThe following source code does not work because I am wrongly setting the txt_pattern.", "\nimport re\n\n# ' ' ' ' ' ' '\ntxt_str = \"edb foooooo jkds Fooooooo kj fooing jdcnj Fooing ujndn ggng sxk foo baring sh foo Bar djw Foo\";\ntxt_pattern = ''#???", "\n\nout_obj = re.match(txt_pattern,txt_str)\nif out_obj:\n print \"match!\"", "\nelse:\n print \"No match!\"", "\n\nWhat am I missing?", "\nHow should I set the txt_pattern?", "\nCan you please suggest me a good tutorial with minimum working examples? ", "At the moment the standard tutorials from the first page of a Google search are very long and detailed, and not so simple to understand.", "\n\nThanks!", "\n\nA:\n\nI am assuming I have to use ^ to match the beginning of a word in a target string (i.e. a prefix).", "\n\nNo, the ^ is an anchor that only matches the start of the string. ", "You can use \\b instead, meaning a word boundary (but remember to escape the backslash inside a string literal, or use a raw string literal).", "\nYou will also have to use re.search instead of re.match because the latter only checks the start of the string, whereas the former searches for matches anywhere in the string.", "\n\nA:\n\n>>> s = 'Foooooo jkds Fooooooo kj fooing jdcnj Fooing ujndn ggng sxk foo baring sh foo Bar djw Foo'\n>>> regex = '((?", "i)(foo)(\\w+)?)'", "\n>>> compiled = re.compile(regex)\n>>> re.findall(compiled, s)\n[('Foooooo', 'Foo', 'oooo'), ('Fooooooo', 'Foo', 'ooooo'), ('fooing', 'foo', 'ing'), ('Fooing', 'Foo', 'ing'), ('foo', 'foo', ''), ('foo', 'foo', ''), ('Foo', 'Foo', '')]\n\n(?", "i) -> case insensitive\n(foo) -> group1 matches foo\n(\\w+) -> group2 matches every other word character \n>>> print [i[0] for i in re.findall(compiled, s)]\n['Foooooo', 'Fooooooo', 'fooing', 'Fooing', 'foo', 'foo', 'Foo']\n\nA:\n\nRegex is the wrong approach. ", "First parse your string into a list of strings with one word per item. ", "Then use a list comprehension with a filter. ", "The split method on strings is a good way to get the list of words, then you can simply do [item for item in wordlist if item.startswith(\"foo\")]\nPeople spend ages hacking up inefficient code using convoluted regexes when all they need is a few string methods like split, partition, startswith and some pythonic list comprehensions or generators.", "\nRegexes have their uses but simple string parsing is not one of them.", "\n\n" ]

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[ "Articles by Spencer Kosior\n\nAbout Spencer Kosior\n\nSpencer Kosior is a multi-faceted lifelong learner with a love of technology and novelty! ", "He works in broadcast as a writer, producer and videographer; helping bring to life stories for organizations like WCVB-TV and MIT." ]

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[ "Trial Of Alleged German Autobahn Shooter Begins\n\nEnlarge this image toggle caption Karl-Josef Hildenbrand/DPA /LANDOV Karl-Josef Hildenbrand/DPA /LANDOV\n\nThe trial of a 58-year-old truck driver who is accused of firing more than 700 shots at other vehicles on German highways over five years began today in the northern Bavarian city of Wuerzburg.", "\n\nThe man, who German media say was born in the former East Germany, was arrested at home in the small town of Kall in western Germany in June 2013. ", "He is being identified by the German media only by his first names and last initial – Michael Harry K. — in accordance with German laws.", "\n\nHe was briefly shown in the courtroom by German network N-TV as his trial began; a mustached brown-haired man wearing an earring and looking rather grim as the judges arrived.", "\n\nThe shooting incidents that mostly took place on highways in western and southern Germany resulted in only one serious injury: a 40-year-old businesswoman who was struck in the neck and crashed off the side of the road near the city where the defendant is now on trial. ", "She survived.", "\n\nProsecutors describe the defendant as a \"frustrated loner\" who they said talked about his \"war on German Autobahns\" or highways. ", "Michael Harry K., in several interviews with German media, claimed he only targeted cargo sections of vehicles.", "\n\nGerman authorities were lambasted for not catching him sooner. ", "But some critics now question whether police went too far in the steps they took to apprehend him.", "\n\nAt issue is whether investigators violated Germany's strict data-protection laws by checking GPS signals of drivers who were on specific highways when and where the attacks occurred, then matching up those signals to photographs taken by specially installed cameras on those highways.", "\n\nThe question may come up at trial, though the main goal of the three-judge panel at this stage is to determine whether the defendant should face attempted murder charges." ]

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[ "Farewell, California, I’ll miss you and I won’t miss you\n\n“He has three fewer children and one million [dollars] less. ", "Do you,” my young male passenger asked his female companion, “still want him to call you?” ", "He was, I assume, joking, but even as I kept my mouth firmly shut, I wasn’t laughing.", "\n\nThat attitude, that prosperity and romance go hand in hand and that they are for the young is driving me away from California, a place of incredible beauty that I will miss a great deal. ", "That beauty, of course, is what makes this a desirable place to live. ", "It is one reason high technology has located here, exacerbating an already high cost of living to such a degree that even the high tech companies are now expanding elsewhere.[1]\n\nThe hell of it is, I don’t really even know why I can’t find a job here. ", "Age discrimination is an obvious possible factor that I obviously can’t prove. ", "The fact that I haven’t held a real job in eighteen years is another. ", "That neither me nor my Ph.D. (the culmination of an education I returned to in that interim) pigeonhole neatly into a job description surely doesn’t help. ", "But not receiving any meaningful feedback (I’m lucky to receive a letter saying they found someone they think is a “better fit”), I really don’t know.", "\n\nWhatever the reason, I know that local resources aren’t helping. ", "The Sonoma County Job Link program offers the same strategy that has failed me for eighteen years straight. ", "And that’s all anyone tells me to do. “", "Keep applying,” they say. “", "It doesn’t work until it does.” ", "Or, “Something will come through.” ", "Or, “I’m sure there’s a niche for you somewhere.”", "\n\nThey’ve been saying that for eighteen years. ", "I will be sixty at the end of this month. ", "I was forty-two when I was laid off (with a warning even then that my age might be a problem). ", "The years that should have gone to building up a nest egg for retirement have been spent in futility instead. ", "A futile job search. ", "A futile Ph.D.\n\nDon’t even dare to ask me what I think of this society that so gleefully leaves me on the side of the road with the trash. ", "And spare me those platitudes.", "\n\nMoving to western Massachusetts, where I’ll have to come up with rent, where I’ll have to deal with real winters, is far from a certain solution. ", "But it is, apparently, a place where education and civic participation are valued.[2]\n\nIn California, what I see is a high technology arrogance that “big data” (mining even for spurious correlations) and “artificial intelligence” (idiocy, actually, heavily reliant on those spurious correlations) can solve all problems. ", "In this view, universities aren’t really for education, no matter what professors might think, but for networking; one should attend only until one finds people to start the next great tech company (which, if not great, will be bought out).", "\n\nElon Musk thinks you need to work eighty hours a week to change the world.[3] He’s wrong,[4] but folks around here carry on like he’s right—insanely long hours are a notorious part of start-up culture. ", "Even if such hours don’t actually lead to better productivity,[5] around here, “disruptive” “start-ups” are the closest thing you’ll find to a deity.", "\n\nAfter the dot-com crash, from which I have not recovered even after eighteen years, I’ve had quite enough disruption. ", "I know that the deification of “start-ups” does not mean they actually have business plans. ", "I know that their capitalist libertarian ideology in fact externalizes a lot of costs, including to accommodate ever worsening traffic, that they deny responsibility for. ", "And having been a computer programmer in my own young adulthood—and now a human scientist—I know their epistemology, they way they “know” what they claim to know, is fucked.", "\n\nIt’s all beyond challenge here. ", "And none of it is doing me any good. ", "Just like the job search strategy that has failed me miserably for eighteen years straight.", "\n\nMy mother won’t live forever. ", "But more than that, there’s no self-respect in living with one’s mother, to the admission that I am not self-supporting, especially at my age. ", "I have to go." ]

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[ "Samantha Vinograd on the lack of action taken against Russia for meddling in the US election: “[Trump] is not fulfilling his job as President … we’re under live attack, Wolf, and we’re doing nothing about it” pic.twitter.com/WpDL5Ybiy3\n\nOn Monday’s broadcast of CNN’s “Situation Room,” CNN National Security Analyst and former member of President Obama’s National Security Council Samantha Vinograd argued President Trump isn’t doing his job as president and is “so focused on his own narcissism, that we’re pointing fingers. ", "We’re stuck in the postgame here of what Obama did or didn’t do, rather than saying, ‘Okay, they meddled. ", "What are we going to do now?'”", "\n\nVinograd said, “It’s clear that he has a massive inferiority complex about how he won this election. ", "That’s clear from all of his tweets, every public statement that he makes. ", "And he’s not fulfilling his job as president, to state the obvious. ", "He’s so focused on his own narcissism, that we’re pointing fingers. ", "We’re stuck in the postgame here of what Obama did or didn’t do, rather than saying, ‘Okay, they meddled. ", "What are we going to do now?’ ", "We’re under live attack, Wolf, and we’re doing nothing about it.”", "\n\n(h/t Mediaite)\n\nFollow Ian Hanchett on Twitter @IanHanchett" ]

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[ "This week, we listened to Slate’s Gentleman Scholar advise a Miss Bianca on how to attract a writerly boyfriend. ", "Though his response was clever indeed, we’re not sure it was overly helpful, so we thought we’d lend a hand by going straight to the source, and finding out what writing men have to say about their ideal women. ", "Now, bear in mind: some of these quotes come from the mouths of characters, and as such must be taken with a grain of salt. ", "That said, we all know that everyone’s characters spring from some part of themselves, so their words bear repeating here. ", "Straight from the horse’s mouth, then: ten male writers on what they look for in a female mate after the jump. ", "Just be warned — the results may make you think twice about wanting to date a literary man.", "\n\n“The perfect woman, you see [is] a working-woman; not an idler; not a fine lady; but one who [uses] her hands and her head and her heart for the good of others.” — ", "Thomas Hardy\n\n“If there were no Frenchwomen, life wouldn’t be worth living.” — ", "Friedrich Engels, Collected Works\n\n“She was everything I wanted. ", "She was beautiful and charming, with a quick sense of humor, and she supported me in everything I did.” — ", "Nicholas Sparks, Message in a Bottle\n\n“She is a woman of honour and smartness whose wild leaves out luck, always taking risks, and there is something in her brow now, that only she can recognize in a mirror. ", "Ideal and idealistic in that shiny dark hair! ", "People fall in love with her. ", "She is a woman I don’t know well enough to hold in my wing, if writers have wings, to harbour for the rest of my life.” ― ", "Michael Ondaatje, The English Patient\n\n“You are the only woman who has a sense of gaiety, a wise tolerance — no more, you seem to urge me to betray you. ", "I love you for that. […] ", "I don’t know what to expect of you, but it is something in the way of a miracle. ", "I am going to demand everything of you — even the impossible, because you encourage it. ", "You are really strong. ", "I even like your deceit, your treachery. ", "It seems aristocratic to me.” — ", "Henry Miller to Anaïs Nin, A Literate Passion: Letters of Anaïs Nin & Henry Miller, 1932-1953\n\n“A goodlookin horse is like a goodlookin woman, he said. ", "They’re always more trouble than what they’re worth. ", "What a man needs is just one that will get the job done.” ― ", "Cormac McCarthy, All the Pretty Horses\n\n“you boys can keep your virgins give me hot old women in high heels with asses that forgot to get old.” ― ", "Charles Bukowski, Love is a Dog from Hell\n\n“…but till all graces be in one woman, one woman shall not come in my grace. ", "Rich she shall be, that’s certain; wise, or I’ll none; virtuous, or I’ll never cheapen her; fair, or I’ll never look on her; mild, or come not near me; noble, or not I for an angel; of good discourse, and excellent musician and her hair shall be of what colour it shall please God.” — ", "William Shakespeare, Much Ado About Nothing\n\n“A being breathing thoughtful breath, A traveller between life and death; The reason firm, the temperate will, Endurance, foresight, strength, and skill; A perfect Woman, nobly plann’d, To warn, to comfort, and command; And yet a Spirit still, and bright With something of angelic light.” — ", "William Wordsworth, “A Perfect Woman”\n\n“A perfect woman’s but a softer man.” — ", "Alexander Pope" ]

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[ "Mortgage Stress Test\n\nThestress test, which came into effect in January this year, now requires homebuyers with 20 percent down payment to demonstrate that they can withstand an interest rate increase of two percent points on their mortgage.", "\n\nThe regulations affect all six of Canada’s big banks, some provincial regulated lenders, like credit unions, are also voluntarily complying with the guidelines.", "\n\nBroadly speaking, the rules mean you may not be able to borrow as much as you would have been able to before the start of the year. ", "If you’re house hunting, you may have to settle for a less-expensive home. ", "If you’re renewing your mortgage, you may be forced to stay with your current lender. ", "This allows you to side-step the stress test but it also means you can’t shop around for a better mortgage. ", "And if you’re hoping to refinance, you may not be able to boost your loan by as much as you’d like – if at all.", "\n\nCanadians who can afford a down payment of 20 per cent or more are currently facing about $500 in monthly mortgage payments for every $100,000 of mortgage debt, assuming a 25-year amortization period. ", "The new rules mean they have to qualify as if their monthly payments were about $600 for every $100,000 worth of mortgage.", "\n\nIf you want to stress test your finances, ask yourself what would happen if you had to pay $600 a month for every $100,000 on your mortgage balance. ", "That’s a useful exercise regardless of whether or not you actually face the test, given that interest rates are rising.", "\n\nB.C. home sales decline blamed on mortgage stress test\n\nAt the tail end of a slow spring for B.C. real estate sales, 8,837 homes exchanged hands on the Multiple Listing Service in May, down 28.7 per cent from May 2017, the British Columbia Real Estate Association (BCREA) reported June 15.", "\n\nEach of the 11 real estate boards across the province that make up the BCREA’s monthly report cited annual sales declines. ", "These range from the relatively minor 6.3 per cent year-over-year decrease seen in the B.C. Northern area that includes Prince George, up to 38.9 per cent down from last year, in Powell River. ", "However, Powell River’s market is small and therefore subject to wide percentage variations, so this does not indicate a trend. ", "Of the larger markets, the Fraser Valley saw the biggest annual decline, down 34.8 per cent." ]

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[ "Lib Dem membership has passed the 100,000 mark following a surge of new joiners since Theresa May announced a snap general election.", "\n\nThe party said it has signed up 12,500 new members since last week - and is expected to reach its highest total in its history \"within days\".", "\n\nLeader Tim Farron said Lib Dems are the only party opposing Mrs May's \"hard Brexit agenda\".", "\n\nHe insisted the party would not enter a coalition with the Tories or Labour.", "\n\nThe biggest membership number the Lib Dems have had since their formation was 101,768 members in 1994.", "\n\nThe recent flurry of interest means more than 50,000 members have joined since last year's European referendum - and more than 67,500 since the party's electoral low point, at the 2015 general election.", "\n\nMr Farron, who pledged to build the membership to 100,000 when he became leader in 2015, said reaching the goal \"tells us that there's an appetite for change in British politics and Liberal Democrats are the vehicle for that change\".", "\n\nHe said: \"People want a strong opposition to Theresa May's hard Brexit agenda and the Liberal Democrats are the only party challenging them up and down the country.\"", "\n\nIn an appeal to would-be supporters, he said: \"This election is your chance to change the direction of our country. ", "If you want to stop a disastrous hard Brexit, if you want to keep Britain in the single market, if you want a strong opposition to fight for an open, tolerant and united Britain - this is your chance.\"", "\n\nThe Lib Dem leader also repeated his insistence that there are \"no circumstances whatsoever\" that the party will go in to a coalition with the Conservatives or Labour after the 8 June election, given the current approaches of those two parties.", "\n\nHe also dismissed an informal arrangement to offer his party's support on budget measures and other key votes to help a minority Tory or Labour administration.", "\n\nOn Sunday he told ITV's Peston on Sunday: \"What Britain needs in this election is clarity and a contest. ", "Theresa May has called this election because she believes it'll be a coronation.", "\n\n\"The Liberal Democrats are determined to make it a contest with a clear alternative position, and I don't want people thinking a vote for the Liberal Democrats is a proxy for anything else.\"" ]

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[ "Liuhang station\n\nLiuhang () is a station on Line 7 of the Shanghai Metro, located in Baoshan District. ", "It opened on June 30, 2011.", "\n\nReferences\n\nCategory:Railway stations in Shanghai\nCategory:Line 7, Shanghai Metro\nCategory:Shanghai Metro stations in Baoshan District\nCategory:Railway stations opened in 2011\nCategory:2011 establishments in China" ]

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

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[ "\n\nBuilding the Next New York Times Recommendation Engine - jprob\nhttp://open.blogs.nytimes.com//2015/08/11/building-the-next-new-york-times-recommendation-engine/\n\n======\nflashman\nI'm really impressed that NYT took the time to document this. ", "It's always\ninteresting to see the different recommendation models evaluated and applied\nto real-world situations.", "\n\nI've been pursuing a collaborative filtering approach to product\nrecommendation lately ('people who bought this also bought that'), but perhaps\nLDA would let me model our products based on their metadata ('people who\nbought products broadly like this also bought products broadly like that').", "\n\n------\nmuktabh\nWe make a contextual recommendation engine as a service for online publishers\nat our startup ParallelDots. ", "We discovered the problem of tags not really\nworking well for recommendations on our clients websites too. ", "We ended up\nusing unsupervised word embeddings and auto encoders on top of them to solve\nthe problem. ", "We dont still use it for personalization though, just\ncontextually similar articles. ", "Great seeing some of similar problems being\nsolved at New York Times too. :)", "\n\n------\nThomPete\nThe way I see it, the primary thing to solve for any recommendation engine is\nto optimize for serendipity. ", "I.e. allowing you to get information you didn't\nknow you wanted.", "\n\nThis means basically also finding ex. ", "articles that are not written by NYT.", "\n\nNewspapers problem is that their primarily omnibus approach to whats relevant\nisn't really doing the waste amount of insightful information available that\nexist out there.", "\n\nSo the whole issue IMO with all newspapers/media these days. ", "They are building\nsilos where none should really exist and this is one of the primary the reason\nwhy people don't consider it valuable anymore.", "\n\n~~~\nvolaski\nMaybe you had no idea but what you describe already exists in the form of\nnative ads and recommendation widgets like outbrain. ", "And here's what I do when\nI run into them: I rarely click them. ", "When I'm on NYT, I don't want to click\nout to some \"recommended\" website that doesn't have high journalism integrity\nas NYT (Let's not get into a needless argument of whether that itself is\ncorrect or not). ", "My point is, I disagree with your argument that \"different\nsource\" has anything to do with serendipity. ", "Also you say silo shouldn't exist\nbut I don't see a reason why. ", "Sure there are clearly cases where certain\ncompanies siloing up their user's data is bad for humanity, but in this case\nit doesn't even make sense (what even is \"silo\" in this context anyway?).", "\nPeople create silos because of demand. ", "Imagine if NYT started opening up and\nlet any random guy on the web write articles on their front page, what did\nthey gain by \"opening up\" their silo? ", "Most readers of NYT are there exactly\nbecause it's a silo that guarantees certain degree of quality. ", "Once they start\n\"opening up\", you'll probably be the first to say \"yeah New york times is done\nnow, it's all low quality now\"\n\n~~~\nThomPete\nI don't think we are talking about the same thing.", "\n\nTo get sense of where I am coming from i would like to refer to some of my\nwriting on the subject.", "\n\n[http://000fff.org/#/slaves-of-the-feed-this-is-not-the-\nrealt...](http://000fff.org/#/slaves-of-the-feed-this-is-not-the-realtime-\nweve-been-looking-for)\n\nand\n\n[http://000fff.org/#/how-to-think-like-facebook-and-\ntwitter](http://000fff.org/#/how-to-think-like-facebook-and-twitter)\n\nIt's about something slightly different than what you seem to imply, sorry if\nthat was imprecise.", "\n\n------\nbcaine\nFun read. ", "Topic modeling can be fascinating to work with.", "\n\nCurious how they measured performance of their model, and whether they found a\n\"best\" number of topics for LDA where their model stopped getting much benefit\nby having more topics.", "\n\nI'd imagine increased number of topics would have some interesting side\neffects where it would create too narrow of recommendations.", "\n\n------\ndoppenhe\nWe have built this and anybody can use it\n[https://Algorithmia.com/recommends](https://Algorithmia.com/recommends). ", "2\nlines of js to implement.", "Currently serving the geekwire.com recs. ", "You can also\nmodify it further (see blog.Algorithmia.com).", "\n\nThe article is awesome though good on NYT.", "\n\n~~~\nbydamn989\nNice product you have there. ", "Not only did it take 10 minutes to run, it also\nmanaged to return no results.", "\n\n~~~\ndoppenhe\nThat should not be the case, sorry you had a not great experience. ", "Please\nshare the url you used at Diego at Algorithmia for com so we can debug and get\nback to you.", "\n\n------\nersii\nI think it'd be great if you'd have this kind of information in your help\nsection later on, for anxious people like me who are very wary of even having\na recommendation engine at a news paper. ", "I was actually on my way to sign up\nfor a subscription after reading \"A Renegade Trawler, Hunted for 10,000 Miles\nby Vigilantes\" by Ian Urbina - but held back for the moment to give it more\nthought.", "\n\nThat said, I guess I could see a point in it maybe retaining users /\nsubscribers if it's good enough. (", "I'd still appreciated it a lot more if this\nfunctionality could be turned off for users who request it though).", "\n\n~~~\nbuckbova\nMy first reaction to your comment is that you're overreacting and targeted\nnews stories based in topics you enjoy is a great thing.", "\n\nBut after some thought on the recommendation engine, this seems more like a\nconfirmation bias engine. ", "Not something I'd want from a \"news\" source.", "\n\n~~~\nuntog\nI'm not really how it would be confirmation bias. ", "The NYT doesn't have\nmultiple stories on the same topic with differing conclusions that it A/B\ntests with.", "\n\nAs the article states, it'll suggest articles about Hillary Clinton if you've\nread articles about her previously, but it doesn't say it'll only give you\npositive ones. ", "There _is_ a chance that it'll narrow people's interests (if\nyou only read sports, for example) but that already happens anyway.", "\n\n" ]

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[ "Q:\n\nValgrind reporting memory leaks in many places that change between runs\n\nI am creating a linked list but I keep getting memory leaks. ", "Sometimes it says the problem is in the at() function and sometimes in the remove() function, but it all looks pretty tight to me. ", "What is causing memory leaks?", "\nHere is my code for the linked list:\nvoid LinkedList::insertHead(int value)\n{\n if (value < 0) {\n return;\n }\n iterator pos(this, head);\n for (int i = 0; i < num_items; i++) {\n if (pos.current->data == value)\n return;\n else\n pos++;\n }\n head = new Node(value, NULL, head);\n if (head->next !", "= NULL)\n head->next->prev = head;\n if (tail == NULL)\n tail = head;\n num_items++;\n}\n\nvoid LinkedList::insertTail(int value)\n{\n if (value < 0) {\n return;\n }\n iterator pos(this, head);\n for (int i = 0; i < num_items; i++) {\n if (pos.current->data == value)\n return;\n else\n pos++;\n }\n if (tail !", "= NULL) {\n tail->next = new Node(value, tail, NULL);\n tail = tail->next;\n num_items++;\n } else\n insertHead(value);\n}\n\nvoid LinkedList::insertAfter(int value, int insertionNode)\n{\n if (value < 0) {\n return;\n }\n iterator pos(this, head);\n for (int i = 0; i < num_items; i++) {\n if (pos.current->data == value)\n return;\n else\n pos++;\n }\n pos = iterator(this, head);\n for (int i = 0; i < num_items; i++) {\n if (pos.current->data == insertionNode)\n break;\n else\n pos++;\n }\n if (pos.current == NULL || pos.current->data !", "= insertionNode) {\n return;\n } /*else if(pos.current==NULL)\n insertTail(value);*/\n else {\n Node *new_node = new Node(value, pos.current, pos.current->next);\n if (pos.current->next !", "= NULL)\n pos.current->next->prev = new_node;\n pos.current->next = new_node;\n num_items++;\n }\n\n}\n\nvoid LinkedList::remove(int value)\n{\n if (value < 0) {\n return;\n }\n iterator pos(this, head);\n for (int i = 0; i < num_items; i++) {\n if (pos.current->data == value)\n break;\n else\n pos++;\n }\n if (pos.current->data !", "= value) {\n return;\n }\n if (pos.current == head) {\n Node *removed_node = head;\n head = head->next;\n delete removed_node;\n if (head !", "= NULL)\n head->prev = NULL;\n else\n tail = NULL;\n num_items--;\n } else if (pos.current == tail) {\n Node *removed_node = tail;\n tail = tail->prev;\n delete removed_node;\n if (tail !", "= NULL)\n tail->next = NULL;\n else\n head = NULL;\n num_items--;\n } else {\n Node *removed_node = pos.current;\n removed_node->prev->next = removed_node->next;\n removed_node->next->prev = removed_node->prev;\n delete removed_node;\n num_items--;\n }\n}\n\nvoid LinkedList::clear()\n{\n if (num_items == 0)\n return;\n if (head !", "= NULL)\n remove(head->data);\n num_items = 0;\n}\n\nint LinkedList::at(int index)\n{\n if (index < 0 || index >= num_items)\n return -1;\n iterator pos(this, head);\n for (int i = 0; i < index; i++)\n pos++;\n return pos.current->data;\n}\n\nint LinkedList::size()\n{\n return num_items;\n}\n\nHere is code for the iterator:\nclass iterator {\n friend class LinkedList;\nprivate:\n LinkedList * parent;\n Node *current;\n iterator(LinkedList * my_parent, Node * position):parent(my_parent),\n current(position) {\n }\npublic:\n int &operator*() const {\n if (current == NULL)\n throw \"Attempt to dereference end()\";\n return current->data;\n }\n\n int *operator->() const {\n if (current == NULL)\n throw \"attempt to dereference end()\";\n return &(current->data);\n }\n\n iterator & operator++() {\n if (current == NULL)\n throw \"Attempt to advance past end()\";\n current = current->next;\n return *this;\n }\n\n iterator & operator--() {\n if (current == parent->head)\n throw \"Attempt to move before begin()\";\n if (current == NULL)\n current = parent->tail;\n else\n current = current->prev;\n return *this;\n }\n\n iterator operator++(int) {\n iterator return_value = *this;\n ++(*this);\n return return_value;\n }\n\n iterator operator--(int) {\n iterator return_value = *this;\n --(*this);\n return return_value;\n }\n\n bool operator==(const iterator & other) {\n return current == other.current;\n }\n\n bool operator!=(const iterator & other) {\n return !", "operator==(other);\n }\n};\n\noutput as requested:\n==18072== Invalid read of size 4\n==18072== at 0x402556: LinkedList::remove(int) (LinkedList.cpp:115)\n==18072== by 0x405946: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== Address 0x0 is not stack'd, malloc'd or (recently) free'd\n==18072== \nsegmentation fault\nThis segmentation fault was most likely caused by insertHead(), insertTail(), insertAfter(), or remove()\n==18072== \n==18072== HEAP SUMMARY:\n==18072== in use at exit: 4,074 bytes in 118 blocks\n==18072== total heap usage: 981 allocs, 863 frees, 158,945 bytes allocated\n==18072== \n==18072== 16 bytes in 1 blocks are still reachable in loss record 1 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x405888: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 32 bytes in 1 blocks are still reachable in loss record 2 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x4020B2: Factory::getLinkedList() (Factory.cpp:21)\n==18072== by 0x40587B: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 32 bytes in 2 blocks are still reachable in loss record 3 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x407AC5: TADuck::insertHead(int) (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x405D91: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 48 bytes in 2 blocks are still reachable in loss record 4 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x4021F1: LinkedList::insertHead(int) (LinkedList.cpp:20)\n==18072== by 0x405D84: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 48 bytes in 2 blocks are indirectly lost in loss record 5 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x40247A: LinkedList::insertAfter(int, int) (LinkedList.cpp:88)\n==18072== by 0x405137: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 192 bytes in 8 blocks are indirectly lost in loss record 6 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x402308: LinkedList::insertTail(int) (LinkedList.cpp:47)\n==18072== by 0x404D9F: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 216 bytes in 9 blocks are indirectly lost in loss record 7 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x4021F1: LinkedList::insertHead(int) (LinkedList.cpp:20)\n==18072== by 0x404341: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 216 bytes in 9 blocks are indirectly lost in loss record 8 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x4021F1: LinkedList::insertHead(int) (LinkedList.cpp:20)\n==18072== by 0x404BAD: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 240 bytes in 10 blocks are indirectly lost in loss record 9 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x402308: LinkedList::insertTail(int) (LinkedList.cpp:47)\n==18072== by 0x4046B1: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 240 bytes in 10 blocks are indirectly lost in loss record 10 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x40247A: LinkedList::insertAfter(int, int) (LinkedList.cpp:88)\n==18072== by 0x404897: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 256 bytes in 1 blocks are still reachable in loss record 11 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x4074AD: std::vector<int, std::allocator<int> >::_M_insert_aux(__gnu_cxx::__normal_iterator<int*, std::vector<int, std::allocator<int> > >, int const&) (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x402B7C: fillMasterList(std::vector<int, std::allocator<int> >&, int) (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x404B82: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 432 bytes in 18 blocks are indirectly lost in loss record 12 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x4021F1: LinkedList::insertHead(int) (LinkedList.cpp:20)\n==18072== by 0x402BFD: initList(LinkedListInterface*, LinkedListInterface*) (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x403F78: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 456 bytes in 19 blocks are indirectly lost in loss record 13 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x4021F1: LinkedList::insertHead(int) (LinkedList.cpp:20)\n==18072== by 0x4039E9: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 480 bytes in 20 blocks are indirectly lost in loss record 14 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x4021F1: LinkedList::insertHead(int) (LinkedList.cpp:20)\n==18072== by 0x402BFD: initList(LinkedListInterface*, LinkedListInterface*) (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x4040DF: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 480 (24 direct, 456 indirect) bytes in 1 blocks are definitely lost in loss record 15 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x4021F1: LinkedList::insertHead(int) (LinkedList.cpp:20)\n==18072== by 0x4039E9: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 480 (24 direct, 456 indirect) bytes in 1 blocks are definitely lost in loss record 16 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x4021F1: LinkedList::insertHead(int) (LinkedList.cpp:20)\n==18072== by 0x402374: LinkedList::insertTail(int) (LinkedList.cpp:52)\n==18072== by 0x404D9F: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 537 bytes in 1 blocks are possibly lost in loss record 17 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x38C88B9F48: std::string::_Rep::_S_create(unsigned long, unsigned long, std::allocator<char> const&) (in /usr/lib64/libstdc++.so.6.0.18)\n==18072== by 0x38C88BAB1A: std::string::_Rep::_M_clone(std::allocator<char> const&, unsigned long) (in /usr/lib64/libstdc++.so.6.0.18)\n==18072== by 0x38C88BABB3: std::string::reserve(unsigned long) (in /usr/lib64/libstdc++.so.6.0.18)\n==18072== by 0x38C8898F75: std::basic_stringbuf<char, std::char_traits<char>, std::allocator<char> >::overflow(int) (in /usr/lib64/libstdc++.so.6.0.18)\n==18072== by 0x38C889D195: std::basic_streambuf<char, std::char_traits<char> >::xsputn(char const*, long) (in /usr/lib64/libstdc++.so.6.0.18)\n==18072== by 0x38C88949A4: std::basic_ostream<char, std::char_traits<char> >& std::__ostream_insert<char, std::char_traits<char> >(std::basic_ostream<char, std::char_traits<char> >&, char const*, long) (in /usr/lib64/libstdc++.so.6.0.18)\n==18072== by 0x4036B6: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 537 bytes in 1 blocks are possibly lost in loss record 18 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x38C88B9F48: std::string::_Rep::_S_create(unsigned long, unsigned long, std::allocator<char> const&) (in /usr/lib64/libstdc++.so.6.0.18)\n==18072== by 0x38C88BAB1A: std::string::_Rep::_M_clone(std::allocator<char> const&, unsigned long) (in /usr/lib64/libstdc++.so.6.0.18)\n==18072== by 0x38C88BABB3: std::string::reserve(unsigned long) (in /usr/lib64/libstdc++.so.6.0.18)\n==18072== by 0x38C8898F75: std::basic_stringbuf<char, std::char_traits<char>, std::allocator<char> >::overflow(int) (in /usr/lib64/libstdc++.so.6.0.18)\n==18072== by 0x38C889D195: std::basic_streambuf<char, std::char_traits<char> >::xsputn(char const*, long) (in /usr/lib64/libstdc++.so.6.0.18)\n==18072== by 0x38C88949A4: std::basic_ostream<char, std::char_traits<char> >& std::__ostream_insert<char, std::char_traits<char> >(std::basic_ostream<char, std::char_traits<char> >&, char const*, long) (in /usr/lib64/libstdc++.so.6.0.18)\n==18072== by 0x403A7C: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 720 (24 direct, 696 indirect) bytes in 1 blocks are definitely lost in loss record 19 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x4021F1: LinkedList::insertHead(int) (LinkedList.cpp:20)\n==18072== by 0x404341: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== 936 (24 direct, 912 indirect) bytes in 1 blocks are definitely lost in loss record 20 of 20\n==18072== at 0x4A068F3: operator new(unsigned long) (in /usr/lib64/valgrind/vgpreload_memcheck-amd64-linux.so)\n==18072== by 0x4021F1: LinkedList::insertHead(int) (LinkedList.cpp:20)\n==18072== by 0x402BFD: initList(LinkedListInterface*, LinkedListInterface*) (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x403F78: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== \n==18072== LEAK SUMMARY:\n==18072== definitely lost: 96 bytes in 4 blocks\n==18072== indirectly lost: 2,520 bytes in 105 blocks\n==18072== possibly lost: 1,074 bytes in 2 blocks\n==18072== still reachable: 384 bytes in 7 blocks\n==18072== suppressed: 0 bytes in 0 blocks\n==18072== \n==18072== For counts of detected and suppressed errors, rerun with: -v\n==18072== ERROR SUMMARY: 7 errors from 7 contexts (suppressed: 2 from 2)\n\nA:\n\nYour valgrind output is reporting memory leaks. ", "However, those can be ignored for now because your program suffered a segmentation fault as a result of an invalid read on memory location 0x0:\n==18072== Invalid read of size 4\n==18072== at 0x402556: LinkedList::remove(int) (LinkedList.cpp:115)\n==18072== by 0x405946: testAll() (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== by 0x401E81: main (in /users/guest/s/scalen/Desktop/To Students/dont_run_me)\n==18072== Address 0x0 is not stack'd, malloc'd or (recently) free'd\n\nsegmentation fault\n\nYou need to find where line 115 is and figure out why the code is trying to deference an invalid memory location. ", "As an example, I will illustrate with the first one I found (I don't know if this is the one that valgrind is complaining about or not, since I do not know what the line numbers are for your code):\n for (int i = 0; i < num_items; i++) {\n if (pos.current->data == value)\n break;\n else\n pos++;\n }\n if (pos.current->data !", "= value) {\n return;\n }\n\nIn the case that there is no match for value, it seems unlikely that pos.current will point to a meaningful entry. ", "So dereferencing it to check if it doesn't match for the early return is probably the wrong thing to do. ", "Instead, check if the for loop actually made it through the entire list:\n int i;\n for (i = 0; i < num_items; i++) {\n //...\n }\n if (i == num_items) {\n return;\n }\n\nAs you encounter the errors reported in valgrind, address the segmentation faults first, then the Invalid reads or Invalid writes, then the memory leaks.", "\n\nFrom your comment, you seemed a little stumped on the process of debugging. ", "This question was about memory leaks, but that turned out to be a symptom of a crash. ", "Hopefully, this answer has helped you to understand a bit better how to understand the output that valgrind reports, but you should spend some time going over its documentation so that you are able to extract the maximum amount of information from it that you can. ", "To that end, your issue has been addressed. ", "However, let me expand this answer slightly to discuss a little bit about debugging.", "\nDebugging is simply a problem solving exercise, and being good at it is a skill. ", "It is a process that can be likened to solving a crime or a mystery, so debugging is when a programmer gets to be the detective. ", "As with most human endeavors, there are people who are much better at debugging than others. ", "But anyone can become a skillful debugger, because it is also true that you can become better a debugging with practice.", "\nI studied a lot of math during high school and college, so I am biased in the belief that debugging is very similar to solving a mathematical problem. ", "With time, you gain an intuition as to how to drive yourself to the solution more quickly, but at a high level, the process I take largely follows the steps laid out by George Polya in his book How to Solve It.", "\n\nFirst: Understand the problem. ", "What is the input? ", "What is the output? ", "What output is the program expected to produce? ", "What assumptions and preconditions are required by your program? ", "Have all those conditions been satisfied?", "\nSecond: Devise a plan. ", "Is the problem new or is it similar to a problem you have faced in the past? ", "Is there a relationship between the aberrant result and a particular part of your program? ", "What assumptions and preconditions are required by that part of your program for it to behave correctly? ", "Are you able to test those conditions?", "\nThird: Carry out the plan. ", "If the problem is not new, resolve the issue by applying a fix similar to what you had done before if possible. ", "Otherwise, inspect the state of the program step by step to make sure all the assumptions and preconditions are being satisfied. ", "Determine at what point the program behavior deviate from what it should have done. ", "At the point of deviation, understand the cause of the deviation, and take the appropriate corrective action.", "\nFourth: Looking back. ", "After the program has been corrected, take the steps needed to convince yourself that the fix is correct. ", "Whatever tests that had passed in the past should still pass. ", "Whatever test had caused the failure should now pass. ", "Identify new tests that may expose other weaknesses in that part of the code. ", "Understand why the problem was introduced, and think of ways that you can change how you write programs in the future that will either make it less likely to make the same error, or make the cause of the problem easier to identify.", "\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ { "analysis_explanation": null, "end": 4113, "entity_type": "PERSON", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 4100 }, { "analysis_explanation": null, "end": 5341, "entity_type": "PERSON", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 5330 }, { "analysis_explanation": null, "end": 20712, "entity_type": "PERSON", "recognition_metadata": { "recognizer_identifier": "SpacyRecognizer_140094861343280", "recognizer_name": "SpacyRecognizer" }, "score": 0.85, "start": 20700 }, { "analysis_explanation": null, "end": 353, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 351 }, { "analysis_explanation": null, "end": 772, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 770 }, { "analysis_explanation": null, "end": 1190, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 1188 }, { "analysis_explanation": null, "end": 2035, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 2033 }, { "analysis_explanation": null, "end": 3054, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 3052 }, { "analysis_explanation": null, "end": 3193, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 3191 }, { "analysis_explanation": null, "end": 3399, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 3397 }, { "analysis_explanation": null, "end": 4935, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 4933 }, { "analysis_explanation": null, "end": 6143, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 6141 }, { "analysis_explanation": null, "end": 6594, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 6592 }, { "analysis_explanation": null, "end": 7091, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 7089 }, { "analysis_explanation": null, "end": 7549, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 7547 }, { "analysis_explanation": null, "end": 8014, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 8012 }, { "analysis_explanation": null, "end": 8473, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 8471 }, { "analysis_explanation": null, "end": 8932, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 8930 }, { "analysis_explanation": null, "end": 9392, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 9390 }, { "analysis_explanation": null, "end": 9853, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 9851 }, { "analysis_explanation": null, "end": 10312, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 10310 }, { "analysis_explanation": null, "end": 10329, "entity_type": "IP_ADDRESS", "recognition_metadata": { "recognizer_identifier": "IpRecognizer_140094861343856", "recognizer_name": "IpRecognizer" }, "score": 0.6, "start": 10327 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[ "# SPDX-License-Identifier: GPL-2.0-only\n#\n# Makefile for ALSA\n# Copyright (c) 2001 by Jaroslav Kysela <perex@perex.cz>\n#\n\nsnd-ali5451-objs := ali5451.o\n\n# Toplevel Module Dependency\nobj-$(CONFIG_SND_ALI5451) += snd-ali5451.o\n" ]

{ "pile_set_name": "Github" }

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[ "Short-, medium-, and long-chain chlorinated paraffins in South African indoor dust and cat hair.", "\nPolychlorinated n-alkanes or chlorinated paraffins (CPs) contain a magnitude of structural isomers and are categorized as short-chain (SCCPs), medium-chain (MCCPs), and long-chain (LCCPs) CPs, according to the carbon chain lengths. ", "In this study the ƩSCCPs, ƩMCCPs, and ƩLCCP concentrations are reported for South African indoor dust and pet cat hair. ", "The median concentrations of the ƩCPs (C9-C37) ranged from 33 to 663 μg/g for freshly collected dust (FD), 36-488 μg/g for dust collected from household vacuum cleaner bags (VD), and 1.2-15 μg/g for cat hair (CH) samples. ", "MCCPs were the dominant CP group, followed by SCCPs and LCCPs. ", "The ƩMCCP concentration ranged from 13 to 498 μg/g in dust and 0.6-6.5 μg/g in cat hair. ", "SCCPs with shorter carbon chains and lower chlorine substitution were observed in cat hair. ", "LCCPs with carbon chains > C20 were detected in dust and hair samples, possibly indicating the use of wax grade LCCP formulations. ", "Non-traditional Kendrick mass defect plots were used to obtain information on the magnitude of CPs and provide evidence of possible interfering compounds. ", "This is the first report on the occurrence of SCCPs, MCCPs, and LCCPs in the South African indoor environment." ]

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[ "Molecular cloning of cDNA from hepatitis A virus strain HM-175 after multiple passages in vivo and in vitro.", "\nHepatitis A virus (HAV) strain HM-175 was passaged six times in marmosets, 59 times in cell culture and purified from infected cell culture supernatant fluid. ", "The viral RNA was extracted, copied into cDNA and the cDNA:RNA hybrids were cloned into the PstI site of plasmid pBR322. ", "The cDNA clones were authenticated by hybridization to RNA extracted from HAV-infected cells and clones representing the 3' end of the genome were identified using a previously authenticated cDNA clone. ", "The clones represented all but 29 bases of the HAV genome. ", "They were compared to HAV strain HM-175 cDNA cloned from viral RNA after three passages in marmosets on the basis of restriction endonuclease mapping and DNA sequencing. ", "No differences were found in either the presence or absence of restriction endonuclease sites using 33 different restriction enzymes. ", "Sequencing of cDNA representing bases 29 to 1002 of the HAV genome revealed eight base changes all of which were within the 5' noncoding region." ]

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[ "Effects of cyanide on selenium metabolism in rats.", "\nAdult male rats were given drinking water containing either 0 or 150 ppm cyanide for 2 weeks. ", "They were then injected with 5 microCi 75Se-selenite, and excretion of radioactivity in urine and feces was determined. ", "No difference in excretion of 75Se occurred during the rapid phase, but the cyanide-treated rats (T1/2 28 days) excreted significantly more 75Se in urine than control (T1/2 38 days) rats. ", "Cyanide had no effect on excretion of 75Se in feces or on the distribution of 75Se in cytosolic proteins in liver, kidney, muscle or testes. ", "In a second experiment weanling male rats were given water with either 0 or 150 ppm cyanide and were killed for glutathione peroxidase assay and selenium analysis in blood, kidney, liver, muscle and testes after 3, 6 or 9 weeks of treatment. ", "Glutathione peroxidase activity and selenium concentrations were significantly reduced by cyanide in all tissues except testes." ]

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[ "Of all the things to love about Pittsburgh, its bridges are perhaps the most visible. ", "There are over 440 bridges, an astounding number for a city of 300,000 people — hence its nickname City of Bridges. ", "I was standing on the Roberto Clemente Bridge, named after the great Pirates outfielder, looking up the Allegheny River at two other huge, majestic steel bridges: the Andy Warhol and the Rachel Carson. ", "The three pale-mustard-color suspension bridges, known as the Three Sisters, are part of a system without which Pittsburgh, which meets at the convergence of the Allegheny, Monongahela and Ohio Rivers, would be a fractured collection of neighborhoods.", "\n\nPittsburgh is also known as Steel City, and while United States Steel still has its headquarters there, the industry collapsed in the 1980s, a devastating blow. ", "But given two options, evolve or perish, Pittsburgh began growing in a new direction. ", "Today, tech companies like Google, Intel and Uber have invested in the city, which has had a real effect on its citizens’ lives: According to a 2014 study, Pittsburgh is ranked second in intergenerational upward mobility. ", "I arrived merely as a tourist, though one with a specific modus operandi — finding the best the city has to offer without straining my frugal budget. ", "What I found was a city that has transformed itself into a vibrant cultural and artistic hub, all while remaining true to its Rust Belt roots.", "\n\nThere are still visual remnants of heavy industry, like the smoke stacks at the Waterfront in neighboring Homestead, Pa., the former site of Homestead Steel Works (now a shopping mall), but the steel mills are mostly gone." ]

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[ "Alleged front panel of upcoming Galaxy Note 3 surfaces\n\nThe latest leaked images of the Samsung Galaxy Note 3 show off what is allegedly the front panel of the devices. ", "While no measurements were provided alongside the images, according to previous leaks the device is set to feature a 5.7-inch diagonal - up from the 5.5\" on the Note II.", "\n\nWhile the panel follows Samsung's design strategy, the corners are more defined than on the Note II as well, which lends itself to a more business-oriented marketing approach (think BYOD).", "\n\nWe'll find out more about the Note 3 at IFA in Berlin on September 4, where Samsung is expected to officially announce the device.", "\n\nThere's word that the phablet will be powered by either a Snapdragon 800 or Exynos 5 Octa chipset, feature 3GB of RAM and run on Android 4.3, so be sure to check back with us then for all the juicy details.", "\n\nUpdate: Several higher resolution shots have since emerged of the same panel, except this time someone remembered to bring a ruler. ", "The display size of the Galaxy Note 3 has now been confirmed at 5.68 inches.", "\n\nAlso revealed is smaller side bezel of only 2.2mm, and an overall panel thickness of 1.8mm." ]

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[ "Compatibility is great, but whether Nintendo plans to release another new edition of the vaunted controller is another story. ", "They had a brief run when Super Smash Bros Wii U came out, but fresh gamepads from that era go for $150 on Amazon. ", "Super Smash Bros. Ultimate comes out on the Nintendo Switch on December 7th, 2018.", "\n\nFollow all the latest news from E3 2018 here!" ]

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[ "MOTUC Director's Commentary #7:Dear Legal, it is \"Zodac\" not \"Zodiac\". ", "This is not a\n\nIf this is your first visit, be sure to\ncheck out the FAQ by clicking the\nlink above. ", "You may have to register\nbefore you can post: click the register link above to proceed. ", "To start viewing messages,\nselect the forum that you want to visit from the selection below.", "\n\nOh boy. ", "Well I will not resort to name calling. ", "If you had read my other post you would know that I don't think TG is a racist in any way. ", "And I was not offended by his remarks. ", "Just thought that he needed to show more care on a subject that can be lightning rod as you can see by this thread\n\nHonestly, I can see right away he was just pointing out the absurdity of calling a person of African descendents on Earth as African Americans (or Canadians or from the Caribbean) on Eternia. ", "Heck, the fact that Eternia is a planet and not a continent, maybe it would have been ok if he said African Earthlings instead...lol. ", "And sure, maybe it is ok to say Black or White Eternian's when it comes to to the Caucasian and Afrocentric humans on Eternia, but if you're gonna start using color, are we suppose to call Jitsu and and Ninjor as Yellow? ", "Should we do like the Wu Tang and call Rio Blast Butter Pecan (scooped in my Ice Cream truck, who tears it up) This all coming from a black man born and raised in Canada with parents from the Caribbean (Grenada), so I am not African American, but Grenadian-Canadian (don't you just love that rhyme scheme? ", "lol) In the end, let's just be happy it wasn't Stratos that got the PC nightmare of race change lol\n\nHonestly, I can see right away he was just pointing out the absurdity of calling a person of African descendents on Earth as African Americans (or Canadians or from the Caribbean) on Eternia. ", "Heck, the fact that Eternia is a planet and not a continent, maybe it would have been ok if he said African Earthlings instead...lol. ", "And sure, maybe it is ok to say Black or White Eternian's when it comes to to the Caucasian and Afrocentric humans on Eternia, but if you're gonna start using color, are we suppose to call Jitsu and and Ninjor as Yellow? ", "Should we do like the Wu Tang and call Rio Blast Butter Pecan (scooped in my Ice Cream truck, who tears it up) This all coming from a black man born and raised in Canada with parents from the Caribbean (Grenada), so I am not African American, but Grenadian-Canadian (don't you just love that rhyme scheme? ", "lol) In the end, let's just be happy it wasn't Stratos that got the PC nightmare of race change lol\n\nHa ha. ", "I actually had no problem with Stratos being black, though I know that wouldn't work and TG lightly touched on it. ", "As you know, \"white\" and \"black\" are culturally accepted names for race in this country. ", "We'll hear those names on TV and read them in print. ", "Yellow, brown, orange, pink, and polka dot are not. ", "And if it ever becomes culturally insensitive to use the terms \"black\" and \"white\" then we'll stop using it. ", "And if African American and Black are synonymous terms, which they are in most circles, then using African American is not absurd in connection with Eternia. ", "When Mattel said they wanted an African American on Eternia, everyone and their mama knew what they were talking about. ", "Including TG. ", "If they said they wanted a Native American we know what they'd be asking for and that character wouldn't have yellow skin. ", "It's communication 101. ", "We use terms people can connect with and relate to even if it technically is not accurate. ", "TG is a \"cool\" guy. ", "You know what that means. ", "It doesn't mean he's cold. ", "That's why the African Americans \"(on Eternia?)\" ", "remark is so unnecessary. ", "Was there a human being on Earth that actually wondered aloud if the fictional planet of Eternia had Africans or Americans? ", "No! ", "So why bring it up? ", "Totally unnecessary" ]

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[ "Adventures in a Golden Age of Storytelling\nby SAMUEL WILSON,\nAuthor of \"Mondo 70,\" \"The Think 3 Institute,\" etc.", "\n\nThursday, May 26, 2016\n\nTHE PULP CALENDAR: May 26\n\nThe main attraction of this 1934 Argosy for me is right on the cover. \"", "Buddha's Whisker\" is a fun standalone Singapore Sammy story by George F. Worts. ", "Sammy Shea is always on the trail of his deadbeat crook of a dad or else raising money to continue the hunt, and in this novelette he and sidekick of the moment Lucifer \"Lucky\" Jones get drawn into a plot to steal a sacred relic that ends with Sammy thisclose to finally catching up with his punk parent. ", "While Worts's Peter the Brazen stories, written under the name of Loring Brent, feature a stalwart, upright hero, the Sammy stories are charmingly disreputable in the almost amoral manner of South Seas or Asian adventure. \"", "Whisker\" is the last Sammy novelette; Worts would bring the character back in three serials over the next two years, including the 1935 three-parter Shark Bait that will be showcased on this blog.", "\n\nThere are no new serials this week as the issue concludes J. Allen Dunn's Forbidden Mountain while continuing F. V. W. Mason's The Barbarian and Frederick \"Evan Evans\" Faust's Montana Rides Again. ", "Anthony M. Rud contributes the novelette \"The Marked Deuce\" set in South America, while Theodore Goodridge Roberts writes a short story, \"The Hero,\" about an unlikely hero who inspires a ship's stand against an infamous pirate and his ship.", "Albert Richard Wetjen usually wrote stories of men at sea but with \"Hammerhead\" he tries his hand at animals at sea and comes up with something reasonably entertaining for the genre. ", "The serials are as entertaining as fragments can be but \"Buddha's Whisker\" and the Wetjen story really make this issue worthwhile. ", "I like The Barbarian enough that I'm gradually piecing it together. ", "I have the next chapter, for instance, but the main attraction of the June 2, 1934 Argosy, as you'll see a week from now, is another Bellow Bill Williams story by Ralph R. Perry. ", "Don't miss it." ]

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[ "No comments:\n\nPost a Comment\n\nI've gotten rid of the word verification for posting comments. ", "To tell the truth, I have trouble reading the new stuff they are using. ", "Feel free to disagree, but spammy or obnoxious comments will not go up.", "\n\nSearch This Blog\n\nAbout Me\n\n... I'm not sure... my head's been in a weird place lately... trying to figure it out. ", "Love my husband, daughter, friends, most of my family. ", "Knitting keeps me centered. ", "Total sports nut. ", "Love to cook, read, garden. ", "Trying to get healthy w/o meds. ", "Usually like my job, love it on Braun's days..." ]

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[ "Welcome to 'The Cool Calm'\n\nHaving exchanged an incredible 43 million messages with people in crisis, it’s safe to say that we’ve learned a lot - about mental health, technology, and the intersection between the two. ", "And we’ve learned it all in less than 4 years! ", "While we’ve shared what we’ve learned in a variety of ways, we haven’t had a central hub from which to share our best stories. ", "Until now!", "\n\nWhy The Cool Calm?", "\n\nAt Crisis Text Line, we’ve always said that the goal of a conversation is to bring texters from a “hot moment to a cool calm” - to take them from a place of painful emotions to a place where they feel safe and able to move forward. ", "The phrase “from a hot moment to a cool calm” has become a vital part of our identity. ", "Naming this blog The Cool Calm represents its position as a place for safe expression.", "\n\n\"The Crisis Text Line Method: From a hot moment to a cool calm.\"", "\n\nGround Rules\n\nTo make sure The Cool Calm lives up to its name, we’ve set a few ground rules for ourselves:\n\nTexter privacy comes first, always.", "\n\nWe take a hopeful, constructive, and solution-oriented approach to the issues we discuss.", "\n\nThis blog is not a resource for counseling. ", "And just like our Crisis Counselors, we don’t give direct advice here.", "\n\n“Naming this blog ‘The Cool Calm’ represents its position as a place for safe expression.”\n\nThe Categories\n\nThe Cool Calm is divided into four categories. ", "Here’s what to expect from each of them:\n\nNews & Announcements: This is where we’re posting big and exciting developments that we want to shout from the rooftops to our whole community. ", "Like, for example, the fact that we’re launching a blog!", "\n\nOur Stories: Crisis Counselors, Staff, friends of the organization, and anyone else with a connection to the work we do will be sharing their personal stories here.", "\n\nInsights: What have we learned? ", "Staff will be writing about topics as varied as self-care, customer service, and the product process here, all drawing from the work we do at Crisis Text Line.", "\n\nTech & Data: Finally, this section is for learnings from our data and technology, which we hope can contribute to the mental health space and beyond.", "\n\n(The Whole Website Is New, btw)\n\nYou’ve probably noticed by now that the launch of The Cool Calm is coinciding with a completely redesigned and rewritten website! ", "We’re thrilled to be unveiling a site that is more informative, better reflects our brand, and better equips our community to spread the word about the service!" ]

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[ "Francesca Busca\n\nFrancesca’s mission is to make Mosaic ROCK. ", "Everything has at least one fascinating feature about it, and she strongly believes that mosaic is the ultimate way to show each one of them.", "\n\nTorn between optimism and surrender, Francesca is haunted by the idea of mankind’s imminent self-destruction. ", "Yet, she believes in a future for humanity of resourceful innovation through reusing, upcycling and recycling. ", "She is fascinated by colours and textures of both artificial and natural elements, which she enthusiastically hunts for in everyday life and restlessly plays with in new combinations, pairing and contrasting noble material with rubbish. ", "Her aim is to prove how even rubbish can be turned into something useful, fun and even beautiful.", "\n\nTo Francesca, art has the same importance as philosophy: its ultimate purpose is to provoke something in the viewer of its time. ", "As an artist, she feels a compelling urge to convey a message, whether a thought or a pure emotion, as strongly as her technical and creative capabilities will allow.", "\n\nABOUT HER\n\n\"Francesca is developing herself as a brilliant mosaic artist. ", "Her works reflect her passionate and strong character; the evidence of this is in the use of vibrant colours and the themes she selects for her pieces. ", "Her creative process is intuitive; she seems to create her mosaics out of pure inspiration.\"", "\n\n(Paula Ligo - artist tutor at Southbank Mosaics, London)\n\nIn her early life Francesca challenged herself by focusing on things that did not come naturally to her (e.g. going into Law after Classics). ", "Yet, she tried for years to placate her internal restlessness by living in different countries and cultures (Pordenone, Padua, Denver, London, Paris, New York...); When she reached 40, with the responsibility of a mother, she settled between London and Trieste and found her outlet in what she liked and did best, namely using her hands to create.", "\n\nArt exhibitions, painting and modelling clay were regular hobbies which never satiated her inherent creative nature. ", "Finally one day, she entered the Scuola Mosaicisti del Friuli, in Spilimbergo: a whole new world of WONDERS opened up.", "\n\nShe wanted to learn how to do it properly. ", "She found a delightful place in London, Southbank Mosaics, where she did a first Award course and a Level 2 Certificate - a place which she still regularly and enthusiastically attends twice a week. ", "She also attends various courses per year at Scuola Mosaicisti del Friuli, Spilimbergo (Roman, Bizantine and Modern mosaic) and elsewhere.", "\n\nHer philosophy is always to learn as much as possible, never to take anything for granted, and then - to make it hers!", "\n\nWhilst visiting the Macalube of Aragona, in Sicily, I was struck by the odd feeling of walking on a lunar landscape: a post-apocalyptic scenery where no-one survived - yet where fresh clay was springing out as a sign that the world was still alive and on the verge of a new dawn.", "\n\nWhat's left of a TV, an apocalyptic scenery behind it: we so cared about trivial things (such as being on TV) that we forgot to save ourselves from extinction. ", "And yes, even more so now, we so wanted to BE in there…!", "\n\nThe natural elements are mixed with both rubbish and specs of millefiori and noble smalti, used sparingly to witness their precious nature as a material which, albeit used lusciously in the past, will be increasingly hard to find: for example, the production of reds and oranges is likely to cease in Italy (and eventually everywhere) in February 2017, as the use of one of their essential elements, cadmium, is highly polluting and will be banned.", "\n\n\"Mami\", 2016. ", "Ceramic and glass on wooden board, direct method (30.5x23cm). ", "Playing with void to create the necklace, experimenting with pigments of different colour in the grout (grey, brown and black).", "\n\n\"Freddie\", 2015. ", "Ceramic, glass and cork on marmox, indirect method (35x35cm). ", "Paying thorough attention to both colours and shapes of individual pieces and playing with geometrical shapes to recreate light and shades in the background.", "\n\n\"Incy Lucky\", 2016 - Ceramic, glass, marble and mirror on plywood, direct method (50x50cm). ", "Opus sectile and opus Palladianum. ", "Inspired by a tiny gold pendant my grandmother Iride had of a seven-legged spider, to which she always held on tight, even through both World Wars: possibly the only possession she managed to keep from her childhood… a spider which made me see her and love her for what she was, beyond her dignified and cold appearance.", "\n\nMosaic & Mixed Media: ceramic, cork, plastic, glass and metal on wooden board, direct method (30.5x40.6cm). ", "95% reused material. ", "Apparently, bees are decreasing at an alarming rate. ", "If they go extinct, it is estimated that the human species would follow in 3 years. ", "But, if we act now and let Nature be, it will grow back and heal itself, giving us ALL a chance to recover. ", "Let us stop pesticides, pollute less, sow wild flowers…help the buzz BEe!!!", "\n\nMosaic & Mixed Media: ceramic, cork, plastic, glass and metal on wooden board, direct method (30.5x30.5cm). ", "50% reused material. ", "Apparently, bees are decreasing at an alarming rate. ", "If they go extinct, it is estimated that the human species would follow in 3 years. ", "But, if we act now and let Nature be, it will grow back and heal itself, giving us ALL a chance to recover. ", "Let us stop pesticides, pollute less, sow wild flowers…help the buzz BEe (and reclaim some space)!", "\n\nMosaic and Mixed Media: ceramic, cork, bark, millefiori, metal and plastic on wooden board, direct method (22x22x30cm). ", "98% reused material. ", "Apparently, bees are decreasing at an alarming rate. ", "If they go extinct, it is estimated that the human species would follow in 3 years. ", "But, if we act now and let Nature be, it will grow back and heal itself, giving us ALL a chance to recover. ", "Let us stop pesticides, pollute less, sow wild flowers…help the buzz BEe (and reclaim some space)!", "\n\n2016. ", "Ceramic, glass, XVI century pipes, fabric, metal, mother of pearl and plastic on wooden board, direct method (30.5x41cm). ", "Hopefully, a good example of how upcycling can turn old material into something useful, fun and even beautiful…\n\nMosaic & Mixed Media: crockery, wood, marble, glass, natural fibres and millefiori on wooden board, direct method (43x24.5 cm). ", "98% reused material. ", "Did you know? ", "In elegant, chaotic, amazing Naples there is a tradition whereby a customer can pay for a coffee for the next stranger who cannot afford it (“caffe’ sospeso”). ", "Coffee is so essential, that no one should be left without it!", "\n\nCeramic, glass, mirror, bones, XVIc pipes, iron, fossil, stones, plastic and millefiori on wooden board, direct method (35x35cm). ", "Made with the ‘treasures’ found mudlarking along the Thames, apparently now one of the cleanest metropolitan rivers in the world, but which used to be regarded as London's garbage bin. ", "Thames mud is anaerobic and preserves whatever it consumes, which makes its shore one of the richest archaeological sites in the country. ", "98% re-used material.", "\n\nI believe that, by definition, artists are restless souls who feel the overwhelming\nneed to externalise their feelings, whether to follow or appease their emotional or\nintellectual turmoil. ", "It could be a sophisticated theory or pure raw basic emotion, but it\nwill be a message as strong as the artist can manage to convey. ", "Whichever way, the\npurpose of art is for this message to come out in order to provoke something in you - to\nmake you feel and think.", "\n\nIsayWe, 2016. ", "A hymn to tolerance in times of fear. ", "IsayWe are better together, IsayWe should agree to disagree, IsayWe should love our differences as they are an essential source of evolution. ", "IsayWe are all the same in the end, IsayWe are all part of Nature and IsayWe should respect it all - earth to air, what lives beneath, between and beyond. ", "Ceramic, glass, marble, crockery, metal, plastic, and love on wooden board, direct method. ", "Mostly recycled/upcycled material (37.5 x 45 x 4cm).", "\n\n2016. ", "Ceramic, glass, shells, beads, metal on wooden board, direct method. ", "There are 3 meanings to this statement: 1. ", "Playing God is natural for men, due to their curiosity - upsetting nature is not. ", "2. ", "Pretending to be God is fun, but being one must be such a lonely state...no one remotely as evolved to talk to to, all the time and power in the world and nothing to strive for... 3. ", "We think we can do anything and that we are free, whilst in fact it is a privilege reserved to a very few...\n\nI have been living in London as a EU citizen for 17 years. ", "I come from Italy, yet I feel more British than most. ", "I speak with little if no accent, thanks to my British friends. ", "I took the citizenship test a few years ago, ready to apply for a UK passport. ", "In view of the Brexit referendum, I felt very anxious about the increasing signs of intolerance around the world and the possibility of Brexit. ", "I felt compelled to let this anxiety out by sending a message of unity and tolerance by as many means as possible. ", "It did not work; I felt like I lost my home overnight, and quite angry both at how misled the campaign to leave seemed to be (in such a democratic country!!!) ", "and how understated it possibly was within the London bubble. ", "Moreover, my worry is not about my legal status, but also about the cultural impoverishment (at least because of the end of lots of EU funds and exchanges on education and research) the UK now faces. ", "Nevertheless, I still love this Country - so I try to take it with humour (which is another 'great British feature') and send out a message of peace.", "\n\n2016. ", "Ceramic, glass, beads, plastic, fossil on wooden board, direct method on mesh (30x41cm). ", "A hand for help or hope? ", "Who’s pulling who out of darkness? ", "Or is light in the middle? ", "Whichever way, a message of fraternity and humility - let us all aim for the light, be it love or knowledge, through an open heart and an open mind.", "\n\nCeramic, glass, mirror and XVIc pipes on wood, direct method (28x28cm). ", "100% recycled material. ", "Inspired by a sublime novel by Borges and drawings by Escher: how immortality devoidens life of a meaning. ", "An initial feeling of omnipotence which pushes us to build incredible things, trying to defy the laws of Nature. ", "And then in turn madness, frustration, resignation, boredom and regression. ", "Why being immortal, when you are just a limited being? ", "Endless time to do so little! ", "Death is essential to our future. ", "Our drive comes from savouring first times again and again and the knowledge that whatever we can do, we must do in the short span of our beautiful lifetime - and keep building on what was done before. ", "Learn from our mistakes and our differences, then make it better, stronger, wiser. ", "Think, feel, err, learn and evolve: do not only validate, but justify the immortality of our species. ", "And this, our children, is the gift and burden we leave to you…with eternal love.", "\n\nCeramic, glass, millefiori on wooden board, direct method (30.5x30.5cm). ", "99% re-used material. ", "I like to believe that, at birth, a part of universal energy (white) gets encased in our limited body, and gains a particular consciousness (colours). ", "When we die, this fragment of energy returns to its whole, which is everywhere anytime, contemporaneously encasing fragments in different beings, before and after the Big Bang, on Earth and elsewhere. ", "The question which torments me is: does it retain any consciousness, any individuality? ", "Any shape or dimension? ", "And if we could choose, which fragment would you be?", "\n\n“Stick your Plastic up your Ars”, 2017. ", "Mosaic and mixed media: bark, smalti, marble, millefiori, plastic (40.5x40.5cm). ", "98% reused material. ", "An example of how to upcycle disposable plastic leftovers. ", "Plastic is quickly accumulating everywhere in our world and hardly dissolving, thereby dramatically contributing to the destruction of our ecosystem. ", "But we CAN make a difference: SAY NO TO DISPOSABLE PLASTIC! ", "And in the meantime, why not reuse what of it is already there… and stick it up your art?", "\n\nMosaic & Mixed Media: ceramic, glass, mirror, XVI Century pipes, shells, beads & millefiori on wooden board, direct method (41x41cm). ", "85% reused material. ", "Ever felt the feeling? ", "Wanting to grab others by their shoulders to make them see the sun going down, but only to see instead what a lunatic you are in their eyes, and retreat? ", "Perhaps it is time to close our devices and open our minds, disconnect from our screens and reconnect with nature, look beyond and climb on that hill. ", "Let us all be Fools, and keep each other company on that hill. ", "We could check if it is true that the sun is not setting where it used to… Shall we?", "\n\n“Matter, Anti-Matter (The AntiMatter Mistery)”, 2016. ", "Mosaic and Mixed Media: smalti, marble, pebbles, plastic, metal, wood and millefiori on wooden board, direct method (40x40cm). ", "A recent experiment at Cern with equal amounts of hydrogen and anti-hydrogen confirmed how, when they come in contact, they annihilate each other and create pure energy. ", "Yet some matter remains (confirming the matter - antimatter asymmetry problem). ", "I find this fascinating: we are so scared of our anthithesis, whilst in fact - at least in our world - it should be the other way around: the black beast is indeed the Matter, eating away the beam of anti-hydrogen. ", "Like Matter, like Man - toward anything in our way?", "\n\n“Birth, Re-”, 2016. ", "Ceramic, glass, millefiori on wooden board, direct method (30.5x30.5cm). ", "99% re-used material. ", "I like to believe that, at birth, a part of universal energy (white) gets encased in our limited body, and gains a particular consciousness (colours). ", "When we die, this fragment of energy returns to its whole, which is everywhere anytime, contemporaneously encasing fragments in different beings, before and after the Big Bang, on Earth and elsewhere. ", "The question which torments me is: does it retain any consciousness, any individuality? ", "Any shape or dimension? ", "And if we could choose, which fragment would you be?", "\n\nMosaic and Mixed Media: smalti, marble, pebbles, plastic, metal, wood, glass and millefiori on wooden board, direct method (40x51cm). ", "Experiments with equal amounts of matter and antimatter confirmed how, when they come in contact, they annihilate each other and create pure energy. ", "Yet some matter remains (confirming the matter - antimatter asymmetry problem). ", "Fascinating. ", "We are so scared of our anthithesis, whilst in fact - at least in our world - it should be the other way around: the black jaws are indeed the Matter, eating away the Antimatter. ", "Is this what a black hole looks like, seen from the other side?", "\n\nMosaic & Mixed Media: plastic, ceramic, mirror and glass on wooden board, direct method (40×40cm). ", "98% recycled material. ", "I must have been 8 and full of excitement on my way to a Carnival party, when a couple of guys sneaked up to me on the street and poured a vial of smelly liquid on my head. ", "To this day I still clearly remember my mind screaming \"WHY?!?\" ", "over and over for what felt like a temporal abyss, and the burning humiliation for suffering such an injustice... traumas help us grow, but pure meanness only generates darkness. ", "Be kind, people. ", "It can affect the world much deeper than we think...\n\nMosaic and mixed media: fabric, plastic, glass, ceramic and mirror on wood and metallic mesh (53x55cm). ", "70% reused material. ", "Pure exuberance: like the lyric poet Pindar with his magnificently articulated words, which made emotions detach from their two dimensional form and come alive in the reader’s mind, so I am frantically trying with colours to detach and jump at the viewer’s mood…I might as well have called it “Folly”. ", "Is it getting to you?", "\n\n“Complementarity”, 2017. ", "Mosaic: fabric on wood (30x30cm). ", "100% reused material. ", "Your old shirts in a new pattern, trying to be as logic as you are. ", "You are the Hence, and I am the But. ", "You are the lines and I am the dots. ", "You think and I feel, you feel and I do. ", "I say…a world can really be made by two.", "\n\nCeramic, glass, XVI century pipes, fabric, metal, mother of pearl and plastic on wooden board, direct method (30.5x41cm). ", "Hopefully, a good example of how upcycling can turn old material into something useful, fun and even beautiful…and a subtle tribute to Matisse's defiance to the traditional use of red and blue (by using blue as a foreground, and red as a background). ", "Merci Henri!!", "\n\nMosaic & Mixed Media: ceramic, cork, plastic, glass and metal on wooden board, direct method (30.5x40.6cm). ", "95% reused material. ", "Apparently, bees are decreasing at an alarming rate. ", "If they go extinct, it is estimated that the human species would follow in 3 years. ", "But, if we act now and let Nature be, it will grow back and heal itself, giving us ALL a chance to recover. ", "Let us stop pesticides, pollute less, sow wild flowers…help the buzz BEe!!!", "\n\nMosaic and Mixed Media: ceramic, cork, bark, millefiori, metal and plastic on wooden board, direct method (22x22x30cm). ", "98% reused material. ", "Apparently, bees are decreasing at an alarming rate. ", "If they go extinct, it is estimated that the human species would follow in 3 years. ", "But, if we act now and let Nature be, it will grow back and heal itself, giving us ALL a chance to recover. ", "Let us stop pesticides, pollute less, sow wild flowers…help the buzz BEe (and reclaim some space)!", "\n\nMosaic & Mixed Media: ceramic, cork, plastic, glass and metal on wooden board, direct method (30.5x30.5cm). ", "50% reused material. ", "Apparently, bees are decreasing at an alarming rate. ", "If they go extinct, it is estimated that the human species would follow in 3 years. ", "But, if we act now and let Nature be, it will grow back and heal itself, giving us ALL a chance to recover. ", "Let us stop pesticides, pollute less, sow wild flowers…help the buzz BEe (and reclaim some space)!!!", "\n\nMosaic and Mixed Media: glass, mirror, stones, fossile, shells and clay on wooden board, direct method (41x41cm). ", "First piece on refugees. ", "THEY are coming: by the hundreds, the thousands. ", "And they will not go back - they have no home to go back to. ", "And we started it. ", "Whilst I would like to hide my face in shame and fear, I think it is time to man up and take responsibility for our actions. ", "As we open the door to our childrens’ closets to fight their fears at night, this time we need to find the strength to open our own, and face our monsters under the sun: we created them and now we face them. ", "How we respond to this issue now will define us as a society, and change our world forever. ", "We need to open that door, for the sake of our children, to save them from a world of hate and fear. ", "Let us lead by example, let us show them. ", "Let us open the door, and meet the monsters. ", "I see their hands, just like ours…" ]

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[ "Q:\n\nASP:Labels not updating on button Click\n\nI know this is probably something so simple that I am just not able to see it. ", " I have an aspx form that has a usercontrol in an updata panel. ", " The user control is a people picker the searches on users from a corporate database. ", " \nWhat I want to see happen is: \n\nThe user clicks on a pick user button\nThe update panel with people picker becomes visible \nThey search for a user and then select the one they want. ", "\nWhen they make the selection and click Done, I get the user id of the user and look them up in our user table.", "\nThe user information should show up in a the form in label fields. ", " \n\nI can step through the code and see that I am getting the user information and that the label text is being set to the values but the page never updates the labels. ", " It is a postback so I would think they would update.", "\n<tr>\n <td colspan=\"4\">\n <asp:UpdatePanel ID=\"CollapseDelegate\" runat=\"server\">\n <ContentTemplate>\n <asp:Panel ID=\"pDelegateHeader\" runat=\"server\">\n <div style=\"padding: 10px 0 10px 20px; height:10px; text-align: left; background-color:#ffffff; color:#000000; border: 2px solid #ccc;\" >\n <asp:Label ID=\"ShowDelegate\" runat=\"server\" /><br />\n </div>\n </asp:Panel>\n <asp:Panel ID=\"pDelegateBody\" runat=\"server\">\n <PP:PeoplePicker ID=\"PP\" runat=\"server\" />\n <asp:Button ID=\"btnOk\" runat=\"server\" Text=\"Done\" CssClass=\"Buttons\" onclick=\"btnOk_Click\" /> \n </asp:Panel>\n <asp:CollapsiblePanelExtender ID=\"CollapsiblePanelExtender3\" runat=\"server\" TargetControlID=\"pDelegateBody\" CollapseControlID=\"pDelegateHeader\" ExpandControlID=\"pDelegateHeader\" Collapsed=\"true\" TextLabelID=\"ShowDelegate\" CollapsedText=\"Pick User...\" ExpandedText=\"Close...\" CollapsedSize=\"0\"></asp:CollapsiblePanelExtender>\n </ContentTemplate>\n </asp:UpdatePanel>\n </td>\n </tr>\n <tr>\n <td><asp:Label ID=\"DelegateNameLabel\" runat=\"server\" Text=\"Name:\" CssClass=\"indentedText\" /></td>\n <td><asp:Label ID=\"DelegateNameValueLabel\" runat=\"server\" CssClass=\"indentedText\" Visible=\"true\"></asp:Label></td>\n <td><asp:Label ID=\"DelegateEmailLabel\" runat=\"server\" Text=\"Email:\" CssClass=\"indentedText\" /></td>\n <td><asp:Label ID=\"DelegateEmailValueLabel\" runat=\"server\" CssClass=\"indentedText\" Visible=\"true\"></asp:Label></td>\n </tr>\n <tr>\n <td><asp:Label ID=\"DelegatePhoneLabel\" runat=\"server\" Text=\"Phone:\" CssClass=\"indentedText\" /></td>\n <td><asp:Label ID=\"DelegatePhoneValueLabel\" runat=\"server\" CssClass=\"indentedText\" Visible=\"true\"></asp:Label></td>\n <td><asp:Label ID=\"DelegateVerifiedLabel\" runat=\"server\" Text=\"Last Verified Date:\" CssClass=\"indentedText\" /></td>\n <td><asp:Label ID=\"DelegateVerifiedValueLabel\" runat=\"server\" CssClass=\"indentedText\" /></td>\n </tr>\n\nprotected void Page_Load(object sender, EventArgs e)\n {\n if (!", "Page.", "IsPostBack)\n {\n string PassedDelegateID = string.", "Empty;\n string Mode = string.", "Empty;\n int delegateId = 0;\n\n if (Request.", "QueryString[\"Id\"] !", "= null)\n {\n PassedDelegateID = Request.", "QueryString[\"Id\"].ToString();\n }\n else\n {\n PassedDelegateID = \"0\";\n }\n\n if (Request.", "QueryString[\"mode\"] !", "= null)\n {\n Mode = Request.", "QueryString[\"mode\"].ToString();\n }\n else\n {\n Mode = \"add\";\n }\n\n if (Mode == \"add\")\n {\n pnlUdpateDelegateText.", "Text = UIConstants.", "ADDDELEGATETEXT.ToString();\n }\n else\n {\n pnlUdpateDelegateText.", "Text = UIConstants.", "UPDATEDELEGATETEXT.ToString();\n if (int.", "TryParse(PassedDelegateID, out delegateId))\n {\n loadDelegateData(delegateId);\n }\n }\n }\n }\n\n protected void btnOk_Click(object sender, EventArgs e)\n {\n TextBox txtSearchValue = (TextBox)PP.FindControl(\"txtSearchResults\");\n string LanId = txtSearchValue.", "Text;\n\n User user = BusinessUtility.", "GetUser(LanId);\n\n DelegateNameValueLabel.", "Text = user.", "Name;\n DelegateEmailValueLabel.", "Text = user.", "Email;\n DelegatePhoneValueLabel.", "Text = user.", "Phone;\n DelegateVerifiedValueLabel.", "Text = DateTime.", "Now.", "ToShortDateString();\n\n }\n\nThanks,\nRhonda\n\nA:\n\nBecause the labels are outside the update panel, only the content inside the update panel is updated from an ajax post-back, that's the whole point of an update panel.", "\nYou will need to either move the labels inside the update panel's content area, or have another update panel for the labels and make it's update mode \"always\" \n\n" ]

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[ "1. ", "Field of the Invention\nThe present invention relates to technology for presenting electronic advertisements to users by using broadcasting. ", "In particular, this invention relates to an advertisement method capable of selectively presenting a specific advertisement to a specific user after considering the time, position, and preference of the user, an advertisement apparatus, an advertisement receiver comprising the apparatus, and a recording medium which programs thereof are stored in.", "\n2. ", "Description of the Related Art\nIn conventional broadcast advertising, a broadcasting station broadcasts the same advertisements to all viewers and listeners, as is the case in over-ground wave television broadcasting and over-ground wave radio broadcasting. ", "The viewers and listeners merely view/listen to the received advertisements in an unaltered state.", "\nSince the range of the radio waves broadcast from the broadcast station is limited, the advertisements consequently have a certain degree of regionality. ", "Nevertheless, the broadcasting is global, making it possible to present advertisements locally in accordance with the position of listeners and viewers.", "\nPublished Japanese Patent translation No. ", "WO96/04633 of PCT proposes a method for presenting to a user in a vehicle details of advertisements relating to areas in the vicinity of the vehicle. ", "The advertisement is transmitted by broadcasting sound and data, the sound being presented to the user in an unaltered state and not accumulating in the vehicle, and the data corresponding to the sound broadcast and accumulating in the vehicle. ", "The advertisement is received by an apparatus provided in the vehicle.", "\nHowever, in the technology disclosed in Japanese Patent Application No. ", "10-505441, details of the advertisement are presented by receiving the data transmission after listening to the sound broadcast. ", "For this reason, it is difficult to reproduce a complete advertisement to the user at any given time. ", "As a consequence, it is difficult to increase the probability that advertisements which are broadcast while the apparatus is not in use will be received.", "\nIn conventional advertisement broadcasting, the valid period of the advertisement depends on the period and duration of the broadcast. ", "However, since it is impossible to link the position of the advertisement with the position of the user, even when advertisements are broadcast only during sales campaigns and the business hours of stores, it is often difficult for users to purchase the advertised products and services during that time. ", "In that case, the users either make the purchase on another occasion or forget about it altogether. ", "Consequently, the company sponsoring the advertisement loses an opportunity for sale.", "\nConventionally, advertisements are inserted during programs which it is estimated that many target users are watching, supposedly presenting advertisements which suit the preferences of the users. ", "However, this method targets only group preferences and does not consider the preferences of individual users." ]

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[ "\"I don't know how long I fought for,\" he says, his eyes, cold at first, becoming listless and blank as he tells his story. ", "The horrors of his life will be there to haunt him for years to come. \"", "All I know is that my hair was about eight inches long by the time I left. ", "Any time we were going to the front line we would feel afraid, would want to run away. ", "But you couldn't. ", "The only time I was happy was when I was shooting. ", "But I still have my bullet wounds and I still limp.\"" ]

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[ "Longitudinal association between air pollution exposure at school and cognitive development in school children over a period of 3.5 years.", "\nRecently, we showed that exposure to traffic-related air pollutants (TRAPs) at school was negatively associated with cognitive development, specifically working memory and inattentiveness, in primary schoolchildren during a course of 12 months. ", "The persistence of such associations over longer periods remains as an open question. ", "To study the longitudinal association between TRAPs at school and cognitive development over a period of 3.5 years. ", "Indoor and outdoor levels of TRAPs (elemental carbon (EC), dioxide nitrogen (NO2), particulate matter (PM2.5) from traffic sources and ultrafine particles (UFP)) were measured at 39 schools across Barcelona during 2012/2013. ", "Working memory, as a measure of cognitive development, was evaluated 4 times in 2012/2013 assessment and was re-evaluated one more time in 2015 using computerized n-back test (3-back d' as main outcome). ", "Linear mixed effects models were used to test the association between TRAPs and 3-back d', adding child and school as random effects to account for the multilevel nature of the data, and school air pollutants levels (one at a time) as predictor. ", "We found detrimental associations between all TRAPs and annual change in 3-back d' (working memory) (i.e. slower development of working memory in children attending schools with higher levels of air pollution). ", "The associations (per one interquartile range increase in exposure) were strongest for outdoor NO2 (Coefficient (Coef) = - 4.22, 95% confidence interval (CI), - 6.22, - 2.22) and indoor UFP (Coef = - 4.12, 95%CI, - 5.68, - 1.83). ", "These reductions were equivalent to - 20% (95%CI, - 30.1, - 10.7) and - 19.9% (95%CI, - 31.5, - 8.4) change in annual working memory development associated with one interquartile range increase in outdoor NO2 and indoor UFP, respectively. ", "Our findings suggest the persistence of the negative association between TRAPs exposure at school and cognitive trajectory measured by n-back test over a period of 3.5 years." ]

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[ " '$Revision: 30.16 $'\n '\nCopyright 1992-2016 AUTHORS.", "\nSee the legal/LICENSE file for license information and legal/AUTHORS for authors.", "\n'\n[\"preFileIn\" self] value\n\n\n '-- Module body'\n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> () From: ( | {\n 'Category: graphical interface\\x7fCategory: ui2\\x7fCategory: System\\x7fCategory: Morphs\\x7fCategory: Basic\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n handMorph = bootstrap define: bootstrap stub -> 'globals' -> 'handMorph' -> () ToBe: bootstrap addSlotsTo: (\n bootstrap remove: 'parent' From:\n bootstrap remove: 'prototype' From:\n globals polygonMorph copyRemoveAllMorphs ) From: bootstrap setObjectAnnotationOf: bootstrap stub -> 'globals' -> 'handMorph' -> () From: ( |\n {} = 'ModuleInfo: Creator: globals handMorph.", "\n\nCopyDowns:\nglobals polygonMorph. ", "copyRemoveAllMorphs \nSlotsToOmit: parent prototype.", "\n\n\\x7fIsComplete: '.", "\n | ) .", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: InitializeToExpression: (30)'\n \n cachedNameWidth <- 30.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: InitializeToExpression: (set copyRemoveAll)'\n \n capabilitySet <- set copyRemoveAll.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: InitializeToExpression: (list copyRemoveAll)\\x7fVisibility: private'\n \n cursorInterest <- list copyRemoveAll.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: InitializeToExpression: (nil)\\x7fVisibility: private'\n \n eventBeingHandledAndForwarded.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: InitializeToExpression: (list copyRemoveAll)\\x7fVisibility: private'\n \n keyboardInterest <- list copyRemoveAll.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n lastCursor <- (0)@(0).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n lastMouseDownEvent.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: InitializeToExpression: (nil)'\n \n metaHand.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n morphToEmbed.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: InitializeToExpression: (set copyRemoveAll)\\x7fVisibility: private'\n \n morphsNotReadyToBeDropped <- set copyRemoveAll.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: InitializeToExpression: (18@12)'\n \n nameOffset <- 18@12.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> () From: ( | {\n 'Category: graphical interface\\x7fCategory: ui2\\x7fCategory: System\\x7fCategory: Morphs\\x7fCategory: Basic\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n handMorph = bootstrap setObjectAnnotationOf: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( |\n {} = 'Comment: A handMorph represents the user\\'s hand in the world,\n and is controlled by a pointing device such as a mouse. ", "The hand\n is invisible and throws no shadow unless it is carrying something.", "\n\n A handMorph distributes events from the the cursor and keyboard\n associated with a particular X display to all objects that have\n expressed interest in (that is, that subscribe to) those events.", "\n The hand also drops certain events into the world at its current\n position. ", "A dropped event typically falls down through the morph\n hierarchy until it reaches some morph that handles it. ", "The world\n absorbs any events that fall all the way through. ", "The hand carries\n morphs by making them submorphs of itself.\\x7fModuleInfo: Creator: traits handMorph.", "\n'.", "\n | ) .", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n parent* = bootstrap stub -> 'traits' -> 'handMorph' -> ().", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: InitializeToExpression: (nil)\\x7fVisibility: private'\n \n untilAllUpClient.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: InitializeToExpression: (list copyRemoveAll)\\x7fVisibility: private'\n \n windowInterest <- list copyRemoveAll.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'modules' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: FollowSlot'\n \n handMorph = bootstrap define: bootstrap stub -> 'globals' -> 'modules' -> 'handMorph' -> () ToBe: bootstrap addSlotsTo: (\n bootstrap remove: 'comment' From:\n bootstrap remove: 'directory' From:\n bootstrap remove: 'fileInTimeString' From:\n bootstrap remove: 'myComment' From:\n bootstrap remove: 'postFileIn' From:\n bootstrap remove: 'revision' From:\n bootstrap remove: 'subpartNames' From:\n globals modules init copy ) From: bootstrap setObjectAnnotationOf: bootstrap stub -> 'globals' -> 'modules' -> 'handMorph' -> () From: ( |\n {} = 'ModuleInfo: Creator: globals modules handMorph.", "\n\nCopyDowns:\nglobals modules init. ", "copy \nSlotsToOmit: comment directory fileInTimeString myComment postFileIn revision subpartNames.", "\n\n\\x7fIsComplete: '.", "\n | ) .", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'modules' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n directory <- 'ui2'.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'modules' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: InitializeToExpression: (_CurrentTimeString)\\x7fVisibility: public'\n \n fileInTimeString <- _CurrentTimeString.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'modules' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: FollowSlot'\n \n myComment <- 'The hand morph.'.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'modules' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: FollowSlot'\n \n postFileIn = ( |\n | \n resend.postFileIn.", "\n handMorph initializePrototype.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'modules' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n revision <- '$Revision: 30.16 $'.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'globals' -> 'modules' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n subpartNames <- 'userProfile\ncapability\n'.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: meta hand\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n absorbHand = ( |\n mphs.", "\n | \n isInWorld ifFalse: [ error: 'this hand not in a world' ].", "\n mphs: (world morphs asList copyFilteredBy: [ | :m |\n (baseBounds intersects: m baseBounds)\n ]).", "\n mphs findFirst: [ | :m | m isHandMorph]\n IfPresent: [ | :m |\n m metaHand: self.", "\n world hands at: (world hands keyOf: self) Put: m.\n world removeMorph: m.\n m privateSetOwner: world.", "\n privateSetOwner: nil.", "\n \"m imageFromPolygonMorph: m.\" ]\n IfAbsent: nil.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: capabilities\\x7fComment: clump is some collection\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n addAllCapabilities: clump = ( |\n | \n clump do: [ | :c | \n addCapability: c ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: capabilities\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n addCapability: c = ( |\n | \n capabilitySet add: c).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: structure\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n addMorph: m = ( |\n | \n \"override to put new morph on top\"\n resend.addMorph: m.\n moveToFront: m).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: attaching\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n attach: m = ( |\n | \n m owner ifNotNil: [ m delete ].", "\n addMorph: m.\n morphsNotReadyToBeDropped add: m.\n \" have to do this after adding cause morphs not laid out\n till in world \"\n\n m globalPosition: globalPosition - (m baseBounds size / 2).", "\n m changed.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: attaching\\x7fComment: Move all the morphs from hand h to me.\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n attachAllFromHand: h = ( |\n | \n h morphs do: [| :m. p. |\n p: m position.", "\n addMorph: m.\n morphsNotReadyToBeDropped add: m.\n m position: p.\n ]).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: basics\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot'\n \n baseBounds = ( |\n | \n resend.baseBounds union: \n ((position + nameOffset) ##\n (cachedNameWidth @ userInfo preferences nameFontSpec size))).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: basics\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot'\n \n baseBoundsOn: c = ( |\n | \n (isNameShownOn: c) ifTrue: [baseBounds] False: [resend.baseBounds]).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: geometry\\x7fComment: True if this morph\\'s base contains the given point. ", " The point\nis in the coordinates of the morph that owns this morph.\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n baseContainsPt: p = ( |\n | \n (resend.baseContainsPt: p) || \n [((position + nameOffset) ## (cachedNameWidth @ userInfo preferences nameFontSpec size)) \n includes: p]).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: drawing\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n baseDrawOn: aCanvas = ( |\n wc.", "\n | \n wc: winCanvasForHand.", "\n wc isNotNil && [aCanvas isSameDisplayAs: wc]\n ifFalse: [ resend.baseDrawOn: aCanvas ].", "\n (isNameShownOn: aCanvas) ifTrue: [drawNameOn: aCanvas].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: carrying morphs\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n carryMorphsEntering: aWindowCanvas = ( |\n | \n desktop servers\n if: aWindowCanvas display serverName\n IsPresentPut: [|:p|\n p isNil || [p x = 'enter'] ifTrue: [\n pair copyX: 'enter' Y: self\n ]\n False: [\n p y !", "= self ifTrue: [attachAllFromHand: p y].", "\n nil\n ]\n ]\n AndDo: []\n IfAbsentPut: [pair copyX: 'enter' Y: self]\n AndDo: [].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: carrying morphs\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n carryMorphsLeaving: aWindowCanvas = ( |\n | \n aWindowCanvas platformWindow ungrabPointer.", "\n desktop servers\n if: aWindowCanvas display serverName\n IsPresentPut: [|:p|\n p ifNil: [\n pair copyX: 'leave' Y: self\n ]\n IfNotNil: [\n p x = 'leave' ifTrue: [ p ]\n False: [\n p y !", "= self ifTrue: [p y attachAllFromHand: self].", "\n nil\n ]\n ]\n ]\n AndDo: []\n IfAbsentPut: [pair copyX: 'leave' Y: self]\n AndDo: [].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: basics\\x7fComment: Overides this method so that a colorChangerMorph for example\nwill also change the screen edges, but not the held objects.\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n colorAll: newC = ( |\n | \n isInWorld ifFalse: [ color: newC. ^ self].", "\n (world morphs asList copyFilteredBy: \n [| :m | (m morphTypeName = screenEdge morphTypeName) && \n [m winCanvas = winCanvasForHand]\n ]\n ) do: [ | :se | se colorAll: newC].", "\n color: newC. \n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: copying\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n copy = ( |\n new.", "\n | \n new: resend.copy.", "\n new cursorInterest: cursorInterest copy.", "\n new keyboardInterest: keyboardInterest copy.", "\n new windowInterest: windowInterest copy.", "\n new userInfo: userInfo copy.", "\n new userInfo hand: new.", "\n new capabilitySet: capabilitySet copy.", "\n new morphsNotReadyToBeDropped: morphsNotReadyToBeDropped copyRemoveAll.", "\n new).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: copying\\x7fComment: Prototype corruption defensiveness\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n copyRemoveAllSubscribers = ( |\n | copy removeAllSubscribers).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: copying\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n copyWithFullCapabilities = ( |\n new.", "\n | \n new: copy.", "\n new addAllCapabilities: fullCapabilitySet.", "\n new).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: copying\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n copyWithNoCapabilities = ( |\n new.", "\n | \n new: copy.", "\n new removeAllCapabilities.", "\n new).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: damageManagement\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n damagedLeft: l Right: r Top: t Bottom: b From: m = ( |\n p.\n | \n \"Override this message to add the shadow offset.\"", "\n\n owner ifNotNil: [| px <- 0. ", "py <- 0. ", "|\n p: position.", "\n px: p x.\n py: p y.\n owner damagedLeft: l + px\n Right: r + px + shadowOffset x\n Top: t + py\n Bottom: b + py + shadowOffset y\n From: m.\n ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: dispatching\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n dispatchFrom: aWindowCanvas = ( |\n e.\n xEvt.", "\n | \n xEvt: (getEventFromWindowCanvas: aWindowCanvas ).", "\n e: (aWindowCanvas ui2Event copyFrom: xEvt LastCursor: lastCursor).", "\n\n xEvt delete.", "\n\n e ignore ifTrue: [ ^self ].", "\n e sourceHand: self.", "\n e adjustForCanvas: aWindowCanvas.", "\n\n e keyEvent ifTrue: [handleAndForward: e To: keyboardInterest. ", "^ self].", "\n e windowEvent ifTrue: [handleAndForward: e To: windowInterest. ", " ^ self].", "\n e wheelMovedInX ifTrue: [handleAndForward: e To: vector. ", " ^ self].", "\n e wheelMovedInY ifTrue: [handleAndForward: e To: vector. ", " ^ self].", "\n\n e mouseMotion ifTrue: [^ handleMouseMotionOn: aWindowCanvas From: e].", "\n\n e mouseUp ifTrue: [^ handleMouseUpOn: aWindowCanvas From: e].", "\n e mouseDown ifTrue: [\n \"a mouse button-down transition; see if it makes a double-click\"\n ^ handleMouseDownOn: aWindowCanvas From: e\n ].", "\n \"fall through for a null event\"\n ('got unknown event: ', e type printString) printLine.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: dispatching\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n doubleClickTime <- 300.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: drawing\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot'\n \n drawNameOn: c = ( |\n h.\n s.\n | \n h: userInfo preferences nameFontSpec size.", "\n s: name ifNil: ['!??'].", "\n c text: s \n At: position + (nameOffset + (0@h))\n FontSpec: userInfo preferences nameFontSpec\n Color: color).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: drawing\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n drawOn: aCanvas = ( |\n wc.", "\n | \n 0 = morphCount ifFalse: [| c |\n c: (aCanvas copyOffset: position + shadowOffset).", "\n c translucentlyDo: [\n c withColor: shadowColor Do: [\n \"draw all morphs with stippled shadowColor\"\n morphsDo: [| :m | m drawShadowOn: c ].", "\n ].", "\n ].", "\n c: (aCanvas copyOffset: position).", "\n morphsReverseDo: [| :m | m drawOn: c ].", "\n ].", "\n baseDrawOn: aCanvas.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: grabbingAndDropping\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n drop: aMorph Event: evt = ( |\n | \n morphsNotReadyToBeDropped remove: aMorph IfAbsent: [].", "\n \"do not send m delete because that would do way too much, e.g. collapse arrows\"\n aMorph owner removeMorph: aMorph.", "\n world fallingMorph: aMorph Event: evt.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n dropEvent: e = ( |\n | \n isInWorld ifTrue: [ \n \"changed to world for mouse wheel scrolling-- dmu\"\n dropEvent: e On: world \"topRootMorphAt: e cursorPoint\"\n ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n dropEvent: e On: m = ( |\n | \n m dispatchEvent: e At: e cursorPoint.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: capabilities\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot'\n \n fullCapabilitySet = ( |\n s.\n | \n s: set copyRemoveAll.", "\n s add: capabilities grabObject.", "\n s add: capabilities editText.", "\n s add: capabilities pressButton.", "\n s add: capabilities middleMouse.", "\n s add: capabilities rightMouse.", "\n s).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: dispatching\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n getEventFromWindowCanvas: wc = ( |\n evt.", "\n | \n evt: wc nextEvent.", "\n evt isMotionEvent ifFalse: [^ evt].", "\n\n \"Note: to improve mouse tracking, a sequence of motion events\n is reported as a single motion event having the coordinates of\n the last motion event in the sequence. ", "This approach would not\n be appropriate in a pen-based application that needs to record\n the complete path of the pointing device.\"", "\n \"The Mac never uses this code, since its\n motion events look like null events at this stage.", "\n But, the VM does it anyway for the Mac.\"", "\n [(0 < wc eventsPending) &&\n [|e. ", "isM| e: wc peekEvent.", "\n isM: e isMotionEvent.", "\n e delete.", "\n isM]\n ] whileTrue: [\n evt delete.", "\n evt: wc nextEvent. ", " \"Read it for good.\"", "\n ].", "\n evt).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: grabbingAndDropping\\x7fComment: Nobody sends this as of 9 - 13 - 95\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n grabAt: p = ( |\n pile.", "\n | \n \"Grab the root morph of the top morph at the given point. ", "That\n is, make the grabbed morph be a submorph of the hand.\"", "\n\n pile: world morphsAt: p.\n pile remove: world.", "\n pile isEmpty ifFalse: [| m |\n m: pile first root.", "\n m changed.", "\n m globalPosition: globalPosition + (m globalPosition - p).", "\n addMorph: m.\n ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: dispatching\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n handleAndForward: e To: subscribers = ( |\n | \n eventBeingHandledAndForwarded: e.\n e mouseMotion ifTrue: [\n subscribers do: [| :s | s mouseMove: e ].", "\n handleMouseMove: e.\n ^self\n ].", "\n e keyDown ifTrue: [\n (capabilitySet includes: capabilities editText) ifFalse: [ ^ self ].", "\n subscribers do: [| :s | s keyDown: e ].", "\n handleKeyDown: e.\n ^self\n ].", "\n e keyUp ifTrue: [\n subscribers do: [| :s | s keyUp: e ].", "\n ^self\n ].", "\n e leftMouseDown ifTrue: [\n subscribers do: [| :s | s leftMouseDown: e ].", "\n handleLeftMouseDown: e.\n subscribers do: [| :s | s mouseMove: e ].", "\n handleMouseMove: e.\n ^self\n ].", "\n e middleMouseDown ifTrue: [\n (capabilitySet includes: capabilities middleMouse) ifTrue: [\n subscribers do: [| :s | s middleMouseDown: e ].", "\n handleMiddleMouseDown: e.\n ].", "\n subscribers do: [| :s | s mouseMove: e ].", "\n handleMouseMove: e.\n ^self\n ].", "\n e rightMouseDown ifTrue: [\n (capabilitySet includes: capabilities rightMouse) ifTrue: [\n subscribers do: [| :s | s rightMouseDown: e ].", "\n handleRightMouseDown: e.\n ].", "\n subscribers do: [| :s | s mouseMove: e ].", "\n handleMouseMove: e.\n ^self\n ].", "\n e leftMouseUp ifTrue: [\n subscribers do: [| :s | s mouseMove: e ].", "\n handleMouseMove: e.\n subscribers do: [| :s | s leftMouseUp: e ].", "\n handleLeftMouseUp: e.\n ^self\n ].", "\n e middleMouseUp ifTrue: [\n subscribers do: [| :s | s mouseMove: e ].", "\n handleMouseMove: e.\n (capabilitySet includes: capabilities middleMouse) ifTrue: [\n subscribers do: [| :s | s middleMouseUp: e ].", "\n handleMiddleMouseUp: e.\n ].", "\n ^self\n ].", "\n e rightMouseUp ifTrue: [\n subscribers do: [| :s | s mouseMove: e ].", "\n handleMouseMove: e.\n (capabilitySet includes: capabilities rightMouse) ifTrue: [\n subscribers do: [| :s | s rightMouseUp: e ].", "\n handleRightMouseUp: e.\n ].", "\n ^self\n ].", "\n e leftDoubleClick ifTrue: [\n subscribers do: [| :s | s mouseMove: e ].", "\n handleMouseMove: e.\n subscribers do: [| :s | s leftDoubleClick: e ].", "\n handleLeftDoubleClick: e.\n ^self\n ].", "\n e middleDoubleClick ifTrue: [\n subscribers do: [| :s | s mouseMove: e ].", "\n handleMouseMove: e.\n subscribers do: [| :s | s middleDoubleClick: e ].", "\n handleMiddleDoubleClick: e.\n ^self\n ].", "\n e rightDoubleClick ifTrue: [\n subscribers do: [| :s | s mouseMove: e ].", "\n handleMouseMove: e.\n subscribers do: [| :s | s rightDoubleClick: e ].", "\n handleRightDoubleClick: e.\n ^self\n ].", "\n e wheelMovedInX ifTrue: [\n subscribers do: [| :s | s mouseMove: e ].", "\n handleMouseMove: e.\n subscribers do: [| :s | s wheelMovedInX: e ].", "\n handleWheelMovedInX: e.\n ^self\n ].", "\n e wheelMovedInY ifTrue: [\n subscribers do: [| :s | s mouseMove: e ].", "\n handleMouseMove: e.\n subscribers do: [| :s | s wheelMovedInY: e ].", "\n handleWheelMovedInY: e.\n ^self\n ].", "\n e windowEvent ifTrue: [\n subscribers do: [| :s | s windowEvent: e ].", "\n ^self\n ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n handleKeyDown: e = ( |\n | \n jumpScrollEvent: e.\n testMetaEscape: e. \n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n handleLeftDoubleClick: e = ( |\n | \n moveTo: e cursorPoint.", "\n untilAllUpClient ifNil: [ dropEvent: e ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n handleLeftMouseDown: e = ( |\n | \n moveTo: e cursorPoint.", "\n \"If carrying something, just drop it:\"\n \"0 = morphCount ifFalse: [ ^ungrabEvent: e ].\"", "\n \"safe to drop morphs that were added while button was down\"\n morphsNotReadyToBeDropped removeAll.", "\n 0 = morphCount ifFalse: [ ^ self].", "\n untilAllUpClient ifNil: [ dropEvent: e ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n handleLeftMouseUp: e = ( |\n | \n moveTo: e cursorPoint.", "\n ungrabEvent: e.\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n handleMiddleDoubleClick: e = ( |\n | \n moveTo: e cursorPoint.", "\n untilAllUpClient ifNil: [ dropEvent: e ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n handleMiddleMouseDown: e = ( |\n | \n moveTo: e cursorPoint.", "\n \"If carrying something, just drop it:\"\n \"0 = morphCount ifFalse: [ ^ungrabEvent: e ].\"", "\n untilAllUpClient ifNil: [ dropEvent: e ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n handleMiddleMouseUp: e = ( |\n | \n moveTo: e cursorPoint.", "\n \"ungrabEvent: e.\"\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: dispatching\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n handleMouseDownOn: aWindowCanvas From: e = ( |\n | \n \"a mouse button-down transition; see if it makes a double-click\"\n \"should move double-click logic to events , dmu 8/99\"\n e doesPlatformReportDoubleClicks not &&\n [ lastMouseDownEvent isNotNil &&\n [(lastMouseDownEvent type = e type) &&\n [(doubleClickTime > (e timeStamp - lastMouseDownEvent timeStamp))]]] ifTrue: [| doubleClick |\n doubleClick: lastMouseDownEvent copy.", "\n 'leftMouseDown' = doubleClick type ifTrue: [ doubleClick type: 'leftDoubleClick' ].", "\n 'middleMouseDown' = doubleClick type ifTrue: [ doubleClick type: 'middleDoubleClick' ].", "\n 'rightMouseDown' = doubleClick type ifTrue: [ doubleClick type: 'rightDoubleClick' ].", "\n handleAndForward: doubleClick To: cursorInterest.", "\n lastMouseDownEvent: nil.", "\n ] False: [\n \"doesn't make a double-click\"\n handleAndForward: e To: cursorInterest.", "\n lastMouseDownEvent: e.\n ].", "\n recordCursorPositionOn: aWindowCanvas From: e).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: dispatching\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n handleMouseMotionOn: aWindowCanvas From: e = ( |\n | \n handleAndForward: e To: cursorInterest. ", "\n recordCursorPositionOn: aWindowCanvas From: e.\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n handleMouseMove: e = ( |\n | moveTo: e cursorPoint).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: dispatching\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n handleMouseUpOn: aWindowCanvas From: e = ( |\n | \n if: e IsOutsideOf: aWindowCanvas Then: [^ self].", "\n\n handleAndForward: e To: cursorInterest. ", "\n e anyMouseIsDown not && [untilAllUpClient isNotNil] ifTrue: [\n \"automatically unsubscribe untilAllUpClient\"\n unsubscribeCursor: untilAllUpClient.", "\n untilAllUpClient: nil.", "\n ].", "\n recordCursorPositionOn: aWindowCanvas From: e).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n handleRightDoubleClick: e = ( |\n | \n moveTo: e cursorPoint.", "\n untilAllUpClient ifNil: [ dropEvent: e ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n handleRightMouseDown: e = ( |\n target.", "\n | \n moveTo: e cursorPoint.", "\n \"If carrying something, just drop it:\"\n \"0 = morphCount ifFalse: [ ^ungrabEvent: e ].\"", "\n untilAllUpClient ifNil: [\n target: (topRootMorphAt: e cursorPoint).", "\n target isWorldMorph ifTrue: [\n dropEvent: e.\n ] False: [\n target selfMenu popUp: e.\n ].", "\n ]. ", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n handleRightMouseUp: e = ( |\n | \n moveTo: e cursorPoint.", "\n \"ungrabEvent: e.\"\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n handleWheelMovedInX: e = ( |\n | dropEvent: e).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n handleWheelMovedInY: e = ( |\n | dropEvent: e).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: dispatching\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n if: evt IsOutsideOf: aWindowCanvas Then: blk = ( |\n | \n \"exclude mouseDowns outside canvas\"\n \"(mac receives them in the scroll bars\"\n (aWindowCanvas boundingBoxInWorld includes: evt cursorPoint )\n ifTrue: [self] False: blk).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: drawing\\x7fComment: Take on the look of the polygonMorph\n-- Randy, 6/12/95\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n imageFromPolygonMorph: pm = ( |\n | \n pm imageAsCursorForHand: self.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: basics\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n initializePrototype = ( |\n | \n color: paint named: 'red'.", "\n position: 10@10.", "\n beRigid.", "\n vertexOffsets:\n ((8@16) & (7@8) & (17@18) & (18@18) & (18@16) & (9@7) & (17@8)) asVector.", "\n removeAllSubscribers.", "\n capabilitySet: fullCapabilitySet copy.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: subscribing\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n isAKeyboardSubscriber: aMorph = ( |\n | keyboardInterest includes: aMorph).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: classification\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n isHandMorph = ( |\n | \n true).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: drawing\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n isNameShownOn: aCanvas = ( |\n wc.", "\n | \n wc: winCanvasForHand.", "\n wc isNotNil && [aCanvas isSameDisplayAs: wc]\n ifTrue: [ userInfo preferences showNameToSelf ]\n False: [ userInfo preferences showNameToOthers ]).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot'\n \n jumpScrollEvent: e = ( |\n a.\n b.\n cs.", "\n i <- 3.", "\n pt <- (0)@(0).", "\n | \n \" Quick Exit \"\n (e commandIsDown || e metaIsDown) ifFalse: [^ self].", "\n\n \" Are we shift jumping? \"", "\n e shiftIsDown ifTrue: [i: 1].", "\n\n \" Setup \"\n cs: winCanvasForHand size.", "\n b: e keyCapsPressed first. \" ", "Hmm. ", "Assuming arrow press is first. ", "RCA 2016-07-25 \"\n a: e keyCaps arrows.", "\n\n \" Set jump direction and distance \"\n b = a left ifTrue: [pt: (cs x / i) negate @ 0 ].", "\n b = a right ifTrue: [pt: (cs x / i) @ 0 ].", "\n b = a up ifTrue: [pt: 0 @ (cs y / i) negate ].", "\n b = a down ifTrue: [pt: 0 @ (cs y / i) ].", "\n\n \" Jump if we need to \"\n pt !", "= (0@0) ifTrue: [world moveHand: self InWorldBy: pt].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: meta hand\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n metaHandEvent: e = ( |\n | \n e isShiftDownForLeftShiftHack ifTrue: [\n shedHand\n ] False: [ \n absorbHand ]. ", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n middleMouseDown: e = ( |\n | \n\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: basics\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n morphTypeName = 'handMorph'.", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n mouseUsageComment = ( |\n | \n 'The mouse buttons are currently assigned the following functions:\n\n left operate (e.g., move a slider or push a button) or\n grab the morph if it has no special behavior\n middle extend the selection in text editors\n right menu').", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: grabbingAndDropping\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n moveTo: p = ( |\n | \n ((0 = morphCount) &&\n [ isInWorld &&\n [(world winCanvases size = 1)]]) ifTrue: [\n \"need not report changed position if:\n 1. ", "hand is not carrying anything and\n 2. ", "world has only one display\n otherwise, must redraw the hand on non-local displays\"\n position: p.\n ^self.", "\n ].", "\n position = p ifFalse: [\n changed.", "\n position: p.\n changed.", "\n ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: name and other userInfo issues\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n name = ( |\n | \n userInfo name).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: name and other userInfo issues\\x7fComment: use this message to change the preferredName in the userInfo\nobject. ", "This will update the hand\\'s cachedNameSize slot.\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n name: s = ( |\n | \n changed.", "\n userInfo preferredName: s.\n setCachedNameWidth.", "\n changed).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: name and other userInfo issues\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n nameFontSpec: fs = ( |\n | \n changed.", "\n setCachedNameWidth.", "\n userInfo preferences nameFontSpec: fs.", "\n changed.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'ModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n parent* = bootstrap stub -> 'traits' -> 'polygonMorph' -> ().", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: dispatching\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n recordCursorPositionOn: aWindowCanvas From: e = ( |\n | \n lastCursor: e cursorPoint + aWindowCanvas offset).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: capabilities\\x7fComment: Better not send this to your hand or\nyour kind of finished for the day.\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n removeAllCapabilities = ( |\n | \n capabilitySet: capabilitySet copyRemoveAll.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: subscribing\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n removeAllKeyboardSubscribers = ( |\n | \n keyboardInterest copy do: [|:subscriber| unsubscribeKeyboard: subscriber].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: subscribing\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n removeAllSubscribers = ( |\n | \n cursorInterest: cursorInterest copyRemoveAll.", "\n removeAllKeyboardSubscribers.", "\n windowInterest: windowInterest copyRemoveAll.", "\n untilAllUpClient: nil.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: capabilities\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n removeCapability: c = ( |\n | \n removeCapability: c IfAbsent: [ error: 'capability not present']).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: capabilities\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n removeCapability: c IfAbsent: blk = ( |\n | \n capabilitySet remove: c IfAbsent: blk).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: name and other userInfo issues\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot'\n \n setCachedNameWidth = ( |\n w.\n | \n isInWorld ifTrue: [| xfnt |\n xfnt: (world anyOpenWindowCanvas structForFontSpec: userInfo preferences nameFontSpec).", "\n cachedNameWidth: (xfnt textWidth: name).", "\n ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: meta hand\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot'\n \n setNewMetaHand = ( |\n | \n metaHand: copy.", "\n metaHand userInfo: userInfo. \"", "Shares with current\"\n metaHand privateSetOwner: nil.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: name and other userInfo issues\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n setUserInfo = ( |\n | \n userInfo setNamesByGuess.", "\n setCachedNameWidth.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: meta hand\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n shedHand = ( |\n w.\n | \n isInWorld ifFalse: [ error: 'hand notInWorld' ].", "\n metaHand ifNil: [setNewMetaHand].", "\n metaHand privateSetOwner: world.", "\n world hands at: (world hands keyOf: self) Put: metaHand.", "\n w: world.", "\n privateSetOwner: nil. \"..", "in theory only, this should not be necessary, but hands are weird.\"", "\n w addMorph: self.", "\n metaHand: nil.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: drawing\\x7fComment: Take on the default window system\nappearance of the cursor.", "\n -- Randy, 6/12/95\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n showDefaultImage = ( |\n | \n (world winCanvasForHand: self) platformWindow undefineCursor.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: subscribing\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n subscribeCursor: subscriber = ( |\n | \n (cursorInterest includes: subscriber) ifFalse: [\n cursorInterest add: subscriber.", "\n ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: subscribing\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n subscribeKeyboard: subscriber = ( |\n | \n (isAKeyboardSubscriber: subscriber) ifFalse: [\n keyboardInterest add: subscriber.", "\n ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: subscribing\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n subscribeKeyboardExclusive: subscriber = ( |\n | \n \"Subscribe the given subscriber, unsubscribing all others.\"", "\n\n keyboardInterest copy do: [|:s| s = subscriber ifFalse: [unsubscribeKeyboard: s]].", "\n keyboardInterest isEmpty ifTrue: [ keyboardInterest add: subscriber ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: subscribing\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n subscribeUntilAllUp: subscriber = ( |\n | \n \"First unsubscribe the old client, if any. ", "There is at most one untilAllUp client\n at any given time. ", "This means clients of subscribeUntilAllUp get exclusive\n access until the mouse button goes up or another client prempts them.\"", "\n\n untilAllUpClient ifNotNil: [ unsubscribeCursor: untilAllUpClient ].", "\n subscribeCursor: subscriber.", "\n untilAllUpClient: subscriber.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: subscribing\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n subscribeWindow: subscriber = ( |\n | \n (windowInterest includes: subscriber) ifFalse: [\n windowInterest add: subscriber.", "\n ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: dispatching\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n testMetaEscape: e = ( |\n | \n \"holding down meta key and typing escape\"\n \"(meta is command on mac)\"\n (e metaIsDown) && [e keyDown && [e keystrokes includes: '\\x1b']] ifTrue: [metaHandEvent: e]).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: event handling\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: private'\n \n topRootMorphAt: p = ( |\n | \n world rootMorphsAt: p Do: [| :m | ^m ].", "\n world).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: grabbingAndDropping\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n ungrabEvent: evt = ( |\n mList.", "\n | \n \"Drop all morphs being carried by the hand.\"", "\n 0 = morphCount ifTrue: [ ^self ].", "\n mList: morphs asList copyFilteredBy: [|:m| \n (morphsNotReadyToBeDropped includes: m) not].", "\n \"use reverse do so that bottommost morphs drop first\"\n mList reverseDo: [| :m | drop: m Event: evt ].", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: subscribing\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n unsubscribeCursor: subscriber = ( |\n | \n untilAllUpClient = subscriber ifTrue: [ \n untilAllUpClient: nil ].", "\n cursorInterest remove: subscriber IfAbsent: nil.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: subscribing\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n unsubscribeKeyboard: subscriber = ( |\n | \n keyboardInterest remove: subscriber IfAbsent: nil.", "\n subscriber keyboardSubscriptionLapsedFor: self.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: subscribing\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n unsubscribeWindow: subscriber = ( |\n | \n windowInterest remove: subscriber IfAbsent: nil.", "\n self).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: grabbingAndDropping\\x7fComment: Simulate dragging the mouse.", "\n-- Ungar, 6/20/95\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n warpTo: p = ( |\n delta.", "\n evt.", "\n | \n \"change the relationship of the cursor to the mouse\"\n isInWorld ifFalse: [ ^ self ].", "\n winCanvasForHand warpCursorTo: p.\n \"handleAndForward: will be distributing this event, must fix its loc\"\n eventBeingHandledAndForwarded ifNotNil: [|:e| e cursorPoint: p].", "\n moveTo: p).", "\n } | ) \n\n bootstrap addSlotsTo: bootstrap stub -> 'traits' -> 'handMorph' -> () From: ( | {\n 'Category: accessing\\x7fComment: get the winCanvas that\nis my home\n-- Ungar, 1/24/95\\x7fModuleInfo: Module: handMorph InitialContents: FollowSlot\\x7fVisibility: public'\n \n winCanvasForHand = ( |\n | \n isInWorld ifFalse: [ ^ nil ].", "\n world winCanvasForHand: self IfAbsent: nil).", "\n } | ) \n\n\n\n '-- Sub parts'\n\n bootstrap read: 'userProfile' From: 'ui2'\n bootstrap read: 'capability' From: 'ui2'\n\n\n\n '-- Side effects'\n\n globals modules handMorph postFileIn\n" ]

{ "pile_set_name": "Github" }

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[ "Introduction {#s1}\n============\n\nUnderstanding how brain synapses, cells, and circuits are persistently modified by experience to store information represents one of the great challenges in neuroscience. ", "Mouse visual cortex has proven to be an excellent model system in which to examine experience-dependent neural response modification. ", "One robust type of visual response plasticity is reliably elicited in adult (\\> P60) mice by simply closing one eyelid. ", "Over the course of 5--7 days of monocular deprivation (MD), the responses in visual cortex evoked by stimulation of the non-deprived eye progressively increase ([@bib48]; [@bib47]). ", "This deprivation-enabled response potentiation is driven by visual experience through the non-deprived eye, as only the responses through one eye are potentiated (*i.e.*, it is input specific) and it fails to occur if both eyelids are closed or if the animals are kept in a dark room ([@bib3]). ", "There is evidence that the response potentiation is mediated in part by \"Hebbian\" strengthening of excitatory synaptic transmission in visual cortex, as induction requires cortical NMDA receptor (NMDAR) activation ([@bib48]) ([@bib47]) and α-calcium/calmodulin-dependent protein kinase II (αCAMKII) expression in principal cells ([@bib44]). ", "This form of ocular dominance (OD) plasticity is likely responsible for the increase in visual acuity that occurs through the non-deprived eye following adult monocular deprivation ([@bib26]), and is of particular interest in the context of recovery of brain function after deprivation, disease, or damage ([@bib9]).", "\n\nAnother robust form of visual response plasticity is induced by exposure of awake mice to oriented visual grating stimuli. ", "Brief daily presentation of a phase-reversing grating of a single orientation causes a large and persistent increase in the peak cortical response to this orientation, as measured by visual evoked potentials (VEPs) or unit recordings ([@bib19]; [@bib13]). ", "This phenomenon is termed stimulus-selective response potentiation (SRP) because only responses to the experienced orientation are increased. ", "Abundant evidence suggests that SRP is also mediated by \"Hebbian\" mechanisms, particularly those revealed by the study of long-term synaptic potentiation ([@bib10]; [@bib11]). ", "The mechanisms utilized for SRP within V1 have also been shown to mediate a fundamental form of long-term visual recognition memory, manifested behaviorally as orientation-selective habituation (OSH) ([@bib12]; [@bib13]).", "\n\nBoth monocular deprivation and selective visual experience trigger input-specific increases in the short latency VEP measured in layer 4 of mouse visual cortex and, as reviewed above, both OD plasticity and SRP share some molecular requirements (*e.g.,* NMDAR activation). ", "Thus, it came as a surprise that response potentiation after monocular deprivation and SRP do not occlude one another ([@bib18]), suggesting that they employ different mechanisms or are expressed by different synapses. ", "We became interested in the possibility of differential involvement of cortical inhibition mediated by the parvalbumin-expressing (PV+) fast spiking neurons. ", "PV+ fast-spiking inhibitory neurons comprise the most numerous sub-class of GABAergic cortical neurons ([@bib52]) and receive substantial feed-forward glutamatergic input from the thalamus ([@bib16]). ", "These interneurons synapse preferentially on the somata and initial axon segments of principal cells, and therefore are in a position to strongly and precisely modulate even short latency visually evoked responses ([@bib15]; [@bib37]; [@bib27]). ", "Moreover, previous studies have suggested that fast-spiking interneurons participate in the expression of cortical eye dominance and OD plasticity in juvenile mice ([@bib53]; [@bib50]). ", "The contribution of this class of neuron to cortical plasticity is also of particular interest given the evidence for cortical PV+ neuron dysfunction in various psychiatric disorders characterized by impaired cognitive function ([@bib20]).", "\n\nIn the current study we used a variety of approaches to understand the contribution of PV+ neurons to adult OD plasticity and SRP. ", "We find that neither the pharmacogenetic silencing of PV+ cells nor the specific deletion of NMDARs within them affect the relative eye dominance or the expression of deprivation-enabled potentiation of VEPs in adult mice. ", "In contrast, and quite unexpectedly, we discovered that the expression of SRP is dependent on PV+ cell activity, and that perturbations of PV+ neuron function, most notably cell-type specific ablation of NMDARs, disrupt the expression of both SRP and its behavioral correlate, familiarity recognition.", "\n\nResults {#s2}\n=======\n\nOcular dominance is maintained in the absence of PV+ neuron activity {#s2-1}\n--------------------------------------------------------------------\n\nIn order to understand the role of PV+ neurons in the expression of experience-dependent visual cortical plasticity, we selectively inactivated these cells using a Dreadd (Designer Receptors Exclusively Activated by Designer Drugs) pharmacogenetic system: Specifically, we expressed a re-engineered G-protein coupled receptor, hM4D(Gi), which is activated exclusively by an otherwise inert small molecule, clozapine-N-oxide (CNO) ([@bib39]). ", "The binding of CNO to the hM4D(Gi) receptor activates intracellular G~i~-mediated signaling and subsequent hyperpolarization of the cell in which the receptors are expressed. ", "We locally expressed hM4D(Gi) receptors in PV+ cells of binocular V1 using an adeno-associated viral vector containing a construct for Cre-selective expression (AAV9-hSyn-DIO-HA-hM4D(Gi)-IRES-mCitrine) in mice that express Cre recombinase only in PV+ cells (B6;129P2-*Pvalb^tm1(cre)Arbr^*/J, PV-Cre). ", "We confirmed the selective expression of hM4D(Gi) receptors in PV+ neurons in binocular V1 using immunohistochemistry ([Figure 1A--E](#fig1){ref-type=\"fig\"}). ", "In order to ensure that PV+ neurons could be inactivated by this method, we took slices of V1 for ex vivo intracellular recordings. ", "Bath application of CNO drastically inhibited current evoked action potential firing of PV+ neurons in Layer 4 (2-way repeated measures ANOVA, interaction of CNO x current injection, F~(8,72)~ = 6.227, P \\< 0.001, n = 10 cells, significant at data points above 100pA: q(8) = 3.716, P = 0.014) but had no effect on neighboring non-expressing cells ([Figure 1F--G](#fig1){ref-type=\"fig\"}). ", "Layer 4 recordings in vivo demonstrated that systemic administration of CNO resulted in the elevation of visually-evoked potential (VEP) magnitude, and an increase in the firing rate of excitatory single units ([Figure 1H--I](#fig1){ref-type=\"fig\"}), which are expected consequences of inactivating PV+ inhibitory neurons in binocular V1.10.7554/eLife.11450.003Figure 1.The hM4D(Gi) DREADD system locally inactivates parvalbumin+ neurons in binocular primary visual cortex (V1).(**A**) An example of V1 expression of hM4D(Gi) in a parvalbumin (PV)-Cre recombinase (Cre) mouse infected locally in binocular V1 with AAV9-hSyn-DIO-hM4D(Gi)-mCitrine. (**", "B**) A DAPI stain for cell nuclei is shown in blue. (**", "C**) Infected cells expressing hM4D(Gi) are labeled in green. (**", "D**) Immuno-labeled PV+ cells are shown in red. (**", "E**) The merged image reveals that hM4D(Gi)-expressing cells are also PV+. (**", "F**) Intracellular current clamp recordings of hM4D(Gi)-infected PV+ layer 4 neurons in *ex vivo* slices of V1 reveal that green-labeled infected cells exhibit a non-adapting fast-spiking phenotype typical of fast-spiking inhibitory neurons (black). ", "These cells do not fire action potentials in the presence of CNO (red), the exogenous ligand for hM4D(Gi) receptors, despite depolarizing current injection. ", "In contrast, neighboring cells that are not mCitrine+ show no impact of CNO application. (**", "G**) HM4D(Gi)-mediated inactivation of putative fast-spiking PV+ inhibitory neurons is here summarized as the number of action potentials resulting from a given current injection before (black) and after CNO application (red). (**", "H**) The effects of hM4D(Gi)-mediated inactivation of putative PV+ fast-spiking inhibitory neurons *in vivo* are apparent from electrophysiological recordings from V1 of awake, head-fixed mice viewing phase-reversing sinusoidal grating stimuli. ", "Averaged Visually Evoked Potential (VEP) recordings recorded in layer 4 reveal increased VEP magnitude in the presence of CNO (red), relative to pre-CNO (baseline) recordings (black), indicative of reduced inhibition. (**", "I**) Phase reversal-evoked action potentials recorded from neurons in layer 4 also exhibit a similar effect with elevated firing rates in the presence of CNO (red) relative to the baseline recording (black). ", "Labeled scale bars are presented throughout. ", "Error bars are standard error of the mean (S.E.M.).**DOI:** [http://dx.doi.org/10.7554/eLife.11450.003](10.7554/eLife.11450.003)10.7554/eLife.11450.004Figure 1---source data 1.Action potential number for current injection.**DOI:** [http://dx.doi.org/10.7554/eLife.11450.004](10.7554/eLife.11450.004)\n\nMouse binocular V1 is \\~2--3 times more strongly activated by the contralateral (contra) eye than the ipsilateral (ipsi) eye, an inherent bias known as ocular dominance (OD). ", "We probed the involvement of PV+ neuron activity in maintaining baseline OD. ", "PV-Cre mice were infected with AAV virus to deliver hM4D(Gi) Dreadd receptors to PV+ neurons in binocular V1 ([Figure 2A](#fig2){ref-type=\"fig\"}). ", "Electrodes were simultaneously implanted into layer 4 of V1 for VEP recordings. ", "VEPs elicited through just contralateral or ipsilateral eyes were acquired consecutively before and after CNO administration ([Figure 2A--B](#fig2){ref-type=\"fig\"}). ", "After CNO injection, VEPs driven through each eye increased significantly in magnitude (2-way repeated measures ANOVA, effect of CNO, F~(7)~ = 75.986, P \\< 0.001; contralateral eye: 222.18 ± 14.79 µV baseline vs. 679.81 ± 64.12 µV CNO, Student-Newman-Keuls (SNK) post hoc test, q~(7)~ = 13.925, n = 8 mice, P \\< 0.001; ipsilateral eye: 105.56 ± 6.78 µV baseline vs. 358.63 ± 35.79 µV CNO, SNK post hoc test, q~(7)~ = 7.711, n = 8 mice, P \\< 0.001, ([Figure 2C](#fig2){ref-type=\"fig\"}), consistent with the occurrence of cortical disinhibition. ", "However, the OD of visual responses in V1 (contra/ipsi ratio) was not significantly altered by CNO injection (2.13 ± 0.12 baseline vs. 1.96 ± 0.18 CNO, student's paired two-tailed t-test, t~(7)~ = 0.859, n = 8 mice, P = 0.42, [Figure 2D](#fig2){ref-type=\"fig\"}). ", "This result suggests that the inherent OD of binocular visual cortex is not dependent on PV+ neuron activity.10.7554/eLife.11450.005Figure 2.Inactivation of parvalbumin+ neurons has no impact on expression of ocular dominance (OD) or the ocular dominance shift as a result of monocular deprivation (MD) in the adult mouse.(**A**) For experiments described in this figure mice were infected across all cortical depths bilaterally in binocular V1 (green). ", "During the same surgical implantation procedure VEP recording electrodes were also positioned in layer 4 and chronically fixed. (**", "B**) Mice (P45-60) were infected and implanted with electrodes and then left for 3 weeks for the AAV9 viral vector to reach maximal expression, after which they underwent habituation to head-fixation and a gray screen for two consecutive days. ", "Following this, on experimental day 0, mice were presented with an X^o^ phase-reversing sinusoidal grating stimulus separately to the left and right eye. ", "VEPs were recorded from each hemisphere in order to determine ocular dominance in binocular V1. ", "Mice were then removed from the recording apparatus and, CNO was delivered systemically half an hour prior to undertaking the same recording procedure, this time using an orthogonal X + 90° visual stimulus. (**", "C**) As is well documented, responses in V1 to stimuli viewed through the contralateral eye (blue) were greater in magnitude than those elicited through the ipsilateral eye (yellow), as measured here by VEP magnitude. ", "After application of CNO (red outlines), VEP magnitude dramatically increased. (**", "D**) This increase was scaled such that the ratio of Contralateral:Ipsilateral VEP magnitude was maintained before (white) and after CNO (red). (**", "E**) In a second group of mice, a similar experimental protocol was observed prior to measuring ocular dominance by recording VEPs in each hemisphere elicited by an X^o^ stimulus through each eye. ", "One hemisphere was then selected and the contralateral eye was sutured closed. ", "After 7 days of monocular deprivation, the eye was opened and VEPs driven through either eye were again recorded, this time elicited by an X + 60° stimulus. ", "Mice were then systemically injected with CNO and, half an hour later, VEPs driven through either eye were recorded, this time elicited by an X - 60° stimulus. (**", "F**) After the adult mice underwent 7 days of MD, there was a significant potentiation of the V1 response to visual input through the ipsilateral eye (yellow). ", "After application of CNO (red outlines), VEPs driven through each eye were elevated in magnitude, but again the increase in VEP magnitude was scaled. (**", "G**) As a result of open eye potentiation after MD, the OD ratio shifted dramatically from the contralateral bias of pre MD (white) to an almost equal cortical response through contralateral and ipsilateral eyes (black). ", "This shifted ratio was unaffected by hM4Di-mediated inactivation of putative fast-spiking inhibitory neurons during CNO application (red), indicating that the expression of OD and its shift as a result of MD in adult mice do not require fast-spiking inhibition. ", "Significant comparisons are labeled with an asterisk and non-significant comparisons with n.s. ", "throughout. ", "Error bars are standard error of the mean (S.E.M.).**DOI:** [http://dx.doi.org/10.7554/eLife.11450.005](10.7554/eLife.11450.005)10.7554/eLife.11450.006Figure 2---source data 1.Ocular dominance and deprivation effects are maintained after PV neuron inactivation.**DOI:** [http://dx.doi.org/10.7554/eLife.11450.006](10.7554/eLife.11450.006)\n\nExpression of adult ocular dominance (OD) plasticity does not require the activity of PV+ neurons {#s2-2}\n-------------------------------------------------------------------------------------------------\n\nThe normal OD ratio is altered in the adult mouse by MD of the contralateral eye over 7 days, resulting in an ocular dominance shift that features potentiation of response through the open ipsilateral eye ([@bib48]; [@bib47]). ", "In a new group of mice we assayed the effect of PV+ neuron inactivation on the expression of the shift in OD caused by MD. ", "We recorded VEPs elicited through each eye from PV-Cre mice expressing hM4D(Gi) receptors in binocular V1 ([Figure 2E](#fig2){ref-type=\"fig\"}). ", "After baseline recordings the mice underwent contralateral eyelid suture and 7 days of monocular deprivation. ", "Subsequently, the contralateral (deprived) eye was opened and VEPs were re-recorded in order to reveal the expression of an OD shift. ", "There was a significant potentiation of VEP magnitude driven through the ipsilateral eye following 7 days of MD (69.5 ± 5.81 µV pre MD vs. 139.5 ± 9.33 µV post MD, n = 10 mice, student's paired one-tailed t-test, t~(9)~ = -10.184, P \\< 0.001, [Figure 2F](#fig2){ref-type=\"fig\"}). ", "This potentiation of response through the ipsilateral (non-deprived) eye resulted in a significant shift in the OD ratio (contra/ipsi ratio, 3.08 ± 0.26 pre MD vs. 1.33 ± 0.10 post MD, 1-way repeated measures ANOVA, SNK post hoc test, q~(2)~ = 11.77, P \\< 0.001, [Figure 2G](#fig2){ref-type=\"fig\"}). ", "Mice were then injected with CNO and re-recorded to assess whether the OD shift would persist in the absence of PV+ neuron activity. ", "CNO injection resulted in an increase in VEP magnitudes ([Figure 2F](#fig2){ref-type=\"fig\"}), but importantly the shift in the contra/ipsi ratio was maintained (1.33 ± 0.10 post MD vs. 1.35 ± 0.18 post MD CNO, SNK post hoc test, q~(2)~ = 0.127, P = 0.93, [Figure 2G](#fig2){ref-type=\"fig\"}). ", "Therefore, the expression of the adult OD shift induced by 7 days of MD persists after a strong reduction in PV+ neuron inhibition.", "\n\nInactivation of PV+ neurons disrupts expression of stimulus-selective response potentiation (SRP) {#s2-3}\n-------------------------------------------------------------------------------------------------\n\nWe next assayed the role of PV+ neurons in the expression mechanism underlying stimulus-selective response potentiation (SRP), a second form of experience-dependent visual cortical plasticity that also manifests as an increase in V1 responses ([@bib19]; [@bib10]). ", "Binocular VEPs were recorded from awake, head-fixed adult mice viewing phase-reversing gratings of a particular orientation (X^o^ stimulus) on each of 6 consecutive days ([Figure 3A and B](#fig3){ref-type=\"fig\"}). ", "On the 7th day mice viewed blocks of the now familiar visual stimulus interleaved with blocks of a novel oriented stimulus (X +/- 60°). ", "To address whether PV+ neuron activity is required for the expression of SRP, familiar and novel oriented grating stimuli were presented before and after mice received CNO ([Figure 3A](#fig3){ref-type=\"fig\"}).10.7554/eLife.11450.007Figure 3.The expression of Stimulus-selective Response Potentiation (SRP) requires activity in PV+ neurons in V1.(**A**) Mice expressing hM4D(Gi) receptors in PV+ cells underwent a standard SRP induction protocol. ", "On day 7, mice viewed a novel oriented stimulus in addition to the familiar stimulus; before and after CNO injection. (**", "B**) We acquired binocular VEPs from awake, head-fixed mice elicited by the same full-field oriented sinusoidal grating stimulus over several days. (**", "C**) As a result of multiple days of experience cortical response was dramatically potentiated such that the familiar stimulus evoked VEPs of significantly greater magnitude than the novel stimulus (black bars). (**", "D**) After application of CNO, VEPs underwent a notable increase in magnitude as a result of disinhibition (red bars). ", "Most notably, CNO rendered response to familiar and novel stimuli equivalent in magnitude. (**", "E**) This lost discrimination of familiar and novel stimuli is reflected as a drop in the ratio of response to familiar and novel stimuli from approximately 2:1 (black) to approximately 1:1 (red). ", "Significant comparisons are labeled with an asterisk and non-significant comparisons with n.s. ", "throughout. ", "Error bars are standard error of the mean (S.E.M.).**DOI:** [http://dx.doi.org/10.7554/eLife.11450.007](10.7554/eLife.11450.007)10.7554/eLife.11450.008Figure 3---source data 1.PV Dreadds SRP induction and expression.**DOI:** [http://dx.doi.org/10.7554/eLife.11450.008](10.7554/eLife.11450.008)10.7554/eLife.11450.009Figure 3---figure supplement 1.CNO has no impact on SRP expression in WT mice.(**A**) C57BL/6 WT mice were bilaterally infected with AAV9-hSyn-DIO-hM4D(Gi)-mCitrine in binocular V1. ", "Because these mice did not express Cre recombinase there was no subsequent expression of hM4D(Gi) DREADDS receptors. ", "After 4 weeks, during which hM4D(Gi) was expressed at high levels in PV-Cre mice, WT mice were taken through a standard SRP protocol of electrode implantation, habituation and visual experience of a single oriented grating. ", "This progressed as usual, resulting in a significant increase in the magnitude of the VEP. (**", "B**) Expression of SRP was then tested on day 7 by interleaving presentations of familiar and novel orientations and VEPs elicited by the familiar orientation were of significantly greater magnitude than the novel. ", "After delivery of CNO, VEPs were again tested in response to the familiar orientation and a second novel orientation. ", "The drug had no impact and a similar degree of significant stimulus selectivity was present. ", "Significant comparisons are marked with an asterisk throughout while non-significant comparisons are marked with n.s. ", "Error bars are standard error of the mean (S.E.M.).**DOI:** [http://dx.doi.org/10.7554/eLife.11450.009](10.7554/eLife.11450.009)10.7554/eLife.11450.010Figure 3---figure supplement 1---source data 1.CNO has no effect on SRP expression in WT mice.**DOI:** [http://dx.doi.org/10.7554/eLife.11450.010](10.7554/eLife.11450.010)\n\nAs is characteristic of SRP, there was a significant increase in the magnitude of the average VEP evoked by the familiar oriented grating stimulus over days (Friedman 1-way repeated measures ANOVA on ranks, n = 10 mice, X^2^~(5)~ = 40.40, P \\< 0.001, [Figure 3C](#fig3){ref-type=\"fig\"}). ", "This potentiation was evident by day 2 (263.3 ± 19.96 µV) in comparison with day 1 (184 ± 17.13 µV, SNK post hoc test, q~(9)~ = 4.472, P \\< 0.05). ", "The stimulus selectivity of VEP magnitude potentiation was apparent on day 7 and significantly affected by inactivating PV+ inhibitory neurons in V1 (2-way repeated measures ANOVA, interaction of treatment x stimulus, F = 78.927~(1,9)~, P \\< 0.001, [Figure 3D](#fig3){ref-type=\"fig\"}): Prior to delivery of CNO the average VEP magnitude driven by the familiar stimulus (324.7 ± 22.18 µV) was significantly greater than that driven by a novel oriented stimulus (162.9 ± 16.31 µV, SNK post hoc test, q~(9)~ = 10.709, P \\< 0.001). ", "Following injection of CNO to inactivate hM4D(Gi)-infected neurons in V1, there was no longer a significant difference in the magnitude of VEPs driven by the familiar stimulus (537.2 ± 66.69 µV) compared with a novel stimulus (525.1 ± 68.30 µV, SNK post hoc test, q~(9)~ = 0.804, P = 0.58). ", "The selectivity of the potentiation to a familiar stimulus can be summarized by plotting the ratio of VEP magnitudes driven by familiar and novel stimuli ([Figure 3E](#fig3){ref-type=\"fig\"}). ", "Mice expressed a significantly larger familiar/novel ratio before CNO injection (2.11 ± 0.17), corresponding to a greater response to the familiar stimulus, compared to after CNO injection (1.03 ± 0.04, Mann Whitney rank sum test, U = 0.00, P \\< 0.001). ", "CNO injection did not affect the stimulus selectivity of SRP in wild type animals infected with virus ([Figure 3---figure supplement 1A--B](#fig3s1){ref-type=\"fig\"}). ", "These animals underwent SRP ([Figure 3---figure supplement 1A](#fig3s1){ref-type=\"fig\"}) and on test day showed significantly larger VEPs to the familiar stimulus, both prior to CNO injection (familiar VEP: 361.06 ± 27.97 µV, novel VEP: 219.25 ± 17.9 µV, 2-way repeated measures ANOVA, n = 8 mice, SNK post hoc test, q~(7)~ = 13.618, P \\< 0.001) and following CNO injection (familiar VEP: 369.00 ± 31.16 µV, novel VEP: 256.75 ± 19.59 µV, SNK post hoc test, q~(7)~ = 10.779, P \\< 0.001, [Figure 3---figure supplement 1B](#fig3s1){ref-type=\"fig\"}). ", "These results show that the inactivation of PV+ neurons in binocular V1 disrupts the expression of SRP.", "\n\nDisruption of SRP by PV+ neuronal inactivation is not due to saturation of responses {#s2-4}\n------------------------------------------------------------------------------------\n\nCortical neurons respond within a dynamic range, and it is possible that discrimination of familiar and novel stimuli would be lost as responses approach saturation. ", "Our observation that OD is maintained after PV+ neuron inactivation ([Figure 2](#fig2){ref-type=\"fig\"}) indicates that V1 can still respond selectively to a strong (contralateral eye) and weak (ipsilateral eye) input. ", "However, to address the possibility that a \"ceiling effect\" contributes to the disruption of SRP expression during PV+ cell inactivation, we conducted an additional experiment in which mice viewed sinusoidal grating stimuli across a range of contrast values (5, 10, 25, 50, 100%). ", "VEPs were progressively greater in magnitude the greater the contrast of the viewed stimulus (2-way repeated measures ANOVA, n = 4 mice, effect of contrast, F~(4,12)~ = 25.908, P \\< 0.001) both before and during PV+ neuronal activation using the hM4D(Gi) system (SNK post hoc test, 5 vs. 100 percent contrast, baseline; q~(4)~ = 5.178, P = 0.013; CNO; q~(4)~ = 17.595, P \\< 0.001, [Figure 4A](#fig4){ref-type=\"fig\"}). ", "Preservation of the approximately linear relationship of contrast and response during PV+ neuron inactivation indicates that responses have not exceeded their dynamic range.10.7554/eLife.11450.011Figure 4.Expression of SRP to two separate contrast values is blocked by hM4D(Gi)-mediated PV+ neuron inactivation, but differential response to contrast is maintained.(**A**) CNO delivery to PV-Cre mice that had been infected with AAV9-hSyn-DIO-hM4D(Gi)-mCitrine impacted VEP magnitude (red) significantly across a range of contrast compared to baseline (black). (**", "B**) SRP was induced to two differently oriented stimuli, each at different contrast values: 50% (gray) and 100% (black). ", "Modest but significant SRP was expressed at 50% contrast prior to CNO application. ", "After CNO application (red outlines), VEPs increased significantly in magnitude but were no longer significantly different for familiar and a second novel orientation. (**", "C**) SRP was also expressed for a different orientation at 100% contrast and, again, VEP magnitude was increased and SRP blocked by delivery of CNO. (**", "D**) The blockade of SRP expression by CNO at 50% contrast was apparent in the reduction in the familiar/novel ratio for VEP magnitude. (**", "E**) The blockade of SRP expression at 100% contrast was also observed as a significant drop in familiar/novel ratio of VEP magnitude after CNO delivery. ", "Significant comparisons are marked with an asterisk throughout while non-significant comparisons are marked with n.s. ", "Error bars are standard error of the mean (S.E.M.).**DOI:** [http://dx.doi.org/10.7554/eLife.11450.011](10.7554/eLife.11450.011)10.7554/eLife.11450.012Figure 4---source data 1.PV-neuron inactivation does not produce ceiling effect.**DOI:** [http://dx.doi.org/10.7554/eLife.11450.012](10.7554/eLife.11450.012)\n\nWe then induced SRP to different orientations in a different set of mice, one stimulus at 50% contrast and the other stimulus at 100% contrast. ", "After 6 days of SRP at 50%, there was a modest but significant difference in VEP magnitude for familiar (188.81 ± 11.80 µV) and novel orientations (145.06 ± 8.11 µV, 2-way repeated measures ANOVA, n = 8 mice, SNK post hoc test, q~(7)~ = 3.608, P = 0.023, [Figure 4B](#fig4){ref-type=\"fig\"}), just as there was for the familiar (259.81 ± 17.66 µV) and novel orientations (192.81 ± 17.27 µV, SNK post hoc test, q~(7)~ = 3.793, P = 0.018, [Figure 4C](#fig4){ref-type=\"fig\"}) at 100% contrast. ", "SRP expression was abolished by PV+ neuronal inactivation using the hM4D(Gi) system at 50% contrast as VEPs elicited by familiar (404.69 ± 59.17 µV) and novel orientations (376.94 ± 56.79 µV) were no longer significantly different (SNK post hoc test, q~(7)~ = 2.289, P = 0.128, [Figure 4B](#fig4){ref-type=\"fig\"}). ", "The same was true at 100% contrast as VEPs evoked by the familiar (532.44 ± 63.82 µV) and novel orientations (514.88 ± 40.38 µV) were also no longer significantly different (SNK post hoc test, q~(7)~ = 0.994, P = 0.494, [Figure 4C](#fig4){ref-type=\"fig\"}). ", "Again, the blockade of SRP expression was also clearly observed in the familiar/novel ratio, which dropped significantly from (1.31 ± 0.05) to (1.08 ± 0.08) with CNO application at 50% contrast (student's paired two-tailed t-test, t~(7)~ = 2.983, P = 0.02, [Figure 4D](#fig4){ref-type=\"fig\"}) and from (1.40 ± 0.10) to (1.02 ± 0.05) with CNO application at 100% contrast (student's paired two-tailed t-test, t~(7)~ = 2.955, P = 0.021, [Figure 4E](#fig4){ref-type=\"fig\"}). ", "Thus, SRP could still be abolished through selective loss of PV+ neuron activity even at reduced contrasts eliciting submaximal responses. ", "The disruption of SRP expression by inactivation of PV+ neurons is not a trivial consequence of a \"ceiling effect\".", "\n\nActivation of PV+ neurons also disrupts expression of SRP {#s2-5}\n---------------------------------------------------------\n\nPV+ neurons have been implicated in the sharpening of orientation selectivity in V1 ([@bib45]; [@bib1]; [@bib2]; [@bib32]; [@bib51]). ", "If orientation selectivity were completely abolished by inactivation of PV+ neurons then the loss of SRP expression could be attributed to a failure of orientation discrimination rather than familiarity. ", "A previous experiment has indicated that activation of PV+ neurons in V1 actually mildly enhances orientation-selectivity and visual discrimination ([@bib32]). ", "Therefore, we used optogenetics to activate PV+ neurons while mice were presented with familiar and novel stimuli to test whether SRP expression would be enhanced, unaffected or disrupted. ", "PV+ neurons in binocular V1 of PV-Cre mice expressed Channel-rhodopsin 2 (ChR2) as a result of infection with AAV5-EF1α-DIO-hChR2(H134R)-eYFP. ", "During the same surgery VEP recording electrodes were implanted and optic fibers chronically implanted to deliver light to the recording site ([Figure 5A](#fig5){ref-type=\"fig\"}). ", "After stable expression 4 weeks after infection, mice were habituated to head-fixation on each of 2 days before undergoing a standard SRP experiment over 6 days ([Figure 5B,C](#fig5){ref-type=\"fig\"}). ", "Mice showed a significant increase in the magnitude of the average VEP evoked by the familiar oriented grating stimulus over days (Friedman repeated measures ANOVA on ranks, n = 11 mice, X^2^~(5)~= 24.818, P \\< 0.001, [Figure 5C](#fig5){ref-type=\"fig\"}). ", "This potentiation was evident by day 2 (237.55 ± 29.01 µV) in comparison with day 1 (182.59 ± 21.97 µV, SNK post hoc test, q~(10)~ = 7.675, P \\< 0.05). ", "On day 7, mice were presented with interleaved blocks of familiar and novel stimuli. ", "Also interleaved were blocks of familiar and novel stimuli in which blue light (473 nm) was continuously delivered via the optic fiber to the recording site in binocular V1. ", "VEPs elicited by the novel X + 90° stimulus were significantly lower in magnitude (221.34 ± 33.55 µV) than those elicited by the familiar stimulus prior to optogenetic activation of PV+ neurons (310.70 ± 36.70 µV, 2-way repeated measures ANOVA, n = 11 mice, SNK post hoc test, q~(10)~ = 11.799, P \\< 0.001, [Figure 5D](#fig5){ref-type=\"fig\"}). ", "Optogenetic activation of PV+ neurons significantly diminished the selectivity of SRP, as VEPs elicited by the familiar stimulus (181.23 ± 26.43 µV) and novel stimulus (157.80 ± 21.05 µV) were more similar in magnitude (interaction of stimulus x laser, F~(1,10)~ = 46.606, P \\< 0.001; familiar vs. novel SNK post hoc test, q~(10)~ = 3.094, P = 0.045, [Figure 5D](#fig5){ref-type=\"fig\"}). ", "The reduction of SRP selectivity is most clearly observed in the significant difference in the familiar/novel ratio without (1.55 ± 0.14) and with optogenetic stimulation (1.16 ± 0.07, student's paired two-tailed t-test, t~(10)~ = 4.423, P = 0.001, [Figure 5E](#fig5){ref-type=\"fig\"}). ", "Laser stimulation did not affect the stimulus selectivity of SRP in wild type animals infected with virus ([Figure 5---figure supplement 1](#fig5s1){ref-type=\"fig\"}), as there was no significant interaction between stimulus and laser (2-way repeated measures ANOVA, F~(1,8)~ = 0.677, P = 0.434). ", "These mice underwent SRP ([Figure 5---figure supplement 1A](#fig5s1){ref-type=\"fig\"}) and on test day showed significantly larger VEPs to the familiar stimulus, both with the laser off (familiar VEP: 273.69 ± 28.25 µV, novel VEP: 200.19 ± 19.53 µV, 2-way repeated measures ANOVA, n = 9 mice, SNK post hoc test, q~(8)~ = 5.234, P = 0.005) and the laser on (familiar VEP: 277.08 ± 29.80 µV, novel VEP: 194 ± 18.39 µV, q~(8)~ = 5.916, P = 0.002, [Figure 5---figure supplement 1B](#fig5s1){ref-type=\"fig\"}). ", "Thus, SRP expression was disrupted with activation of PV+ neurons, just as it was with inactivation ([Figure 3D--E](#fig3){ref-type=\"fig\"}). ", "This result implies that PV+ neurons play a specific role in SRP expression beyond any role in enhancing orientation tuning.10.7554/eLife.11450.013Figure 5.Optogenetic stimulation of PV+ inhibitory neurons prevents SRP expression.(**A**) Blue light was delivered locally into V1 via optic fibers chronically implanted at a 45° angle to target the VEP recording site in layer 4 of binocular V1 of PV-Cre mice infected with AAV5-EF1α-DIO-hChR2(H134R)-eYFP. (**", "B**) Experimental timeline showing that after viral infection, electrode implantation, and ChR2 expression; mice were accustomed to head-fixation and gray screen viewing. ", "Subsequently, they underwent a standard SRP induction protocol over 6 days. ", "On day 7, mice viewed a novel oriented stimulus in addition to the familiar stimulus and, on 50% of presentations of each stimulus, blue light (473 nm) was delivered to cortex to optogenetically activate PV+ cells. (**", "C**) Significant SRP was induced over 6 days as VEPs underwent a typical potentiation. (**", "D**) On day 7, SRP was expressed through significantly larger VEP magnitude in response to the familiar X^o^ orientation than a novel X + 90° stimulus when blue light was not delivered (Black bars). ", "In the presence of blue light (blue bars), VEPs were suppressed, and there was a significant reduction in the differential magnitude of VEPs driven by familiar and novel stimuli. (**", "E**) The ratio of VEP magnitude elicited by familiar/novel stimuli was significantly reduced by optogenetic activation of PV+ neurons, reflecting a decrement in SRP expression. ", "Significant comparisons are marked with an asterisk and post hoc test p values are reported in **D** to emphasize the impact of laser stimulation on SRP selectivity. ", "Error bars are standard error of the mean (S.E.M.).**DOI:** [http://dx.doi.org/10.7554/eLife.11450.013](10.7554/eLife.11450.013)10.7554/eLife.11450.014Figure 5---source data 1.PV-neuronal activation.**DOI:** [http://dx.doi.org/10.7554/eLife.11450.014](10.7554/eLife.11450.014)10.7554/eLife.11450.015Figure 5---figure supplement 1.Blue light has no impact on SRP expression.(**A**) To check that light itself had no effect on cortical physiology in the optogenetic experiments, WT mice were infected bilaterally with AAV5-EF1α -DIO-hChR2(H134R)-eYFP in binocular V1. ", "After 4 weeks, during which ChR2 was expressed at high levels in PV-Cre mice, WT mice were taken through the standard SRP protocol described above. ", "Again, significant SRP occurred. (**", "B**) On test day, during interleaved presentations of a familiar and novel oriented stimulus together with either blue light (473 nm) or no light stimulation delivery to V1, VEPs were significantly greater in magnitude for the familiar than the novel stimulus, regardless of the presence of blue light. ", "Significant comparisons are marked with an asterisk throughout while non-significant comparisons are marked with n.s. ", "Error bars are standard error of the mean (S.E.M.).**DOI:** [http://dx.doi.org/10.7554/eLife.11450.015](10.7554/eLife.11450.015)10.7554/eLife.11450.016Figure 5---figure supplement 1---source data 1.Laser does not effect VEPs in WT animals.**DOI:** [http://dx.doi.org/10.7554/eLife.11450.016](10.7554/eLife.11450.016)\n\nFull expression of SRP requires NMDA receptors (NMDARs) expressed in PV+ neurons {#s2-6}\n--------------------------------------------------------------------------------\n\nMultiple lines of evidence indicate that SRP is dependent upon the NMDA class of glutamate receptors ([@bib19]; [@bib13]). ", "Given the additional clear requirement for normal PV+ inhibitory cell function in SRP ([Figure 3D,E](#fig3){ref-type=\"fig\"}) we selectively ablated the NMDAR from just PV+ cells by crossing the PV-Cre line of mice with a line in which the mandatory GluN1 subunit of NMDAR is excised by Cre recombinase activity (B6.129S4-*Grin1^tm2Stl^*/J, GluN1 fl/fl). ", "The progeny of this cross, in which both alleles of Grin1 (the gene encoding GluN1) were floxed, are henceforth described as either PV-GluN1 KO or Wildtype (WT)-GluN1 fl/fl depending on whether, respectively, Cre was expressed or not. ", "We implanted PV-GluN1 KO (n = 14) and littermate WT-GluN1 fl/fl mice (n = 17) with VEP recording electrodes in layer 4, binocular V1. ", "After recovery and 2 daily sessions of habituation we recorded VEPs elicited by an X^o^ oriented grating stimulus. ", "Immediately apparent was the significantly greater basal magnitude of VEPs recorded in the PV-GluN1 mice (242.45 ± 20.20 µV) relative to their littermate controls (130.88 ± 9.69 µV, student's two-tailed t-test, t~(29)~ = -5.269, P \\< 0.001), consistent with the occurrence of disinhibition as a result of reduced glutamatergic drive on cortical PV+ inhibitory cells ([Figure 6A](#fig6){ref-type=\"fig\"}). ", "We then presented the same stimulus to these mice over several consecutive days and observed a significant difference in SRP across genotypes (2-way repeated measures ANOVA, interaction of genotype x day, F~(4,116)~ = 3.835, P = 0.006, [Figure 6A](#fig6){ref-type=\"fig\"}). ", "Beyond day 3, VEP magnitudes were no longer significantly different between the PV-GluN1 KO mice (289.15 ± 24.57 µV) and WT-GluN1 fl/fl littermates (239.94 ± 20.72 µV, SNK post hoc test, q~(29)~ = 2.242, P = 0.119), suggesting an occlusion of SRP by the already elevated basal VEP magnitude in the PV-GluN1 KO mice. ", "The significant deficit in SRP is clearly apparent when the data are normalized to day 1 values (2-way repeated measures ANOVA, interaction of genotype x day, F~(4,116)~ = 12.326, P \\< 0.001, [Figure 6B](#fig6){ref-type=\"fig\"}). ", "Again, a significant deficit in SRP emerged by day 3 in the PV-GluN1 KO mice (119.26 ± 10.13% day 1) compared with WT-GluN1 fl/fl littermates (183.33 ± 15.83% day 1, SNK post hoc test, q~(29)~ = 4.727, P = 0.002), demonstrating that SRP is compromised by a loss of NMDAR expressed in PV+ neurons.10.7554/eLife.11450.017Figure 6.Loss of NMDA receptors selectively from parvalbumin+ cells impacts SRP but not adult OD plasticity.(**A**) VEPs recorded from mice in which the mandatory GluN1 subunit of the NMDA receptor was genetically ablated from PV+ cells using Cre recombinase technology (PV GluN1 KO, gray) were significantly greater in magnitude than those recorded from WT littermates (black), suggesting disinhibition of the visual response. ", "In these same PV GluN1 KO mice, SRP was also significantly impacted as there is was significantly less gain in magnitude over days of repeated presentation of an X° stimulus than observed in WT littermates. (**", "B**) This significant reduction in the magnitude of SRP was most clearly observed if VEP magnitude was normalized to the magnitude on day 1. (**", "C**) After SRP, both PV GluN1 KO mice and their WT littermates exhibited a significantly greater VEP magnitude elicited by the now familiar stimulus than interleaved presentations of a novel oriented stimulus. ", "However, consistent with the observed difference in magnitude on day 1, VEPs elicited by a novel X + 90° stimulus in PV GluN1 KO mice were significantly greater in magnitude than those in WT littermate mice. ", "No significant difference was observed for VEPs elicited by the familiar stimulus. (**", "D**) A significant difference in the ratio of VEP magnitude elicited by the familiar and novel stimuli reveals a deficit in SRP expression in PV GluN1 KO mice. (**", "E**) In contrast, PV GluN1 KO mice exhibited a normal adult OD shift after 7 days of MD, resulting from open eye potentiation (yellow outlines). (**", "F**) Wild-type (WT) littermates exhibited the same significant open eye potentiation (yellow bars) after 7 days of MD. (**", "G**) A comparison of the degree of OD shift as a result of 7 days of MD reveals a significant shift in OD ratio in both genotypes but no difference between genotypes, indicating that NMDA receptors in PV+ cells are not required for induction or expression of the OD shift. (**", "H**) To confirm genetic ablation of NMDARs selectively from parvalbumin (PV+) neurons in the PV-GluN1 KO; mice were injected with an AAV5 vector to express GFP in a Cre-dependent fashion in PV+ cells only. ", "After 1 month, fluorescence-guided intracellular recordings were performed from *ex vivo* slices of visual cortex. ", "NMDAR-mediated synaptic transmission was normal in excitatory control cells but abolished in PV+ cells. ", "This is expressed here as the NMDAR EPSC/AMPAR EPSC ratio in excitatory cells (black outline) and PV+ cells (green outline). ", "Sample EPSC traces mediated by the AMPAR (downward) and NMDAR (upward) are shown at the top of the panel. ", "Significant comparisons are marked with an asterisk throughout while non-significant comparisons are marked with n.s. ", "Error bars are standard error of the mean (S.E.M.).**DOI:** [http://dx.doi.org/10.7554/eLife.11450.017](10.7554/eLife.11450.017)10.7554/eLife.11450.018Figure 6---source data 1.PV-GluN1 KO**DOI:** [http://dx.doi.org/10.7554/eLife.11450.018](10.7554/eLife.11450.018)\n\nWe also tested for the stimulus-selectivity of SRP expression by presenting both groups of animals with interleaved blocks of the familiar X^o^ stimulus and a novel X + 90° stimulus ([Figure 6C](#fig6){ref-type=\"fig\"}). ", "Significant stimulus selectivity was present in both genotypes (2-way repeated measures ANOVA, stimulus, F~(1)~ = 67.397, P \\< 0.001, interaction of genotype x stimulus, F~(1,29)~ = 2.359, P = 0.135, [Figure 6C](#fig6){ref-type=\"fig\"}): Although PV-GluN1 KO mice showed significant differences in VEP magnitude for familiar (340.24 ± 27.96 µV) and novel orientations (242.54 ± 24.40 µV, SNK post hoc test, q~(13)~ = 6.372, P \\< 0.001) the difference was more pronounced in the WT-GluN1 fl/fl mice (SNK post hoc test, q~(16)~ = 10.254, P \\< 0.001), in which the familiar stimulus elicited VEPs 318.74 ± 25.19 µV in magnitude and the novel stimulus elicited VEPs 176.06 ± 11.55 µV in magnitude. ", "The familiar stimulus evoked VEPs that were not significantly different in the WT-GluN1 fl/fl mice (318.74 ± 25.19 µV) and the PV-GluN1 KO mice (340.24 ± 27.96 µV, SNK post hoc test, q~(29)~ = 0.947, P = 0.507) but those evoked in the WT-GluN1 fl/fl by the novel stimulus (176.06 ± 11.55 µV) were significantly lower in magnitude than in the PV-GluN1 KO mice (242.54 ± 24.40 µV, SNK post hoc test, q~(29)~ = 2.926, P = 0.045). ", "The significant deficit in SRP expression in the PV-GluN1 KO mice is most apparent when the familiar/novel ratio of VEP magnitude (1.48 ± 0.13) is compared with the WT-GluN1 fl/fl littermates (1.83 ± 0.13, Mann Whitney rank sum test, U = 60.000, P = 0.020, [Figure 6D](#fig6){ref-type=\"fig\"}). ", "Thus, loss of NMDAR function selectively within PV+ neurons impairs the full expression of SRP.", "\n\nAdult OD plasticity does not require NMDARs expressed in PV+ neurons {#s2-7}\n--------------------------------------------------------------------\n\nWe also examined if loss of NMDAR from PV+ neurons has an effect on OD plasticity. ", "We implanted VEP recording electrodes in a second cohort of 11 PV--GluN1 KO and 7 WT-GluN1 fl/fl mice. ", "After recovery and habituation over 2 days, monocular VEPs were acquired through each eye. ", "After 7 days of MD, PV-GluN1 KO mice exhibited a significant potentiation of response through the open ipsilateral eye (187.91 ± 25.52 µV) compared with day 0 (90.64 ± 10.69 µV, 2-way repeated measures ANOVA, SNK post hoc test, q~(16)~ = 8.849, P \\< 0.001, [Figure 6E](#fig6){ref-type=\"fig\"}). ", "Similarly, WT-GluN1 fl/fl mice also showed a significant potentiation of the open ipsilateral eye-response (154.57 ± 7.60 µV) after 7 days of MD compared with responses measured on day 0 (97.57 ± 15.85 µV, SNK post hoc test, q~(16)~ = 4.137, P = 0.01, [Figure 6F](#fig6){ref-type=\"fig\"}). ", "Comparisons of OD ratios prior to MD in the adult PV-GluN1 KO (3.40 ± 0.29) and WT-GluN1 fl/fl mice (2.57 ± 0.33) did not reveal any significant difference (2-way repeated measures ANOVA, effect of genotype, F~(1)~ = 3.424, P = 0.083). ", "Significant shifts in the OD ratio occurred as a result of 7 days of MD in the adult PV-GluN1 KO (1.28 ± 0.33, SNK post hoc test, q~(16)~ = 10.6, P \\< 0.001) and WT-GluN1 fl/fl mice (1.19 ± 0.09, SNK post hoc test, q~(16)~ = 5.517, P = 0.001). ", "The shifted OD ratio also did not differ significantly across genotype (2-way repeated measures ANOVA, interaction of genotype and MD, F~(1,16)~ = 2.638, P = 0.124, [Figure 6G](#fig6){ref-type=\"fig\"}). ", "Thus, the loss of NMDAR function from PV+ neurons did not have a significant impact on either the induction or the expression of adult OD plasticity, in contrast to SRP.", "\n\nIn order to confirm the removal of NMDARs selectively from PV+ cells, the PV-GluN1 KO mice were injected with an AAV5 vector to express GFP in a Cre-dependent fashion in PV+ cells only. ", "After 1 month, fluorescence-guided intracellular recordings were performed from *ex vivo* slices of visual cortex. ", "NMDAR-mediated synaptic transmission was normal in excitatory control cells but abolished in PV+ neurons ([Figure 6H](#fig6){ref-type=\"fig\"}). ", "This is expressed as significantly reduced NMDAR EPSC/AMPAR EPSC ratio in PV+ cells (0.040 ± 0.011, n = 8 cells from 5 mice) compared to neighboring non-fluorescent excitatory control cells (0.345 ± 0.039, n = 10 cells from 4 mice, student's one-tailed t-test, t~(16)~ = -6.819, P \\< 0.001).", "\n\nAcute ketamine treatment reversibly eliminates SRP expression {#s2-8}\n-------------------------------------------------------------\n\nA group of non-competitive, open-channel NMDAR blockers, including ketamine, PCP and MK801 are known to have the paradoxical impact of increasing net neuronal activity in the brain. ", "It is thought that this apparent disinhibition arises from the preferential impact of these molecules on fast-spiking neurons, due to the tonic activation and the increased open-time of NMDAR expressed within these cells ([@bib24]; [@bib49]). ", "Interestingly, these compounds are also psychotomimetic and can reproduce, at high sub-anesthetic doses, most of the symptoms of schizophrenia ([@bib30]). ", "Here we tested the possibility that a single acute dose of one of these substances, ketamine, would have an impact on the expression of SRP due to its action on NMDAR expressed in PV+ fast spiking inhibitory neurons.", "\n\nWe implanted VEP recording electrodes in layer 4 of binocular V1 in a group of 10 C57BL/6 mice. ", "After recovery and a standard SRP protocol we recorded VEP magnitudes driven by familiar and novel stimuli before, during and 2 days after recovery from systemic injection (i.p.) ", "of a high but sub-anesthetic dose of ketamine (50 mg/kg) ([Figure 7A](#fig7){ref-type=\"fig\"}). ", "Ketamine had a significant effect on SRP expression (2-way repeated measures ANOVA, interaction of treatment x stimulus, F~(2,18)~ = 29.479, P \\< 0.001, [Figure 7B](#fig7){ref-type=\"fig\"}). ", "After SRP but prior to ketamine delivery the familiar X^o^ stimulus elicited VEPs of significantly greater magnitude (245.47 ± 21.00 µV) than a novel X + 60° stimulus (138.86 ± 9.32 µV, SNK post hoc test, q~(9)~ = 9.228, P \\< 0.001) in these mice. ", "After an hour of respite from head-fixation, mice were injected with ketamine and, 15 min later, they were returned to head-fixation and VEP magnitudes were again recorded. ", "Under the influence of ketamine, the familiar X^o^ stimulus elicited VEPs of significantly increased magnitude (381.90 ± 37.25 µV) relative to pre ketamine (245.47 ± 21.00 µV, SNK post hoc test, q~(9)~ = 7.223, P \\< 0.001). ", "However, VEPs elicited by a second novel X - 60° stimulus were increased relative to pre-ketamine by an even greater extent (397.53 ± 37.62 µV) relative to pre ketamine (138.86 ± 9.32 µV, SNK post hoc test, q~(9)~ = 13.695, P \\< 0.001), such that VEPs were no longer significantly different in magnitude in response to familiar and novel stimuli (SNK post hoc test, q~(9)~ = 1.353, P = 0.349). ", "After 2 day's rest, allowing for complete recovery from drug effects, the mice were returned to the head-fixation apparatus and exposed to the familiar X^o^ stimulus and a third novel stimulus, X + 90°. ", "Just as observed prior to the ketamine injection, the X^o^ stimulus evoked VEPs of significantly greater magnitude (267.46 ± 26.13 µV) than the novel X + 90° stimulus (149.40 ± 9.85 µV, q~(9)~ = 10.219, P \\< 0.001) ([Figure 7A and B](#fig7){ref-type=\"fig\"}).10.7554/eLife.11450.019Figure 7.Ketamine prevents expression of SRP through blockade of NMDA receptors expressed in parvalbumin+ neurons but does not impact expression of the adult OD shift.(**A**) Mice were bilaterally implanted with VEP recording electrodes in layer 4 of binocular V1. ", "After habituation to head-fixation and a gray screen for 2 days, SRP was induced over 4 days by repeatedly presenting sessions of an X° stimulus. ", "On day 5, SRP expression was tested by presenting interleaved blocks of the familiar X° stimulus and a novel X + 60° stimulus. ", "In order to test the acute impact of blocking NMDA receptors on SRP expression, 50 mg/kg of ketamine was then delivered systemically 15 min before re-acquiring VEPs elicited by the familiar X° stimulus and interleaved presentations of a second novel X - 60° stimulus. ", "Mice were then allowed 2 days recovery and a complete washout of ketamine before re-testing SRP expression by again testing VEP magnitude in response to the familiar X° stimulus and a third novel X + 90° stimulus on day 7. (**", "B**) Significant SRP was expressed on experimental day 5 prior to ketamine delivery as the familiar X° stimulus elicited VEPs of greater magnitude than the novel stimulus. ", "Delivery of 50 mg/kg ketamine (purple) had two notable impacts on the VEP: First, the overall magnitude of the VEP increased. ", "Second, and most importantly, the significant difference in magnitude of VEPs elicited by familiar and novel stimuli was no longer present. ", "This effect was acute, as SRP expression was again significantly apparent 2 days later. (**", "C**) The ratio of VEP magnitude elicited by the familiar stimulus over the novel. ", "This ratio was close to 2 and not significantly different prior to or after recovery from ketamine administration but dropped significantly to approximately 1 during ketamine exposure. (**", "D**) We tested whether ketamine had a differential impact on VEP magnitude in PV GluN1 KO mice and WT littermate mice. (**", "E**) In the WT littermate mice (white bars) 50 mg/kg ketamine had a significant potentiating effect on VEP magnitude, consistent with our previous observation. ", "In contrast, ketamine had no significant impact on VEP magnitude in the PV GluN1 KO mice (gray bars). (**", "F**) The selectivity of ketamine's impact on the WT mice is observed by comparing the ratio of VEP magnitude during ketamine over baseline, which was significantly greater for WT mice than the PV GluN1 KO mice, in which the ratio was approximately 1. (**", "G**) In a separate group of mice, a similar protocol was then used to determine whether the OD ratio is affected by ketamine. (**", "H**) Ketamine impacted both the VEPs driven through the contralateral eye (blue) and ipsilateral eye (yellow) equally. (**", "I**) This scaled effect is demonstrated by a lack of significant difference between OD ratios prior to (white) and during 50 mg/kg ketamine (purple). (**", "J**) We next tested whether ketamine has any impact on the expression of adult OD plasticity by recording VEP magnitudes through either eye in a new group of adult mice before taking them through a standard 7 day MD protocol. (**", "K**) As anticipated, 7 days of contralateral eye MD induced a significant ipsilateral eye potentiation (yellow) and ketamine then further potentiated VEPs elicited through both contralateral (blue) and ipsilateral eyes. (**", "L**) The OD ratio shifts significantly from a ratio heavily biased towards the contralateral eye, to a less biased ratio. ", "Ketamine administration did not significantly affect the magnitude of the OD shift. ", "Significant comparisons are marked with an asterisk throughout while non-significant comparisons are marked with n.s. ", "Error bars are standard error of the mean (S.E.M.).**DOI:** [http://dx.doi.org/10.7554/eLife.11450.019](10.7554/eLife.11450.019)10.7554/eLife.11450.020Figure 7---source data 1.Ketamine impact on cortical plasticity.**DOI:** [http://dx.doi.org/10.7554/eLife.11450.020](10.7554/eLife.11450.020)\n\nThis significant effect of ketamine on the discrimination of familiar and novel stimuli is summarized by the ratio of VEP magnitude driven by the familiar/novel stimulus (1-way repeated measures ANOVA, F~(2,18)~ = 24.683, P \\< 0.001, [Figure 7C](#fig7){ref-type=\"fig\"}). ", "This familiar/novel ratio dropped significantly from 1.76 ± 0.10 prior to ketamine to 0.96 ± 0.02 after ketamine (SNK post hoc test, q~(9)~ = 8.443, P \\< 0.001). ", "Upon recovery, the familiar/novel ratio significantly recovered (1.79 ± 0.16, SNK post hoc test, q~(9)~ = 8.759, P \\< 0.001) and was not significantly different from the first test after SRP but prior to ketamine injection (SNK post hoc test, q~(9)~ = 0.316, P = 0.826). ", "Thus, the psychotomimetic non-competitive NMDAR antagonist ketamine disrupts SRP. ", "The fact that this is an acute effect on already established SRP that recovers after drug washout indicates that the role for NMDAR in PV+ fast-spiking GABAergic neurons may be in memory retrieval rather than learning.", "\n\nKetamine affects V1 responses through NMDARs expressed in PV+ neurons {#s2-9}\n---------------------------------------------------------------------\n\nKetamine blocks NMDAR expressed in all cell types throughout the CNS and is also known to have targets other than the NMDAR ([@bib8]). ", "In order to determine if ketamine has its effect on V1 responses specifically through NMDAR expressed in PV+ cells, we tested if there was a differential effect of ketamine on VEP magnitude in PV-GluN1 KO mice and WT-GluN1 fl/fl mice. ", "After a typical implantation and habituation protocol ([Figure 7D](#fig7){ref-type=\"fig\"}) we tested VEP magnitudes elicited by a novel oriented X^o^ stimulus in WT-GluN1 fl/fl mice (178.11 ± 38.41 µV, n = 8) and PV-GluN1 KO mice (260.79 ± 50.75 µV, n = 8) ([Figure 7E](#fig7){ref-type=\"fig\"}). ", "We then removed mice from head-fixation and allowed them to recover in their home-cage before delivering 50 mg/kg ketamine (i.p.). ", "After 15 min, the mice were returned to head-fixation and we observed the impact of ketamine on VEPs elicited by a novel X + 90° oriented stimulus, which was significantly different in its effect on the two genotypes (2-way repeated measures ANOVA, interaction of genotype x treatment, F~(1,14)~ = 18.454, P \\< 0.001). ", "In the control WT-GluN1 fl/fl mice there was a significant potentiation of VEP magnitude as a result of ketamine application (386.65 ± 70.75 µV) in comparison to pre treatment (178.11 ± 38.41 µV, SNK post hoc test, q~(7)~ = 8.505, P \\< 0.001, [Figure 7E](#fig7){ref-type=\"fig\"}), replicating our previous finding ([Figure 7B](#fig7){ref-type=\"fig\"}). ", "However, in the PV-GluN1 KO mice, ketamine had no ostensible significant impact (258.67 ± 44.86 µV) in comparison to pre treatment (260.79 ± 50.75 µV, SNK post hoc test, q~(7)~ = 0.087, P = 0.952). ", "A ratio of VEP magnitudes pre and post ketamine treatment reveals the significant difference between ketamine's action on WT-GluN1 fl/fl mice (2.40 ± 0.25) and PV-GluN1 KO mice (1.12 ± 0.13, student's two-tailed t-test, t~(14)~ = 4.610, P \\< 0.001) ([Figure 7F](#fig7){ref-type=\"fig\"}). ", "Thus, while ketamine has a wide range of effects in the CNS, it exerts itself on the response of V1 to visual input selectively through NMDAR expressed in PV+ cells.", "\n\nKetamine has no effect on the expression of the adult OD shift {#s2-10}\n--------------------------------------------------------------\n\nWe then tested whether or not ketamine would disrupt either the OD ratio or the shift induced by 7 days of MD in the adult mouse. ", "Again, C57BL/6 mice (n = 8) were implanted with VEP electrodes and taken through a standard surgery recovery and habituation protocol before measuring the OD ratio prior to 50 mg/kg ketamine and 15 min after ketamine delivery ([Figure 7G and H](#fig7){ref-type=\"fig\"}). ", "The normal contra/ipsi OD ratio exhibiting contralateral eye dominance prior to ketamine (2.84 ± 0.18) was not significantly altered by ketamine (2.61 ± 0.19, student's paired two-tailed t-test, t~(7)~ = 0.871, P = 0.413) ([Figure 7I](#fig7){ref-type=\"fig\"}). ", "A separate group of mice (n = 11) then underwent a standard 7 day MD protocol. ", "VEPs elicited by an X^o^ oriented stimulus were recorded at baseline, followed by the deprivation period. ", "After eye opening VEP magnitudes were re-tested with a novel X + 60°stimulus (the standard protocol to avoid contamination of the OD shift by SRP \\[[@bib18]\\]). ", "These mice were then tested again with a second novel X - 60°stimulus after 1 hr rest and an additional 15 min after systemic 50 mg/kg ketamine administration ([Figure 7J](#fig7){ref-type=\"fig\"}). ", "As expected, VEPs elicited through the open ipsilateral eye (93.73 ± 12.85 µV) were significantly potentiated by 7 days of MD in the adult mouse (155.73 ± 15.86 µV, 2-way repeated measures ANOVA, SNK post hoc test, n = 11 mice, q~(10)~ = 7.102, P \\< 0.001), reflecting the well-documented OD shift. ", "These same ipsilateral VEPs were then further potentiated by ketamine administration (232.03 ± 22.19 µV, SNK post hoc test, q~(10)~ = 8.741, P \\< 0.001). ", "However, ketamine had a similar significant potentiating effect on the contralateral VEP (279.07 ± 14.53 µV), relative to pre-ketamine (180.14 ± 11.22 µV, SNK post hoc test, q~(10)~ = 11.333, P \\< 0.001, [Figure 7K](#fig7){ref-type=\"fig\"}), suggesting a uniform scaling of response through the two eyes. ", "This observation is confirmed by the fact that the OD ratio, significantly shifted from (2.84 ± 0.29) to (1.23 ± 0.11, Friedman repeated measures ANOVA on ranks, n = 11 mice, X^2^~(2)~ = 16.545, p\\<0.001, SNK post hoc test, q~(10)~ = 5.126, P \\< 0.05) by 7 days of MD, was not further significantly affected by delivery of ketamine (1.28 ± 0.09, SNK post hoc test, q~(10)~ = 0.426, P \\> 0.05, [Figure 7L](#fig7){ref-type=\"fig\"}). ", "Thus, while ketamine prevents SRP expression through action on NMDAR expressed in PV+ cells, it does not significantly affect the adult OD shift after 7 days of MD, consistent once again with PV+ cells contributing to the expression of SRP but not adult OD plasticity.", "\n\nVisual novelty detection requires PV+ neuron activity within V1 {#s2-11}\n---------------------------------------------------------------\n\nGiven the clear involvement of PV+ neurons in the expression of SRP we wanted to determine if loss of PV+ neuronal function local to V1 would have any behavioral impact. ", "Head-restrained mice viewing a phase reversing visual grating stimulus are known to exhibit a stereotyped motor response called a visually-induced fidget, or vidget ([@bib13]). ", "Vidgets can be measured via a piezoelectric sensor located beneath the forepaws of the mouse ([Figure 8A](#fig8){ref-type=\"fig\"}). ", "Importantly, it has been shown that the magnitude of the vidget response is inversely correlated to the familiarity of the visual stimulus. ", "That is, a visual stimulus that is very familiar to the animal will on average evoke a relatively weak vidget behavioral response. ", "In contrast, the presentation of a novel stimulus will on average evoke a vidget of significantly greater magnitude. ", "Therefore, this behavioral response reflects the ability of the animal to discriminate and respond to a novel visual stimulus in its environment. ", "Importantly, genetic and pharmacological manipulations local to V1 that inhibit SRP also disrupt the behavioral discrimination of familiar and novel stimuli ([@bib13]), demonstrating that this differential vidget response to familiar and novel stimuli is dependent on the plasticity in visual cortex. ", "Since PV+ neuron inactivation disrupted the expression of SRP, we tested whether this manipulation would likewise disrupt visual novelty detection.10.7554/eLife.11450.021Figure 8.Discrimination of familiar and novel oriented stimuli involves PV+ neurons in V1 and NMDAR expressed within PV+ neurons.(**A**) Using the same protocol as described in [Figure 3B](#fig3){ref-type=\"fig\"}, mice were progressively familiarized with a specific oriented stimulus. ", "On the test day, as mice viewed familiar and novel stimuli, vidget behavioral responses were measured via a piezoelectric sensor located beneath the forepaws of the head-fixed mouse. (**", "B**) After a standard SRP protocol, mice expressing hM4D(Gi) receptors selectively within PV+ cells of binocular V1 were exposed to both familiar and novel stimuli. ", "Prior to application of CNO, mice exhibited significant behavioral evidence of discriminating this familiar orientation from interleaved presentations of a novel oriented stimulus (black bars). ", "After application of CNO, there was no longer successful discrimination of familiar and novel stimuli (red bars). ", "Averaged vidget responses are displayed at the top of this panel. (**", "C**) A significant difference was observed in the ratio of response to familiar and novel stimuli from pre CNO (black) to post CNO (red). (**", "D**) A deficit in OSH was also apparent in PV GluN1 KO mice as vidget recordings demonstrated a failure to significantly discriminate familiar from novel orientations (gray bars). ", "WT littermates exhibited significantly greater vidget magnitudes for novel than familiar stimuli, indicating unimpaired discrimination of familiarity from novelty (white bars). ", "Averaged behavioral responses are displayed above with accompanying scale bars. (**", "E**) The significant deficit of PV GluN1 KO mice in discriminating familiar from novel stimuli is apparent in the ratio of behavior elicited by the familiar over the novel stimulus in comparison to WT littermates. ", "Significant comparisons are marked with an asterisk throughout while non-significant comparisons are marked with n.s. ", "Error bars are standard error of the mean (S.E.M.).**DOI:** [http://dx.doi.org/10.7554/eLife.11450.021](10.7554/eLife.11450.021)10.7554/eLife.11450.022Figure 8---source data 1.Novelty detection after PV+ neuronal disruption.**DOI:** [http://dx.doi.org/10.7554/eLife.11450.022](10.7554/eLife.11450.022)10.7554/eLife.11450.023Figure 8---figure supplement 1.Cumulative distributions of average vidget behavioral response to familiar and novel stimuli for each individual animal included in analysis presented in [Figure 8D](#fig8){ref-type=\"fig\"} and [Figure 8E](#fig8){ref-type=\"fig\"}.(**A**) Prior to CNO administration, average behavioral response to the familiar stimulus (light gray) and the novel stimulus (black) of each individual animal bilaterally expressing hM4D(Gi) in PV+ neurons of binocular V1. ", "Dotted line represents behavior no greater than pre stimulus baseline. (**", "B**) Average behavioral response of the same animals to the familiar and a new novel stimulus during PV+ neuron inactivation via CNO delivery, revealing consequent deficit in discrimination of familiar and novel stimuli. (**", "C**) Cumulative distributions of average vidget behavioral response to the familiar stimulus (light gray) and the novel stimulus (black) of each individual WT GluN1 fl/fl mouse. (**", "D**) Average vidget behavioral response of each PV-GluN1 KO mouse to the familiar and a new novel stimulus, revealing deficit in discrimination of familiar and novel stimuli. ", "Dotted line represents behavior no greater than pre stimulus baseline.**DOI:** [http://dx.doi.org/10.7554/eLife.11450.023](10.7554/eLife.11450.023)10.7554/eLife.11450.024Figure 8---figure supplement 1---source data 1.Per animal plots of Novelty detection after PV+ neuronal disruption.**DOI:** [http://dx.doi.org/10.7554/eLife.11450.024](10.7554/eLife.11450.024)\n\nA group of PV-Cre mice expressing hM4D(Gi) receptors in PV+ cells (n = 19), underwent a SRP protocol similar to the previous experiment ([Figure 3A](#fig3){ref-type=\"fig\"}) in which mice viewed phase-reversing gratings of a particular orientation (X^o^ stimulus) each day for 6 days. ", "On the 7th day mice viewed blocks of the now familiar visual stimulus interleaved with blocks of a novel oriented stimulus (X + 60°). ", "On day 7, vidget behavioral responses were acquired via a piezoelectric device situated underneath the forepaws of the mice ([Figure 8A](#fig8){ref-type=\"fig\"}), in order to measure the animal's discrimination of familiar and novel stimuli. ", "On day 8, PV+ cells in V1 were then inactivated by systemic delivery of CNO (i.p.) ", "and vidget responses were acquired to the familiar X^o^ stimulus and a second X - 60° novel stimulus. ", "Inactivation of PV+ neurons in V1 significantly affected stimulus discrimination (2-way repeated measures ANOVA, interaction of treatment x stimulus, F~(1,18)~ = 13.644, P = 0.002, [Figure 8B](#fig8){ref-type=\"fig\"}): Prior to CNO, mice exhibited significantly larger vidget responses to the novel visual stimulus (3.64 ± 0.32 a.u.) ", "than the familiar stimulus (1.95 ± 0.26 a.u., ", "SNK post-hoc test, q~(18)~ = 9.237, P \\< 0.001). ", "During PV+ cell inactivation in V1, behavioral responses to the familiar (2.01 ± 0.16 a.u.) ", "and novel visual stimuli (2.46 ± 0.22 a.u.) ", "were no longer significantly different (SNK post-hoc test, q~(18)~ = 2.503, P = 0.086). ", "The deleterious effect of PV+ cell inactivation in V1 on the animal's ability to discriminate familiar and novel stimuli is most obvious when a ratio of response to familiar/novel visual stimuli is calculated. ", "Prior to CNO delivery this ratio was significantly lower (0.54 ± 0.04) than during CNO treatment (1.00 ± 0.15, Wilcoxon signed rank test, W = 138.000, Z = 2.777, P = 0.004, [Figure 8C](#fig8){ref-type=\"fig\"}). ", "These findings indicate that PV+ neuron activity is required not only for the expression of SRP, but also for visual novelty detection.", "\n\nDiscrimination of familiar and novel stimuli requires NMDAR within PV+ neurons {#s2-12}\n------------------------------------------------------------------------------\n\nFinally, given the observation that the discrimination of familiar and novel visual stimuli is diminished by inactivation of PV+ neurons in V1, we tested whether a similar failure would occur in the PV-GluN1 KO mice (n = 17) compared with WT-GluN1 fl/fl littermates (n = 15, 2-way repeated measures ANOVA, stimulus, F~(1)~ = 14.632, P \\< 0.001, [Figure 8D](#fig8){ref-type=\"fig\"}). ", "In the PV-GluN1 KO mice, the familiar stimulus produced less behavioral response (2.75 ± 0.42 a.u.) ", "than a novel stimulus (3.67 ± 0.79 a.u.). ", "However, the difference was not significant (SNK post hoc test, q~(16)~ = 2.570, P = 0.079). ", "In comparison, the concurrently tested WT-GluN1 fl/fl littermate mice showed a suppression of behavioral response to the familiar stimulus (1.76 ± 0.26 a.u.) ", "relative to the novel stimulus (4.08 ± 0.51 a.u.) ", "that was significant (SNK post hoc test, q~(14)~ = 5.008, P = 0.001). ", "This observation was reinforced by a comparison of the ratio of behavior produced by familiar and novel stimuli ([Figure 8E](#fig8){ref-type=\"fig\"}), in which there was a significant difference between the PV-GluN1 KO mice (0.59 ± 0.11) and their WT-GluN1 fl/fl littermates (0.94 ± 0.14, student's one-tailed t-test, t~(30)~ = -1.992, P = 0.028), reflective of the deficit in discrimination of familiar and novel stimuli as a result of lost NMDAR function in PV+ cells. ", "Individual animals' average vidget responses to familiar and novel stimuli ([Figure 8---figure supplement 1](#fig8s1){ref-type=\"fig\"}) reveal significantly decreased stimulus selectivity subsequent to CNO administration ([Figure 8---figure supplement 1A--B](#fig8s1){ref-type=\"fig\"}), and in the PV GluN1 KO mice as compared to WT-GluN1 fl/fl littermate controls ([Figure 8---figure supplement 1C--D](#fig8s1){ref-type=\"fig\"}). ", "Thus, not only do NMDAR in PV+ cells contribute to SRP expression but they are also involved in its behavioral correlate.", "\n\nDiscussion {#s3}\n==========\n\nOur experiments reveal a surprising role for PV+ inhibitory neuron activity in the expression of SRP but not of eye dominance or deprivation-enabled potentiation of the non-deprived eye after MD in the adult mouse. ", "The data show that NMDARs in PV+ neurons are critically important for the expression of SRP, and that familiarity recognition and novelty detection measured behaviorally are compromised both by loss of PV+ neuron activity within V1 and loss of NMDAR from PV+ neurons.", "\n\nPV+ interneurons and OD plasticity in V1 {#s3-1}\n----------------------------------------\n\nThere has been a long-standing interest in the possible roles of PV+ neurons in juvenile OD plasticity. ", "These include modulation of the sensitivity of visual cortex to the effects of MD ([@bib17]; [@bib22]; [@bib25]; [@bib7]) and the functional expression of the OD shift ([@bib35]; [@bib53]; [@bib50]). ", "Our findings indicate that expression of OD plasticity in adult mice does not require participation of the PV+ neurons. ", "In interpreting the current findings, it is important to recognize how juvenile and adult OD plasticity differ. ", "In juvenile mice (\\< \\~P35), a rapid and reliable consequence of MD is depression in cortex of responses mediated by the deprived eye. ", "This is followed by a progressive compensatory increase in responses through the non-deprived eye ([@bib18]). ", "In adult mice maintained under standard laboratory conditions, depression of deprived-eye responses can be a weak and variable consequence of MD, but potentiation of the non-deprived eye still occurs reliably ([@bib48]; [@bib47]). ", "This deprivation-enabled response potentiation is not mediated by homeostatic synaptic scaling because it requires visual experience through the non-deprived eye ([@bib3]), activation of cortical NMDA receptors ([@bib48]; [@bib47]), and is unaffected (in adults) by genetic deletion of TNFα that abolishes scaling ([@bib44]). ", "These features are consistent with an alternative hypothesis that the adult OD shift occurs because deprivation of the dominant contralateral eye causes a metaplastic shift in the LTP threshold, enabling visual experience through the weaker ipsilateral eye to drive \"Hebbian\" synaptic strengthening ([@bib14]). ", "This interpretation is supported by evidence that light deprivation promotes LTP in visual cortex ([@bib29]; [@bib41]; [@bib40]) and that αCaMKII mutants that lack LTP also lack adult OD plasticity ([@bib44]), and it is compatible with our finding that expression of the adult OD shift is not dependent on the activity of PV+ inhibitory neurons.", "\n\nSaiepour and colleagues also recently observed that ocular dominance index (ODI) values of V1 neurons are not altered by PV+ interneuron suppression in monocularly deprived adult mice ([@bib46]). ", "Using single unit recordings they first showed that monocular deprivation caused a shift in ODI values towards the non-deprived eye, as expected. ", "They then tested the dependence of this shift on PV+ cell activity by measuring ODI values of V1 neurons during optogenetic suppression of PV+ cells. ", "This optogenetic-suppression did not alter the deprivation-induced shift in ODI values. ", "Our results using VEP recordings and PV+ suppression via hM4Di Dreadd receptors are in agreement with these results from Saiepour and colleagues, demonstrating that suppression of PV+ cell activity after deprivation does not interfere with the expression of the adult OD shift. ", "Although the findings that PV+ neurons are not necessary for expression of OD plasticity do not rule out a modulatory role in the induction mechanisms, we note that the adult OD shift still occurred in mutant mice in which PV+ neurons lack NMDARs.", "\n\nPV+ interneurons and SRP in V1 {#s3-2}\n------------------------------\n\nIn contrast to the adult OD shift, we found that the expression of SRP relies on PV+ neuron circuitry. ", "This finding came as a surprise, as SRP reflects the potentiation of short-latency synaptic currents and increased spiking activity in layer 4 ([@bib13]), and previous experiments had strongly indicated that SRP might be considered a naturally occurring form of LTP. ", "For example, induction of SRP is input-specific, dependent upon NMDA receptor activation and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) insertion in principal cells ([@bib19]), and reversed by infusion of the zeta-inhibitory peptide (ZIP) that also erases LTP ([@bib10]). ", "Furthermore, LTP elicited by theta-burst stimulation of the thalamus occludes and is occluded by SRP ([@bib10]). ", "Altogether, these findings suggest a modification of feed-forward excitatory synaptic transmission.", "\n\nBefore assigning a specific role to inhibition in the expression of SRP, two relatively trivial explanations must be addressed. ", "The first is that the loss of discrimination of familiar and novel orientations could be accounted for simply by a failure of orientation selectivity and not by a failure of memory. ", "Throughout the experiments presented here we have used orientations that are at least 60° and often 90° different, meaning that orientation discrimination should be as unchallenging as possible. ", "Given the modest impact on orientation tuning of suppressing PV+ interneuron activity in V1 ([@bib45]; [@bib1]; [@bib51]) we believe that this explanation is improbable. ", "However, we took a direct approach to testing this possibility by stimulating activity in PV+ cells using channelrhodopsin-2 (ChR2) while mice are viewing familiar and novel oriented stimuli. ", "Stimulation of PV+ inhibition has been shown to actually mildly enhance orientation-selectivity ([@bib32]) and yet our experiments reveal that the difference between visual cortical response to familiar and novel orientations is significantly diminished by activation PV+ neurons. ", "This result casts PV+ neurons in a very specific role in the recognition of familiar stimuli in addition to modest participation in orientation-selectivity.", "\n\nA second concern is that, after the suppression of PV+ inhibition, V1 may be operating outside the dynamic range where discrimination is possible. ", "However, we show that the cortex responds to input from the contralateral eye with a response of approximately double the magnitude of that elicited by input through the ipsilateral eye even after silencing the PV+ cells, suggesting that the response of the cortex is not saturated. ", "We also find that PV+ neuron silencing affects SRP even when it is induced using lower contrast stimuli that evoke submaximal responses. ", "Moreover, it is also worth noting that less specific pharmacological approaches to suppressing inhibition in V1 ([@bib28]) result in much greater magnitude of response to visual input than we observe here for PV+ neuron inactivation, PV-GluN1 KO or ketamine application, indicating that our manipulations do not encroach on a physiological ceiling.", "\n\nOne relatively simple explanation for the current findings is that SRP results from lasting homosynaptic (*i.e.* input-specific) long-term depression (LTD) of glutamatergic input to PV+ inhibitory neurons. ", "Thereafter, presentation of a familiar stimulus evokes a greater response in V1 due to selective disinhibition of cortical circuitry. ", "This hypothesis is consistent with our observation that SRP is deficient if NMDARs are no longer expressed on PV+ cells. ", "However, because we used a non-reversible genetic modification in our initial PV-GluN1 KO experiment, we were initially unable to show if these receptors were important for the storage of information or the retrieval of information already stored. ", "Ketamine, which among other actions serves as a non-competitive NMDAR antagonist, has been shown to preferentially antagonize NMDARs on PV+ cells ([@bib24]; [@bib49]). ", "By using ketamine to induce a temporary blockade of these receptors, which we confirmed by showing that there was no impact of ketamine on V1 responses in the PV-GluN1 KO mice, we were able to demonstrate that interference with NMDARs on PV+ cells disrupts *expression* of SRP even after it has been induced and saturated. ", "Importantly, acute application of ketamine did not affect the maintenance or stability of stored information, because a strong bias for the familiar stimulus returned after ketamine washout. ", "If SRP is indeed accounted for by homosynaptic depression of excitatory synapses carrying information about the familiar stimulus orientation, this LTD would need to be expressed by a synapse-specific reduction in NMDAR-mediated responses in order to account for these findings.", "\n\nHowever, this simple model is difficult to reconcile with the findings reviewed above that SRP depends on LTP-like mechanisms, *e.g.*, NMDAR-dependent AMPAR delivery in principal cells. ", "Considered together, the findings to date indicate that induction and maintenance of SRP occur by modification of excitatory synapses onto excitatory neurons, but that expression of SRP is mediated by stimulus-selective modulation of PV-cell activity in V1. ", "Obviously a polysynaptic circuit is required to yield these properties, and dissecting this essential cortical circuitry will require much more work. ", "However, it is interesting to note a recent study by Makino and Komiyama who showed, in addition to a stimulus-selective reduction in PV+ neuron activity in V1 as mice were repeatedly exposed to a specific visual stimulus, an experience-dependent increase in the responsiveness of somatostatin-positive interneurons ([@bib36]). ", "This result is particularly interesting as it is known that many interneuron types innervate one another and, therefore, that the activity of these cell types are interdependent. ", "It is not difficult to sketch circuits in which stimulus-selective, feed-forward polysynaptic inhibition of PV+ cells accounts for SRP expression. ", "Clearly, experiments aimed at teasing apart the involvement of other interneuron types in SRP should now be a high priority.", "\n\nWe note that other studies have suggested that PV+ neurons may be important for plasticity following repeated exposure to sensory stimuli. ", "For instance, Meyer and colleagues, studying infero-temporal cortex (IT) in monkeys, showed that familiarity resulted in a sharpening of cortical responses to dynamic visual stimuli, which was likely orchestrated by local fast-spiking putative PV+ cells ([@bib38]). ", "Additionally, mice constitutively lacking neuronal activity-regulated pentraxin (NARP), a synaptic protein specifically enriched at excitatory synapses on PV+ cells, displayed a reduction in excitatory synapses onto PV+ cells and impairment in SRP-like effects ([@bib6]; [@bib21]). ", "Intriguingly, however, the NARP KO mice also failed to exhibit both juvenile and adult OD plasticity. ", "In juvenile animals, it is well established that reducing inhibition can impair induction of OD plasticity ([@bib43]) and delay the developmental decline in the mechanism of deprived-eye depression ([@bib22]; [@bib25]). ", "We speculate that the loss of OD plasticity in the adult NARP KO may be related to disruption of the developmental switch from juvenile to adult-type OD plasticity ([@bib23]).", "\n\nOur findings indicate that although open-eye potentiation as a result of MD in the adult and SRP are superficially similar, the expression mechanisms of these two forms of plasticity are quite distinct. ", "Based on evidence provided here as well as by others ([@bib48]; [@bib44]; [@bib46]), the deprivation enabled potentiation of the open eye is consistent with a potentiation of synapses between excitatory cells and is independent of PV+ cell inhibition. ", "However, further work will be necessary to confirm that open eye potentiation in the adult animal is expressed by synaptic alterations between excitatory cells, and to determine whether these processes are present at the level of thalamocortical synapses or intracortical synapses.", "\n\nPV+ interneurons and familiarity recognition {#s3-3}\n--------------------------------------------\n\nSRP correlates with OSH ([@bib13]), a form of visual learning which is dependent upon NMDARs in V1, and which enables the animal to make the critically important discrimination between familiarity and novelty. ", "We have shown here that modulation of PV+ neuron activity in V1 is required for this selective recognition of familiarity and consequent novelty detection. ", "Loss of NMDAR function in these same cells also impairs familiarity recognition. ", "The cognitive symptoms of schizophrenia, and other psychiatric disorders, are characterized by deficits in habituation and familiarity ([@bib4]; [@bib42]) and individuals with schizophrenia display impairment in visual cortical plasticity ([@bib5]). ", "Dysfunction of PV+ inhibitory neurons and the NMDARs expressed on PV+ cells have also been implicated in these same psychiatric disorders through a range of approaches ([@bib34]; [@bib20]; [@bib33]). ", "This notably includes observations of the profound psychotomimetic effect in humans of non-competitive NMDAR antagonists such as ketamine ([@bib30]; [@bib31]), a substance that, as we show here, prevents SRP expression. ", "We suggest that understanding the cortical physiology underlying the processes of familiarity recognition and novelty detection may yield great insight into dysfunction underlying some symptoms of these disorders and that, because these processes are as important to mice as they are to humans, they are likely to be experimentally tractable.", "\n\nMaterials and methods {#s4}\n=====================\n\nMice {#s4-1}\n----\n\nAll procedures adhered to the guidelines of the National Institutes of Health and were approved by the Committee on Animal Care at MIT, Cambridge, MA, USA. ", "For all experiments mice were male, aged between P60-90 and on a C57BL/6 background (Charles River laboratory international, Wilmington, MA). ", "They were housed in groups of 2--5 with food and water available *ad libitum* and maintained on a 12 hr light-dark cycle. ", "For hM4D(Gi) experiments, mice were Parvalbumin-Cre recombinase knock-in mice (B6;129P2-*Pvalb^tm1(cre)Arbr^*/J, PV-Cre) on a C57BL/6 background. ", "For GluN1 knockdown experiments, these PV-Cre mice were bred with homozygous mice in which the Grin1 gene, which encodes the GluN1 sub-unit was flanked by LoxP sites (B6.129S4-*Grin1^tm2Stl^*/J, GluN1 fl/fl), enabling Cre-dependent ablation of this mandatory subunit of the NMDA receptor. ", "Multiple generations were required to set up crosses yielding offspring that were homozygous GluN1 fl/fl and Cre-expressing. ", "Of these approximately 50% expressed Cre and 50% served as wild-type littermates on the GluN1 fl/fl background. ", "All experiments were conducted blind to genotype and treatment.", "\n\nSurgery {#s4-2}\n-------\n\nMice were first injected with 0.1 mg/kg Buprenex sub-cutaneously (s.c.) ", "to provide analgesia. ", "They were then anesthetized with an intraperitoneal (i.p.) ", "injection of 50 mg/kg ketamine and 10 mg/kg xylazine. ", "Prior to surgical incision, 1% lidocaine hydrochloride anesthetic was injected under the mouse's scalp. ", "The skull was then cleaned with iodine and 70% ethanol. ", "A steel head post was affixed to the skull anterior to bregma using cyanoacrylate glue. ", "Burr holes (\\< 0.5 mm) were then drilled in the skull over binocular V1 (3.1 mm lateral of lambda). ", "Tapered tungsten recording electrodes (FHC, Bowdoinham, ME, US), 75 μm in diameter at their widest point, were implanted in each hemisphere, 450 μm below cortical surface. ", "Silver wire (A-M systems, Sequim, WA, US) reference electrodes were placed over prefrontal cortex. ", "Mice were allowed to recover for at least 24 hr prior to head-fixation.", "\n\nViral infections {#s4-3}\n----------------\n\nFor hM4D(Gi) experiments, we infected V1 of P30-60 PV-Cre mice or wild-type littermates with an AAV9-hSyn-DIO-HA-hM4D(Gi)-IRES-mCitrine virus (UNC viral core -- generated by Dr. Brian Roth's laboratory) and for optogenetic experiments we infected mice from the same line with AAV5-EF1α-DIO-hChR2(H134R)-eYFP (UNC viral core -- generated by Dr. Karl Deisseroth's laboratory). ", "Using a glass pipette and nanoject system (Drummond scientific, Broomall, PA, US), we delivered 81 nl of virus at each of 3 cortical depths: 600, 450, and 300 µm from the cortical surface, and allowed 5 min between re-positioning for depth. ", "Mice were allowed 3--4 weeks recovery for virus expression to peak before experiments were initiated.", "\n\nDrug delivery {#s4-4}\n-------------\n\nClozapine-N-oxide (CNO, Enzo Life Sciences) was diluted in saline and injected i.p. ", "at a dosage of 5 mg/kg 30 min prior to stimulus delivery. ", "Ketamine hydrochloride (Vedco) was diluted in water and delivered i.p. ", "at 50 mg/kg 15 min prior to stimulus delivery.", "\n\nStimulus delivery {#s4-5}\n-----------------\n\nVisual stimuli consisted of full-field, 100% contrast, sinusoidal gratings that were presented on a computer monitor. ", "Visual stimuli were generated using custom software (<http://bearlab-s1.mit.edu/supp6/PlxStimOne_Opto.zip>) written in either C++ for interaction with a VSG2/2 card (Cambridge Research systems, Kent, U.K.) or Matlab (MathWorks, Natick, MA, U.S.) using the PsychToolbox extension (<http://psychtoolbox.org>) to control stimulus drawing and timing. ", "The display was positioned 20 cm in front of the mouse and centered, thereby occupying 92° × 66° of the visual field. ", "Visual stimuli consisted of full-field sinusoidal grating stimuli phase reversing at a frequency of 2 Hz. ", "Mean stimulus luminance was 27 cd/m^2^. Grating stimuli spanned the full range of monitor display values between black and white, with gamma-correction to ensure constant total luminance in both gray-screen and patterned stimulus conditions. ", "For data described in [Figures 1](#fig1){ref-type=\"fig\"}--[3](#fig3){ref-type=\"fig\"} and [6](#fig6){ref-type=\"fig\"}, experiments were fully automated and each stimulus block consisted of 200 phase reversals with 30-s intervals between each stimulus presentation, during which the screen was gray but of equivalent luminance. ", "For experiments described in [Figures 4](#fig4){ref-type=\"fig\"} and [5](#fig5){ref-type=\"fig\"} stimulus blocks were also 200 phase reversals in length but each was triggered directly by the experimenter, meaning that the interval was approximately 30-s. Throughout, stimulus orientation varied such that a novel orientation was always a minimum of 25° different from any experienced previously by the individual mouse and was never within 20° of horizontal because these orientations are known to elicit VEPs of greater magnitude than vertical or oblique stimuli. ", "If more than 1 orientation was shown within a session, stimuli were pseudo-randomly interleaved such that 3 consecutive presentations of the same stimulus never occurred. ", "For monocular presentation an occluding paddle was positioned in front of one eye to limit stimulus presentation to the opposite eye.", "\n\nIn vivo electrophysiology {#s4-6}\n-------------------------\n\nVEP recordings were conducted in awake, head-restrained mice. ", "Prior to recording, mice were habituated to the restraint apparatus by sitting in situ in front of a gray screen for a 30-minute session on each of two consecutive days. ", "For experiments in which monocular VEPs were subsequently acquired, mice were also habituated to the occluding paddle positioned in front of each eye. ", "On stimulus presentation days, mice were presented with 5 blocks of 200 phase reversals of each oriented stimulus separated by gray screen presentation for \\~30 s. For monocular presentations, recordings were conducted in sequence for each eye. ", "VEP magnitude was then quantified by measuring trough-peak response magnitude averaged over all phase reversals.", "\n\nRecordings presented in [Figures 1](#fig1){ref-type=\"fig\"}--[3](#fig3){ref-type=\"fig\"} and [6](#fig6){ref-type=\"fig\"} were amplified and digitized using the Recorder-64 system (Plexon Inc., Dallas, TX). ", "Two recording channels were dedicated to recording EEG/VEPs from V1 in each implanted hemisphere and a third recording channel was reserved for the Piezo-electrical input carrying the behavioral information. ", "Recordings presented in [Figures 4](#fig4){ref-type=\"fig\"} and [5](#fig5){ref-type=\"fig\"} were amplified using DAM80 amplifiers (World Precision Instruments, Florida, U.S.) and digitized using a custom National Instruments system (National Instruments, Texas, U.S.)). ", "Local field potential was recorded from V1 with 1 kHz sampling and a 500 Hz low-pass filter. ", "Data was extracted from the binary storage files and analyzed using custom software (<http://bearlab-s1.mit.edu/supp6/VEP_Analysis.zip>) written in C++, Matlab and Labview. ", "VEPs were averaged across all phase reversals within a block and trough-peak difference measured during a 200-millisecond period from phase reversal.", "\n\nEx vivo electrophysiology {#s4-7}\n-------------------------\n\nFor experiments concerning Dreadd receptor expression in PV+ cells presented in [Figure 1](#fig1){ref-type=\"fig\"}: Three weeks after infection with AAV9-hSyn-DIO- HA-hM4D(Gi)-IRES-mCitrine virus, visual cortical slices were prepared from the injected mice as previously described ([@bib41]). ", "After dissection 350-µm-thick coronal slices recovered for 30 min at 32°C and then for an additional 2 hr at room temperature, in a holding chamber filled with warmed artificial cerebrospinal fluid (ACSF), which contained: 124 mM NaCl, 3.5 mM KCl, 1.25 mM Na~2~PO~4~, 26 mM NaHCO~3~, 1.2 mM MgCl~2~, 2 mM CaCl~2~, and 10 mM dextrose, saturated with 95% O~2~, 5% CO~2~. Whole cell patch clamp recordings were performed at 30°C from the parvalbumin-positive interneurons in the layer 4, identified by the ECFP fluorescence. ", "Pipette tip resistances were 3--5 MΩ. ", "Internal solution contained: 20 mM KCl, 100 mM Na-gluconate, 10 Hepes, 4 mM MgATP, 0.3 mM Na2GTP, 7 mM phosphocreatine-Tris, 0.2% biocytin with pH adjusted to 7.2 and osmolarity adjusted to 300 mOsm. ", "All recordings were made using Axopatch 200B (Molecular Devices, Sunnyvale, CA) at 10 kHz sampling rate. ", "Cells with the series resistance \\<30 MΩ were included for analysis. ", "Data analysis was done using pClamp (Molecular Devices) and custom-written python scripts. ", "For experiments concerning NMDAR EPSCs and AMPAR EPSCs in PV-GluN1 KO mice as presented in [Figure 6H](#fig6){ref-type=\"fig\"}: 4 PV-GluN1 KO mice were infected with AAV5-EF1α-DIO-hChR2(H134R)-eYFP, to allow for fluorescence-guided intracellular recordings of PV+ cells. ", "Four weeks after infection, visual cortical slices were prepared as describe above. ", "For fluorescently labeled PV+ cells and unlabeled neighboring excitatory cells: EPSCs were recorded at -70 mV and +40 mV with pipettes filled with balanced intracellular solutions (in mM): 115 cesium methane-sulfonate (CsMeSO3), 2.8 NaCl, 0.4 EGTA, 4 ATP-Mg^2+^, 10 Na^+^-phosphocreatine, 0.5 Na^+^-GTP, 5 TEA-Cl^-^, 5 QX-314 Br^-^ buffered with 20 HEPES, pH 7.25, osmolarity 290 mOsm. ", "Synaptic events were evoked by stimulation of the white mater (150 μs, 0.1 Hz, glass electrode, and stimulator A365 from WPI). ", "AMPA component was measured from EPSCs at -70 mV in the presence of PTX (100 μM) and glycine (1 μM) and NMDA component was measured from EPSCs at +40 mV in the presence of DNQX (20 μM).", "\n\nBehavior {#s4-8}\n--------\n\nAll behavioral experiments were performed during the mouse subject's light cycle. ", "A piezo-electrical recording device (C.B. Gitty, Barrington, NH, USA) was placed under the forepaws of head-restrained mice during all sessions. ", "Mice became accustomed to the apparatus by sitting in situ in front of a gray screen for a 30-min session on each of 2 days. ", "Before stimulus presentation on each day mice also underwent 5 min of gray screen presentation after the experimenter had left the room. ", "A continuous voltage signal was recorded from the piezo device for the entire session. ", "Movements were detected as a shift in the voltage signal. ", "The recording system was automated so that no one was ever present in the closed room for any of the recording period and white noise was played at 67 dB in order to mask outside noise.", "\n\nFor vidget scoring, the continuous voltage signal was down-sampled to 100 Hz. ", "The period of interest in the experiments described here lasted from 2 s prior to stimulus onset until 5 s after stimulus onset (which was the first 10 phase reversals in a block). ", "Quantification of movement driven by the onset of the stimulus (the vidget) was calculated by taking the Root Mean Square (SQRT(X^2^)) of the voltage signal. ", "Post-stimulus signal was then normalized to the average magnitude during the 2-s period prior to stimulus onset. ", "The average normalized magnitude across the 5-s period subsequent to stimulus presentation was then used to quantify the degree of stimulus-driven movement and this is described throughout in arbitrary units (a.u.).", "\n\nOptogenetics {#s4-9}\n------------\n\nAfter viral infection mice were also bilaterally implanted with VEP recording electrodes positioned in layer 4. ", "Ready-made optic fibres (200 µm girth) mounted in stainless steel ferrules (1.25 mm diameter, 2 mm fibre projection, Thor labs, Newton, NJ, US) were then implanted positioned lateral (3.5 mm lateral to lambda) to the recording site and at a 45° angle to the recording electrode, 0.1 mm below surface in each hemisphere. ", "1 month later, after peak of viral expression, mice were habituated to the head-fixation apparatus over 2 days before conducting optogenetic experiments. ", "We delivered 31-s long continuous pulses of blue light (473 nm, 150 mW) into V1 using a laser (Optoengine LLC, Midvale, UT, US). ", "These light pulses were delivered simultaneous to 50% of the 30-s long visual stimulus presentations, commencing 30 ms prior to visual stimulus onset and ending 30 ms after offset. ", "Animals were sacrificed and perfused within a week after this experiment for histological analysis.", "\n\nImmunohistochemistry {#s4-10}\n--------------------\n\nMice were deeply anaesthetized with fatal plus (pentobarbital) and perfused with saline followed by 4% paraformaldehyde in 0.1 M phosphate buffer. ", "The brain was removed and post-fixed for 24 hr at room temperature. ", "After fixation, the brain was sectioned into 60 µm coronal slices using a vibratome. ", "Slices were incubated with blocking solution (10% fetal bovine serum in PBS with 0.2% Triton X-100) for 1 hr at room temperature and then with anti-Parvalbumin mouse primary antibody (MAB1572, Millipore, Billerica, MA; 1:1000) and anti-GFP antibody (Ab290, Abcam, Cambridge, United Kingdom; 1:7000) details diluted in blocking solution overnight at 4 degrees Celsius. ", "Slices were then washed three times with PBS and incubated with the secondary antibody for 1 hr at room temperature (Alexa488-conjugated anti-rabbit IgG, Invitrogen, Carlsbad, CA; 1:500, Alexa594-conjugated anti-mouse IgG, Invitrogen; 1:500). ", "Slices were washed three times with PBS and mounted with 49,6-diamidino-2 phenylindole (DAPI)-containing Vectashield (Vector Laboratories, Burlingame, CA). ", "Fluorescence images were taken with a confocal fluorescence microscope (Olympus, Tokyo, Japan).", "\n\nStatistics {#s4-11}\n----------\n\nIn the results section, all data is expressed as a mean ± standard error of the mean (S.E.M). ", "Sigmaplot was used for statistical analysis. ", "Normality of distribution and homogeneity of variation was tested and parametric ANOVAs (for multiple groups) or t-tests (for 2 groups) were performed when data passed these tests. ", "Otherwise, non-parametric ANOVAs or t-tests on ranks were used. ", "If ANOVAs yielded significance, Student-Newman-Keuls post-hoc tests with adjustment for multiple comparisons were applied for individual comparisons. ", "Repeated measures ANOVAs or paired t-tests were applied for all within subject comparisons. ", "For other comparisons unpaired ANOVAs or t-tests were used. ", "Individual tests used are described in the results. ", "P \\< 0.05 is used as a threshold for significance throughout but exact P values are given for all comparisons for which the P value is above 0.001. ", "Post-hoc power analyses were used to determine that comparisons reached a power of \\> 0.8 for an alpha value of 0.05. ", "Technical replicates were only used as N for the ex vivo electrophysiological test of hM4D(Gi) efficacy, when 10 cells were recorded from 7 mice, and the test of NMDAR functional loss in PV-GluN1 KO mice, when 8 cells were recorded from 5 mice. ", "Throughout the remainder of the study we report the N is an individual animal (biological replicate). ", "Technical replicates (secondary samples within each animal) were not undertaken for in vivo electrophysiology. ", "Although both hemispheres were implanted initially, a decision was made as to the best hemisphere, based on response magnitude, morphology and binocularity after the very first recording (prior to any measure of plasticity). ", "Technical replicates were undertaken for the behavior, with 10, 6 (for PV-HM4D(Gi) experiments) or 5 stimulus onsets (for PV-GluN1 KO experiment) being delivered per day, although we only report the daily average (biological replicate). ", "There variations in protocol were due experiments being conducted by different experimenters at different times. ", "However, protocols were completely consistent across treatments/genotypes. ", "The individual technical replicates are available in the uploaded source data files.", "\n\nFunding Information\n===================\n\nThis paper was supported by the following grants:\n\n- http://dx.doi.org/10.13039/100000053National Eye Institute 5R01EYO23037 to Eitan S Kaplan, Sam F Cooke, Robert W Komorowski, Alexander A Chubykin, Lena A Khibnik, Mark F Bear.", "\n\n- http://dx.doi.org/10.13039/100000025National Institute of Mental Health 1T32MH074249 to Eitan S Kaplan.", "\n\n- http://dx.doi.org/10.13039/100000011Howard Hughes Medical Institute to Eitan S Kaplan, Sam F Cooke, Robert W Komorowski, Alexander A Chubykin, Lena A Khibnik, Mark F Bear.", "\n\nThis research was supported by the Howard Hughes Medical Institute, the National Eye Institute (5R01EYO23037) and The Picower Institute Innovation Fund. ", "ESK was supported in part by National Institute for Mental Health training grant (1T32MH074249), and RWK was supported in part by the Junior Faculty Development Program of the JPB Foundation. ", "We thank Marie Carlen for helping to initiate our use of PV-GluN1 KO mice. ", "We also thank Arnie Heynen, Jason Shepherd and Emily Osterweil for helpful scientific discussions. ", "We express our ongoing gratitude to Erik Sklar, Amanda Coronado, and Gerald for technical assistance and Suzanne Meagher for invaluable administrative support.", "\n\nAdditional information {#s5}\n======================\n\nThe authors declare that no competing interests exist.", "\n\nESK, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article.", "\n\nSFC, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article.", "\n\nRWK, Conducted unit recordings presented in Figure 1, Analysis and interpretation of data, Drafting or revising the article.", "\n\nAAC, Conducted intracellular recordings conducted in Figure 1, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article.", "\n\nAT, Conducted intracellular recordings conducted in Figure 6, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article.", "\n\nLAK, Conception and design, Drafting or revising the article, Contributed unpublished essential data or reagents.", "\n\nJPG, Provided critical expertise for the optogenetic experiments conducted in Figure 5, and provided methodological resources, Conception and design, Drafting or revising the article, Contributed unpublished essential data or reagents.", "\n\nMFB, Conception and design, Analysis and interpretation of data, Drafting or revising the article.", "\n\nAnimal experimentation: This study was performed in strict accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. ", "All procedures were approved by the institutional animal care and use committee (IACUC) protocol (\\#0612-050-15), and the Department of Comparative Medicine at the Massachusetts Institute of Technology. ", "All surgery was performed under ketamine/xylazine anesthesia, and every effort was made to minimize suffering.", "\n\n10.7554/eLife.11450.025\n\nDecision letter\n\nMrsic-Flogel\n\nThomas D\n\nReviewing editor\n\nUniversity of Basel\n\n,\n\nSwitzerland\n\nIn the interests of transparency, eLife includes the editorial decision letter and accompanying author responses. ", "A lightly edited version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included.", "\n\nThank you for submitting your work entitled \\\"Contrasting Roles for Parvalbumin-Expressing Inhibitory Neurons in Two Forms of Adult Visual Cortical Plasticity\\\" for consideration by *eLife*. ", "Your article has been reviewed by three peer reviewers, including Thomas Mrsic-Flogel, who is a member of our Board of Reviewing Editors, and overseen by Gary Westbrook as the Senior Editor.", "\n\nThe reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.", "\n\nSummary:\n\nThis manuscript provides evidence that PV-expressing interneurons do not contribute to the expression of an ocular dominance shift in adult V1, but are involved in the expression of selective response potentiation in V1 as shown with visual evoked responses in V1 and at the behavioral level. ", "The authors also show that ketamine interferes with the expression of SRP, but not with the expression of an adult OD shift. ", "Finally the authors provide evidence for the contribution of NMDA-receptors on PV interneurons to SRP and its prevention by ketamine. ", "The experiments provide novel insights into how PV-expressing interneurons contribute to different forms of plasticity in adult V1. ", "The study will appeal to scientists working on cortical plasticity and provides information relevant for understanding psychiatric disorders (especially schizophrenia).", "\n\nEssential revisions:\n\nHere is the summary of the main suggestions for revision, which we think you will be able to address in your revision.", "\n\n1\\) The suggestion that ketamine acts mostly on the NMDAR receptors of PV interneurons is interesting (and potentially relevant to schizophrenia research). ", "However, the claim that NMDAR in PV cells are solely responsible for the ketamine effect on SRP is not convincing, as it is possible that ketamine also affects SRP through NMDA receptors on excitatory neurons or by acting through sites other than the NMDA receptor. ", "The reviewers therefore think it would be pertinent to investigate whether GluN1 was knocked out in all PV interneurons. ", "If not, it would explain the leftover SRP in the PV GluN1 KO mice (and possibly the leftover effect of ketamine on SRP). ", "One way (but not the only way) to test the completeness of KO in the floxed line is to use GluN2A immunocytochemistry. ", "The logic here is that GluN2A remains cytoplasmic in NMDAR1 deficient cells. ", "One could then in principle detect whether there is a fraction of PV cells that do not have GluN2A in the cytoplasm. ", "This control (or some other control experiment addressing the cell-type specificity of ketamine dependence of SRF) might be sufficient to explain your results and strengthen your claims.", "\n\n2\\) All reviewers found that the discussion about mechanisms underlying SRP was not sufficiently specific or detailed. ", "For example, it is not clear where in the circuit the changes are occurring, and whether SRP relates to spiking or is only apparent at the synaptic level. ", "In particular, do stimulus-selective changes in VEPs reflect enhanced spiking of principal neurons, of inhibitory neurons, changes of feed-forward thalamocortical synaptic drive onto which neuron class, changes of top-down modulation (e.g. Makino and Komiyama 2015)? ", "It is also not clear whether PV cells are required for the induction of SRP, which would be predicted by some models of cortical plasticity. ", "Finally, it is not sufficiently discussed how PV neuron activity could modulate VEPs in a stimulus-specific manner while accounting for the fact that the Bear lab has previously shown that LTP-like phenomena (AMPAR insertion, NMDAR-dependence, occlusion by thalamocortical LTP) are critical for SRP and OSH expression (Frenkel et al. ", "2006, Cooke and Bear 2010). ", "We therefore strongly encourage you to propose a coherent, defendable and detailed mechanistic view about SRP, and how this is different from OD plasticity, in the Discussion.", "\n\n3\\) Can the (variability of) behavior of the animal influence the measurement and quantification of SRP results? ", "The reviewers request additional quantification to ensure that behavioral differences cannot explain neural response differences (i.e. does the VEP response precede any behavioral response?).", "\n\n4\\) We encourage you to acknowledge the findings by Saiepour 2015 (expression of OD plasticity not strongly affected by PV manipulations). ", "Although this work reduces some of the novelty of the results about OD plasticity, the reviewers still found it an important dataset in this manuscript.", "\n\n10.7554/eLife.11450.026\n\nAuthor response\n\n*This manuscript provides evidence that PV-expressing interneurons do not contribute to the expression of an ocular dominance shift in adult V1, but are involved in the expression of selective response potentiation in V1 as shown with visual evoked responses in V1 and at the behavioral level. ", "The authors also show that ketamine interferes with the expression of SRP, but not with the expression of an adult OD shift. ", "Finally the authors provide evidence for the contribution of NMDA-receptors on PV interneurons to SRP and its prevention by ketamine. ", "The experiments provide novel insights into how PV-expressing interneurons contribute to different forms of plasticity in adult V1. ", "The study will appeal to scientists working on cortical plasticity and provides information relevant for understanding psychiatric disorders (especially schizophrenia).*", "\n\n*Essential revisions:*\n\n*Here is the summary of the main suggestions for revision, which we think you will be able to address in your revision. ", "1) The suggestion that ketamine acts mostly on the NMDAR receptors of PV interneurons is interesting (and potentially relevant to schizophrenia research). ", "However, the claim that NMDAR in PV cells are solely responsible for the ketamine effect on SRP is not convincing, as it is possible that ketamine also affects SRP through NMDA receptors on excitatory neurons or by acting through sites other than the NMDA receptor. ", "The reviewers therefore think it would be pertinent to investigate whether GluN1 was knocked out in all PV interneurons. ", "If not, it would explain the leftover SRP in the PV GluN1 KO mice (and possibly the leftover effect of ketamine on SRP). ", "One way (but not the only way) to test the completeness of KO in the floxed line is to use GluN2A immunocytochemistry. ", "The logic here is that GluN2A remains cytoplasmic in NMDAR1 deficient cells. ", "One could then in principle detect whether there is a fraction of PV cells that do not have GluN2A in the cytoplasm. ", "This control (or some other control experiment addressing the cell-type specificity of ketamine dependence of SRF) might be sufficient to explain your results and strengthen your claims.*", "\n\nWe are aware that besides acting on NMDARs on PV+ cells, ketamine acts upon a variety of other molecular targets, including NMDARs expressed on principal cells. ", "We thank the reviewers for highlighting our lack of clarity on this issue. ", "The purpose of our application of ketamine in the PV-GluN1 knockout was to demonstrate that, in specific regard to increases in the magnitude of the VEP, the selective loss of NMDAR function in PV+ cells was sufficient to completely abolish the impact of ketamine, which is the result that we show in [Figures 7E](#fig7){ref-type=\"fig\"} and F. A range of other physiological consequences of ketamine may well be unimpaired by loss of NMDAR function selectively in PV+ cells but are not the focus of investigation in this particular study. ", "We note that the effect of ketamine to significantly increase VEP magnitude in wild-type mice is paradoxical because a glutamate receptor blocker might be expected to reduce excitatory transmission in the brain. ", "This finding is, however, consistent with other observations that the drug reduces cortical inhibition and therefore increases cortical excitation by acting preferentially (but by no means exclusively) on GABAergic fast-spiking cells in the cortex through NMDAR (Houmayoun 2007; and reviewed by Seamans 2008).", "\n\nThe reviewers suggest that there may be some residual SRP in the PV-GluN1 KO mice due to incomplete genetic deletion of the receptors in those cells. ", "In order to address this question directly, we conducted fluorescence-guided intracellular recordings from ex vivo slices if V1 to confirm the loss of NMDAR-mediated currents in PV+ cells from the PV-GluN1 KO mice. ", "As expected, recordings from PV+ interneurons in V1 revealed a lack of any significant NMDAR-mediated excitatory postsynaptic currents (EPSCs), while showing normal AMPAR-mediated EPSCs ([Figure 6H](#fig6){ref-type=\"fig\"}). ", "Conversely, neighboring principal cells displayed both NMDAR and AMPAR-mediated EPSCs. ", "The selective loss of NMDAR EPSCs in PV+ neurons in the PV-GluN1 KO mice is reflected by plotting the NMDAR/AMPAR EPSC ratio in PV+ cells as well as neighboring principal cells. ", "Thus, PV+ neurons sampled from V1 in the PV-GluN1 knockout mice failed to express NMDA receptors. ", "This data has been added to the manuscript as [Figure 6H](#fig6){ref-type=\"fig\"}.", "\n\nUnfortunately, immunohistochemistry for any of the NMDAR subunits proved extremely challenging (largely due to the quality of commercially available antibodies) and we were unable to convince ourselves that this method could be used to confirm that every single PV+ neuron in V1 lacked NMDAR function. ", "However, given the consensus within the literature on ketamine's actions through NMDAR expressed within PV+ neurons, we believe that the fact that we observed no effect whatsoever of ketamine on VEP magnitude in the PV-GluN1 KO mice, in contrast to their wild-type littermates, indicates that the genetic deletion of GluN1 within PV+ cells must be close to complete across all PV+ neurons within V1 of these knockout animals.", "\n\nWe agree that it is an important issue to understand more deeply what mechanism has accounted for the remaining SRP that exists in the PV-GluN1 knockout mouse, which is not observed with acute ketamine blockade. ", "As a result of our confirmation that NMDAR-mediated currents are completely absent from at least all sampled PV+ cells in the PV-GluN1 KO mice, we hypothesize that the residual potentiation in the PV-GluN1 may derive from some form of developmental compensation that could occur through another subclass of neuron or another receptor type. ", "Acute manipulation of NMDARs via ketamine would not allow for such compensation to occur, and therefore could explain the complete abolishment of SRP expression in the ketamine experiment that was not apparent in the PV-GluN1 knockout. ", "It is possible that in SRP, NMDARs may be involved not only on PV+ cells but also on principal cells (Frenkel 2006). ", "In this case, the effect of ketamine on NMDARs expressed on principal cells may also contribute to the complete lack of SRP expression in these experiments (even if it cannot account for the action of ketamine on VEP magnitude), in comparison to the PV-GluN1 KO mouse experiments. ", "In order to test this hypothesis, future studies will probe the involvement of NMDARs on principal cells in various cortical layers in SRP. ", "The alternative explanation, that another class of receptor compensates for the loss of NMDAR in the PV-GluN1 KO is also worthy of further investigation.", "\n\n*2) All reviewers found that the discussion about mechanisms underlying SRP was not sufficiently specific or detailed. ", "For example, it is not clear where in the circuit the changes are occurring, and whether SRP relates to spiking or is only apparent at the synaptic level. ", "In particular, do stimulus-selective changes in VEPs reflect enhanced spiking of principal neurons, of inhibitory neurons, changes of feed-forward thalamocortical synaptic drive onto which neuron class, changes of top-down modulation (e.g. Makino and Komiyama 2015)? ", "It is also not clear whether PV cells are required for the induction of SRP, which would be predicted by some models of cortical plasticity. ", "Finally, it is not sufficiently discussed how PV neuron activity could modulate VEPs in a stimulus-specific manner while accounting for the fact that the Bear lab has previously shown that LTP-like phenomena (AMPAR insertion, NMDAR-dependence, occlusion by thalamocortical LTP) are critical for SRP and OSH expression (Frenkel et al. ", "2006, Cooke and Bear 2010). ", "We therefore strongly encourage you to propose a coherent, defendable and detailed mechanistic view about SRP, and how this is different from OD plasticity, in the Discussion.*", "\n\nWe appreciate the need for clear overall insight and have modified the Discussion section to accommodate those possible interpretations of the underlying mechanisms of SRP that we can currently envisage. ", "It is becoming increasingly clear that this is a far more complex phenomenon than we had previously realized and may, therefore, be more interesting in many ways.", "\n\nPreviously published data has provided evidence that SRP is apparent at the synaptic level as well as being expressed as changes in neural spiking. ", "Multi-unit recordings from Layer 4 of wild-type animals showed that peak firing rate in response to a familiar stimulus was significantly elevated compared to those evoked by a novel stimulus (Cooke et al., ", "2015). ", "In response to a phase reversing visual stimulus, the negative-going component of the VEP occurs simultaneously with a short latency spiking response to the visual stimulus. ", "Familiar stimuli drive larger VEPs and increased neural spiking in Layer 4 in comparison to novel stimuli. ", "By using laminar probes that span the cortical layers, we have also explored how familiarity changes the laminar flow of current sinks and sources and using current source density analysis (Cooke et al., ", "2015). ", "From this we have observed alterations across multiple V1 layers resulting from experience, but the most striking effects are apparent in the short-latency layer 4 current sink, where familiar stimuli drive a larger current sink and increase the spiking of L4 neurons. ", "Our current findings indicate that this increased spiking in L4 in part derives from removal of inhibition mediated by PV+ neurons.", "\n\nAlthough it is known that experience drives changes in synaptic and spiking activity, we do not yet know how changes in spiking relate directly to individual cell types, which is an area of active investigation. ", "Previously published data has also revealed that although there is evidence for thalamocortical (TC) LTP-like phenomena as a mechanism underlying SRP (Frenkel et al., ", "2006, Cooke and Bear 2010), selectivity for familiar and novel stimuli cannot be fully explained by changes occurring at the TC synapse in Layer 4. ", "Isolation of the TC synaptic response by silencing intra-cortical spiking revealed a loss of SRP expression, suggesting that although changes may be occurring at the level of the TC synapse, downstream intra-cortical network alterations are involved (Cooke and Bear, 2014). ", "We propose that these LTP-like changes previously reported are critical in the induction and maintenance of the stored information related to the familiar stimulus. ", "Alterations in PV+ cell activity are necessary, however, for the retrieval/expression of this information. ", "Since the major focus of this paper was on the expression mechanisms of SRP, the role of PV+ cells in the induction process remains unknown but we plan to pursue this further. ", "A discussion of this hypothesis and how it differs from adult OD plasticity is presented in the revised Discussion section of the manuscript.", "\n\n*3) Can the (variability of) behavior of the animal influence the measurement and quantification of SRP results? ", "The reviewers request additional quantification to ensure that behavioral differences cannot explain neural response differences (i.e. does the VEP response precede any behavioral response?).*", "\n\nThe reviewers certainly raise an understandable concern, that differences in cortical physiology could be reflective of behavioral events rather than the other way round. ", "In our previous paper (Cooke et al. ", "2015, Nature Neuroscience) we have discussed this issue at length and presented data showing that the visually induced behavioral response (vidget) commences \\~150 ms after stimulus onset, a good 100 ms after the peak negativity of the first VEPs that we record. ", "More importantly, we have reported that behavioral responses do not occur on all stimulus presentations and for the 5 stimulus onsets (gray to phase reversing grating) that occur on each recording day, only a subset will produce a behavioral response. ", "However, the VEPs evoked during each of these stimulus blocks are similar in magnitude, regardless of whether a behavioral response has occurred or not and the difference in cortical response between familiar and novel stimuli is maintained even for all of those stimulus blocks where no behavior occurred. ", "Thus, the behavior itself does not account in any way for VEP magnitude or the phenomenon of SRP.", "\n\n*4) We encourage you to acknowledge the findings by Saiepour 2015 (expression of OD plasticity not strongly affected by PV manipulations). ", "Although this work reduces some of the novelty of the results about OD plasticity, the reviewers still found it an important dataset in this manuscript.*", "\n\nWe agree that the findings of Saiepour 2015 are of great importance and that our results confirm their earlier study. ", "Using optogenetics and Dreadds to inactivate PV+ cells in V1 they have revealed that the activity of these cells is not necessary for the expression of the adult OD shift. ", "It is heart-warming to us that these two studies, using different recording methods, have arrived at the same conclusion in regards to the expression mechanisms involved in adult OD plasticity, which only adds to the striking contrast with SRP expression mechanisms that we describe in our manuscript. ", "We now devote a considerably larger portion of our Discussion section to this important study and its implications.", "\n\n[^1]: These authors contributed equally to this work.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "POPULAIRE\n⋆⋆½ out of four stars\nRated: R for a scene of sexuality.", "\nTheater: Edina.", "\n\n“Populaire” is a frothy little French period piece with a taste of gender-role history tucked into its boy-meets-secretary romance.", "\n\nIt’s 1958, and shy, pretty and naive Rose Pamphyle (Deborah Francois) longs to dig into “the latest fashion” — becoming a secretary. ", "She teaches herself to type. ", "Then she takes the bus to the big city.", "\n\nLouis Echard (Romain Duris) is an insurance agent in need of a secretary, a dashing, dismissive fellow with a hint of “cad” about him. ", "He doesn’t think much of her klutziness, but he sees in Rose a champion speed-typist, a woman who can win glory for herself and maybe her competitive boss. ", "She gets the job.", "\n\nTyping competitions take over the picture, slowing things down. ", "The leads are charming, the supporting players (Berenice Bejo plays Echard’s old flame; Shaun Benson is that old flame’s go-getter/wisecracking American husband) are stellar.", "\n\n“Populaire” is never less than cute.", "\n\nROGER MOORE, McClatchy News Service\n\nBATTLE OF THE YEAR\n⋆⋆ out of four stars\nRated: PG-13 for language and some rude behavior\n\nThe formulaic \"Battle of the Year\" touches on how the rest of the world has embraced B-boy culture, but how they’re no longer perceived as cutting edge or “cool” in the United States.", "\n\nThat worries the Sean Combs-like impresario, Dante (Laz Alonso), who seeks to put American B-boys back on top. ", "He hires an old dance buddy, W.B. (for \"Wonder Bread\"), now a grieving, alcoholic ex-basketball coach (Josh Holloway of “Lost”). ", "W.B. has to get himself up to speed on the current state of dance, then recruit and coach a “dream team” to take on the rest of the world, which has passed America by and long dominated the annual B-boy Olympics known as “BOTY,” the Battle of the Year.", "\n\nThat team consists of assorted arrogant, chip-on-their-shoulder show-offs, because that’s what it takes to succeed at this. ", "Actual star dancers such as Do Knock and Flipz are mixed in with others, including singer/tabloid darling Chris Brown. ", "Josh Peck, once of TV’s “Drake & Josh,” has a small supporting role but is given top billing.", "\n\nThe movie does hit this genre right in the bull’s-eye. ", "But then, the beauty of “Step Up” and all its tired imitators is that the audience they’re shooting for has no idea that there have been 20 or 30 movies exactly like this one that came before it.", "\n\nROGER MOORE, McClatchy News Service\n\nINFORMANT\n⋆⋆⋆ out of four stars\nNot rated. • ", "Theater: St. Anthony Main.", "\n\nJeremy Piven-looking Brandon Darby is an ever-present if somewhat slippery narrator of his own dramatic political about-face. ", "He went from way-left community organizer in post-Katrina New Orleans to an informant who helped the FBI build a case against two young protesters at the 2008 GOP convention in St. Paul, both of whom went to prison for making (but not using) Molotov cocktails.", "\n\nAnyone interested in movement politics in the 21st century will get plenty to ponder in this well-made doumentary.", "\n\nCLAUDE PECK\n\nTHE PATIENCE STONE\n⋆⋆⋆ out of four stars\nRated: R for sexual content, some violence and language.", "\nTheater: Lagoon.", "\n\nAn unnamed woman (Iranian actress Golshifteh Farahani) lives in a small house behind a walled courtyard, where she has two young daughters and a husband. ", "He is lying comatose, a bullet in his neck, a tube with serum going into his mouth. ", "The man (Hamidrez Javdan — not exactly a fun part) is much older. ", "She was 17 when she married him — or married a photograph of him. ", "He was away.", "\n\nAnd now, in this quietly fierce condemnation of fundamentalist Muslim society’s treatment of women, she begins to speak truths she dared not utter when he was awake. “", "The Patience Stone,” adapted from the Atiq Rahimi novel and directed by the author — aided by Thierry Arbogast’s remarkable cinematography — finds the woman telling her husband about the men who fathered her daughters, because he was impotent. ", "She talks of her longings, her rage. ", "After weeks of these confessions, something stirs, breaks free. ", "She meets a soldier (Massi Mrowat), and they make love.", "\n\nAlthough the country goes unnamed in this powerful, parable-like film, it is clearly Afghanistan, torn by war, and dominated by men, by mullahs.", "\n\nWhat comes across more than anything — in Farahani’s character, in the wisdom and wild humor displayed by her aunt (Hassina Burgan) — is the resilience of women. ", "Beneath the hijabs and the burqas that conceal them, a spirit burns fast and strong." ]

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[ "london_chrisc\n\nHomeopathy: The London Overdose\n\n\n\nSimon Singh risks his life for science. ", "On Saturday morning, a hundred scientists, skeptics and rationalists gathered in Holborn to overdose on homeopathic medicine. ", "You won't be surprised to hear that no-one died, though most had a very pleasant sugar rush. ", "The overdose, organised by the 10:23 Campaign, set out to prove that homeopathic tablets are nothing more than sugar pills, and that any recovery after taking homeopathy is certainly not due to the contents of the tablets.", "\n\nWhat is homeopathic medicine? ", "Well, consider this novel cure for insomnia: dilute some caffeine (stay with us, folks), and shake it vigourously against some leather. ", "Next, dilute that dilution, and shake it again. ", "Now, do that twenty-eight more times. ", "You'll be left with 100% water; but as if by magic, the water will remember the caffeine - and the more you dilute it, the stronger the water's memory gets. ", "Finally, drip your water onto a sugar tablet - and hey presto, you've got yourself a homeopathic remedy!", "\n\nThe healing power of homeopathy is pure placebo. ", "Sadly, that hasn't stopped it becoming a multi-million pound business. ", "The NHS spends £4 million a year on homeopathy, and Boots sell homeopathic pills alongside proper medicine, even though they admit there is no evidence to show they work. ", "The campaign hoped to raise awareness of this, and all the protesters made sure to take Boots own-brand homeopathic tablets.", "\n\nThe protest had support from some prominent personalities. ", "Simon Singh gave a rousing speech reminding the campaigners of the dangers of letting people get away with selling sugar pills as medicine; Evan Harris MP, a firm supporter of evidence-based medicine, talked about the excellent progress of parliamentary select committees in getting homeopaths to explain themselves; and Dave Gorman said that after taking his overdose of homeopathic arnica, which allegedly cure bruises and aches, he'll \"never bruise again\", challenging anyone to punch him to put this to the test. ", "Never before have we seen a finer example of science in action.", "\n\nWhy is this campaign important?. ", "Simply put, when people take sugar pills instead of life-saving medicine, they die. ", "The protest was fun, but the message behind the campaign is vitally important. ", "We mustn’t forget that tragedy can befall people who shun evidence-based medicine in favour of unproven alternatives.", "\n\nWith any luck, the 100% survival rates of the overdosers will go some way to showing people that homeopathic pills really are just sugar. ", "As the campaign says, \"Homeopathy: there's nothing in it.\"", "\n\nImage by the ten23campaign" ]

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[ "Antimicrobial PLGA ultrafine fibers: interaction with wound bacteria.", "\nThe structure and functions of polymer nanofibers as wound dressing materials have been well investigated over the last few years. ", "However, during the healing process, nanofibrous mats are inevitably involved in dynamic interactions with the wound environment, an aspect not explored yet. ", "Potential active participation of ultrafine fibers as wound dressing material in a dynamic interaction with wound bacteria has been examined using three wound bacterial strains and antimicrobial fusidic acid (FA)-loaded electrospun PLGA ultrafine fibers (UFs). ", "These were developed and characterized for morphology and in-use pharmaceutical attributes. ", "In vitro microbiological studies showed fast bacterial colonization of UFs and formation of a dense biofilm. ", "Interestingly, bacterial stacks on UFs resulted in a remarkable enhancement of drug release, which was associated with detrimental changes in morphology of UFs in addition to a decrease in pH of their aqueous incubation medium. ", "In turn, UFs by allowing progressively faster release of bioactive FA eradicated planktonic bacteria and considerably suppressed biofilm. ", "Findings point out the risk of wound reinfection and microbial resistance upon using non-medicated or inadequately medicated bioresorbable fibrous wound dressings. ", "Equally important, data strongly draw attention to the importance of characterizing drug delivery systems and establishing material-function relationships for biomedical applications under biorelevant conditions." ]

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[ "Institutional change: embracing the initiative to train more generalists.", "\nDartmouth Medical School was one of 16 U.S. medical schools that received a Generalist Physician Initiative (GPI) grant from The Robert Wood Johnson Foundation in 1994. ", "This article describes institutional change at the school, noting that while the context in which the GPI was launched was receptive, the grant enabled Dartmouth to accelerate institutional changes already under way. ", "Perhaps even more important is that Dartmouth used an approach to change that worked, and although the specific actions may not generalize to other schools, the authors hope the principles will. ", "Key among these principles were capitalizing on a sense of urgency for change, creating and empowering a guiding coalition, developing and communicating the vision, generating short-term wins, consolidating gains, and anchoring new approaches to the existing institutional culture. ", "Changes at Dartmouth are described in the areas of admission and recruitment, undergraduate and graduate medical education, and supporting community practice. ", "The authors also describe shortcomings in developing the program, such as maintaining the guiding coalition in the face of the changing health care system and clinical pressures, developing a vision and strategy in areas managed by the state, and engagement of a broad-based group." ]

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[ "“Why is it,” Mr. Warner asked, the American prosecutors “believe that they have a right to the World Cup?”", "\n\nAs dramatic background music swelled, he went on, holding up The Onion article again, to accuse the United States of hypocrisy for accepting the right to host the (entirely fictional) “Summer World Cup, 2015, from the very same organization that they are accusing of being corrupt. ", "That has to be double standards.”", "\n\nIn the video, Mr. Warner also said he was “consoled by the fact that many of you on the blogs, on Twitter, on Facebook, on other channels, throughout were very supportive of me and still are.” ", "He assured his supporters that, “At the end of the day, all of the allegations against me shall be proven to be unfounded.”", "\n\n“You see, it is not when you’re up that you know who your friends are,” he said, “it’s when you are perceived to be down.”", "\n\nAfter Mr. Warner’s error in mistaking The Onion for a news source was mocked on social networks, the video disappeared without explanation from his website and social media accounts.", "\n\nTwo hours later, it was replaced by an edited version, missing 63 seconds and all references to The Onion.", "\n\nMr. Warner is far from the first person to mistake The Onion for a genuine news source. ", "In 2012, an Iranian news agency backed by hard-liners reprinted an Onion poll that found rural voters in West Virginia preferred Mahmoud Ahmadinejad to President Obama." ]

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[ "ODD i thought but i did believe him. ", "Im a very believing person the first few times out. ", "Takes me several times before i say oh wait a minute maybe he is not being fully honest here. ", "Seriously it takes me several times – my first instinct is to believe folks tell the truth. ", "Im not like the other sharp folks who, when i told them about Alexander Graham saying “i’m not aware of that” , they all immediately said “oh yeah right.”", "\n(Dang do i gotta get me boots out for u too Alex!)", "\n\nI didnt even get it when the VRS interpreter signed “sounds like he has put you on speaker phone”\n\nyes i found it ODD but still i figured – why would he lie?", "\n\nSo as i promised i would in our VP call – AFA sent him an email with links about both cases and asked for AG Bell’s position on their Circle Alliance partners being in hot water re: cochlear implants. ", "No reply. ", "I called back but no answer or call back.", "\n\nIt’s been more than a week.", "\n\nSo maybe he didn’t hear me? ", "Maybe his is metaphorically “deaf”?", "\n\nOr shall we assume that his statement was truthful that he is metaphorically “dumb”? ", "That he as CEO of one of the LARGEST agencies / organizations serving the Deaf and Hard of Hearing has no idea what his Circle Alliance partners have been up to?", "\n\nwell maybe he will learn more about it at the AG Bell Conference which starts today in Fla because Advanced Bionics and Cochlear Americas (both CI companies that got hit with big fines for wrong doings with CIs) are not just AG Bell’s Circle Alliance partners to help promote their common values and services but they are also SPONSORS at the AG Bell conference. ", "So hopefully there Alexander will get some education and no longer remain in the dark.", "\n\nHope springs eternal in my lately.", "\n\nLooking forward to getting AG Bell’s statement re: their position on partnering with CIs co. that have manufactured, sold and marketed harmful products and/or engaged in unethical practices of kickbacks to drive up the cost and marketing of their particular CI.", "\n\nsince i blogged about Barry’s video in which he stole someone else’s video and added captions and intertitles condemning Deaf leaders and stated he was sending the video to CA senators – his video and blog entry have now gone missing (this note added 6/25/2010 after confirmation that Barry’s pointless and nitpiky video letter to CA senators that involved copyright infringement was removed from DR/DVTV/Youtube and his own blogsite – cuz the original creator of the video and husband reported the misuse and abuse of their property. ", "Thanks Michelle & husband for standing firm and strong – see comment below)\n\nBarry does have a blog entry up about Saving Faces – no not his – not his darling. ", "Just cuz he is claiming credit and thanking folks for heeding his advice in “winning” AB 2072 – AS IF – he is definitely not trying to save face (i.e. read this opposite or backwards or hold up a mirror to see the truth)\n\nboy u r getting so obvious now it ain’t even fun Barry. ", "You accuse the folks who worked their BUTTS off – really the Oppose 2072 folks were STRONG, were BUSY, were AWAKE, were UNIFYING – and u have the gall to prance in via a couple of blog entries to say they are just making up this victory – that THEY ARE SPINNING and SAVING FACE.", "\n\noh gosh – kettle so black here darling.", "\n\nits just so ODD that u would commit so many blogs about AB 2072 as if it was a PERFECT bill and Mendoza was a GREAT guy and all the opposition folks were CRAZY and that journalist was just bonky and eugenics is dead (wishful thinking, love) and somehow when the bill is basically tossed and three new amendments are inserted – YOU claim credit for it\n\nwow – ODD… if the shoe fits or shall we say boots?", "\n\nyes, i got me boots on Barry. ", "for splashing in puddles each time u and ur pals try to rain on our parades and for each time u and ur pals are spreading so much bull$hit higher and deeper – i need me whimsical boots. ", "they make me happy. ", "and they help me whisper a prayer instead of a curse.", "\n\nbut right now i wanna know oh GREAT tactic man, he who knows strategies, he who is media savvy, he who has v/blogged by buckaroo, ohbuckaroo, gurusays, theholism, and more –\n1. ", "what did the CA dept of justice think of ur letter of b.s. ", "re: CAD and their bylaws?", "\n2. ", "what did the CA senators think of your video about “lies and myths of Deaf leaders” which contained illegal obtained material by you and was full of your own myths and lies?", "\n3. ", "why did u call the Deaf Business conference folks “ghetto” people just cuz they wanted verification that you did receive a ‘Death Threat’ – ya know so they could plan for security and all that?", "\n4. ", "why do u blog about peaCOCKS and not chickens?", "\n5. ", "why do you call the folks in DVTV dummies and kiddies?", "\n6. ", "why are you always attacking folks who are doing good stuff and not the folks who are doing bad stuff\n7. ", "why do you want to make DR and DVTV in to “a desert and call it peace”\n\nbut what i really want to know –\n8. ", "ain’t u tired of the bull$hit by now?", "\n\nI’m ok with u wanting to be deafless. ", "I’m ok with u valuing audism over liberation and equality. ", "that is your personal choice and OPTION.", "\n\nI ain’t ok with u lying, and spreading bull$hit, and twisting and spinning and ATTACKING. ", "it just ain’t smart. ", "it ain’t good strategy, tactics, or media savvy.", "\n\nsummary – not transcript:\nA wish and gratitude for the Stop 2072 folks\nTmw u r meeting before the Senate Health Committee – thank you for speaking our TRUTH and taking a stand. ", "May the blessings of our ancestors – Veditz, Hotchkiss, Robert McGregor, Agath Tiegel Hason, Laurent Clerc, Alice Cogswell, and Gallaudet be with u. Please consider when all is said and done to put all the documents and good work u have generated into a Deaf related archives – Gallaudet, NTID, CSUN, anywhere – it should be bound up and preserved for all to see as a model and testament. ", "REQUIRING parents to see an audiologist is not an OPTION. ", "Promoting numerous so called options that ban natural sign language – programs that actively omit and exclude signing language DENYING the option to natural language – that is not really an OPTION.", "\nAlso I want to express my sorrow that you have been getting some ____ from folks – like the person who grabbed a video and showed a person signing “doctor” and sent DVDs of it to Senators in CA. ", "Or a person who has been blogging repeatedly saying folks havent read the bill. ", "We have read it and see it for what it is – how it is attached to a larger already passed law requiring the testing, identifying and TRACKING of Deaf children – TRACKING.", "\nWe see in wisconsin the blood testing going to the State Dept of Hygiene. ", "Hygiene – yuck. ", "That is a word the Nazis used in their quest for a perfect Aryan race – it was a euphemism “racial hygiene” We see in Idaho how a judge can order parents to make their Deaf daughter wear her CIs all her waking hours. ", "Where is their OPTIONS and their RIGHTS.", "\nWhere is the Deaf child’s rights in all of this? ", "S/he has 0 options – ZEROLink to blog explaining how AB 2072 is optionLESSlink to blog explaining about the latest myth and lie\n\nThis bill now requires that after the screening and labeling and tracking of the “babe that failed the hearing test” (i.e. the Deaf baby) that the PARENTS BE REQUIRED TO GO TO AN AUDIOLOGIST for a follow up meeting.", "\n\nHmmmm? ", "You can really require this in law?", "\n\nReally?", "\n\nYou can proclaim and apparently legislate the virtues of “options” by MANDATING someone take their baby to an AUDIOlogist?", "\n\nKinda like in Wisconsin where you are required to have your baby’s blood tested for various “disorders” so it can be recorded in the State Dept of Hygiene (this is happening in 2010 folks) – they just expanded the law to include homebirths too – gotta get every babies’ blood registered.", "\n\nIn Wisc. ", "you are only exempt if u can prove some type of religious reason for objecting to this blood taking, testing, and collecting. ", "Hmmm how about “the–its-none-of-your-bloody-business-state-government” religion – unless I want the testing and request the testing.", "\nInformed consent anyone?", "\n\nOr maybe we can look at the HFEB – a bill that became law in the U.K. that has a big ole fat clause in it prohibiting anyone from selecting Deaf genes – only allowed to use the “normal” genes after pre-implanting screening.", "\n\nDeaf genes are very hot commodities in lots of places folks. ", "Patent on one Deaf gene – done. ", "Deaf couples are constantly being asked if they want the embryo to be tested for deafness with the option for abortion. ", "Genetic engineering is big.", "\n\nWe can ignore the fact that there is a cochlear implant surgeon in New Mexico that makes parents sign papers that they will raise their child oral / aural only and if they don’t, he won’t perform the surgery. ", "Parents who truly want option for their kids and also want CIs have had to cross state lines to have CI surgery done in a different state where the doctors don’t have this non-option requirement.", "\n\nAnd never mind about how CIs are now operated by remote control so that oral programs, audiologists, speech pathologists, and parents will not need to ask the Deaf child if they “are on,” they will just click the remote to activate the devices. ", "Cuz apparently the child’s OPTIONS are unimportant here.", "\n\nBut I digress – back to the sunny state of CA and the proposed bill REQUIRING that parents go to AUDIOlogists whether they want to or not – ya know so they can learn about their “OPTIONS. ” (", "ya all should be saying WTF now – no I don’t mean Wow That’s Fabulous)\n\nWhat’s the problem?", "\nWell….", "\nSuppose the parents don’t want to.", "\nLet’s just suppose the parents think they still live in the U.S. of A. and they might even have a crazy and radical notion that its ok to be Deaf kinda like Feminism Is The Radical Notion That Women Are People. ", "So suppose these enlightened parents (don’t care if they are Deaf or Hearing as folks fall all over the spectrum from audism to Deafhood regardless of their dB) and just suppose these parents are not freaked out by their offspring springing off the chart in terms of dB. Perhaps even a few of these parents are happy about it (gasp).", "\n\nCan a state mandate and legislate that these parents MUST go to an AUDIOlogist under the pretense of mandating they get “neutral” information?", "\n\nNeutrality ain’t real folks – look at Switzerland during WW II.", "\n\nIf you are looking for a place to get unbiased information on options – why an audiologist office???", "\n\nReally, Seriously.", "\n\nThis is a hard concept to grasp? ", "That some folks might say – its BAD ENUF that you mandate this test and charge the parents for the test and there is all this tracking stuff – Now ya gonna require me and MY BABY to go to an audiologist. ", "SHOULDN’T T H A T be my OPTION. ", "Shouldn’t that be MY CHOICE – MY DECISION. ", "I didn’t have a choice over if my kid was gonna be Deaf or not but shouldnt i at least have the CHOICE of who to go see?", "\n\nWhat’s next – a judge will order parents to make their Deaf child wear two cochlear implants all her waking hours regardless of if one is working or not? ", "HA. ", "Oh not funny – See the case currently before a court in Idaho. (", "and all the other stuff i mentioned above and all the other stuff i havent even learned about yet but is still happening)\n\nNow im not saying audiologists = bad. ", "I am not saying that so stop getting ready to leap and spin oh dear black kettle of unholiness.", "\n\nI am simply saying – audiologists are trained to make folks hear – that is their job, their speciality, their function, their expertise, and their duty.", "\n\nAnd I’m saying there is this little thing called KICK BACKS and there was a little Department of Justice announcement last week where Cochlear Americas had to pay $880,000 for kickbacks with physicians (i.e. doctors) and audiologists and other specialists and were jacking up the price of their CIs and making the govt foot the bill.", "\n\nOh and Advanced Bionics got hit with a $1.1 million dollar penalty for its faulty CIs that actually shocked infants and children and adults. ", "Another lawsuit in process. ", "These devices had been recommended by AUDiologists as one of the options for parents to consider.", "\n\nSupposing parents of THE Deaf baby at moment of diagnosis say – great, cool, Deaf baby – me wanna talk to some Deaf folks, you know the people who know what it means to be Deaf in the first place. ", "Call me crazy but just intuitively I’m being called to meet up with some Deaf folks. ", "Why isn’t anyone requiring me to see them????", "\n\nAnd me wanna get my hands on materials to do for the eye NATURALLY (and hands tactile if Deaf-Blind baby) what the audiologist wants to do to my babes ears ARTIFICIALLY and AGGRESSIVELY.", "\n\nWhat am I to do if there is a LAW saying I MUST see the audiologist???", "\n\nI must report to an audiologist?", "\n\nI must? ", "It’s a law???", "\n\nAll together folks – WTF!", "\n\nNow suppose ALL me wanna make sure my baby knows is:\n#1. ", "we love her/him as s/he is\n#2. ", "Its good to be Deaf – it s a blessing\n#3. ", "Its good to live in a multicultural – multilingual world\n#4. ", "I’m glad you are here little one – lets get busy learning a language u can understand naturally and completely and let’s make sure you learn the majority culture’s language too and if a parent wants to throw in some other stuff – that is their choice.", "\n\nSo just as NO LAW should be passed forbidding parents from going to an audiologist etc NO LAW should be passed mandating that they do.", "\n\nThis is not a life threatening condition folks. ", "In fact some people believe to be Deaf is actually a life enriching condition.", "\n\nDeaf does NOT equal Death\n\nfor more TRUTHFUL information on the Stop AB 2072 campaign go tohttp://www.opposeab2072.com/\nTo all the Oppose 2072 folks – U Rock Big Time.", "\n\nREAD the bill and SEE that by mandating folks to go to an audiologist they are actually REMOVING options.", "\n\nFolks this is REAL important stuff – “First they came for….” ", "applies here.", "\n\nNow before the naysayers get all excited and start screaming extremists and closed mindedness or shouting out about the right to be non-deaf – keep spreading myths and lies and twisting – oh how you twist – and folks are gonna keep digging and more and more parents are gonna start to question just how fair and just and good is an oral / aural only experience for my child. ", "How is a program that excludes ASL and visual acuity (i.e. anything that comes natural to my child) really an option at all??", "\n\nWhere is the CHILD’s option and choice in oral / aural / AVT / CIs????", "\n\nBelow the video box he states: “Hard copies of this video is being sent to California State Senators”\n\n(this note added 6/25/2010 after confirmation that Barry’s pointless and nitpiky video letter to CA senators that involved copyright infringement was removed from DR/DVTV/Youtube and his own blogsite – cuz the original creator of the video and husband reported the misuse and abuse of their property. ", "Thanks Michelle & husband for standing firm and strong) em>\n\nAll the below is still valid – especially if he did send the DVDs to the CA senators and especially if he never did (i.e. myths and lies and leadership – whistle is a blowing. ", "Tea anyone?)", "\n\nNow back to the “fact”? ", "where Barry said he sent this video to CA senators:\nWhich Senators – all of them?", "\nDoes it matter? ", "Nah, guess not (cuz maybe he isn’t really sending them – kinda like the letter to the CA Dept of Justice b.s.)", "\n\nIt is an awful lot of DVD burning and mailing from Arizona – costly investment of a worthless and fraudulent endeavor – but sadly not the first one.", "\n\nHopefully this will be the last one though. ", "Hope spring eternal in me.", "\n\nAnd for what purpose was this video letter to CA senators made by Barry??? – ", "to show that a person signed “DOCTOR” when discussing AB 2072 and thus somehow that makes the whole protest moot and the activist guilty of “spreading lies and myth” – OH MY HEAVENS the kettle is so black here, dear.", "\n\nI will quote what the man signed (no I ain’t using your transcript Barry cuz that might be copyright infringement and cuz it has bad verb tense usage)\n“We are gathered here to protest against AB 2072. ", "That bill is related to newborn Deaf babies. ", "Understand that this bill depends on audiologists and doctors to make decisions about their lives and upbringing.”", "\n\nAB 2072 states that it is an addition to the existing law, the Newborn Infant Hearing Screening, Tracking and Intervention Act which “requires every general acute care hospital with licensed perinatal services to offer every newborn a hearing screening test for the identification of hearing loss, as specified, and provide written information on the availability of community resources and services for children with hearing loss to the parents of those who are diagnosed with a hearing loss.”", "\n\nSo who exactly is gonna be doing all that screening, identification, and providing of written information in the hospital???", "\n\nYou guessed it (if you ain’t a dummie or dumb and deafless)\n\nDOCTORS. ", "You know folks who are trained to see Deaf as health issue, disease, disorder, affliction, etc.", "\n\nIts already happening folks…EVERY DAY – EVERY WHICH WAY YOU TURN\n\nThus the gentlemen’s use of the sign doctor is still applicable. ", "Even if it weren’t – Barry do you have no clue of how petty you look to be making a video that involves copyright infringement and having an intertitle frame that states:\n\n“Watch the video carefully. ", "This is one of many lies and myths being spread by some of the deaf leaders.”", "\n\nSpooky music absent may be playing in the mind of the creator of this video letter to CA senators.", "\n\nSeriously this is the BEST BEST BEST most damaging evidence you can muster to take the time to mis-caption, illegally download, illegally distribute via your holism site, and illegally reproduce, burn and MAIL to senators? ", "Holy crude boy – your logic totally worries me.", "\n\nTaking illegally obtained materials and mailing them to out of state senators to prove someone else’s WRONG DOINGS??? ", "When –\n1. ", "he really did nothing wrong\n2. ", "ya stole someone else’s property in your quest to out-do myth makings – at the very LEAST Barry you could have cited the source of your stolen materials – make a little effort to set a good example would ya.", "\n3. ", "That is the lamest lamest lamest example of a lie or a myth “and doctor” that I have ever seen and it screams out “look at me I am bloody desperate here – would you folks give me some real b.s. ", "to work with.” ", "No sorry love. ", "We will not. ", "Firm with love all the way here. ", "We are on a truth campaign. ", "See Gandhi’s soulforce / truthfoce. ", "Yes, I know you hate it and yes I know it hurts.", "\n\nThere are MANY MANY MANY shortcomings in this bill and we totally ain’t dumb. ", "The fact that you can not see them, ur unholiness, does not surprise me but it does make me sad. ", "Stop by http://www.opposeab2072.com/ oodles and oodles of facts on the bill and see the truth. ", "It only REQUIRES that you open your eyes.", "\n\nSo Barry Sewell – you might want to heed your own advice before you go lying to the Senators in CA or the CA Dept of Justice or a licensing board or……\n\n“True leaders do not lie to their own people and spread myths like that.” ", "Barry Sewell\n\nwould that you could heed your own advice\n\nFolks – careful where u step b.s. ", "is everywhere and that stuff sure do stink. ", "Wipe your shoes before coming into the house, eh.", "\n\nNow if folks would like to know a bit about Barry Sewell’s own lies and myth spreading – check out the below.", "\n\nLooks like your spinner landed on black with this latest myth in Twister, Bar.", "\n\nDR/DVTV thanks for pulling Barry’s “Evidence of Myths & Lies on AB 2072” blog and vlog entry. ", "Cyberbullying and copyright infringement ain’t cool.", "This has a strike through now – 6/25/2010 because we just learned that DR/DTV did not do this removing on their own accord. ", "It seems the human editors at DR and owner at DVTV still can’t discern what they should publish and what they should not without a little help. ", "to modify and amend Barry’s quote to the CA Senators ““True leaders do not lie to their own people and spread myths NOR DO AGGREGATORS and WEBSITES PUBLISH THIS LIBEL, SLANDER, and CYBERDEFAMATION like that.” ", "The credit really goes to Michelle and her husband for reporting the abuse and misuse of their property by Barry.", "\n\nLooking forward to when the other ones get pulled cuz good publishers, aggregators, and website administrators don’t carry lies and myths that attack people and organizations." ]

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[ "Scapular insertion of the rabbit latissimus dorsi muscle: gross anatomy and fibre-type composition.", "\nThis paper defines the characteristics and significance of the scapular insertion of the latissimus dorsi muscle (LDM) of the rabbit. ", "In a study of the New Zealand White species (n = 10) the scapular insertion was found to be a consistent anatomical feature of the LDM that made up 12.3% (+/-2.3) of the total muscle weight. ", "The fibres arise from the medial aspect of the body of the LDM and run in a caudocranial direction to be inserted into a broad, thin tendon beneath the scapula ridge. ", "This is morphologically different from the scapular component of the human LDM which is a well-recognized but inconsistent feature and consists of no more than a small leash of fibres running around the lower pole of the scapula. ", "The scapular insertion was deeper red in colour than the body of the muscle and fibre-typing demonstrated a mean slow-fibre composition of 49% (+/-2.6) compared to 16% (+/-1.7) for the body of the muscle (p < 0.01). ", "Mapping of the fibre types throughout the remainder of the LDM confirmed that the body of the muscle was of fast phenotype but with significantly more slow fibres in the superomedial segment of the muscle than elsewhere. ", "This region of the muscle contributes mainly to the scapular insertion and it is proposed that this part of the muscle takes on a predominantly postural role in stabilising the scapula during movement of the forelimb." ]

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[ "ISTANBUL, Turkey — Gezi Park today is a serene place, where books are read and couples romance. ", "In nearby Taksim Square, the heart of virulent anti-government protests earlier this summer, wandering foreign tourists have returned with cameras in hand.", "\n\nBored-looking Turkish police officers keep watch.", "\n\nBut the “Occupy Gezi” movement — a grassroots initiative to oppose a government plan to destroy one of Istanbul’s greenest parks in favor of a replica military barracks — is not yet defeated.", "\n\nThe movement morphed into massive, nationwide protests against the government and its increasingly lavish development plans in June. ", "The government drive to modernize the country — often at the expense of the country’s heritage — frightened and angered many Turks.", "\n\nMore from GlobalPost: Turkey protests: about more than a shopping mall\n\nBut routed by police forces from their original hub at the park in central Istanbul, the Gezi Park demonstrators have since fanned out into the city’s suburbs, squatting in dozens of common areas and engaging local communities with public lectures and film screenings.", "\n\nTheir dispersal into the city’s boroughs has kept their message of defiance alive, by reaching more Istanbul residents in their own neighborhoods.", "\n\nBecause their initial demonstrations marked the most serious popular threat to the government in a decade, local government councils are now battling the activist squatters for space, sponsoring their own initiatives to woo voters ahead of council elections next year.", "\n\n“Gezi Park was something [that stood] for freedom, for peace,” said Nourettin, a pro-Gezi demonstrator who has since settled in with a group of protesters near Ozgurluk Park in Istanbul’s Kadikoy district.", "\n\n“We wanted to continue what we started there in the local areas of Istanbul, and that’s why we came here,” he said.", "\n\nSome of the protester groups have hung up pictures of police beating protesters, next to makeshift cafes where they discuss and debate with locals. ", "They also host public lectures and awareness campaigns on things like the environment and peaceful resistance.", "\n\nTheir demands are varied. ", "Some want Prime Minister Recep Tayyip Erdogan to resign. ", "Others just want to talk to the government.", "\n\nElsewhere in Kadikoy district, at a seaside park in Moda, the roughly 80 protesters camped out here are popular with the local residents.", "\n\nThey recently organized an outdoor screening of “Even the Rain,” a film about a Bolivian popular movement that fought the privatization of a city’s water supply, for an audience of about 100.", "\n\nThe residents of the area have for the most part embraced their presence at the park, demonstrators say.", "\n\nOn a recent summer night at Ozgurluk Park, some 50 protesters projected a film onto a large sheet strung up between two trees. ", "Alongside it were pictures of some of the demonstrators killed in clashes with police earlier this summer.", "\n\nSixty yards away, around 250 people came to hear renditions of Mozart, Bach and other popular composers on a recent weekend night — entirely at the expense of local authorities.", "\n\nLocal government councils have not given up on control of these parks. ", "And the protesters find it hard to compete.", "\n\nDuring the Muslim holy month of Ramadan in July and August, protesters hosted a feast for those breaking their daylong fast — but no more than half a dozen people showed up.", "\n\nMeanwhile, in the auditorium close by, the local government council had organized a free concert of traditional Turkish music, with around 500 people in attendance. ", "One woman who earlier in the evening had sat with protesters now took a front row seat at the concert.", "\n\n“We will stay here for as long as we need to,” Nourettin said. “", "Until we know our parks are safe.”", "\n\n" ]

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[ "In recent years, with the rapid development of semiconductor technology, portable electronic products and flat panel display products have also emerged. ", "Thin film transistor (TFT) liquid crystal displays have become standard output devices for various data products because of their advantages such as low operating voltage, no radiation scattering, light weight, small size etc. ", "A thin film transistor liquid crystal display is generally composed of a matrix of pixels arranged in both a horizontal direction and a vertical direction. ", "When the thin film transistor liquid crystal display performs display, it needs to generate a gate input signal and sequentially scan various rows of pixels from a first row to a last row. ", "In the thin film transistor liquid crystal display, this is done by an appropriate gate driver. ", "In general, the gate driver is composed of a plurality of stages of shift registers connected in series, wherein an output signal of a previous stage of shift register is used as an input signal of a next stage of shift register.", "\nIn order to reduce the production cost of the thin film transistor liquid crystal display, manufacturers in the industry manufacture multiple stages of amorphous silicon shift registers and a gate driving circuit (i.e., a GOA driving circuit) directly on a glass substrate of a panel by using an amorphous silicon process to replace a gate driver in the related art, so as to reduce the production cost of the liquid crystal display.", "\nIn the GOA driving circuit, a simple group of frame start signals STV and a clock control signal CLK are input, a gate signal is transmitted stage by stage through a cascaded circuit on the panel, and the STV and CLK signals have the same output levels. ", "However, in practice, due to the difference in resistances of fan-out areas of panels of thin film transistors and the difference in process characteristics of the panels, it is easy to cause a difference in charging voltages of different rows, and thereby a vertical line defect due to insufficient charging occurs on the panel." ]

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[ "306 F.3d 241\nUNITED STATES of America, Plaintiff-Appellant,v.Cheryl Yvonne STONE, Defendant-Appellee.", "\nNo. ", "01-51041.", "\nUnited States Court of Appeals, Fifth Circuit.", "\nSeptember 12, 2002.", "\n\nJoseph H. Gay, Jr., Asst. ", "U.S. Atty., ", "San Antonio, TX, for Plaintiff-Appellant.", "\nJoe F. Taylor, Austin, TX, for Defendant-Appellee.", "\nAppeal from the United States District Court for the Western District of Texas.", "\nBefore SMITH and BENAVIDES, Circuit Judges, and FITZWATER, District Judge.*", "\nBENAVIDES, Circuit Judge:\n\n\n1\nDefendant Cheryl Yvonne Stone (\"Stone\") was indicted by a single count superseding indictment, charging a violation of 18 U.S.C. § 922(g) [Felon in Possession of a Firearm] (\"Section 922(g)\"). ", "It was further alleged that Stone qualified for a sentence enhancement pursuant to the Armed Career Criminal Act [18 U.S.C. § 924(e)] (\"Section 924(e)\").1 Stone was convicted after a jury trial and sentenced to 71 months' imprisonment. ", "In sentencing Stone, the district court refused to enhance Stone's sentence pursuant to Section 924(e), and the United States appeals. ", "Because the grounds given for the denial are unsupported by law, we vacate and remand for re-sentencing.", "\n\nI.\n\n2\nStone was arrested when a search of her home uncovered three firearms: a .22 caliber rifle; a .30-.30 caliber rifle; and a 12 gauge shotgun. ", "The Pre-Sentence Investigation Report (the \"PSI\") established that Stone had two prior burglary convictions and a conviction for aggravated battery. ", "The former convictions appear to be based on burglaries of two different buildings, occurring a month apart.", "\n\n\n3\nAs noted above, the district court declined to enhance Stone's sentence pursuant to Section 924(e). ", "It reasoned that Apprendi v. New Jersey, 530 U.S. 466, 120 S.Ct. ", "2348, 147 L.Ed.2d 435 (2000) barred the enhancement because the jury was not asked to find that Stone had committed three previous violent felonies or serious drug crimes. ", "The district court also appeared to conclude that Stone's criminal history consisted of only two prior violent felonies for the purposes of Section 924(e) because Stone's two burglary convictions stemmed from a single arrest.", "\n\nII.", "\n\n4\nThe applicability of Apprendi to this case is a question of law that we review de novo. ", "See, e.g., United States v. Trennell, 290 F.3d 881, 889 (7th Cir.2002). ", "We have yet to address in a published opinion, post-Apprendi, whether the Fifth and Sixth Amendments require that a Section 924(e) enhancement be based on a jury finding. ", "Cf. ", "United States v. Doggett, 230 F.3d 160, 166 (5th Cir.2000) (holding that the sentencing court did not err in using prior convictions to enhance a sentence pursuant to Section 841(b)(1)(C), even though the prior convictions were not submitted to the jury). ", "We now join every circuit addressing the issue in concluding that they do not.2\n\n\n5\nIn United States v. Affleck, 861 F.2d 97 (5th Cir.1988), we held that \"because [Section] 924(e)(1) does not create a separate offense but is merely a sentence enhancement provision,\" neither the statute nor the Constitution requires a jury finding on the existence of the three previous felony convictions required for the enhancement. ", "Id. at 98-9. ", "Absent a clear contrary statement from the Supreme Court or en banc reconsideration of the issue, we are bound by Affleck. ", "Allison v. Citgo Petroleum Corp., 151 F.3d 402, 411 n. 3 (5th Cir.1998); Valero Refining, Inc. v. M/T Lauberhorn, 813 F.2d 60, 62 (5th Cir.1987). ", "Neither has occurred.", "\n\n\n6\nIn Apprendi the Court did hold that \"any fact that increases the penalty for a crime beyond the prescribed statutory maximum must be submitted to a jury, and proved beyond a reasonable doubt.\" ", "Apprendi, 530 U.S. at 490, 120 S.Ct. ", "2348. ", "In so holding, however, the Court explicitly excepted enhancements like that provided by Section 924(e), which are based upon prior convictions. ", "Id.3 Accordingly, Stone's Apprendi challenge fails.", "\n\nIII.", "\n\n7\nWhether Stone's two prior burglary convictions should be treated as a single \"violent felony\" for the purposes of Section 924(e) merely because they stemmed from a single arrest is also a question of law we review de novo.4 As noted above, Section 924(e) provides for a sentencing enhancement applicable to offenders who have committed three felonies \"on occasions different from one another.\" ", "We recognize that the fact that multiple convictions stemmed from a single arrest could possibly be relevant to the determination whether the underlying felonies were \"committed on occasions different from one another.\" ", "That fact is not, however, dispositive.5 See United States v. Herbert, 860 F.2d 620, 622 (5th Cir.1988) (holding that \"multiple convictions arising from multiple criminal transactions should be treated as separate convictions, regardless of the number of judicial proceedings involved in the conviction.\"); ", "United States v. Ressler, 54 F.3d 257, 259-260 (5th Cir. ", "1995) (focusing on whether the crimes were committed simultaneously or sequentially); see also United States v. Riddle, 47 F.3d 460, 462 (1st Cir.1995) (\"Congress, thinking primarily about the protection of the public, adopted a definition of armed career criminal that ignores the duration of the career or the youthfulness of the adult offender or the lack of lengthy intervals or arrests between the crimes.\"); ", "United States v. Letterlough, 63 F.3d 332, 337 (4th Cir.1995).6\n\nCONCLUSION\n\n8\nIn light of the foregoing discussion, the sentence of the district court is hereby VACATED and this matter is REMANDED for re-sentencing.", "\n\n\n\nNotes:\n\n\n*\n District Judge of the Northern District of Texas, sitting by designation\n\n\n1\n Section 924(e) provides, in pertinent part: \"In the case of a person who violates section 922(g) of this title and has three previous convictions by any court referred to in section 922(g)(1) of this title for a violent felony or a serious drug offense, or both, committed on occasions different from one another, such person shall be fined not more than $25,000 and imprisoned not less than fifteen years, and, notwithstanding any other provision of law, the court shall not suspend the sentence of, or grant a probationary sentence to, such person with respect to the conviction under section 922(g).\"", "\n\n\n2\n See United States v. Santiago, 268 F.3d 151, 154-57 (2d Cir.2001); United States v. Sterling, 283 F.3d 216, 219-220 (4th Cir.2002); United States v. Skidmore, 254 F.3d 635, 642 (7th Cir.2001); United States v. Abernathy, 277 F.3d 1048, 1049-1050 (8th Cir.2002); United States v. Summers, 268 F.3d 683, 688-89 & n. 3 (9th Cir.2001), cert. ", "denied, 534 U.S. 1166, 122 S.Ct. ", "1182, 152 L.Ed.2d 124 (2002); United States v. Dorris, 236 F.3d 582, 586-88 (10th Cir.), ", "cert. ", "denied, 532 U.S. 986, 121 S.Ct. ", "1635, 149 L.Ed.2d 495 (2001); United States v. Thomas, 242 F.3d 1028, 1035 (11th Cir.), ", "cert. ", "denied, 533 U.S. 960, 121 S.Ct. ", "2616, 150 L.Ed.2d 770 (2001).", "\n\n\n3\n This exception is consistent with the Court's holding inAlmendarez-Torres v. United States, 523 U.S. 224, 118 S.Ct. ", "1219, 140 L.Ed.2d 350 (1998), in which the Court held that Congress could treat recidivism as a sentencing factor rather than an element of the offense when codifying the penalties for a violation of 8 U.S.C. § 1326(a). ", "The Court in Apprendi expressly declined to overrule Almendarez-Torres. ", "Apprendi, 530 U.S. at 489-490, 120 S.Ct. ", "2348.", "\n\n\n4\n Stone argues that we need not address the applicability of Section 924(e) because her PSI is not part of the appellate record. ", "Even a cursory review of the docket demonstrates that Stone is mistaken\n\n\n5\n It is unclear, but it appears from the transcript of the sentencing hearing that the district court may have conflated Section 924(e)'s separate and distinct transactions requirement with U.S.S.G. § 4A1.2's \"relatedness\" inquiry. ", "We have previously held, however, that when determining if a defendant has three felonies for the purposes of Section 924(e), whether felonies are \"related\" for the purposes of U.S.S.G. § 4A1.2 is irrelevantUnited States v. Medina-Gutierrez, 980 F.2d 980, 983 (5th Cir.1992).", "\n\n\n6\n We do not address the question whether the burglary convictions at issue arose from distinct criminal transactions as this issue was not addressed by the district courtCf. ", "Herbert, 860 F.2d at 622 n. 1 (\"The crimes for which the appellant was convicted occurred on separate days at separate locations and with two intervening days during which the appellant, presumably, was not engaged in criminal activity. ", "Under these circumstances, we have no difficulty in holding that these instances were separate criminal transactions. ", "We need not and do not address the issue of whether multiple convictions for crimes committed over a period of days or hours as part of a criminal spree constitute single or multiple criminal transactions.\").", "\n\n\n" ]

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[ "1. ", "Field of the Invention\nThe present invention relates to food or beverage which contains fucoidan and has an excellent physiological effect as well.", "\n2. ", "Description of the Related Art\nFucoidan is a polysaccharide containing sulfated fucose which is contained in seaweed, trepang, etc. ", "No attempt for researching and developing fucoidan and for positively using it in food and beverage has been known yet.", "\nThe object of the present invention is to offer fucoidan-containing materials, and to offer fucoidan-containing food and beverage having a physiological activity which is useful for good health and having an excellent taste." ]

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[ "yandere guy(79 posts, 29003 views) Posted: about 1 year ago by Sogno in I'm Looking For...\nsilverstorm i've seen liar x liar so many times on batoto and here and always th ought to check it out... but now u said that... i HAVE to check it cuz u r right, i looooove that XD\n\nmileen i loved the moon rises!!! ", "i was kinda iffy on the yandere part, but i really like th ...\n\nyandere guy(79 posts, 29003 views) Posted: about 1 year ago by Sogno in I'm Looking For...\n^ i've seen this on batoto a lot, thought maybe it had a yan but didn't venture to try it out. ", "thanks! ...", "\n\nyandere guy(79 posts, 29003 views) Posted: about 1 year ago by Sogno in I'm Looking For...\n^Metronome has some English translations, but not any recently. ", "i think the translating group went defunct >.>\n\nQuote from theLettuceGarden04\n\nYou sure about Jaehee? ", "She's a woman though, unless you're talking about Jumin then yes he has ...\n\nyandere guy(79 posts, 29003 views) Posted: about 1 year ago by Sogno in I'm Looking For...\nhave ya''ll be playing mystic messenger ?? ", "it's on android and ios.", "\n\nthere's one extremely possessive lead (so far, i've played all but one route) who is arguably a yandere, though he doesn't really show much dere in the beg ...\n\nNew Poll - Bad Characteristics(25 posts, 2969 views) Posted: about 1 year ago by Sogno in News\ni don't know, only reason i've ever stopped reading manga is because it was too rapey (some shoujo) or too ecchi (fairy tail) or just kinda got boring (shounen and shoujo alike), never because of a specific characteristic ...\n\nNew Poll - Classic Manga(41 posts, 4195 views) Posted: about 1 year ago by Sogno in News\nyes! ", "though idk the names. ", "i'm constantly reading new manga. ", "and i mean new as in new to me. ", "if it's a good story i don't care how long ago it was created ^^ unfortunately mostly classic shoujo manga i don't like, they're sooo dr ...\n\nNew Poll - Translating Jokes/Puns(12 posts, 1364 views) Posted: about 1 year ago by Sogno in News\ni went with replacing with English equivalent with translation, mainly bc of the way i read manga -- i just zoom right through it; i dont like to stop and think. ", "if it is a pun/joke that means that it is supposed to be funny, but if i don't get the joke then it has lost its funny. ...", "\n\nyandere guy(79 posts, 29003 views) Posted: about 1 year ago by Sogno in I'm Looking For...\nsaw this in another thread, it's not completed but i saw a spoiler anyways there's two yanderes here, one male and one female\n\nToo old for shoujo manga?(24 posts, 3722 views) Posted: about 1 year ago by Sogno in Shoujo/Josei\n26 and it's mostly what i read haha. ", "i mean i never got my own romance ya know? ", "so it's fun to read ...\n\nNew Poll - RPG Class(24 posts, 2460 views) Posted: about 1 year ago by Sogno in News\nwhere's the \"chef\" option. ", "i dont wanna do anything but eat ...\n\nthe whole \"it's fiction so it's not hurting anybody\" just doesn't sell me.", "\n\n/shrugs ...\n\nNew Poll - Forgetting the Story(16 posts, 1814 views) Posted: about 1 year ago by Sogno in News\njust a few weeks typically... i have a bad memory and i read lots of the same genre so they're all kind of similar lol ...\n\nyandere guy(79 posts, 29003 views) Posted: over 2 years ago by Sogno in I'm Looking For...\n@Silverstorm yeah i finished yuri's route, someone on tumblr told me he was yandere and well he was pretty darn close, what with the locking up at all. ", "lol. ", "but his route was the only one i played, although his bro is super cute, i really can't handle the tra ...\n\ni went for \"fufufufu\" because it's used in comedy manga all the time and always makes me laugh ...\n\nyandere guy(79 posts, 29003 views) Posted: over 2 years ago by Sogno in I'm Looking For...\ngeez ya'll giving all these recommendations but they either have only 1-2 translated chapters or none at all.", "\n\nreckon i'm out of luck T_T\n\nle sigh but anyways if u play mobile otome Arithmetic has some yanderes in their games (and smut!). ", "however for u ...\n\nGangsta. ", "goes on Hiatus(3 posts, 2965 views) Posted: over 2 years ago by Sogno in Gangsta\nlet's hope she gets better!!!! ", "too many mangakas stay on indefinite hiatus due to poor health... ...\n\nGirl chose 2nd guy instead of the one she initially liked.(13 posts, 3506 views) Posted: over 2 years ago by Sogno in I'm Looking For...\ni know this thread is like 3 years old but i wanted to know if there's any more recent ones or recently translated that have this theme, where the rival/2nd guy gets the girl other than what has already been mentioned here. ", "thanks! ...", "\n\nClingy male lead(13 posts, 6324 views) Posted: over 2 years ago by Sogno in I'm Looking For...\nyeah i have read/am reading all those... i pretty much have already gone through the tags. ", "big yandere/possessive lover/etc fan here (why i don't know someone pls explain). ", "also i read tons of korean webtoons both Naver and Daum so yeah.", "\n\ni just know th ...\n\nyandere guy(79 posts, 29003 views) Posted: over 2 years ago by Sogno in I'm Looking For...Ookami Shoujo to Kuro Ouji has shown a yandere in the latest chapters. ", "It's waaay late in manga though and def not the main interest but anyways\n\nSpoiler (mouse over to view)\n\nhe slaps her though >.> well it's not like we're not used to ya ...\n\nClingy male lead(13 posts, 6324 views) Posted: over 2 years ago by Sogno in I'm Looking For...\nblergh i've read/am reading/have tried all those >.> there's just never enough is there XD ...\n\nClingy male lead(13 posts, 6324 views) Posted: over 2 years ago by Sogno in I'm Looking For...\nany more for clingy male lead??", "\n\ni know there's \"possessive\" tags but i think being clingy has a bit of a sort of different meaning.. kind of cuter maybe? ", "idk lol. ..." ]

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