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[ "Q:\n\nCreate HTML lists from PHP arrays\n\nI am trying to create various, standard HTML list styles from PHP arrays for a movie database I'm building as part of my final year project at university, however I'm having some trouble accessing/understanding how to do this. ", "I've got the relevant data from the various APIs I'm using, but I'd like to create the entire list dynamically, dropping in the correct bits of information where appropriate.", "\nDetails of the two list styles I'm looking to create are below.", "\nList style 1 - Character/Cast details\nFor the first style of list, I'd like to create it as:\n<ul>\n <li>Cast name - Character name</li>\n <li>Cast name - Character name</li>\n <li>etc. ", "etc.</li>\n<ul>\n\nMy data set direct from the array looks like this:\nArray\n(\n\n[abridged_cast] => Array\n (\n [0] => Array\n (\n [name] => Daniel Craig\n [id] => 162687443\n [characters] => Array\n (\n [0] => James Bond\n )\n\n )\n\n [1] => Array\n (\n [name] => Javier Bardem\n [id] => 162661456\n [characters] => Array\n (\n [0] => Silva\n )\n\n )\n\n [2] => Array\n (\n [name] => Judi Dench\n [id] => 162652435\n [characters] => Array\n (\n [0] => M\n )\n\n )\n\n [3] => Array\n (\n [name] => Ralph Fiennes\n [id] => 162653681\n [characters] => Array\n (\n [0] => Gareth Mallory\n [1] => Mallory\n )\n\n )\n\n [4] => Array\n (\n [name] => Naomie Harris\n [id] => 162705781\n [characters] => Array\n (\n [0] => Eve\n )\n\n )\n\n )\n\nIn the above example, there's five cast members w/ their respective character names, however on some other examples, there's more or less than five, so, ideally, I'd want the system to know however many cast members were given and create a list for each, up to a maximum of 10 names.", "\nList style 2 - Videos\nSimilar to the last style, however this list will hopefully look like this:\n<ul>\n <li><a href='<http://youtube.com/<dynamically generated URL direct to the clip>'><img src='dynamically generated URL to the clip's thumbnail' /></a></li>\n <li>same as above...</li>\n</ul>\n\nThe source array looks like this:\nArray\n(\n[id] => 37724\n[youtube] => Array\n (\n [0] => Array\n (\n [name] => Trailer\n [size] => HQ\n [source] => 24mTIE4D9JM\n )\n\n [1] => Array\n (\n [name] => Official Trailer\n [size] => HD\n [source] => 6kw1UVovByw\n )\n\n [2] => Array\n (\n [name] => Trailer 1\n [size] => HD\n [source] => 1Uyjf5Pp0Ko\n )\n\n [3] => Array\n (\n [name] => Trailer 2\n [size] => HD\n [source] => 5Ejo9_3iUpw\n )\n\n )\n\n)\n\nApologies for the length of this post, thanks in advance to anyone who may be able to assist!", "\n\nA:\n\nThe thing you are looking for is called a foreach loop. ", "For your first example it would look something like this:\nforeach($dataSet['abridged_cast'] as $castMember){\n echo '<li>'.$castMember['name'].'-'.implode(', ', $castMember['characters']). '", "</li>';\n}\n\nNow this example is purely illustratory though it most definetely be the begginers approach.", "\nStill, I would strongly recommend investigating MVC patterns and PHP frameworks, like for example YII. ", "If deployed and configured right YII with all its goodness should make all the repetitive work done for you here.", "\nI've seen that your question contains two parts, though I am not willing to write a sample for the second one, since it is practically the same as the first and with proper attention - you will get on track and figure it out.", "\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "The present invention relates to programmable devices, and more particularly relates to a structure for storing information for controlling operation of a device including a plurality of programmable cells.", "\nA programmable device, typified by FPGA (Field Programmable Gate Array), includes a number of programmable cells which perform various operations, with each programmable cell carrying out a specific operation corresponding to the processing to be realized by the programmable device. ", "Such a programmable device, in which a large number of programmable cells are simultaneously operated to execute enormous operations typified by multimedia processing, has been attracting much attention recently. ", "Configuration information indicates what operation is to be executed by each programmable cell, and this configuration information is stored in an internal memory in each programmable cell.", "\nIn a known programmable device technique, all of the programmable cells have the same structure and include internal memories of the same structure (see U.S. Pat. ", "No. ", "6,281,703).", "\nIn this known structure, however, every time the programmable device is powered on, configuration information must be stored in all of the programmable cells included in the programmable device. ", "The known technique thus has a problem in that the amount of time required for the configuration (which will be hereinafter referred to as a “configuration time”) is increased.", "\nAlso, the above-described programmable device, in which all of the programmable cells have the same structure and include internal memories of the same structure, has another problem in that the internal memories occupy a large circuit area in the device." ]

{ "pile_set_name": "USPTO Backgrounds" }

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[ "Cornwall’s Industrial Heritage\n\nThe historical importance of Cornwall lies in its industrial heritage\n\nCornwall was already established as the mining capital of the world, with the extraction of tin reaching its zenith in the 19th century, and latterly English China Clay. ", "It is world famous for its Camborne School of Mines, and today Cornwall is recognised as the Cornish Mining World Heritage Site.", "\n\nRemains of the crown mine at Botallack, part of the Cornwall Mining World Heritage Landscape\n\nA LEADER IN COMMUNICATIONS\n\nCornwall had always lead the way in communications throughout the ages, and it was at the forefront of the communications revolution. ", "In the days of sail Falmouth was the departure and arrival port for the Falmouth Packet Ships and effectively the mail hub of communications across the world before the arrival of steam.", "\n\nFollowing that, telegraph cables laid on the seabed from each of the different continents around the world, arrived ashore in the cove of Porthcurno on the western tip of Cornwall. ", "It is considered the most connected valley on the planet, and from there the communications were fed to London.", "\n\nLater still Poldhu Wireless Centre, West Cornwall, became the site of one of the main technological advances of the early twentieth century when, on 12 December 1901, a wireless signal was sent in Poldhu to St John’s, Newfoundland, and received by Marconi. ", "The technology was a precursor to radio, television, satellites and the internet, with the earth station at Goonhilly Downs a nearby example. ", "Indeed Goonhilly was at one time the largest satellite earth station in the world, with more than 25 communications dishes in use and over 60 in total.", "\n\nCORNWALL AND THE START OF THE INDUSTRIAL REVOLUTION\n\nCornwall was also made famous by Richard Trevithick for his invention of the high-pressure steam engine, and the importance this played in starting the industrial revolution in Britain, and indeed across the world.", "\n\nAn early high pressure steam engine farm vehicle in Cornwall\n\nRichard Trevithick’s advances in steam engine technology – originally motivated by the need to pump water out of mines – ultimately enabled the development of steam trains, changing the world forever through the mass movement of people and goods." ]

{ "pile_set_name": "Pile-CC" }

[ 0.0006464591715484858, 0.0008768873522058129, 0.0005902756820432842, 0.0007206872687675059, 0.0005967351025901735, 0.0006583171198144555, 0.0006419814890250564, 0.0006801089039072394, 0.0006755691138096154, 0.0006233283784240484, 0.0006694059702567756 ]

[ "Introduction {#s1}\n============\n\nTick-borne encephalitis virus (TBEV) is a zoonotic tick-borne virus in the *Flaviviridae* family (genus *Flavivirus*). ", "It is the causative agent of tick-borne encephalitis (TBE), a serious neurological disease in humans. ", "During the last few decades, TBE has become a widespread public health concern in Eurasia with endemic regions extending from Western and Central Europe to Siberia and parts of Asia (Süss, [@B39]). ", "The various strains of TBEV are subdivided into three main subtypes that are closely related genetically and antigenically: European (Eu), Siberian (Sib), and Far-Eastern (FE) (Gritsun et al., [", "@B11]; Mansfield et al., [", "@B29]). ", "TBEV-Eu is widely distributed in Europe, including the European regions of Russia, while TBEV-Sib is mainly found in Russia, the Baltic countries and Finland (Mansfield et al., [", "@B29]; Kovalev and Mukhacheva, [@B23]). ", "TBEV-FE is present in Far-Eastern Russia and parts of China, Japan, and the Republic of Korea (Mansfield et al., [", "@B29]). ", "Human infections with TBEV can range from mild flu-like symptoms to severe or fatal neuroinvasive disease, often with long-term neurological symptoms. ", "There is a correlation between the TBEV subtype and severity of disease. ", "TBEV-FE is associated with severe neurological disease and a case fatality rate of approximately 30--40%, while the case fatality rates for TBEV-Sib and TBEV-Eu are approximately 6--8% and 1--2%, respectively (Gritsun et al., [", "@B11]; Tonteri et al., [", "@B43]). ", "Although the incidence rates vary from year to year and between subtypes, several thousand human TBE cases are reported annually (CDC Tick-borne Encephalitis, [@B4]).", "\n\nIn nature, the *Ixodes ricinus* tick is the primary vector for TBEV-Eu while the *Ixodes persulcatus* tick is the main vector for the TBEV-Sib and TBEV-FE (Gritsun et al., [", "@B12]). *", "I. ricinus* is widely distributed throughout Europe, extending to Turkey, and northern Iran, while *I. persulcatus* is distributed across the Urals, Siberia, Far-Eastern Russia, and parts of China and Japan (Gritsun et al., [", "@B11]; Lindquist and Vapalahti, [@B27]). ", "A sympatric zone exists in northern Baltics, western Finland and northwestern Russia where the habitats for *I. ricinus* and *I. persulcatus* overlap and multiple TBEV subtypes have been recorded (Lindquist and Vapalahti, [@B27]; Süss, [@B39]; Kovalev and Mukhacheva, [@B23]). ", "TBEV is maintained in natural transmission cycles involving ixodid ticks and wild-living mammalian hosts. ", "When infected with TBEV, a tick is supposed to remain infected throughout its life cycle (Gritsun et al., [", "@B11]). ", "Transovarial transmission of TBEV from an infected female tick to the egg mass can occur, but this route of tick infection is not entirely efficient at maintaining TBEV within the natural tick population (Danielová et al., [", "@B5]). ", "During the tick feeding process, TBEV-infected ticks can transmit the virus to susceptible vertebrate hosts, but they can also transmit TBEV to uninfected ticks that are co-feeding on the same host (Mansfield et al., [", "@B29]; Randolph, [@B34]). ", "During co-feeding, TBEV can be transmitted even non-viremically i.e., when the ticks feed on a non-viremic or virus- immune host (Labuda et al., [", "@B25], [@B26]). ", "The local skin site of tick feeding is understood to be an important focus for early TBEV replication, and immune cell infiltrates to this feeding site are believed to serve as vehicles for TBEV transmission between co-feeding ticks (Labuda et al., [", "@B24]).", "\n\nInfectious agents transmitted by ticks are delivered to the vertebrate host together with saliva at the tick feeding site. ", "Tick-borne viruses are transmitted to the host very early during the tick feeding process. ", "TBEV can be transmitted from the saliva of an *I. ricinus* tick to the cement cone in the skin of a host as early as 1 h after the tick attaches and initiates feeding (Alekseev et al., [", "@B1]). ", "As *I. ricinus* and *I. persulcatus* ticks feed, TBEV replicates to higher viral titers than in unfed ticks (Alekseev and Chunikhin, [@B2]; Belova et al., [", "@B3]; Slovák et al., [", "@B38]). ", "The dynamic nature of TBEV replication in ticks has also been demonstrated in field-collected ticks. ", "In partially engorged *I. ricinus* nymphs removed from humans, TBEV prevalence was higher than in questing, unfed nymphs collected in the same region (Süss et al., [", "@B40]). ", "Experimental data suggest that in nature, ticks secrete repeated \"pulses\" of a few infectious virus particles over the course of feeding (Kaufman and Nuttall, [@B19]). ", "Thus, virus transmission from an infected tick to a host is a very dynamic process that begins soon after the tick initiates feeding.", "\n\nIxodid ticks must remain attached to their hosts for several days to successfully acquire a bloodmeal and complete development, and have evolved salivary countermeasures directed against the host\\'s immune and hemostatic defenses. ", "Tick salivary glands produce complex cocktails of biologically active molecules that facilitate blood feeding and pathogen transmission by modulating host hemostasis, pain/itch responses, wound healing, and both innate and adaptive immunity. ", "Bioactive tick salivary molecules include those with anti-pain/itch, antiplatelet, anticoagulation, vasodilatory, immunomodulatory, and anti-inflammatory activities (Ribeiro et al., [", "@B35], Francischetti et al., [", "@B8]; Kazimírová and Štibrániová, [@B20]; Wikel, [@B44]; Šimo et al., [", "@B41]). ", "As the course of tick feeding progresses, salivary gland genes are differentially expressed, reflecting the dynamic and complex composition of tick saliva (Ribeiro et al., [", "@B35]; Šimo et al., [", "@B41]).", "\n\nThe skin is the first host organ that tick saliva and a tick-borne pathogen contact during the tick feeding process. ", "The cutaneous interface between the tick, pathogen, and host is crucial for influencing the initial host response to tick infestation and pathogen transmission (Kazimírová et al., [", "@B22]; Šimo et al., [", "@B41]). ", "A prior study examined the tick-induced changes in cutaneous gene expression and histopathology during the early stages of uninfected *Ixodes scapularis* feeding. ", "Early transcriptional and histopathological changes at the feeding site of uninfected *I. scapularis* nymphs are initially characterized by modulation of host responses in resident cells, followed by progression to a neutrophil-dominated immune response after 12 h of tick feeding (Heinze et al., [", "@B14]). ", "Similarly, a complex proinflammatory environment was observed at the Powassan virus (POWV), a North American tick-borne flavivirus, infected tick feeding site. ", "Together these findings from the cutaneous interface provide evidence of an immunologically privileged micro-environment at the tick feeding site that is established during the early stages of POWV-infected tick feeding (Hermance and Thangamani, [@B16]; Hermance et al., [", "@B15]).", "\n\nIn the present study, Illumina Next Generation Sequencing (NGS) and immunohistochemistry are utilized to understand host immunomodulation induced by TBEV-infected *I. ricinus* feeding at the earliest stages of TBEV transmission. ", "By studying the interactions between the host immune response and tick-mediated immunomodulation during the early hours of infected tick feeding, we can begin to understand the immunologic processes that facilitate transmission of a tick-borne flavivirus to a host.", "\n\nMaterials and methods {#s2}\n=====================\n\nEthics statement\n----------------\n\nAll experiments involving mice were performed in accordance with the animal use protocol approved by the State Veterinary and Food Administration of the Slovak Republic (permit number 1335/12-221).", "\n\nAnimals\n-------\n\nFive-week-old female BALB/c mice were purchased from Dobra Voda Breeding Station, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences (SAS). ", "The animals were housed at the Institute of Virology, Biomedical Research Center, SAS (Bratislava, Slovakia) under standard conditions. ", "Food and water were provided *ad libitum*. ", "Upon arrival, mice were allowed to adapt to the local environment before being incorporated into the study. ", "Mice were 6 weeks old at the start of the study. ", "At the end of the experiment animals were euthanized by cervical dislocation under anesthesia induced by carbon dioxide.", "\n\nVirus and tick infection\n------------------------\n\n*I. ricinus* ticks were obtained from a laboratory colony maintained at the Institute of Zoology SAS (Bratislava, Slovakia). ", "The F1 generation of laboratory-bred *I. ricinus* females was used for virus inoculation. ", "TBEV (Hypr strain prepared as a 10% mouse brain suspension of 1.1 × 10^9^ PFU/ml in Leibovitz\\'s L-15 medium) was provided by the Institute of Virology, Biomedical Research Center, SAS. ", "Fasting *I. ricinus* females were inoculated into the haemocoel with TBEV (5.5 x 10^4^ PFU per tick) through the coxal plate of the second pair of legs using a digital microinjector TM system (MINJ-D-CE; Tritech Research, Inc., USA) (Kazimírová et al., [", "@B21]). ", "By this procedure, \\~100% of the ticks were found to acquire TBEV infection (Slovák et al., [", "@B38]). ", "Inoculated ticks were incubated at room temperature and 85% relative humidity in a desiccator for 21 days prior to the infestation experiments.", "\n\nInfestation of mice by ticks\n----------------------------\n\nTwo groups of mice (*n* = 6 per group) were infested with either TBEV-infected or uninfected (control) *I. ricinus* females. ", "Ticks were placed in small neoprene capsules glued on the shaved backs of the mice (two capsules per mouse, four tick females per capsule) (Kazimírová et al., [", "@B21]; Hermance and Thangamani, [@B16]). ", "Ticks in each capsule were allowed to feed for either 1 or 3 h. After the allotted feeding time, skin biopsies were taken from euthanized mice, at each tick feeding site using a Premier Uni-Punch (Premier Products Co., Plymouth Meeting, PA). ", "For immunohistochemical analysis, skin biopsies (*n* = 3) were harvested with attached ticks and placed in 4% formaldehyde. ", "For RNA extraction, the attached ticks were removed from the skin biopsies and the biopsies (*n* = 3) were placed in RNALater (Ambion, Life Technologies, Carlsbad, CA). ", "Control biopsies were taken from the shaved skin of naïve tick-free mice and stored in either 4% formaldehyde or RNALater.", "\n\nCutaneous immune response\n-------------------------\n\nTotal RNA was extracted as previously described (Heinze et al., [", "@B14]; Hermance and Thangamani, [@B16]) and RNAseq analysis (Illumina deep sequencing / NGS) was performed on these samples. ", "Briefly, 1 μg of total RNA from mouse skin biopsies (*n* = 3) was poly A+ selected and fragmented using divalent cations and heat (94°C, 8 min). ", "Illumina TruSeq v2 sample preparation kits (Illumina Inc., San Diego, CA) were used for the RNA-Seq library construction. ", "Each sample library was uniquely indexed to allow combining libraries during sequencing and subsequent separation post-sequencing. ", "NGS was performed at the NGS core facility, Sealy Center for Molecular Medicine, The University of Texas Medical Branch (UTMB). ", "Sample libraries were analyzed by the Illumina HiSeq 1500 using a 2 × 50 base paired end run protocol, with TruSeq v3 sequencing-by-synthesis chemistry. ", "Reads were aligned to the mouse mm10 reference genome using TopHat version v2.0.4. ", "Cuffdiff version 2.0.2 was used to estimate differential gene expression between TBEV-infected and uninfected feeding sites after 1 or 3 h of tick feeding. ", "The total dataset of 23,000 genes was filtered for *p*-values ≤ 0.05 and a fold change ≤ −1.5 or ≥ +1.5. ", "The Log~2~(fold change) and *p*-value data for each gene expression comparison (Supplement Table [1](#SM1){ref-type=\"supplementary-material\"}) were then uploaded to Ingenuity Pathway Analysis (IPA) software (Ingenuity Systems, Redwood City, CA) for further transcriptional analysis of the early cutaneous immune response, as previously described (Heinze et al., [", "@B14]; Hermance and Thangamani, [@B16]).", "\n\nReal-time PCR validation\n------------------------\n\nReal-time PCR was used to validate the NGS data (Supplement Table [1](#SM1){ref-type=\"supplementary-material\"}). ", "Skin biopsies were harvested from the feeding sites of TBEV-infected and uninfected ticks as described above. ", "At each time point, biopsies from three mice were used for the real-time PCR validation. ", "Fifteen gene targets were selected for real-time PCR analysis. ", "We selected these genes based our previous studies with POWV where these genes were shown to be modulated genes of interest during the host anti-tick response to POWV infection (Hermance and Thangamani, [@B16], [@B17]). ", "This list also includes genes that were not differentially modulated as per RNASeq analysis. ", "Primers were purchased from Integrated DNA Technologies and the primer sequences are provided in Supplement Table 2. ", "Primers were mixed with IQ SYBR green supermix (Bio-Rad) and loaded into iCycler IQ PCR 96-well plates (Bio-Rad) to create customized PCR arrays where each gene was measured in triplicate. ", "For each PCR plate, 1 μg of total RNA extracted from skin biopsies was converted into cDNA using the RT^2^ First Strand kit (Qiagen). ", "cDNA was loaded onto the 96-well PCR plates, which were run on an iCycler iQ5 real-time PCR instrument (Bio-Rad) with the following cycling protocol: 10 min at 95°C; 15 s at 95°C, 1 min 60°C for 40 cycles, and an 80-cycle (+0.5°C /cycle) 55--95°C melt curve. ", "Every array included GAPDH as an endogenous control gene and a no-template control. ", "The iCycler\\'s software was used to calculate the threshold cycle (C~T~) values for all analyzed genes. ", "The delta-delta C~T~ method was used to calculate fold-changes in gene expression between TBEV-infected and uninfected tick feeding sites. ", "Data normalization was achieved by correcting all C~T~ values to the average C~T~ values of the GAPDH housekeeping gene. ", "Statistically significant differences in gene expression between the 1 vs. 3 h tick feeding time points were determined by the Student\\'s *t*-test. *", "P*-values less than 0.05 were considered significant. ", "SPSS statistical software was used.", "\n\nImmunohistochemistry\n--------------------\n\nThe skin biopsies with attached ticks were formalin-fixed for a minimum of 48 h in 4% formaldehyde. ", "These biopsy samples were treated with Decal (Decal Chemical Corp, Tallman, NY) for 2 h, and then paraffin-embedded (Heinze et al., [", "@B14]). ", "Five micron paraffin sections were taken from each sample and adhered to glass slides. ", "The slides were deparaffinized in xylene and then rehydrated in decreasing concentrations of ethanol (Hermance et al., [", "@B15]). ", "For antigen retrieval, the slides were treated with 10 mM Tris Base + 0.05% Tween 20 (pH 10) for 20 min with microwave heating. ", "Upon returning to room temperature, endogenous peroxidase quenching was performed by incubating the slides in 4% H~2~O~2~ for 30 min. ", "The primary antibody for TBEV detection used in this study was a Hyper Mouse Immune Ascitic Fluid (HMIAF) antibody against TBEV; therefore, the Mouse-On-Mouse kit (MOM, Vector labs, Burlingame, CA) was used in order to reduce the endogenous mouse Ig background staining generated when mouse primary antibodies are used on mouse tissue (Santos et al., [", "@B36]). ", "Slides were incubated for 1 h at room temperature with the MOM mouse Ig blocking reagent. ", "The HMIAF primary antibody against TBEV was diluted 1:250 in the MOM diluent and incubated for 30 min at room temperature. ", "Secondary antibody consisted of MOM biotinylated horse anti-mouse IgG reagent, which was incubated for 30 min at room temperature. ", "The biotinylated secondary antibody was detected with a streptavidin-peroxidase ultrasensitive polymer (Sigma-Aldrich, St. Louis, MO) followed by staining with the NovaRED HRP substrate kit (Vector Laboratories Inc., Burlingame, CA). ", "Slides were counterstained with Harris hematoxylin and coverslips were mounted using Permount (ThermoFisher Scientific, Waltham, MA). ", "Uninfected skin and tick biopsy sections generated from uninfected tick feeding sites were used as negative controls to verify the specificity of the MIAF anti-TBEV primary antibody. ", "Secondary antibody only (no primary antibody) controls were used to confirm that the MOM biotinylated anti-mouse IgG reagent did not bind non-specifically to cellular components.", "\n\nResults and discussion {#s3}\n======================\n\nIn the present study, the host cutaneous immune response to TBEV-infected *I. ricinus* feeding after 1 and 3 h of tick attachment was investigated by Illumina NGS and immunohistochemistry. ", "No prior studies have examined the early host immune response at the feeding site of a TBEV-infected tick. ", "We also used the RNASeq data to check for the presence of TBEV at the infected tick feeding site by aligning the sequences against a TBEV reference genome (NM_001672). ", "TBEV sequences were detected in the 3 hpi (hours post infection), but not in the 1 hpi samples (Figure [1A](#F1){ref-type=\"fig\"}).", "\n\n). **(", "E)** The immune genes selected for validation were shown to be modulated genes of interest during the host anti-tick response in previous studies. ", "Pre-optimized primers were purchased from IDT and used for the real-time PCR validation. ", "The delta-delta CT method was used to calculate fold-changes in gene expression between TBEV-infected and uninfected tick feeding sites as described in the methods section. ", "GAPDH was used as an endogenous control gene. ", "Statistically significant differences in gene expression between the 1 vs. 3 h tick feeding time points were determined by the Student\\'s *t*-test. *", "P*-values less than 0.05 were considered significant. ", "Significant differences are indicated by asterisks.](fcimb-07-00494-g0001){#F1}\n\nThe differences in the total number of significantly up- and downregulated host genes (*p* ≤ 0.05) between TBEV-infected and uninfected tick feeding sites as well as between TBEV-infected feeding sites 1 and 3 h post tick attachment are shown in Figure [1B](#F1){ref-type=\"fig\"}. ", "When the TBEV-infected and uninfected tick feeding sites were compared, the total number of significantly upregulated genes decreased from 1 to 3 h, while there was an overall increase in significantly downregulated genes from 1 to 3 h tick attachment. ", "An online tool (Oliveros, [@B30]) was used to generate a Venn diagram showing the overlap of significantly modulated genes between the 1 and 3 h comparison of the TBEV-infected vs. uninfected tick feeding sites (Figure [1C](#F1){ref-type=\"fig\"}). ", "10.2% of significantly modulated genes were shared between the three comparisons; however, the majority of significantly modulated genes were unique to either the 1 h TBEV-infected vs. 1 h uninfected tick feeding site (18.7%), the 3 h TBEV-infected vs. 3 h uninfected tick feeding site (25.7%), or the 3 h TBEV-infected vs. 1 h TBEV-infected tick feeding site (14%). ", "Additionally, a list of all modulated genes at either time point in the study was used to generate a heat map (Figure [1D](#F1){ref-type=\"fig\"}). ", "This heat map suggests that after 1 h of TBEV-infected tick feeding, there was a pattern of mostly upregulated cutaneous genes; however, after 3 h, the pattern changed to downregulation. ", "This pattern of gene expression was further validated by the real-time PCR data. ", "Though we could not recapitulate the exact fold changes of the selected immune genes observed by RNASeq data, our data clearly concur with the expression pattern of the selected genes: upregulation at 1 hpi and downregulation at 3 hpi (Figure [1E](#F1){ref-type=\"fig\"}). ", "Together these data suggest that a distinctive cutaneous immune response profile exists after 1 h of TBEV-infected tick feeding, but it changes to reflect a new and unique profile after 3 h. This change in gene expression profile could be attributed to the dynamic salivary secretion and physical injury during tick attachment/feeding mechanisms.", "\n\nIngenuity pathway analysis\n--------------------------\n\nIn total, 1,548 genes were analyzed by Ingenuity Pathway Analysis (IPA) software (Supplement Table [1](#SM1){ref-type=\"supplementary-material\"}). ", "The focus of the present study is on the cutaneous immune response observed at the TBEV-infected vs. the uninfected tick feeding sites after 1 and 3 h of tick feeding. ", "The networks generated from IPA analysis illustrate the interrelationships between genes and the temporal changes in gene modulation. ", "The top IPA-generated networks are shown for the TBEV-infected vs. uninfected tick feeding sites after 1 h of tick feeding (Figure [2A](#F2){ref-type=\"fig\"}), the TBEV-infected vs. uninfected tick feeding sites after 3 h of tick feeding (Figure [2B](#F2){ref-type=\"fig\"}), and the TBEV-infected tick feeding site after 3 h of tick feeding vs. the TBEV-infected tick feeding site after 1 h of feeding (Figure [2C](#F2){ref-type=\"fig\"}). ", "The three bio-functions most associated with the networks representing the TBEV-infected vs. uninfected comparisons (Figures [2A,B](#F2){ref-type=\"fig\"}) are cellular movement, organismal injury and abnormalities, and hematological system development and function. ", "After 1 h of TBEV-infected tick feeding, 19 host genes shown in the Figure [2A](#F2){ref-type=\"fig\"} network were downregulated and 16 host genes were upregulated. ", "After 3 h of TBEV-infected tick feeding, 22 host genes in the Figure [2B](#F2){ref-type=\"fig\"} network were downregulated, 12 were upregulated, and one gene (Ngp) had a fold change of zero. ", "Thus, as 1 h progressed to 3 h of TBEV-infected tick feeding, the network displayed a slight shift toward cutaneous gene downregulation (Figure [2](#F2){ref-type=\"fig\"}). ", "The IPA-generated network for the TBEV-infected 3 h vs. the TBEV-infected 1 h tick feeding site (Figure [2C](#F2){ref-type=\"fig\"}) is unique from the Figures [2A,B](#F2){ref-type=\"fig\"} networks, as it lacks Ccl2, KLF2, and ZBTB16, but instead includes 20 unique genes which contribute to this network\\'s association with bio-functions such as molecular transport, organismal injury and abnormalities, and cellular movement.", "\n\n{#F2}\n\nIn both the 1 and 3 h comparisons between TBEV-infected vs. uninfected tick feeding sites, inflammatory response was the primary predicted host response. ", "Based on the IPA transcriptional immunoprofiling, the inflammatory response was projected to be activated in the 1 h comparison of the TBEV-infected vs. uninfected tick feeding site (activation z-score = 1.549), and inhibited in the 3 h comparison (activation z-score = −1.26). ", "Temporal changes in gene expression for all genes predicted to have direct correlative relationships with the inflammatory response were plotted after 1 or 3 h of TBEV-infected vs. uninfected tick feeding (Figure [3](#F3){ref-type=\"fig\"}). ", "Transcriptional levels of cytokines Ccl2, Ccl12, Cxcl1, Cxcl2, Cxcl5, IL6, and IL10 were all upregulated after 1 h of TBEV-infected tick feeding, thus contributing to the overall activation of the inflammatory response (Figure [3](#F3){ref-type=\"fig\"}). ", "At the 3 h time point, the majority of these cytokine transcriptional level were still upregulated, with the exception of Cxcl5 and IL10, which were both slightly downregulated. ", "Real-time PCR validation of a few selected immune genes followed the general pattern observed in the Illumina NGS analysis (Figure [1E](#F1){ref-type=\"fig\"}). ", "All of the enzymes projected to have a direct, correlative relationship with the inflammatory response were downregulated at 3 h, further contributing to the predicted inhibition of the inflammatory response at the feeding site of a TBEV-infected tick (Figure [3](#F3){ref-type=\"fig\"}). ", "Additionally, transcript expression of several receptors (CCR1, CCR5, and Sell) were all significantly upregulated after 1 h of TBEV-infected tick feeding (Figure [3](#F3){ref-type=\"fig\"}), likely contributing to the overall accumulation of immune cells to the tick attachment site. ", "In summary, the cutaneous gene expression analysis indicates that the inflammatory response is activated after only 1 h of TBEV-infected tick feeding, and that increased recruitment and accumulation of immune cells is expected at the 1 h time point. ", "However, after 3 h of TBEV-infected tick feeding, the cutaneous inflammatory response is predicted to undergo slight inhibition, as demonstrated by the downregulated expression of over half of the genes shown to have a correlative relationship with the inflammatory response (Figure [3](#F3){ref-type=\"fig\"}).", "\n\n{#F3}\n\nAn IPA core comparison analysis was used to analyze changes in host cutaneous gene expression in response to TBEV-infected tick feeding vs. uninfected tick feeding observed across the two experimental time points (1 and 3 h). ", "Figure [4](#F4){ref-type=\"fig\"} shows activation status prediction networks for the top five immune responses or bio-functions generated from the IPA core comparison analysis. \"", "Maintenance of leukocytes\" was the top predicted bio-function in the core comparison analysis (Figure [4](#F4){ref-type=\"fig\"}). ", "This IPA category moniker refers to bio-functions associated with the normal cellular activities that maintain cellular homeostasis, including engulfment, phagocytosis, regulation, and stasis of cells. ", "The maintenance of leukocytes was predicted to be inhibited at both the 1 and 3 h comparisons of TBEV-infected vs. uninfected tick feeding (activation z-score = −2 for both time points). ", "At both the 1 and 3 h time points, GATA3 transcription was downregulated (Figure [4](#F4){ref-type=\"fig\"}). ", "GATA3 is a transcription factor required for both the maintenance and development of Th2 cells (Pai et al., [", "@B31]). ", "Furthermore, IL34, which is highly expressed by keratinocytes in the epidermis and plays an important role in the maintenance and development of Langerhans cells (Greter et al., [", "@B10]), was also downregulated after 1 and 3 h of TBEV-infected tick feeding (Figure [4](#F4){ref-type=\"fig\"}). ", "CCR4 knockout (CCR4^−/−^) bone marrow-derived dendritic cells are less efficient in the maintenance of Th17 responses compared to wild type dendritic cells (Poppensieker et al., [", "@B32]); therefore, the downregulation of CCR4 transcription in the present study contributes to the inhibition of leukocyte maintenance at the 1 and 3 h time points. ", "Mouse integrin subunit beta 7 (ITGB7) is necessary for the maintenance of memory T lymphocytes expressing the CD4 protein (Yang et al., [", "@B46]). ", "Since ITGB7 is downregulated in the present transcriptional immunoprofiling study, it likely contributes to the inhibited maintenance of memory CD4+ T cells after 1 and 3 h of TBEV-infected tick feeding.", "\n\n{#F4}\n\n\"Mobilization of phagocytes\" was the second predicted bio-function in the core comparison analysis. ", "After 1 and 3 h of TBEV-infected vs. uninfected tick feeding, the mobilization of phagocytes was predicted to be activated (activation z-score = 1.982 for both time points) (Figure [4](#F4){ref-type=\"fig\"}). ", "Monocytes, macrophages, neutrophils, dendritic cells, and mast cells are several of the professional phagocytic cells. ", "In mice, there are two Ccl2 homologs, Ccl2 and Ccl12, both of which are potent phagocyte chemoattractants. ", "The transcript levels of these two chemokines are upregulated at both the 1 and 3 h time points, thereby increasing the mobilization and chemotaxis of phagocytes at the TBEV-infected tick feeding site (Figures [3](#F3){ref-type=\"fig\"}, [4](#F4){ref-type=\"fig\"}). ", "CCR5 is known to regulate accumulation of activated macrophages in the West Nile virus-infected mouse brain (Glass et al., [", "@B9]), and upregulated transcription of this chemokine receptor in the present study likely contributes to the activated mobilization of phagocytes. ", "Mast cells and tissue resident macrophages release the potent neutrophil chemoattractants, Cxcl1 and Cxcl2 (De Filippo et al., [", "@B7], [@B6]). ", "In response to tissue inflammation, mast cells positioned near the vasculature initiate neutrophil infiltration from the circulation by releasing Cxcl1 and Cxcl2, while tissue resident macrophages also release Cxcl1 and Cxcl2, recruiting neutrophils deeper into the inflamed tissue (De Filippo et al., [", "@B6]). ", "In the present study transcript levels of both these chemokines are both upregulated during TBEV-infected tick feeding, thus contributing to the activated mobilization of neutrophils that infiltrate the tick feeding site very early (Figures [3](#F3){ref-type=\"fig\"}, [4](#F4){ref-type=\"fig\"}).", "\n\nThe third predicted bio-function generated in the IPA core comparison analysis was \"accumulation of helper T lymphocytes.\" ", "The activation z-score for this bio-function decreased from 2.19 at 1 h post-TBEV-infected tick feeding to 1.452 at the 3 h time point. ", "Transcript levels of CCR1 and Cxcl2 are upregulated at both time points in the present study and these genes are associated with the recruitment and accumulation of helper T lymphocytes at the cutaneous site of TBEV-infected tick feeding (Figure [4](#F4){ref-type=\"fig\"}). ", "Selectin L (SELL) is a cellular adhesion molecule found on the surface of most lymphocytes that mediates lymphocyte capture and rolling at sites of inflammation (Tedder et al., [", "@B42]). ", "In the present study, SELL transcription was upregulated at the 1 h time point, contributing to the IPA prediction that helper T lymphocytes are accumulating, but the downregulated transcription of SELL at 3 h is inconsistent with the predicted activation pattern, as depicted by the yellow arrow in Figure [4](#F4){ref-type=\"fig\"}. ", "TLR9, a receptor that preferentially binds unmethylated CpG sequences in bacterial and viral DNA, was downregulated in the present study (Figure [4](#F4){ref-type=\"fig\"}). ", "Here, the downregulation of TLR9 transcription is predicted to activate the accumulation of T lymphocytes at the skin feeding site of a TBEV-infected tick. ", "This prediction is supported by a recently developed mouse model of cutaneous lupus that is dependent on the expression of TLR7 and the loss of TLR9, which ultimately results in extensive accumulation of IFNγ-producing T lymphocytes (Mande et al., [", "@B28]). ", "Distal-less 3 (DLX3) is a transcription factor involved in the terminal differentiation of keratinocytes. ", "In a mouse model with epidermal ablation of DLX3, there was an increase of IL17-producing CD4^+^ T cells, CD8^+^ T cells, and γδ T cells in the skin and draining lymph nodes (Hwang et al., [", "@B18]); thus, the downregulated transcription of DLX3 in the skin biopsies from the present study likely contributes to the accumulation of helper T lymphocytes at the cutaneous feeding site of infected ticks (Figure [4](#F4){ref-type=\"fig\"}).", "\n\n\"Maintenance of cells\" was the fourth predicted bio-function in the IPA core comparison analysis. ", "This bio-function was predicted to be inhibited at both experimental time points (1 h activation z-score = −1.342, 3 h activation z-score = −2.236). ", "The \"maintenance of cells\" activation network is very similar to the top predicted network, \"maintenance of leukocytes\"; however, the only difference is that Sonic hedgehog (SHH) is present in the \"maintenance of cells\" network (Figure [4](#F4){ref-type=\"fig\"}). ", "The touch dome, a highly specialized mechanosensory epidermal structure composed of distinct keratinocytes in close association with innervated Merkel cells, is maintained by signaling with SHH to tissue-specific stem cells (Xiao et al., [", "@B45]). ", "In the present study SHH transcription is upregulated after 1 h of TBEV-infected tick feeding, a finding that is inconsistent with the predicted pattern of inhibited cell maintenance (depicted by the yellow arrow in Figure [4](#F4){ref-type=\"fig\"}); however, at the 3 h time point, SHH transcription was downregulated, contributing to the predicted inhibition of touch dome cell maintenance (Figure [4](#F4){ref-type=\"fig\"}). ", "Some damage to the perineural skin microenvironment is likely to occur because of the mechanical injury induced by tick feeding, and this could ultimately impact SHH signaling and the touch dome homeostasis.", "\n\nThe \"activation of neutrophils\" was the fifth predicted bio-function in the core comparison analysis. ", "After 1 h of TBEV-infected vs. uninfected tick feeding, neutrophil activation was predicted to be activated (activation z-score = 1.342); however, after 3 h, neutrophils were predicted to be inhibited (activation z-score = −2.236) (Figure [4](#F4){ref-type=\"fig\"}). ", "The upregulated transcription of Cxcl5 and TREML2 at the 1 h time point, followed by the downregulation of these genes at the 3 h time point contribute to this phenomenon because Cxcl5 is a chemokine involved in the activation of neutrophils (Proost et al., [", "@B33]) and TREML2 potentiates neutrophil activation in response to G protein-coupled receptor signaling (Halpert et al., [", "@B13]). ", "Likewise, Lipocalin-2 (LCN2) transcription was upregulated at 1 h post-TBEV-infected tick feeding and downregulated at 3 h. LCN2 is expressed in neutrophils and is a potent inducer of their chemotaxis and migration to sites of inflammation (Schroll et al., [", "@B37]); thus, its upregulation at the 1 h time point further contributes to the activation of neutrophils at the feeding site of TBEV-infected ticks. ", "VTCN1 belongs to the B7 family of costimulatory proteins. ", "VTCN1 inhibits the expansion of neutrophils from their progenitors, as demonstrated by VTCN1-deficient mice that display enhanced neutrophil-mediated innate immunity (Zhu et al., [", "@B47]); therefore, the downregulation of VTCN1 transcription after 1 h, and its upregulation after 3 h, contributes to the activation of neutrophils at the cutaneous feeding site of a TBEV-infected tick (Figure [4](#F4){ref-type=\"fig\"}).", "\n\nImmunohistochemistry\n--------------------\n\nImmunohistochemical analysis was performed at the feeding sites of TBEV-infected and uninfected *I. ricinus* to determine if the gene expression data could be correlated to the tissue morphology and inflammation. ", "The tick feeding site is characterized by extravasated erythrocytes and leucocytes, and with a steady influx of inflammatory cells. ", "As early as 1 h post-TBEV-infected tick feeding, neutrophils were observed at both infected and uninfected tick feeding sites, with a marked increase at the infected tick feeding site. ", "After 3 h of TBEV-infected tick feeding, increased recruitment of inflammatory cells was observed at the infected tick feeding site compared to the uninfected tick feeding site. ", "Among these, TBEV antigens were localized in fibroblasts and mononuclear cells, but not in neutrophils (Figure [5](#F5){ref-type=\"fig\"}). ", "These immunohistochemistry observations support the cutaneous immune gene expression data, showing an inflammatory micro-environment at the feeding site of TBEV-infected ticks. ", "The recruitment of inflammatory cells appears to be much more pronounced in the TBEV-infected tick feeding site than the uninfected tick feeding site.", "\n\n{#F5}\n\nConclusions {#s4}\n===========\n\nThe present study demonstrates that TBEV-infected *I. ricinus* adult ticks create an inflammatory environment at the murine cutaneous interface within 1 h of feeding. ", "Significant differences in immune responses were observed between hosts infested with TBEV-infected vs. uninfected ticks. ", "Furthermore, genes associated with neutrophil activation and mobilization were modulated in the presence of TBEV, suggesting that there is an influx of neutrophils and other phagocytic inflammatory cells to the tick feeding site after only 1 and 3 h of infected tick feeding. ", "Immunohistochemistry further supported the cutaneous immune gene expression analysis, demonstrating pronounced recruitment of inflammatory cells, especially neutrophils, to the feeding site of TBEV-infected ticks. ", "Taken together with our earlier study on POWV-infected tick feeding sites (Hermance and Thangamani, [@B16]), and the current study, it is clearly evident that during the earliest stages of flavivirus-infected tick feeding, a complex, inflammatory micro-environment is created in the host\\'s skin. ", "The present study serves to expand our understanding of the immunological events that occur at the cutaneous interface during the early stages of tick-borne flavivirus transmission to a host.", "\n\nAuthor contributions {#s5}\n====================\n\nConceived the idea: ST; Provided reagents and materials: ST and MK; Performed experiments: ST, MK, MH, RS, SW, MS, and DH; Data analysis: ST, MH, and SW; Wrote manuscript: ST and MH. ", "All authors critically read and revised the manuscript.", "\n\nConflict of interest statement\n------------------------------\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.", "\n\nThe authors wish to thank Dr. Boris Klempa and Marta Siebenstichova from the Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences (Bratislava, Slovakia) for providing TBEV MBS for tick inoculations.", "\n\n**Funding.** ", "ST is supported by NIH/NIAID grants R01AI127771 and R21AI113128. ", "MK was supported by the Slovak Research and Development Agency (contract no. ", "APVV-0737-12).", "\n\nSupplementary material {#s6}\n======================\n\nThe Supplementary Material for this article can be found online at: <https://www.frontiersin.org/articles/10.3389/fcimb.2017.00494/full#supplementary-material>\n\n###### \n\nClick here for additional data file.", "\n\n###### \n\nClick here for additional data file.", "\n\n[^1]: Edited by: Jose De La Fuente, Instituto de Investigación en Recursos Cinegéticos (CSIC-UCLM-JCCM), Spain\n\n[^2]: Reviewed by: Jianfeng Dai, Soochow University, China; Janakiram Seshu, University of Texas at San Antonio, United States; Nicholas Johnson, Animal Health and Veterinary Laboratories Agency, United Kingdom\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Baritone horn\n\nThe baritone horn, or sometimes just called baritone, is a low-pitched brass instrument in the saxhorn family. ", "It is a piston-valve brass instrument with a bore that is mostly conical (like the higher pitched flugelhorn and alto (tenor) horn) but it has a narrower bore than the similarly pitched euphonium. ", "It uses a wide-rimmed cup mouthpiece like that of its peers, the trombone and euphonium. ", "Like the trombone and the euphonium, the baritone horn can be considered either a transposing or non-transposing instrument. ", "\n\nIn the UK, the baritone horn is part of the standardised instrumentation of brass bands. ", "In concert band music, there is often a part marked baritone, but these parts are most commonly intended for, and played on, the euphonium. ", "A baritone can also play music written for a trombone due to similar pitches.", "\n\nA person who plays a baritone horn is a baritone (horn) player (UK) or baritonist (US).", "\n\nConstruction and general characteristics \n\nThe baritone, like the trombone and euphonium, is a nine-foot brass tube. ", "Valves are most often piston-style. ", "It is predominately of conical bore, like the euphonium, but has a narrower bore than the euphonium. ", "The smaller bore renders its attack more distinct than the rounder attack of the euphonium, and also provides it with a brighter sound than the dark-sounding euphonium.", "\n\nKey\nThe baritone is pitched in concert B, meaning that when no valves are actuated, the instrument will produce partials of the B harmonic series. ", "Music for the baritone horn can be written in either the bass clef or the treble clef. ", "When written in the bass clef, the baritone horn is a non-transposing instrument. ", "However, when written in the treble clef, it is often used as transposing instrument, transposing downward a major ninth from the music as written, so that written middle C for the baritone is concert B below low C (B2 in scientific pitch notation), with the fingerings thus matching those of the trumpet but sounding an octave lower. ", "It is often used to play parts written for the similarly pitched tenor trombone or euphonium.", "\n\nRange\nThe baritone is part of the tenor section of a band. ", "Its second partial with no valves pressed is concert B on the second line from the bottom of the bass clef (B2 in scientific pitch notation). ", "The eighth partial with no valves pressed is concert B in the center of the treble clef (B4). ", "Virtuosi can reach certain pedal tones below the E2 second partial with all valves depressed, which is the nominal lowest note on the instrument, and several half-tones above the B4, which is the nominal top of the instrument's range.", "\n\nTone\nThe baritone sounds with a timbre between the brightness of the trombone and the more mellow tone of the euphonium.", "\n\nDistinguishing the baritone horn from the euphonium \n\nAlthough both baritone horn and euphonium produce partials of the B harmonic series in the same range, and both have a nine-foot-long main tube, the baritone horn tends to have a smaller and more cylindrical bore than the euphonium. ", "The baritone horn usually has a tighter wrap and a smaller bell, and is thus smaller and lighter overall, and produces a \"lighter\" sound versus the more solid, brassy timbre of the euphonium.", "\n\nThere is a common misconception that three-valve instrument is a baritone and that the four-valve instrument is a euphonium. ", "Euphoniums often have a fourth valve as an alternate fingering for 1&3 split fingering with improved intonation. ", "The fourth valve can also be viewed in the same way as an F trigger on trombone, repitching the instrument to expand the lower range. ", "A fourth valve is rarely seen on baritones, but absence of a fourth valve is not a defining characteristic.", "\n\nAn \"American baritone\", featuring three valves on the front of the instrument and a curved forward-pointing bell, was common in American school bands throughout most of the twentieth century. ", "While this instrument is in reality a conical-cylindrical bore hybrid, neither truly euphonium nor baritone, it was almost universally labeled a \"baritone\" by both band directors and composers.", "\n\nMarching baritone horn\n\nSpecially wrapped versions of the baritone horn have been created for use in marching bands and drum and bugle corps. ", "They have three valves and a front-facing bell and are the tenor voice of a drum and bugle corps, below the soprano voice of the trumpet, the alto voice of alto horn or mellophone, and above the low tubas.", "\n\nArtists\nNotable artists who are today referenced as great baritone horn and/or euphonium players include Mel Sykes, Simone Mantia, Steven Mead, Brian Bowman, and Leonard Falcone. ", "The Leonard Falcone International Tuba and Euphonium Festival is a notable venue for aspiring artists on euphonium, but its namesake played baritone horn on his many recordings.", "\n\nTrumpeter Maynard Ferguson used a baritone horn in the song \"Gospel John\" and in one of his three solos (the other two involving a valved trombone and a trumpet) in a live performance of his song \"Great Guns\". ", "\n\nJapanese free-improvisation trumpeter Toshinori Kondo has played baritone horn on some dates and recordings (e.g., Jazz Bunker), as has saxophonist Ralph Carney (e.g., Night on Earth).", "\n\nReferences \n\nCategory:B-flat instruments\nCategory:Brass instruments\nCategory:Horns" ]

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

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[ "985 F.2d 579\nU.S.v.", "Damato*\nNO. ", "92-4101\nUnited States Court of Appeals,Eleventh Circuit.", "\nJan 27, 1993\n\nAppeal From: S.D.Fla.", "\nREVERSED AND VACATED.", "\n\n\n\n*\n Fed.", "R.App.", "P. 34(a); 11th Cir.", "R. 34-3\n\n\n" ]

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[ "s the closest to -1/3? ", " (a) l (b) 5 (c) 4\na\nSuppose 0 = 3*x - 5*x + 10. ", "Let z be 2/14*5/x. Suppose -5*w - m = 5, 2*w - m + 25 = -6*m. ", "What is the nearest to w in z, 2, 5?", "\nz\nLet u(d) = d**3 + 6*d**2 + 3*d - 5. ", "Let b be u(-5). ", "Let q = -11 + 10.2. ", "Let i = q + 0.7. ", "What is the closest to -1/2 in -4, b, i?", "\ni\nLet c = 3.02 - 0.02. ", "Let q = 90 - 272/3. ", "What is the closest to 2/3 in c, q, -4?", "\nq\nLet w be 4 - (-2 + 3 - (-9)/3). ", "Which is the nearest to 0? ", " (a) -1 (b) w (c) -0.3\nb\nLet r = 5.4 + -5. ", "Let n = 5 + -5. ", "Which is the nearest to 1? ", " (a) -0.5 (b) r (c) n\nb\nLet l be 1 - 1*(-3 + 2). ", "Let j be 2 - (l - 6/(-8)). ", "Let i = 8/71 + 228/497. ", "What is the nearest to 1/4 in j, 0, i?", "\n0\nLet j = 75 - 451/6. ", "Let h = 0.41 - 0.01. ", "Which is the closest to j? ", " (a) 0.5 (b) -2/7 (c) h\nb\nLet k = 8 + -8.1. ", "Let j(p) = -21*p**3 + p. Let s be j(-1). ", "Suppose -6*r - s = -r. ", "What is the nearest to k in -3, r, -2?", "\n-2\nLet k = -138 + 137.4. ", "Which is the nearest to 0.1? ", " (a) 2/5 (b) k (c) -2/9\na\nLet x = 4 + -9. ", "Let u = x + 4.6. ", "What is the closest to 0.1 in 4, u, 0.1?", "\n0.1\nLet w = 1.7 - 2. ", "Let b(z) = -2*z + 61. ", "Let p be b(30). ", "What is the nearest to p in 1, 0, w?", "\n1\nLet p = 18 + -16. ", "What is the nearest to p in -3, 1/4, 4?", "\n1/4\nLet h = -30 + 48.7. ", "Let u = 19 - h. Which is the nearest to 1? ", " (a) 0.5 (b) 5 (c) u\na\nLet z = -457 - -458. ", "Let x be ((-9)/7)/(-1) - 1. ", "What is the closest to x in -2, 2, z?", "\nz\nLet v = -0.05 + 0.05. ", "Which is the closest to v? ", " (a) 2/21 (b) 0.4 (c) 5\na\nLet w be 4/(-6)*6/(-8). ", "Let k be (-1)/(-3 - (-21)/6). ", "What is the nearest to w in k, -0.2, 2/5?", "\n2/5\nLet w be 0 + -1746587*(-1)/(-63). ", "Let d = w + 27728. ", "Let s = d + -30/7. ", "What is the nearest to 1/2 in 1, s, 0.3?", "\n0.3\nLet z = -20/9 - -14/9. ", "Let s = -0.1 + 2.1. ", "Suppose a - 4*a = -4*m + 1, 0 = -4*a + 4*m. ", "What is the closest to a in z, s, 0.5?", "\n0.5\nLet t = -0.01 + -10.99. ", "Let a = -15 + 8. ", "Let r = a - t. What is the nearest to -0.1 in 0, r, 3?", "\n0\nLet m = 2.3 - -0.7. ", "Let j = 0.9 + 1.1. ", "Which is the nearest to 1? ", " (a) j (b) -0.3 (c) m\na\nLet r = 0.6 + -1. ", "Suppose -20 = t + 4*t. ", "What is the nearest to 0 in t, 2, r?", "\nr\nLet o be 45/36*2/(-5). ", "Let r = 0 - -2. ", "Which is the nearest to -1? ", " (a) r (b) o (c) -3/5\nc\nLet g = -0.67 + 1.17. ", "Let h = -3 + 3.1. ", "Which is the nearest to h? ", " (a) 2/11 (b) g (c) 6\na\nLet g = -2 - 0. ", "Suppose -3*o = 4*v - 0*o - 4, 0 = -4*v - 4*o. ", "Let t be (3 - -1)/v*1. ", "Which is the nearest to -1/3? ", " (a) t (b) -1/4 (c) g\nb\nLet w = 68 - 69. ", "Which is the closest to w? ", " (a) -23 (b) 0.5 (c) -3/4\nc\nLet t = -2.6 + 0.6. ", "Let o be (-2)/9 + (-17)/45. ", "Which is the closest to 2? ", " (a) t (b) 3 (c) o\nb\nLet r = -0.1 + 0.3. ", "Let n = -12 - -5. ", "Let l = n + 8. ", "What is the nearest to l in 0.5, r, -0.5?", "\n0.5\nLet j = -0.8 + 1.8. ", "Let y = -0.02 - -0.42. ", "Suppose 0 = 2*m + 2*m - 4*i + 8, 5*m - 2*i = -7. ", "Which is the closest to 1? ", " (a) j (b) m (c) y\na\nLet i = -2 - -2. ", "Let d = -3 + 2. ", "Let k be (-3)/(-4) - 44/80. ", "Which is the closest to d? ", " (a) k (b) i (c) -1/4\nc\nLet h = 157/3 - 53. ", "Let y = 104 + -316/3. ", "Let k(p) = 2*p + 2. ", "Let f be k(-1). ", "Which is the nearest to f? ", " (a) -4 (b) h (c) y\nb\nLet r = -5.2 + 5.7. ", "Let j be (4/(-6))/((-8)/12). ", "Let f = 0 - j. Which is the nearest to f? ", " (a) -1 (b) 1 (c) r\na\nLet q = -8.479 - -0.739. ", "Let m = q - -0.54. ", "Let f = m - -7. ", "What is the nearest to -3 in f, 2/11, 2?", "\nf\nLet o = 6.2 + -6.4. ", "Which is the nearest to -1? ", " (a) o (b) -4 (c) -0.09\na\nLet v = 0.1 + 0. ", "Let d(m) = -m**3 - 6*m**2 - 7*m - 5. ", "Let x be d(-5). ", "Let l be 2/30*x/(-2). ", "Which is the nearest to v? ", " (a) 1/4 (b) l (c) -3/5\na\nLet o = 1.1 + 9.9. ", "Let h = o - 10.7. ", "Which is the closest to h? ", " (a) -2 (b) -0.3 (c) -1/4\nc\nLet z = -0.1 + 0.2. ", "Let g be ((-2)/6)/(-1)*6. ", "Which is the closest to z? ", " (a) g (b) 0 (c) -1/6\nb\nLet o be (150/(-45))/(4/(-6)). ", "Suppose 6 = 2*m + m - 4*l, -4*m = l - 8. ", "Let s(w) = -w. ", "Let g be s(m). ", "Which is the closest to 0? ", " (a) o (b) g (c) -4\nb\nLet f = 5 - 4.7. ", "Let u = f - -0.2. ", "Let h = -40 + 45. ", "What is the closest to -1 in -3/4, u, h?", "\n-3/4\nLet l = -20 + 20.4. ", "Let k = -35 - -35.5. ", "Which is the closest to 0.1? ", " (a) k (b) -2 (c) l\nc\nLet i = 0.003 - -0.017. ", "Let y = -2 - -2.4. ", "Which is the nearest to i? ", " (a) 2/3 (b) y (c) -0.5\nb\nLet n = -0.4 - 0. ", "Let w be (-2 + 8)/(4 + -6). ", "Which is the closest to -2? ", " (a) n (b) w (c) 3\nb\nLet j = 0.04 + 1.96. ", "Which is the nearest to 1? ", " (a) j (b) -0.1 (c) 6\na\nLet m = 0.1 - 0.3. ", "Let p = -0.4 - m. Which is the nearest to -2/5? ", " (a) p (b) 2 (c) 0.5\na\nLet u(w) = w + 13. ", "Let v be u(-9). ", "Which is the closest to -2? ", " (a) 2/3 (b) v (c) 0.5\nc\nLet l = 0.7 - 11.1. ", "Let n = -10 - l. Which is the closest to 0? ", " (a) -2 (b) -2/3 (c) n\nc\nSuppose -3*m - 3*y = -75, -3*y + 30 = m + 7. ", "Suppose 4*c + n + m = 3*n, -2*n + 31 = -5*c. ", "What is the nearest to 0.2 in c, -3, 1/7?", "\n1/7\nLet y = 3 - 3. ", "Let o = -0.5 + 0.4. ", "Let s = -5 + 6. ", "What is the nearest to s in o, -1, y?", "\ny\nLet q = 0 - -0.3. ", "Let y = 7 - 6. ", "Let j = -6 + y. Which is the closest to q? ", " (a) 5 (b) j (c) 1/3\nc\nLet i = -0.779 + 5.709. ", "Let o = i - -0.07. ", "Let h = -0.3 - 0. ", "Which is the nearest to 1? ", " (a) h (b) o (c) 0.4\nc\nLet k = -1698/7 + 242. ", "Which is the nearest to 0.1? ", " (a) 3/4 (b) k (c) -2\na\nSuppose 2*g - 6*g = 5*l + 7, 3*g + 3 = -3*l. ", "Let u = -0.16 - 0.84. ", "Let c = u - -1.1. ", "What is the closest to -0.1 in -1, c, l?", "\nc\nLet c be ((-2)/34)/(2/(-2)). ", "What is the nearest to -1 in -2, -1, c?", "\n-1\nLet k be 0 - 1/(35/5). ", "What is the nearest to k in 0, 2, -1/2?", "\n0\nLet t(d) = -d**2 - 10*d - 12. ", "Let i be t(-8). ", "Suppose 0*x - 2*x - 3*n = 23, 4*n + 4 = i*x. ", "Which is the nearest to -0.2? ", " (a) 0 (b) x (c) 5\na\nLet g = 31 + -21. ", "Suppose -2*j - g = -4*j. ", "Let o(u) = -u**3 - 9*u**2 + 10*u - 2. ", "Let z be o(-10). ", "What is the nearest to z in j, -0.5, 0.3?", "\n-0.5\nLet z(d) = 3*d - 14. ", "Let k be z(5). ", "Which is the closest to 0? ", " (a) -3 (b) k (c) -0.2\nc\nLet k = 49/244 - -3/61. ", "Which is the closest to k? ", " (a) 2 (b) -1 (c) -4\nb\nLet z = 0.083 + 4.917. ", "Which is the closest to 0? ", " (a) z (b) -4/3 (c) 4\nb\nLet x = 977/30 - 29/10. ", "Let n = x - 30. ", "Let y = -297/520 + -3/104. ", "Which is the closest to 0? ", " (a) 0.3 (b) n (c) y\na\nSuppose -5*r + 15 + 5 = 0. ", "What is the nearest to 2/7 in -4, r, 1?", "\n1\nLet y = 240 - 240. ", "Let v = 467/7 + -67. ", "What is the closest to v in -0.1, y, -5?", "\n-0.1\nLet u = -4 - -1. ", "Suppose 4*o = 3 - 7. ", "Let i be o*u*(-4)/30. ", "Which is the closest to 0? ", " (a) i (b) 3 (c) -1/7\nc\nLet d = 0.3 + -0.8. ", "Suppose -2*i - 2*i = -4, f = -4*i + 5. ", "Which is the closest to f? ", " (a) d (b) 0 (c) -2/23\nb\nLet h = 21 - 17. ", "Let d = 0.08 + -2.08. ", "Which is the nearest to d? ", " (a) h (b) 4/3 (c) 0.1\nc\nLet j be (-4)/(14/(3 - 5)). ", "Which is the closest to 0.2? ", " (a) 0.3 (b) -1 (c) j\na\nLet j = 0 + 0. ", "Let l(v) = -v**2 + 13*v + 33. ", "Let a be l(15). ", "What is the nearest to j in 2/3, -1, a?", "\n2/3\nLet u be (6/(-3))/(-4)*(-4 + 4). ", "Let d = -3 + 0. ", "Let n = -3 - d. What is the nearest to n in -2, u, -5?", "\nu\nLet a(w) = w**2 - 10*w - 12. ", "Let q be a(11). ", "Let c be (q - -2) + 1/(-4). ", "What is the nearest to -0.1 in 3/2, c, -0.4?", "\n-0.4\nLet p be 5/((-45)/24) + 3. ", "Which is the closest to p? ", " (a) -4/5 (b) -0.3 (c) 0.5\nc\nLet i(x) = x**2 + 10*x + 1. ", "Let d be i(-10). ", "Which is the closest to d? ", " (a) -5 (b) -0.5 (c) 0\nc\nLet h = 153 - 152. ", "Let r = -16/3 - -4. ", "Let m = 0 - 0.1. ", "Which is the nearest to h? ", " (a) r (b) m (c) 0.3\nc\nLet i be (-4)/26 + (-410)/(-130). ", "Let s = 0.9 - 3.9. ", "What is the closest to s in -0.2, i, 1/3?", "\n-0.2\nLet v = -1.5 + 1. ", "Which is the nearest to 2? ", " (a) 0.3 (b) 2/7 (c) v\na\nLet p = 77.7 - 78. ", "Let w = -10 - -6. ", "Which is the closest to -2/7? ", " (a) -2/21 (b) w (c) p\nc\nLet b = 88/5 + -17. ", "Let q = 244 - 1706/7. ", "What is the nearest to q in 2/5, b, -5?", "\n2/5\nLet r = 0.3 - -0.7. ", "Let o = r + -0.9. ", "Let h = 0.4 + o. What is the nearest to -2/3 in h, -2/13, 0.3?", "\n-2/13\nLet x(k) = k**2 + 8*k + 9. ", "Let l be x(-6). ", "Let u be l/(39/12*6). ", "Let o = 0 - -2. ", "What is the nearest to 0 in u, -3, o?", "\nu\nLet u be -1 + 2 - (-1)/(-3). ", "Let s be ((-6)/(-4) - 1) + -1. ", "What is the closest to 0 in -1, u, s?", "\ns\nLet v = 41 + -41.4. ", "What is the nearest to -3 in v, -3/4, -1/6?", "\n-3/4\nSuppose -36 = 7*s - 4*s. ", "What is the closest to 1/2 in s, 1, 5?", "\n1\nLet g = -2099/8 + 262. ", "Let n be 27/180 - 2/5. ", "What is the closest to 2/5 in g, n, -3?", "\nn\nSuppose -84 = 4*w - 0*v + 2*v, 0 = w - 4*v + 30. ", "Let d = w + 21. ", "Which is the nearest" ]

{ "pile_set_name": "DM Mathematics" }

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[ "Video data is generally processed and transferred in the form of bit streams. ", "Typical video compression coders and decoders (“CODECs”) gain much of their compression efficiency by forming a reference picture prediction of a picture to be encoded, and encoding the difference between the current picture and the prediction. ", "The more closely that the prediction is correlated with the current picture, the fewer bits that are needed to compress that picture, thereby increasing the efficiency of the process. ", "Thus, it is desirable for the best possible reference picture prediction to be formed.", "\nIn many video compression standards, including Moving Picture Experts Group (“MPEG”)-1, MPEG-2 and MPEG-4, a motion compensated version of a previous reference picture is used as a prediction for the current picture, and only the difference between the current picture and the prediction is coded. ", "When a single picture prediction (“P” picture) is used, the reference picture is not scaled when the motion compensated prediction is formed. ", "When bi-directional picture predictions (“B” pictures) are used, intermediate predictions are formed from two different pictures, and then the two intermediate predictions are averaged together, using equal weighting factors of (½, ½) for each, to form a single averaged prediction. ", "In these MPEG standards, the two reference pictures are always one each from the forward direction and the backward direction for B pictures." ]

{ "pile_set_name": "USPTO Backgrounds" }

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[ "‘We’ll double India presence by 2015’\n\nUS-based global hospitality chain Carlson that owns and operates hotel brands such as Radisson, Park Plaza and Country Inns & Suites plans to have around 100 hotel properties in the country by 2015. ", "India is important to Carlson’s global expansion plans, Hubert Joly, president and CEO told HT. ", "Excerpts:\n\nbusinessUpdated: Oct 15, 2010 01:53 IST\n\nVivek Sinha Hindustan Times\n\nUS-based global hospitality chain Carlson that owns and operates hotel brands such as Radisson, Park Plaza and Country Inns & Suites plans to have around 100 hotel properties in the country by 2015. ", "India is important to Carlson’s global expansion plans, Hubert Joly, president and CEO told HT. ", "Excerpts:\n\nYour expansion plans for India seem ambitious. ", "Did the 26/11 attacks on Mumbai influence your strategy?Well, we are in an industry that is subject to be affected by such events... terror attacks, volcanic ash cloud in Europe or such things. ", "But we tend not to focus on the negativities and look at India from a very strategic focus.", "\n\nThere will be certain bumps along our way but the opportunities and positives far outweigh. ", "For instance, there is about 0.1 hotel rooms per 1000 people in India — compared to 15 per thousand in the US and 10 per thousand in Europe. ", "Even China has close to 2 rooms per thousand people. ", "With India’s fantastic growth there is great business potential.", "\n\nHow are you growing in India?We had around 28 hotels in our kitty in 2009 and will have around 36 in 2010. ", "By 2015 we plans to have around 100 hotels across 42 cities. ", "We might also pick up minority stakes in some hotel projects in the country.", "\n\nThe importance of India for Carlson’s global business…Carlson’s ambition is to grow its hotel portfolio by more than 50 per cent by 2015. ", "In 2009 India accounted for around 3 per cent of out hotels but by 2015 this will touch 7 per cent.", "\n\nDo you own these hotel properties?We focus on managing hotels as opposed to building hotels and owning them. ", "We provide services and our brand name. ", "It is a fee-based-revenue-share model.", "\n\nWhat about smaller cities?We already have a presence in smaller cities. ", "We plan a big push in mid-scale cities such as Vijaywada, Cochin and Ludhiana." ]

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[ "Urban malaria in Nazareth, Ethiopia: parasitological studies.", "\nCross-sectional surveys for parasite infection, and factors that possibly influence human malaria transmission were carried out to characterize the epidemiology of urban malaria in Nazareth. ", "Thick and thin blood films for parasite diagnosis were collected from individuals residing in 6 representative kebeles in the town. ", "A questionnaire was used to obtain socioeconomic information. ", "An overall parasite rate of 2.8%, P. falciparum (1.6%) and P. vivax (1.2%)- was observed among the 3890 individuals examined during the 4 surveys. ", "Significant intra-urban differences (X2 = 27.31; P < 0.0001), in parasite rates, were observed with a much higher prevalence in the peripheral kebeles. ", "A marked seasonal variation in parasite rates was evident during the sampling period and the peak occurred in Sept./Oct. ", "There was no apparent decrease in parasite rate with increase in age, suggesting a delayed acquired immunity, typical of hypoendemic settings. ", "The study has indicated that in Nazareth the prevalence of malaria is seasonally variable and relatively low, showing that it is unstable. ", "Hence, if appropriate control measures are not instituted, malaria situation in -Nazareth is subject to epidemics." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Paragraph or Speech on “A Visit To A Circus” Complete Paragraph or Speech for Class 10, Class 12 and Graduation and other classes.", "\n\nA Visit To A Circus\n\nLast month, the Apollo Circus Company visited our city. ", "They pitched their tents at an open place outside the city. ", "Soon, the circus became the talk of the city. ", "One evening I, along with my friend, Rakesh, went to see the circus show. ", "There was a great rush at the booking window. ", "We managed to get seats in the gallery. ", "A group of players was entertaining the spectators with light music. ", "As the show began, all the artists and circus animals came forward and introduced themselves to the audience in their own way. ", "An elephant stood on his hind legs and greeted everyone. ", "Other animals also came forward to greet us in different ways. ", "As they left, swings of ropes became the object of interest. ", "It was nice display of fun and trick. ", "At once, the lights were switched off. ", "The artist jumped from one swing to another, changed side and performed a number of tricks. ", "Now came in the arena a group of elephants. ", "They performed the Ganesh Pooja before they climbed a wooden staircase one by one. ", "Now some dogs came and played football. ", "Their feat was lost in the noise of children. ", "Next came a group of cyclists who displayed a wonderful control in their vehicles. ", "A girl cycled over a taut rope. ", "Then came the horses, monkeys and bears. ", "They played wonderful tricks. ", "Next, the lions and tigers put up a good show. ", "We saw the lions jump through ring of fire. ", "At long last, we saw a motorcyclist racing round the Dome of Death. ", "As he went up and down in a big iron cage, our hearts came in to our mouths. ", "After each item, two jokers came forward and amused the audience with their tricks. ", "The circus clowns made the spectators laugh every now and then. ", "Our visit to the circus was very delightful.", "\n\nThe main objective of this website is to provide quality study material to all students (from 1st to 12th class of any board) irrespective of their background as our motto is “Education for Everyone”. ", "It is also a very good platform for teachers who want to share their valuable knowledge." ]

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[ "WKUW-LD\n\nWKUW-LD, virtual channel 40 (UHF digital channel 28), is a low-powered television station licensed to White House, Tennessee, United States and serving the Nashville television market. ", "It is a translator of Lebanon-licensed MeTV affiliate WJFB (channel 44) which is owned by HC2 Holdings. ", "WKUW-LD's transmitter is located in Whites Creek, Tennessee.", "\n\nHistory\n\nAs a TBN translator in Bowling Green\nOriginally licensed to Bowling Green, Kentucky, the station began broadcasting on October 17, 2002, as a Trinity Broadcasting Network (TBN) translator (relay) station, under the call sign W60DC, and was owned and operated by TBN.", "\n\nOn October 5, 2004, TBN announced they were selling the translator to Budd Broadcasting. ", "The sale was finalized on December 1, 2004. ", "A year later, on June 9, 2005, Budd Broadcasting changed the call sign to WKUW-LP.", "\n\nThe silent years and relocation to Nashville\nOn December 31, 2010, Budd Broadcasting took WKUW off the air temporarily to upgrade the station to digital operations. ", "Budd also relocated the station to White House, Tennessee where the station also serves the Nashville market area some to the south. ", "In the process, the station turned off its analog signal on channel 60 and signed on a digital signal on channel 40. ", "Through the use of PSIP, digital television receivers display the station's virtual channel as its current UHF digital channel 40 rather than its former analog channel 60. ", "This channel was among the high band UHF channels (52–69) that were removed from broadcasting use when the digital transition in the United States saw the switchover from analog to exclusively digital broadcasting of terrestrial television television programming in June 2009. ", "The call sign was also changed to WKUW-LD.", "\n\nDTV America ownership\nIn 2015, it was announced that WKUW-LD and Bowling Green sister station WKUT-LD would be operated by DTV America Corporation, alongside Bowling Green-based Antenna TV and MyNetworkTV dual affiliate WCZU-LD. ", "On July 17, 2015, DTV America took full control of WKUW and now owns and operates the station outright.", "\n\nWKUW-LD returned to the air on November 23 as an affiliate of the Doctor Television Channel (DrTV). ", "The station now transmits from a tower near Whites Creek close to the Interstate 24 interchange with Old Hickory Boulevard, sharing tower space with television stations WUXP, WNTU-LP, WPGD, WRTN-LD, and WJNK-LD, and radio station WGFX.", "\n\nOn December 8, 2015, WKUW changed affiliations from DrTV to Buzzr—a network broadcasting mostly classic TV game shows. ", "WKUW was supposed to add DrTV to a forthcoming second subchannel, however, this never happened. ", "Instead, The Liquidation Channel (now Shop LC) was added to its second subchannel on January 27, 2016. ", "WKUW also launched a third subchannel as an affiliate of Escape (now Court TV Mystery) on January 27, 2016.", "\n\nOn April 1, 2016, WKUW added Newsmax TV on DT4 and QVC Over the Air on DT6. ", "The fifth subchannel was silent until April 13, 2016, when it returned with The Country Network. ", "It was discontinued on January 11, 2016, and replaced with a full-time feed from the Sinclair-owned American Sports Network (ASN). ", "On September 6, 2017, ASN was folded into Stadium, a multi-platform sports network.", "\n\nIn May 2016, Newsmax TV was dropped from WKUW-LD4 and replaced with The Country Network. ", "QVC Plus replaced the Country Network on WKUW-LD5.", "\n\nOn November 1, 2016, the full-time Retro TV network replaced Escape, which moved to WSMV-TV's second subchannel of 4.2 replacing Heartland.", "\n\nIn December 2016, WKUW added a seventh digital subchannel carrying infomercials, under the \"Revenue Frontier\" branding; however, on February 1, 2018, the infomercials were replaced with Jewelry Television (JTV).", "\n\nOn February 28, 2018, The Country Network was replaced with Quest on WKUW's fourth subchannel.", "\n\nUnder new ownership\nWKUW was one of several dozen DTV America stations that were purchased by HC2 Holdings in October 2017.", "\n\nOn October 1, 2018, WKUW added CBN News Channel to its sixth subchannel, replacing QVC.", "\n\nOn March 5, 2019, WKUW discontinued Stadium from its third subchannel and QVC 2 from its fifth subchannel; both networks were replaced with infomercials. ", "On April 8, 2019, infomercials were replaced on DT3 by the Soul of the South Network. ", "This marked the return of the network to Nashville where it had been aired previously by WJDE-LD's channel 31.2.", "\n\nAs a WJFB translator\nOn the weekend of September 21, 2019, WKUW-LD eliminated all of its channels and underwent a channel reconstructing. ", "WKUW-LD ran a Test Pattern on its main channel while Heroes & Icons was added on 40.2, Start TV on 40.3, Decades on 40.4 and Movies! ", "on 40.5. ", "This mirrored the channel lineup of sister station WJFB, although it continues to run Tri-State Christian Television (TCT) on its sixth subchannel and Light TV on its seventh subchannel. ", "WKUW-LD became a WJFB translator on September 23. ", "The former WKUW-LD affiliations which include Buzzr, Shop LC, Soul of the South Network, Quest, Revenue Frontier, CBN News Channel and Jewelry Television continue to be seen on sister station WCTZ-LD (which itself was a former translator of WKUW-LD).", "\n\nDigital television\n\nDigital channels\nThe station's digital signal is multiplexed:\n\nSpectrum reallocation\nIn 2017, due to the FCC's 2016 incentive auction, WKUW filed for a construction permit for its digital subchannel to relocate to digital UHF channel 28 due to spectrum re-packing. ", "Channels will be changing over a transition period, which will take place between September 7, 2019, and October 18, 2019. ", "However, on October 19, 2018, WKUW went off the air temporarily to prepare for the transition and relocation to UHF channel 28. ", "WKUW-LD returned to the air briefly on January 30, 2019, and went off the air again at 3:25 p.m. that day after testing its signal in preparation for its permanent return. ", "WKUW-LD officially returned to the air on UHF channel 28 on February 1, 2019 at 1:30 p.m.\n\nReferences\n\nExternal links\n\nWKUW-LD REC Broadcast Query\n\nCategory:MeTV affiliates\nCategory:Heroes & Icons affiliates\nCategory:Start TV affiliates\nCategory:Decades (TV network) affiliates\nCategory:Movies! ", "affiliates\nCategory:Television channels and stations established in 2002\nKUW-LD\nCategory:Stadium (sports network) affiliates\nCategory:Digital low-power stations\nCategory:DTV America\nCategory:Quest (American TV network) affiliates" ]

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

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[ "Jordan Gavaris Explains It All\n\nShare\n\nI first met Jordan Gavaris during a press junket on set in Toronto when he was shooting the fifth season of Orphan Black. ", "We were sitting in a conference room at the soundstage and he came in wearing a gray sweatshirt and Adidas sneakers with a rainbow spatter on the sides. ", "From interviews and watching panels, I knew he was a smart and well-spoken person, particularly when it came to discussions around sexuality, but that he hadn’t talked about it in a personal capacity. ", "So, I asked, and he answered: Yes, he’s gay.", "\n\nWith that out of the way, we were free to expand the conversation further: Gavaris talked about the importance of playing Felix Dawkins, the tough and loyal brother of Sarah Manning on Orphan Black, and how the character, who is gay, allowed him to explore and better understand his femininity. ", "We talked about misogyny, Hollywood’s obsession with masculinity, whether he is afraid of losing work after coming out, and the interview process itself.", "\n\nAfter that initial interview, we ended with the promise to talk again. ", "So we made time for another sit-down in a far more comfortable setting, downstairs at the Nomad Hotel in New York where he was doing press alongside his castmates ahead of the final season. ", "He felt more assured this time around — confident, but still voluble — and we dove deeper into the politics of coming out in Hollywood. ", "We also touched on his love of acting, celebrity, and how he met his partner, fellow actor and writer Devon Graye.", "\n\nAn edited, condensed version of both conversations follows.", "\n\nToronto, February 2017\n\nWhen you were first building Felix as a character, did you focus on physicality?Physicality was one of the things that came first; he was a cat. ", "Sometimes animal exercises can help you get in touch with parts of yourself that you don’t access day to day. ", "In my day-to-day physicality, I’m a little bit like a terrier. ", "I’ve always been described as a dog. ", "I’m kind of goofy and a little dopey looking sometimes. ", "But that wasn’t right for this character. ", "I knew I had to go to a different part of myself, which for some reason, I was certain that the cat was going to access — it did. ", "It was precise, it was fluid. ", "It was a bit ballet — something poised and postured. ", "And then it started to make sense. ", "You start with one thing and then you build and go, “Does this make sense?” ", "He’s someone who is probably oppressed and has been victimized multiple times throughout his life. ", "He’s always posturing. ", "It’s how he moves through the world: in a constant state of defense.", "\n\nYou started Orphan Black when you were 22. ", "Do you feel like there’s less of a safety net for younger actors coming up in the industry?I’ve been really fortunate in that I’ve been employed for the last five years, but I know our unions, bless them, as much as they do work hard to negotiate on our behalf, the daily rate has gone down considerably. ", "There’s more pressure to have more representatives, so you end up with less money after all your commission’s been deducted. ", "I’ve never really had an issue with paying taxes, but there’s this pressure that a lot of studios face now to hire names. ", "I mean, movies are the worst, because the movie business is failing terribly and they think they have some amazing model that’s going to fix it all, and it all involves hiring a girl with 2 million Instagram followers. ", "Hasn’t worked yet. ", "And then in television it’s the same thing. ", "Parts are offered to these YouTube sensations.", "\n\nThere was a guy in Canada who created this set of YouTube videos called “Shit Girls Say.” ", "It was super sexist and a little odd. ", "YouTube gave him $13 million to go produce a television called Coming In about a gay man who wakes up one day and realizes he’s straight. ", "Like, what the fuck? ", "I think he’s an openly gay actor, but that doesn’t necessarily negate the stark politics of a decision like that. ", "That doesn’t negate the fact that the show is offensive and he’s just terribly unfunny. ", "So you have these people in positions of power with all this capital, handing it over to somebody who has no experience running their own show, no experience writing in long-form narratives, and giving him a television show because their YouTube video got 8 million hits. ", "So that is how the freelance paradigm is affecting actors and content creators, where then you have other actors who spend years toiling on working their craft and perfecting what it is they do, and they’re losing jobs to people like that guy, or to people like Bella Thorne, or whatever. ", "Who are these people? ", "They’re who’s. ", "I sound like such an asshole because I’m sure they’re nice people and I’m sure they’re very talented, but I wouldn’t put money on them if I was in a position of power. ", "I would never invest in those people. ", "There’s not enough there. ", "Not to say Bella Thorne couldn’t be a fantastic actress or that she’s not tremendously talented, but there’s not been enough investigation. ", "There’s not enough of a commitment. ", "And I just wouldn’t feel comfortable if I was the one investing money in someone like that. ", "If you put her and someone like Tat Maslany side by side — so, you’ve got $13 million, who do you want to invest in? ", "I’m going to invest in the other girl.", "\n\nHave you taken a chance to reflect on what the past five years have meant to you?I’m 27 and I started this when I was 22. ", "Your 20s are already this wildly formative decade where you meet yourself. ", "You meet yourself for the first time, whether it’s in relationships or in the workplace or just as a person — it’s an opportunity to really come to grips with who you are. ", "All of your character flaws and the parts of yourself that you’re resistant to admit are there. ", "I’ve learned so much about myself through the character. ", "I’d never really explored my femininity before Felix. ", "I mean, I had a sense of it. ", "I grew up with two older sisters and my mom is awesome and was very present, and I think one of the biggest things I learned was that I need to carry what I’ve learned about femininity with me to other characters that don’t walk or talk like Felix. ", "In the same way that we’re celebrating women playing characters that have a lot of masculine qualities, I think we need to start also celebrating and writing more characters that are much the same. ", "I’ve [learned] so much about my activism and my sexuality … probably in another life if I wasn’t actor, I’d be working for the ACLU. ", "Especially now.", "\n\nIt’s a scary thing to have to own who you are publicly. ", "I think that’s largely why I waited. ", "I always kind of knew if somebody asked I would starttalking.", "\n\nWhat is your sexual orientation?Oh, I’m gay.", "\n\nI wasn’t sure. ", "Nobody ever asks me. ", "I’ve never been asked. ", "Like, the whole course of the series.", "\n\nI guess that’s where I’m at in terms of coming out publicly: I had this position when I started on the show that it shouldn’t matter. ", "And I believe that. ", "I hope that one day, the world gets to a place where you don’t need to politicize your sexuality any more than someone needs to politicize their race — that we can just act and we can exist in this Zeitgeist, telling stories about one another. ", "And that no one’s afraid, maybe, to come out. ", "But also that no one’s really hyperobsessed with knowing whether or not someone’s gay. ", "That would be an amazing world to live in, where people don’t feel the need to protect themselves and other people don’t feel the need to launch an inquisition.", "\n\nWell, there’s also a real fear of losing work. ", "I was talking to Noah Galvin, who was the star of The Real O’ Neals …Oh, yeah! ", "Noah, I don’t know him. ", "But after reading the article, I looked at my partner, and I just said, “He’s very young and he does not understand.” ", "His paradigm will shift as he gets older, and he’s a very smart kid. ", "He’s hyperintelligent. ", "But what struck me the most and what was troublesome about his interview was the amount of cynicism. ", "That made me nervous because I don’t often see that from young people, myself included, as a young person. ", "I am full of optimism. ", "The world hasn’t beaten it out of me yet. ", "And I’m going to work very hard to make sure that they don’t. ", "But I just saw tremendous cynicism in him. ", "Just struck me as very odd. ", "And I hope he realizes now why what he said was a problem. ", "Which, I don’t know if he does.", "\n\nDo you think you’ll have fewer job opportunities as an openly gay actor?Ultimately, the answer is probably yes. ", "This is a tricky thing to say and I’ve never actually said it out loud before, but I do believe that jobs will be lost and I do believe jobs will be gained. ", "Maybe not even for the right reasons. ", "There’s been a lot of conversation in the industry about hiring openly gay actors for gay parts, and I think that’s really important. ", "But frankly, I’m not interested in doing any kind of work where I couldn’t bring myself in totality to the character. ", "And if that would mean that I am ultimately not the right fit in terms of casting, then I probably shouldn’t play that part anyways. ", "That’s not to say that’s an open license to discriminate against openly gay actors. ", "There’s a big distinction. ", "It’s just that if whatever somebody sees as gayness, whether it’s femininity or hypersexuality or whatever they’ve decided constitutes being gay — if those parts are not right for their character, chances are I don’t want to work with those people and I probably don’t want to play that character. ", "I’m much more interested in playing characters, even hetero characters, where I can bring all of myself. ", "All of my sexuality. ", "Everything I’ve learned about my own femininity and my own gender fluidity, I’d be interested in playing characters that explore that. ", "And I think we’re going to start seeing more of them.", "\n\nI just read for an attorney this morning. ", "He’s not a gay man. ", "There’s no reason I can’t play this person, being a gay man, in that our experiences are not dissimilar. ", "And all it means is that I’m bringing everything I know about being oppressed, being an outsider, being an alien, feeling weird about myself. ", "I’m bringing all of that to this other character and reappropriating it. ", "We’ve created this association between femininity and being gay and it’s not real. ", "It’s just a loose, ridiculous association. ", "It has nothing to do with anything.", "\n\nIn general in our culture, feminine men have been villainized.", "Yeah, and it’s so stupid because it’s actually misogyny. ", "It’s not even about femininity and men, it’s about the idea that men hate women so much.", "\n\nYou can see that in the gay community too.", "Oh my god. ", "No femmes, masc-only. ", "Give me a fucking break. ", "And it is frustrating because I’m someone who spends a lot of time thinking about these things. ", "I actively investigate them; it’s part of my job if I want to understand people. ", "I know you; I understand what’s going on right now. ", "I understand what’s happening while your arms are crossed. ", "I know what you’re actually feeling. ", "I know what you’re doing right now. ", "Very aware.", "\n\nWhat am I doing right now?Let’s see. ", "There’s some manipulation happening. ", "There’s some excitement brewing. ", "There’s some fodderfor a really great interview that maybe I’m not even aware of, but I probably am aware of it and that’s why I’m saying it. ", "You’re protecting yourself with your arms crossed right now. ", "If you uncross your arms and then kind of sit, it’s scarier, because then you’re immediately more open. ", "And it’s weird because as soon as I got more excitable and aggressive, the arms got crossed because that’s just a natural thing to do. ", "Needless to say, I’m aware of all this stuff in myself, therefore, I’m aware of it in other people. ", "How did I get started on this? ", "What was your question? ", "Fuck.", "\n\nI think originally we were talking about misogyny.", "Oh, women, that’s right. ", "And I don’t want to say that all men hate women; I don’t think all men hate women. ", "But I think that we have a culturally systemic subjugation of feminine attributes. ", "And those things are being emotional, being vulnerable, and as a result, you see with a lot of actors in leading parts, there’s an addiction to cool. ", "There’s an addiction to a facsimile of maleness, of masculinity: I’m unaffected by things. ", "I’m not an emotional person. ", "I don’t have to be vulnerable. ", "I’m cool and collected and suave and I do this thing and it wins me Oscars. ", "And it’s a problem because there’s so much more there. ", "Andit’s not real. ", "They’re aspiring to a set of attributes that doesn’t really exist. ", "And that, I take issue with. ", "It’s a problem.", "\n\nRelated Stories\n\nWhat I like about Orphan Black is that it’s about female relationships and all of their complications: They can be contentious, beautiful, aggressive, loving, nurturing. ", "It reminds me of the Elena Ferrante Neapolitan novels.", "Women have always been incredible. ", "They’ve always been amazing. ", "For thousands of years, people have written about these iconic and powerful women. ", "In polytheism, they had goddesses that represented all the different sides of women, like these weren’t just secretaries or moms. ", "These were women who, for all intents and purposes, had a lot of male attributes. ", "Thousands and thousands of years ago. ", "These were icons for women to look to for spiritual guidance in terms of how to investigate and develop themselves. ", "And I think women are having a moment right now, because a bunch of men noticed in the last 20 years that women are interesting and incredible. ", "And I think that’s something that working on this show and working with Tat and watching these women develop as characters, it’s showing me, Oh yeah, women have always been great.", "\n\nWhile shooting the show, were you worried about how your butt looked?Yeah, I’m a human person. ", "I was of course worried about how my butt looked. ", "I was very vain. ", "I grew up always feeling a bit like an alien. ", "Not just because I was gay, although I’m sure that played a part. ", "I just always felt like a weirdo. ", "I was an artist and my dad’s an immigrant. ", "He came from Greece. ", "I had a bit of second-class-citizen syndrome happening by way of inheritance. ", "And it was my own doing. ", "I could’ve stopped that, but I wasn’t in a place that, at 15 or 16, to know how to get out of myself or get out of my head or get out of my ego. ", "So, yeah, I was self-conscious and I think I was just worried about being told my butt was ugly. ", "And that I was ugly by consequence — I was ugly and I was unworthy and people wouldn’t like me. ", "And that I had to have a nice, pert butt in order to be liked by people, which is just not true. ", "And I did realize that after shooting, and it was a great lesson for me. ", "Like, you’re not going to win more love just because your butt looks better than somebody else’s, and if you do win more love because your butt looks better than somebody else’s, it’s not real. ", "It’s not real love.", "But it’s seductive love. ", "It’s very seductive, that kind of attention.", "\n\nYou’re not going to win more love just because your butt looks better than somebodyelse’s.", "\n\nIt is seductive. ", "It has power that people recognize that you can turn into value.", "Yes. ", "There’s a currency there that you can trade in. ", "And ultimately, I think many people are faced with that quandary at some point in their career. ", "Especially the people that are born just with the natural biology that lends itself to that. ", "And they can make the decision to trade in that currency or not. ", "I’m glad I look the way I do. ", "I look like a normal person.", "\n\nMm, you’re an actor.", "I mean I’m glad my features are just slightly asymmetrical. ", "Maybe I will be faced with that one day. ", "Maybe I’ve already been at that intersection, but knowing that the attention and value that you can get from that is just not something that I’m interested in. ", "I want the other thing: I’d like to be valued just because I work hard at what I do and I can maybe even move people. ", "That would be incredible.", "\n\nNew York, June 2017\n\nGavaris in Orphan Black.", "Photo: Orphan Black IV Productions Limited\n\nSo where did we leave off? ", "That particular day I was very excitable, I don’t know why. ", "Most of the journalists that cover the show are, not paint by numbers necessarily, but they have a list of questions, and they just ask those questions. ", "I get asked the same thing about 20 times, so I think I was surprised by you.", "\n\nIs that a compliment? ", "Absolutely. ", "I was surprised by your candor and your intelligence. ", "You’re challenging, and I really like that. ", "Do you find that in journalism you like to have conversations instead of …?", "\n\nYes. ", "I’m assuming that you get to know the person. ", "Does that affect your portrait of them?", "\n\nCertainly. ", "I try to be the best listener I can be. ", "Generally, I have the great fortune of talking to people I think are actually interesting. ", "And my goal is to get into it with them, whether it’s about craft or politics or biography. ", "And you enjoy challenging them too, right?", "\n\nYeah. ", "And have you ever come up against someone obstinate, or someone who’s offended by your prescription?", "\n\nI try to be diplomatic. ", "Disagreeing with someone shouldn’t be seen as a bad thing, but it generally doesn’t happen in this dynamic.", "Yeah, I do this all the time in interviews — I’ll be less aggressive, I’ll be less confrontational, I’ll be less of a son of a bitch. ", "Not that I’m a son of a bitch all the time. ", "I’ve been thinking about this a lot, the difference between kindness and niceness. ", "Because to be kind, it’s a very authentic thing, it’s very genuine to be kind, and I’ve come across a lot of very kind people who are not nice at all. ", "They’re passionate, they’re outspoken, they’re firm, they’re fiery — sometimes off-putting — but very kind. ", "I’ve encountered a lot of nice people who I mistook to be kind, and then was disappointed in the long run. ", "I feel like that’s a journey pretty typical of anybody in any industry. ", "And maybe just something that’s very typical of being in your 20s and starting to delineate the true types of people.", "\n\nDo you have an Instagram? ", "No. ", "I have Twitter, and everything I put out there on Twitter is public. ", "I don’t hide anything. ", "I don’t intend to hide anything. ", "I’m comfortable with everybody going back and seeing what I’ve written to people, and I’ve written some pretty inflammatory things.", "\n\nI see that you get into it.", "I do. ", "And sometimes, I’ll be in a particular mood, and someone will say something I normally don’t reply to, but there will just be something that really grinds my gears. ", "Especially when the contrary argument is so obvious. ", "But what I’ve come to realize is that a lot of these people really do believe what they’re writing. ", "I think I was in disbelief of that. ", "That’s part of why the election in the United States rattled me as much as it did, because it shattered my world. ", "I knew racism existed, I knew homophobia existed, and I thought it was probably bad in towns no one had heard of in the middle of nowhere. ", "I had no idea to the extent that it existed all over the United States — California included. ", "I was quite shattered, actually.", "\n\nI wasn’t expecting when you asked me that day in that interview, I had no idea, I wasn’t expecting to have to answer that question.", "\n\nWhether you were gay or not?Yeah, whether I was gay or not. ", "I’ve had opportunities to talk about it before, and I said nobody has ever asked me. ", "There was one journalist in a radio interview in the second year of Orphan Black who asked me. ", "I knew why he was asking. ", "I knew he just wanted a sound bite, and I thought it was really unfair. ", "I evaded and that was the only time I had ever done that. ", "I didn’t say no. ", "I just said I didn’t want to talk about that. ", "I felt bad afterward, not for him — I couldn’t give a shit about him. ", "I felt bad because I thought, “I had an opportunity and I didn’t take it.” ", "It wasn’t the right time. ", "I look at myself at 22, when I first started doing this show and I first started playing this character.", "\n\nI came out at 19, and my family knew I had been out in the industry always. ", "I have never hidden anything. ", "I think about what I knew at 22 versus what I know now and how aware I am of how little I know. ", "I don’t know very much. ", "I just think 22 is not old enough to start talking — not unless you’re some savant. ", "I would have regretted some of the things I would have said. ", "I was too much of a totalitarian. ", "I didn’t have enough experiences with other people. ", "I wanted to make sure that I would represent well and I would say something thoughtful.", "\n\nI’m sure on a deeper level I was just scared. ", "I think one of the scariest things to do is to stand up publicly and to say, This is who I am. ", "Probably no one is even going to care or think about it. ", "Maybe half the people already assume I am and the other half couldn’t give a shit. ", "It’s just me; it’s not about other people. ", "It’s just a scary thing to have to own who you are publicly. ", "I think that’s largely why I waited. ", "I always kind of knew if somebody asked I would start talking. ", "I was comfortable with you, and obviously I knew a bit of your background. ", "I just think right now it’s time for myself. ", "I wouldn’t make that decision for anyone else.", "\n\nWhat was coming out to your family like for you?Scary. ", "My mom and dad are wonderful. ", "We grew up nonreligious. ", "We grew up just outside of Toronto, right on the cusp of this suburban pocket, Brampton. ", "I knew gay kids in school. ", "I went to an arts high school. ", "I don’t think it was until university that I even started to feel comfortable with myself enough to tell my parents. ", "I didn’t fear I was going to be kicked out of the house. ", "I didn’t worry about strange questions. ", "It was emotional and awkward. ", "It’s like confessing to them that you want to be romantic and have sex with other people. ", "There’s the sexual component. ", "There’s the romance component. ", "It’s a vulnerable thing to confess this to your parents. ", "At 19, I thought it was gross. ", "I was like, “Oh my god, this is gross. ", "I have to tell them this thing and now they’re going to know that I’m interested in these guys and I want to date these guys and I want to sleep with these guys. ", "This is so weird. ", "Now they know I’m sexually active.” ", "There’s this whole other thing that comes into play that makes it awkward no matter how nonjudgmental or liberal or supportive your parents are, and mine were and are very supportive. ", "They love Devon [Graye], my partner. ", "They acclimate very quickly and it becomes the new normal. ", "It just was never a question. ", "I never doubted my parents love for me, and I never doubted that there was anything I could do short of something truly heinous or criminal that would ever cost me their love. ", "But [it was] still awkward. ", "I’m sure it was just awkward for everybody.", "\n\nHow did you and Devon meet?We actually kind of met on Twitter. ", "He was a friend of Tatiana Maslany’s. ", "They had worked on a show together years ago. ", "He wrote her something and I saw it and attached was a photograph of himself. ", "I started stalking a little bit and I was like, “I think I have to know this guy.” ", "I wrote him some cheesy line over Twitter. ", "Thank god he found it funny because he wrote me back and we started messaging. ", "We organized a time when I was in L.A. to get together, and I was 45 minutes late and he waited. ", "I got to Intelligentsia in Silver Lake and we started talking, and within about ten minutes I was like, “Oh boy.” ", "I was half seeing somebody else at the time, just casually, and I had to break that off after our first coffee date. ", "Then the next morning we met up before I went to the airport, and we only had an hour to talk on that coffee date, and it felt like no time. ", "We talked and talked and talked and talked about life and family and relationships. ", "He was just so thoughtful and challenging. ", "Then I left on my plane to go back home because I had to work. ", "I was just starting the second season of the show. ", "We talked every day, and he sent me a gift on my birthday a week later, and then I think we were exclusive a week from when we met. ", "We did a lot of it long distance. ", "Skype saved us. ", "Then I moved to L.A. as soon as the second season of the show wrapped and I got an apartment. ", "This September will be four years.", "\n\nSince it’s been awhile since we first talked, have you thought about the impact that your official “coming out” might have?Yes. ", "Then of course, my brain comes in and says, “Well aren’t you arrogant for thinking it would have any impact.” ", "The worst part of me is angered that I could be arrogant enough for thinking anybody is paying attention, but then the better part of me knows, “Yeah, but there are people paying attention.” ", "Maybe I wouldn’t have the same impact as someone like Colton Haynes or Gus Kenworthy or something. ", "But even one person who feels more comfortable, who sees themselves represented in some way — that just started to be more important than protecting myself. ", "Of course, there’s the selfish liberation as well. ", "You always feel like, “Now I feel like I can really talk about all of the things that I want to talk about in terms of gay rights and politics.”", "\n\nI’ve shared more with Tat as Sarah and me as Felix than I have as Jordan and Tat. ", "It’s a strange thing to feel like your relationship with somebody exists in an ether, anotherworld.", "\n\nDid you have a conversation with your professional team?I did. ", "I talked to them all and they were nothing but supportive. ", "I have a really amazing team. ", "Again, I had the incredible fortune of accidentally falling in with people that were really encouraging of me being my authentic self. ", "There was no emphasis on how to make myself a product or brand. ", "Ultimately, it’s entirely inconsequential. ", "When I go to love my scene partner onscreen, I bring what I know about loving my partner — it doesn’t matter if it’s a man or a woman at all. ", "If it were true that gay men have no chemistry with women, we would have been in trouble in Hollywood a long time ago.", "\n\nRock Hudson wouldn’t have had a career.", "Precisely. ", "I’m pretty sure that those people have obliterated this illusion. ", "I truly believe that the smart people know that that isn’t the case. ", "I think the concern is maybe in this idea of not being able to sell movie tickets. ", "I think it’s probably a financial decision, which, you know, okay.", "\n\nWhat do you think of the state of LGBT representation on TV?I think we are still stuck and preoccupied with legitimizing being gay on television, or legitimizing gay couples. ", "There’s still a lot of coming-out stories. ", "There’s still a lot about a struggle with what it means to be gay in a homophobic world. ", "There’s nothing wrong with those stories. ", "I love those stories, but we need other stories, too. ", "I appreciate shows like Looking that examine nontraditionalism, like polyamory, open relationships, because that is a cross-section of the gay community. ", "I’m really interested in stories, like mysteries, for example, with gay protagonists. ", "Why not? ", "Their preoccupation is not with their coming out. ", "The story is not about their sexuality. ", "London Spy touched on it, which I really loved, regardless of whether or not the show was good. ", "My partner and I started talking — I was offered a show after Orphan Black was over. ", "It was a comedy. ", "They’d been given $13 million to do this comedy. [", "Editor’s note: Gavaris clarified that this is not the same $13 million TV series he mentioned earlier in the conversation.] ", "It just wasn’t my cup of tea. ", "I didn’t understand the writing, and it was a lot of money for a comedy. ", "I just looked at Dev and said, “This is crazy that they’ve given someone $13 million to write this. ", "Maybe it will find an audience, maybe someone will think this is great. ", "I think this is boring television.”", "\n\nWhat was the character?He was gay, and he was coming home to his family and reintegrating himself into his family unit, and they’re all a bit dysfunctional. ", "I felt like the characters weren’t developed enough. ", "I felt like they need another year in the incubator. ", "I knew there was something there and that’s what intrigued me, but ultimately I just thought, “No. ", "I can’t do this. ", "It’s not there yet. ", "If it goes to camera as is, I fear it’s going to be really bad.” ", "I wished then all the best. ", "Maybe it improved in development.", "\n\nTo return to Orphan Black, what was the last day on set like? ", "Weird. ", "I don’t really know how I felt. ", "I didn’t cry. ", "I think I cried a few times before that at different moments. ", "I’d just get teary-eyed and kind of wistful. ", "It was out of body really. ", "I don’t think I really absorbed what was going on until later. ", "You go through the five stages of grief because these characters become very real. ", "It’s strange because the relationships with these actors that I’ve formed over the last five years have been through the conduit of the character. ", "I know them more intimately and we’ve shared more intimate things as our characters. ", "I’ve shared more with Tat as Sarah and me as Felix than I have as Jordan and Tat. ", "It’s a strange thing to feel like your relationship with somebody exists almost in an ether, another world. ", "And then you get to know each other outside of these characters when it’s all over. ", "That has been a strange, discombobulating process. ", "As a character, you share so much of yourself, and then I feel the reflex to close, or sometimes to disconnect. ", "It’s not anything I’m going to do, but it’s interesting. ", "I’ve clocked it and been like, that’s interesting, that I want to protect myself from being known as Jordan to this group of people when I’ve spent so long being known as this character.", "\n\nAre you wary of being known as Jordan to a wider public? ", "Yeah, I am. ", "Not for any crazy reason, other than I’m not everybody’s cup of tea. ", "There’s the fear of, if I show you who I am, inevitably, some people are not going to like it. ", "There’s this fear of being confronted with the fact that not everybody likes me, which I already know, intellectually, is not real. ", "Of course not everybody likes me. ", "To think anything other than that would be completely asinine — but being confronted with the reality of that is scary." ]

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[ "Q:\n\nJava UTF-8 encoding not set to URLConnection\n\nI'm trying to retrieve data from http://api.freebase.com/api/trans/raw/m/0h47\nAs you can see in text there are sings like this: /ælˈdʒɪəriə/.\nWhen I try to get source from the page I get text with sings like &#250; etc.", "\nSo far I've tried with the following code:\nurlConnection.setRequestProperty(\"Accept-Charset\", \"UTF-8\");\nurlConnection.setRequestProperty(\"Content-Type\", \"application/x-www-form-urlencoded;charset=utf-8\");\n\nWhat am I doing wrong?", "\nMy entire code:\nURL url = null;\nURLConnection urlConn = null;\nDataInputStream input = null;\ntry {\nurl = new URL(\"http://api.freebase.com/api/trans/raw/m/0h47\");\n} catch (MalformedURLException e) {e.printStackTrace();}\n\ntry {\n urlConn = url.openConnection(); \n} catch (IOException e) { e.printStackTrace(); }\nurlConn.setRequestProperty(\"Accept-Charset\", \"UTF-8\");\nurlConn.setRequestProperty(\"Content-Type\", \"text/plain; charset=utf-8\");\n\nurlConn.setDoInput(true);\nurlConn.setUseCaches(false);\n\nStringBuffer strBseznam = new StringBuffer();\nif (strBseznam.length() > 0)\n strBseznam.deleteCharAt(strBseznam.length() - 1);\n\ntry {\n input = new DataInputStream(urlConn.getInputStream()); \n} catch (IOException e) { e.printStackTrace(); }\nString str = \"\";\nStringBuffer strB = new StringBuffer();\nstrB.setLength(0);\ntry {\n while (null !", "= ((str = input.readLine()))) \n {\n strB.append(str); \n }\n input.close();\n} catch (IOException e) { e.printStackTrace(); }\n\nA:\n\nThe HTML page is in UTF-8, and could use arabic characters and such. ", "But those characters above Unicode 127 are still encoded as numeric entities like &#250;. ", "An Accept-Encoding will not, help, and loading as UTF-8 is entirely right.", "\nYou have to decode the entities yourself. ", "Something like:\nString decodeNumericEntities(String s) {\n StringBuffer sb = new StringBuffer();\n Matcher m = Pattern.compile(\"\\\\&#(\\\\d+);\").matcher(s);\n while (m.find()) {\n int uc = Integer.parseInt(m.group(1));\n m.appendReplacement(sb, \"\");\n sb.appendCodepoint(uc);\n }\n m.appendTail(sb);\n return sb.toString();\n}\n\nBy the way those entities could stem from processed HTML forms, so on the editing side of the web app.", "\n\nAfter code in question:\nI have replaced DataInputStream with a (Buffered)Reader for text. ", "InputStreams read binary data, bytes; Readers text, Strings. ", "An InputStreamReader has as parameter an InputStream and an encoding, and returns a Reader.", "\ntry {\n BufferedReader input = new BufferedReader(\n new InputStreamReader(urlConn.getInputStream(), \"UTF-8\")); \n StringBuilder strB = new StringBuilder();\n String str;\n while (null !", "= (str = input.readLine())) {\n strB.append(str).append(\"\\r\\n\"); \n }\n input.close();\n} catch (IOException e) {\n e.printStackTrace();\n}\n\nA:\n\nTry adding also the user agent to your URLConnection:\nurlConnection.setRequestProperty(\"User-Agent\", \"Mozilla/5.0 (Macintosh; Intel Mac OS X 10_10_3) AppleWebKit/537.36 (KHTML, like Gecko) Chrome/44.0.2403.155 Safari/537.36\");\n\nThis solved my decoding problem like a charm.", "\n\n" ]

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[ "Unfortunately, I wasn’t able to find the version 2.0 of this model so i bought this one. ", "Actually the kit is good but it’s a little bit hard to make it stand. ", "Maybe because of the bulky rocket boosters attached on the legs.", "\n\nI repainted it first with RED and painted the shoulder horns with yellow.", "\n\nAfter a day of drying, i started to weather it using buds. ", "Dipping it on thinner and black paint and scrubbed it on the whole figure." ]

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[ "Technology insight: MammoSite--a new device for delivering brachytherapy following breast-conserving therapy.", "\nThe MammoSite (Cytyc Corporation, Marlborough, MA) breast brachytherapy applicator was designed to overcome the logistic problems created by external-beam radiation therapy (EBRT) and the technical difficulties associated with multicatheter-based interstitial brachytherapy. ", "The MammoSite catheter has been shown to treat a volume of tissue equivalent to that treated by multicatheter-based brachytherapy. ", "Using ultrasound guidance, the MammoSite applicator can be placed using an open technique at the time of lumpectomy or post-lumpectomy. ", "Initial results have shown favorable cosmesis and few significant side effects. ", "NSABP B-39/RTOG 0413 randomizes patients between EBRT and partial-breast irradiation (PBI). ", "The PBI arm consists of interstitial brachytherapy, MammoSite brachytherapy, or 3D conformal EBRT. ", "This trial has the potential to provide a definitive answer regarding the benefits of PBI for certain subgroups of patients, and hence lead to more women undergoing breast conservation therapy." ]

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[ "by BRIAN NADIG\n\nSaint Tarcissus, Saint Cornelius and Saint Thecla parishes reportedly would be combined into one parish beginning July 1, 2020, under the Archdiocese of Chicago’s “Renew My Church” initiative, according to Aug. 18 parish bulletins.", "\n\nThe archdiocese is planning to list possible scenarios for the future of the three parishes in their Aug. 18 bulletins and to hold meetings with each parish in August. ", "The archdiocese is taking feedback from the discernment team at each parish and plans to announce a final consolidation plan for the parishes in November.", "\n\nSaint Tarcissus Church, 6020 W. Ardmore Ave. (", "Photo by Kevin Gross)\n\nUnder the merger plan it is possible that worship services would continue at all three church sites. ", "However, the archdiocese also is considering scenarios in which services would be held at only one or two of the churches, essentially leading to the closing of one or two of the parish campuses.", "\n\nA new name reportedly would be chosen for the combined parish, but the existing church buildings on each campus could retain their current parish name.", "\n\nIt also is possible that a ministry could operate out of a closed campus or a portion of the site could be leased or sold. ", "The Chicago Public Schools has been looking at converting the former Saint Cornelius School, 5252 N. Long Ave., ", "into an early education center, but the project has been delayed for several years.", "\n\nThe plan also reportedly would impact Saint Thecla School, 6323 N. Newcastle Ave., ", "and the north campus of Pope Francis Global Academy, which is located inside the former Saint Tarcissus School, 6040 W. Ardmore Ave. ", "It is believed that they would be merged into one school and be operated by the new combined parish.", "\n\nSaint Thecla Church, 6323 N. Newcastle Ave. (", "Photo by Kevin Gross)\n\nThe school could be split over two campuses, Saint Thecla and Saint Tarcissus, but each campus would house different grades. ", "The other scenario reportedly calls for operating the school on just one of the campuses.", "\n\nThe Pope Francis academy’s south campus, which is located inside the former Saint Pascal School at 6143 W. Irving Road, would not be part of the merger plan. ", "The Saint Pascal Parish is in a different “Renew My Church” grouping which could go through the process next year.", "\n\nIn 2017, the archdiocese announced a series of groupings for Chicago parishes, which were encouraged to share resources in an effort to make each parish more sustainable.", "\n\n\n\n\n\n\n\n\n\nAt the time former Saint Tarcissus pastor Mike Solazzo, wrote in a parish bulletin: “We all see a decrease in priest personnel, contributions and volunteers. ", "All of our parishes are aging, and younger families and individuals are less visible in parish life, including Sunday worship.", "\n\n“This is a phenomenon happening all across the archdiocese, and I suspect across the country. ", "The increasing secularization of our society is a reality we live with. ", "Yet we must find a way to counteract it.”", "\n\nThe archdiocese reportedly takes into consideration several key factors when deciding whether to consolidate parishes, including worship attendance, a parish’s operating income and any deferred debt.", "\n\nSaint Cornelius Church, 5430 W. Foster Ave. (", "Photo by Kevin Gross)\n\nThe number of people attending Mass on weekends at Saint Cornelius, Saint Tarcissus and Saint Thecla reportedly is closer to 700 at each location, below the 800-benchmark set by the archdiocese.", "\n\n“Renew My Church” meetings are scheduled for 10:45 a.m. Sunday, Aug. 18, and 7 p.m. Monday, Aug. 19, at Saint Thecla Church, 6725 W. Devon Ave., ", "6:30 p.m. Monday, Aug. 19, at Saint Cornelius Church, 5430 W. Foster Ave., ", "and 7 p.m. Tuesday, Aug. 27, at Saint Tarcissus Church, 6020 W. Ardmore Ave.", "\n\n“One initiative of ‘Renew My Church’ is focused on increasing the vitality of our local communities. ", "Cardinal (Blasé) Cupich has asked our parish to come together with the other parishes in our grouping … to start a process of reflection, discernment and planning to consider how we can collaborate and combine resources so that we are better equipped to bring Jesus Christ to the world today,” the meeting announcement in the Saint Tarcissus newsletter said." ]

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[ "15.10.12 Photograph Jamie Forbes. ", "East Dunbartonshire Council Headquarters 12 Strathkelvin Place Kirkintilloch G66 1TJ\n\nThe administration formed as a result of the SNP becoming the single biggest party after May’s local elections, with seven councillors.", "\n\nBut the LibDem and Tory groups, who have six councillors apiece, have consistently voted down the administration.", "\n\nThis happened again last month when councillors voted to cut the maximum added years for pensionable employees from 10 to three, reduce the maximum discretionary payments from 66 weeks to 30, and introduce a maximum payback period of two years.", "\n\nOn November 9, Liberal Democrat and Tory councillors voted to defeat the SNP administration and Labour councillors to cut the terms of the council’s voluntary severance arrangements.", "\n\nIt instructs management to issue 90-day notices next March to all staff who do not agree to the changes voluntarily, terminating their current contracts and re-engaging them on the new terms and conditions.", "\n\nUnions condemned the move, while the ruling minority SNP administration accused the Tories and Lib Dems of treating council employees with “abject contempt” by announcing the decision ahead of consulting the workforce.", "\n\nLast night, the SNP made a last-ditch bid to have the decision taken by the LibDem and Conservative groups in November set aside. ", "But this was rejected by 12 votes to nine - with one Labour councillor and Independabt voting with the SNP. ", "One other Labour councillor is on paternity leave.", "\n\nNow the SNP have resigned en masse in protest following a stormy meeting at council HQ last night and leaves East Dunbartonshire without a governing party.", "\n\nIn a resignation letter former SNP council leader Councillor Gordon Low, said: “With a majority of 12 out of 22 councillors, the two main opposition groups have always had it in their own hands to choose how to exercise that majority." ]

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[ "Q:\n\nHow to enable Windows Authentication in AspNetCore SignalR Alpha\n\nHow do I configure SignalR to Authenticate/Authorize to a server that is must be protected by Windows Authentication. ", " There appears to be no way to make the JavaScript Client send Credentials with the request.", "\n\nA:\n\nWindows authentication should be handled by the browser and you should not have to do anything special. ", "The problem is that Chrome does not seem to handle Windows Authentication correctly. ", "There is a thread on github that contains more details.", "\nAlso, SignalR MVC 5 Websocket no valid Credentials seems still to apply as the issue is browser related (i.e. external to SignalR).", "\n\n" ]

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[ "The correlation of T1 bladder tumour history with prognosis and follow-up requirements.", "\nThe histories of 332 T1 bladder cancer patients were studied to determine the natural history in this tumour population. ", "Each was followed for at least 5 years or to earlier tumour death and the approach to treatment was conservative. ", "Patients were potentially at serious risk of disease progression and death if they presented with tumours of G2 or G3 grade and grew new ones again after treatment or if they exhibited a continuous high level of tumor neogenesis. ", "Fourteen developed urothelial tumours beyond the bladder, evidence of widespread urothelial instability. ", "Tumour deaths accounted for only 12% of the series, justifying a conservative approach to treatment, and a further 25% died from unrelated causes. ", "Those remaining tumour-free at 5 years had a low malignant potential and their natural history supported discontinuing routine cystoscopy after that time." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "US leaves CAR amid security woes\n\nAFPA soldier ensures the security during a women's march in Bangui against the conflict in their country.", "\n\nBangui, Central African Republic -\n\nSecurity concerns deepened in the capital of Central African Republic on Friday after the US ambassador and his diplomatic team were evacuated out of the country by plane overnight amid fears rebels could try to take the capital.", "\n\nUS officials said about 40 people were evacuated on an US Air Force plane bound for Kenya. ", "The officials spoke on condition of anonymity because they weren't authorised to discuss the details of the operation.", "\n\nThe evacuation came after President Francois Bozize on Thursday urgently called on former colonial ruler France and other foreign powers to help his government fend off rebels who are quickly seizing territory and approaching the capital.", "\n\nThe UN's most powerful body condemned the recent violence and expressed concern about the developments.", "\n\n“The members of the Security Council reiterate their demand that the armed groups immediately cease hostilities, withdraw from captured cities and cease any further advance towards the city of Bangui,” the statement said.", "\n\nCentral African Republic has a history of violent change in government. ", "The current president himself came to power nearly a decade ago in the wake of a rebellion in this resource-rich yet deeply poor country.", "\n\nSpeaking to crowds in Bangui, a city of about 600 000, Bozize pleaded with foreign powers to do what they could. ", "He pointed in particular to France, Central African Republic's former colonial ruler. ", "About 200 French soldiers are already in the country, providing technical support and helping to train the local army, according to the French defence ministry.", "\n\n“France has the means to stop (the rebels) but unfortunately they have done nothing for us until now,” Bozize said.", "\n\nFrench President Francois Hollande said on Thursday that France wants to protect its interests in Central African Republic and not Bozize's government. ", "The comments came a day after dozens of protesters, angry about a lack of help against rebel forces, threw rocks at the French Embassy in Bangui and stole a French flag.", "\n\nParis is encouraging peace talks between the government and the rebels, with the French Foreign Ministry noting in a statement that negotiations are due to “begin shortly in Libreville (Gabon).” ", "But it was not immediately clear if any dates have been set for those talks.", "\n\nFrench Foreign Minister Laurent Fabius spoke via phone with Bozize, asking the president to take responsibility for the safety of French nationals and diplomatic missions in Central African Republic.", "\n\nBozize's government earlier reached out to longtime ally Chad, which pledged to send 2,000 troops to bolster Central African Republic's own forces.", "\n\nThis landlocked nation of about 4.4 million people has suffered decades of army revolts, coups and rebellions since gaining independence in 1960 and remains one of the poorest countries in the world.", "\n\nThe rebels behind the most recent instability signed a 2007 peace accord allowing them to join the regular army, but insurgent leaders say the deal wasn't fully implemented. ", "The rebel forces have seized at least 10 towns across the sparsely populated north of the country, and residents in the capital now fear the insurgents could attack at any time, despite assurances by rebel leaders that they are willing to engage in dialogue instead of attacking Bangui.", "\n\nThe rebels have claimed that their actions are justified in light of the “thirst for justice, for peace, for security and for economic development of the people of Central African Republic.”", "\n\nDespite Central African Republic's wealth of gold, diamonds, timber and uranium, the government remains perpetually cash-strapped. ", "Filip Hilgert, a researcher with Belgium-based International Peace Information Service, said rebel groups are unhappy because they feel the government doesn't invest in their areas.", "\n\n“The main thing they say is that the north of the country, and especially in their case the northeast, has always been neglected by the central government in all ways,” he said.", "\n\nThe rebels also are demanding that the government make payments to ex-combatants, suggesting that their motives may also be for personal financial gain. - ", "Sapa-AP\n\nComment Guidelines\n\nHas a comment offended you? ", "Hover your mouse over the comment and wait until a small triangle appears on the right-hand side. ", "Click triangle () and select \"Flag as inappropriate\". ", "Our moderators will take action if need be.", "\n\nVerified email addresses: All users on Independent Media news sites are now required to have a verified email address before being allowed to comment on articles. ", "You are only required to verify your email address once to have full access to commenting on articles. ", "For more information please read our comment guidelines" ]

{ "pile_set_name": "Pile-CC" }

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[ "Ukrainian quartet DakhaBrakha combine textured hand percussion, layered group vocals, and droning cello and accordion in a simultaneously minimalist and expansive approach they call \"ethno-chaos.\" ", "In their effort to reinterpret Ukrainian folk music with a host of other reference points—from African polyrhythms to Western pop music—DakhaBrakha come off as both stately and playful. ", "They play here at an installment of Central Park Sessions dubbed the \"Small World Session\": Also on the bill is New Orleans-based singer Sasha Masakowski and her band, and New Hampshire flamenco/gypsy-swing hybridizers Ameranouche. —", "Scott Gordon\n\nBetween his infectious garage-punk canon with The Spaceshits, his mighty multi-tasking as the BBQ half of the King Khan & BBQ Show, or just being a one-man garage-rock tour de force in his solo work, Montreal-based multi-instrumentalist Mark Sultan has been refining his dirty, bare-bones guitar-pop for over 25 years. ", "His latest BBQ EP, Mark Sultan, dropped in late 2015 and its four tunes are packed with the same infectiously nasty and highly influential pop-rock tunes that so many contemporaries take a crack at and can’t quite imitate. “", "The Other Two” rides on a few jangly chords and a stripped-down rhythm, as Sultan's melodically yearning vocals wail above. ", "Closing tune “Rock Me” touches on the charms of soulful doo-wop without the backing harmonies, as his mighty voice shakes and quivers convincingly through hook after hook. —", "Joel Shanahan\n\nBearing witness to a live performance from Pennsylvania-based percussion experimentalist Tatsuya Nakatani is brain-bending, to say the least. ", "We’re grateful that he keeps cruising through Madison, as we could never tire of Nakatani’s seemingly peerless expansion of both the traditional sonic and physical possibilities of a percussion performance. ", "He twists up elements of organic drone and free jazz into something totally pure, and leaves no corner of any piece in his arsenal of instruments unbowed, untapped, or un-battered. ", "The dynamics of every dimension in the avant-percussionist’s moves feel both entirely deliberate and completely spontaneous, as his limbs constantly work in a tasteful frenzy, with one foot working the kick drum, one hand bowing a gong, and the other hand both bowing and spinning an array of harmonizing singing bowls. ", "Cymbals are bent and slammed, as they sing and screech and are rubbed abrasively over the head of his tom drum, gongs growl and sing, and a floating and shape-shifting groove somehow keeps soaring through the backdrop. ", "It’s a constant conversation where every word means something—and you can hear more voices in one of Nakatani's performances than you probably would from an ensemble of synthesizers. —", "JS\n\nThe Madison Public Library's Bubbler program opens three new art shows and kicks off a new artist residency at this loosely but intriguingly themed event. ", "Artists Brandon Norsted, Kandy Watson, and Mackenzie Reynolds all explore memory and left-behind artifacts, from Reynolds's hauntingly modified family photos to Norsted's photos of cars in a junkyard. ", "During the evening, the Bubbler's newest artist-in-residence, Danika Brubaker, will lead attendees in an experiment incorporating found art and social media. —", "SG\n\nThe newest Madison ensemble to celebrate Brazilian music, Wolbaianos, will make their debut here with a performance of the album Acabou Chorare, released in 1972 by a band called Novos Baianos. ", "Followers of Brazilian music treasure the album for its rich weave of samba rhythms and its nods to contemporary styles of pop and psychedelic rock. ", "Fellow Madison outfit Metabaque offers another perspective on Brazilian music, combining the Afro-Brazilian maracatu genre with hip-hop rhythms. ", "Madison jazz sextet Lovely Socialite, while not explicitly focused on Latin music, are rangey, strange, and playful enough to fit in here. —", "SG\n\nThe Sugar Maple Traditional Music Festival generally tries to offer a window into American roots music—from Cajun music to bluegrass to ragtime—and highlight younger artists who are trying to keep the old-timey stuff relevant and lively. ", "It doesn't usually aim for the \"alternative country\" part of the spectrum, but Jay Farrar of Son Volt and Uncle Tupelo will be there in a trio format Saturday, performing songs from Son Volt's 1995 debut album, Trace. ", "Seems like a bit of an outlier, but based on videos and reviews from the trio's performances earlier this year, even more rocking numbers like \"Drown\" and \"Route\" will get a sparse treatment here, with just two guitars, pedal steel, and fiddle. ", "More typical of Sugar Maple will be Friday's set from young Nashville western-swing duo Music City Doughboys, and a Saturday set of traditional Cajun and Creole music from Jesse Legé, Ed Poullard and Charlie Terr. —", "SG\n\nIt's been a productive summer for Madison hip-hop, with campus-nurtured artists and young Madison natives releasing new albums and EPs and a respectable string of singles, and this show is as good an introduction as any. ", "Broadway, an MC studying in UW-Madison's First Wave program, has dropped two singles recently (\"StageFace\" and \"Make Me Rich\") that showcase her intricately structured and brilliantly slippery flows. ", "This is in preparation for a project she's said will come out sometime this summer, so we're hoping for some more solid new material in her set here. ", "Fellow First Waver Rich Robbins recently released an ambitious second album, and young Madisonians like Red and Trebino have been offering a grittier vision in their singles, while Charles Grant contributes a downtrodden but spirited voice in recent songs like \"Dope Man Guilt.\" ", "The lineup here is a varied and admirable effort to bring together hip-hop acts of different backgrounds and stylistic bents. ", "Their (relative) elder DJ Pain 1 will be presiding over it, after a year that's seen him collaborate with artists including Royce Da 5'9\" and Sole. —", "SG\n\nSay what you want about Def Leppard in all their cringe-worthy cheese, goofy hooks, and overall hair-metal bombast. ", "In their partnership with producer Mutt Lange, they wrote some of the most compelling, memorable, and sonically interesting pop tunes of the 1980s. ", "Some folks will only argue for the role they played in the New Wave Of British Heavy Metal and their work with ex-guitarist-vocalist Pete Willis, but this writer would rather argue for the era when tasteful guitar stylist Phil Collen joined the band and Rick Allen learned how to play a drumset with one fucking arm. ", "Seriously. ", "Just listen to “Animal,” from 1987’s Hysteria: Those gorgeous, chorus-laden guitars in the verses, the endearingly tinny guitar hooks in the chorus, and vocalist Joe Elliott’s swaggering hooks hold up. ", "Not to mention all the weird synth bits and atmospheric production of “Love Bites.” ", "Plus, there are all of those bizarrely reverberated electronic drum sounds that pummel throughout the album. ", "With the hits in particular, it’s tough to ignore the meticulous attention to detail that plays out in the tiniest sonic flourishes of not just the anthemic choruses and verses, but even in the tiniest corners of every intro and pre-chorus. ", "I mean, yeah, it’s still Def Leppard and there are probably moments in every tune that feel borderline embarrassing to listen to, but this somehow doesn’t really take away from how expertly crafted those tunes are on every level. —", "JS\n\nOnce a fixture in Madison's tiny but remarkable experimental scene, Chicago-based sound designer and synthesist Connor Camburn began crafting his distinctive and murky voice with the raw, pulsing railroad electronics of his former Slag Heap moniker. ", "As the years have passed, Camburn has further refined his bleak and distant vision in his work under the name Litüus. ", "On his latest EP, 19805.-_1990, which dropped in 2015 through avant-techno producer Shifted’s Avian imprint, Camburn zooms in on a series of unsettling pulses that linger in the air like a ghostly installation—relying more on subtle alterations and tweaks than traditional movement. ", "Every slight shift in the core synth patch for each piece—be it the filter, resonance, or delay—makes each gritty anti-tone slither through the listener’s skull a bit differently, The haunting stillness of Camburn’s tunes should provide the perfect counterpoint to the more immediate industrial-pop stylings of Hide, the other Chicago-based act on the bill. ", "Hide’s latest 12-inch —2015’s Flesh For The Living—offers a nostalgic nod to Wax Trax-era EBM, but strips away much of the kitsch in favor of something a bit more polished and sinister. ", "The title track barrels in with a hammering four-on-the-floor kick, as a pulsing, droning bassline stutters under ominous vocals of Heather Gabel. ", "Madison’s own psychedelic goth-pop voyager Samantha Glass will fill out the bill. —", "JS\n\nSpace Jam is that strange film that seems to exist in the limbo-like pop-cultural state of existence between “holding up” and “not holding up.” ", "It’s just barely insane enough to be worth rewatching, but it’s simply not a good enough film where the act of watching it is that much more enjoyable than simply contemplating the possibility of watching it. ", "Believe it or not, getting Michael Jordan involved in a basketball game alongside the Loony Tunes in space against a team of aliens who call themselves The Monstars requires more suspension of disbelief than most adults are able to muster. ", "Then again, maybe I’m just the grump raining on everyone’s parade. ", "For those of us with enough childlike sense of wonder to enjoy it with zero irony, I say go with God. ", "For everyone else, enjoy it for the 1996 time-capsule wild ride of an absurd train wreck that it is. —", "Chris Lay\n\nMinneapolis band Posh Lost make post-punk songs with a tasteful balance of Joy Division austerity and sleek, gloomy melody. ", "The band's recent self-titled EP stands out for guitarist Jeff Cornell's earnest (if very Ian Curtis-channeling) vocals and its sharp grasp of arrangements and dynamics: \"Impulse\" begins with a chugging, distorted bass line and martial drum pattern that hint at aggression, but instead the band deftly layers on soulful overdriven guitar leads and shimmering synth pads. ", "And for all those lush elements, Posh Lost retains a poignant sense of coldness and restraint. —", "SG\n\nOK, so there was that whole Jazzcat fiasco, but the annual Jazz At Five series deserves some credit here for managing to include a few of Madison's fresher jazz acts in its lineup. ", "One is Major Vistas, playing the 5 p.m. set at this installment. ", "The trio recently released its debut album, Minor Anthems, which finds guitarist Chris Bucheit, keyboard player Mike Weiser, and drummer Geoff Brady crafting surprisingly moody tunes informed by both pop structure and jazz improvisation. ", "Bucheit and Weiser talked with us about the album on a recent podcast. —", "SG\n\n&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;a href=\"http://majorvistas.bandcamp.com/album/minor-anthems-2\"&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;Minor Anthems by Major Vistas&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;/a&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;\n\nOn the 2015 full-length Never Were The Way She Was, violin artisan Sarah Neufeld and reed explorer Colin Stetson (who are both Arcade Fire collaborators) join forces for a series of enveloping compositions that flutter adeptly between the lushest highs and growling, discombobulating lows. ", "Album-opener “The Sun Roars Into View” never seems to stop ascending into the heavens, as whirling and colorful reed lines climb up columns of galloping violin work. ", "The duo traverse some serious Reich-ian territory on “In The Vespers,” as lightning-quick counter melodies between sax and violin bounce off each other wildly before dropping into a freefall of rippling, bowed notes and screeching drones. ", "The journey takes a couple of beautifully unexpected twists in the creepy, growling, (presumably) bass-clarinet-led trudge of “With The Dark Hug Of Time” and the asymmetrical groove of “The Rest Of Us.” ", "On the latter song, the rhythmic backbone seems to be processed by the externally mic’d and processed keys of Stetson’s sax, as Neufeld’s hypnotic bowing patterns circle overhead. —", "JS" ]

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[ "Recent structural insights into the expanding world of carbohydrate-active enzymes.", "\nEnzymes that catalyse the synthesis and breakdown of glycosidic bonds account for 1-3% of the proteins encoded by the genomes of most organisms. ", "At the current rate, over 12 000 glycosyltransferase and glycoside hydrolase open reading frames will appear during 2006. ", "Recent advances in the study of the structure and mechanism of these carbohydrate-active enzymes reveal that glycoside hydrolases continue to display a wide variety of scaffolds, whereas nucleotide-sugar-dependent glycosyltransferases tend to be grafted onto just two protein folds. ", "The past two years have seen significant advances, including the discovery of a novel NAD+-dependent glycosidase mechanism, the dissection of the reaction coordinate of sialidases and a better understanding of the expanding roles of auxiliary carbohydrate-binding domains." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "This study is a clinical trial of a multi-component telehealth intervention for informal caregivers of rural older adults, an understudied population thought to be at greater risk for negative physical and mental health outcomes. ", "The intervention, based on the Perceived Stress Model of Caregiver Burden (Chwalisz, 1996) will be administered by telephone and includes components targeted to caregiver knowledge (caregiver role/process, knowledge of services/resources, information about care-recipient's condition), skills (social problem solving skills), behavior (enhancing social interaction/support), and affect (cognitive-behavioral therapy to manage negative affect). ", "Two delivery mechanisms will be compared in a randomized controlled trial design: a 9-session structured telephone counseling intervention and a call-in help line (in which all treatment components are available but delivery is tailored to individual participants based on presenting concerns and assessed needs). ", "Treatment outcome data will be compared with outcome data from a \"service-as-usual\" control group. ", "It is hypothesized that caregivers who receive the telehealth services will have greater improvement in physical health (self-assessed health, health care service utilization), mental health (caregiver burden, symptoms of depression and anxiety), and psychosocial functioning (social support, interpersonal relationship conflict, social role functioning) than controls. ", "It is further hypothesized that caregivers who receive the entire treatment package will have better outcomes than help line participants, although there is a competing hypothesis that interventions tailored to caregivers' situations and need are more effective. ", "The variable use of the help line treatment condition will allow for tests of dose-effect, and perhaps dismantling, relationships. ", "Tracking help line usage, and comparisons between individuals who are referred for the intervention, but do not participate/dropout, will also provide information invaluable to developing services for rural caregivers. ", "Other notable methodological features include treatment manualization, training, and implementation tracking. ", "Specific treatment components (e.g., telehealth modality, culturally sensitive services/outreach, stakeholder involvement) have been designed in order to reach a more diverse group of caregivers, including caregivers who are underrepresented in research (e.g., racial/ethnic minorities, overburdened caregivers)." ]

{ "pile_set_name": "NIH ExPorter" }

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[ "1. ", "Field of the Invention\nThe present invention relates to a photoconductor for electrophotography, and particularly to a photoconductor for electrophotography which contains a novel azo or disazo compound in the photosensitive layer thereof formed on an electroconductive substrate.", "\n2. ", "Description of the Prior Art\nPhotosensitive materials which have heretofore been used in photoconductors for electrophotography include inorganic photoconductive substances such as selenium and selenium alloys, dispersions of inorganic photoconductive substances such as zinc oxide and cadmium sulfide in resin binders, organic polymeric photocondutive substances such as poly-N-vinylcarbazole and polyvinylanthracene, organic photoconductive substances such as phthalocyanine compounds and bisazo compounds, and dispersions of such organic polymeric photoconductive substances in resin binders.", "\nPhotoconductors are required to have the characteristics of maintaining a surface electric charge in the dark, generating an electric charge upon receiving light, and transporting an electric charge upon receiving light. ", "They are classified into two photoconductor types namely, so-called monolayer type photoconductors, and so-called laminate type photoconductors. ", "The former comprises a single layer having all of the above-mentioned three characteristics, and the latter comprises functionally distinguishable laminated layers, one of which contributes mainly to the generation of electric charge, and another of which contributes to the retention of surface electric charge in the dark and electric charge transportation upon receiving light. ", "An electrophotographic method using a photoconductor of the kind as mentioned above, is for example the Carlson's system and is applied to image formation. ", "The image formation according to this system comprises the steps of subjecting a photoconductor in the dark to corona discharge to charge the photoconductor, illuminating the surface of the charged photoconductor with imagewise light based on a manuscript or copy bearing, e.g., letters and/or pictures to form a latent electrostatic image, developing the formed latent electrostatic image with a toner, and transferring the developed toner image to a support such as a paper sheet to fix the toner image on the support. ", "After the toner image transfer, the photoconductor is subjected to the steps of removal of the electric charge, removal of the remaining toner (cleaning), neutralization of the residual charge with light (erasure), and so on to be ready for reuse.", "\nPhotosensitive members for electrophotography in which use is made of an organic material(s) have recently been put into practical use by virtue of the advantageous feature(s) of the organic material(s), such as flexibility, thermal stability, and/or a film forming capacity. ", "They include a photoconductor comprising poly-N-vinylcarbazole and 2,4,7-trinitrofluoren-9-one (disclosed in U.S. Pat. ", "No. ", "3,484,237), a photoconductor using an organic pigment as the main component (disclosed in Japanese Patent Laid-Open No. ", "37,543/1972), and a photoconductor using as the main component a eutectic complex composed of a dye and a resin (disclosed in Japanese Laid-Open Patent Application No. ", "10,785/1972). ", "A number of novel hydrazone compounds have also been put into practical use for photosensitive members.", "\nAlthough organic materials have a number of advantageous features mentioned above with which inorganic materials are not endowed, the fact is that there have been obtained no organic materials fully satisfying all the characteristics required of a material to be used in photoconductors for electrophotography at present. ", "Particular problems involved in organic materials have been concerned with photosensitivity and characteristics in continuous repeated use." ]

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[ "Q:\n\nWhat is the best name for true-tellers, liars and normals\n\nIn the world exists a lot of puzzles based on variations of true-tellers, liars and normals (sometimes lies, sometimes not). ", "There are plenty of names for these characters, for example see the questions (or many others similar around the Internet):\nKnights and jokers\nIsland inhabitants: Who lies and who tells the truth?", "\nNine togglers, one truth teller, and only a single question\nTruths, Lies, and Xors\nWhat is the most correct name for this puzzle and the characters?", "\nWhat is the most common name for this puzzle and the characters?", "\nWhat is the most popular name for this puzzle and the characters?", "\nI know, this question demands answers strongly based on opinion, but still I would like to know, what do you think and why.", "\nBecause:\nI believe a lot of scientific/popular literature about this logic puzzles exists, and maybe in this literature is some common/correct name suggested.", "\nAlso the first historical appearance of these puzzles could be the clue.", "\n\nA:\n\nThere will be no right answer for this question since it is subjective.", "\nThe oft-used adjectives are Knights and Knaves for truth-tellers and liars respectively (as Peter LeFanu Lumsdaine and alexwlchan pointed out). ", "Often the normals are described as such - since they are usually not normal per se, but rather do something like lie or tell the truth according to a uniform random variable (are \"unpredictables\").", "\nI quite like these somewhat archaic English terms soothsayers, mythomaniacs, and quixotics for truth-tellers, liars, and unpredicatables.", "\nWe could also try to give them individual names; some with somewhat relevant meanings one could use are as follows (I'm sure there are more).", "\nFor the truth-teller:\n\nAlethea (Greek: aletheia = truth)\nAmin (Arabic: amin = truthful)\nSati (Sanskrit: sati = truthful)\nSidika (Turkish: sidika = truth)\nVerity (English: verity = truth)\n\nFor the liar:\n\nBellona (Latin: bellare = fight)\nDrake (Old Norse: draki = dragon)\nLileth (Akkadian: lilitu = of the night)\nMark / Marcus / Martin (Greek: Mars = the god of war)\n\nFor the normal / unpredictable\n\nAlf / Alfred (Old Norse: Alfr = elf)\nCaprice (English capricious = unpredictable)\nDougal (Gaelic dubh = dark\", gall \"stranger\")\nNemo (Latin: nemo = nobody)\nPeter (Greek: petros = stone)\nThomas (Aramaic: a'oma' = twin)\n\nOr how about being a little tongue in cheek and going for something like: Frank (to be frank); Phoebe (fibber) or Lyle (liar); and Norman (normal).", "\n\n" ]

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[ "What's that, my deer? ", "The cat that's begun an unlikely relationship at a zoo\n\nNuzzling his new friend, this deer seemed to enjoy the affections of a rather unusual playmate as onlookers at a zoo watched in amazement.", "\n\n\n\nThe heartwarming scene at Odessa Zoo, Ukraine saw the confident ginger cat approaching the young roe deer before rubbing its face against the buck\n\nPhotographer Vitaly Ktach stumbled across the pair by accident but couldn't resist taking these adorable pictures.", "\n\nFawning over each other: The ginger cat nuzzled itself against the young deer\n\nHe said:' I saw them by accident when walking in the zoo with my camera and could not resist stopping to take pictures.", "\n\n'The affectionate behaviour of the cat towards the young deer had myself and other visitors watching in disbelief. '", "\n\n\n\nFeline friendly: The cat sauntered up to the unwitting deer\n\nHe added: 'The cat seemed to really be taking its time to run its fur along the deer, which must have felt very nice.", "\n\n\n\n'It then sat down and they enjoyed gently rubbing their faces together. ", "They looked in bliss\n\n\n\n'Evidently real love doesn't know taboo. ", "These animals don't care about the opinion of others.'", "\n\nRoe-mantic: The deer returns the feeling and gently nuzzles the cat\n\n\n\n" ]

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[ "Everton vs. Norwich\n\nEverton V Norwich Preview\n\nEverton will be looking to bounce back following the disappointment of last weekend as they take on a Norwich side who will be on cloud nine at Goodison Park on Saturday. ", "Everton suffered a bitterly disappointing 2-1 loss to Reading, a result that ended their 9 game losing streak and also dropped them out of the top 4. ", "Norwich on the other hand had a massive 1-0 win over Manchester United, a result that saw them move up to 13th. ", "Everton will not be able to get away with a similar performance than the one they put in during the 2nd half of last weekend with the Goodison crowd on their backs and they will be expecting a much better performance and the 3pts as they seek to regain the 4th spot which they succumbed to an impressive West Brom outfit.", "\n\nVital Quotes:\n\nEverton midfielder Thomas Hitzlsperger urged the side to focus ahead of the Norwich game saying\n\n\"Personally I have been happy with the way things are going, apart from the result at Reading, I`m not happy with that, Norwich is a game that we have to win, especially after Saturday. ", "It was so frustrating for us not to get the three points or at least one point. ", "We have to focus on the game against Norwich, get three points and then we are back on track again. ", "We can`t let our heads drop and say that it is bad. ", "We have to lift ourselves again and look forward to the next game.\"", "\n\n'He [Ruddy] will enjoy going back to Everton and will look for the opportunity to catch up with old friends. ", "It is only a good day though if you get something from it. ", "That is always pleasing for a goalkeeper and a back four but it is a real team effort. ", "The back four have a group of players in front of them who are giving them good resistance.", "We will be severely tested but we are buoyed by the good spells we have had this season.'", "\n\nEverton Team News:\n\nEverton have a couple injury and suspension worries ahead of this match. ", "Influential big man Marouane Fellaini will miss the Norwich match due to the Belgian picking up his 5th yellow last weekend. ", "They will also be without club captain Phil Neville, as it was revealed last weekend that he needed knee surgery and will miss 6-8wks. ", "In some good news for the club, the side could finally regain the services of Darron Gibson after he played 60mins for the reserve side last weekend and could be in line for a return to the starting XI after missing since the start of September. ", "Hibbert is also edging closer to a return to the side following his calf injury. ", "Mirallas is described as a 50-50 as he attempts to recover from a hamstring injury. ", "And finally, striker Victor Anichebe is also listed as questionable for the match.", "\n\nPlayer to watch: Steven Pienaar\n\nSince his return to Everton from Spurs, it is safe to say, for the larger part he has been outstanding, however, in the last few weeks, the the South African hasn't been at his sparkling best, and it has reflected on the whole side as Everton, although sitting in 5th, haven't been at their best. ", "With Fellaini out, the large burden left with his absence will fall squarely onto Pienaar and his partnership with Baines on the left. ", "The combination of Pienaar and Baines is the best partnership in the league, they have shredded sides single handedly and Everton will be hoping those two can do the same against Norwich on Saturday.", "\n\nNorwich Team News:\n\nNorwich are slightly better off than the hosts, however, there are a couple issues for the visitors ahead of the match. ", "The major question mark is the fitness over centre back Michael Turner. ", "Other than that, the only certain absentees for the Canaries will be youngster Harry Kane and defender Russell Martin, both through injuries.", "\n\nPlayer to watch: Grant Holt\n\nShowed last season he can be a menace against Everton scoring a couple times against this Everton side. ", "The major worry will be his physicality, especially if Moyes decides to go with Jagielka and Heitinga, who aren't the strongest centre backs. ", "I would assume that Everton would largely dominate the possession with Norwich sitting and absorbing the pressure, therefore it is vital the Everton defenders do not give the big man any space and more so no chances, because as he showed last season, he will stick a chance away if given the shot.", "\n\nMatch Facts & Stats\n\n1. ", "Prior to last weekend, Everton came back from conceding the 1st goal in the last 6 games to grab a draw or a win. ", "Last weekend, they scored first and they ended up losing. ", "their first in 9 matches and only their 2nd in the last 21 matches.", "\n\n2. ", "This will be Moyes' 200th match as Everton manager at Goodison Park, of which he has 104 wins with only 46 defeats\n\n3. ", "This will be Leighton Baines' 300th league start, of which, 150 have been for Everton\n\n4. ", "Last weekend was the first time in the club's history that the starting XI had 11 full internationals playing.", "\n\nMatch Prediction:\n\nEverton need to bounce back, they need to forget the Reading match and focus on a dangerous Canary side who will be full of confidence following their 1-0 win over United. ", "Everton's home form has been outstanding, think the last time they lost was back in March, and some of the performances during that time have been outstanding and the fans will be hoping to see the Everton side that started the season so emphatically. ", "Fellaini will be a major loss, but with the possible returns of Gibson and Mirallas, it would serve as a massive boost for the side. ", "Due to Everton playing at home, I will go for a 3-1 win to Everton. ", "COYB!!! ", "NEED TO GET THE 3PTS LADS!!!", "\n\nCookie Policy\nAt Vital Football, we along with most other modern websites use small files called 'cookies' to create the most secure, effective and functional website possible for our users. ", "Without these files our business model, based on advertising, breaks down and we would be unable to continue to provide the services that you are here to utilise. ", "By continuing to use this website after seeing this message, you consent to our use of cookies on this device unless you have disabled them. ", "For full details please read our Cookie Policy which can be found here. ", "However, if you would like to disable cookies on this device, please view our Cookie Policy which contains an opt-out tool for disabling advertising cookies. ", "Please also visit our information pages on 'How to manage cookies' if you would also like to block all other types of cookies. ", "Please be aware that parts of this site will not function correctly if you disable cookies." ]

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[ "Challenges to preventing infectious complications, decreasing re-hospitalizations, and reducing cost burden in long-term survivors after allogeneic hematopoietic stem cell transplantation.", "\nEven though the overall outcome after allogeneic transplant has improved significantly in the last decades, late infectious diseases are still the most important causes of late morbidity and mortality. ", "Here, impaired immune reconstitution and therapy of chronic graft-versus-host disease (GVHD) represent the major risk factors. ", "In this review, we give a comprehensive overview of late infectious complications and summarize possible diagnostic and therapeutic interventions to prevent these complications." ]

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[ "Check this crazy wedding video from Dagestan . ", "They have some really bizarre wedding traditions :)Learn more about Dagestan wedding traditions here" ]

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[ "Tilted Kilt sponsors martial arts fight team\n\nThe Tilted Kilt, a 50-unit pub chain, has gone from being a place for guests to watch mixed martial arts fight matches on TV to becoming the first restaurant brand to step into the ring with the sponsorship of an Ultimate Fighting Championship team.", "\nThe Tempe, Ariz.-based chain has agreed to fund a lineup of MMA competitors, the Tilted Kilt Fight Team, which president Ron Lynch is convinced will drive national exposure during pay-per-view fights and strengthen the Tilted Kilt’s ...\n\nRegister to view this article\n\nIt’s free but we need to know a little about you to continually improve our content.", "\n\nWhy Register?", "\n\nRegistering allows you to unlock a portion of our premium online content. ", "You can access more in-depth stories and analysis, as well as news not found on any other website or any other media outlet. ", "You also get free eNewsletters, blogs, real-time polls, archives and more.", "\n\nAttention Print Subscribers: While you have already been granted free access to NRN we ask that you register now. ", "We promise it will only take a few minutes!" ]

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[ "Rallying behind school reform\n\nPosted: Monday, August 03, 2009\n\nBy Richard N. Bond, Bill McInturff and Alex Bratty\n\nMany issues have created a \"politics as usual\" atmosphere on Capitol Hill recently, but when it comes to educating our children, it appears President Obama and the Republican Party share some views. ", "This commonality of interest provides the president and the GOP a rare opportunity to cooperate on a major issue.", "\n\nIn a March address on education, the president proposed several reforms, three of which the Republican Party has been championing for years.", "\n\nFirst, he called for merit pay for teachers:\n\n\"Good teachers will be rewarded with more money for improved student achievement, and asked to accept more responsibilities for lifting up their schools.\"", "\n\nNext, he called for removing ineffective teachers:\n\n\"Let me be clear: If a teacher is given a chance ... but still does not improve, there is no excuse for that person to continue teaching. ", "I reject a system that rewards failure and protects a person from its consequences.\"", "\n\nFinally, he called for the expansion of public charter schools:\n\n\"Provided ... greater accountability, I call on states to reform their charter rules, and lift caps on the number of allowable charter schools, wherever such caps are in place.\"", "\n\nIt is no accident the GOP has consistently supported these ideas - they embody some of the party's core beliefs: Good performance should be rewarded, failure should have consequences and individuals should have freedom of choice. ", "These reforms only make sense. ", "Why would we not want to choose the most suitable school for a child, reward a teacher for producing outstanding results or fire a teacher who is bad at his or her job?", "\n\nUnlike congressional Democrats, who answer to teachers unions, Obama and the GOP have the same laser focus: These are our children we're talking about, our future, the country's future.", "\n\nThe public understands that these are good ideas, too. ", "Arguably the most controversial is the idea of removing failed teachers from the classroom. ", "It has met with considerable resistance from teachers unions over the years, but when put to the test in a recent NBC-Wall Street Journal survey of 1,005 adults, a staggering 78 percent said they approved of President Obama's proposal to make \"it easier for schools to dismiss teachers who are shown to be poor performers.\" ", "With a number like that, you'd be right to assume there is agreement across the political spectrum: 80 percent of Democrats, 73 percent of independents and 82 percent of Republicans say they approve of this proposal.", "\n\nIt is also no coincidence that part of President Obama's education plan builds on work being done by Republican governors around the country, such as Tim Pawlenty's efforts in Minnesota to implement a system of post-tenure review for teachers or Sonny Perdue's support in Georgia of merit pay for teachers and incentive pay for principals. ", "In fact, over the past five years, 17 Republican governors have proposed education reforms related to merit or incentive pay, dismissing failed teachers and expanding charter schools, while only five Democratic governors have addressed these issues.", "\n\nAs a party, Republicans out in the states are far ahead on these reforms, so why not get on board in Washington, as well? ", "At a time when critics are trying to define the GOP as the party of no, here is a clear opportunity to say yes. ", "And let's not forget there's a reason Obama has talked a lot about these proposals but done nothing significant about them yet: They are going to split the Democratic base and threaten the unwavering support the Democrats have received from teachers unions over the years.", "\n\nBut that's all the more reason for Republicans to push for cooperation on these reforms - to find out if Obama plans to follow through on what he's saying. ", "It's a fine case of Reaganesque \"trust, but verify.\" ", "And Republicans should be mindful that not all of Obama's education reforms are to their liking; for instance, Obama recently signed a bill that places the future of Washington, D.C.'s popular voucher program in doubt, to the dismay of thousands of African American families.", "\n\nSo while Washington may be gearing up for some big legislative battles, education need not be one that leads to failure. ", "By finding common ground with President Obama, the Republican Party can demonstrate its bipartisan spirit while creating a fissure among the Democrats. ", "But, most important, the party can achieve what it has been working toward for many years: making sure our children learn from the best teachers and get the best education we can provide.", "\n\n• Richard N. Bond is a government relations consultant in Washington. ", "Bill McInturff is co-founder and partner and Alex Bratty is vice president, of Public Opinion Strategies, a Republican polling firm." ]

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[ "All structures have their own unique \"natural\" or \"resonant\" frequency which is the physical vibration point at which a structure will exhibit violent, even self-destructive vibrations. ", "Those destructive vibrations occur as energy at a specific frequency is applied to an object. ", "A common household example is the washing machine. ", "When a washing machine enters its spin cycle, the wash load must be relatively evenly balanced about the drum. ", "Otherwise, as the drum spins faster and faster, a strong vibrational force will be produced. ", "As this vibration nears the unique natural frequency of the washing machine, the machine will shake violently. ", "If the vibration remains at this frequency, the machine will likely shake itself apart.", "\nAnother historical example of destructive resonant vibration on a larger scale is the Tacoma Narrows Bridge disaster in Tacoma, Wash. The bridge was designed as a suspended plate girder bridge and as a result caught wind passing through the span. ", "As the wind intensity increased on Nov. 7, 1940, to 42 m.p.h., ", "a continuous oscillation or rocking motion was created throughout the span of the bridge that grew in intensity until the bridge finally tore apart. ", "Like a washer and the Tacoma Bridge, organs and tissues in the human body have natural resonant frequencies at which they will resonate, resulting in tissue specific destruction.", "\nVarious medical devices have been created for removing body tissues and in particular, fat. ", "The differences between these devices essentially depends upon the physical properties of the instrument and the particular tissue to be removed. ", "For example, an ultrasonic device (using high frequency sound waves) can be used to break apart a kidney stone but would have little to no effect on less dense objects such as fat or muscle. ", "A kidney stone is compact and a high frequency ultrasound device can break the stone into smaller pieces for removal. ", "Body fat, on the other hand, is more like a firm gelatin and would simply wiggle if a sound wave was applied.", "\nSome researchers have developed an ultrasonic cannula that vibrates rapidly, destroying neighboring tissue by \"melting\" the tissues. ", "Unfortunately, nerve, artery and tissue burns result at the ultrasonic frequencies required to break apart fat cells because these frequencies are not specific for fat. ", "This results in scars and other unwanted side effects. ", "Another example of a device used for removing tissue is a laser, which can be used, for example, in cutting atherosclerotic plaques from arteries. ", "This device uses a light wave to incinerate an object, but again, because many tissues absorb laser energy, neighboring nerves and blood vessels are injured concomitantly with fat removal. ", "These medical devices are not useful for removing fat because they employ ultrasonic and laser frequencies not specifically absorbed by fat.", "\nOnly when a device employs frequencies of energy at or near the natural frequency of a tissue can complete and safe removal be achieved. ", "Fat, or adipose tissue, is unique in its physical characteristics, requiring a special technique for removal. ", "Being a very distensible tissue, fat easily moves away from any applied force. ", "Presently, the common technique for removing fat and other soft tissues from the body is suctioning tissues into a cannula and subsequent removal with a shearing force. ", "This unfortunately results in excessive damage to lymphatics, nerves and blood vessels, as well as leading to scar formation. ", "Currently, all cannulas used to remove soft tissues such as fat rely on such shearing forces.", "\nAs seen in the foregoing discussion, it is preferable for any medical device employed in tissue removal to address the unique \"resonant\" features of the tissue. ", "As a result, there is a need for a new surgical instrument, designed to remove a variety of tissues, which has the versatility to address the unique resonant properties of the particular tissue, fat in particular, to optimize the removal while decreasing damage to neighboring tissues." ]

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[ "Maybe the plan shown in the slide is undertake research that would distinguish between the Ptolemaic and Copernican hypotheses.", "\n\n-- Edward Tufte\n\nResponse to Block That Metaphor! ", "The NASA Space Exploration Map\n\nDo I detect a graphic heritage from the 1991 NYC subway map?", "\n\nIf so, I think the fastest way from earth to mars, if starting on the Green train, is to transfer to the express Red train at Low Earth Orbit. ", "If one just misses the Red train, then stay on the local Green train.", "\n\nMost likely the graphic heritage here is from the Washington, DC metro map. ", "Note how the junction indicators at Earth, LEO, and HEO/the Moon closely match the major junction indicators for the DC metro map (Metro Center, Rosslyn, etc). ", "On the metro map they indicate places where you can switch lines.", "\n\nOn the NASA map, they indicate that someone in charge is equating a subway system with space travel. ", "Scary.", "\n\nThe metro-map itself fails to tell anything substantive.", "\nViewing Earth in a gravity well, all rocket trips would\nbe \"up\", hence Venus, Mercury and the Sun would present\na more technical and payload challenge than Earth L1/L2.", "\nThere were 100's of LEO shots compared to Pioneers, etc.", "\n\nA Napoleon's March, tracing the number of flights to\neach end-point in our gravity well (logorithmically),\nwould be far more useful as a teaching tool graphic.", "\nThrow in an elliptic super- of the solar system, with\nan Audubon's illustration of the space birds, wha-lah!", "\n\nBut I'd like to see a Napoleon's March of the US:Soviet\nCold War nuclear weapons production:destruction cycles,\nbeginning in 1945 to the present. ", "Underneath, a mirror-\ngraphic of US citizen treasure spent, and so destroyed!", "\n\nIt is often the case that metaphor somehow tarnishes the original - the\nHollywood version of Hopper's Nighthawks being an example. ", "But here the\nquality of Becks' work on the London Underground is pointed up by the\ncatastrophic failure of the NASA slide." ]

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[ " UNPUBLISHED\n\n UNITED STATES COURT OF APPEALS\n FOR THE FOURTH CIRCUIT\n\n\n No. ", "19-1795\n\n\nJAMEL ELLERBEE,\n\n Petitioner,\n\n v.\n\nANNETT HOLDINGS, INC., ", "d/b/a TMC Transportation; UNITED STATES\nDEPARTMENT OF LABOR,\n\n Respondents.", "\n\n\n\nOn Petition for Review of an Order of the Department of Labor. (", "2019-0059; 2019-STA-\n00011)\n\n\nSubmitted: December 17, 2019 Decided: December 19, 2019\n\n\nBefore KING, FLOYD, and HARRIS, Circuit Judges.", "\n\n\nPetition denied by unpublished per curiam opinion.", "\n\n\nJamel Ellerbee, Appellant Pro Se. ", "Alyssa C. George, UNITED STATES DEPARTMENT\nOF LABOR, Washington, D.C.; Matthew Christopher Burke, Dana Hefter Hoffman,\nYOUNG MOORE & HENDERSON, PA, Raleigh, North Carolina, for Appellees.", "\n\n\nUnpublished opinions are not binding precedent in this circuit.", "\n\fPER CURIAM:\n\n Jamel Ellerbee petitions for review of an order of the Department of Labor’s (DOL)\n\nAdministrative Review Board (ARB) dismissing as untimely his petition for review of the\n\nAdministrate Law Judge’s (ALJ) decision dismissing his complaint alleging violations of\n\nthe Surface Transportation Assistance Act of 1982 (STAA), see 49 U.S.C. § 31105 (2012).", "\n\nInitially, Ellerbee has forfeited our review of the ARB’s determination that his petition for\n\nreview of the ALJ’s decision was untimely. ", "See Jackson v. Lightsey, 775 F.3d 170, 177\n\n(4th Cir. ", "2014) (“The informal brief is an important document; under Fourth Circuit rules,\n\nour review is limited to issues preserved in that brief); United States v. Copeland, 707 F.3d\n\n522, 530 (4th Cir. ", "2013) (recognizing that this Court generally does not consider arguments\n\nnewly raised in reply). ", "And, because Ellerbee failed to timely petition the ARB for review,\n\nwe lack authority to exercise judicial review over the ALJ’s decision. ", "See 49 U.S.C.\n\n§ 31105(d) (requiring STAA judicial review to conform with Administrative Procedure\n\nAct (APA)); 29 C.F.R. §§ 1978.109(e), 1978.110(a), (b) (2019); see also Darby v.\n\nCisneros, 509 U.S. 137, 147, 152-53 (1993) (recognizing circumstances under which\n\nregulation may establish intra-agency appeal as prerequisite to judicial review under APA).", "\n\n Accordingly, we deny the petition for review. ", "We grant Ellerbee’s motions to\n\nsubmit on the briefs and to amend the record. ", "We dispense with oral argument because the\n\nfacts and legal contentions are adequately presented in the materials before this court and\n\nargument would not aid the decisional process.", "\n\n PETITION DENIED\n\n\n\n 2\n\f" ]

{ "pile_set_name": "FreeLaw" }

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[ "Video description: George Campbell is the nation's No. ", "11 overall football prospect. ", "But one person has never seen George play live: his father. ", "Recruiting reporter Derek Tyson joins ESPN's Phil Murphy to discuss the impact of a dad's 36-year prison sentence." ]

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[ "ATP sensitive potassium channels (KATP) in surface membrane (sKATP) and mitochondria (mKATP) of heart have both been implicated in the protective phenomenon called ischemic preconditioning (IPC). ", "Proposed mechanisms for IPC are complex. ", "The relative importance of mKATP and sKATP for IPC is controversial, in part because of heavy reliance on KATP pharmacology as well as the unknown molecular nature of mKATP. ", "The sulfonylurea receptor subunit SUR2 regulates pharmacology and nucleotide interactions for sKATP, but the role of SUR2 in mKATP is unknown. ", "In the last project period our goal was to develop transgenic mouse models that ablated SUR2 to determine the role of SUR2 in IPC and mKATP. ", "Using three independent models of IPC, we found that an SUR2 mutant mouse was constitutively protected from ischemia even in the absence of IPC. ", "This was surprising in view of the usual finding that KATP opening by drugs induced protection and that KATP block by drugs abrogated protection. ", "We used a newly created panel of SUR2 antibodies and discovered novel short variants (Kd120, 68, 55, 28) in mouse heart mitochondria, with the SUR2-55 form uniquely in mitochondria and not the surface. ", "The mutant surprisingly retained SUR2-68 and 55, but not 120 and 28; it was only a partial knockout. ", "We determined the sequence of SUR2-55 and showed it persisted in the mutant because of a novel intraexonic splicing event that jumped the disruption vector. ", "We also found that IPC in WT mice down-regulated SUR2 except for SUR2-68 and SUR2-55A, a pattern similar to the mutant mouse. ", "We hypothesize that mKATP subunits SUR2-68 and 55A when unopposed by other SUR2 subunits confer ischemic protection. ", "The results also make the provocative suggestion that pharmacology of mKATP may change during IPC. ", "The role of these novel mitochondrial variants of SUR2 in the mechanism of IPC, mKATP, and mitochondrial function will be investigated in five aims. ", "Aim 1 will determine the mechanisms for targeting of SUR2-variants to mitochondria, and mechanisms for persistence or down-regulation in IPC. ", "Aim 2 will determine the associations of SUR2 variants with other proteins in the mKATP multi-protein complex. ", "Aim 3 will assess the pharmacology and physiology of SUR2 variants combined with pore forming subunits in COS- 1 cells to allow interpretation of mechanisms suggested by the pharmacology of IPC. ", "Aim 4 will investigate IPC in transgenic mice designed to have full and selective ablation of cardiac SUR2 and create specific rescue of mSUR2 variants to define mechanisms of protection. ", "Aim 5 will determine mKATP and mitochondrial function in these mice to determine mechanisms of mSUR2 effects on mKATP, mitochondrial function, and IPC. ", "The molecular nature of mKATP is a key gap in knowledge, and its role in IPC is controversial. ", "This proposal utilizes transgenic animals as a novel non-pharmacological approach to fill these gaps and address the controversy. ", "The results may suggest more specific therapeutic targets in the SUR2 variants, and it will also provide important new information on mitochondrial structure and function in heart." ]

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[ "<?", "php\n\n/**\n * Null cache object to use when no caching is on.", "\n */\nclass HTMLPurifier_DefinitionCache_Null extends HTMLPurifier_DefinitionCache\n{\n\n /**\n * @param HTMLPurifier_Definition $def\n * @param HTMLPurifier_Config $config\n * @return bool\n */\n public function add($def, $config)\n {\n return false;\n }\n\n /**\n * @param HTMLPurifier_Definition $def\n * @param HTMLPurifier_Config $config\n * @return bool\n */\n public function set($def, $config)\n {\n return false;\n }\n\n /**\n * @param HTMLPurifier_Definition $def\n * @param HTMLPurifier_Config $config\n * @return bool\n */\n public function replace($def, $config)\n {\n return false;\n }\n\n /**\n * @param HTMLPurifier_Config $config\n * @return bool\n */\n public function remove($config)\n {\n return false;\n }\n\n /**\n * @param HTMLPurifier_Config $config\n * @return bool\n */\n public function get($config)\n {\n return false;\n }\n\n /**\n * @param HTMLPurifier_Config $config\n * @return bool\n */\n public function flush($config)\n {\n return false;\n }\n\n /**\n * @param HTMLPurifier_Config $config\n * @return bool\n */\n public function cleanup($config)\n {\n return false;\n }\n}\n\n// vim: et sw=4 sts=4\n" ]

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[ " United States Court of Appeals\n Fifth Circuit\n F I L E D\n IN THE UNITED STATES COURT OF APPEALS\n FOR THE FIFTH CIRCUIT June 22, 2005\n\n Charles R. Fulbruge III\n Clerk\n No. ", "04-51002\n Conference Calendar\n\n\n\nUNITED STATES OF AMERICA,\n\n Plaintiff-Appellee,\n\nversus\n\nJOSE LUIS GOMEZ-GARCIA,\n\n Defendant-Appellant.", "\n\n --------------------\n Appeal from the United States District Court\n for the Western District of Texas\n USDC No. ", "2:04-CR-62-1-AML\n --------------------\n\nBefore WIENER, BENAVIDES, and DENNIS, Circuit Judges.", "\n\nPER CURIAM:*\n\n Jose Luis Gomez-Garcia appeals his sentence imposed\n\nfollowing his guilty plea to illegal reentry after deportation.", "\n\nHe was sentenced to 77 months of imprisonment and three years of\n\nsupervised release. ", " Gomez-Garcia argues that his sentence is\n\nillegal pursuant to United States v. Booker, 125 S. Ct. ", "738\n\n(2005). ", " Gomez-Garcia has not established plain error with regard\n\nto his Booker claim because he has not established that being\n\nsentenced under a mandatory guidelines scheme affected his\n\n\n *\n Pursuant to 5TH CIR. ", "R. 47.5, the court has determined that\nthis opinion should not be published and is not precedent except\nunder the limited circumstances set forth in 5TH CIR. ", "R. 47.5.4.", "\n\f No. ", "04-51002\n -2-\n\nsubstantial rights. ", " The record does not indicate that the\n\ndistrict court “would have reached a significantly different\n\nresult” under a sentencing scheme in which the guidelines\n\nwere advisory only. ", " See United States v. Mares, 402 F.3d 511,\n\n520-22 (5th Cir. ", "2005), petition for cert. ", "filed (Mar. 31, 2005)\n\n(No. ", "04-9517); United States v. Valenzuela-Quevedo, 407 F.3d 728,\n\n733-34 (5th Cir. ", "2005); United States v. Malveaux, __F.3d__,\n\nNo. ", "03-41618, 2005 WL 1320362 at *1 n.9 (5th Cir. ", "Apr. 11, 2005).", "\n\n Gomez-Garcia also asserts that, under the reasoning of\n\nApprendi v. New Jersey, 530 U.S. 466 (2000), 8 U.S.C. § 1326(b)\n\nis unconstitutional because it treats a prior conviction as an\n\nelement of the offense rather than a sentence enhancement. ", " As\n\nGomez-Garcia concedes, his argument is foreclosed by\n\nAlmendarez-Torres v. United States, 523 U.S. 224, 235 (1998), but\n\nhe seeks to preserve the issue for possible Supreme Court review.", "\n\nThis court must follow Almendarez-Torres “unless and until the\n\nSupreme Court itself determines to overrule it.” ", " United States\n\nv. Dabeit, 231 F.3d 979, 984 (5th Cir. ", "2000) (internal quotation\n\nmarks and citation omitted).", "\n\n Accordingly, the district court’s judgment is AFFIRMED.", "\n\f" ]

{ "pile_set_name": "FreeLaw" }

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[ "Q:\n\nПеревести SQL-запрос в LINQ\n\nЕсть два DataGridView. ", "В одном главные записи, во втором детали по нему. ", "\n\nДелаю так\nlist = model.", "Contracts\n .Include(c => c.ListSubjects)\n .ToList();\ndataGridView1.DataSource = list;\n\nContracts item = list\n .Find(c => c.Id == Convert.", "ToInt32(dataGridView1.SelectedRows[0].Cells[0].Value));\ndataGridView2.DataSource = item.", "ListSubjects\n .ToList();\n\nТогда во втором DataGridView вижу только записи для нужного Contracts. ", "Но там только числа. ", "Как мне подтянуть Title от Subjects и показывать во втором DataGridView только его. ", "\nДругими словами, выполнять запрос:\nSELECT s.Title \nFROM Contracts c, ListSubjects ls, Subjects s\nWHERE c.ID = ls.", "ID_Contract AND s.ID = ls.", "ID_Subject\n\nA:\n\nvar title = (from cont in model.", "Contracts\n join lsSub in model.", "ListSubjects on lsSub.", "Id_Contract equals cont.", "Id \n join subj in model.", "Subjects on subj.", "ID equals lsSub.", "ID_Subject\n where cont.", "ID == Convert.", "ToInt32(dataGridView1.SelectedRows[0].Cells[0].Value))\n select subj.", "Title\n );\n\nКак-то так. ", "Если что-то не так - просьба сильно не пинать так, как написано было на коленке.", "\n\n" ]

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[ "**To the Editor:** In 2015, a locally acquired, multidrug-resistant *Shigella flexneri* infection was identified in Montreal, Quebec, Canada, in an HIV-positive man who had sex with men (MSM). ", "In September, the 53-year-old man consulted his physician at an outpatient clinic after experiencing abdominal pain, fatigue, and diarrhea without blood in stools or fever. ", "The week before the symptom onset, although he had not traveled, he had unprotected oral and anal sexual contact in a Montreal bathhouse with a man visiting Canada from an unknown country. ", "The patient did not work in daycare centers or healthcare facilities, and he was not a food handler. ", "He did not have sex during illness.", "\n\nHe was HIV positive and was receiving antiretroviral treatment; recent CD4 cell count was 480 × 10^6^/L, and HIV viral load was \\<40 copies/mL. *S. flexneri* was isolated from his culture of a fecal sample, and *Neisseria gonorrhoeae,* diagnosed by PCR, was found in a throat specimen. ", "The patient did not have a medical record of other past sexually transmitted infections.", "\n\nPhenotypic identification of the *S. flexneri* was confirmed at Laboratoire de Santé Publique du Québec ([@R1]). ", "Serologic identification, pulsed-field gel electrophoresis (PFGE), and antimicrobial susceptibility testing were performed as described ([@R1]). ", "This *S. flexneri,* serotype 2a pulsovar 21 (a new PFGE combination pattern in the province of Quebec), was resistant to ampicillin, trimethoprim/sulfamethoxazole (TMP/SMX), nalidixic acid, ciprofloxacin, tetracycline, and chloramphenicol. ", "The isolate was also nonsusceptible to azithromycin and amoxicillin/-clavulanic acid, and susceptible to ceftriaxone, cefixime, ertapenem, and gentamicin ([Table](#T1){ref-type=\"table\"}). ", "The *mph*(A) gene, which codes for the macrolide 2′-phosphotransferase, tested positive by PCR ([@R1]).", "\n\n###### Antimicrobial susceptibility of the *Shigella flexneri*,serotype 2a pulsovar 21, isolated in Montreal, Quebec, Canada, 2015\\*\n\n Antimicrobial agent Disk diffusion, mm MIC, mg/L Interpretation\n ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ -------------------- ----------- ----------------\n Ampicillin 6 ≥32 R\n TMP/SMX 6 ≥320 R\n Ciprofloxacin 12 ≥4 and 8 R\n Nalidixic acid 6 NA R\n Ceftriaxone 33 ≤0.25 S\n Cefixime 26 0.25 S\n Azithromycin† 6 \\>256 NS\n Tetracycline 6 32 R\n Chloramphenicol NA \\>256 R\n Amoxicillin-clavulanic acid 14 16 I\n Ertapenem NA ≤0.5 S\n Gentamicin 21 ≤1 S\n \\*I, intermediate; NA, not available; NS, nonsusceptible; R, resistant; S, susceptible; TMP/SMX, trimethoprim/sulfamethoxazole.", "
†Azithromycin epidemiologic cutoff values for wild-type (MIC ≤8 mg/L) and non--wild-type (MIC ≥16 mg/L) *Shigella flexneri* (*2*) and the susceptibility and resistance breakpoints for the other 11 antimicrobial agents were CLSI *Enterobacteriaceae*breakpoints (*2*). ", " \n\nOn day 10 of diarrhea, the patient was treated with ceftriaxone, 250-mg dose, intramuscularly, followed by cefixime, 800 mg/day, for 5 days; the patient's condition showed progressive improvement. ", "Two control cultures of fecal specimens were negative 7 and 16 days, respectively, after completion of a regimen of cefixime.", "\n\n*Shigella* spp. ", "are transmitted from person-to-person through low inocula of the bacteria, directly or indirectly ([@R1]*,*[@R3]*--*[@R5]). ", "In MSM, *Shigella* spp. ", "are mostly transmitted sexually, with clusters documented in many countries ([@R1]*,*[@R3]*--*[@R5]). ", "In Canada and the United States, *Shigella* isolates have high levels of resistance to ampicillin and TMP/SMX ([@R1]*,*[@R3]*--*[@R6]). ", "In adult patients, when antimicrobial drug treatment is indicated, ciprofloxacin and azithromycin are, respectively, the agents of first and second choices for treating *Shigella* infections ([@R1]*,*[@R3]*--*[@R5]).", "\n\nIn the United States, *Shigella* spp. ", "resistant to at least nalidixic acid and azithromycin have been found in surveillance isolates: 1/293 in 2011 (*Shigella* spp.), ", "1/353 in 2012 (*S. sonnei*), and 1 of 344 in 2013 (*S. flexneri*) ([@R6]). ", "In Illinois and Montana, during September 2014--April 2015, 3 of 5 patients infected with multidrug-resistant *S. sonnei* (resistant to ampicillin, TMP/SMX, ciprofloxacin, and nalidixic acid and nonsusceptible to azithromycin), identified themselves as MSM, and 2 of these patients had diarrhea for \\>14 days ([@R3]).", "\n\nClinical treatment failure has been reported in patients infected with azithromycin-nonsusceptible *Shigella* isolates treated with this drug ([@R7]*,*[@R8]), including 1 of our patients (unpub. ", "data). ", "In a previous study, the *mph*(A) gene was acquired by 4 of 7 locally acquired *Shigella* pulse types infecting MSM. ", "This raises concern that reduced *Shigella* susceptibility to azithromycin is developing rapidly ([@R1]). ", "Azithromycin epidemiologic cutoff values for wild- and non--wild-types of *S. flexneri* and *S. sonnei* are newly reported by CLSI ([@R8]). ", "In recent years, ciprofloxacin-resistant and/or azithromycin-nonsusceptible *Shigella* spp. ", "acquired during international travel or acquired locally were reported in the United States and in our hospital center (*1,3--6*; unpub. ", "data). *", "S. flexneri* that is resistant to ceftriaxone and ciprofloxacin has been reported in the United States ([@R9]). ", "Infections with multidrug-resistant *Shigella* spp. ", "may be of longer duration and have higher costs ([@R3]).", "\n\nWhen evaluating patients with diarrhea, physicians should identify risk factors and request bacterial cultures of fecal specimens. ", "Antimicrobial drug susceptibility testing of *Shigella* isolates is essential for effective antimicrobial drug treatment. ", "Serologic identification and PFGE are essential for epidemiologic purposes for ascertaining clusters or multidrug-resistant *Shigella* isolates ([@R1]*,*[@R3]*--*[@R5]). ", "Patients with *Shigella* infection should be advised about preventive practices such as frequent handwashing and precautions when handling food and water ([@R3]). ", "MSM should use barriers during oral, anal, and genital sex and wash their genitals, anus, and hands before and after sex ([@R1]*,*[@R3]*--*[@R5]).", "\n\nWe suggest obtaining 2 control cultures of fecal specimens on days 2 and 3 after the patient completes antimicrobial treatment for infection with multidrug-resistant *Shigella* spp. ", "Patients should avoid sex during symptomatic infections and wait for 2 negative stool cultures. ", "Montreal public health officials investigated and counselled this patient as they do for every patient with *Shigella* infections. ", "In Quebec, physicians and microbiology laboratories are notified of *Shigella* clusters and multidrug-resistant *Shigella* infections.", "\n\nTo our knowledge, no other ciprofloxacin-resistant and azithromycin-nonsusceptible *Shigella flexneri* isolates have been documented in the province of Quebec. ", "No PFGE matches to *S. flexneri* serotype 2a pulsovar 21 have been identified in Canada. ", "Multidrug-resistant *Shigella* isolates, including those with both resistance to ciprofloxacin and nonsusceptibility to azithromycin, may be underestimated and incidence may be increasing ([@R1]*,*[@R3]*--*[@R5]).", "\n\n*Suggested citation for this article*: Gaudreau C, Pilon PA, Cornut G, Marchand-Senecal X, Bekal S. *Shigella flexneri* with ciprofloxacin resistance and reduced azithromycin susceptibility, Canada, 2015 \\[letter\\]. ", "Emerg Infect Dis. ", "2016 Nov \\[*date cited*\\]. ", "<http://dx.doi.org/10.3201/eid2211.160883>\n\nWe thank Guy Lapierre and the personnel of bacteriology sections of Centre Hospitalier de l'Université de Montréal--Hôpital Saint-Luc and of Laboratoire de Santé Publique du Québec for their assistance.", "\n" ]

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[ "Coffee futures on IntercontinentalExchange, the commodities trading market, for arabica beans (not the cheaper, nastier robusta) traded below $1.30 per pound today for the first time since March 5, 2010. ", "That continues a decline in prices since the April 29, 2011 high of $2.99 per pound.", "\n\nThis three-year low comes after heavy rains in Brazil’s growing regions failed to suppress the harvest as expected, and stockpiles of the bean remain high. ", "The long-term decline in prices has prompted coffee makers J.M. Smucker and Kraft to lower the prices of their Maxwell House and Folgers brands. ", "Starbucks has followed suit with its pre-packaged coffee, but hasn’t dropped prices for its over-the-counter beverages. ", "So don’t go waving the graph above indignantly at your barista—there’s nothing he or she can do about it." ]

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[ "package datadog.trace.instrumentation.opentelemetry;\n\nimport datadog.trace.bootstrap.instrumentation.api.", "AgentSpan;\nimport io.opentelemetry.trace.", "SpanContext;\nimport io.opentelemetry.trace.", "SpanId;\nimport io.opentelemetry.trace.", "TraceFlags;\nimport io.opentelemetry.trace.", "TraceId;\nimport io.opentelemetry.trace.", "TraceState;\n\npublic class OtelSpanContext extends SpanContext {\n private static final TraceFlags FLAGS = TraceFlags.builder().setIsSampled(true).build();\n private final AgentSpan.", "Context delegate;\n\n OtelSpanContext(final AgentSpan.", "Context delegate) {\n this.delegate = delegate;\n }\n\n @Override\n public TraceId getTraceId() {\n return new TraceId(0, delegate.getTraceId().toLong());\n }\n\n @Override\n public SpanId getSpanId() {\n return new SpanId(delegate.getSpanId().toLong());\n }\n\n @Override\n public TraceFlags getTraceFlags() {\n return FLAGS;\n }\n\n @Override\n public TraceState getTraceState() {\n return TraceState.getDefault();\n }\n\n @Override\n public boolean isRemote() {\n // check if delegate is a ExtractedContext\n return false;\n }\n\n AgentSpan.", "Context getDelegate() {\n return delegate;\n }\n}\n" ]

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[ "[Hybridization of low molecular weight nuclear RNA with nuclear RNA and DNA restriction fragments].", "\nBlot hybridization of 125I or 32P labeled 4.5S, U1 or U2 RNAs with EcoRI, HindIII, BamHI or SalG1 restriction fragments of high molecular weight DNA was performed. ", "All these RNAs hybridized with fragments of ribosomal DNA and with 5.55-kb BamHI lines of rat. ", "U1 ind 4.5S RNAs hybridized also with 3.6-kb HindIII lines. ", "125I labeled U1 RNA was hybridized with nuclear RNA in formamide. ", "The hybrid molecules were formed which migrate in polyacrylamide gel as a broad peak slower than 28S rRNA. ", "Our data indicate that snRNAs may participate in processing and/or splicing of hnRNA and in some other still poorly understood processes." ]

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[ "Inulin effects on bioavailability of soy isoflavones and their calcium absorption enhancing ability.", "\nThe effect of inulin on isoflavone absorption and the effect of isoflavones and synergy with inulin on calcium absorption in rats was investigated. ", "Rats (n = 48) were divided into three groups and fed inulin (50 mg/g), isoflavone (8 mg/g) or inulin + isoflavone (50 mg/g + 8 mg/g) diets for 21 days. ", "After a 2-h fast, rats were given (45)Ca orally or intraperitoneally, together with 25 mg of calcium as calcium acetate. ", "Blood and femurs were collected 4 days later. ", "Sera were analyzed for isoflavones using HPLC-MS, femurs for (45)Ca by beta-scintillation counting, and total femoral calcium by atomic absorption spectroscopy. ", "Both groups fed isoflavones had similar and significantly higher weight-adjusted total femoral calcium content compared to the inulin-fed group (p < 0.0001). (", "45)Ca absorption was significantly higher (p < 0.01) when isoflavones were added to the diet, and serum equol was significantly lower (p < 0.01) when inulin was added to the diet containing isoflavones. ", "We conclude that isoflavones enhance calcium absorption, without synergy from inulin, and that inulin decreases equol production." ]

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[ "Berlin\n\nDer Ostbeauftragte der Bundesregierung, Christian Hirte ( CDU), hat angesichts der jüngsten Erhebung über den Rückgang der Einwohnerzahl in Ostdeutschland gefordert, die ländlichen Räume nicht zu vernachlässigen. „", "Die Erhebung belegt sehr deutlich: Ursache des massiven Bevölkerungsverlusts ist die schlechte Entwicklung im Osten nach der Teilung unseres Landes“, sagte er dem RedaktionsNetzwerk Deutschland (RND). „", "Das verursacht einen Teil des Frustes und der gesellschaftlichen Probleme heute.“ ", "Gleichzeitig sei die seit 1989 bestehende Möglichkeit, gefahrlos den Wohnort zu wechseln, aber auch „Ausdruck der angestrebten und gewollten Freiheit“. ", "Hirte fügte hinzu, er „unterstütze ausdrücklich die Forderung“, bei der staatlichen Strukturförderung „den ländlichen Raum nicht zu vernachlässigen“.", "\n\nEiner am Mittwoch bekannt gewordenen Erhebung des ifo-Instituts Dresden zufolge ist die Einwohnerzahl in Ostdeutschland auf den Stand des Jahres 1905 zurückgefallen. ", "Zugleich leben auf dem Gebiet der alten Bundesrepublik so viele Menschen wie nie zuvor, teilte das Institut mit. ", "Verantwortlich für diese Entwicklung sei die deutsche Teilung.", "\n\nAnzeige\n\nDer Westen gewinnt\n\n1905 lebten in Ostdeutschland 13,6 Millionen Menschen. ", "Prognosen zufolge sei das auch das Niveau des Jahres 2019, hieß es vom ifo-Institut. ", "Auf westdeutschem Gebiet leben mittlerweile dagegen mehr als 68 Millionen Menschen – Anfang des 20. ", "Jahrhunderts waren es nur 32,6 Millionen. ", "Die Einwohnerzahlen in Ost und West drifteten nahezu ungebremst auseinander, erklärte ifo-Forscher Felix Rösel. ", "Diese Entwicklung werde häufig übersehen. ", "Der ländliche Raum im Osten sei regelrecht ausgeblutet und müsse speziell gefördert werden.", "\n\nWeitere MAZ+ Artikel\n\nDer Bevölkerungsschwund im Osten sei eine Folge der deutschen Teilung, so der Forscher weiter. ", "Von 1949 bis zum Mauerbau 1961 hätten zahlreiche gut ausgebildete Menschen den Osten verlassen. ", "In der DDR stagnierten dann die Einwohnerzahlen – während der Westen auch durch Zuwanderung gewann. ", "Der nächste große Einschnitt im Osten folgte laut ifo-Institut durch die Abwanderung nach 1989. ", "Vor der deutschen Teilung hätten sich Ost- und Westdeutschland dagegen nahezu parallel entwickelt.", "\n\nVon Markus Decker/RND" ]

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[ "Following shooting, Walmart pledges $400,000 to help El Pasoans recover\n\nBy Gary Dinges gdinges@gatehousemedia.com\n\nFriday\n\nAug 9, 2019 at 2:39 PM\n\nFollowing a shooting at one of its stores that left 22 people dead, Walmart has announced plans to provide $400,000 in grants to members of the El Paso community.", "\n\nThe money will go to the El Paso Community Foundation’s Shooting Victims’ Fund and the Paso del Norte Community Foundation’s El Paso Victims Relief Fund. ", "Both funds are providing assistance to those affected by the shooting.", "\n\n“Our hearts ache for El Pasoans,” Greg Foran, president and CEO of Walmart's U.S. division, said in a written statement. “", "As we work on helping our associates through this tragedy, we also want to help ensure the community has the resources it needs by providing funds to support the important work the El Paso Community Foundation and the Paso del Norte Community Foundation are doing during this difficult time. ", "We want to support the people of El Paso every step of the way.”", "\n\nWalmart and Sam's Club say they have also been providing water and food to the family reunification center that was set up following the shooting, as well as three hospitals where victims are being treated.", "\n\nThe Walmart store where the shooting happened, as well as an adjacent Sam's Club, remain closed, according to El Paso TV station KVIA. ", "Workers are being transferred to other area locations to ensure they continue to get paid.", "\n\nAffiliated Delaware Papers\n\nOriginal content available for non-commercial use under a Creative Commons license, except where noted.", "\nSmyrna/Clayton Sun-Times ~ 24 W. Main St., Middletown, DE 19709 ~ Privacy Policy ~ Terms Of Service" ]

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[ "The Trump administration took the unusual step Tuesday of unveiling intelligence discrediting Russia’s attempts to shield its ally, Syrian President Bashar al-Assad, from blame in last week’s deadly chemical attack.", "\n\nThe newly released details of\n\na U.S. intelligence assessment, which officials said demonstrated Syrian culpability in the April 4 assault that killed at least 70 people, added to rapidly escalating tensions with the Kremlin and signaled a move away from hopes for U.S. rapprochement with Russia.", "\n\nOfficials said their case against the Syrian government included signals and aerial intelligence — combined with local reporting and samples taken from victims of the attack — that showed a Russian-made, Syrian-piloted SU-22 aircraft dropped at least one munition carrying the nerve agent sarin.", "\n\nThe declassified findings formed part of a coordinated broadside against Russia from the White House, State Department and Pentagon. ", "The choreographed critiques appeared to show a desire to impose order on what has been the administration’s chaotic, often contradictory public stance on national security matters.", "\n\nThe increasingly hostile stance toward Russia takes place less than a week after the administration, in a sign of its rapidly evolving foreign policy positions, launched a barrage of missile strikes on a Syrian air base in retaliation for the chemical attack in the rebel-held town of Khan Sheikhoun.", "\n\n\n\n\n\nWhite House press secretary Sean Spicer said the time had come for Russia to rethink its support for the Syrian government, which has been blamed for repeated atrocities in Syria’s ongoing civil war.", "\n\n“In this particular case we’re going to be very forceful . . . ", "to make sure that we let Russia know that they need to live up to the obligations it has made,” he said.", "\n\n[Tillerson brings tough line to Moscow over Russia’s backing for Syrian regime]\n\nSpicer’s remarks came as Secretary of State Rex Tillerson made his first official visit to Moscow, where he is expected to press Russia to choose between Syria and the West.", "\n\nAccording to U.S. officials who spoke about intelligence findings on the condition of anonymity, U.S. surveillance tracked the aircraft as it took off from a base near the city of Homs, loitered over the strike area in Idlib province and delivered its deadly yield. ", "U.S. intelligence also detected the presence of individuals associated with Syria’s chemical weapons program at the Shayrat air base in the days surrounding the attack.", "\n\nDozens of people died of exposure to sarin in Khan Sheikhoun, including numerous children, officials said. ", "Many more were injured, among them first responders.", "\n\nThe officials said that nothing from an array of intelligence and publicly available material provided any credence to the alternative account put forward by Syria and Russia, which claimed that routine bombing struck an opposition chemical weapons depot.", "\n\n(Reuters)\n\n“I have personally reviewed the intelligence, and there is no doubt the Syrian regime is responsible for the decision to attack and for the attack itself,” Defense Secretary Jim Mattis told reporters at the Pentagon later in the day.", "\n\nHe warned Syria that it would pay a “very, very, very stiff price” for further chemical attacks.", "\n\nBut Mattis and other officials said the U.S. government has not yet reached a consensus on whether Russia knew about the assault ahead of time.", "\n\nU.S. officials suggested that it was unlikely that Russian troops, stationed at the air base that was singled out last week, would have been kept in the dark.", "\n\n[Where are Russian and U.S. troops in Syria?]", "\n\n“We do think it is a question worth asking the Russians, about how is it possible that their forces­ were co-located with the forces­ that planned, prepared and carried out the chemical weapons attack at the same installation and did not have foreknowledge?” ", "one senior official said.", "\n\nRussia’s entry into the Syrian conflict in 2015 has proved to be a lifeline for Assad, who has relied on both Moscow and Tehran for financial and military support.", "\n\nThe officials slammed Russian President Vladi­mir Putin’s government for a “clear pattern of deflecting blame” for its actions and those of Assad’s forces, and for trying to use disinformation to hide the Syrian government’s role in what occurred.", "\n\n“I think it’s clear that the Russians are trying to cover up what happened there,” another official said.", "\n\nOfficials also provided their fullest accounting so far of what they believe was the Syrian government’s motivation in launching the Khan Sheikhoun attack.", "\n\nThey said that the Syrian military had used the weapons to prevent the loss of a key airfield that was threatened by a recent rebel advance on the strategic city of Hama.", "\n\n“They were losing in a particularly important area, and that’s what drove them,” said one of the senior officials. ", "Khan Sheikhoun was seen as a “rear” in that assault.", "\n\n[American strikes against Syria prompt both praise and condemnation]\n\nThe Assad regime, after six years of war, is down to as few as 18,000 soldiers, according to some estimates. ", "Officials said the reliance on chemical weapons was intended to help make up for those manpower deficiencies.", "\n\nThe orchestrated U.S. government message Tuesday was in sharp contrast to earlier weeks of the young administration. ", "On key issues, such as China, North Korea and NATO, President Trump’s off-the-cuff tweets and improvised pronouncements have sometimes contradicted those of his key advisers and even his own earlier statements.", "\n\nThe mixed messages have been especially prevalent when it comes to Syria. ", "Over the course of the past two weeks, administration officials have suggested that the White House was no longer focused on removing Assad from power, a position that held in the immediate aftermath of the attacks only to be abandoned by Tillerson on the eve of his trip to Moscow this week.", "\n\nSignaling a step back from Trump’s earlier suggestions of warmer U.S.-Russia relations, Tillerson has had sharp words for the Kremlin in the lead-up to his Moscow visit, saying that Russia either failed to embrace its obligations as a guarantor for the Syrian regime or had been incompetent.", "\n\n“This distinction doesn’t much matter to the dead,” Tillerson said.", "\n\nMoscow played a central role in the international process to remove chemical weapons from Syria in 2013, in the wake of an earlier chemical attack. ", "According to the U.S. government, last week’s attack showed that the Syrian government retained stockpiles of its most deadly chemicals.", "\n\nRussian officials stepped up their own response to events in Syria on Tuesday, as Putin raised questions about the capabilities of U.S. intelligence agencies and asserted that rebels were planning to plant chemical materials elsewhere in Syria and blame the Assad government.", "\n\nThe Russian military also warned the United States against further missile strikes, which it said would be “unacceptable.”", "\n\nDespite the recriminations on both sides, Mattis expressed confidence that tensions between the United States and Russia will not spiral out of control. ", "The two governments continue to communicate, he said, and Russia is likely to act in its own self-\n\ninterest to prevent a dangerous deterioration in relations.", "\n\nMattis described last week’s U.S. counterstrike as an isolated incident that would not affect the U.S. campaign against the Islamic State, which has been an American priority since 2014.", "\n\n“This was a separate issue,” he said. “", "We addressed that militarily, but the rest of the campaign stays on track, exactly as it was before Assad’s violation.”", "\n\nCarol Morello and David Filipov in Moscow and Jenna Johnson, Anne Gearan and Ashley Parker in Washington contributed to this report.", "\n\nRead more:\n\nExpectations of a new U.S.-Russia relationship were tanking even before missile strike\n\nRattled by U.S. strike, Assad lashes out at ‘arrogant aggression’\n\nHow two weeks and one deadly chemical strike changed U.S. policy toward Syria" ]

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[ "F1 Merchandise Shop, racing posters & memorabilia\n\nVintage 1958 Plaque given to Mike Hawthorn at the 1958 Grand Prix of Portugal\n\n1958 Plaque, Portugal Grand Prix given to Mike Hawthorn.", "\n\nWe are pleased to be able to offer for sale this fabulous piece of motoring history:\n\nThis plaque was given to Mike Hawthorn for competing in the 1958 Portugal Grand Prix at Porto race track.", "\n\nMike drove a Ferrari 246 and set the second fastest qualifying time behind Stirling Moss in his Vanwall. ", "During the race, Mike set the fastest lap time (almost 2 seconds faster than Moss's pole time!) ", "but still came in second after Moss.", "\n\nThis was of course all in Mike's Championship Winning year and it was the second to last time that Mike would race in a Grand Prix...\n\nThis is what Mike said after the race:\n\n\"I was upset to find that my race number was 22. ", "Both Pete [Collins] and Luigi [Musso] had been killed on cars with 2 as their number, and the sight of 22 on mine really put the wind up me. ", "I rushed off to Tavoni and asked if I might have 24, which was Taffy's number, and he and Taffy both agreed; only the numbers were changed, not the actual cars.\"", "\n\nThis medal went straight from Mike's estate, in 1959, to an important collector from whom we acquired it directly.", "\n\nA truly unique opportunity to acquire a piece of memorabilia from Hawthorn's personal possession.", "\n\nIt measures approximately 3.4 x 1.5 inches.", "\n\nFeel free to contact us with any questions you may have at info@macora.com.", "\n\nWe offer FREE shipping to ANY destination in the world on this item but, given its value, we advise you to take the optional insurance on it.", "\n\nVintage 1958 Plaque given to Mike Hawthorn at the 1958 Grand Prix of PortugalVintage 1958 Plaque given to Mike Hawthorn at the 1958 Grand Prix of PortugalVintage 1958 Plaque given to Mike Hawthorn at the 1958 Grand Prix of Portugal" ]

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[ "See How To Get Involved At CES 2019\n\nBest Buy Mobile Beating Expectations\n\nBest Buy’s wireless operation,\ndeveloped with and co-owned\nby European partner Carphone\nWarehouse (CPW) , had a\n“transformational year” in which\ncellphone activations rose more\nthan 30 percent to 5.5 million\nfor the 12 months, ended April\n3, suggesting a 4 percent to 5\npercent share of all U.S. handset\nsales for the period, CPW said.", "\n\nWhat’s more, earnings before\ninterest and taxes (EBIT)\nfor Best Buy Mobile soared 475\npercent to $71 million over the\nsame 12-month period.", "\n\nIn a fourth-quarter earnings\nannouncement last month that\nshed light on both the mobile\nunit and Best Buy’s new “connected\nworld” strategy, CPW chairman\nCharles Dunstone noted,\n“Best Buy Mobile U.S. is outperforming\neven our expectations”\nthanks to strong sales and operational\nefficiencies.", "\n\nThe freestanding stores and\nwireless departments, which first\nappeared in 2006, are differentiated\nby their full carrier offering, a knowledgeable — and impartial —\nnon-commissioned sales staff, and a\nsimplified customer experience.", "\n\nEBIT is expected to grow at a more\nmoderate 15 percent to 20 percent pace\nduring the current fiscal year as Best\nBuy Europe, the joint retail venture\nthat runs Best Buy Mobile, continues\nto invest in online operations and standalone\nstores.", "\n\nIndeed, Best Buy CEO Brian Dunn\ntold The Financial Times last month\nthat the partners may eventually open\nas many 1,000 freestanding Mobile\nstores across the U.S. in pursuit of their\nlong-term goal of a 15 percent share of\nthe domestic wireless market.", "\n\nThere are currently 1,147 Best Buy\nMobile sites throughout the U.S.,\nrepresenting an 8 percent uptick during\nCPW’s Apri l-through-March\nfiscal year. ", "The locations are comprised\nof 1,070 departments within all Best\nBuy flagship stores (up 4.6 percent year\nover year), and 77 stand-alone stores,\nwhich is nearly double the 2009 count.", "\n\nIn its own fourth-quarter earnings announcement,\nBest Buy said it planned to\nopen between 75 and 100 small-format stores during its current fiscal year, comprised\nmostly of Mobile stores. ", "Chief\nfinancial officer Jim Muehlbauer told\nanalysts during a recent conference call\nthat the 1,500-square-foot shops —\nlocated in high-traffic areas like shopping\nmalls and focused on selling “margin-\nrich” connections for wireless devices\n— generate greater margin per square\nfoot than Best Buy’s big-box locations.", "\n\nThe freestanding stores also attract a\ndifferent customer base, notably women,\nso that “the vast majority” of Mobile\nsales are incremental and do not can- nibalize the company’s flagship stores,\nDunn noted during\nthe call.", "\n\nA key profit\ndriver for both the\nfreestanding and\nin-store shops is\nthe dramatic adoption\nrate of smartphones,\nwhich will\nrepresent about 83\npercent of all cellphones\nby 2013,\nCPW projected.", "\nThe average revenue\ngenerated by a\nsmartphone activation\nis presently 3 percent\nhigher than that\nof non-smartphones,\nthe U.K.-based wireless\nretailer reported,\nwhile Geek Squad\nservice attachments\nrates are 44 percent\nfor smartphones vs.\n35 percent for nonsmartphones,\nand attachment rates of\naccessories are 36 percent for smartphones,\ncompared with 14 percent for\nless sophisticated handsets.", "\n\nSome analysts believe the strong results\ngenerated by Best Buy Mobile, and\nthe current glut of cheap retail space,\nshould put to rest rumors that chief executives\nDunn and Dunstone are planning\nto purchase RadioShack, which is\nsimilarly shifting to a mobility and connectivity-\ncentric strategy.", "\n\nMeanwhile, CPW provided a preview\nof what Best Buy stores, or at least\nthe center of their sales floors, may look\nlike in the coming months and years.", "\nCPW’s Wireless World chain, which\nincludes 29 stores in the U.K. and seven\nin Spain, is the embodiment of the\n“connected world” strategy, espoused by\nboth partners, in which CE hardware\nserves as the foundation for sales of accessories,\nsubscriptions and services.", "\n\nElements of the Wireless World format\nwill likely be incorporated into\n“connectivity centers” in the middle of\nBest Buy’s stores that will supplant slowturning\nentertainment software with\nbundled content solutions, including\nmobile and wireless broadband services\nand streaming content. ", "Dunn acknowledged\nthat various components are now\nbeing tested at Wireless World stores in\nthe U.K., and that the centers will serve\nas a “stage” in which “hardware is really\nthe starting point, not the end.”", "\n\nFor its part, CPW expressed confidence\nthat its Wireless World format is\nworking, as it “stretches the brand to incorporate\nall things connected” and prepares\nto open more than 64 new stores\nover the next 12 months.", "\n\nSeparately, Best Buy and CPW\nopened the first big-box Best Buy store\nin the U.K. last week. ", "The 50,000-\nsquare-foot unit, located in East\nLondon, is the first of eight to 10 largeformat\nstores planned for the British\nIsles this year and 60 to 150 envisioned\nfor the future." ]

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[ "<?", "php\n/**\n * SimplePie\n *\n * A PHP-Based RSS and Atom Feed Framework.", "\n * Takes the hard work out of managing a complete RSS/Atom solution.", "\n *\n * Copyright (c) 2004-2016, Ryan Parman, Sam Sneddon, Ryan McCue, and contributors\n * All rights reserved.", "\n *\n * Redistribution and use in source and binary forms, with or without modification, are\n * permitted provided that the following conditions are met:\n *\n * \t* Redistributions of source code must retain the above copyright notice, this list of\n * \t conditions and the following disclaimer.", "\n *\n * \t* Redistributions in binary form must reproduce the above copyright notice, this list\n * \t of conditions and the following disclaimer in the documentation and/or other materials\n * \t provided with the distribution.", "\n *\n * \t* Neither the name of the SimplePie Team nor the names of its contributors may be used\n * \t to endorse or promote products derived from this software without specific prior\n * \t written permission.", "\n *\n * THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS \"AS IS\" AND ANY EXPRESS\n * OR IMPLIED WARRANTIES, INCLUDING, BUT NOT LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY\n * AND FITNESS FOR A PARTICULAR PURPOSE ARE DISCLAIMED. ", "IN NO EVENT SHALL THE COPYRIGHT HOLDERS\n * AND CONTRIBUTORS BE LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL, EXEMPLARY, OR\n * CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS OR\n * SERVICES; LOSS OF USE, DATA, OR PROFITS; OR BUSINESS INTERRUPTION) HOWEVER CAUSED AND ON ANY\n * THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY, OR TORT (INCLUDING NEGLIGENCE OR\n * OTHERWISE) ARISING IN ANY WAY OUT OF THE USE OF THIS SOFTWARE, EVEN IF ADVISED OF THE\n * POSSIBILITY OF SUCH DAMAGE.", "\n *\n * @package SimplePie\n * @copyright 2004-2016 Ryan Parman, Sam Sneddon, Ryan McCue\n * @author Ryan Parman\n * @author Sam Sneddon\n * @author Ryan McCue\n * @link http://simplepie.org/ SimplePie\n * @license http://www.opensource.org/licenses/bsd-license.php BSD License\n */\n\n/**\n * Used for data cleanup and post-processing\n *\n *\n * This class can be overloaded with {@see SimplePie::set_sanitize_class()}\n *\n * @package SimplePie\n * @todo Move to using an actual HTML parser (this will allow tags to be properly stripped, and to switch between HTML and XHTML), this will also make it easier to shorten a string while preserving HTML tags\n */\nclass SimplePie_Sanitize\n{\n\t// Private vars\n\tvar $base;\n\n\t// Options\n\tvar $remove_div = true;\n\tvar $image_handler = '';\n\tvar $strip_htmltags = array('base', 'blink', 'body', 'doctype', 'embed', 'font', 'form', 'frame', 'frameset', 'html', 'iframe', 'input', 'marquee', 'meta', 'noscript', 'object', 'param', 'script', 'style');\n\tvar $encode_instead_of_strip = false;\n\tvar $strip_attributes = array('bgsound', 'expr', 'id', 'style', 'onclick', 'onerror', 'onfinish', 'onmouseover', 'onmouseout', 'onfocus', 'onblur', 'lowsrc', 'dynsrc');\n\tvar $add_attributes = array('audio' => array('preload' => 'none'), 'iframe' => array('sandbox' => 'allow-scripts allow-same-origin'), 'video' => array('preload' => 'none'));\n\tvar $strip_comments = false;\n\tvar $output_encoding = 'UTF-8';\n\tvar $enable_cache = true;\n\tvar $cache_location = './cache';\n\tvar $cache_name_function = 'md5';\n\tvar $timeout = 10;\n\tvar $useragent = '';\n\tvar $force_fsockopen = false;\n\tvar $replace_url_attributes = null;\n\n\tpublic function __construct()\n\t{\n\t\t// Set defaults\n\t\t$this->set_url_replacements(null);\n\t}\n\n\tpublic function remove_div($enable = true)\n\t{\n\t\t$this->remove_div = (bool) $enable;\n\t}\n\n\tpublic function set_image_handler($page = false)\n\t{\n\t\tif ($page)\n\t\t{\n\t\t\t$this->image_handler = (string) $page;\n\t\t}\n\t\telse\n\t\t{\n\t\t\t$this->image_handler = false;\n\t\t}\n\t}\n\n\tpublic function set_registry(SimplePie_Registry $registry)\n\t{\n\t\t$this->registry = $registry;\n\t}\n\n\tpublic function pass_cache_data($enable_cache = true, $cache_location = './cache', $cache_name_function = 'md5', $cache_class = 'SimplePie_Cache')\n\t{\n\t\tif (isset($enable_cache))\n\t\t{\n\t\t\t$this->enable_cache = (bool) $enable_cache;\n\t\t}\n\n\t\tif ($cache_location)\n\t\t{\n\t\t\t$this->cache_location = (string) $cache_location;\n\t\t}\n\n\t\tif ($cache_name_function)\n\t\t{\n\t\t\t$this->cache_name_function = (string) $cache_name_function;\n\t\t}\n\t}\n\n\tpublic function pass_file_data($file_class = 'SimplePie_File', $timeout = 10, $useragent = '', $force_fsockopen = false)\n\t{\n\t\tif ($timeout)\n\t\t{\n\t\t\t$this->timeout = (string) $timeout;\n\t\t}\n\n\t\tif ($useragent)\n\t\t{\n\t\t\t$this->useragent = (string) $useragent;\n\t\t}\n\n\t\tif ($force_fsockopen)\n\t\t{\n\t\t\t$this->force_fsockopen = (string) $force_fsockopen;\n\t\t}\n\t}\n\n\tpublic function strip_htmltags($tags = array('base', 'blink', 'body', 'doctype', 'embed', 'font', 'form', 'frame', 'frameset', 'html', 'iframe', 'input', 'marquee', 'meta', 'noscript', 'object', 'param', 'script', 'style'))\n\t{\n\t\tif ($tags)\n\t\t{\n\t\t\tif (is_array($tags))\n\t\t\t{\n\t\t\t\t$this->strip_htmltags = $tags;\n\t\t\t}\n\t\t\telse\n\t\t\t{\n\t\t\t\t$this->strip_htmltags = explode(',', $tags);\n\t\t\t}\n\t\t}\n\t\telse\n\t\t{\n\t\t\t$this->strip_htmltags = false;\n\t\t}\n\t}\n\n\tpublic function encode_instead_of_strip($encode = false)\n\t{\n\t\t$this->encode_instead_of_strip = (bool) $encode;\n\t}\n\n\tpublic function strip_attributes($attribs = array('bgsound', 'expr', 'id', 'style', 'onclick', 'onerror', 'onfinish', 'onmouseover', 'onmouseout', 'onfocus', 'onblur', 'lowsrc', 'dynsrc'))\n\t{\n\t\tif ($attribs)\n\t\t{\n\t\t\tif (is_array($attribs))\n\t\t\t{\n\t\t\t\t$this->strip_attributes = $attribs;\n\t\t\t}\n\t\t\telse\n\t\t\t{\n\t\t\t\t$this->strip_attributes = explode(',', $attribs);\n\t\t\t}\n\t\t}\n\t\telse\n\t\t{\n\t\t\t$this->strip_attributes = false;\n\t\t}\n\t}\n\n\tpublic function add_attributes($attribs = array('audio' => array('preload' => 'none'), 'iframe' => array('sandbox' => 'allow-scripts allow-same-origin'), 'video' => array('preload' => 'none')))\n\t{\n\t\tif ($attribs)\n\t\t{\n\t\t\tif (is_array($attribs))\n\t\t\t{\n\t\t\t\t$this->add_attributes = $attribs;\n\t\t\t}\n\t\t\telse\n\t\t\t{\n\t\t\t\t$this->add_attributes = explode(',', $attribs);\n\t\t\t}\n\t\t}\n\t\telse\n\t\t{\n\t\t\t$this->add_attributes = false;\n\t\t}\n\t}\n\n\tpublic function strip_comments($strip = false)\n\t{\n\t\t$this->strip_comments = (bool) $strip;\n\t}\n\n\tpublic function set_output_encoding($encoding = 'UTF-8')\n\t{\n\t\t$this->output_encoding = (string) $encoding;\n\t}\n\n\t/**\n\t * Set element/attribute key/value pairs of HTML attributes\n\t * containing URLs that need to be resolved relative to the feed\n\t *\n\t * Defaults to |a|@href, |area|@href, |blockquote|@cite, |del|@cite,\n\t * |form|@action, |img|@longdesc, |img|@src, |input|@src, |ins|@cite,\n\t * |q|@cite\n\t *\n\t * @since 1.0\n\t * @param array|null $element_attribute Element/attribute key/value pairs, null for default\n\t */\n\tpublic function set_url_replacements($element_attribute = null)\n\t{\n\t\tif ($element_attribute === null)\n\t\t{\n\t\t\t$element_attribute = array(\n\t\t\t\t'a' => 'href',\n\t\t\t\t'area' => 'href',\n\t\t\t\t'blockquote' => 'cite',\n\t\t\t\t'del' => 'cite',\n\t\t\t\t'form' => 'action',\n\t\t\t\t'img' => array(\n\t\t\t\t\t'longdesc',\n\t\t\t\t\t'src'\n\t\t\t\t),\n\t\t\t\t'input' => 'src',\n\t\t\t\t'ins' => 'cite',\n\t\t\t\t'q' => 'cite'\n\t\t\t);\n\t\t}\n\t\t$this->replace_url_attributes = (array) $element_attribute;\n\t}\n\n\tpublic function sanitize($data, $type, $base = '')\n\t{\n\t\t$data = trim($data);\n\t\tif ($data !", "== '' || $type & SIMPLEPIE_CONSTRUCT_IRI)\n\t\t{\n\t\t\tif ($type & SIMPLEPIE_CONSTRUCT_MAYBE_HTML)\n\t\t\t{\n\t\t\t\tif (preg_match('/(&(#(x[0-9a-fA-F]+|[0-9]+)|[a-zA-Z0-9]+)|<\\/[A-Za-z][^\\x09\\x0A\\x0B\\x0C\\x0D\\x20\\x2F\\x3E]*' . ", "SIMPLEPIE_PCRE_HTML_ATTRIBUTE . '", ">)/', $data))\n\t\t\t\t{\n\t\t\t\t\t$type |= SIMPLEPIE_CONSTRUCT_HTML;\n\t\t\t\t}\n\t\t\t\telse\n\t\t\t\t{\n\t\t\t\t\t$type |= SIMPLEPIE_CONSTRUCT_TEXT;\n\t\t\t\t}\n\t\t\t}\n\n\t\t\tif ($type & SIMPLEPIE_CONSTRUCT_BASE64)\n\t\t\t{\n\t\t\t\t$data = base64_decode($data);\n\t\t\t}\n\n\t\t\tif ($type & (SIMPLEPIE_CONSTRUCT_HTML | SIMPLEPIE_CONSTRUCT_XHTML))\n\t\t\t{\n\n\t\t\t\tif (!", "class_exists('DOMDocument'))\n\t\t\t\t{\n\t\t\t\t\tthrow new SimplePie_Exception('DOMDocument not found, unable to use sanitizer');\n\t\t\t\t}\n\t\t\t\t$document = new DOMDocument();\n\t\t\t\t$document->encoding = 'UTF-8';\n\n\t\t\t\t$data = $this->preprocess($data, $type);\n\n\t\t\t\tset_error_handler(array('SimplePie_Misc', 'silence_errors'));\n\t\t\t\t$document->loadHTML($data);\n\t\t\t\trestore_error_handler();\n\n\t\t\t\t$xpath = new DOMXPath($document);\n\n\t\t\t\t// Strip comments\n\t\t\t\tif ($this->strip_comments)\n\t\t\t\t{\n\t\t\t\t\t$comments = $xpath->query('//comment()');\n\n\t\t\t\t\tforeach ($comments as $comment)\n\t\t\t\t\t{\n\t\t\t\t\t\t$comment->parentNode->removeChild($comment);\n\t\t\t\t\t}\n\t\t\t\t}\n\n\t\t\t\t// Strip out HTML tags and attributes that might cause various security problems.", "\n\t\t\t\t// Based on recommendations by Mark Pilgrim at:\n\t\t\t\t// http://diveintomark.org/archives/2003/06/12/how_to_consume_rss_safely\n\t\t\t\tif ($this->strip_htmltags)\n\t\t\t\t{\n\t\t\t\t\tforeach ($this->strip_htmltags as $tag)\n\t\t\t\t\t{\n\t\t\t\t\t\t$this->strip_tag($tag, $document, $xpath, $type);\n\t\t\t\t\t}\n\t\t\t\t}\n\n\t\t\t\tif ($this->strip_attributes)\n\t\t\t\t{\n\t\t\t\t\tforeach ($this->strip_attributes as $attrib)\n\t\t\t\t\t{\n\t\t\t\t\t\t$this->strip_attr($attrib, $xpath);\n\t\t\t\t\t}\n\t\t\t\t}\n\n\t\t\t\tif ($this->add_attributes)\n\t\t\t\t{\n\t\t\t\t\tforeach ($this->add_attributes as $tag => $valuePairs)\n\t\t\t\t\t{\n\t\t\t\t\t\t$this->add_attr($tag, $valuePairs, $document);\n\t\t\t\t\t}\n\t\t\t\t}\n\n\t\t\t\t// Replace relative URLs\n\t\t\t\t$this->base = $base;\n\t\t\t\tforeach ($this->replace_url_attributes as $element => $attributes)\n\t\t\t\t{\n\t\t\t\t\t$this->replace_urls($document, $element, $attributes);\n\t\t\t\t}\n\n\t\t\t\t// If image handling (caching, etc.) ", "is enabled, cache and rewrite all the image tags.", "\n\t\t\t\tif (isset($this->image_handler) && ((string) $this->image_handler) !", "== '' && $this->enable_cache)\n\t\t\t\t{\n\t\t\t\t\t$images = $document->getElementsByTagName('img');\n\t\t\t\t\tforeach ($images as $img)\n\t\t\t\t\t{\n\t\t\t\t\t\tif ($img->hasAttribute('src'))\n\t\t\t\t\t\t{\n\t\t\t\t\t\t\t$image_url = call_user_func($this->cache_name_function, $img->getAttribute('src'));\n\t\t\t\t\t\t\t$cache = $this->registry->call('Cache', 'get_handler', array($this->cache_location, $image_url, 'spi'));\n\n\t\t\t\t\t\t\tif ($cache->load())\n\t\t\t\t\t\t\t{\n\t\t\t\t\t\t\t\t$img->setAttribute('src', $this->image_handler . ", "$image_url);\n\t\t\t\t\t\t\t}\n\t\t\t\t\t\t\telse\n\t\t\t\t\t\t\t{\n\t\t\t\t\t\t\t\t$file = $this->registry->create('File', array($img->getAttribute('src'), $this->timeout, 5, array('X-FORWARDED-FOR' => $_SERVER['REMOTE_ADDR']), $this->useragent, $this->force_fsockopen));\n\t\t\t\t\t\t\t\t$headers = $file->headers;\n\n\t\t\t\t\t\t\t\tif ($file->success && ($file->method & SIMPLEPIE_FILE_SOURCE_REMOTE === 0 || ($file->status_code === 200 || $file->status_code > 206 && $file->status_code < 300)))\n\t\t\t\t\t\t\t\t{\n\t\t\t\t\t\t\t\t\tif ($cache->save(array('headers' => $file->headers, 'body' => $file->body)))\n\t\t\t\t\t\t\t\t\t{\n\t\t\t\t\t\t\t\t\t\t$img->setAttribute('src', $this->image_handler . ", "$image_url);\n\t\t\t\t\t\t\t\t\t}\n\t\t\t\t\t\t\t\t\telse\n\t\t\t\t\t\t\t\t\t{\n\t\t\t\t\t\t\t\t\t\ttrigger_error(\"$this->cache_location is not writable. ", "Make sure you've set the correct relative or absolute path, and that the location is server-writable.\", ", "E_USER_WARNING);\n\t\t\t\t\t\t\t\t\t}\n\t\t\t\t\t\t\t\t}\n\t\t\t\t\t\t\t}\n\t\t\t\t\t\t}\n\t\t\t\t\t}\n\t\t\t\t}\n\n\t\t\t\t// Get content node\n\t\t\t\t$div = $document->getElementsByTagName('body')->item(0)->firstChild;\n\t\t\t\t// Finally, convert to a HTML string\n\t\t\t\t$data = trim($document->saveHTML($div));\n\n\t\t\t\tif ($this->remove_div)\n\t\t\t\t{\n\t\t\t\t\t$data = preg_replace('/^<div' . ", "SIMPLEPIE_PCRE_XML_ATTRIBUTE . '", ">/', '', $data);\n\t\t\t\t\t$data = preg_replace('/<\\/div>$/', '', $data);\n\t\t\t\t}\n\t\t\t\telse\n\t\t\t\t{\n\t\t\t\t\t$data = preg_replace('/^<div' . ", "SIMPLEPIE_PCRE_XML_ATTRIBUTE . '", ">/', '<div>', $data);\n\t\t\t\t}\n\t\t\t}\n\n\t\t\tif ($type & SIMPLEPIE_CONSTRUCT_IRI)\n\t\t\t{\n\t\t\t\t$absolute = $this->registry->call('Misc', 'absolutize_url', array($data, $base));\n\t\t\t\tif ($absolute !", "== false)\n\t\t\t\t{\n\t\t\t\t\t$data = $absolute;\n\t\t\t\t}\n\t\t\t}\n\n\t\t\tif ($type & (SIMPLEPIE_CONSTRUCT_TEXT | SIMPLEPIE_CONSTRUCT_IRI))\n\t\t\t{\n\t\t\t\t$data = htmlspecialchars($data, ENT_COMPAT, 'UTF-8');\n\t\t\t}\n\n\t\t\tif ($this->output_encoding !", "== 'UTF-8')\n\t\t\t{\n\t\t\t\t$data = $this->registry->call('Misc', 'change_encoding', array($data, 'UTF-8', $this->output_encoding));\n\t\t\t}\n\t\t}\n\t\treturn $data;\n\t}\n\n\tprotected function preprocess($html, $type)\n\t{\n\t\t$ret = '';\n\t\t$html = preg_replace('%</?(?:html|body)[^>]*?'.", "'>%is', '', $html);\n\t\tif ($type & ~SIMPLEPIE_CONSTRUCT_XHTML)\n\t\t{\n\t\t\t// Atom XHTML constructs are wrapped with a div by default\n\t\t\t// Note: No protection if $html contains a stray </div>!", "\n\t\t\t$html = '<div>' . ", "$html . '", "</div>';\n\t\t\t$ret .= '<!", "DOCTYPE html>';\n\t\t\t$content_type = 'text/html';\n\t\t}\n\t\telse\n\t\t{\n\t\t\t$ret .= '<!", "DOCTYPE html PUBLIC \"-//W3C//DTD XHTML 1.0 Strict//EN\" \"http://www.w3.org/TR/xhtml1/DTD/xhtml1-strict.dtd\">';\n\t\t\t$content_type = 'application/xhtml+xml';\n\t\t}\n\n\t\t$ret .= '<html><head>';\n\t\t$ret .= '<meta http-equiv=\"Content-Type\" content=\"' . ", "$content_type . '; ", "charset=utf-8\" />';\n\t\t$ret .= '</head><body>' . ", "$html . '", "</body></html>';\n\t\treturn $ret;\n\t}\n\n\tpublic function replace_urls($document, $tag, $attributes)\n\t{\n\t\tif (!", "is_array($attributes))\n\t\t{\n\t\t\t$attributes = array($attributes);\n\t\t}\n\n\t\tif (!", "is_array($this->strip_htmltags) || !", "in_array($tag, $this->strip_htmltags))\n\t\t{\n\t\t\t$elements = $document->getElementsByTagName($tag);\n\t\t\tforeach ($elements as $element)\n\t\t\t{\n\t\t\t\tforeach ($attributes as $attribute)\n\t\t\t\t{\n\t\t\t\t\tif ($element->hasAttribute($attribute))\n\t\t\t\t\t{\n\t\t\t\t\t\t$value = $this->registry->call('Misc', 'absolutize_url', array($element->getAttribute($attribute), $this->base));\n\t\t\t\t\t\tif ($value !", "== false)\n\t\t\t\t\t\t{\n\t\t\t\t\t\t\t$element->setAttribute($attribute, $value);\n\t\t\t\t\t\t}\n\t\t\t\t\t}\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\t}\n\n\tpublic function do_strip_htmltags($match)\n\t{\n\t\tif ($this->encode_instead_of_strip)\n\t\t{\n\t\t\tif (isset($match[4]) && !", "in_array(strtolower($match[1]), array('script', 'style')))\n\t\t\t{\n\t\t\t\t$match[1] = htmlspecialchars($match[1], ENT_COMPAT, 'UTF-8');\n\t\t\t\t$match[2] = htmlspecialchars($match[2], ENT_COMPAT, 'UTF-8');\n\t\t\t\treturn \"&lt;$match[1]$match[2]&gt;$match[3]&lt;/$match[1]&gt;\";\n\t\t\t}\n\t\t\telse\n\t\t\t{\n\t\t\t\treturn htmlspecialchars($match[0], ENT_COMPAT, 'UTF-8');\n\t\t\t}\n\t\t}\n\t\telseif (isset($match[4]) && !", "in_array(strtolower($match[1]), array('script', 'style')))\n\t\t{\n\t\t\treturn $match[4];\n\t\t}\n\t\telse\n\t\t{\n\t\t\treturn '';\n\t\t}\n\t}\n\n\tprotected function strip_tag($tag, $document, $xpath, $type)\n\t{\n\t\t$elements = $xpath->query('body//' . ", "$tag);\n\t\tif ($this->encode_instead_of_strip)\n\t\t{\n\t\t\tforeach ($elements as $element)\n\t\t\t{\n\t\t\t\t$fragment = $document->createDocumentFragment();\n\n\t\t\t\t// For elements which aren't script or style, include the tag itself\n\t\t\t\tif (!", "in_array($tag, array('script', 'style')))\n\t\t\t\t{\n\t\t\t\t\t$text = '<' . ", "$tag;\n\t\t\t\t\tif ($element->hasAttributes())\n\t\t\t\t\t{\n\t\t\t\t\t\t$attrs = array();\n\t\t\t\t\t\tforeach ($element->attributes as $name => $attr)\n\t\t\t\t\t\t{\n\t\t\t\t\t\t\t$value = $attr->value;\n\n\t\t\t\t\t\t\t// In XHTML, empty values should never exist, so we repeat the value\n\t\t\t\t\t\t\tif (empty($value) && ($type & SIMPLEPIE_CONSTRUCT_XHTML))\n\t\t\t\t\t\t\t{\n\t\t\t\t\t\t\t\t$value = $name;\n\t\t\t\t\t\t\t}\n\t\t\t\t\t\t\t// For HTML, empty is fine\n\t\t\t\t\t\t\telseif (empty($value) && ($type & SIMPLEPIE_CONSTRUCT_HTML))\n\t\t\t\t\t\t\t{\n\t\t\t\t\t\t\t\t$attrs[] = $name;\n\t\t\t\t\t\t\t\tcontinue;\n\t\t\t\t\t\t\t}\n\n\t\t\t\t\t\t\t// Standard attribute text\n\t\t\t\t\t\t\t$attrs[] = $name . '", "=\"' . ", "$attr->value . '\"';", "\n\t\t\t\t\t\t}\n\t\t\t\t\t\t$text .= ' ' . ", "implode(' ', $attrs);\n\t\t\t\t\t}\n\t\t\t\t\t$text .= '>';\n\t\t\t\t\t$fragment->appendChild(new DOMText($text));\n\t\t\t\t}\n\n\t\t\t\t$number = $element->childNodes->length;\n\t\t\t\tfor ($i = $number; $i > 0; $i--)\n\t\t\t\t{\n\t\t\t\t\t$child = $element->childNodes->item(0);\n\t\t\t\t\t$fragment->appendChild($child);\n\t\t\t\t}\n\n\t\t\t\tif (!", "in_array($tag, array('script', 'style')))\n\t\t\t\t{\n\t\t\t\t\t$fragment->appendChild(new DOMText('</' . ", "$tag . '", ">'));\n\t\t\t\t}\n\n\t\t\t\t$element->parentNode->replaceChild($fragment, $element);\n\t\t\t}\n\n\t\t\treturn;\n\t\t}\n\t\telseif (in_array($tag, array('script', 'style')))\n\t\t{\n\t\t\tforeach ($elements as $element)\n\t\t\t{\n\t\t\t\t$element->parentNode->removeChild($element);\n\t\t\t}\n\n\t\t\treturn;\n\t\t}\n\t\telse\n\t\t{\n\t\t\tforeach ($elements as $element)\n\t\t\t{\n\t\t\t\t$fragment = $document->createDocumentFragment();\n\t\t\t\t$number = $element->childNodes->length;\n\t\t\t\tfor ($i = $number; $i > 0; $i--)\n\t\t\t\t{\n\t\t\t\t\t$child = $element->childNodes->item(0);\n\t\t\t\t\t$fragment->appendChild($child);\n\t\t\t\t}\n\n\t\t\t\t$element->parentNode->replaceChild($fragment, $element);\n\t\t\t}\n\t\t}\n\t}\n\n\tprotected function strip_attr($attrib, $xpath)\n\t{\n\t\t$elements = $xpath->query('//*[@' . ", "$attrib . ']');", "\n\n\t\tforeach ($elements as $element)\n\t\t{\n\t\t\t$element->removeAttribute($attrib);\n\t\t}\n\t}\n\n\tprotected function add_attr($tag, $valuePairs, $document)\n\t{\n\t\t$elements = $document->getElementsByTagName($tag);\n\t\tforeach ($elements as $element)\n\t\t{\n\t\t\tforeach ($valuePairs as $attrib => $value)\n\t\t\t{\n\t\t\t\t$element->setAttribute($attrib, $value);\n\t\t\t}\n\t\t}\n\t}\n}\n" ]

{ "pile_set_name": "Github" }

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[ "Q:\n\nHow to create functional Methods\n\nWhat I want to approach is to create a custom Function that looks like this:\naccess('h1').content('Hello World');\n\nAnd this is how I tried to accomplish that:\nfunction access(Tag)\n{\n var Element = document.getElementsByTagName(Tag)[0];\n\n this.content = function(Content)\n {\n if (Content !", "== undefined)\n return Element.innerHTML = Content;\n else return Element.innerHTML;\n }\n\n return Element;\n}\n\nSo this Function shall be in the verge of changing the Content or just returning it.", "\nUnfortunately it does not work this Way.", "\nSo far I played with it for about an Hour to rewrite it and find a Solution on my own, but I have not been successfull and I also do not know how to describe this Problem to Google it.", "\nHow can I solve this it?", "\n\nA:\n\nReplace this with Element in your code.", "\n\nfunction access(Tag)\r\n {\r\n var Element = document.getElementsByTagName(Tag)[0];\r\n \r\n Element.content = function(Content)\r\n {\r\n if (Content !", "== undefined)\r\n return Element.innerHTML = Content;\r\n else return Element.innerHTML;\r\n }\r\n \r\n return Element;\r\n }\r\n \r\naccess('h1').content('Hello World');\n<h1>Hello</h1>\n\nOr try something like this. ", "\n\nfunction access(Tag)\r\n {\r\n var Element = document.getElementsByTagName(Tag)[0];\r\n \r\n var content = function(Content)\r\n {\r\n if (Content !", "== undefined)\r\n return Element.innerHTML = Content;\r\n else return Element.innerHTML;\r\n }\r\n \r\n return {content: content};\r\n }\r\n \r\naccess('h1').content('Hello World');\n<h1>Hello</h1>\n\n" ]

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[ "Aberrant mRNA translation in cancer pathogenesis: an old concept revisited comes finally of age.", "\nAs the molecular processes that control mRNA translation and ribosome biogenesis in the eukaryotic cell are extremely complex and multilayered, their deregulation can in principle occur at multiple levels, leading to both disease and cancer pathogenesis. ", "For a long time, it was speculated that disruption of these processes may participate in tumorigenesis, but this notion was, until recently, solely supported by correlative studies. ", "Strong genetic support is now being accrued, while new molecular links between tumor-suppressive and oncogenic pathways and the control of protein synthetic machinery are being unraveled. ", "The importance of aberrant protein synthesis in tumorigenesis is further underscored by the discovery that compounds such as Rapamycin, known to modulate signaling pathways regulatory of this process, are effective anticancer drugs. ", "A number of fundamental questions remain to be addressed and a number of novel ones emerge as this exciting field evolves." ]

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[ "Introduction {#s1}\n============\n\nThe heavy-ion beam is an effective and unique mutagen that can induce mutations at a high rate and on a broad spectrum. ", "It has been widely used in the mutation breeding of plants and microbes because of their distinct physical and biological advantages. ", "The most important physical aspect of the heavy-ion beam is the greater linear energy transfer (LET) than X-rays, gamma rays, and electrons. ", "LET represents the energy deposition of ionizing radiations on their per unit track. ", "This high concentration of deposited energy can cause more severe damage to the target biomolecules, such as, proteins, membrane lipids, and nucleic acids. ", "Hence, the heavy-ion beam provides a higher relative biological effectiveness (RBE) than the low LET radiation (Tanaka et al., [", "@B46]; Kazama et al., [", "@B16]; Nagata et al., [", "@B29]; Zhou et al., [", "@B57]). ", "For plant mutation breeding, various mutant populations have been generated by heavy-ion beam irradiation: for instance, those of *Arabidopsis thaliana* (Tanaka et al., [", "@B47], [@B45]), *Lotus japonicus* (Oka-Kira et al., [", "@B32]; Luo et al., [", "@B26]), Rice (*Oryza sativa* L.) (Ishikawa et al., [", "@B15]; Phanchaisri et al., [", "@B35]; Morita et al., [", "@B28]), Petunia (*Petunia hybrid*), Hase et al., [", "@B9]), *Tricyrtis hirta* (Nakano et al., [", "@B31]), Chrysanthemum (Matsumura et al., [", "@B27]), Wandering Jew (He et al., [", "@B11]), Geranium (Yu et al., [", "@B56]), and so on.", "\n\nThe creation of such mutations is an essential resource tool to better link phenotype screening, gene isolation, and function mining, in both forward and reverse genetics. ", "DNA, carrying the genetic information, was originally thought as the main target of radiation. ", "The radiation-induced DNA damage involved direct injury caused by thermal, dynamic, and ionization, as well as the indirect injury caused by the cytotoxic reaction to energy deposition (Ravanat et al., [", "@B36]; Kovacs and Keresztes, [@B19]; Alizadeh et al., [", "@B1]; Tokuyama et al., [", "@B50]). ", "The mutagenic effects and molecular characteristics of mutations induced by heavy-ion beam are important in two respects: (1) For choosing the most suitable kinds of ionizing radiation; and (2) For elucidating the molecular profile and rate of mutations induced by heavy-ion beam at DNA level. ", "Together, they form an important subject that is multi-disciplinary, such as radiobiology, molecular biology, genetics, biochemistry, etc. ", "In the last century, the characterization of mutations induced by radiation was done by focusing on the phenotype, chromosome aberration, genetic polymorphism or sequencing analysis of specific genes only (Shikazono et al., [", "@B41]; Kazama et al., [", "@B16]; Hase et al., [", "@B10]; Hirano et al., [", "@B14]; Yan et al., [", "@B7]). ", "However, whether restricted by detecting technology or by high operating costs, we still lack the investigation at whole genome level.", "\n\nIn response to the urgent demands of genome-wide studies, next generation sequencing (NGS) \\[also called the high-throughput sequencing (HTS)\\] techniques (Schuster, [@B39]; Shendure and Ji, [@B40])---such as, Illummia/Solexa, Roche/454, and AB/SOLiD---were rapidly developed to enable the fast sequencing and mutation scanning for genomic mutation identification, species evolution, genetic diseases, etc. (", "Uchida et al., [", "@B51]; Belfield et al., [", "@B2]; Bolon et al., [", "@B3]; Xia et al., [", "@B54]; Zhou et al., [", "@B58]; Tiwari et al., [", "@B49]; Lehrbach et al., [", "@B22]; Tao et al., [", "@B48]). ", "For instance, using NGS techniques, mutations induced by ethylmethane sulphonate (EMS) were found to be mainly consist of G/C--A/T transitions (Uchida et al., [", "@B51]). ", "An EMS-induced causal mutation in *CTR1* required for boron-mediated root development by low-coverage genome re-sequencing in *A. thaliana* was successfully identified though association of re-sequencing and rough map-based cloning (Tabata et al., [", "@B43]). ", "An efficient protocol, based on the NGS, to map and identify EMS-induced mutations in *Caenorhabditis elegans* were reported in 2017 (Lehrbach et al., [", "@B22]). ", "Moreover, results obtained from NGS techniques have shown that the variations induced by radiation were, to some extent, different from the publications which have been previously reported. ", "Taking the fast neutron exposure for instance: it was deemed to predominantly induce large deletions in size more than a kilo base in *A. thaliana* by the southern blot analysis of the restricted loci. ", "However, a re-sequencing analysis of six mutants derived from fast neutron exposure indicated that the proportion of substitutions prevails over insertion-deletion (INDELs) mutations and that small deletions were more common than large fragment deletions (Bruggemann et al., [", "@B4]; Belfield et al., [", "@B2]; O\\'Rourke et al., [", "@B33]). ", "Therefore, utilizing the NGS techniques would complement and complete our knowledge of the actual nature of mutations induced by ionizing radiation. ", "The corresponding algorithm tools, such as, the Sequence Alignment/Map (SAM) (Li et al., [", "@B25]), Bowtie (Langmead et al., [", "@B20]), the SHORE pipeline (Schneeberger et al., [", "@B38]), and VarScan (Koboldt et al., [", "@B17], [@B18]), have been rapidly developed for processing big datasets obtained by NGS. ", "Specifically, the flow of the Illummia/Solexa, one of the most mainstream NGS platforms, is as the following: (1) fragment the genomic DNA; (2) perform end-joining, followed by adding A to 3′ end; (3) ligation of the Solexa adapter; (4) recover and purify the target fragment, then amplify it via PCR; (5) cluster amplification and sequencing-by-synthesis reads obtained by sequencing, (6) data processing. ", "For whole genome re-sequencing of model organisms, the clean reads are mapped against the reference genome (associated with bioinformatics analysis). ", "The genomic mutations (i.e., the sequence and structure variants) are then called by using the corresponding algorithm tools.", "\n\nIn the current study, we re-sequenced 11 mutagenesis progeny (M3) *A. thaliana* lines---nine mutants with visible and heritable traits, and two M3 mutagenesis progeny with inconspicuous phenotypes---derived from carbon-ion beam (CIB) irradiation by using the Illumina sequencing platform. ", "Focusing on substitutions and small INDELs, we revealed the genome-wide molecular profile and rate of mutations induced by CIB irradiation in *A. thaliana*.", "\n\nMaterials and methods {#s2}\n=====================\n\nIrradiation of CIB and mutant screening\n---------------------------------------\n\nThe seeds of laboratory wild type *A. thaliana* (Lab-WT)---Columbia genetic background---were exposed to ^12^C^6+^ ions at 200 Gy (energy, 43 MeV/nucleon; average LET within samples, 50 keV/μm) generated by the Heavy Ion Research Facility in Lanzhou (HIRFL) at the Institute of Modern Physics, Chinese Academy of Sciences (IMP-CAS). ", "Methods of plant growth and mutation screening were described in a previous study (Yan et al., [", "@B7]). ", "Nine mutant lines (M3) that displayed visible and heritable traits (C7, C116, C197, C352, C357, C541, C600, C828, C941), as well as two mutagenesis progeny (M3) lines which with inconspicuous mutant phenotypes (C1001, C1322), along with the Lab-WT line were chosen for whole genome re-sequencing.", "\n\nWhole genome re-sequencing\n--------------------------\n\nYoung leaves were collected from the Lab-WT line and 11 M3 lines derived from CIB. ", "Genomic DNA was extracted by using the routine protocol of CTAB (cetyltrimethylammonium bromide). ", "The genomic re-sequencing was performed by the IIIumina HiSeq^TM^ 2500 system (Illumina, Inc.; San Diego, CA, USA) at the Biomarker Technologies Company (Beijing, China). ", "Raw data were filtered following the standard process of Illumina, and the clean data obtained were then mapped onto the reference genome of Col-0 (TAIR10, <http://www.ncbi.nlm.nih.gov/assembly/GCF_000001735.3>) by using the Burrows-Wheeler Alignment tool (<http://bio-bwa.sourceforge.net/bwa.shtml>, v.0.7.15; Li and Durbin, [@B24]) and SAMtools (<http://www.htslib.org/workflow/#mapping_to_variant>, v.1.3.1; Li et al., [", "@B25]). ", "The average depth of the re-sequenced lines had a 23--33-fold range, while those reads with a depth \\>10-fold accounted for up to 98.87% of the total reference genome, on average (Table [S1](#SM1){ref-type=\"supplementary-material\"}).", "\n\nIdentification of the variants\n------------------------------\n\nThe VarScan 2 algorithms (v.3.9, <http://varscan.sourceforge.net>) were used to read the SAMtools mpileup output, and the substitutions and small INDELs were called with settings described below:\n\nMin coverage: Minimum read depth at a position to make a call is eight;\n\nMin reads2: Minimum supporting reads at a position to call variants is two;\n\nMmin-var-freq: Minimum variant allele frequency threshold is 0.01;\n\n*P*-value: Default *p*-value threshold for calling variants is 0.99.", "\n\nThe true candidate mutations induced by CIB were screened as followed steps:\n\n1. ", " Following the VarScan 2 algorithms, to filter the background mutations in the Lab-WT line---and to identify the particular mutations of each mutagenesis progeny---only those mutation sites with a variant allele frequency by read count were between 25--100% in a sample, while 0--10% in other samples were reserved; those variants with a variant allele frequency of ≥75% were called homozygous. ", "Against this, the sites shared by the 12 sequenced lines were called as the background mutations.", "\n\n2. ", " Although the filtering standard of step (1) was effective at reducing the rate of false positives, to ensure the accuracy of mutation detection, the candidate mutations derived from step (1) of each sequenced line were visually confirmed in the Integrative Genomics Viewer (<http://software.broadinstitute.org/software/igv/>, v.2.3).", "\n\nMutation annotation\n-------------------\n\nVariant annotation and predicted effects were performed by the SnpEff toolbox (<http://snpeff.sourceforge.net/index.html>, v.4.2).", "\n\nVerification of the mutation sites by sanger sequencing\n-------------------------------------------------------\n\nThe specific primers of mutation sites obtained by re-sequencing were designed by PRIMER3 (<http://bioinfo.ut.ee/primer3-0.4.0/>). ", "The primers used for PCR are P1 (5′-TTTGCTGTTGGTAGTGTGCC-3′, 5′-TGGAAGTAGAGTGCAGCGAT-3′), P2 (5′-TATGCTTGCACGTTTGCTTC-3′, 5′-GGCTTGAGAGTTGGGTGAAC-3′), P3 (5′-CACTTCTTTTCCCCAACGGT-3′, 5′-TACATGCTTGCATCACCCAC-3′), P4 (5′-GACGACCTCCCAGATATGCC-3′, 5′-GGAGATTGTGGGGTCCCAAG-3′), P5 (5′-CAGGAGCAACTTACCAACGG-3′, 5′-GAACAATACAGGTGGCGTGG-3′), P6 (5′-TGTGATCAAGAGTGTCGGCT-3′, 5′-ACGTCAAAACTTCCTCCCCA-3′) and P7(5′-CCCCTGATAAGTTGCGTTTAAGT-3′, 5′-ACTTGATGACATGGGAGGCA-3′). ", "Genomic DNA was extracted by using the routine protocol of CTAB. ", "PCR amplification was performed with an initial denaturation step at 95°C for 5 min, followed by 38 cycles at 94°C for 30 s, 58°C for 30 s, and 72°C for 30 s, with a final extension step at 72°C for 10 min. ", "The PCR products were then detected by electrophoresis on a 1.5% agarose gel; only the qualified PCR products were used for Sanger sequencing.", "\n\nData availability\n-----------------\n\nThe whole-genome sequencing data reported in this study have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics, 2017) in BIG Data Center (Nucleic Acids Res, 2017), Beijing Institute of Genomics (BIG), Chinese Academy of Sciences, under accession number [CRA000464](CRA000464) that is publicly accessible at <http://bigd.big.ac.cn/gsa>.", "\n\nResults {#s3}\n=======\n\nCIB irradiation and mutagenesis progeny\n---------------------------------------\n\nThe Lab-WT *A. thaliana* seeds were exposed to CIB irradiation with the aim (though not the focus of the present study) of constructing a comprehensive carbon-ion-induced mutation resource collection for *A. thaliana*. ", "The M2 seedlings were screened for abnormal phenotypes by comparison with the Lab-WT; meanwhile, several lines lacking obvious mutant traits were also reserved. ", "In total, more than 1,000 independent plants were isolated. ", "Our subsequent analyses were based on nine mutant lines (M3) that displayed visible and heritable traits (i.e., C7, C116, C197, C352, C357, C541, C600, C828, C941), as well as two mutagenesis progeny (M3) lines which with inconspicuous mutant phenotypes (i.e., C1001, C1322), together with the Lab-WT line were chosen for whole genome re-sequencing. ", "The phenotypes of the nine stable lines are shown in Figure [1](#F1){ref-type=\"fig\"}.", "\n\n{#F1}\n\nMutations shared by the 12 sequenced lines\n------------------------------------------\n\nDNA sequence data from a single Lab-WT line and other 11 mutagenesis progeny lines were aligned to the *A. thaliana* Information Resource (TAIR 10) (<http://www.arabidopsis.org>) Col-0 reference genome by using BWA, Samtools, and VarScan 2. ", "The mapping results for the mutant sequencing reads for each line are shown in Table [S1](#SM1){ref-type=\"supplementary-material\"}. ", "Before the variants analysis, we surmised that there were a number of substitutions and INDELs which might be the background discrepancies that originally existed between the Lab-WT and Col-0 reference genomes. ", "To identify those variations truly induced by CIB irradiation, it was reasonable to rule out these background discrepancies firstly. ", "Analyzed by group, since the 11 mutagenesis progeny lines were in the same background (Columbia), the variants shared by the 12 sequenced lines were considered as the background mutations. ", "On this premise, a total of 2,973 substitutions and 1,407 INDELs were identified (Figure [2](#F2){ref-type=\"fig\"}).", "\n\n{#F2}\n\nTo verify whether the background mutations were indeed correct, seven sites shared by the 12 sequenced lines were selected for Sanger sequencing. ", "To increase the credibility, another M3 line (C172), one not re-sequenced by NGS, was also included. ", "The Sanger sequencing results indicated that those sites obtained by NGS were indeed common background mutations in our Lab-WT (Figure [3](#F3){ref-type=\"fig\"}). ", "These background mutations were unevenly distributed in the Lab-WT genome: the highest mutation number was observed on chromosome 4, with a change rate of one per 14,407 nucleotide base pairs along the genome. ", "Interestingly, substitutions and INDELs tended to occur in the peri-centromeric regions of each chromosome as clusters, especially in chromosome 1. ", "This result is basically consistent with the spontaneous mutations in *A. thaliana* in previous report (Ossowski et al., [", "@B34]), although the mechanism of such a mutational bias remains unexplored.", "\n\n{#F3}\n\nDistribution and rates of mutations induced by CIB irradiation\n--------------------------------------------------------------\n\nTo identify the exclusive mutations of each mutagenesis progeny line, combining the mutation calling by VarScan 2 and the visual confirmation by the Integrative Genomics Viewer (IGV), a total of 320 substitutions and 124 INDELs were detected, and the ratio of substitutions to INDELs was calculated as 2.58:1 (Figures [4](#F4){ref-type=\"fig\"}, [5A](#F5){ref-type=\"fig\"}). ", "The number of variations per line ranged from 20 to 62, and their distribution across the chromosomes in each of the 11 lineages is shown in Figure [4](#F4){ref-type=\"fig\"}. ", "However, no remarkable regularity in variant rate of single base substitutions and small INDELs across each chromosome were found in the 11 re-sequenced lines (Table [1](#T1){ref-type=\"table\"}). ", "At the genome-wide scale, 67.57% of the 444 detected CIB irradiation-induced mutations occurred in the upstream and downstream regions, 4.50% in the 3′/5′-untranslated regions (UTR), 25.00% in exon, 0.68% in the splice region, 0.23% in intron, and 2.03% in the intergenic region (Figure [5B](#F5){ref-type=\"fig\"}).", "\n\n{#F4}\n\n{#F5}\n\n###### \n\nVariant rate of the single base substitutions and small INDELs across each chromosome in the 11 re-sequenced lines.", "\n\n **Line** **Chromosome 1** **Chromosome 2** **Chromosome 3** **Chromosome 4** **Chromosome 5** \n ---------- ------------------ ------------------ ------------------ ------------------ ------------------ ---------- ---- ---------- ---- ----------\n C7 17 1789863 9 2188699 10 2345983 8 2323132 13 2075039\n C116 7 4346810 10 1969829 9 2606648 10 1858506 10 2697550\n C197 6 5071279 9 2188699 8 2932479 4 4646264 8 3371938\n C352 5 6085534 3 6566096 3 7819943 8 2323132 1 26975502\n C357 14 2173405 6 3283048 11 2132712 3 6195019 9 2997278\n C541 7 4346810 5 3939658 3 7819943 0 / 11 2452318\n C600 10 3042767 10 1969829 9 2606648 12 1548755 18 1498639\n C828 2 15213836 5 3939658 2 11729915 1 18585056 3 8991834\n C941 13 2340590 9 2188699 8 2932479 16 1161566 11 2452318\n C1001 8 3803459 3 6566096 2 11729915 8 2323132 5 5395100\n C1322 10 3042767 10 1969829 9 2606648 11 1689551 22 1226159\n\n*Variants indicate the number of mutations in each chromosome*.", "\n\n*Rate equals to length of chromosome/variants. ", "Length (bp) of chromosome 1 to 5 is 30427671, 19698289, 23459830, 18585056, and 26975502, respectively*.", "\n\nMutations involved in missense, stop gained/lost, frame shift, in-frame deletion, and 3′/5′-UTR, are usually predicted to affect gene function more probably. ", "Classifying all the above sites including both heterozygous and homozygous, 103 mutations located in 97 genes were sorted, and the number of mutated genes affected by irradiation in the M3 lines ranged from 3 to 15 (Table [2](#T2){ref-type=\"table\"} and Table [S2](#SM2){ref-type=\"supplementary-material\"}). ", "The homozygous mutations in M3 were used to estimate the M1 heterozygous mutation events caused by CIB irradiation followed Mendelian principles (Belfield et al., [", "@B2]). ", "The total number of single base substitutions, single base insertions, and single base deletions in M1 of the 11 sequenced lines were 362.67, 18.67, and 69.33, respectively (Table [S3](#SM3){ref-type=\"supplementary-material\"}). ", "After correcting the spontaneous mutations by using the Col-0 MA line mutation rates (Ossowski et al., [", "@B34]), on average the single base mutation rate was estimated to be 3.37 × 10^−7^ per site per genome (Figure [6](#F6){ref-type=\"fig\"}). ", "The mutation rate of the 200-Gy CIB irradiation was nearly 47-fold that of the spontaneous rate (7.1 × 10^−9^ per site). ", "Since the phenotypes of C7, C357, C116, and C541 were heritable, the homozygous mutations in M3 were used to detect whether there was any common mutations at the genomic level. ", "However, no shared genetic factors were found between C116 and C541, or between C7 and C357. ", "To some extent, this indicated that the CIB irradiation was able to induce mutation in multiple genes which could give rise to similar traits (Figure [7](#F7){ref-type=\"fig\"}).", "\n\n###### \n\nNumbers of genes predicted to occur function changes in the 11 re-sequenced lines.", "\n\n **Homozygous** **Heterozygous** **Total mutated genes[^c^](#TN5){ref-type=\"table-fn\"}** \n ------- ---------------- ------------------ --------------------------------------------------------- --- --- --- --- --- ----\n C7 2 4 1 0 2 3 3 1 13\n C116 0 5 2 1 1 0 0 0 9\n C197 0 0 0 0 2 4 0 1 7\n C352 0 2 2 0 0 0 0 0 4\n C357 1 6 3 0 0 3 1 1 15\n C541 0 1 1 0 1 2 1 0 6\n C600 1 1 0 0 2 6 5 0 15\n C828 0 0 0 0 1 1 1 0 3\n C941 2 3 1 0 1 4 2 0 13\n C1001 0 1 1 0 0 1 1 0 4\n C1322 0 0 0 0 2 6 1 0 9\n\n*Non-synonymous mutations include those mutations with the effect of missense, stop gained, stop lost, and initiator codon variant*.", "\n\n*Disruptive inframe_del indicates that the mutation lead one codon changed, and one or more codons are deleted*.", "\n\n*When multiple mutations are located in the same gene in one re-sequenced line, and these mutations are viewed as a single gene-mutated*.", "\n\n{#F6}\n\n{#F7}\n\nSingle base substitutions induced by CIB irradiation\n----------------------------------------------------\n\nExposure to CIB irradiation induced plenty of substitutions. ", "Their type may be classified into two categories: transition (mutations that happen among the same type of bases; e.g., purine \\> purine or pyrimidine \\> pyrimidine) and transversion (mutations that happen among the different types of bases; e.g., purine \\> pyrimidine or pyrimidine \\> purine). ", "A total of 320 CIB irradiation-induced substitutions were identified and classed, yielding a transition to transversion (Ti/Tv) ratio of 0.99. ", "This indicated that the CIB irradiation was able to induce transitions and transversions at nearly the same frequency (Figure [8A](#F8){ref-type=\"fig\"}). ", "The G:C \\> A:T were the most frequently observed substitutions in the re-sequenced mutagenesis progeny lines: 51 of the 320 detected CIB-induced mutations were G \\> A transitions, 55 were C \\> T mutations (Table [S4](#SM4){ref-type=\"supplementary-material\"}). ", "The C \\> T transitions hold the biggest ratio of substitutions induced by the CIB. ", "By analyzing the flanking DNA sequences of the most prominent substitutions of C \\> T variations, it was found that 37 of these (67.2%) occurred at the pyrimidine dinucleotide sites (Table [3](#T3){ref-type=\"table\"}). ", "In addition, the substitutions seemed more likely to happen at the C base site (87) rather than at other base sites (A, G, and T) (Figure [8D](#F8){ref-type=\"fig\"}).", "\n\n{#F8}\n\n###### \n\nPyrimidine dinucleotide analyses at C \\> T substitutions sites in 11 CIB irradiated M3 lines.", "\n\n **Line** **Chromosome** **Loci** **Mutation** **Flanking sequence** **Pyr-Pyr**\n ---------- ---------------- ---------- -------------- ----------------------- -----------------------------\n C7 5 1496355 C \\> T AATT[**C**]{.ul}TTGA T[**C**]{.ul} [**C**]{.ul}T\n C7 5 1454369 C \\> T CCTT[**C**]{.ul}ACAG T[**C**]{.ul}\n C7 5 3829172 C \\> T TCAA[**C**]{.ul}ATCA \n C7 5 16650819 C \\> T GACT[**C**]{.ul}TCCA T[**C**]{.ul} [**C**]{.ul}T\n C116 2 6339827 C \\> T GGCT[**C**]{.ul}TCAA T[**C**]{.ul} [**C**]{.ul}T\n C116 3 8857172 C \\> T AGTA[**C**]{.ul}GCGT \n C116 3 13445052 C \\> T CAGT[**C**]{.ul}GTTG T[**C**]{.ul}\n C116 3 21948981 C \\> T TTCT[**C**]{.ul}CACT T[**C**]{.ul} [**C**]{.ul}C\n C116 5 8571804 C \\> T CCTT[**C**]{.ul}AGGT T[**C**]{.ul}\n C116 5 14749784 C \\> T ACAA[**C**]{.ul}TGTC [**C**]{.ul}T\n C197 1 27664800 C \\> T TTTG[**C**]{.ul}TTTT [**C**]{.ul}T\n C197 2 7777170 C \\> T CTCT[**C**]{.ul}AGCT T[**C**]{.ul}\n C197 2 3980109 C \\> T CGGG[**C**]{.ul}GATG \n C197 3 5423074 C \\> T TTAA[**C**]{.ul}AGGC \n C197 3 20612671 C \\> T AATA[**C**]{.ul}ACGT \n C197 4 4989792 C \\> T ACGC[**C**]{.ul}CAAT C[**C**]{.ul} [**C**]{.ul}C\n C197 5 12293490 C \\> T CTCT[**C**]{.ul}ATGT T[**C**]{.ul}\n C197 5 5133036 C \\> T ATTG[**C**]{.ul}AACA \n C352 1 26491174 C \\> T TTTT[**C**]{.ul}AGTA T[**C**]{.ul}\n C352 4 17139849 C \\> T TCTA[**C**]{.ul}ATAT \n C357 1 5147165 C \\> T ATAT[**C**]{.ul}AGAT T[**C**]{.ul}\n C357 1 13896252 C \\> T TGTT[**C**]{.ul}TCAC T[**C**]{.ul} [**C**]{.ul}T\n C357 2 2382455 C \\> T ACAC[**C**]{.ul}AGGA C[**C**]{.ul}\n C357 2 9045207 C \\> T TGCA[**C**]{.ul}AACA \n C357 3 959295 C \\> T AGTT[**C**]{.ul}TTGC T[**C**]{.ul} [**C**]{.ul}T\n C357 3 21754406 C \\> T GAAG[**C**]{.ul}ATTT \n C357 4 3608407 C \\> T ACTA[**C**]{.ul}TATC [**C**]{.ul}T\n C357 5 11079083 C \\> T TGTT[**C**]{.ul}AACG T[**C**]{.ul}\n C541 1 27821135 C \\> T TAGG[**C**]{.ul}AAGA \n C541 3 13945744 C \\> T TGTT[**C**]{.ul}CGCG T[**C**]{.ul} [**C**]{.ul}C\n C541 5 16565496 C \\> T GTTT[**C**]{.ul}TTCT T[**C**]{.ul} [**C**]{.ul}T\n C600 1 15506551 C \\> T ACTG[**C**]{.ul}AGAG \n C600 2 629920 C \\> T CACT[**C**]{.ul}TGAT T[**C**]{.ul} [**C**]{.ul}T\n C600 3 7132293 C \\> T GAAA[**C**]{.ul}GAGA \n C600 4 12005191 C \\> T AACA[**C**]{.ul}ATTT \n C600 5 7896135 C \\> T CTGA[**C**]{.ul}ATTC \n C828 5 9262872 C \\> T AGCA[**C**]{.ul}ATTT \n C941 1 1654865 C \\> T AAAT[**C**]{.ul}AGCA T[**C**]{.ul}\n C941 1 16595744 C \\> T AACT[**C**]{.ul}TAAA T[**C**]{.ul} [**C**]{.ul}T\n C941 1 18884415 C \\> T GAAA[**C**]{.ul}AAGG \n C941 2 12645936 C \\> T TCTT[**C**]{.ul}GCTC T[**C**]{.ul}\n C941 4 4481201 C \\> T TTAA[**C**]{.ul}TTTT [**C**]{.ul}T\n C941 4 6924288 C \\> T AGCA[**C**]{.ul}CAGC [**C**]{.ul}C\n C941 4 13051872 C \\> T ATTA[**C**]{.ul}TTCA [**C**]{.ul}T\n C941 4 14525988 C \\> T GATT[**C**]{.ul}TACT T[**C**]{.ul} [**C**]{.ul}T\n C941 4 17299998 C \\> T TAAA[**C**]{.ul}AGTT \n C941 5 14679245 C \\> T CCAA[**C**]{.ul}TCCT [**C**]{.ul}T\n C1001 1 17132595 C \\> T TTAT[**C**]{.ul}ATGT T[**C**]{.ul}\n C1001 3 20688685 C \\> T AAAA[**C**]{.ul}CTAA [**C**]{.ul}C\n C1001 5 10126078 C \\> T ATAC[**C**]{.ul}ACCT C[**C**]{.ul}\n C1322 1 23839536 C \\> T AATG[**C**]{.ul}GTTT \n C1322 2 8613063 C \\> T CTCT[**C**]{.ul}AATA T[**C**]{.ul}\n C1322 4 980039 C \\> T GAAT[**C**]{.ul}CATC T[**C**]{.ul} [**C**]{.ul}C\n C1322 5 1431634 C \\> T TTTC[**C**]{.ul}TTTC C[**C**]{.ul} [**C**]{.ul}T\n C1322 5 6887544 C \\> T GGTT[**C**]{.ul}TGTT T[**C**]{.ul} [**C**]{.ul}T\n\n*The C base occurring in the substitution sites are in bold and underlined*.", "\n\nSmall INDELs induced by CIB irradiation\n---------------------------------------\n\nFor a long time, deletions were considered the main mutation type induced by heavy-ion beam irradiation, or at least had a similar frequency to substitutions, judging from the sequencing analysis of specific genes only. ", "In present study, at a genome-wide scale, 124 small INDELs were detected, of which 103 (83.06%) were deletion mutations, whereas only 21 (16.94%) were insertions (Figure [8B](#F8){ref-type=\"fig\"}). ", "Among the 103 small deletions, 35 (33.98%) multiple bases deletions (≥2 bp) ranging in size from 2--21 bp were detected (Figures [8B,C](#F8){ref-type=\"fig\"}). ", "In addition, 68 (66.02%) single base deletions were detected as well, which seemed the most common class of deletion mutation. ", "Meanwhile, 17 (80.95%) of the 21 insertions were single base mutations, of which only four (19.05%) has a size ≥2 bp. ", "Interestingly, for the single-base INDELs, we noticed that there was a bias to the A and T bases: 45 of the 68 single base deletions and 15 of the 17 single base insertions were A and T (Figure [8D](#F8){ref-type=\"fig\"}). ", "To explore the rule of small INDELs occurring, we investigated the flanking sequence of 63 small INDELs in six randomly selected sequenced lines (Table [4](#T4){ref-type=\"table\"}). ", "Eight (88.89%) of the nine single base insertions and 29 (82.86%) of the 35 single base deletions, along with 16 (84.21%) of the 19 INDELs that had a size ≥2 bp occurred within or near the homopolymer or polynucleotide repeats.", "\n\n###### \n\nFlanking sequences analysis of the small INDELs in six randomly selected re-sequenced lines.", "\n\n **Line** **Chromosome** **Loci** **INDEL size (bp)** **Sequence**\n ---------- ---------------- ---------- --------------------- ----------------------------------------------------------------\n C7 1 16803045 +1 AAAAATAATT[**A**AAAAA]{.ul}CGAAA\n C7 1 17871566 +1 GATGAGTCTC[**T**TT]{.ul}GACAATGA\n C7 2 2330971 +1 CTAATCTCTG[**T**TTTTTTTTTT]{.ul}\n C7 3 14218519 +1 AAAAACCGAT**C**AGAAGAATTC\n C7 3 10963641 +1 AACATGTGGC[**A**AAAA]{.ul}TAAATT\n C7 5 15938548 +1 TAAAGTTAGA[**T**TTTTT]{.ul}ATTTT\n C116 4 16566783 +1 TTTTTTTTTC[**T**TTTTTTTTTT]{.ul}\n C352 4 12840961 +1 TTT[AAAAAAA**C**]{.ul}TATTCACAAT\n C357 3 16396219 +1 CAAACTTTCT[**A**AAAA]{.ul}CTCAGC\n C7 1 2500882 −1 AAACCTAATA[**G**GAA]{.ul}AAGGGAC\n C7 1 7060076 −1 TGCGGCCTTG[**C**GGG]{.ul}AGCAATC\n C7 1 23165210 −1 ATCAATGGCT[**A**AAAAA]{.ul}CCATC\n C7 1 30364445 −1 AATGCAAGAG[**A**AA]{.ul}GCATTTCA\n C7 2 3736597 −1 GTGTATGACC[**T**TT]{.ul}ATATTTTT\n C7 2 16776720 −1 ATCCATAACA[**T**TTTTTTTTT]{.ul}G\n C7 3 12880551 −1 AGAATGCTCA[**T**TT]{.ul}ATCTCATT\n C7 3 15247466 −1 AAATCAT[ACG**A**CG]{.ul}AACACTAC\n C7 4 13256395 −1 TGCTCTTGCC[**A**AGG]{.ul}TTAGTTC\n C7 5 10287067 −1 CCAAGATCCG[**A**ACC]{.ul}TAGAAAT\n C7 5 15120725 −1 AATAGATTTC[**T**TTT]{.ul}ATCGAAA\n C7 5 15424664 −1 TGTTTTTTT[**G**TGTGT]{.ul}TTTCTT\n C116 1 6787418 −1 CAAGAGCGT**C**CACGACGAGTT\n C116 1 899668 −1 TGGAGCTGC**T**TCATAAGTTC\n C116 2 14954774 −1 AAGCGAAAC[**T**TTT]{.ul}ATTGCTA\n C116 3 3201387 −1 AGCGGTT[AT**A**T]{.ul}ACATCATAA\n C116 5 14227661 −1 TTTTTTTTTC[**T**TTTTTTTT]{.ul}AA\n C116 5 11032451 −1 CAATTACA[**GG**AA]{.ul}TGTCGATTT\n C197 2 9064276 −1 GAGAACCAAT**C**AAGCCCTAAG\n C197 2 17412340 −1 GGAAAGTAAT**A**AGAGCGTTTT\n C197 3 15116009 −1 TAGATAAGTA[**G**GTT]{.ul}TTTGCGC\n C197 4 11372899 −1 AAGAAAATTG**A**ATAGAAAAAA\n C352 2 13175805 −1 GTTGCTGCAA[**C**CAA]{.ul}TAGAGCA\n C352 3 20903968 −1 GCGCTTGGAA[**T**TTTTTT]{.ul}AATT\n C352 3 22734373 −1 AGTGGTTAAA[**G**GG]{.ul}TTCCAGCC\n C352 4 5256307 −1 CTAAATTCAG[**A**AAAAAAAA]{.ul}CA\n C357 1 24487663 −1 ATGTTACAGT[**A**AAAAAAAAAA]{.ul}\n C357 2 6789742 −1 ACTAAAG[TTG**T**TG]{.ul}CTGCTGAT\n C357 3 8430932 −1 ATTCTACTTG**T**CCTCTGAAAT\n C357 5 3418139 −1 CACCTCTAAC[**A**AAA]{.ul}GTCTTAG\n C357 5 7522732 −1 TGAGAATCTC[**T**TTTT]{.ul}CTCATT\n C357 5 14755177 −1 AAACAATTTC[**A**AA]{.ul}GTCCAACC\n C541 1 2611420 −1 CCACGT[ATAT]{.ul}**G**GTAATCACAA\n C541 3 5203766 −1 GAAAACTGGT[**G**GG]{.ul}AGGTGATC\n C541 5 17816447 −1 GACTTGAGAG[**T**TTT]{.ul}AACAGAA\n C7 3 4723240 −2 GTAGTCATTT[**TA**TATATATA]{.ul}GA\n C7 4 1435510 −2 AAAACCCCAA[**AT**AT]{.ul}AATACTAC\n C116 3 4315154 −2 TTTATAACTC[**TG**TG]{.ul}CAGTGCTA\n C7 2 3072553 −4 AAACGCTCGG**CGAT**GGTGATGATT\n C7 3 5701019 −5 TATTAAAAAG[**CCAA**]{.ul}**C**TTGGTAAAAA\n C7 2 8793345 −5 AGCCCATGGA**ATGCT**AATGATTTTG\n C116 3 16824813 −5 GGGTGTG[AAAA]{.ul}**CTGGT**CAGTTAATAG\n C541 1 18202184 −5 TCCTCTCAGT[**TCTC**]{.ul}**A**TCTGTGGCAT\n C7 4 10587368 −6 AGAATTAATC**CACTC**[**T**TTTT]{.ul}CTTTTT\n C7 1 22655118 −6 ACTCCGAAGC**TGTAGA**TGTCTGATTT\n C116 1 27885672 −6 CATTTTTATA**TCG**[**TTT**T]{.ul}GATGGTGAT\n C197 1 10625807 −6 TCGGTTGATG**AAGACA**ATGGTAACAT\n C197 4 15198376 −7 TTTATCTCCA**AG**[**TTTTC**]{.ul}CATCTTTCTC\n C357 3 442084 −7 CTGAACCTGTG**AACCA**GGAACCCAGTC\n C357 5 20249679 −8 ACTTTAAGTT**ACTT**[**TCTC**]{.ul}ACCAAAAAAA\n C197 2 11198490 −9 TTTACTTATG**AATCCTGCT**[AATT]{.ul}GAATGAT\n C357 1 10405785 −9 TACAGTACA[T**AATAA**]{.ul}**GTAG**ATAAGTGTAA\n C116 3 11700393 −15 CTGCCTT[CCCC**C**]{.ul}**ATTTGCAGGAC**[**TTT**]{.ul}CATTGTTATA\n C116 1 29852923 −18 GGCCTAGGTA**GATTAAGAGGCTTAA**[**GCT**GCT]{.ul}GTTGAAT\n\n*Homopolymeric and polynucleotide stretches are underlined; the inserted or deleted base is in bold*.", "\n\nDiscussion {#s4}\n==========\n\nIn this study, we re-sequenced 11 mutagenesis progeny lines (M3) of *A. thaliana* lines derived from CIB irradiation. ", "Based on the obtained data, we could reveal the mutation effects of CIB irradiation on *A. thaliana* at whole genome level, as well as its related molecular mutation spectrum and mutation rates. ", "In contrast to previous studies, we preferred to filter the background mutations shared by multiple re-sequenced lines, rather than rely on the published reference genome. ", "This step was an essential premise for detecting the mutations caused by CIB irradiation. ", "To reduce false positives, we verified the detected mutations by using the IGV, a high-performance visualization tool for the interactive exploration of large, integrated genomic datasets.", "\n\nHeavy-ion beam irradiation is thought to generate mutations in the form of substitutions, small INDELs and structure variants (i.e., large fragment deletion, inversions, intra-chromosomal translocations, and inter-chromosomal translocations; Tanaka et al., [", "@B46]). ", "In this study, we found that the CIB irradiation-induced substitutions prevailed over the INDELs, with the ratio of substitutions to INDELs of 2.58:1 (Figure [5A](#F5){ref-type=\"fig\"}). *", "Brachypodium distachyon* mutant line which was induced by chronic gamma radiation, its ratio was 11.90:1 (Lee et al., [", "@B21]). ", "As for the fast neutron irradiation, this ratio was 1.45:1 in *A. thaliana*, and 1.26:1 in rice mutant line (Belfield et al., [", "@B2]; Li et al., [", "@B23]). ", "Among the 124 small INDELs detected here, the number of deletions was more than those of insertions, and the single base INDELs were more prevalent than those in size equal to or greater than 2 bp (Figures [8B,C](#F8){ref-type=\"fig\"}). ", "Although our current result showed a similar tendency to gamma and fast neutron irradiation (induced more substitution mutations), the proportion of INDELs varied with the quality of radiations. ", "The high LET particles irradiation (i.e., CIB and fast neutron) induced more INDELs than the low LET irradiation. (", "Belfield et al., [", "@B2]; Li et al., [", "@B23]; Lee et al., [", "@B21]). ", "In fact, we have tried to detect the large INDELs, by simultaneously using both the Pindel (<https://trac.nbic.nl/pindel/>; Ye et al., [", "@B55]) and Break Dancer Max (<http://breakdancer.sourceforge.net/breakdancermax.html>; Chen et al., [", "@B5]). ", "Although hundreds of large deletions were eventually detected (Table [S5](#SM5){ref-type=\"supplementary-material\"}), most of them were turned out to be false positives after validating them by IGV. ", "This outcome may due to that most commonly used re-sequencing strategy in current is based on the paired-end libraries with an insertion size of 350 bp, for which the read length is 2 × 125 bp rather than the mate pair sequencing libraries whose inserts size can reach up to 2--5 kb. ", "Actually, the long-insert paired-end libraries may be much more suitable for structural variant detection. ", "Secondly, the LET value of the CIB irradiation used in this study was only 50 keV/μm. ", "Previous studies showed that the deletion size and complexity of DNA damage is closely related to the LET value of irradiation (Hada and Georgakilas, [@B8]; Sage and Harrison, [@B37]; Hirano et al., [", "@B13]). ", "For example, by using a high resolution melting (HRM) technique, CIB irradiation around 30 keV/μm mainly induced substitutions or deletions/insertions, ranging in size from 1 to 53 bp, which was on par with the mutagenesis efficiency of classical chemical mutagen EMS (Kazama et al., [", "@B16]). ", "Hirano et al. ", "have reported that heavy-ion beam of 290 keV/μm led to an increased proportion of large deletions (\\>1 kb) and chromosomal rearrangements (Hirano et al., [", "@B14]). ", "Thirdly, the majority of severe DNA damage, including large deletions (from kb to Mb) induced by radiation, cannot be inherited to the offspring, as these non-heritable mutations may be involved in genes that are vital for gamete development or viability. ", "In general, progeny could inherit mutations of 1- or 4-bp deletions (Naito et al., [", "@B30]). ", "Considering all these reasons above, to ensure the accuracy and reliability of results in the present study, it was reasonable to focus on substitutions and small INDELs. ", "On the other hand, the mutation rate of the 200-Gy CIB (50 keV/μm) irradiation might be underestimated in this study, because it omitted the detection for the non-transmissible mutations. ", "Our sequencing analyses were based on nine mutagenesis progeny lines (M3) with visible and heritable mutation phenotypes (C7, C116, C197, C352, C357, C541, C600, C828, and C941), as well as two M3 lines with inconspicuous mutation phenotypes (C1001, C1322). ", "In fact, there were still several mutations been detected in C1001, C1322 genomes. ", "This suggests that it is too simple and imprudent to correlate the visible phenotypes to the molecular mutations. ", "Besides, it will underestimate or neglect the potential mutants without eyeable mutation traits. ", "Yan et al. ", "also reported that the effects of the CIB irradiation were underestimated by counting the plants that only displayed abnormal and visible phenotypes (Yan et al., [", "@B7]). ", "Otherwise, we previously thought that there might be some mutation hotspot in genome, for example, whether CIB irradiation was prone to induce mutations that were located on certain specific chromosomes? ", "However, based on the variant rate statistics of mutations across each chromosome in the 11 re-sequenced lines, our answer is that so-called hotpots were not observed.", "\n\nAmong the detected substitutions, the ratio of transitions to transversions induced by CIB irradiation was 0.99 in this study. ", "This value differs greatly from the 2.73 of spontaneous substitutions reported in the mutation accumulation line (Ossowski et al., [", "@B34]), but closes to the 0.86 reported in a fast neutron-induced mutation line (Belfield et al., [", "@B2]). ", "It suggests that artificial mutagenesis can balance the ratio of transitions and transversions. ", "Although an obvious bias of G:C \\> A:T transitions was observed in this study, compared to mutations induced by EMS which mostly were G:C \\> A:T substitutions (about 88%), the proportion of this kind of mutations is much lower when treated by CIB irradiation (Henry et al., [", "@B12]). ", "For the single base INDELs, however, we found a different bias of A and T bases from the substitutions, and the majority of small INDELs happened at, or adjacent to, homopolymeric or polynucleotide repeats (especially those of A or T bases). ", "Actually, such biases were also prominent in other radiation, such as UV (Daya-Grosjean and Sarasin, [@B6]) and fast neutron (Belfield et al., [", "@B2]). ", "Radiation exposure could induce C \\> T transitions by causing the formation of covalent linkages between neighboring pyrimidine residues (for instance, CC, CT, TC, and TT) in the DNA sequence, thus resulting in a predominance of UV-induced C \\> T mutations at the dipyrimidine sequences (Daya-Grosjean and Sarasin, [@B6]). ", "We had speculated that CIB irradiation-induced C \\> T mutations likewise followed the mechanisms of preferentially anchoring to pyrimidine dinucleotide sites. ", "By investigating the flanking sequencing of all the 55 C \\> T mutation sites, 67.27% did occur at the pyrimidine dinucleotide. ", "Given the associations among the UV irradiation, fast neutron, and CIB analyses to date, we infer that radiation of different qualities share a common characteristic of pyrimidine dinucleotide-related C \\> T transitions. ", "It has been reported that the single base INDELs may be caused by replication slippage at homopolymer or polynucleotide repeat regions (Viguera et al., [", "@B52]). ", "To verify this view, the flanking sequence of small INDELs was investigated in the present study. ", "It was found that most of the single base insertions and deletions and the 19 INDELs having sizes ≥2 bp occurred at or close to the homopolymer or polynucleotide repeats. ", "This indicates that CIB irradiation might induce the occurrence of DNA replication slippage.", "\n\nAccording to genetic variant annotation and the effect prediction analysis of the 444 detected mutations in the 11 re-sequenced lines, a total of 97 genes---that is to say less than nine genes on average in each genome---incurred relatively high-impact mutations (such as, missense, nonsense, frame shift, or 3′/5′-UTR), which were capable of disrupting the corresponding gene functions. ", "Hence, only a minor proportion of genes would be affected by CIB. ", "Similar results were also observed for Ar-ion (290 keV/μm) and Fe-ion (640 keV/μm) induced mutations (Hirano et al., [", "@B13]). ", "This feature possessing by heavy-ions might be a promising tool for plant breeding, because the heavy-ion beam irradiation could alter some characteristics of interest without interfering with other key traits.", "\n\nAlthough the main objective of present study is to investigate the mutation spectrum and rate of single base substitutions and small INDELs induced by CIB, it is an essential issue to excavate the mutation resource genes that are associated with plant traits at post-genomics era. ", "Among the 11 re-sequenced lines, C7, C116, C197, C352, C357, C541, C600, C828, and C941 were mutants with stable phenotypes, therefore according to the VarScan 2, homozygous variants were sorted out and performed Gene Ontology (GO) annotation. ", "The detail information of gene ID, family, and biological process involved in were listed in Table [S6](#SM6){ref-type=\"supplementary-material\"}, the pseudogenes and hypothetic protein genes were filtered out. ", "The rough map based cloning of C197, C352, and C357 were completed in our previous study (Yan et al., [", "@B7]). ", "C197 displayed frostbite-like, and uneven leaves. ", "Its mutation sites was located on chromosome 1 (26305380) and chromosome 4 (14740942) respectively, based on the re-sequencing results. ", "AT4G31320, the only gene encoding an SAUR-like auxin-responsive protein family known to be involved in auxin response, was associated with the rough mapping region. ", "C352 displayed an analogous phenotype to the *var2* mutant characterized by a variegated stem, leaves, sepals, and siliques (Takechi et al., [", "@B44]). ", "Targeting this trait, we previously performed rough map-based cloning, and the mutated genes were closely linked to the marker T20P8 (Chr 2, 11595846). ", "Fortunately, among the four candidate mutation sites (Figure [4](#F4){ref-type=\"fig\"}) of C352, one site (chromosome 2, 13175805) with a deletion of a single cytosine which led to the frame shift variant of *var2* gene, was identified. ", "The mutation site of C357 displaying short petiole and compact growth pattern was positioned on the chromosome 3 (989952). ", "Six candidate genes (AT3G02260, AT3G03780, AT3G11540, AT3G12830, AT3G13235, and AT3G44910) were provided by re-sequencing. ", "To ensure the accuracy of results, strict data filtering criterion can minimize the false positive variants. ", "However, it may lead to miss detection. ", "But to a certain extent, the association analysis of rough mapping and whole-genome re-sequencing can provide crucial clues for identifying the corresponding mutations. ", "In fact, to identify gene or locus which are responsible for the interested trait, whole genome re-sequencing analysis, bulked-segregant analysis (BSA), as well as MutMap sequencing strategies have been successfully used for rapidly mapping mutant genes in plant species (Song et al., [", "@B42]; Win et al., [", "@B53]).", "\n\nConclusion {#s5}\n==========\n\nThis study revealed molecular profile and rate of substitutions and small INDELs mutations induced by CIB irradiation in *A. thaliana* at the whole genome level. ", "As heavy-ion beam mutagenesis is an effective and unique mutagen, we will continue our efforts to develop genome sequencing and mutation detection strategies that are more suitable for and more targeted at mutation breeding induced by heavy-ion beam irradiation in the near future. ", "We hope our data could provide valuable clues for explaining the potential mechanism of plant mutation breeding by CIB irradiation.", "\n\nAuthor contributions {#s6}\n====================\n\nLZ coordinated and supervised the project. ", "YD designed the experiments and wrote the manuscript. ", "YD and SL analyzed the data. ", "YD, XL, JY, TC, LY, HF, YC, JM, and XC performed experiments. ", "WJL, QS, TG, and WLL corrected the manuscript. ", "All authors read and approved the final manuscript.", "\n\nConflict of interest statement\n------------------------------\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.", "\n\nWe are very grateful to members of the biophysics group at our institute for the *A. thaliana* mutation screening and planting. ", "We appreciate Dr. P Li from Medical Physics Group at IMP-CAS for helping us modify the English grammar and academic writing.", "\n\n**Funding.** ", "This work was supported by National Key Research and Development Program (2016YFD0102106), the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS) (No. ", "XDA08040111), the National Natural Science Foundation of China (Nos. ", "11205218, 11275171, U1432126), the Light of West China Program (Nos. ", "Y506020, Y606020), and the Youth Innovation Promotion Association (No. ", "2015337) of CAS.", "\n\nSupplementary material {#s7}\n======================\n\nThe Supplementary Material for this article can be found online at: <https://www.frontiersin.org/articles/10.3389/fpls.2017.01851/full#supplementary-material>\n\n###### \n\nClick here for additional data file.", "\n\n###### \n\nClick here for additional data file.", "\n\n###### \n\nClick here for additional data file.", "\n\n###### \n\nClick here for additional data file.", "\n\n###### \n\nClick here for additional data file.", "\n\n###### \n\nClick here for additional data file.", "\n\n[^1]: Edited by: Michael Deyholos, University of British Columbia, Canada\n\n[^2]: Reviewed by: Chengdao Li, Murdoch University, Australia; Mehboob-ur-Rahman, NIBGE, Pakistan\n\n[^3]: This article was submitted to Plant Genetics and Genomics, a section of the journal Frontiers in Plant Science\n\n[^4]: †These authors have contributed equally to this work.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Q:\n\nSplit a string with delimiters in the value\n\nI am trying to parse the response from a REST call. ", "The response header comes back in the format of a dictionary. ", "The ultimate goal is to decode all the properties (value of x-ms-properties) to strings.", "\nThe response is in the format.", "\n{'Last-Modified': 'Mon, 06 May 2019 09:32:13 GMT', 'ETag': '\"0x8D6D205B880F304\"', 'Server': 'abc', 'x-ms-properties': 'anotherprop=dGVzdA==,source=YWJj', 'x-ms-namespace-enabled': 'true', 'x-ms-request-id': '45839301-401f-0003-1202-04d929000000', 'x-ms-version': '2018-03-28', 'Date': 'Mon, 06 May 2019 11:54:29 GMT'}\n\nI would like to parse the value of the key x-ms-properties. ", "If you see, the value is in the form of key- value pairs. ", "And the value is base64 encoded. ", "\nI can decode the value dGVzdA== statically using the code.", "\nimport base64\nb1=\"dGVzdA==\"\n# Decoding the Base64 bytes\nd = base64.b64decode(b1)\n# Decoding the bytes to string\ns2 = d.decode(\"UTF-8\")\nprint(s2)\n\nBut how do I parse the response and then do this generically?", "\nI have read the forum posts and tried something like \noriginalresp={'Last-Modified': 'Mon, 06 May 2019 09:32:13 GMT', 'ETag': '\"0x8D6D205B880F304\"', 'Server': 'abc', 'x-ms-properties': 'anotherprop=dGVzdA==,source=YWJj', 'x-ms-namespace-enabled': 'true', 'x-ms-request-id': '45839301-401f-0003-1202-04d929000000', 'x-ms-version': '2018-03-28', 'Date': 'Mon, 06 May 2019 11:54:29 GMT'}\n\nproperties=originalresp[\"x-ms-properties\"]\n\ndict(item.split(\"=\") for item in properties.split(\",\"))\n\nBut of course it fails, as my properties has \"==\" in the value, because of the base64 encoding.", "\nHow to get the value for this key and then proceed on to my decoding?", "\n\nA:\n\nThe only thing missing in the code is you need to tell split('=') to only consider the first equals, which you can do by item.split(\"=\",1) \nFrom the docs: https://docs.python.org/3/library/stdtypes.html#str.split\n\nstr.split(sep=None, maxsplit=-1)\n Return a list of the words in the string, using sep as the delimiter string. ", "If maxsplit is given, at most maxsplit splits are done (thus, the list will have at most maxsplit+1 elements).", "\n\nSo making this change, we see\noriginalresp={'Last-Modified': 'Mon, 06 May 2019 09:32:13 GMT', 'ETag': '\"0x8D6D205B880F304\"', 'Server': 'abc', 'x-ms-properties': 'anotherprop=dGVzdA==,source=YWJj', 'x-ms-namespace-enabled': 'true', 'x-ms-request-id': '45839301-401f-0003-1202-04d929000000', 'x-ms-version': '2018-03-28', 'Date': 'Mon, 06 May 2019 11:54:29 GMT'}\n\nproperties=originalresp[\"x-ms-properties\"]\n\n#Changed the split on equals here with maxsplit=1\ndct = dict(item.split(\"=\",1) for item in properties.split(\",\"))\nprint(dct)\n\nThe output will be \n{'anotherprop': 'dGVzdA==', 'source': 'YWJj'}\n\nNow your original code will work as expected :)\nimport base64\n# Decoding the Base64 bytes\nd = base64.b64decode(dct['anotherprop'])\n# Decoding the bytes to string\ns2 = d.decode(\"UTF-8\")\nprint(s2)\n\nThe output will be test\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "// Copyright (c) Microsoft. ", "All rights reserved.", "\n// Licensed under the MIT license. ", "See LICENSE file in the project root for full license information.", "\n\nusing Microsoft.", "Protocols.", "TestTools.", "StackSdk.", "Asn1;\n\nnamespace Microsoft.", "Protocols.", "TestTools.", "StackSdk.", "ActiveDirectory.", "Adts.", "Asn1CodecV3\n{\n\n public class UpdateStats : Asn1SequenceOf<UpdateStats_element>\n {\n public UpdateStats()\n {\n this.", "Elements = null;\n }\n\n public UpdateStats(UpdateStats_element[] val)\n : base(val)\n {\n }\n }\n}\n" ]

{ "pile_set_name": "Github" }

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[ "Share this page\n\nAs we’ve made clear in our How To Evaluate series, decent data is a bedrock of good evaluation. ", "We need to know about the people, firms or places affected by the policy we’re testing, as well as those in control groups. ", "And crucially, we need to be able to follow treatment and control groups over time.", "\n\nSo how do we collect this? ", "It’s tempting to gather it yourself. ", "But this is expensive, especially in large-scale programmes, and may be hard to do in practice (as I’ll discuss below). ", "Often, much of the information Local Authorities and LEPs need may already be available through secondary datasets. ", "Rather than expensively re-inventing the wheel, local policymakers are usually better off working with what’s already out there, and gathering bespoke information only when essential.", "\n\nGetting the most out of secondary data is easier than you think, though it requires going beyond the usual sources for local government, such as Nomis, Neighbourhood Statistics, or the new ONS website. ", "In particular, different kinds of 'big data' can help, from the private sector, government and even from the local environment.", "\n\nIn this blog I'll take a look at the concept of ‘big data’ and the kinds of datasets and analytical tools that local authorities and LEPs can draw on. ", "In a later blog I'll discusses how these might be applied to real-world evaluations, and some of the challenges involved.", "\n\nSo what is 'big data'? ", "A common way to talk about it is with reference to the Four V’s. ", "The first three are: volume (massive, often millions or billions of observations); velocity (available at real time or close to it) and variety (internet search records, company customer data or large government datasets). ", "The fourth V is veracity – raw data is often ‘unstructured’ in the jargon. ", "At the least, it needs cleaning and validating before it’s good to go. ", "More worryingly, some datasets may be incomplete, systematically missing out some places and people. ", "More on all this in the next post.", "\n\nFor our purposes, there are three flavours of big data. ", "The first is commercial: business-built datasets available for free or low-ish cost to researchers and government, typically through APIs. ", "Some of this is ‘raw’ output from sites like Flickr, Twitter or Yelp; some of it is packaged up, as with Google Trends. ", "Academics are already using these sources, most commonly to explore urban amenities or quality of life [PDF] that regular data can’t see.", "\n\nPaid-for offerings often use machine-learning to turn raw data into modelled variables. ", "The 2016 Tech Nation report, which looks at UK technology clusters, used machine-learnt data from Growth Intelligence alongside other commercial datasets on tech labour markets (via online job ads) and professional communities (via websites for hosting code, and sites for organising meetups). [", "Full disclosure: I’m working with Growth Intelligence data at the moment, and Google has funded research I’ve done in the past.]", "\n\nThe second kind of big data comes from towns and cities themselves, usually from sensor networks embedded in buses, trains or light rail, as well as static objects in the urban environment. ", "Some of this is already being collected by local government and made public; for example, travel apps like Citymapper are powered by public datasets (you can see some examples in the London Datastore).", "\n\nThe third flavour is administrative data. ", "This may surprise you, but governments already collect huge amounts of information on people and firms through official surveys like the National Pupil Database, Annual Population Survey and Business Structure Database, which covers 99% of UK enterprises. ", "These are available through the UK Data Service. ", "These massive datasets are increasingly available in raw form, and can often be linked together. ", "What’s more, they are generally free to policymakers and academic researchers. ‘", "Administrative big data’ on firms is already widely used by academics. ", "For example, I’m currently working with a panel of 10 million observations built from the Business Structure Database, Companies House and Growth Intelligence data. ", "And data on individuals is getting better. ", "As Henry points out here, we can now connect DWP, HMRC and DfE datasets, which will help us test the impact of apprenticeships and employment training programmes far better than previously.", "\n\nWhat can these datasets get you that survey data can’t? ", "Let’s take a couple of examples. ", "First, a common problem in many evaluations is that we need to follow people or firms some time after the policy has finished, and response rates to surveys often drop off markedly (even if people are paid to respond, as in this study). ", "The worse this ‘attrition’ problem gets, the harder it is to assess the impact of the policy. ", "To get around this, researchers in one US study [PDF here] used big administrative datasets to follow participants in a labour market RCT many months after the intervention. ", "Similarly, in a new RCT with a UK tech incubator, we plan to use industry big data resources such as Crunchbase to follow participants in ways that would be impossible otherwise.", "\n\nSecond, big data can also shed light on things that we can’t easily see. ", "Alongside the Twitter / Flickr / Yelp examples above, in a new paper Ed Glaeser and colleagues champion the use of Google Street View data to model neighbourhood ‘quality’, and predict local property prices. ", "Such clever analytics can reveal further insights – for example, machine learning can model emerging sectors that don’t show up in SIC codes, such as ‘digital economy’ firms (see here), or provide alternative measures of innovation such as company product launches. (", "However, Glaeser and co. don’t dwell on some of the challenges in bringing these kind of data to the table: I’ll discuss more of these in the next post).", "\n\nSo crucially, we are talking about more than datasets here – as Hal Varian explains [PDF here], the data science field also covers data management tools (databases such as Hadoop, which handle massive volumes of information), access tools (such as APIs and web crawlers) and analytical techniques (notably, machine learning routines). ", "Some of this is way outside what we need for evaluation. ", "But overall, it’s this combination of datasets, access platforms and analytics that offers real potential for local policymakers." ]

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[ "A clinical guide to the occupational and environmental medicine patient in a busy family practice: the two-task, four-prototype approach in the SC/EHAP initiative. ", "Part III.", "\nA four-prototype approach to the occupational and environmental medicine (OEM) patient in a busy primary care setting is described. ", "A 2 x 2 table illustrates the two diagnostic, interrelated tasks during the outpatient, non-urgent visit: (a) sick? ", "yes/no, and (b) exposed? ", "yes/no. ", "One may have the basic skills for task (a) but feel insecure for task (b). ", "With OEM experience, creative use of resources (databases and consultants), and patient cooperation, a better balance between task (a) and task (b) can be achieved. ", "The Environmental Medicine Curriculum Committee (EMCC) initiative described in Part I and Part II of this study has developed this patient-centered model to help the resident in training cope as he or she tries to deal with emerging patient concerns from the workplace and beyond. ", "In November 1996, an expert panel of consultants representing OEM, public health, and family medicine endorsed the prototype OEM patient model for further development." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Q:\n\nParse un-named paired PHP ini file\n\nI have a .ini file with the following contents\nSIGNALBOX/LOCATION\nSTATION\nSTATION CONCOURSE\nSTATION PLATFORM\nSTATION STEPS/STAIRS\nTRACK\nTUNNEL\nWORKSHOP\n\nAnd I'm trying to parse this with parse_ini_file function, however it's unable to parse it. ", "\nI want to avoid locations[] = before each value in the ini file, is there any way around this, to just create an array containing all of the values in the ini file? ", "\n\nA:\n\nThe PHP-function file() will read the file to an array where each line is an element.", "\nSee: http://php.net/manual/en/function.file.php\nFor example:\n<?", "php\n $locations = file('locations.ini');\n print_r($locations);\n?", ">\n\nAdditionally, to get rid of the newline-characters after each element and to ignore empty lines in the file, you may add flags (use the bitwise OR-operator to add multiple) to the function, like so:\n<?", "php\n $locations = file('locations.ini', FILE_IGNORE_NEW_LINES | FILE_SKIP_EMPTY_LINES);\n print_r($locations);\n?", ">\n\n" ]

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[ "/// Copyright (c) 2009 Microsoft Corporation \n/// \n/// Redistribution and use in source and binary forms, with or without modification, are permitted provided\n/// that the following conditions are met: \n/// * Redistributions of source code must retain the above copyright notice, this list of conditions and\n/// the following disclaimer. ", "\n/// * Redistributions in binary form must reproduce the above copyright notice, this list of conditions and \n/// the following disclaimer in the documentation and/or other materials provided with the distribution. ", " \n/// * Neither the name of Microsoft nor the names of its contributors may be used to\n/// endorse or promote products derived from this software without specific prior written permission.", "\n/// \n/// THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS \"AS IS\" AND ANY EXPRESS OR\n/// IMPLIED WARRANTIES, INCLUDING, BUT NOT LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS\n/// FOR A PARTICULAR PURPOSE ARE DISCLAIMED. ", "IN NO EVENT SHALL THE COPYRIGHT OWNER OR CONTRIBUTORS BE LIABLE\n/// FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL, EXEMPLARY, OR CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT\n/// LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES; LOSS OF USE, DATA, OR PROFITS; OR BUSINESS\n/// INTERRUPTION) HOWEVER CAUSED AND ON ANY THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY,\n/// OR TORT (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE OF THIS SOFTWARE, EVEN IF\n/// ADVISED OF THE POSSIBILITY OF SUCH DAMAGE.", "\n\n\nES5Harness.registerTest({\n\n id: \"15.4.4.14-3-21\",\n\n path: \"TestCases/chapter15/15.4/15.4.4/15.4.4.14/15.4.4.14-3-21.js\",\n\n description: \"Array.prototype.indexOf - 'length' is an object that has an own valueOf method that returns an object and toString method that returns a string\",\n\n test: function testcase() {\n\n var toStringAccessed = false;\n var valueOfAccessed = false;\n\n var obj = {\n 1: true,\n length: {\n toString: function () {\n toStringAccessed = true;\n return '2';\n },\n\n valueOf: function () {\n valueOfAccessed = true;\n return {};\n }\n }\n };\n\n return Array.prototype.indexOf.call(obj, true) === 1 && toStringAccessed && valueOfAccessed;\n },\n\n precondition: function prereq() {\n return fnExists(Array.prototype.indexOf);\n }\n\n});\n" ]

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[ "Posts Tagged ‘dinosaur jr’\n\nThis is supposed to be about getting married, going to France, moving to a new town, etc., ", "but I lack the time and patience to explore that at this juncture. ", "Instead, here’s my usual (though sometimes useful and entertaining) bullshit about music I like.", "\n\nExploring YouTube today, I found two things I wasn’t looking for, which is always the best way to find anything.", "\n\nThe first is a J Masic song that I, against all logic and credibility, prefer to most of the classic Dinosaur Jr. canon. ", "I love the slow-loose-Crazy Horse feel. ", "There’s some quiet backing vocals by Robert Pollard, not to mention an inspired video.", "\n\nThe second is a song by Bettie Serveert that I’d forgotten how much I liked. ", "Carol Van Dyk has a lot of Chrissie Hynde in her, and that’s a good thing." ]

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[ "Hey all here is another cool illustration I did for the Sketch Lottery blog, this time the theme was \"Rick Deckard\". ", "This theme refers to the main character form the the Film Blade Runner. ", "Enjoy!Please head on over to sketch lottery and look at all the other cool versions of this theme here is the link.", "I created this using pen and ink with my micron pens and my sable brush with black Speedball ink.", "Here are some other places you can follow me and see more of my work.", "FacebookTumblerTwitterPintrestInstagram" ]

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[ "Bad art and the Church\n\nI have to admit it. ", "Like many, I’m something of an art snob. ", "I know what I like and dislike, what attracts or repels me, what I find provocative or deathly dull. ", "I am somewhat surprised, then, to find myself defending the use of “bad” art, at least in religious settings, and I should admit from the beginning that I write in partial hope of persuading myself in the wake of Trinity Sunday, when we’ve realized the degree to which our conceptions fail to grasp the mystery of God’s being.", "\n\nI think there are at least three purposes for bad religious art (including painting, sculpture, music, etc.).", "\n\nThe first is the most important: bad religious art cuts against our desire to portray our faith exclusively in terms of our current canons of beauty, harmony, and order. ", "It prevents us form assuming that God, the angels, or the saints are actually like our portrayals. ", "I am guided here by Pseudo-Dionysius, in his treatise The Celestial Hierarchy, regarding the purpose of shocking or ‘base’ imagery in Scripture and liturgy:\n\nThere is a likelihood, with regard to the more sublime representations … that we should be led astray … and, in order that those who had considered nothing more exalted than the brightly shining beauties might not suffer, the upwardly-ordering wisdom of the hallowed theologians descended sacredly, even to unfitting dissimilarities, not allowing our material part to remain fixed in these shameful images, but urging the ascending part and goading it by the ugliness of the composition … (Celestial Hierarchy 2.3)\n\nWe find the mystical theologians sacredly plastering dishonorable forms not only around the revelations of the heavenly orders, but also around the revelations of the divinity … but I will also add something which seems more dishonorable and unfitting: those magnifying divine things have handed it down that God plasters around himself the image of a worm. (", "Celestial Hierarchy 2.5)\n\nThe wisdom of the scriptural authors has itself “descended sacredly” into ugly images. ", "God has chosen the shameful for himself, forcing us to admit that the Holy One and his saints are not like our portrayals. ", "There is no neat correspondence. ", "Bad art, perhaps even deliberately bad art, can thus prevent us from lapsing into idolatry. ", "We have to remember that when God wanted to show us the beauty of his love, he put forth the bleeding, wracked body of Jesus Christ and his profession, “I am a worm and no man” (Ps. ", "22:6). ", "Bad art humbles us and our aesthetic pretensions and reflects God’s own manner of portraying himself. ", "It is not that God is more like the “ugly compositions” than the beautiful ones. ", "It is rather that he is unlike our most beautiful ideas and representations and unlike our ugliest. ", "The hideous simply does a better job of reminding us of the divine dissimilarity.", "\n\nThe second purpose of bad art, therefore, is to retrain our taste. ", "If we cannot trust our own conceptions, we must submit to a long discipline and learn to embrace what repels us, albeit for a specific purpose. ", "We are not the arbiters of the ecclesiastical aesthetic, a point for which we should be thankful. ", "We might otherwise be enslaved to one era’s artistry.", "\n\nThis brings us to the third purpose of bad art, which could be misleadingly considered the populist purpose: namely, even signally tasteless, sentimental, discordant, schmaltzy, and jarring art, music, and writing may shine with the radiance of divine grace, in that it serves a specific purpose by which God transforms us. ", "There is surely a place in the Church for the highest productions, executed by the greatest, most eminent, and well-trained artists in the world. ", "But God has “scattered the proud in the imagination of their heart; he has put down the mighty from their seat and exalted the humble and meek” (Luke 1:51-2). ", "If it were not so, the Church would be some sort of godly salon, an institution of elites and for elites.", "\n\nNow, assuming (perhaps wrongly) that you are cut to the heart, I will answer the question, “What, then, shall we do?”", "\n\nIdeally, let every church and household have a mix of beautiful and base religious art, in order to reflect the God whose name is “Love” and “worm.” ", "At least one piece of kitsch, please, prominently displayed. ", "The same applies to church music: let there be one song of unabashed, disgusting cheese each quarter, preferably ill-composed (“I can’t believe it’s not Rutter,” as one friend said), or one Sunday when the choir just ruins everything. ", "We need that sort of thing. ", "It’s good for us.", "\n\nWe also need to travel, though, whether locally or through more extended pilgrimage. ", "It’s a good thing to see art, hymns, and liturgy outside the narrow confines of our own locality, even though we return. ", "For nothing is worse than an idolatry of place, nothing more abominable than a church of “taste.”", "\n\nOf course, it can’t be all bad all the time. ", "That would simply be another distortion; there remains a place for the beautiful. ", "We can’t reduce our variety to some sickening mean of precisely measured mediocrity. ", "In other words, there is no formula. ", "Rather, there is a warning and a lesson. ", "Bad art has its purposes. ", "It can, no less than the beautiful (and often more than it), lift our minds to the praise of God. ", "It can detach us from the false belief that wonderful, beautiful, orderly art or liturgy is necessarily more honorable to God. ", "It can detach us from the idea that such beauty is what God has chosen for himself.", "\n\nFor he has not chosen such things, not exclusively. ", "He has chosen the base, the meek, the shameful, and the ugly; he has plastered imagery around himself such as no one would choose for him. ", "He has hallowed bad art, as well as good.", "\n\nAbout The Author\n\nDr. Zachary Guiliano is an associate editor of The Living Church, and editor of Covenant. ", "A collection of his posts may be found here.", "\n\nHis research focuses on the spiritual interpretation of Scripture in the late patristic period and early middle ages. ", "His dissertation examined the early history and manuscripts of the homiliary of Paul the Deacon, an anthology of patristic homilies and sermons, commissioned and authorized by Charlemagne for use in the Daily Office. ", "It became one of the most widely-used books in the Middle Ages and was a component part of the Roman Breviary." ]

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[ "Q:\n\ncan you rename \"table of contents\" in the sphinx sidebar?", "\n\nMore generally how do you rename Sphinx default elements (e.g. Quick Search to Search)? ", "Can you?", "\n\nA:\n\nHere is how you could change \"Quick search\" to something else by overriding a template:\n\nCreate a folder called templates in the Sphinx project directory.", "\nCopy <Sphinx install dir>/themes/basic/searchbox.html to templates.", "\nIn conf.py, add \ntemplates_path = [\"templates\"]\n\nRename 'Quick search' to whatever you want in the copy of searchbox.html.", "\n\nBut I would not do it this way. ", "\nA more flexible approach is to create a gettext MO file and set up the configuration as described in the documentation for locale_dirs. ", "Like this:\n\nThe template file <Sphinx install dir>/locale/sphinx.pot contains all the strings that can be translated. ", "Copy that file to a local sphinx.po file.", "\nAdd your changes to sphinx.po. ", "\nUse msgfmt.py to compile sphinx.po into sphinx.mo.", "\nPut sphinx.mo in the proper directory (<your_locale_dir>/en/LC_MESSAGES for English).", "\n\nSee also http://docs.python.org/library/gettext.html#internationalizing-your-programs-and-modules. ", " \n\n" ]

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[ "In this part of our series we further explore the pre-scientific efforts at transcending the limits of humanity. ", "As the Renaissance period emerged in Europe, men felt more open about seeking things that had hitherto been closed to most Christians under the Catholic Church. ", "But the genie as we say, had been let out of the bottle. ", "The Renaissance And The Rediscovery of Alchemy in Europe With the rediscovery of the in Western Europe of the Arabic writings preserving the works of ancient Greek authors, an awakening took place, especially in Italy. ", "One of the shining figures of this age was Giovanni Pico della Mirandola. ", "In his famous book Oration On The Dignity Of Man, Mirandola defended religion, philosophy, natural philosophy and magic. ", "If there ever was a transhumanist manifesto, this is it. ", "Apart from the religious foundation he begins with, in regards to Adam and creation story, one must see the foundation of his thought as being of a spirit which places man and not religion at the center of the universe. …", "the Great Artisan mandated that this creature who would receive nothing proper to himself shall have joint possession of whatever nature had been given to any other creature. ", "He made man a creature of indeterminate and indifferent nature, and, placing him in the middle of the world, said to him “Adam, we give you no fixed place to live, no form that is peculiar to you, nor any function that is yours alone. ", "According to your desires and judgment, you will have and possess whatever place to live, whatever form, and whatever functions you yourself choose. ", "All other things have a limited and fixed nature prescribed and bounded by our laws. ", "You, with no limit or no bound, may choose for yourself the limits and bounds of your nature. ", "We have placed you at the world’s center so that you may survey everything else in the world. ", "We have made you neither of heavenly nor of earthly stuff, neither mortal nor immortal, so that with free choice and dignity, you may fashion yourself into whatever form you choose. ", "To you is granted the power of degrading yourself into the lower forms of life, the beasts, and to you is granted the power, contained in your intellect and judgment, to be reborn into the higher forms, the divine.” ", "We include a video of his portion of Mirandola’s book recited and annotated by professors of the renaissance. ", "If you cannot see the embedded video, here is the link: http://youtu.be/_W2iy17ZVsI. Paracelsus & Nicholas Flamel Paracelsus Paracelsus otherwise known as Philippus Aureolus Theophrastus Bombastus von Hohenheim, was a Swiss renaissance physician, botanist, alchemist astrologer and occultist. ", "Paracelsus, famous for many notable achievements in medicine and chemistry, also worked with alchemy creating his famous Elixir Proprietatis, which he claimed “…was to potent as to continue health and long life to the utmost possible limits.” ", "He further stated that by using this elixir a man “…should live as long as Methuselah.” ", "That this was widely believed is evident from this ad that was placed in a book published in 1690 in England.", "\n\nParacelsus also claimed that this tincture, this universal medicine, this philosopher’s stone, was in use by ancient Egyptian priests.", "\n\n…Paracelsus the Great in his writings constantly reiterates this belief, and claims that some of the primitive Egyptian philosophers lived, by means of a tincture distilled from the Philosopher’s Stone for one hundred and fifty years, and that the lives of many had been prolonged several centuries. ‘", "For its power is so remarkable that it extends the life of the body beyond what is possible to its congenial nature, and keeps it so firmly in that condition that it lives on in safety from all infirmities. ", "And although, indeed, the body at length comes to old age, nevertheless, it still appears as though it were established in its primal youth. ", "The Tincture of the Philosophers is a Universal Medicine, and consumes all diseases, by whatsoever name they are called, just like an invisible fire. ", "The dose is very small, but the effect is very powerful.’", "\n\nHome of Nicholas Flamel Paris\n\nNicholas Flamel (1330-1418) This rather obscure Parisian notary and book seller is believed to have met with a Jewish Kabbalist alchemist named Abraham Eleazar. ", "This lastly mentioned individual is believed by most to be a totally fictitious character. ", "It is generally believed that the acknowledged editor of the book ascribed to Eleazer is the true author. ", "This argument however, has been disproven by Raphael Patai in his book titled, The Jewish Alchemists: A History And Source Book. ", "Flamel is credited with the writing of on alchemical book titled Exposition of the Hieroglyphicall Figures.", "\n\nAccording to one account, Flamel had a dream in which an angel appeared to him and showed him a book which he said Flamel would one day understand. ", "As the angel was to hand him the book Flamel awoke from the dream. ", "Sometime later a stranger came into his book shop and showed him this very same book which Flame purchased. ", "This was manuscript was titled, The Book by Abraham The Jew. ", "For 21 years, Flamel tried to interpret the book to no avail. ", "Flamel eventually made a vow to St. James of Compostela and made the pilgrimage to Spain also for the purpose of conferring with Spanish Jewish Kabbalists who might help him interpret the book. ", "After this trip, when he returned to France, he became rich. ", "So rich that he was able to establish many charities and hospitals for the poor. ", "Some of these organizations exist in France to this day. ", "He also is claimed to developed the elixir of life, which according to the stories about him allowed him to avoid death and prolong his life indefinitely.", "\n\nCardinal Richelieu\n\nThe book that was given to Flamel has an interesting history. ", "He left in his will to his will to his nephew Perrier. ", "This last will was republished in France in 1750. ", "This Book by Abraham the Jew passed through the families hands from father to son for 200 years. ", "As to what became of the book no one knows for sure. ", "There is an interesting encounter with this book and one of the most powerful men in France in the 1600s – Cardinal Richelieu.", "\n\nA descendant of Flamel, named Dubois, who must still have possessed a supply of the projection powder, threw off the wise reserve of his ancestor and used the powder to dazzle his contemporaries. ", "In the presence of the King, he changed leaden balls with it into gold. ", "As a result of this experiment, it is known he had many interviews with Cardinal de Richelieu, who wished to extract his secret. ", "Dubois, who possessed the powder but was unable to understand either Flamel’s manuscripts or the book of Abraham the Jew, could tell him nothing and was soon imprisoned at Vincennes. ", "It was found that he had committed certain offences in the past, and this enabled Richelieu to get him condemned to death and confiscate his property for his own benefit. ", "At the same time the proctor of the Chitelet, no doubt by order of Richelieu, seized the houses that Flamel had owned and had them searched from top to bottom. ", "Through whatever means, it is believed Richelieu took possession of the book of Abraham the Jew. ", "He built a laboratory at the Chateau of Rueil, which he often visited to read through the master’s manuscripts and to try to interpret the sacred hieroglyphs. ", "On the death of the cardinal, all traces of the book were lost, or rather, all traces of the text, for the diagrams have often been reproduced. ", "Indeed, the book must have been copied, for it is recorded in the seventeenth century that the author of the Tresor des Recherches et Antiquites Gauloises made a journey to Milan to see a copy which belonged to the Seigneur of Cabrieres. ", "In any case, the mysterious book has now disappeared. ", "Perhaps a copy or the original itself rests under the dust of some provincial library.", "\n\nVolume 1 of Lucas’ Four Volume Series\n\nAs for Flamel’s death, here is the information we have. ", "Paul Lucas physician to King Louis XIV writes in a book titled, Voyage dans la Turquie, published in 1719 that Flamel was still alive at that time.", "\n\nAt Broussa Paul Lucas made the acquaintance of a kind of philosopher, who wore Turkish clothes, spoke almost every known language and, in outward appearance, belonged to the type of man of whom it is said that they ” have no age.” ", "Thanks to his own cultured presence, Lucas came to know him fairly well, and this is what he learned. ", "This philosopher was a member of a group of seven philosophers, who belonged to no particular country and traveled all over the world, having no other aim than the search for wisdom and their own development. ", "Every twenty years they met at a pre-determined place, which happened that year to be Broussa. ", "According to him, human life ought to have an infinitely longer duration than we admit; the average length should be a thousand years. ", "A man could live a thousand years if he had knowledge of the Philosopher’s Stone, which, besides being knowledge of the transmutation of metals, was also knowledge of the Elixir of life. ", "The sages possessed it and kept it for themselves. ", "In the West, there were only a few such sages. ", "Nicolas Flamel had been one of them. ", "Paul Lucas was astonished that a Turk, whom he had met by chance at Broussa, should be familiar with the story of Flamel. ", "He was still more astonished when the Turk told him how the book of Abraham the Jew had come into Flamel’s possession, for hitherto no one had known this.", "\n\nAs shocking as this conversation was so far, Lucas writes even more amazing things,\n\n“Abraham the Jew was a member of our group,” the man told him. “", "He had determined not to lose sight of the descendants of his brothers who had taken refuge in France. ", "He had a desire to see them, and in spite of all we could do to dissuade him he went to Paris. ", "He made the acquaintance there of a rabbi who was seeking the Philosopher’s Stone, and our friend became intimate with the rabbi and was able to explain much to him. ", "But before he left the country the rabbi, by an act of treachery, killed our brother to get possession of his book and papers. ", "The rabbi was arrested, convicted of this and other crimes and burned alive. ", "The persecution of the Jews in France began not long afterwards, and they were expelled from the country. ", "The book of Abraham was sold to Flamel by a Jewish man who did not know its value and was anxious to get rid of it before leaving Paris. ", "Having discovered the Philosopher’s Stone, Flamel was able to remain alive in the physical form he possessed at the time of his discovery. ", "Pernelle’s and his own funerals and the minute care he bestowed on the arrangements for them had been nothing but clever shams.”", "\n\nThis Turk continued to explain to Lucas things that we are sure he could hardly believe,\n\nBut the most amazing thing that Paul Lucas heard was the statement made by the Turk that both Flamel and his wife Pernelle were still alive! ", "Having discovered the Philosopher’s Stone, Flamel had been able to remain alive in the physical form he possessed at the time of his discovery. ", "Pernelle’s and his own funerals and the minute care he bestowed on the arrangements for them had been nothing but clever shams. ", "He had started out for India, the country of the initiates, where he still lived.", "\n\nAccording to our source, the publication in France of Lucas’ book created a great sensation. ", "Normally we would not mention such a thing, except that Lucas was a highly respected rational person.", "\n\nWe include two videos which show some of the sites connected with Flamel’s existence. ", "There has been a series of fiction books written using him as a fictional character. ", "Of course the Harry Potter first series the Philosopher’s Stone deals with Flamel. ", "If you cannot see the embedded video here is the link: http://bit.ly/jwXLHE." ]

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[ "1540s, originally \"guinea fowl\" (Numida meleagris), a bird imported from Madagascar via Turkey, and called guinea fowl when brought by Portuguese traders from West Africa. ", "The larger North American bird (Meleagris gallopavo) was domesticated by the Aztecs, introduced to Spain by conquistadors (1523) and thence to wider Europe. ", "The word turkey first was applied to it in English 1550s because it was identified with or treated as a species of the guinea fowl, and/or because it got to the rest of Europe from Spain by way of North Africa, then under Ottoman (Turkish) rule. ", "Indian corn was originally turkey corn or turkey wheat in English for the same reason.", "\n\nThe Turkish name for it is hindi, literally \"Indian,\" probably influenced by Middle French dinde (c. 1600, contracted from poulet d'inde, literally \"chicken from India,\" Modern French dindon), based on the then-common misconception that the New World was eastern Asia.", "\n\nAfter the two birds were distinguished and the names differentiated, turkey was erroneously retained for the American bird, instead of the African. ", "From the same imperfect knowledge and confusion Melagris , the ancient name of the African fowl, was unfortunately adopted by Linnæus as the generic name of the American bird. [", "OED]\n\nThe New World bird itself reputedly reached England by 1524 at the earliest estimate, though a date in the 1530s seems more likely. ", "The wild turkey, the North American form of the bird, was so called from 1610s. ", "By 1575, turkey was becoming the usual main course at an English Christmas. ", "Meaning \"inferior show, failure,\" is 1927 in show business slang, probably from the bird's reputation for stupidity. ", "Meaning \"stupid, ineffectual person\" is recorded from 1951. ", "Turkey shoot \"something easy\" is World War II-era, in reference to marksmanship contests where turkeys were tied behind a log with their heads showing as targets. ", "To talk turkey (1824) supposedly comes from an old tale of a Yankee attempting to swindle an Indian in dividing up a turkey and a buzzard as food." ]

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[ "Information\n\nMotorcycle Helmet Stickers\n\nMotorcycle helmet stickers are awe-inspiring likable and charming stickers which instantly gain the attention of the passerby. ", "Our custom motorcycle helmet stickers are a just right and most spectacular choice due to their brilliant features like die cutting, strong glue, waterproof, UV covering and highly creative designing. ", "Distinct sizes of personalized helmet stickers motorcycle are available in the marketplace that can serve the beautification of your helmets. ", "Motorcycle helmet stickers are used on the motorbikes to display some message or just for the entertainment of the spectators." ]

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[ "The American right could use a lot fewer talk-radio shouters and a lot more policy intellectuals. ", "But that doesn't mean intellectuals are especially good at grasping what's going on in the minds of Republican voters.", "\n\nIntellectuals of all stripes have spent a lot of time since Donald Trump rose to the top of the Republican primary field during the fall of 2015 trying to figure out just what's going on in the GOP. ", "Many conservative intellectuals, especially the so-called \"reformocons\" who spent the Obama years trying to persuade Republican politicians that the party should espouse a more economically populist policy agenda, have tended to assume that Trump succeeded in winning the Republican nomination and then the presidency at least in part by rudely and clumsily tapping into a latent desire among GOP voters for economically populist policies.", "\n\nBut is it true?", "\n\nThree of America's smartest right-of-center intellectuals certainly seem to think so. ", "In a stimulating and thoughtful conversation, New York Times columnist Ross Douthat, Henry Olson of the Ethics and Public Policy Center, and Daniel McCarthy, the former editor of The American Conservative and the newly appointed editor of the quarterly journal Modern Age, discuss the future of the GOP and conclude that economic populism (and, in McCarthy's case, a shift toward realism and restraint in foreign policy) is where the party needs to go in trying to respond to the needs and desires of its base.", "\n\nWhere they disagree is mainly over the extent to which President Trump himself helps or hinders the cause of shifting the party away from zombie Reaganism (upper-income tax cuts with no direct help for the struggling working class; a reflexively hawkish foreign policy) and toward an agenda that would turn the GOP into something like the \"workers party\" that Stephen Bannon and Trump himself have exhorted it to become. ", "But about the need for that shift they are very much on the same page.", "\n\nA year ago — even as recently as a few months ago — I would have endorsed something like this view myself. ", "But no more. ", "The president's low-but-incredibly-stable approval ratings, combined with some recent in-depth opinion polls of Republican voters, show us that the GOP base is at once sharply divided about public policy and almost entirely indifferent to it. ", "And this means that the Republican future that Douthat, Olson, and McCarthy hope to midwife is exceedingly likely to be stillborn.", "\n\nHow do we know this? ", "Because the polls simply don't support the claim that Republican and Republican-leaning voters as a whole (or anything close to a whole) want their representatives to break from Reaganism and embrace an economically populist agenda. ", "What the polls show is that the party is sharply divided, with between one-third and two-fifths of voters supporting a continuation of Reaganism (lower corporate taxes and lower taxes on household income over $250,000/year) and slightly more than half favoring the same or higher rates. ", "The same sharp divisions show up on questions touching on immigration, free trade, and gay rights.", "\n\nThat's a portrait of a party lacking any consensus, across a range of policy issues, of what to do.", "\n\nBut how can that be, when President Trump continues to enjoy the approval of around 80 percent of Republicans? ", "Given the deep fissures in the party over policy and Trump's decision to go along with Reagan-inspired tax cuts and efforts at stripping millions of their health insurance while breaking almost all of his more populist promises, you'd expect a much bigger chunk of the party to revolt: \"Hey Orange Man, where's the massive infrastructure bill we were promised? ", "And how about NAFTA repeal? ", "Or that trade war with China?\"", "\n\nBut we've seen nothing of the sort. ", "The Republican electorate continues to like Trump — whether he's cheering for corporate tax cuts, or pushing (and failing) to dismantle ObamaCare, or trying (and failing, repeatedly) to impose a travel ban on Muslims from a continually shifting list of countries, or failing even to bring up the subject of infrastructure.", "\n\nThe only plausible explanation is that Republican and Republican-leaning voters don't particularly care about policy at all. ", "What they care about is the only distinctive thing that Trump provides them — a potent and vicariously satisfying display of rhetorical animus directed against Democrats and their supposed enablers in the media, without any consistent or coherent link to a policymaking agenda.", "\n\nIt's all negative partisanship, all the way down.", "\n\nAs long as this remains true — and I see nothing that's likely to change the dynamic anytime soon — the debate about policy among conservative intellectuals will be beside the point. ", "It will amount to intellectuals talking to each other about what should happen without anything like it actually happening. ", "That's because doubling down on Reaganism won't unify and galvanize the party, and neither will Sens. ", "Mike Lee and Marco Rubio co-sponsoring a big infrastructure bill.", "\n\nThe only thing that will unify and galvanize the party is red meat — flagrant and ever-more-rabid displays of raw partisanship in which Democrats and the media are treated like foreign invaders out to destroy all that is good and great about America.", "\n\nThat’s what President Trump gives them, and that’s all that Republican-style populism is ever likely to amount to." ]

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[ "Denis Shapovalov proved he can produce some of his best tennis with his back against the wall. ", "Though he wasn't pushed completely to the limit on Tuesday in his first U.S. Open qualifying match, he did show that same ability to bounce back.", "\n\nIn his quest to qualify for the Grand Slam event that begins next week in New York City, Shapovalov defeated American Denis Kudla in straight sets (6-3, 6-4).", "\n\nSIGN UP to watch WTA and ATP tour events on DAZN\n\nShapovalov lost breaks in each set that put him behind the eight-ball, but bounced back with breaks of his own to change the momentum of the match en route to victory.", "\n\nIn the first set, each player held serve in the first four games before Kudla managed to get a game of Shapovalov's serve to make it 3-2. ", "But that would be the last game Kudla would win of the set; Shapovalv produced a break of his to even the game score at 3-3, and rolled from there, winning the next three games including a second break to take the opening set off Kudla 6-3.", "\n\nA few action photos of Denis #Shapovalov today in first-round action. ", "He's into Round 2 of qualies at the #USOpen pic.twitter.com/w0aX0zoWLP — Ash Marshall (@AMarshallSport) August 22, 2017\n\nIn the second set, Kudla again produced a break to put himself in the driver's seat, this time to go up 4-2.", "\n\nBut Shapovalov again showed the resolve that helped him through a surprise run at Rogers Cup in Montreal a few weeks ago, winning four straight games, including two breaks, to take the second set 6-4, and the match.", "\n\nThough Shapovalov didn't win any points at the net on Tuesday, he was successful on his serve, producing 10 aces, while Kudla had none.", "\n\nUnreal support today at @usopen. ", "Thanks so much to everyone who came to watch❤ #DontStopFighting — Denis Shapovalov (@denis_shapo) August 22, 2017\n\nPlaying in front of a hometown crowd at Rogers Cup, Shapovalov pulled a stunning upset against World then No. ", "2 and tournament top-seed Rafael Nadal, doing so after dropping the first set. ", "Likewise, three of Shapovalov's four victories at the tournament required him to come-from-behind after losing the opening set. ", "In his first matchup against Brazilian Rogerio Dutra Silva, Shapovalov had to recover and save four match points before squeaking out the three-set victory (4-6, 7-6 (10-8), 6-4).", "\n\n\"It really helped me bring out my fighting spirit in every match that I had,\" Shapovalov said.", "\n\nMORE: Shapovalov poised to try to qualify for U.S. Open, wants to 'lift Grand Slam'\n\nShapovalov will now play Gastao Elias of Portugal, who won his opening-round qualifier against countryman Goncalo Oliveira (6-4, 4-6, 6-1). ", "That match will take place Thursday at 11 a.m. ET. ", "Shapovalov would need to win one more match after that to advance to the main bracket, which begins play Monday, Sept. 2.", "\n\nIn other qualifying action, Canadian Felix Auger-Aliassime, one of Shapovalov's best friends and training partners, also won his opening-round matchup, defeating Japanese challenger Hiroki Moriya (6-3, 6-3).", "\n\nShapovalov and Auger-Aliassime are two of five Canadians on the men's side attempting to qualify, along with Peter Polansky, Frank Dancevic and Brayden Schnur. ", "The other three begin their qualifying quests on Wednesday.", "\n\nOn the women's side, Francoise Abanda and Bianca Andreescu are each attempting to qualify." ]

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[ "/*\r\n * Copyright 1999-2018 Alibaba Group Holding Ltd.\r\n *\r\n * Licensed under the Apache License, Version 2.0 (the \"License\");\r\n * you may not use this file except in compliance with the License.", "\r\n * You may obtain a copy of the License at\r\n *\r\n * http://www.apache.org/licenses/LICENSE-2.0\r\n *\r\n * Unless required by applicable law or agreed to in writing, software\r\n * distributed under the License is distributed on an \"AS IS\" BASIS,\r\n * WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.", "\r\n * See the License for the specific language governing permissions and\r\n * limitations under the License.", "\r\n */\r\npackage com.alibaba.druid.sql.parser;\r\n\r\npublic class NotAllowCommentException extends ParserException {\r\n\r\n private static final long serialVersionUID = 1L;\r\n\r\n public NotAllowCommentException(){\r\n this(\"comment not allow\");\r\n }\r\n\r\n public NotAllowCommentException(String message, Throwable e){\r\n super(message, e);\r\n }\r\n\r\n public NotAllowCommentException(String message){\r\n super(message);\r\n }\r\n\r\n}\r\n" ]

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[ "\n\n\n\nby Ashley Jones Alternate Current Radio Network\n\nThe Red Pill Radio Show Broadcasts 4 nights a week on Alternate Current Radio Network Find us on the web at Alternate Current Radio Network broadcasting your favorite talk shows, music and news 24/7.", "\n\nIf you think the last few days of record setting snow and cold in Parts of upstate New york is just a freak event, than your not going to like what I am about to tell you. ", "According To NASA Scientist/Climatologist John Casey that is just the beginning of what is to come during this next 30 yr cycle of Extreme cold which will be caused by a historic decline in the Suns energy output that will impact the entire world\n\nIf Casey Is right, than not only will a mass number of the worlds people die by freezing and starving to death due to the extreme cold killing 50 percent of the worlds food supply, but you can also expect Super earthquakes, and more powerful volcanic eruptions across the globe.", "\n\nWith nasty cold fronts thrusting an icy and early winter across the continental U.S. – along with last winter described by USA Today as “one of the snowiest, coldest, most miserable on record” – climatologist John L. Casey thinks the weather pattern is here to stay for decades to come.", "\n\nIn fact, Casey, a former space shuttle engineer and NASA consultant, is out with the provocative book Dark Winter: How the Sun Is Causing a 30-Year Cold Spell, which warns that a radical shift in global climate is underway, and that Al Gore and other environmentalists have it completely wrong. ", "The earth, he says, is cooling, and cooling fast.", "\n\nAnd unless the scientific community and political leaders act soon, cold, dark days are ahead. ", "Casey says the evidence is clear that the earth is rapidly growing colder because of diminished solar activity. ", "He says trends indicate we could be headed for colder temperatures similar to those seen in the late 1700s and early 1800s when the sun went into a “solar minimum” – a phenomenon with significantly reduced solar activity, including solar flares and sunspots.", "\n\nIf he’s right, that would be very bad news. ", "Dark Winter posits that a 30-year period of cold has already begun. ", "Frigid temperatures and the food shortages that inevitably result could lead to riots and chaos.", "\n\nCasey tells Newsmax, “All you have to do is trust natural cycles and follow the facts, and that leads you to the inevitable conclusion that the sun controls the climate, and that a new cold era has begun.” ", "Casey is president of the Space and Science Research Corp., an Orlando, Fla., climate research firm. ", "His new book debunks global warming orthodoxy. ", "For more than a decade, he reports, the planet’s oceans have been cooling. ", "And since 2007, the atmospheric temperature has been cooling as well.", "\n\n“The data is pretty solid,” Casey says. “", "If you look at the 100-year global temperature chart, you look at the steep drop-off we’ve had since 2007. ", "It’s the steepest drop in global temperatures in the last hundred years.”", "\n\nRead Here: http://www.sott.net/article/289105-Former-NASA-consultant-climatologist-John-L-Casey-a-radical-shift-in-global-climate-is-underway-30-Year-cold-spell-will-strike-Earth\n\nIf you would like to express your opinions or concerns on the air during the live broadcast of The Red Pill Radio Show please call 567-704-7851 code 379417#\n\nBe sure to tune in to Red Pill Radio Monday – Thursday at 8pm-10pm EST. ", "Red Pill Radio broadcasts daily for 2 hours to discuss current events, and interview some of our nation’s most interesting patriots & controversial guests.", "\n\nPlease “LIKE”, share and recommend this story..\n\nWe welcome your comments in our Facebook comment thread!", "\n\nFair Use Notice: This article contains some copyrighted material whose use has not been authorized by the copyright owners. ", "We believe that this not-for-profit, educational, and/or criticism or commentary use on the Web constitutes a fair use of the copyrighted material (as provided for in section 107 of the US Copyright Law. ", "If you wish to use this copyrighted material for purposes that go beyond fair use, you must obtain permission from the copyright owner. ", "Fair Use notwithstanding we will immediately comply with any copyright owner who wants their material removed or modified, wants us to link to their web site, or wants us to add their photo" ]

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[ "Q:\n\nPHP: Included function versus call to a static function. ", "Is one better than the other?", "\n\nI have a message class that I use like so:\nRedirectMsg::go('somepage.php', MessageType::ERROR, 'Your message here.');", "\n\nWould it be better to use a regular function? ", "Or is this a personal preference issue?", "\nredirectMsg('somepage.php', MessageType::ERROR, 'Your message here.');", "\n\nA:\n\nObjects Classes help provide a sudo pseudo-namespace for functions so that they don't overlap, which can be very helpful. ", "Have a large number of functions in the global namespace is a naming disaster waiting to happen. ", "If you're using PHP 5.3 you might want to look into namespaces.", "\n\n" ]

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[ "Q:\n\nWhats the best way to retrieve array data from MySql\n\nI'm storing a object / data structure like this inside a MySql (actually a MariaDb) database:\n{\n idx: 7,\n a: \"content A\",\n b: \"content B\",\n c: [\"entry c1\", \"entry c2\", \"entry c3\"]\n}\n\nAnd to store it I'm using 2 tables, very similar to the method described in this answer: https://stackoverflow.com/a/17371729/3958875\ni.e.\nTable 1:\n+-----+---+---+\n| idx | a | b |\n+-----+---+---+\n\nTable 2:\n+------------+-------+\n| owning_obj | entry |\n+------------+-------+\n\nAnd then made a view that joins them together, so I get this:\n+-----+------------+------------+-----------+\n| idx | a | b | c |\n+-----+------------+------------+-----------+\n| 7 | content A1 | content B1 | entry c11 |\n| 7 | content A1 | content B1 | entry c21 |\n| 7 | content A1 | content B1 | entry c31 |\n| 8 | content A2 | content B2 | entry c12 |\n| 8 | content A2 | content B2 | entry c22 |\n| 8 | content A2 | content B2 | entry c32 |\n+-----+------------+------------+-----------+\n\nMy question is what is the best way I can get it back to my object form? (", "e.g. I want an array of the object type specified above of all entries with idx between 5 and 20)\nThere are 2 ways I can think of, but both seem to be not very efficient.", "\nFirstly we can just send this whole table back to the server, and it can make a hashmap with the keys being the primary key or some other unique index, and collect up the different c columns, and rebuild it that way, but that means it has to send a lot of duplicate data, and take a bit more memory and processing time to rebuild on the server. ", "This method also won't be very pleasant to scale if we have multiple arrays, or have arrays within arrays.", "\nSecond method would be to do multiple queries, filter Table 1 and get back the list of idx's you want, and then for each idx, send a query for Table 2 where owning_obj = current idx. ", "This would mean sending a whole lot more queries.", "\nNeither of these options seems very good, so I'm wondering if there is a better way. ", "Currently I'm thinking it can be something that utilizes JSON_OBJECT(), but I'm not sure how. ", "\nThis seems like a common situation, but I can't seem to find the exact wording to search for to get the answer.", "\nPS: The server interfacing with MySql/MariaDb is written in Rust, don't think this is relevant in this question though\n\nA:\n\nYou can use GROUP_CONCAT to combine all the c values into a comma-separated string.", "\nSELECT t1.idx, t1.a, t1.b, GROUP_CONCAT(entry) AS c\nFROM table1 AS t1\nLEFT JOIN table2 AS t2 ON t1.idx = t2.owning_obj\nGROUP BY t1.idx\n\nThen explode the string in PHP:\n$result_array = [];\nwhile ($row = $result->fetch_assoc()) {\n $row['c'] = explode(',', $row['c']);\n $result_array[] = $row;\n}\n\nHowever, if the entries can be long, make sure you increase group_concat_max_len.", "\nIf you're using MySQL 8.0 you can also use JSON_ARRAYAGG(). ", "This will create a JSON array of the entry values, which you can convert to a PHP array using json_decode(). ", "This is a little safer, since GROUP_CONCAT() will mess up if any of the values contain comma. ", "You can change the separator, but you need a separator that will never be in any values. ", "Unfortunately, this isn't in MariaDB.", "\n\n" ]

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[ "Role of videoendoscopy in pulmonary surgery: present experience.", "\nVideothoracoscopic techniques were utilized in managing 88 consecutive patients. ", "The series was composed of 36 patients with pneumothorax, 44 cases of single and 9 of multiple pulmonary nodules and 1 patient with diffuse lung disease. ", "In 14 cases (15.9%) conversion to open thoracotomy was necessary while in the remaining 74 patients the procedure (30 blebectomies, 2 bullectomies, 37 wedge resections, 6 lobectomies and one multiple biopsies) were carried out as planned. ", "In each lobectomy and in six wedge resections an accessory small incision was necessary; we consider only this video-assisted thoracic surgery (VATS). ", "Benign disease, aside from the blebs and bullae, was found in 12 cases of solitary pulmonary nodules and in 1 case of multiple lesions, while malignant lesions were detected in 31 patients. ", "Primary carcinoma was diagnosed in nine cases after a wedge resection had been performed on a suspicious solitary nodule. ", "In two of these wedge resection had to suffice because of poor lung function, while in the remaining seven cases, a lobectomy was carried out through an open thoracotomy in two patients, and in five cases VATS was attempted successfully in four, while in one case a formal thoracotomy was necessary due to bleeding. ", "Solitary metastases were found in 14 patients and were managed by 12 wedge resections and 2 lobectomies. ", "Seventy-one patients (97.3%) had an uneventful postoperative course while 2 (2.7%) had only minor complications. ", "No recurrences were observed, however follow-up is limited. ", "Videothoracoscopy techniques are very useful and are good alternatives to conventional thoracotomy in managing cases of pneumothorax, benign pulmonary lesions and in taking biopsies.(ABSTRACT TRUNCATED AT 250 WORDS)" ]

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[ "Q:\n\nsklearn kfold returning wrong indexes in python\n\nI am using kfold function from sklearn package in python on a df (data frame) with non-contious row indexes.", "\nthis is the code:\nkFold = KFold(n_splits=10, shuffle=True, random_state=None)\nfor train_index, test_index in kFold.split(dfNARemove):...\n\nI get some train_index or test_index that doesn't exist in my df.", "\nwhat can I do?", "\n\nA:\n\nkFold iterator yields to you positional indices of train and validation objects of DataFrame, not their non-continuous indices. ", "You can access your train and validation objects by using .iloc pandas method:\nkFold = KFold(n_splits=10, shuffle=True, random_state=None)\nfor train_index, test_index in kFold.split(dfNARemove):\n train_data = dfNARemove.iloc[train_index]\n test_data = dfNARemove.iloc[test_index]\n\nIf you want to know, which non-continuous indices used for train_index and test_index on each fold, you can do following:\nnon_continuous_train_index = dfNARemove.index[train_index]\nnon_continuous_test_index = dfNARemove.index[test_index]\n\n" ]

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[ "Amphotericin B treatment dissociates in vivo replication of the scrapie agent from PrP accumulation.", "\nScrapie and related animal and human disorders are neurodegenerative diseases characterized by the formation of a modified, partly proteinase-resistant protein (PrP) of the host, which tends to aggregate as amyloid fibrils and accumulate in the brain of infected individuals. ", "There is a general consensus that the pathological form of PrP (PrPSc) is essential for the clinical appearance of the disease, but whether it is part of the scrapie agent or a by-product of viral infection is still controversial. ", "Here we report that treatment of scrapie-infected hamsters with amphotericin B delays the accumulation in the brain of the proteinase-resistant portion of PrPSc by about 30 days without affecting scrapie replication. ", "The consequence is that hamsters treated with amphotericin B developed clinical signs of disease later than infected controls. ", "We argue that the proteinase-resistant portion of PrPSc is necessary for the development of the disease but that it is unlikely to be essential for scrapie replication." ]

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[ "Kristanna Loken has been starring in television shows and movies since 1995. ", "With her breakout action performance in Terminator 3: Rise of the Machines she became a household name. ", "Now, she's got a new movie out and TMS had a chance to talk to her about action films, Black Rose, motherhood, and the future of how we watch movies.", "\n\n\n\n\n\nTMS: You've been keeping really busy these days. ", "You've got a steady string of new movies coming out. ", "But, I'm sure you get asked about Terminator 3 all the time? ", "How do you think that film helped elevate your status as an actress?", "\n\n\n\n\n\nKL: Well, I think it just opened so many doors on the sheer scale and scope of the film. ", "Really the level of outreach. ", "All of a sudden, people worldwide knew who I was. ", "I had done quite a bit of work before then but certainly nothing on a global scale. ", "Not only did the film go over the world but I went all over the world promoting the film. ", "I think it was just getting out there and meeting the people that made a difference in their awareness of me.", "\n\n\n\n\n\nTMS: In a male dominated field, we know a lot of these action roles go to men, how do you continue pushing yourself to get work and what do you do to set yourself apart from other actresses that are trying to get these parts?", "\n\n\n\n\n\nKL: Good question. ", "I think it's really letting the work speak for itself in all honesty, and trying to stay a little bit ahead of the game in that sense. ", "I'm launching a new production company called Trio Entertainment. ", "We've got a slate of ten films and TV series. ", "So really taking more overall creative control in the selection of films we're going to produce, my role in them, in front of the camera and also behind the camera. ", "I think that the more you/yourself can call the shots, you'll certainly be better off trying to create.", "\n\n\n\n\n\n\n\n\n\nTMS: A lot of the movies you've done have been action. ", "What draws you to that genre? ", "And if you could pick another genre to work in, what would it be?", "\n\n\n\n\n\nKL: Well, I was at this festival last night to celebrate women in action, predominantly the stunt performers. ", "For me, my physicality lent itself to action. ", "I grew up on a fruit farm. ", "I'm an athletic person by nature. ", "And I like getting down and dirty and physical. ", "I'm six feet tall. ", "I have a certain type of presence. ", "I think it lent itself to these strong female roles. ", "I think you need to have a certain stature almost or ability certainly on screen. ", "I had the pleasure of honoring Cynthia Rothrock last night for her lifetime achievements. ", "She was a pioneer for women in martial arts. ", "I have appreciation for that. ", "I think that's a very important aspect for me doing action.", "\n\n\n\n\n\nAs far as what I'd like to do more of, I'd love to do more comedy, frankly. ", "I'd like to do more straight dramatic roles. ", "I've been getting the question lately if I'm going to direct. ", "I'm really feeling ready now in my career after 24 years of being in front of the camera and doing some producing. ", "I'd really like to direct.", "\n\n\n\n\n\nTMS: I know you're a new mom. ", "How has that changed your perspective?", "\n\n\n\n\n\nKL: Immensely. ", "I think in every possible way. ", "I had no idea. ", "It changes your life. ", "In every possible way I feel like a better human being. ", "I feel more like the woman that I've always wanted to become and I feel like my decision making process has become much more acute because it's like looking in the mirror all day long making a decision that's going to directly effect the well being of your child.", "\n\n\n\n\n\nThor had a rough start to life. ", "He had three different G.I. birth defects. ", "It was a real struggle for us in the beginning. ", "But through that I feel like a student. ", "I feel like he's been a teacher. ", "I feel like a better person from all we went through. ", "It's been an incredible journey.", "\n\n\n\n\n\nTMS: So, what kind of movie is Black Rose?", "\n\n\n\n\n\nKL: Black Rose is a thriller suspense film definitely with some action. ", "What I liked about my character was her duality and her complexity. ", "She is a police profiler and is playing with the boys in the big league. ", "This is her first case and she's investigating a string of murders. ", "It deeply effects her on a level that startles her. ", "I think through and through Emily Smith is a humanitarian and that's why she went into profiling, so she can really save lives and find the perpetrators before the next murder happens.", "\n\n\n\n\n\nTMS: Robert Davi is the ultimate character actor. ", "What was it like working with him on this?", "\n\n\n\n\n\nKL: Robert is great, really a professional. ", "Really a joy to have on set. ", "He's always willing to try to make the scene the best it could be from every angle. ", "I love that. ", "He's really great to work with.", "\n\n\n\n\n\nI worked with Bruce Dern wh is such a legend. ", "He said, \"Acting with a partner is like doing a dance. ", "When it goes well it's like Fred Astaire and Ginger Rogers.' ", "That's so true. ", "And Robert Davi was a great dance partner.", "\n\n\n\n\n\nTMS: I noticed the film was made in 2014. ", "Was there a reason it was held back?", "\n\n\n\n\n\nKL: (laughter) This business still mystifies me, frankly. ", "I know it came out in Russia and was a European release. ", "With these independent films, you truly don't know where they're going to land especially with all the different media outlets. ", "When I heard that after 3-4 years we were finally getting not only a VOD release, but that people really liked the film, it was really exciting.", "\n\n\n\n\n\nTMS: Getting into your history a little bit, what actresses made you decide to try your hand at acting?", "\n\n\n\n\n\nKL: I always wanted to be an actress. ", "Growing up on a farm in upstate New York, I did all kinds of summer stock theater and dance. ", "I loved to perform. ", "I really love Helen Mirren. ", "She's a pioneer for strong female roles. ", "She's just remarkable. ", "I would love the opportunity to work with her some day. ", "She's been a real inspiration. ", "But, I might add, on another side, my father has been a real inspiration for me too. ", "He did some acting when he was younger and he always supported my dreams and still does. ", "I collaborated with him. ", "He was also a writer on a film that Bruce Dern played my father, Fighting For Freedom that we shot in my parent's barn in upstate New York.", "\n\n\n\n\n\nTMS: If you could pick one iconic female comic book hero or action hero, who would you pick?", "\n\n\n\n\n\nKL: As in one that I haven't already played? (", "laughter) That's a really good question. ", "I think of Jane Vasco in Painkiller Jane. ", "That was an awesome character. ", "There's so many that I've already enjoyed embodying, I haven't really given it any thought as to who else I would prefer. ", "Maybe there's one I could create.", "\n\n\n\n\n\nTMS: How do you think the industry has changed since you started? ", "Is it easier or harder?", "\n\n\n\n\n\nKL: That's actually a priceless question because the business has changed so much. ", "It's changed yearly. ", "You almost have to be around the next curve of what's next. ", "When I moved fairly recently and was going through my attic, I was finding TV Guides. ", "Think about that. ", "Most people don't even know what a TV Guide is. ", "It wasn't that long ago. ", "I think in a way it's easier to get films made because there's all these micro budget films and so many platforms. ", "However, I think it's harder for you film to get noticed and distributed for that exact same reason. ", "There's so much content out there. ", "What we've been trying to distill in our company is 'what's next?' ", "and what will be the most beneficial for the way we release content? ", "How will it reach the most people. ", "How can we make films that stand apart from the rest? ", "It's a really good question.", "\n\n\n\n\n\n\n\n\n\nBlack Rose is in limited theaters on April 28, 2017 and hits VOD and DVD on May 2nd.", "\n\n\n\n\n\n\n\n" ]

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[ "Q:\n\nGo interface to enforce same argument type between methods (but can be any type)\n\nThe title is confusing, I'm sure, but it's hard to describe what I mean. ", "\nI want to create a Go interface that has two methods; the first one returns a value, and the second one accepts a value. ", "I want to ensure that method 1 returns the same type as method 2 accepts, without specifying what the type is (other than it being a struct). ", "For example:\ntype MyInterface interface {\n Method1() MyType\n Method2(MyType) error\n}\n\nWhere MyType can be any type (of struct), as long as it's the same in both Method 1 and Method 2.", "\nIs there any way to do this in Go?", "\nEDIT:\nBased on @iLoveReflection's answer, I've tried the following:\npackage main\n\ntype MyInterface interface {\n GetType() interface{}\n\n UseType(input interface{})\n}\n\ntype MyImplementation struct{}\n\ntype MyType struct {\n}\n\nfunc (i MyImplementation) GetType() MyType {\n return MyType{}\n}\nfunc (i MyImplementation) UseType(input MyType) {\n return\n}\n\nfunc test(input MyInterface) {\n return\n}\n\nfunc assertArgAndResult() {\n var v MyImplementation\n v.UseType(v.", "GetType())\n}\n\nfunc main() {\n test(MyImplementation{})\n}\n\nSo basically, I'm specifying an interface (MyInterface), and I want to ensure that a given implementation of that interface (MyImplementation, which would be created by the user of my package) meets the requirement stated in the original post.", "\nassertArgAndResult() is working as expected, and ensures that MyImplementation meets the requirements. ", "However, I get a compile error in the main() function: \ncannot use MyImplementation literal (type MyImplementation) as type MyInterface in argument to test:\n MyImplementation does not implement MyInterface (wrong type for GetType method)\n have GetType() MyType\n want GetType() interface {}\n\nA:\n\nAdd the following function to a package to ensure that the input and output types match at compile time:\nfunc assertArgAndResult() {\n var v MyInterface\n v.Method2(v.", "Method1())\n}\n\nThis function will not be included in the executable as long as the function is not called.", "\nThere is no compile time check that will ensure that MyType is a struct type as specified in the question.", "\nThe reflect package can be used to check type types completely.", "\n// checkItf returns true of the interface value pointed to by\n// pi has Method1 with some return type T and Method2 with\n// argument type T.\nfunc checkItf(pi interface{}) bool {\n t := reflect.", "TypeOf(pi)\n if t.Kind() !", "= reflect.", "Ptr {\n return false // or handle as error\n }\n t = t.Elem()\n if t.Kind() !", "= reflect.", "Interface {\n return false // or handle as error\n }\n m1, ok := t.MethodByName(\"Method1\")\n\n // Method1 should have no outputs and one input.", "\n if !", "ok || m1.Type.", "NumIn() !", "= 0 || m1.Type.", "NumOut() !", "= 1 {\n return false\n }\n\n // Method2 should have one input and one output.", "\n m2, ok := t.MethodByName(\"Method2\")\n if !", "ok || m2.Type.", "NumIn() !", "= 1 || m2.Type.", "NumOut() !", "= 1 {\n return false\n }\n\n e := reflect.", "TypeOf((*error)(nil)).Elem()\n s := m1.Type.", "Out(0)\n\n // The type must be a struct and\n // the input type of Method2 must be the same as the output of Method1 and\n // Method2 must return error.", "\n return s.Kind() == reflect.", "Struct &&\n m2.Type.", "In(0) == s &&\n m2.Type.", "Out(0) == e\n}\n\nCall it like this:\nfunc init() {\n if !", "checkItf((*MyInterface)(nil)) {\n panic(\"mismatched argument and return time son MyInterface\")\n }\n}\n\n" ]

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[ "The Dec Baps Today had a most interesting piece about a Chattanooga conference on the Civil War. ", "I'm writing Johnny Pierce a letter for Publication and also have started a blog on the topic.", "\n\nHere is what Pierce reported Bruce Gourley said last fall in Chattanooga:\n\nQuoting from John Pierce story in December 2015 BT:\n\nIn Dec. of 1822 Richard Furman President of the SC SBC penned a public letter to the SC Governor that represented a \"tipping point among white Baptists in the South, \" said Gourley.", "\n\nFurman's \"very pro-slavery stance\" in the letter affirmed that slavery is never actually condemned in the Bible, and he assured the governor of the state's Baptist support in preventing future insurrections.", "\n\n\"Prior to 1880, most white Baptists in the South were either opposed to slavery of ambivalent, \" Said Gourley. \"", "Richard Furman's letter changed things in the South\"" ]

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[ "---\nbibliography:\n- 'bibfile.bib'\n---\n\nYITP-14-44\\\n[ **Calculating the mass fraction of primordial black holes**]{}\\\nSam Young $^{a}$, Christian T. Byrnes $^{a}$, Misao Sasaki $^{b}$\\\n$^{a}$Department of Physics and Astronomy, Pevensey II Building, University of Sussex, BN1 9RH, UK\\\n$^{b}$ Yukawa Institute for Theoretical Physics, Kyoto University, Kyoto 606-8502, Japan\\\nE-mail: sy81@sussex.ac.uk, cbt22@sussex.ac.uk, misao@yukawa.kyoto-u.ac.jp\\\n\\\n\nWe reinspect the calculation for the mass fraction of primordial black holes (PBHs) which are formed from primordial perturbations, finding that performing the calculation using the comoving curvature perturbation $\\mathcal{R}_{c}$ in the standard way vastly overestimates the number of PBHs, by many orders of magnitude. ", "This is because PBHs form shortly after horizon entry, meaning modes significantly larger than the PBH are unobservable and should not affect whether a PBH forms or not - this important effect is not taken into account by smoothing the distribution in the standard fashion. ", "We discuss alternative methods and argue that the density contrast, $\\Delta$, should be used instead as super-horizon modes are damped by a factor $k^{2}$. We make a comparison between using a Press-Schechter approach and peaks theory, finding that the two are in close agreement in the region of interest. ", "We also investigate the effect of varying the spectral index, and the running of the spectral index, on the abundance of primordial black holes.", "\n\nIntroduction\n============\n\nIt is believed that primordial black holes (PBHs) could have formed in the early universe from the collapse of large density fluctuations, and if so, could have observational implications - either from their gravitational effects, or the effects of their Hawking radiation (see [@Carr:2009jm; @Josan:2009qn] for recent lists of the constraints). ", "They have not been observed, but this fact is enough that they can be used to constrain the early universe (i.e. [@Bugaev:2012ai; @Young:2013oia; @Green:1997sz; @Byrnes:2012yx; @Shandera:2012ke]) - and provide the only known tool for probing the primordial universe on extremely small scales (i.e. [@Scott:2012kx]). ", "However, the constraints from PBHs on small scales are much weaker than those on cosmological scales, for example, the constraints from the cosmic microwave background from Planck.", "\n\nDuring inflation, the Hubble horizon shrinks on a comoving scale, and quantum fluctuations become classical density perturbations once they exit the horizon. ", "Once inflation ends, the horizon begins to grow and perturbations begin to reenter the horizon. ", "If a perturbation is large enough, it will collapse to form a PBH almost immediately after horizon reentry - and there has been extensive research into the nature of this collapse and how large a perturbation must be in order to collapse [@Shibata:1999zs; @Hawke:2002rf; @Niemeyer:1999ak; @Musco:2004ak; @Musco:2008hv; @Musco:2012au; @Niemeyer:1997mt].", "\n\nCalculations for the critical value of the density contrast, $\\Delta$, or comoving curvature perturbation, $\\mathcal{R}_{c}$, above which a region will collapse to form a PBH are typically of order 0.5 or 1 respectively - and so an insignificant number of PBHs will form unless the power spectrum on small scales is much larger than on large scales, by several orders of magnitude. ", "This is possible in several models, such as the running mass model [@Drees:2011hb], axion inflation [@Bugaev:2013fya], a waterfall transition during hybrid inflation [@Bugaev:2011wy], from passive density fluctuations [@Lin:2012gs], or during inflation with small field excursions [@Hotchkiss:2011gz]. ", "For a recent summary of PBH forming models see [@Green:2014faa]. ", "Alternatively, the constraint on the formation criteria can be relaxed during a phase transition in the early universe, causing PBHs to form preferentially at that mass scale (i.e. [@Jedamzik:1999am]).", "\n\nIn this paper, we will review the calculation of the PBH abundance. ", "The calculation typically computes the fraction of the universe which is above the critical value - in terms of $\\Delta$ or $\\mathcal{R}_{c}$. This is typically done using the theory of peaks, which calculates the number density of peaks above the critical value, or a Press-Schechter approach, which computes the volume of the universe above the critical value. ", "in order to calculate the abundance of PBHs on different scales, the distribution is convolved with a smoothing function to smooth out modes smaller than the horizon, whilst leaving the horizon and super-horizon modes. ", "When $\\mathcal{R}_{c}$ is used to do the calculation in this manner, the super-horizon modes have a large impact on the calculation - we will argue that they should not affect the calculation and that using $\\mathcal{R}_{c}$ can be misleading and give errors of many orders of magnitude compared to using $\\Delta$.\n\nIn Section 2, we will discuss the formation criteria for PBHs explaining these arguments, and in Section 3, we will briefly review the calculation of the mass of a PBH dependant on the scale it forms at. ", "In Section 4 we discuss the different ways the abundance of PBHs and constraints on the early universe can be calculated for different models. ", "We conclude our arguments in Section 5.", "\n\nFormation criteria\n==================\n\nThe abundance of PBHs is normally stated in terms of $\\beta$, the mass fraction of the Universe contained within PBHs at the time of their formation. ", "Typically, $\\beta$ is given as a function of their mass (which, we will see later, is a function of the time at which they form) - so that $\\beta$ can be used to describe the mass spectrum of PBHs. ", "In order to determine whether a region of the early universe will collapse to form a PBH, then typically either the density or curvature of that region is compared to a threshold value, which itself is typically calculated from numerical simulations.", "\n\nTraditionally, the density contrast $\\Delta=\\frac{\\delta\\rho-\\rho}{\\rho}$ had been used to calculate $\\beta$. However, following the paper by Shibata and Sasaki in 1999 [@Shibata:1999zs] which calculated the threshold value in terms of a metric perturbation $\\psi$, and the paper by Green, Liddle, Malik and Sasaki (GLMS) in 2004 [@Green:2004wb], it became more common to use the comoving curvature perturbation $\\mathcal{R}_{c}$ (for example, [@Bugaev:2012ai; @Shandera:2012ke])[^1].", "\n\nIn figure \\[dontusezeta\\] we demonstrate the danger of using $\\mathcal{R}_{c}$ to calculate $\\beta$. By simply comparing the height of either peak, one would be drawn to the conclusion that the first (left hand) peak will collapse to form a PBH and the second (right hand) peak will not. ", "However, because the long wavelength mode is well outside the horizon, it is unobservable at the expected time of collapse and invoking the separate universe approach (see [@Wands:2000dp]) means that it should not affect the local evolution of the universe. ", "Therefore, the universe looks locally identical to observers at either peak - either both peaks should collapse to form a PBH or neither should[^2].", "\n\n![", "Here, as an example, we show a universe with two sharp (gaussian) peaks in $\\mathcal{R}_{c}$ which sit on top of a long wavelength mode. ", "The two thick black boxes represent the size of the visible universe to an observer at the centre of the peaks at the time of PBH formation, whilst the dotted red line represents the hypothetical threshold value for collapse. ", "Both universes appear the same locally to each observer, and so the evolution of each patch should be identical (until the long wavelength becomes observable).[]{data-label=\"dontusezeta\"}](dontusezeta){width=\"\\linewidth\"}\n\nIt should be noted that papers which have calculated a critical value in terms of $\\mathcal{R}_{c}$ (i.e. [@Shibata:1999zs; @Nakama:2013ica]) assume that $\\mathcal{R}_{c}$ drops quickly to zero outside of the perturbation - so these values can be used if one assumes that there are no super-horizon perturbations affecting your calculation. ", "Therefore it may be possible to use $\\mathcal{R}_{c}$ to calculate $\\beta$ if one takes care to exclude super-horizon modes from the calculation (one possibility is to simply subtract the long wavelength modes - although this is strongly dependant on what is considered to be a long wavelength.), ", "and in Section 4.5 we will consider an approximation where only the value of the power spectrum at horizon entry is used.", "\n\nA more formal way to consider this to investigate the effect of super-horizon modes on local observables, such as the density contrast and the spatial 3-curvature. ", "Figure \\[curvature density\\] shows the same universe as figure \\[dontusezeta\\] but in terms of the spatial curvature and density contrast.", "\n\n![", "The same universe as shown in figure \\[dontusezeta\\], but this time showing the spatial curvature and the density contrast at the time the scale of the small peaks enter the horizon. ", "We now see that both peaks look identical - and so should evolve in the same manner. ", "We see that the peaks in the spatial curvature and density contrast are very similar, both having a Mexican hat profile (rather than the gaussian shape in the comoving curvature perturbation) - note that the difference in the height of the peaks is due to the arbitrary scaling we have used in the figure.[]{data-label=\"curvature density\"}](curvaturedensity){width=\"\\linewidth\"}\n\n*Spatial curvature* - consider the perturbed, spatially flat FRW metric $$\\label{metric}\nds^{2}=-N^{2}dt^{2}+g_{ij}\\left(dx^{i}+N^{i}dt\\right)\\left(dx^{j}+N^{j}dt\\right); g_{ij}=e^{2\\alpha}\\delta_{ij},$$ where we have chosen a comoving slicing, and $$\\alpha=\\ln a(t) + \\mathcal{R}_{c},$$ with $a(t)$ the scale factor of some flat background and $\\mathcal{R}_{c}$ the comoving curvature perturbation. ", "A constant value of $\\mathcal{R}_{c}$ can be absorbed into the scale factor by defining $$\\bar{a}(t)=a(t)e^{\\mathcal{R}_{c}},$$ and so a constant $\\mathcal{R}_{c}$ corresponds only to a rescaling of the spatial coordinates, as perhaps clear from the form of the metric (\\[metric\\]). ", "The spatial curvature is given by $$R^{(3)}=-\\frac{2}{e^{2\\alpha}}\\delta^{ij}\\left(2\\alpha,_{ij}+\\alpha,_{i}\\alpha,_{j}\\right),$$ and the spatial curvature of the metric is then $$\\label{spatial curvature}\nR^{(3)}=-\\frac{2}{e^{2\\alpha}}\\left(2\\nabla^{2}\\mathcal{R}_{c}+(\\vec{\\nabla}\\mathcal{R}_{c})^{2}\\right).$$ If we consider a very long wavelength $\\mathcal{R}_{c}$ mode, which appears constant on horizon scales, we see that the spatial curvature due to this mode is negligible due to the derivatives in Eq. (", "\\[spatial curvature\\]).", "\n\n*Density contrast* - on comoving slices, there is a simple relation at linear order between the comoving curvature perturbation and the density contrast [@Green:2004wb] $$\\label{density contrast}\n\\Delta(t,k)=\\frac{2(1+\\omega)}{5+3\\omega}\\left(\\frac{k}{aH}\\right)^{2}\\mathcal{R}_{c}(k),$$ where $\\omega$ is the equation of state $\\omega=p/\\rho$, which during radiation domination is $\\frac{1}{3}$.[^3] In real space this is $$\\Delta(t,x)=\\frac{2(1+\\omega)}{5+3\\omega}\\left(\\frac{1}{aH}\\right)^{2}\\nabla^{2}\\mathcal{R}_{c}(x).$$ Again, we see that this depends on the second derivative of $\\mathcal{R}_{c}$ - and so the effect of super-horizon $\\mathcal{R}_{c}$ modes is negligible. ", "At linear order, the density contrast is therefore equivalent to the spatial curvature. ", "However, there has been extensive research into the threshold value of $\\Delta$ but not for $R^{(3)}$, we therefore advocate the use of the density contrast in order to calculate the mass fraction, $\\beta$.\n\nThere has been extensive research on the threshold value for the density contrast above which a PBH will form. ", "Carr [@Carr:1975qj] was the first to derive a threshold value for the formation of PBHs, $\\Delta_{c}\\approx\\omega$ where $\\omega$ is the equation of state, by calculating the density necessary for gravity to overcome pressure forces. ", "In recent years, numerical simulations of gravitational collapse have been used to investigate the collapse of different shapes of the initial density profile. ", "Niemeyer and Jedamzik [@Niemeyer:1999ak] studied initial shapes including gaussian, Mexican hat, and polynomial, finding $\\Delta_{c}\\approx0.7$. Musco et al [@Musco:2004ak; @Musco:2008hv; @Musco:2012au][^4] later studied PBH formation, finding $\\Delta_{c}\\approx0.45$. More recently, Harada et al [@Harada:2013epa] studied a top hat shape, finding an analytic formula $\\Delta_{c}=\\sin^{2}[\\pi\\sqrt{\\omega}/(1+3\\omega)]=0.41$ during radiation domination, and Nakama et al [@Nakama:2013ica] studied generalised shapes to determine the crucial parameters in the shape and size of an overdensity. ", "See also [@Hawke:2002rf]. [", "^5].", "\n\nPrimordial black hole mass\n==========================\n\nIn order to calculate the mass spectrum, or mass function, of PBHs, it is necessary to relate the horizon scale at the time of formation to the mass of PBH formed. ", "We will first review the calculation of the horizon mass carried out by GLMS [@Green:2004wb]. ", "The horizon mass is $$M_{H}=\\frac{4\\pi}{3}\\rho(H^{-1})^{3}.$$ In co-moving units, the horizon scale during radiation domination is $R=(aH)^{-1}\\propto a$, and expansion at constant entropy gives $\\rho\\propto g_{*}^{-1/3}a^{-4}$ (where $g_{*}$ is the number of relativistic degrees of freedom, which is expected to be of order 100 in the early universe). ", "This allows the horizon mass at a given reentry scale to be related to the horizon mass at matter radiation equality, $$M_{H}=\\frac{3}{2}M_{H,eq}(k_{eq}R)^{2}\\left(\\frac{g_{*,eq}}{g_{*}}\\right)^{1/3},$$ where we use $k_{eq}=0.07\\Omega_{m}h^{2}$Mpc$^{-1}$, $g_{*,eq}\\approx 3$ and $g_{*}\\approx 100$. $M_{H,eq}$ is given by $$M_{H,eq}=\\frac{4\\pi}{3}2\\rho_{rad,eq}H_{eq}^{-3}=\\frac{8\\pi}{3}\\frac{\\rho_{rad,0}}{k_{eq}^{3}a_{eq}},$$ where we take $a_{eq}^{-1}=24 000\\Omega_{m}h^{2}$ and $\\Omega_{rad,0}h^{2}=4.17\\times10^{-5}$. Taking $\\Omega_{m}h^{2}=0.14$ gives $M_{H,eq}=7\\times10^{50}g$ (for this calculation, we have used the same numbers as GLMS [@Green:2004wb]).", "\n\nNow that the horizon mass has been calculated, it remains to determine fraction of the horizon mass which goes into the PBH, $f_{H}$. Several papers (for example, [@Hawke:2002rf; @Niemeyer:1999ak]) have noted that, when the density is close to the critical value, the mass of PBH formed depends on the size of the over-density, obeying a simple power law, $$f_{H}=C\\left(\\Delta-\\Delta_{c}\\right)^{\\gamma},$$ where $C$ and $\\gamma$ are constants - although the values calculated depend on the shape of the initial over-density. ", "Chisholm [@Chisholm:2006qc] summarises the different measurements, as well as discussing a minimum bound on the PBH mass from entropy constraints. ", "Typical values for these parameters which we will consider here are $C=3$, $\\Delta_{c}=0.5$, and $\\gamma=0.3$. For these values, the mass of PBH formed is only significantly smaller than than the horizon mass, $M_{PBH}<0.1M_{H}$, for values of $\\Delta$ in the range $$0.5<\\Delta<0.500012,\n\\label{close to critical}$$ and so we will assume that PBHs form with a mass approximately equal to the horizon mass for the remainder of this paper. ", "PBHs of significantly larger mass could form in regions where $\\Delta$ is substantially larger than 0.5, but the abundance of these regions is exponentially suppressed, and are thus extremely rare.", "\n\nPrimordial black hole abundance\n===============================\n\nWe will now discuss the calculation of the PBH mass fraction, $\\beta$. The density contrast on a comoving slicing, $\\Delta$, is smoothed on a given scale $R$, and the fraction of the universe with a density contrast above the critical value is calculated. ", "The smoothed density contrast $\\Delta(R,x)$ is calculated by convolving the density contrast with a window function $W(R,x)$: $$\\Delta(R,x)=\\int_{-\\infty}^{\\infty}d^{3}x' W(R,x-x')\\Delta(x').$$ The variance of $\\Delta(R,x)$ is given by $$\\label{density variance}\n\\langle\\Delta^{2}\\rangle=\\int_{0}^{\\infty}\\frac{dk}{k}\\tilde{W}^{2}(R,k)\\mathcal{P}_{\\Delta}(k),$$ where $\\tilde{W}(R,k)$ is the fourier transform of the window function, and $\\mathcal{P}_{\\Delta}(k)$ is the density power spectrum. ", "Using equation (\\[density contrast\\]) this can be related to the comoving curvature perturbation power spectrum as, $$\\langle\\Delta^{2}\\rangle=\\int_{0}^{\\infty}\\frac{dk}{k}\\tilde{W}^{2}(R,k)\\frac{4(1+\\omega)^{2}}{(5+3\\omega)^{2}}\\left(kR\\right)^{4}\\mathcal{P}_{\\mathcal{R}_{c}}(k).$$\n\nThroughout this paper, we will use a volume-normalised gaussian window function, such that the fourier transform is given by $$\\label{window function}\n\\tilde{W}(R,k)=\\exp\\left(-\\frac{k^{2}R^{2}}{2}\\right).$$\n\nIn the remaining portion of this section, we discuss the difference between using a peaks theory or Press-Schechter approach, and the predicted mass spectra of PBHs for a scale invariant curvature spectrum, a power law spectrum and for a spectrum with a running of the spectral index.", "\n\nPeaks theory vs Press-Schechter\n-------------------------------\n\nThe initial mass fraction of the Universe $\\beta$, that went into PBHs can be calculated either using a peaks theory approach, or a Press-Schechter approach. ", "A comparison of these two methods was carried out by GLMS [@Green:2004wb] who compared the mass spectra calculated using the curvature perturbation, with peaks theory, and the density contrast, using a Press-Schechter approach. ", "In their calculation it was necessary to assume a blue primordial power spectrum, $n_{s}>1$, and they found the two to be in close agreement[^6]. ", "We will repeat the calculation here for the density contrast only - finding that using peaks theory or a Press-Schechter are not in as close agreement previously found in [@Green:2004wb] but still similar, to within a factor of order 10.", "\n\nTo investigate the difference between the two methods, we will use a variable $\\nu=\\Delta/\\sigma$[^7], where $\\sigma$ is the square root of the variance $\\langle\\Delta^{2}\\rangle$ given by equation (\\[density variance\\]) and is a function of the form of the power spectrum and the smoothing scale (the calculation of $\\sigma$ is the same for either method).", "\n\nIn the theory of peaks, the number density of peaks above a height $\\nu_{c}$ is given by [@Bardeen:1985tr] $$n_{peaks}(\\nu_{c},R)=\\frac{1}{(2\\pi)^{2}}\\left(\\frac{\\langle k^{2}\\rangle(R)}{3}\\right)^{\\frac{3}{2}}\\left(\\nu_{c}^{2}-1\\right)\\exp\\left(-\\frac{\\nu_{c}^{2}}{2}\\right),\n\\label{peaks}$$ where $\\langle k^{2}\\rangle$ is the second moment of the smoothed density power spectrum $$\\langle k^{2}\\rangle(R)=\\frac{1}{\\langle\\Delta^{2}\\rangle(R)}\\int_{0}^{\\infty}\\frac{dk}{k}k^{2}\\tilde{W}^{2}(k,R)\\mathcal{P}_{\\Delta}(k).$$ If we assume a power law spectrum $\\mathcal{P}_{\\mathcal{R}_{c}}=A_{\\mathcal{R}_{c}}(k/k_{0})^{n_{s}-1}$, and a gaussian window function (equation (\\[window function\\])), we obtain $$\\langle k^{2}\\rangle(R)=\\frac{n_{s}+3}{2R^{2}},$$ assuming that $n_{s}>-3$. The number density of peaks above the threshold can be related to the density parameter $\\Omega_{PBH,peaks}$ (which is equal to the mass fraction $\\beta$ for a flat universe) by $\\Omega_{PBH,peaks}(\\nu_{c})=n_{peaks}(\\nu_{c},R)M(R)/\\rho$, where $M(R)$ is the mass of PBH associated with the horizon size $R$, $M(R)=(2\\pi)^{3/2}\\rho R^{3}$. Finally, we have $$\\beta_{peaks}(\\nu_{c})=\\Omega_{PBH,peaks}(\\nu_{c})=\\frac{(n_{s}+3)^{3/2}}{6^{3/2}(2\\pi)^{1/2}}\\nu_{c}^{2}\\exp\\left(-\\frac{\\nu_{c}^{2}}{2}\\right).", "\n\\label{beta peaks}$$\n\nBy contrast, the Press-Schechter calculation simply integrates the probability distribution function (PDF), $$P(\\nu)=\\frac{1}{\\sqrt{2\\pi}}\\exp\\left(-\\frac{\\nu^{2}}{2}\\right),$$ over the range of values that form a PBH: $$\\beta_{PS}(\\nu_{c})=2\\int_{\\nu_{c}}^{\\infty}P(\\nu)d\\nu=2\\int_{\\nu_{c}}^{\\infty}\\frac{1}{\\sqrt{2\\pi}}\\exp\\left(-\\frac{\\nu^{2}}{2}\\right)d\\nu.$$ This can be written in terms of the complimentary error function simply as $$\\beta_{PS}(\\nu_{c})=\\textrm{erfc}\\left(\\frac{\\nu_{c}}{\\sqrt{2}}\\right),$$ and using the asymptotic expansion of erfc$(\\nu_{c})$ this can be written as $$\\beta_{PS}(\\nu_{c})\\approx\\sqrt{\\frac{2}{\\pi}}\\frac{1}{\\nu_{c}}\\exp\\left(-\\frac{\\nu_{c}^{2}}{2}\\right).$$\n\nFigure \\[peaks vs PS\\] shows the difference in the predicted values of $\\beta$ for either calculation - the two are in relatively close agreement (differing by a factor of order 10), whilst $\\nu$ is not too large[^8]. ", "For larger values of $\\nu_{c}$, $\\beta_{peaks}$ is systematically higher than $\\beta_{PS}$. However, the difference between these methods is small compared to the error due to uncertainties in the threshold value $\\Delta_{c}$ (see figure \\[spectral index\\] for an example).", "\n\n![", "Here we compare the value of $\\beta$ calculated using peaks theory or Press-Schechter against $\\nu_{c}=\\frac{\\Delta_{c}}{\\sigma}$.[]{data-label=\"peaks vs PS\"}](peaksPS){width=\"0.7\\linewidth\"}\n\nScale invariant power spectrum\n------------------------------\n\nIn the case where the primordial curvature power spectrum is scale invariant, $\\mathcal{P}(k)=A_{\\mathcal{R}_{c}}$, where $A_{\\mathcal{R}_{c}}$ is a constant, then the variance of the smoothed density field during radiation domination, $\\omega=1/3$, is $$\\langle\\Delta^{2}\\rangle=\\int_{0}^{\\infty}\\frac{dk}{k}\\tilde{W}^{2}(k,R)\\frac{4(1+\\omega)^{2}}{(5+3\\omega)^{2}}A_{\\mathcal{R}_{c}}\n=\\frac{8}{81}A_{\\mathcal{R}_{c}}.", "\n\\label{scale invariant density variance}$$ Note that, as expected for a scale invariant spectrum, this is now independent of the smoothing scale $R$ - and so predicts that $\\beta$ is independent of the mass of the PBHs[^9]. ", "Using peaks theory: $$\\beta=\\frac{1}{2^{3/2}(2\\pi)^{1/2}}\\frac{81\\Delta_{c}^{2}}{8A_{\\mathcal{R}_{c}}}\\exp\\left(-\\frac{81\\Delta_{c}^{2}}{16A_{\\mathcal{R}_{c}}}\\right).", "\n\\label{scale invariant beta}$$\n\n### Constraints on the power spectrum\n\nUsing the relation between the (scale invariant) comoving curvature perturbation power spectrum and $\\beta$, equation (\\[scale invariant beta\\]), it is simple to calculate a constraint on the power spectrum from the constraint on $\\beta$ at a given scale. ", "We will here consider a constraint of size $\\beta<10^{-20}$, with $\\Delta_{c}=0.5$, and give the constraints one would calculated from peaks theory and Press-Schechter, seeing that the two are in very close agreement: $$\\begin{aligned}\n\\mathcal{P}_{\\mathcal{R}_{c},peaks}<0.026, \\nonumber \\\\\n\\mathcal{P}_{\\mathcal{R}_{c},PS}<0.029.", "\n\\label{constraints}\\end{aligned}$$\n\nPower law power spectrum\n------------------------\n\nIn order to compare with the GLMS paper [@Green:2004wb], we will consider a power law spectrum (see also Drees and Erfani [@Drees:2011hb]). ", "The form of the power spectrum is given by $$\\mathcal{P}_{\\mathcal{R}_{c}}(k)=A_{0}\\left(\\frac{k}{k_{0}}\\right)^{n_{s}-1},$$ where $A_{0}$ is the amplitude of the power spectrum defined on some pivot scale $k_{0}$, and we will consider only blue spectra, $n_{s}>1$. In this case, the variance of the smoothed density field during radiation domination, given by equation (\\[density variance\\]) is $$\\langle\\Delta^{2}\\rangle=\\frac{8}{81}\\frac{A_{0}}{(k_{0}R)^{n_{s}-1}}\\Gamma\\left(\\frac{n_{s}+3}{2}\\right),$$ and $\\beta$ is given by equation (\\[beta peaks\\]). ", "For the purposes of making a specific calculation we will take $A_{0}=2.2\\times10^{-9}$ and $k_{0}=0.05$ Mpc$^{-1}$, loosely based on observations. ", "Figure \\[spectral index\\] shows the predicted mass spectra for a range of different spectral indexes $n_{s}$, and threshold values of the density contrast $\\Delta_{c}$ - here, we only consider a blue spectrum (it is possible to consider a red spectrum on small scales in which case $\\beta$ is larger for more massive PBHs, but a complicated model is needed to produce a significant number of PBHs and be consistent with observations).", "\n\nWe can place a limit on the spectral index from the observational constraints on the abundance of PBHs - as has been done previously (for example, [@Green:1997sz]). ", "Taking $\\Delta_{c}=0.5$ and using the constraint $\\beta<10^{-20}$ for PBHs in the mass range $10^{8}$g$<M_{PBH}<10^{10}$g [@Josan:2009qn], the constraint on the spectral index is $n_{s}<1.34$. Because there is a minimum mass of PBHs, at the Planck mass, then we can also place a minimum value on $n_{s}$ which is required to form a significant number of PBHs. ", "Approximately 70 efoldings of inflation are required after todays horizon scale exited during inflation in order for the horizon to reach a sufficiently small scale corresponding to the Planck mass. ", "Typical inflationary models predict that the current horizon scale exited the Hubble scale during inflation about 55 efoldings before the end of inflation [@Liddle:2003as]. ", "In that case, the mass contained in the horizon scale at the end of inflation is approximately $e^{30}M_{\\rm Planck}\\sim 10^8$g. ", "If we require that $\\beta>10^{-20}$ for PBHs of mass $M_{PBH}=10^{-5}$g then the spectral index must be $n_{s}>1.26$. In order for a significant number of PBHs to form, then $n_{s}$ must lie in the range $$1.26<n_{s}<1.34.$$\n\n![", "This figure shows the predicted PBH mass spectra for different values of $n_{s}$ and $\\Delta_{c}$. A smaller spectral index produces PBHs of smaller masses. ", "Note that the calculation has been artificially cut off when $\\beta$ becomes large as it is only valid for rare peaks (where $\\beta$ is small), as well as for PBHs smaller than the Planck mass ($M\\approx 10^{-5}g$).[]{data-label=\"spectral index\"}](spectralindex){width=\"\\linewidth\"}\n\nRunning of the spectral index\n-----------------------------\n\nOver the large range of scales considered here, the spectral index is unlikely to be a constant. ", "We will therefore consider a running of the spectral index, $\\alpha$, defined as $$\\alpha=\\frac{dn_{s}}{d\\ln(k)},$$ leading to an expression for the comoving curvature perturbation power spectrum given by $$\\mathcal{P}_{\\mathcal{R}_{c}}(k)=A_{0}\\left(\\frac{k}{k_{0}}\\right)^{n_{0}-1+\\frac{1}{2}\\alpha\\ln(k/k_{0})},$$ where $A_{0}$ and $n_{0}$ are the values of the power spectrum and spectral index respectively, defined at a pivot scale $k_{0}$. If values are given for parameters $k_{0}$, $A_{0}$, $n_{0}$ and $\\alpha$ then the PBH mass spectra can be calculated as before, calculating the variance of the smoothed density contrast using equation (\\[density variance\\]) and finding $\\beta$ using equation (\\[beta peaks\\]).", "\n\nThe same as in the previous section, we will take $A_{0}=2.2\\times10^{-9}$ and $k_{0}=0.05$ Mpc$^{-1}$. The Planck collaboration [@Ade:2013uln] found a spectral index $n_{s}=0.9603\\pm0.0073$, but no statistically significant running of the spectral index, $\\alpha=-0.0134\\pm0.0090$. We will therefore take $n_{0}=0.96$ and allow $\\alpha$ to vary - see figure \\[running\\]. ", "A positive running is necessary to produce a significant number of PBHs, and the smallest value we will consider is $\\alpha=0.01$.\n\nPBHs of masses greater than $M_{PBH}\\approx 10^{8}$g are well constrained by observations [@Josan:2009qn; @Carr:2009jm], and we see from figure \\[running\\] that these values of the running produce too many PBHs, and would be ruled out by observational constraints. ", "We therefore state an upper bound on the running of the spectral index, $\\alpha<0.0162$ (again, using the constraint $\\beta<10^{-20}$ for PBHs in the mass range $10^{8}$g$<M_{PBH}<10^{10}$g [@Josan:2009qn]). ", "Although, again, we note that there is no reason to assume the running of the spectral index will be constant over a large range of scales.", "\n\nWe will not consider the running of the running in this paper, although it has been considered by Erfani [@Erfani:2013iea], who places an upper limit on the running of the running by considering the non-production of (long lived) PBHs.", "\n\n![", "This figure shows the predicted PBH mass spectra for different values of the running of the spectral index $\\alpha$. Again, the calculation has been artificially cut off when $\\beta$ becomes large.[]{data-label=\"running\"}](running){width=\"\\linewidth\"}\n\nApproximation using the comoving curvature perturbation power spectrum\n----------------------------------------------------------------------\n\nThe power spectrum is, formally, the variance of the amplitude of the Fourier modes at a certain scale. ", "Less formally, one can consider it to be the characteristic size of perturbations at that scale. ", "We show in this section that one can quickly find an approximate value for the PBH mass fraction using the comoving curvature perturbation by only considering perturbations at the exact scale of horizon crossing, without using window functions - this is the approach used in previous papers [@Byrnes:2012yx; @Young:2013oia]. ", "At horizon crossing, the relation between the density contrast and the comoving curvature perturbation becomes even simpler, as the factor $(k/aH)=1$: $$\\Delta(t_{H},k)=\\frac{2(1+\\omega)}{5+3\\omega}\\mathcal{R}_{c}(k)=\\frac{4}{9}\\mathcal{R}_{c}(k),$$ where $t_{H}$ is the time at horizon entry, and $\\omega=1/3$ is the equation of state during radiation domination. ", "As $\\Delta$ is proportional to $\\mathcal{R}_{c}$ at horizon entry, it is reasonable to assume that peaks in the smoothed density contrast correspond to peaks in the comoving curvature perturbation (ignoring other scales).", "\n\nWe will assume that the power spectrum at a given scale gives the variance of the comoving curvature perturbation at that scale and use a Press-Schechter approach to calculate $\\beta$: $$\\beta=2\\int_{\\mathcal{R}_{c,crit}}^{\\infty}P(\\mathcal{R}_{c})d\\mathcal{R}_{c},$$ where $P(\\mathcal{R}_{c})$ is the (gaussian) probability distribution function. ", "Writing this in terms of the complimentary error function gives $$\\beta=\\textrm{erfc}\\left(\\frac{\\mathcal{R}_{c,crit}}{\\sqrt{2 \\mathcal{P}_{\\mathcal{R}_{c}}}}\\right).", "\n\\label{zeta approx}$$ Compare this to the expression one would derive using the density contrast for a scale invariant power spectrum, where $\\langle\\mathcal{R}_{c}^{2}\\rangle$ is given by equation (\\[scale invariant density variance\\]), $$\\beta=\\textrm{erfc}\\left(\\frac{9\\Delta_{c}}{4\\sqrt{\\mathcal{P}_{\\mathcal{R}_{c}}}}\\right).", "\n\\label{beta spectral index}$$ These two expressions will be exactly equal if $\\Delta_{c}\\approx\\frac{2\\sqrt{2}}{9}\\mathcal{R}_{c,crit}$. However, these methods cannot be considered identical, which is evident if a power law spectrum is considered, $\\mathcal{P}_{\\mathcal{R}_{c}}(k)=A_{0}(k/k_{0})^{n_{s}-1}$. Equation (\\[zeta approx\\]) is unchanged, but equation (\\[beta spectral index\\]) becomes $$\\beta=\\textrm{erfc}\\left(\\frac{9\\Delta_{c}}{4\\sqrt{\\mathcal{P}_{\\mathcal{R}_{c}}\\Gamma{\\left(\\frac{3+n_{s}}{2}\\right)}}}\\right).$$ However, provided that $\\Gamma\\left(\\frac{3+n_{s}}{2}\\right)\\approx 1$ (which is satisfied if $n_{s}\\approx 1$) and $\\Delta_{c}=\\frac{2\\sqrt{2}}{9}\\mathcal{R}_{c,crit}$, these two expressions will be approximately equal. ", "Figure \\[zeta approx and density\\] shows a specific example of these calculations, showing that they still agree closely.", "\n\nWe now compare the constraints on the power spectrum calculated in this method to the constraints calculated earlier (equation (\\[constraints\\])). ", "Using $\\mathcal{R}_{c,crit}=1.2$ [@Shibata:1999zs; @Green:2004wb], and $\\beta<10^{-20}$ gives the constraint $$\\mathcal{P}_{\\mathcal{R}_{c}}<0.024,$$ which is in close agreement with the previously calculated bound, equation (\\[constraints\\]).", "\n\n![", "We show the mass spectra of PBHs calculated, for a power law power spectrum $\\mathcal{P}_{\\mathcal{R}_{c}}(k)=A_{0}(k/k_{0})^{n_{s}-1}$, using the density contrast (method described in Section 4.3) and the comoving curvature perturbation (method described in Section 4.5). ", "The values we have used in this figure are $A_{0}=2.2\\times10^{-9}$, $k_{0}=0.05$Mpc$^{-1}$, $n_{s}=1.3$, $\\Delta_{c}=0.4$ and $\\mathcal{R}_{c,crit}=1.2$[]{data-label=\"zeta approx and density\"}](zetaapproximation){width=\"\\linewidth\"}\n\nConclusions\n===========\n\nWe have placed the calculation of the PBH abundance on a more solid grounding. ", "Using the comoving curvature perturbation $\\mathcal{R}_{c}$ can be misleading and care needs to be taken if one wishes to use $\\mathcal{R}_{c}$ to perform this calculation, due to the effect of super-horizon modes. ", "The problem with using $\\mathcal{R}_{c}$ is most easily seen when one considers either a red or scale-invariant power spectrum, which causes the variance of $\\mathcal{R}_{c}$ to diverge (it is possible to complete the calculation when a blue spectrum is considered but the results differ drastically from using $\\Delta$, see Appendix). ", "We therefore advocate the use of the density contrast to perform the calculation, which does not suffer from the same problem due to the $k^{2}$ dependance of super-horizon modes. ", "In addition, calculations and simulations to calculate the critical threshold for collapse most often use $\\Delta$. However, it is more convenient to calculate $\\mathcal{R}_{c}$ when studying inflationary models, and finding the constraints on the small scale power spectrum from PBHs - an approximation for $\\beta$ can be quickly calculated using $\\mathcal{R}_{c}$ if the power spectrum, $\\mathcal{P}_{\\mathcal{R}_{c}}$, is used rather than using the variance, $\\langle\\mathcal{R}_{c}^{2}\\rangle$ (although this can only ever be an approximation as modes of a similar scale can affect the production of PBHs - which this calculation ignores). ", "It is therefore important that calculations using $\\Delta$ or $\\mathcal{R}_{c}$ give the same results, and we have provided a method for doing so.", "\n\nWe have considered both a Press-Schechter approach and a peaks theory approach, finding that there is a significant discrepancy between the two - however, this is dwarfed by the error due to uncertainty in the critical value of the density contrast above which PBHs are assumed to form, $\\Delta_{c}$. In this paper, we use the peaks theory method, which has a better theoretical grounding. ", "The implications of this paper will be explored further in future papers.", "\n\nAcknowledgements\n================\n\nSY is supported by an STFC studentship, and would like to thank Yukawa Institute for Theoretical Physics for its hospitality during a month long stay which was supported by the Bilateral International Exchange Program (BIEP). ", "CB was supported by a Royal Society University Research Fellowship. ", "The authors would like to thank Will Watson, Aurel Schneider, David Seery, Shaun Hotchkiss, Anne Green, Andrew Liddle, John Miller and Ilia Musco for useful discussion which brought about the production of this paper.", "\n\nAppendix\n========\n\nFor completeness, we include the calculation of the PBH mass fraction $\\beta$ using the comoving curvature perturbation, and compare it to the calculation using the density contrast. ", "This was initially done by GLMS [@Green:2004wb] who incorrectly calculated the density contrast power spectrum at the time of PBH formation - we will now correct the calculation. ", "Assuming a blue power spectrum, $\\mathcal{P}_{\\mathcal{R}_{c}}=A_{0}\\left(k/k_{0}\\right)^{n_{s}-1}$ where $n_{s}>1$, the variance of the smoothed comoving curvature perturbation is $$\\langle\\mathcal{R}_{c}^{2}\\rangle(R)=\\int^{\\infty}_{0}\\frac{dk}{k}\\tilde{W}^{2}(k,R)\\mathcal{P}_{\\mathcal{R}_{c}}(k)=\\frac{A_{0}}{2(k_{0}R)^{n_{s}-1}}\\Gamma\\left(\\frac{n_{s}-1}{2}\\right).$$ The second moment of the power spectrum is given by $$\\langle k^{2}\\rangle=\\frac{1}{\\langle\\mathcal{R}_{c}^{2}\\rangle(R)}\\int^{\\infty}_{0}\\frac{dk}{k}k^{2}\\tilde{W}^{2}(k,R)\\mathcal{P}_{\\mathcal{R}_{c}}(k)=\\frac{n_{s}-1}{2R^{2}},$$ leading us to the final expression for $\\beta$ using equation (\\[peaks\\]) for comoving curvature perturbation instead of density contrast: $$\\beta(R)=\\frac{(n_{s}-1)^{3/2}}{6^{3/2}(2\\pi)^{1/2}}\\frac{\\mathcal{R}_{c,crit}^{2}}{\\langle\\mathcal{R}_{c}^{2}\\rangle(R)}\\exp\\left(\\frac{\\mathcal{R}_{c,crit}^{2}}{2\\langle\\mathcal{R}_{c}^{2}\\rangle(R)}\\right)$$\n\nThe differences between this calculation and the calculation for the density contrast are shown in figure \\[density v curvature\\] - we can see that they differ by many orders of magnitude.", "\n\n![", "We have used $\\Delta_{c}=0.5$, $\\mathcal{R}_{c,crit}=1$, $n_{s}=1.3$, $A_{0}=2.2\\times10^{-9}$ and $k_{0}=0.05$ Mpc$^{-1}$. Both curves represent the mass spectrum of PBHs formed from identical comoving curvature perturbation power spectra - but differ drastically due to the different methods used in the calculation.[]{data-label=\"density v curvature\"}](densityvscurvature){width=\"0.7\\linewidth\"}\n\n[^1]: The comoving curvature perturbation $\\mathcal{R}_{c}$ is equal to the curvature perturbation on uniform density slices $\\zeta$ on super-horizon scales, and because sub-horizon modes are smoothed out, it is common to use $\\zeta$ instead of $\\mathcal{R}_{c}$.\n\n[^2]: Note that we are assuming that a PBH will form shortly after entering the horizon, or not at all. ", "It is possible for the PBH formation process to last several e-foldings after horizon entry [@Musco:2012au] in which case the long wavelength mode will become important, but only for values extremely close to the threshold value - although this is thought to be rare, see equation (\\[close to critical\\]) (however, the effect of a perturbation sitting inside a much larger scale perturbation has not been well studied).", "\n\n[^3]: Josan, Green and Malik [@Josan:2009qn] derive an alternative formula valid on super- and sub-horizon scales during radiation domination, $$\\Delta(t,k)=-\\frac{4}{\\sqrt{3}}\\left(\\frac{k}{aH}\\right)j_{1}\\left(\\frac{k}{\\sqrt{3}aH}\\right)\\mathcal{R}_{c}(k),$$ where $j_{1}$ is a spherical Bessel function. ", "However, after smoothing, there is little difference between this and equation (\\[density contrast\\]).", "\n\n[^4]: Musco et al note that the difference in value obtained by Niemeyer and Jedamzik can be explained because they only considered a pure density perturbation imposed at the time of horizon crossing. ", "Later work included only growing modes accounting for the effect of the perturbation in the velocity field.", "\n\n[^5]: It was previously thought that there was an upper bound above which density perturbations would form a separate closed universe rather than a PBH, however, this has been shown not to be the case [@Kopp:2010sh]. ", "This is relatively unimportant in practice, as the effect of an upper bound is negligible because higher peaks are exponentially suppressed.", "\n\n[^6]: In the appendix, we correct their calculation, finding that calculating $\\beta$ in the different methods disagree strongly.", "\n\n[^7]: We note here that with peaks theory, the critical value is stated in terms of the peak value of a fluctuation, but in a Press-Schechter approach, it is the average value of the fluctuation. ", "The relationship between the peak value and the average depends on the shape of the fluctuation - but typically, these are expected to differ only by a factor of order unity, with the peak value being higher. ", "The difference in the critical value of the peak value and the average is therefore within the error of the predicted critical value from different sources. ", "We also note the fact that looking for peaks above a certain value in a smoothed distribution is equivalent to looking for patches with an average density above that value - and so the distinction here is only a technical note.", "\n\n[^8]: However, this uncertainty in $\\beta$ has little effect on the uncertainty of $\\nu_{c}$ which would be calculated, as it depends only on $\\log(\\beta)$ (see [@Young:2013oia]).", "\n\n[^9]: It is also worth noting that for either a red or scale invariant power spectrum $\\langle\\mathcal{R}_{c}^{2}\\rangle\\rightarrow\\infty$.\n" ]

{ "pile_set_name": "ArXiv" }

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[ "Archives for: February 2003\n\nSTUDY: Body fat distribution is a more powerful predictor than is BMI for risk factors, diseases, and mortality\n\nJOURNAL: Am J Clin Nutr. ", "2002; 76:743-9; 699-700\n\nAUTHORS: Michael J. Lean and Thang S. Han\n\nABSTRACT: Waist circumference is a better indicator of cardiovascular (CV) risk than is body mass index (BMI), according to results from the National Health and Nutrition Examination Survey (NHANES) III published the American Journal of Clinical Nutrition.", "\n\nCOMMENTARY: Body fat distribution is a more powerful predictor than is BMI for risk factors, diseases, and mortality. ", "Measurements that are more sensitive to individual differences in abdominal fat might be more useful than BMI for identifying obesity-associated risk factors.", "\n\nWaist circumference correlated more directly than did BMI with overall CV risk. ", "Cutoffs of 90 cm (35 inches) for men and 83 cm (33 inches) for women we found. ", "To minimize CV risk, they recommend advising patients with waist circumference at least as large as the cutoff value to lose weight.", "\n\nWaist circumference is more closely linked to CV disease risk factors than is BMI [so] it is inappropriate to base waist circumference thresholds on their association with BMI thresholds.", "\n\nABSTRACT: A comparison of two different surgical techniques used to fuse vertebrae together and thereby repair unstable sections of the back found that while men experienced fewer temporary complications after undergoing the less-invasive operation, they were much more likely to suffer ejaculation problems caused by nerve damage.", "\n\nCOMMENTARY: During the more invasive \"mini-open\" procedure, doctors reach the diseased vertebrae by making a series of small incisions, while in the less invasive laparoscopic or \"keyhole\" approach, doctors use a small video camera and specialized tools inserted through even smaller incisions to repair the area.", "\n\nResearchers based at the Emory Clinic in Atlanta, Georgia, reviewed the records of 98 patients who had undergone either mini-open or laparoscopic procedures, and found that nearly 18% of mini-open patients experienced complications, as opposed to only 4% of those given the laparoscopic procedure.", "\n\nHowever, the investigators also found that 45% of men who underwent laparoscopy experienced a condition known as retrograde ejaculation after the procedure, during which they are able to become aroused and have an erection, but cannot ejaculate any semen. ", "This complication was seen in only 6% of the men who received the mini-open surgery, the authors note. ", "The researchers were unable to determine how long the problem lasted.", "\n\nAccording to the report in Neurosurgery, Haid's team found that preparation and procedure time was longer in patients who underwent laparoscopy, while patients often needed to stay in the hospital a bit longer after the mini-open procedure.", "\n\nHaid explained that given the relatively high risk of ejaculation problems following the laparoscopic approach, he often recommends that younger men opt for the mini-open procedure. ", "Losing the ability to ejaculate will affect a man's fertility, he pointed out, and also likely cause some significant emotional effects.", "\n\nABSTRACT: Continuous hormonal replacement therapy (HRT) is associated with an increased risk of lobular breast cancer but not of ductal carcinoma.", "\n\nCOMMENTARY: \"The incidence of invasive lobular carcinoma has been increasing among post-menopausal women in some parts of the U.S,\" writes Janet R. Daling, PhD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington, and colleagues. \"", "Part of this may be due to changes in classification over time. ", "However, the use of combined estrogen and progestin HRT has also increased during the last decade and may account in part for the increase in invasive lobular breast cancer.\"", "\n\nThis study used data from the NICHD Women's Contraceptive and Reproductive Experiences (CARE) Study, a large case-control breast cancer study of white and African-American women. ", "The investigators conducted in-person interviews of 1,749 postmenopausal women diagnosed with their first invasive breast tumor before the age of 65 years, and compared their responses with those of 1,953 postmenopausal controls identified through random digit dialing.", "\n\nHistory of use of unopposed estrogen therapy was not associated with an increase in risk of any histologic type of breast cancer. ", "Women currently using combined HRT had twice the risk of invasive lobular breast cancer.", "\n\nAlthough the increase in risk was greater for mixed lobular-ductal than for the pure lobular type, this difference was not statistically significant.", "\n\nWomen who used continuous combined HRT (more than 25 days per month of progestin) for at least five years appeared to be at greater risk of lobular breast cancer than those who used sequential HRT (fewer than 25 days per month of progestin. ", "Use of combined HRT was not associated with risk of ductal breast cancer.", "\n\n\"Post-menopausal women who take combined HRT appear to be at an increased risk of lobular breast cancer,\" the authors write.", "\n\nData from this study suggest that neither unopposed estrogen-HRT use nor combined HRT substantially increase the risk of ductal breast cancer among women less than 65 years of age.", "\n\nCOMMENTARY: The researchers studied 15 patients with hyperhomocysteinemia and coronary artery disease. ", "They were randomized to daily treatment with folic acid 5 mg in combination with cobalamin 400 mcg or to placebo.", "\n\nAt the end of the 6-month study, homocysteine levels fell by 31% in the\n\ncombination group, but did not change in placebo patients.", "\n\nFurthermore, although at baseline, all patients showed severe coronary\n\nABSTRACT: Some vitamin and dietary supplements are sporting a new certification seal from the U.S. Food and Drug Administration (FDA) designated representative in hopes of assuring consumers that the product lives up to its ingredient labeling claims.", "\n\nCOMMENTARY: The United States Pharmacopeia (USP), an independent agency that serves as the government's official compendium for dietary supplement standards, has begun to issue the certification on hundreds of products that it has independently tested as part of its Dietary Supplement Verification Program (DSVP).", "\n\nThis new program is voluntary and open to all manufacturers of dietary supplements operating in the U.S., a $17-billion-a-year market that includes vitamins, minerals, herbs, botanicals, and sports supplements sold over the counter and consumed by two of every three Americans.", "\n\nTo receive the certification, manufacturers must submit products they select to a \"vigorous\" seven-step testing and evaluation process that the USP says it ensures meets all labeling claims — first in independent laboratories and then on store shelves. ", "This process includes testing and auditing of declared ingredients, their amounts or dosages, and meeting requirements of limits on contaminants.", "\n\nSo far, hundreds of supplements by two leading manufacturers have been tested and issued the certification. ", "Products that will receive the certification label include those by Nature Made, which just began to hit shelves at some 30,000 stores nationwide, and those under the Kirkland brand, which will be displayed at Costo stores beginning next week.", "\n\nTogether, Nature Made and Kirkland produce about 30% of all vitamins and minerals consumed nationally, and about 20% of the total supplement market, said Richard Wailes, USP's head of sales and marketing. ", "Four other manufacturers have signed up for the certification program and their products will carry the \"Dietary Supplement Verified\" certification in 2003.", "\n\nUnder the program, manufacturers can submit any products they choose and pay for all testing by USP, which has been establishing drug and other product standards since 1820 and has worked hand-in-hand with the FDA since the federal agency was created in 1938.", "\n\nBecause the FDA regulates dietary supplements as foods and not \"conventional\" medicines, manufacturers typically do not have to get FDA approval before producing or selling dietary supplements. ", "The FDA can take action only if a product is deemed unsafe and is already on the market.", "\n\nSTUDY: Muscle strength and the degree of abdominal obesity were directly related to BMD\n\nJOURNAL: J Int Med 2002;252:000-000.", "\n\nAUTHORS: Dr. Kerry J. Stewart\n\nABSTRACT: Although mild exercise has been shown to reduce the risk of heart disease, it does not appear to be osteoprotective, according to findings from a recent study.", "\n\nCOMMENTARY: Mild physical activity does not seem to be \"sufficient to hold off or attenuate the age-related decline in bone with aging,\" said lead author Dr. Kerry J. Stewart, from Johns Hopkins University in Baltimore.", "\n\nWhile mild activity and aerobic fitness did not affect bone mineral density (BMD), muscle strength and the degree of abdominal obesity were directly related to BMD, according to the report published in the Journal of Internal Medicine.", "\n\nAlthough being fat may be good for bone density, gaining weight is not the answer because of the harmful effects of obesity on many other aspects of health.", "\n\nDr. Stewart's team studied the effects of mild physical activity in 38 men and 46 women, 55 to 75 years of age, with high normal blood pressure or mild hypertension. ", "None of the participants exercised on a regular basis.", "\n\nNeither overall aerobic fitness nor participation in mild physical activity had a significant effect on BMD, the researchers note. ", "But muscle strength, as well as abdominal obesity, was associated with denser bones.", "\n\nThey found that being more fat and having stronger muscle, which is common in fatter people, along with hormone replacement therapy, had the most influence on bone. ", "In particular, having more abdominal fat was most strongly linked to bone density.", "\n\nExactly how abdominal obesity may promote increases in BMD is unclear, but Dr. Stewart suggested that the hormone leptin may be involved. ", "Leptin levels tend to be higher in obese people, he explained, and findings from animal studies indicate that leptin increases the activity of bone cells.", "\n\nSTUDY: TSH level between 3.0 and 5.0 uU/ml ...should be considered suspect.", "\n\nJOURNAL:\n\nAUTHORS:\n\nABSTRACT: Major Reversal at American Association of Clinical Endocrinologists Regarding TSH Levels and Diagnosing Hypothyroidism\n\nCOMMENTARY: In what constitutes a fairly dramatic reversal of its previous doctrine regarding how hypothyroidism should be diagnosed, the American Association of Clinical Endocrinologists (AACE) has said that:\n\n\"Even though a TSH level between 3.0 and 5.0 uU/ml is in the normal range, it should be considered suspect since it may signal a case of evolving thyroid underactivity.\"", "\n\nThis is the first time a conventional U.S. medical organization has acknowledged that the upper half of the TSH test's normal range may not in fact be normal, but rather, evidence of developing hypothyroidism, or a level that is potentially able to cause hypothyroidism symptoms in patients.", "\n\nThe conventional endocrinology doctrine has, for several decades, dictated that a TSH level that is in the so-called \"normal range\" indicate a \"euthyroid\" -- or normal -- state for the thyroid, and thus does not warrant treatment, despite clinical symptoms.", "\n\nIn fact, most patients who have numerous clinical symptoms of hypothyroidism, as well as a family history of thyroid disease -- and even those who have tested positive for the presence of thyroid antibodies indicative of autoimmune Hashimoto's Disease -- are declined treatment by endocrinologists and other physicians unless TSH levels are elevated above the laboratory's \"normal range\" -- which is typically a TSH level anywhere from 4.7 to 6.0 uU/ml.", "\n\nMany people who are suffering thyroid symptoms. . . ", "may now be considered hypothyroid and eligible to be diagnosed and treated.", "\n\nThe AACE's acknolwedgement lags years behind the efforts of a number of pioneering physicians and patient advocates -- as well as what patients themselves have suspected.", "\n\nAlmost four years ago, for example, Dr. A P Weetman, a professor of medicine, wrote in the article \"Fortnightly review: Hypothyroidism: screening and subclinical disease\" which appeared in the 19 April 1997 issue of the British Medical Journal, the following groundbreaking statement:\n\n\". . . ", "even within the reference range of around 0.5-4.5 mU/l, a high thyroid stimulating hormone concentration (>2 mU/l) was associated with an increased risk of future hypothyroidism. ", "The simplest explanation is that thyroid disease is so common that many people predisposed to thyroid failure are included in a laboratory's reference population, which raises the question whether thyroxine replacement is adequate in patients with thyroid stimulating hormone levels above 2 mU/l.\"\n\n\"Why are we following a test which has no correlation with clinical presentation? ", "The thyroidologists by consensus have decided that this test is the most useful for following treatment when in fact it is unrelated to how the patient feels. ", "The consequences of this have been horrendous. ", "Six years after their consensus decision Chronic fatigue and Fibromyalgia appeared. ", "These are both hypothyroid conditions. ", "But because their TSH was normal they have not been treated. ", "The TSH needs to be scrapped and medical students taught again how to clinically recognize low thyroid conditions.\"", "\n\nOther physicians have been working with antibodies testing to evaluate thyroid function, and in some cases treating patients with normal range TSH values who had thyroid antibodies evident of the autoimmune disease process.", "\n\nElizabeth Vliet, MD, who runs the popular women's health centers, Her Place and who is author of the bestselling book, Screaming to be Heard: Hormonal Connections Women Suspect...and Doctors Ignore, has never believed that TSH tests are the indicator of a woman's thyroid health. ", "Since the mid 1990s, Dr. Vliet has been saying that symptoms, along with elevated thyroid antibodies and normal TSH, may be a reason for treatment with thyroid hormone. ", "Here's a quote from her book:\n\n\"The problem I have found is that too often women are told their thyroid is normal without having the complete thyroid tests done. ", "Of course, what most people, and many physicians, don't realize is that...a 'normal range' on a laboratory report is just that: a range. ", "A given person may require higher or lower levels to feel well and to function optimally. ", "I think we must look at the lab results along with the clinical picture described by the patient...I have a series of more than a hundred patients, all but two are women, who had a normal TSH and turned out to have significantly elevated thyroid antibodies that meant they needed thyroid medication in order to feel normal. ", "This type of oversight is particularly common with a type of thyroid disease called thyroiditis, which is about 25 times more common in females than males...a woman may experience the symptoms of disease months to years before TSH goes up...\"\n\nThe current TSH levels used by laboratories to define the \"normal\" range of thyroid function, and the use of the TSH test as primary means of diagnosis need to be significantly reevaluated. ", "The .5 to 5.5 \"normal range\" for thyroid function is just not enough information for diagnosis anymore.", "\n\nResearch reported in the British Medical Journal found that TSH levels above 2 are likely not normal, and instead include people at high risk to develop thyroid disease. ", "This means that the real \"normal range\" is probably far narrower, and more concentrated in the lower end of the range.", "\n\nNew studies need to be conducted to look at this issue comprehensively, evaluating the true normal range for a population of individuals who have no thyroid antibodies, and who do not ever go on to develop thyroid disease in their lifetimes.", "\n\nIn February of 2000, a groundbreaking study estimated that as many as 13 million Americans had undiagnosed thyroid disease. ", "The vast majority of these people would be women, suffering from undiagnosed hypothyroidism. ", "This Colorado Thyroid Disease Prevalence Study used the standard diagnostic criteria to define hypothyroidism -- that the TSH had to exceed the lab's normal range, which for the purposes of this study, was 5.1 uU/ml. ", "Broadening the lab diagnostic criteria then, to levels above 3 would mean that the Colorado Thyroid Disease Prevalence Study suggests that many more than 13 million Americans are likely to be defined as hypothyroid.", "\n\nABSTRACT: Frequent mountain-biking may reduce fertility in men, according to a small Austrian study that adds fodder to a debate over cycling and male sexual function.", "\n\nCOMMENTARY: The research suggests frequent jolts and vibration caused by biking over rough terrain may cause abnormalities, including small scars within the scrotum and impaired sperm production.", "\n\nThe abnormalities were found in professional mountain bikers and other “extreme” bikers who logged at least 3,000 miles yearly — or an average of more than two hours a day, six days a week.", "\n\nDr. Ferdinand Frauscher, a urology-radiology specialist at University Hospital in Innsbruck, Austria, said he studied about 55 avid mountain bikers and found nearly 90 percent had low sperm counts and scrotal abnormalities.", "\n\nOnly 26 percent of the 35 non-bikers he studied had similar damage, according to research presented at this week’s annual meeting of the Radiological Society of North America.", "\n\nWhether the abnormalities were severe enough to make fathering a child difficult is uncertain, though some of the bikers studied had already experienced difficulty conceiving.", "\n\nParticipants were aged 17 to 44. ", "His study looked at fertility rather than impotence, which was linked to recreational cycling in research heavily publicized in 1997. ", "The earlier findings, by Boston University impotence specialist Dr. Irwin Goldstein, were construed by many cycling aficionados to suggest that men should avoid any cycling sports.", "\n\nSome doctors thought Goldstein’s findings were overstated, but the issue has prompted a mini-industry of bicycle seats designed to avoid the compression of penile arteries that Goldstein said occurs during cycling.", "\n\nSuch problems may occur on narrow, racing-type seats, Frauscher said. ", "Some newer, wider designs feature holes or gaps to avoid pressure, but these likely would have no effect on the scrotal damage found in the Austrian study, which may be caused by jolting over rough terrain rather than artery compression, Frauscher said.", "\n\nFrauscher said men shouldn’t avoid mountain biking because of the study, but should perhaps consider investing in bikes with shock absorbers or suspension systems designed to reduce the jolting.", "\n\nStanford University urologist Dr. Robert Kessler said he was skeptical of Frauscher’s findings. ", "Scrotal varicose veins, which were among the abnormalities Frauscher linked to mountain biking, are usually congenital and not linked to trauma, Kessler said.", "\n\nDr. Eduardo Randrup, a urologist at Ochsner Clinic in New Orleans, said the link is plausible but not necessarily cause for alarm. ", "The damage Frauscher found “may well be reversible” and likely would not occur from recreational cycling, Randrup said.", "\n\nDr. Sangili Chandran, a sports medicine specialist at Christ Hospital and Medical Center in the Chicago suburb of Oak Lawn, said other studies have found similar results but, like Frauscher’s, have been too small to be conclusive.", "\n\nEven if the results are corroborated in future studies, very few mountain biking enthusiasts are logging enough miles to worry about any fertility impairment.", "\n\nABSTRACT: The production of cytokines after melatonin stimulation by mononuclear cells from patients with asthma suggests that melatonin may exacerbate their symptoms, according to a report in the American Journal of Respiratory and Critical Care Medicine.", "\n\nCOMMENTARY: Patients with nocturnal asthma show circadian variations in airflow limitation, the authors explain, and melatonin is a key regulator of circadian rhythms as well as an important immunomodulatory in allergic diseases.", "\n\nDr. E. Rand Sutherland and colleagues from National Jewish Medical and Research Center and the University of Colorado Health Sciences Center in Denver, Colorado evaluated the effect of melatonin stimulation on peripheral blood mononuclear cell (PBMC) cytokine production at 4 a.m. and 4 p.m. in 5 normal control subjects, 6 patients with nocturnal asthma, and 12 patients with non-nocturnal asthma.", "\n\nMelatonin stimulation significantly increased the production of IL-1, IL-6, and TNF-alpha by zymosan-stimulated PBMCs in all subject groups at both stimulation times, the authors report.", "\n\nNocturnal asthma patients had higher IL-1 production levels than normal subjects did, the report indicates, though (for both groups) 4 a.m. and 4 p.m. levels did not differ. ", "Patients with non-nocturnal asthma had IL-1 production levels similar to controls subjects at 4 a.m., but these levels increased nearly 5-fold at 4 p.m.\n\nMelatonin-stimulated IL-6 production patterns were very similar to those seen with IL-1 production, the results indicate.", "\n\nIn contrast, both nocturnal asthma patients and non-nocturnal asthma patients showed substantially higher melatonin-stimulated TNF-alpha production at 4 p.m. than at 4 a.m., the researchers note, whereas control subjects showed similar increases at both times.", "\n\nThese results suggest differential immunomodulatory effects of melatonin based on asthma clinical phenotype and may indicate an adverse effect of exogenous melatonin in asthma. ", "For these patients, avoidance of melatonin may be appropriate until further information about the clinical effect of melatonin in asthma becomes available.", "\n\nABSTRACT: Most women over 30 can skip the annual Pap test for cervical cancer, and instead safely have the check only every two to three years, the American Cancer Society said.", "\n\nCOMMENTARY: Cervical cancer grows so slowly that women have plenty of time to be tested and have any preventive treatment, the organization advised.", "\n\nThe new guidelines will have a major impact on the number of women who are over-screened and over-treated.", "\n\nBecause most cervical precancers grow slowly, having a test every two to three years will find almost all cervical precancers and cancers while they can be removed or treated successfully.", "\n\nCervical cancer affects nearly 500,000 worldwide every year. ", "Detected early, it can be easily treated but it will kill an estimated 300,000 women this year, mostly in the developing world where screening is not routine.", "\n\nIn the United States, the American Cancer Society estimates that 13,000 women will develop cervical cancer this year, and about 4,100 women will die.", "\n\nCervical cancer is usually caused by the sexually transmitted human papilloma virus. ", "Pre-cancerous changes can be detected with the Pap smear test, and suspect areas removed before cancer develops.", "\n\nThe new guidelines say testing every two to three years is usually sufficient for women older than 30 who have had several “clear” tests.", "\n\n\"A doctor may suggest getting the test more often if a woman has certain risk factors such as human immunodeficiency virus (HIV) infection or a weakened immune system. ", "Women 70 years of age and older who have had three or more normal Pap test results and no abnormal results in the last 10 years may choose to stop cervical cancer screening,” the society said in a statement.", "\n\nAs long as you have had clean paps and no risks then you can spread out your screening exams.", "\n\nABSTRACT: A landmark study offers the strongest evidence yet that simmering, painless inflammation deep within the body is the single most powerful trigger of heart attacks, worse even than high cholesterol.", "\n\nCOMMENTARY: The latest research is likely to encourage many doctors to make blood tests for inflammation part of standard physical exams for middle-aged people, especially those with other conditions that increase their risk of heart trouble.", "\n\nThe study, based on nearly 28,000 women, is by far the largest to look at inflammation’s role, and it shows that those with high levels are twice as likely as those with high cholesterol to die from heart attacks and strokes.", "\n\nOver the past five years, research by Dr. Paul Ridker of Boston’s Brigham and Women’s Hospital has built the case for the “inflammation hypothesis.” ", "With his latest study, many believe the evidence is overwhelming that inflammation is a central factor in cardiovascular disease, by far the world’s biggest killer.", "\n\nInflammation can be measured with a test that checks for C-reactive protein, or CRP, a chemical necessary for fighting injury and infection. ", "The test typically costs between $25 and $50.", "\n\nDiet and exercise can lower CRP dramatically. ", "Cholesterol-lowering drugs called statins also reduce CRP, as do aspirin and some other medicines.", "\n\nDoctors believe inflammation has many possible sources. ", "Often, the fatty buildups that line the blood vessels become inflamed as white blood cells invade in a misguided defense attempt. ", "Fat cells are also known to turn out these inflammatory proteins. ", "Other possible triggers include high blood pressure, smoking and lingering low-level infections, such as chronic gum disease.", "\n\nInflammation is thought to weaken the fatty buildups, or plaques, making them more likely to burst. ", "A piece of plaque can then lead to a clot that can choke off the blood flow and cause a heart attack.", "\n\nFor the first time, Ridker’s study establishes what level of CRP should be considered worrisome, so doctors can make sense of patients’ readings. ", "However, experts are still divided over which patients to test and how to treat them if their CRP readings are high.", "\n\nSome, such as Dr. Richard Milani of the Ochsner Clinic in New Orleans, recommend a CRP check for virtually anyone getting a cholesterol test. “", "If I have enough concern to check a patient’s cholesterol, it seems naive not to include an inexpensive test that would give me even more information,” he said.", "\n\nRidker said he believes a high CRP reading can help doctors persuade people with low cholesterol that they still need to diet and exercise.", "\n\n“The CRP test can predict risk 15 to 25 years in the future,” Ridker said. “", "We have a long time to get our patients to change their lifestyles, and the change does not have to be huge — modest exercise, modest weight loss and stop smoking.”", "\n\nRidker’s latest study is based on an eight-year follow-up of 27,939 volunteers in the Women’s Health Study. ", "About half of heart attacks and strokes occurred in those with seemingly safe levels of LDL, the bad cholesterol.", "\n\nThe lowest risk was in women whose CRP readings were below one-half milligram per liter of blood. ", "It more than doubled when readings went over about three.", "\n\nYou've heard it before: Eat sensibly and get some exercise. ", "But new findings on the dangers of inflammation offer still another reason to shape up.", "\n\nDoctors say that both inactivity and obesity increase inflammatory proteins that can trigger heart attacks. ", "People can substantially lower their levels of these proteins simply by improving their living habits. ", "Even modest changes help, though studies show that vigorous exercise and a strict diet can cut inflammation levels in half in just three months.", "\n\nSome research suggests that moderate alcohol consumption and fish oil are good for inflammation levels.", "\n\nSo too are giving up smoking and keeping blood pressure under control.", "\n\nA variety of drugs and supplements may also do the trick. ", "Ask your doctor to test you.", "\n\nSTUDY: People taking vitamin E supplements for at least 10 years were less likely to die from bladder cancer.", "\n\nJOURNAL: Am J Epidemiol 2002;156:1002-1010\n\nAUTHORS: Dr. Jacob\n\nABSTRACT: People who take vitamin E regularly are less likely than those in the general population to die of bladder cancer, researchers report, but it is not clear if the vitamin itself or some lifestyle factor is responsible for the reduced risk.", "\n\nCOMMENTARY: Researchers tracked nearly 1 million US adults for 16 years and interviewed them about their diet. ", "Those who reported taking vitamin E supplements for at least 10 years were less likely to die from bladder cancer, compared with adults who reported shorter durations of use.", "\n\nIn contrast, there was no association between regular vitamin C use and bladder cancer mortality, report researchers in the December issue of the American Journal of Epidemiology.", "\n\nThe current findings support those of two previous studies that showed an inverse relationship between bladder cancer risk and vitamin E intake.", "\n\nExactly how vitamin E may protect against bladder cancer is unclear. ", "It might result from its antioxidant effect in neutralizing DNA-damaging free radicals. ", "Alternatively, vitamin E may boost the immune system or prevent the formation of carcinogenic nitrosamines.", "\n\nHowever, if vitamin E's antioxidant properties are responsible for the protective effect, it is not clear why vitamin C use confers no protection against the malignancy.", "\n\nDr. Jacob emphasized that further studies are needed to verify the current results and to possibly shed light on vitamin E's mechanism of action.", "\n\nABSTRACT: The blockbuster arthritis drug Celebrex doesn’t protect the stomach from dangerous bleeding ulcers as well as thought, a study suggests.", "\n\nCOMMENTARY: CELEBREX AND two similar new anti-inflammatory drugs are heavily advertised as being safer for arthritis patients based on earlier research that found they caused fewer ulcers and other gastrointestinal complications than older anti-inflammatory medicines.", "\n\nTogether, the three new drugs have annual sales exceeding $6 billion.", "\n\nBut their safety has been called into question recently. ", "The new study, which focused on arthritis patients at high risk of recurrent ulcers, escalates the controversy involving Celebrex, showing nearly 10 percent each year would develop another bleeding ulcer.", "\n\nThe study found the same thing for an older anti-inflammatory drug combined with ulcer medicine Prilosec, which doctors often give arthritis patients to protect their stomachs. ", "In addition, neither treatment protected as many patients from dangerous kidney complications as past studies showed, the researchers said.", "\n\nThe Hong Kong researchers and some other experts said the results, while showing the treatments work the same, indicate more study is needed on preventing bleeding stomach ulcers in vulnerable older people who for years ease joint pain with nonsteroidal anti-inflammatory drugs, or NSAIDs.", "\n\n“I think patients and doctors need to be aware ... there is a risk of gastrointestinal bleeding and there is a risk of renal toxicity,” so high-risk patients should be monitored closely by their doctor, said Dr. John H. Klippel, medical director of the Arthritis Foundation.", "\n\nThese drugs, which also include Vioxx and Bextra, do not block action of the cox-1 enzyme, which protects the lining of the stomach. ", "Older NSAIDs such as diclofenac block both cox enzymes, and so can cause stomach irritation and exacerbate ulcers.", "\n\nOf the study patients receiving Celebrex, about 5 percent had recurrent bleeding during the six months of research, compared with about 6.5 percent for those getting diclofenac and Prilosec.", "\n\nHowever, that equates to annual rates of about 9 percent and 11 percent, respectively, Dr. David Y. Graham of the Veterans Affairs Medical Center in Houston wrote in an accompanying editorial. “", "The results were unexpected: Neither regimen provided a good or even acceptable level of protection from recurrent bleeding,” Graham wrote.", "\n\nBoth treatments did a good job in reducing pain and enabling patients to perform daily activities over the six-month experiment.", "\n\nBut about 25 percent of those in the Celebrex group and 31 percent in the diclofenac/Prilosec group suffered kidney complications, including high blood pressure and swollen ankles; about 6 percent in each group suffered life-threatening kidney failure.", "\n\nKlippel said that shows doctors must monitor high-risk patients on these anti-inflammatory drugs for increased pain and bloody stools indicating an ulcer flareup. ", "They also should watch for swelling in the extremities and elevated blood pressure — signs the kidneys can’t excrete enough fluid.", "\n\n“Physicians should avoid prescribing these drugs to patients with known kidney diseases, poorly controlled hypertension and heart failure.\"", "\n\nWe have many alternatives to these drugs. ", "Let's make sure that we educate patients as to the best choices for them.", "\n\nABSTRACT: People who are overweight at 40 are likely to die at least three years sooner than those who are slim, meaning that in terms of life expectancy, being fat during middle age is just as bad as smoking.", "\n\nCOMMENTARY: Nonsmokers who were classified as overweight, but not obese, lost an average of three years off their lives. ", "Obese people died even sooner. ", "Obese female nonsmokers lost an average 7.1 years, while men lost 5.8 years.", "\n\nScientists have long known that overweight people have shorter life expectancies, but few large-scale studies have been able to pinpoint how many years they lose.", "\n\n“This study is saying that if you are overweight by your mid-30s to mid-40s, even if you lose some weight later on, you still carry a higher risk of dying,” said Dr. Serge Jabbour, director of the weight-loss clinic at Thomas Jefferson University Hospital in Philadelphia. “", "The message is that you have to work early on your weight. ", "If you wait a long time, the damage may have been done.”", "\n\nFor smokers, the results were even worse. ", "Obese female smokers died 7.2 years sooner than normal-weight smokers, and 13.3 years sooner than normal-weight nonsmoking women. ", "Obese male smokers lived 6.7 years less than trim smokers, and 13.7 years less than normal-weight nonsmokers.", "\n\nThe results were culled from vital statistics collected from 3,457 volunteers in Framingham, Mass., from 1948 to 1990. ", "The data were analyzed by researchers at Erasmus Medical Center and the University of Gronigen in the Netherlands.", "\n\nObesity is defined as having a body-mass index of 30 or above. ", "The index is a measure of weight relative to height. ", "Healthy weight is a BMI of less than 25." ]

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[ "All U.S. Cellular Phones Free, Dec.17 - 24\n\nU.S. Cellular is No. ", "6 among the U.S. carriers, but it's received accolades of late. ", "And, they just announced a promotion that's hard to pass up: all their phones will be free from Dec. 17 through Christmas Eve.", "\n\nThat's right, every phone, including their five Android phones are free. ", "Their Android phones are:\n\nSamsung Acclaim\n\nHTC Desire\n\nSamsung Mesmerize (Galaxy S variant)\n\nLG Apex\n\nLG Optimus U\n\nNew customers purchasing a smartphone will receive a $100 credit towards their first bill (existing customers adding a smartphone line will, as well).", "\n\nOf course, U.S. Cellular is a regional network, not nationwide, but if you are covered by their service, this is could be a great deal. ", "The full press release follows:\n\nCHICAGO (December 15, 2010) – U.S. Cellular, which was recently recognized in a survey by Consumer Reports as the best wireless carrier in the country, is helping holiday shoppers with last-minute gifts by offering every phone for free, including the latest Android-powered smartphones. ", "U.S. Cellular is spreading the joy even further by offering a $100 credit to new customers purchasing a smartphone or existing customers adding a new smartphone line. ", "Customers can stop by any U.S. Cellular store for more details and pick out their free phones while supplies last.", "\n\nShoppers can make this holiday season memorable by giving Android-powered phones like the HTC Desire, LG Optimus U or Samsung Mesmerize (a Galaxy S device), which is the highest-rated smartphone by Consumer Reports. ", "All of U.S. Cellular’s phones, including advanced smartphones like the BlackBerry Bold and Curve, are free after mail-in rebates. ", "All devices are backed by U.S. Cellular’s high-speed nationwide network and the valuable benefits of The Belief Project, which include faster phone upgrades, overage cap, discounts for autopay and paperless billing, and “no contract after the first.”", "\n\n“Our extensive lineup of cutting-edge phones offers something for everyone. ", "We have devices and plans for heavy texters, businesspeople, music fans, gamers and folks who want a basic phone without the advanced features,” said Edward Perez, vice president of marketing and sales operations for U.S. Cellular. “", "The All Phones Free sale is the perfect opportunity for customers to find the one that best fits their lifestyle.”", "\n\nThe Android-powered Samsung Mesmerize and HTC Desire are ideal for those who want everything in a smartphone. ", "Their large touchscreens and blazing fast 1 GHz processors are great for watching videos, playing games and zipping through business and entertainment applications.", "\n\nThe LG Optimus U is designed for first-time smartphone customers ready to experience the power of Android 2.2 technology. ", "It has a virtual QWERTY keyboard with Swype technology that allows users to input text quickly by sliding a finger over the keyboard in one continuous motion. ", "All six of U.S. Cellular’s Android-powered devices can be enhanced by the more than 100,000 applications in the Android Market, many of which are free.", "\n\nThe BlackBerry Bold and Curve are popular smartphones that pack lots of helpful apps for business and personal use. ", "Both have Wi-Fi access and global travelers will like the Bold’s ability to connect on wireless networks around the world.", "\n\nCustomers who prefer a phone for calling, texting and taking pictures can select devices like the Samsung Profile Freeform and Exec, the Motorola Grasp and LG Mystique. ", "These feature-rich devices have expandable memory for music fans who want to take their tunes everywhere.", "\n\nU.S. Cellular also offers a wide range of national bundled plans through The Belief Project. ", "Its National Single Line and Family Belief Plans offer affordable voice, text and data packages. ", "Customers who text, e-mail and download more than they talk may prefer the new Primary Plus Plan for $69.99 per month that comes with 5GB of data, unlimited text, picture and video messaging, free GPS navigation and free unlimited incoming calls, nights and weekends, and mobile-to-mobile calls. ", "Customers also can opt for the Premium Plus Family Plan for $179.99, which includes two lines with unlimited minutes and messaging, 5GB of data per line, Phone Replacement and GPS navigation.", "\n\nNew customers who sign up for a Belief Plan and fulfill an initial two-year commitment will never have to sign another one with U.S. Cellular’s “no contract after the first.” ", "Current U.S. Cellular customers who signed up for a Belief Plan and are already eligible for a phone upgrade can get promotional prices without signing another contract. ", "Customers automatically get valuable rewards that can be used for faster phone upgrades in as little as 10 months, additional lines, phones, accessories and ringtones.", "\n\nAbout The Belief Project\nLaunched Oct. 1, The Belief Project recognizes customer loyalty with national bundled rate plans that offer customers the freedom to enjoy industry-leading benefits without signing continuous contracts – like guaranteed upgrades to the newest phones at promotional prices every 18 months.", "\n\nWith “no contract after the first,” new customers fulfill an initial two-year commitment and never have to sign another contract again. ", "Existing customers who switch to the new Belief Plans can simply finish the remainder of their term without extending their current contract.", "\n\nCustomers automatically get valuable rewards just for being a customer that can be used for even faster phone upgrades in as little as 10 months. ", "Rewards can also be used to get additional lines, phones, accessories and ringtones.", "\n\nThe Belief Project also includes the industry’s only Phone Replacement program. ", "If a customer’s phone accidentally breaks or stops working, U.S. Cellular replaces it with the same or similar model at no additional cost. ", "Customers also can save up to 5 percent on their monthly plans for setting up autopay and paperless billing.", "\n\nThese innovative initiatives were developed to address consumers’ common frustrations with wireless, elevate the customer experience and create a human relationship, not a contractual one. ", "For more information about The Belief Project, visit uscellular.com." ]

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[ "\n65 So.3d 379 (2010)\nLakyra ELLIOTT,\nv.\nNAVISTAR, INC., ", "and IC Bus, LLC.", "\nNequaisha Bland,\nv.\nNavistar, Inc., and IC Bus, LLC.", "\nSeville Briggs,\nv.\nNavistar, Inc., and IC Bus, LLC.", "\nIshakey Bennett,\nv.\nNavistar, Inc., and IC Bus, LLC.", "\nFreddie Washington,\nv.\nNavistar, Inc., and IC Bus, LLC.", "\nPhillip Hinton,\nv.\nNavistar, Inc., and IC Bus, LLC.", "\nYolanda Moore,\nv.\nNavistar, Inc., and IC Bus, LLC.", "\nKyle Rose,\nv.\nNavistar, Inc., and IC Bus, LLC.", "\nAnthoni T. Moore,\nv.\nNavistar, Inc., and IC Bus, LLC.", "\nLawanda Jefferson,\nv.\nNavistar, Inc., and IC Bus, LLC.", "\nTassarian Fletcher,\nv.\nNavistar, Inc., and IC Bus, LLC.", "\nCharles Ford,\nv.\nNavistar, Inc., and IC Bus, LLC.", "\nShirley Ann Davidson, as mother and next friend of Joe Davidson, a minor,\nv.\nNavistar, Inc., and IC Bus, LLC.", "\nJames O. Garth,\nv.\nNavistar, Inc., and IC Bus, LLC.", "\nDawon Massey,\nv.\nNavistar, Inc., and IC Bus, LLC.", "\n1090152, 1090153, 1090154, 1090155, 1090156, 1090159, 1090160, 1090161, 1090162, 1090163, 1090164, 1090165, 1090166, 1090167 and 1090168.", "\nSupreme Court of Alabama.", "\nDecember 3, 2010.", "\n*381 Douglas J. Fees of The Cochran Firm-Huntsville, Huntsville, for appellants.", "\nDe Martenson and Anna Katherine Bowman of Huie, Fernambucq & Stewart, LLP, Birmingham, for appellees.", "\nSTUART, Justice.", "\nLakyra Elliott, Nequaisha Bland, Seville Briggs, Ishakey Bennett, Freddie Washington, Phillip Hinton, Yolanda Moore, Kyle Rose, Anthoni T. Moore, Lawanda Jefferson, Tassarian Fletcher, Charles Ford, James O. Garth, Dawon Massey, and Shirley Ann Davidson, as mother and next friend of Joe Davidson, a minor (\"the plaintiffs\"), asserted products-liability, breach-of-warranty, and negligence and/or wantonness claims against Navistar, Inc., formerly known as International Truck & Engine Corporation, Inc., and its wholly owned subsidiary IC Bus, LLC, formerly known as IC Corporation (collectively referred to as \"the bus companies\"), in the Madison Circuit Court, seeking damages for injuries sustained in an accident involving a school bus designed, manufactured, and sold by the bus companies. ", "The trial court entered a summary judgment in favor of the bus companies, and the plaintiffs appeal. ", "We reverse and remand.", "\n\nI.\nOn November 20, 2006, a school bus transporting approximately 40 students from Lee High School in Huntsville to the Huntsville Center for Technology was struck by another vehicle while traveling on an elevated portion of U.S. Interstate 565 in Huntsville. ", "As a result of the collision, the bus ran over a 32-inch high concrete barrier on the left side of the roadway and fell approximately 30 feet to the ground below, killing four students and injuring the other students to varying degrees.", "\nOn February 9, 2007, 14 of the plaintiffs filed separate complaints in the Madison Circuit Court asserting claims against Laidlaw Transit, Inc., which owned and operated the bus involved in the accident; Anthony Scott, an employee of Laidlaw Transit who was driving the bus at the time of the accident; and Tony Williams, the driver of the other car involved in the accident. ", "Those plaintiffs also identified as fictitiously named defendants \"those persons, corporations, associations, firms, or other entities, who or which designed, manufactured, marketed, advertised, sold, or otherwise placed into the stream of commerce, the school bus, or any component thereof\"; however, they did not assert any claims against those fictitiously named defendants at that time.[1]\n*382 Multiple other complaints were filed around this same time by other students who were injured in the bus accident, and, on October 29, 2007, the 26 cases stemming from the bus accident that were then pending in the Madison Circuit Court were assigned to the same judge. ", "Some of those cases named the bus companies as defendants and included claims asserted against them; however, at that time the plaintiffs' cases did not.", "\nThe trial court thereafter officially consolidated the cases for pretrial purposes, and the parties engaged in discovery. ", "Eventually, the plaintiffs entered into settlement agreements with Laidlaw Transit, Scott, and Williams. ", "However, after settling their claims against those defendants, the plaintiffs retained a new attorney, and, in April, May, and June 2009, they filed amended complaints asserting products-liability, breach-of-warranty, and negligence and/or wantonness claims against the bus companies.[2] On approximately June 29, 2009, the bus companies moved for a summary judgment on all the claims asserted against them, arguing that the claims were barred by the applicable statute of limitations because they were not asserted until, at the earliest, April 2009—more than two years after the November 20, 2006, bus accident. ", "The bus companies also argued that the claims were barred by the doctrine of waiver and the doctrine of laches.", "\nThe plaintiffs opposed the bus companies' summary-judgment motion, arguing that the injured parties were all minors at the time of the accident and that, under Alabama law, the statute of limitations for their claims was therefore tolled until their 19th birthdays and that the doctrines of waiver and laches did not apply. ", "On September 16, 2009, the trial court granted the bus companies' motion for a summary judgment, noting that \"[t]he Plaintiffs' claims against [the bus companies] are barred by the doctrine of laches, the doctrine of waiver and ... the applicable statute of limitations.\" ", "On October 26, 2009, the plaintiffs filed timely notices of appeal to this Court. ", "On August 4, 2010, the clerk of this Court entered an identical order in each of these 15 appeals remanding this case to the trial court. ", "That order stated:\n\"It appearing to the Court that claims stated against Tony Lamar Williams, Anthony Tyrone Scott, and Laidlaw Transit, Inc., have not been adjudicated,[3] these causes are remanded to you for a determination as to whether to (1) make the interlocutory order of September 16, 2009, in favor of [the bus companies] and against the plaintiffs, a final judgment, pursuant to the provisions of Rule 54(b), Alabama Rules of Civil Procedure; or (2) adjudicate the remaining claims, thus making the interlocutory orders of September 16, 2009, final and appealable; or (3) do nothing, in which event the appeals will be dismissed as from a non-final order.\"", "\nFollowing an extension of time for responding to the remand order, the trial court filed a supplemental record on appeal on September 24, 2010, certifying the interlocutory order of September 16, 2009, in favor of the bus companies as final pursuant to Rule 54(b), Ala. R. Civ. ", "P.[4]\n\n\n*383 II.", "\nThe plaintiffs argue that the trial court erred by entering a summary judgment in favor of the bus companies because none of the grounds cited by the trial court—statute of limitations, waiver, and/or laches— apply to the claims they have asserted against the bus companies. ", "We consider each of those grounds in turn.", "\nThe plaintiffs first argue that the trial court erred in holding that their claims against the bus companies were barred by the statute of limitations because, they argue, the trial court failed to give effect to § 6-2-8(a), Ala.Code 1975. ", "The bus companies, however, argue that the summary judgment was correctly entered because, they argue, § 6-2-8(a) does not apply. \"", "Because the resolution of this issue is a matter of mere statutory construction, the standard of review is de novo.\" ", "Arthur v. Bolen, 41 So.3d 745, 748 (Ala.2010) (citing Ex parte Birmingham Bd. ", "of Educ., ", "45 So.3d 764, 767 (Ala.2009)). ", "Our inquiry is governed by the following well settled principles of statutory construction:\n\"`The fundamental rule of statutory construction is that this Court is to ascertain and effectuate the legislative intent as expressed in the statute. ", "League of Women Voters v. Renfro, 292 Ala. 128, 290 So.2d 167 (1974). ", "In this ascertainment, we must look to the entire Act instead of isolated phrases or clauses; Opinion of the Justices, 264 Ala. 176, 85 So.2d 391 (1956).'", "\n\"Darks Dairy, Inc. v. Alabama Dairy Comm'n, 367 So.2d 1378, 1380 (Ala.1979) (emphasis added). ", "To discern the legislative intent, the Court must first look to the language of the statute. ", "If, giving the statutory language its plain and ordinary meaning, we conclude that the language is unambiguous, there is no room for judicial construction. ", "Ex parte Waddail, 827 So.2d 789, 794 (Ala.2001). ", "If a literal construction would produce an absurd and unjust result that is clearly inconsistent with the purpose and policy of the statute, such a construction is to be avoided. ", "Ex parte Meeks, 682 So.2d 423 (Ala.1996).\"", "\nCity of Bessemer v. McClain, 957 So.2d 1061, 1074-75 (Ala.2006).", "\nSection 6-2-8(a) provides:\n\"If anyone entitled to commence any of the actions enumerated in this chapter, to make an entry on land or enter a defense founded on the title to real property is, at the time the right accrues, below the age of 19 years, or insane, he or she shall have three years, or the period allowed by law for the commencement of an action if it be less than three years, after the termination of the disability to commence an action, make entry, or defend. ", "No disability shall extend the period of limitations so as to allow an action to be commenced, entry made, or defense made after the lapse of 20 years from the time the claim or right accrued. ", "Nothing in this section shall be interpreted as denying any imprisoned person the right to commence an action enumerated in this chapter and to make any proper appearances on his or her behalf in such actions.\"", "\nThe plaintiffs have submitted evidence establishing that the injured students were all under the age of 19 at the time of the bus accident and that the plaintiffs amended their individual complaints to assert claims against the bus companies within the two-year period after the injured students turned 19; accordingly, they argue, their claims are timely because the plain language of § 6-2-8 indicates that the two-year statute of limitations applicable to *384 their claims was tolled during the pendency of their minority.[5]\nThe bus companies, however, argue that § 6-2-8 does not apply in cases, such as these, where injured minors are represented by guardians or next friends who, in fact, initiated actions on their behalf while the injured parties were still minors.[6] In support of that argument, the bus companies cite Lee v. Wood, 85 Ala. 169, 170, 4 So. ", "693, 693 (1888), in which this Court held that the general rule that \"statutes of limitation do not run against those laboring under a personal disability, such as infancy ... does not apply to infants, or other persons disabled, who have a trustee capable of suing\"; and Spann v. First National Bank of Montgomery, 240 Ala. 539, 545, 200 So. ", "554, 559 (1941), in which this Court stated:\n\"It is clear enough there is here shown no such exception. ", "The guardian all along not only had the power but was also under the duty to rescind the transactions and bring the suit. ", "Not having done so, the bar of the statute of limitation of six years presents a bar to the suit by the guardian and likewise is applicable to the ward.\"", "\nThe plaintiffs counter by arguing that Lee and Spann are distinguishable inasmuch as they involved appointed guardians or trustees who had a duty to bring an action on behalf of the minor parties they represented—not next friends who had no duty to assert claims such as those asserted here—a distinction the plaintiffs argue was recognized by this Court in Emerson v. Southern Ry., ", "404 So.2d 576, 579 (Ala. 1981) (\"It is clear to us, however, that failure on the part of the representative to file or pursue this claim within the limitation period does not bar recovery where § 6-2-8 is applicable.\").", "\nWe agree with the plaintiffs that § 6-2-8 applies to the claims they asserted against the bus companies and that those claims accordingly are not barred by the statute of limitations. ", "Section 6-2-8(a) clearly provides that a minor entitled to commence \"any of the actions enumerated in this chapter ... shall have three years, or the period allowed by law for the commencement of an action if it be less than three years, after the termination of the disability to commence an action....\" This language is unambiguous; there is, accordingly, no room for judicial construction. ", "Ex parte Waddail, 827 So.2d 789, 794 (Ala.2001). ", "The claims asserted by the plaintiffs against the bus companies were subject to a two-year statute of limitations (see supra note 5), and they were accordingly entitled to assert those claims at any time before the injured parties turned 21. ", "Section 6-2-8 contains no exception indicating that the statute ceases to have application merely because a minor's representative pursued some claims belonging to the minor while failing to bring other claims, and \"courts have no authority to engraft exceptions, which are not found in the statutes.\" ", "Barclay v. Smith, 66 Ala. 230, 232 (1880). ", "This Court has also indicated on previous occasions that the statute of limitations does not run on a minor's *385 claims regardless of whether the minor's representative failed to or elected not to pursue claims on the minor's behalf, negligently pursued claims on the minor's behalf, or even if the minor's representative pursued some claims while failing to pursue others. ", "See Emerson, 404 So.2d at 579 (stating that, although a representative may file a claim on behalf of an injured minor, the failure to do so does not bar the minor from later doing so if § 6-2-8 is applicable); Spurling v. Fillingim, 244 Ala. 172, 176, 12 So.2d 740, 743 (1943) (holding that a minor, who initiated an action through her next friend within the applicable one-year limitations period, seeking damages for injuries sustained in an automobile accident was permitted to amend her action to add another defendant even after that one-year period expired because her right to maintain an action would continue for one year after she reached the age of majority); Hood v. Johnston, 210 Ala. 617, 619, 99 So. ", "75, 77 (1924) (stating that plaintiff was entitled to sue in his own name upon reaching the age of majority regardless of \"whatever may or may not have been done by his guardian\"); and McLaughlin v. Beyer, 181 Ala. 427, 437, 61 So. ", "62, 65 (1913) (\"The neglect or dereliction of a next friend, in the prosecution of a suit or in allowing a dismissal thereof, ought not to be allowed to prejudice the rights or remedies of the infant, and such seems to be the weight of the authority on the subject.\"). ", "To the extent Lee and Spann are in conflict with these cases and with the plain language of § 6-2-8, we hereby overrule them.", "\nIt is undisputed that the plaintiffs asserted their claims against the bus companies before the injured parties reached the age of 21. ", "The trial court therefore erred by relying on the statute of limitations as a basis for entering a summary judgment in favor of the bus companies.", "\n\nIII.", "\nThe plaintiffs next argue that the trial court erred by holding that they had waived their rights to assert claims against the bus companies. ", "Before the trial court, the bus companies argued that the plaintiffs had waived their rights to pursue claims against them because, the bus companies argued, the bus companies' role in designing and manufacturing the bus was always known—as evidenced by the fact that other students injured in the bus accident had named the bus companies as defendants in actions filed the same month as the plaintiffs' actions—yet the plaintiffs nevertheless took no action to name the bus companies as defendants for over two years while they actively pursued claims against Laidlaw Transit, Scott, and Williams. ", "The plaintiffs deny that their conduct in this litigation demonstrated an intent to waive their rights to pursue claims against the bus companies, and they argue that, if they had intended to waive such claims they would not have identified as fictitiously named defendants in their complaints \"those persons, corporations, associations, firms, or other entities, who or which designed, manufactured, marketed, advertised, sold, or otherwise placed into the stream of commerce, the school bus, or any component thereof.\"", "\nThis Court has stated that\n\"`[a] waiver consists of a \"voluntary and intentional surrender or relinquishment of a known right,\" Dominex, Inc. v. Key, 456 So.2d 1047, 1058 (Ala.1984), and the burden of proof in establishing a waiver rests upon the party asserting the claim.' ", "Bentley Sys., ", "Inc. v. Intergraph Corp., 922 So.2d 61, 93 (Ala.2005). ", "Moreover, whether a party has voluntarily or intentionally waived a known right is normally a jury question. ", "See Edwards v. Allied Home Mortgage Capital *386 Corp., 962 So.2d 194, 209 (Ala. 2007).\"", "\nHorne v. TGM Assocs., ", "L.P., 56 So.3d 615, 624 (Ala.2010). ", "A summary judgment should be entered only if there is no genuine issue of material fact when the record is viewed in the light most favorable to the nonmovant. ", "Payton v. Monsanto Co., 801 So.2d 829, 832-33 (Ala.2001). ", "Assuming, without deciding, that a delay in asserting a claim not subject to a statute-of-limitations defense can work a waiver of that claim, we first note that \"[w]hether there has been a waiver is a question of fact,\" Bentley Sys., ", "Inc. v. Intergraph Corp., 922 So.2d 61, 93 (Ala.2005), and, in light of the record in this case, we cannot agree with the trial court that there is no question that the plaintiffs intended to voluntarily relinquish their right to assert their claims against the bus companies.[7] The summary judgment entered by the trial court cannot stand on the basis of the doctrine of waiver.", "\n\nIV.", "\nThe plaintiffs' final argument is that the trial court erred in concluding that their claims against the bus companies should be barred by the doctrine of laches. \"", "`Laches' is defined as neglect to assert a right or a claim that, taken together with a lapse of time and other circumstances causing disadvantage or prejudice to the adverse party, operates as a bar.\" ", "Ex parte Grubbs, 542 So.2d 927, 928 (Ala.1989) (citing Black's Law Dictionary 787 (5th ed.1979)). ", "It is an equitable doctrine applied by the courts to prevent a party that has delayed asserting a claim to assert that claim after some change in conditions has occurred that would make belated enforcement of the claim unjust. ", "Ex parte Grubbs, 542 So.2d at 929. ", "A party asserting laches as a defense is generally required to show that the plaintiff has delayed in asserting a claim, that that delay is inexcusable, and that the delay has caused the party asserting the defense undue prejudice. ", "Id. The plaintiffs argue that laches cannot bar a claim if the statute of limitations has not yet run on that claim; they also argue that, regardless, they did not delay in asserting their claims against the bus companies and that, even if this Court were to find that they had delayed, there is no evidence indicating that the bus companies were unduly prejudiced by any such delay. ", "The bus companies argue that the doctrine of laches may bar a claim even if the statute of limitations has not expired and that the plaintiffs did in fact delay in asserting their claims and that that delay has caused the bus companies undue prejudice.", "\nThe bus companies have cited numerous cases in support of their argument that the doctrine of laches should be applied in this case, regardless of whether the statute of limitations has run, see Multer v. Multer, 280 Ala. 458, 463, 195 So.2d 105, 109 (1966), Alabama Cablevision Co. v. League, 416 So.2d 433, 435 (Ala.Civ.", "App. ", "1982), and United States of America v. Olin Corp., 606 F.Supp. ", "1301, 1309 (N.D.Ala.1985); however, none of those cases involved a claim for money damages subject to a statute of limitations. ", "In Ballenger v. Liberty National Life Insurance Co., 266 Ala. 407, 410, 96 So.2d 728, 731 (1957), this Court addressed this specific issue and stated:\n\"There is competent authority elsewhere based on unassailable rationale holding that where the issue involved is *387 a legal one and does not lie within the breast or conscience of the chancellor the statute of limitation is the applicable rule and the defense of laches may not properly be interposed.\"", "\nAfter reviewing the caselaw from Kentucky to which it referred, see Gover's Administrator v. Dunagan, 299 Ky. 38, 184 S.W.2d 225 (1944), and Crawford's Administrator v. Ross, 299 Ky. 664, 186 S.W.2d 797 (1945), the Ballenger Court concluded:\n\"The principle enunciated by the Kentucky Court impresses us as being thoroughly sound. ", "Therefore, the issue now under consideration is, we think, ruled by the stated principle. ", "A claim for conversion is a legal one cognizable at law, with the result that the defense of laches may not be applied, even though the claim `got into equity' under the removal statute. ", "If the contrary view should be upheld, untoward illogical consequences would obtain. ", "It would be purposeless to multiply the many ridiculous illustrations, but it is conceivable that under such a view most all actions at law could be moved into equity so the defendant could plead laches and thereby subvert the right of trial by jury and operation of the applicable statute of limitation.\"", "\n266 Ala. at 411, 96 So.2d at 733. ", "Applying the holding of Ballenger to the present case—which involves a claim for money damages—we agree with the plaintiffs that the doctrine of laches should not be applied to bar their claims because, as discussed supra, the statute of limitations has not yet run on their claims. ", "Accordingly, the trial court erred to the extent the summary judgment in favor of the bus companies was based on the doctrine of laches.", "\n\nV.\nThe trial court entered a summary judgment in favor of the bus companies, stating in its order that \"[t]he [p]laintiffs' claims against [the bus companies] are barred by the doctrine of laches, the doctrine of waiver and ... by the applicable statute of limitations.\" ", "However, the plaintiffs have established that none of those grounds, in fact, apply to their claims against the bus companies. ", "The judgment entered in favor of the bus companies is accordingly reversed, and the cause is remanded for further proceedings consistent with this opinion.", "\n1090152—REVERSED AND REMANDED.", "\n1090153—REVERSED AND REMANDED.", "\n1090154—REVERSED AND REMANDED.", "\n1090155—REVERSED AND REMANDED.", "\n1090156—REVERSED AND REMANDED.", "\n1090159—REVERSED AND REMANDED.", "\n1090160—REVERSED AND REMANDED.", "\n1090161—REVERSED AND REMANDED.", "\n1090162—REVERSED AND REMANDED.", "\n1090163—REVERSED AND REMANDED.", "\n1090164—REVERSED AND REMANDED.", "\n1090165—REVERSED AND REMANDED.", "\n1090166—REVERSED AND REMANDED.", "\n*388 1090167—REVERSED AND REMANDED.", "\n1090168—REVERSED AND REMANDED.", "\nCOBB, C.J., and LYONS, SMITH, BOLIN, PARKER, and MURDOCK, JJ., ", "concur.", "\nWOODALL, J., concurs in the result.", "\nNOTES\n[1] The 15th plaintiff, Garth, filed a similar complaint on February 7, 2008.", "\n[2] The new attorney retained by the plaintiffs was already involved in this litigation representing other students who had been injured in the bus accident and who had previously asserted claims against the bus companies.", "\n[3] Apparently, although the plaintiffs' claims against Williams, Scott, and Laidlaw Transit had been settled, the trial court had not yet dismissed the claims against those defendants.", "\n[4] These cases were assigned to Justice Stuart on September 27, 2010.", "\n[5] The plaintiffs further note that their wantonness claims are actually subject to a six-year statute of limitations and that the trial court erred by failing to recognize that fact; however, the bus companies argue that the plaintiffs failed to raise this issue in the trial court and argue that the plaintiffs cannot now raise it. ", "Our resolution of this appeal ultimately makes it unnecessary to consider these issues.", "\n[6] The original complaints in the underlying cases were styled to reflect that the injured minors were suing by and through a parent. ", "The notices of appeal in 14 of the appeals name only the injured parties.", "\n[7] The plaintiffs have responded to the argument that they waived their claims against the bus companies only by arguing that there is insufficient evidence indicating such a waiver; they have not addressed the issue whether a party can waive a claim by a delay in its assertion that does not extend beyond the applicable limitations period.", "\n" ]

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[ "William Hearn\n\nWilliam Hearn may refer to:\n\n William Hearn (legal academic) (1826–1888), Australian university professor and politician\n William Hearn (umpire) (1849–1904), English cricketer and Test umpire\n William Hearn (rower) (1850–?), ", "New Zealand sculler" ]

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

[ 0.0006504079210571945, 0.20689545571804047 ]

[ "Introduction\n============\n\nα-Imino esters play a very important role in the field of imine chemistry \\[[@R1]--[@R3]\\], because the ester group can serve as an activator to enhance the reactivity of the C=N double bond, thus making the following nucleophilic addition easier \\[[@R4]--[@R5]\\]. ", "More attractively, the transformation of α-imino esters can provide an easy access to various natural and unnatural α-amino acid esters \\[[@R6]--[@R10]\\]. ", "Up to now, a series of nucleophilic substrates have been reported to react with α-imino esters, such as enamine \\[[@R11]--[@R14]\\], carbamate ammonium ylide \\[[@R15]\\], 1,3-dipolar cycle \\[[@R16]\\], boronic acid \\[[@R17]\\], acetylide \\[[@R18]\\], proparygylic anion \\[[@R19]\\] and ketene silyl acetal \\[[@R20]\\]. ", "These resulted α-amino acid derivatives are useful building blocks in modern organic synthetic and medicinal chemistry \\[[@R21]--[@R22]\\]. ", "For example, we can easily find the active participation of α-imino esters in the total synthesis of the bioactive molecule fumimycin \\[[@R23]\\]. ", "Moreover, α-amino acids are the most general fragments constituting peptides and proteins, especially for human insulin \\[[@R24]--[@R28]\\].", "\n\nOne of the most straightforward methods to prepare α-amino esters is the direct reduction of α-imino esters \\[[@R29]--[@R30]\\]. ", "Several heterocyle-based reduction reagents have been developed for this transformation in the past years \\[[@R31]--[@R35]\\]. ", "They usually served as mild hydrogen donors, but the use of them also made the purification difficult at the same time. ", "Hydrogen gas is a traditional reduction source \\[[@R36]\\] and silanes and boranes are also well documented as the choices of reduction reagents \\[[@R37]--[@R39]\\].", "\n\nRecently, our groups have developed a new type of chiral phosphonyl auxiliaries for imines \\[[@R40]--[@R44]\\]. ", "Compared with the reported sulfinyl auxiliaries ([Fig. ", "1](#F1){ref-type=\"fig\"}) \\[[@R45]--[@R48]\\], the phosphonyl ones exhibited advantages in the concise preparation method from readily available starting materials, an easy modification of the auxiliary and a highly diastereoselective control. ", "Furthermore, the phosphonyl auxiliaries can do favor in the final purification, and it did not need any column chromatography or recrystallization, which was summarized as GAP (group assisted purification) \\[[@R49]--[@R51]\\]. ", "So far, a number of *N*-phosphonyl aldimines ([Fig. ", "1](#F1){ref-type=\"fig\"}) have been synthesized and successfully used in many asymmetric additions \\[[@R52]--[@R54]\\]. ", "In our continuous efforts on the chiral *N*-phosphonyl imine chemistry, we tried to develop novel *N*-phosphinyl protected α-imino esters and to use them for the asymmetric synthesis of α-amino esters. ", "Herein, we report for the first time the synthesis of *N*-phosphinyl-protected α-imino esters ([Fig. ", "1](#F1){ref-type=\"fig\"}), followed by the reduction of these α-imino esters by L-selectride, to give the corresponding α-amino esters with excellent yields (88--98%) and virtually complete diastereoselectivities.", "\n\n{#F1}\n\nResults and Discussion\n======================\n\nPreparation of the *N*-phosphinyl-protected α-imino esters\n----------------------------------------------------------\n\nAfter screening the classical procedures for the synthesis of α-imino esters \\[[@R3],[@R55]--[@R56]\\], we initially tried an approach with chlorophosphine and ester oxime as starting materials, which proceeded through rearrangement at low temperature ([Scheme 1](#C1){ref-type=\"fig\"}). ", "^31^P NMR and TLC of the crude product disclosed that several byproducts formed in this system. ", "The isolation of the *N*-phosphinyl α-imino esters was very difficult and only 26% isolated yield of this product was obtained.", "\n\n{#C1}\n\nThis unacceptable result shifted our attention to the previously reported methods for the preparation of *N*-phosphonyl aldimines, which was the condensation between aldehyde and phosphonyl amide \\[[@R40]--[@R41]\\]. ", "Then, we carried out the optimization of the reaction conditions for the condensation of keto-ester **2a** and phosphinyl amide **1** ([Table 1](#T1){ref-type=\"table\"}). ", "Common dehydrating reagents, like 4 Å molecular sieves and magnesium sulfate, resulted in no desired product neither at room temperature nor under reflux ([Table 1](#T1){ref-type=\"table\"}, entries 1--4). ", "Very poor chemical yields of α-imino ester **3a** were detected when tetraethoxytitanium or tetraisopropoxytitanium was used as condensing reagent ([Table 1](#T1){ref-type=\"table\"}, entries 5--8). ", "Further treatment with titanium tetrachloride/triethyl amine gave a positive result and 46% chemical yield was obtained ([Table 1](#T1){ref-type=\"table\"}, entry 9). ", "Then, further investigation revealed that the best yield (47%) was observed when the reaction was conducted in the presence of TiCl~4~/Et~3~N at room temperature for 12 h ([Table 1](#T1){ref-type=\"table\"}, entries 9--16). ", "^31^P NMR of the crude product predicted almost complete consumption of phosphinyl amide **1** but yields were very low. ", "After careful study, we found that the obtained α-imino ester was not stable and decomposed slowly along with column chromatography purification and storage. ", "For this reason, this α-imino ester was directly used in the following reaction after column chromatography to avoid decomposition.", "\n\n###### \n\nOptimization of the synthesis of α-imino ester **3a** by the condensation method.^a^\n\n ------------------------------------------- -------------------- ---------- ------------ ---------- --------------\n ![](", "Beilstein_J_Org_Chem-10-653-i001.jpg) \n \n entry reagent *T* (°C) solvent time (h) yield (%)^b^\n \n 1 4 Å MS rt CH~2~Cl~2~ 24 NR\n 2 4 Å MS reflux CH~2~Cl~2~ 24 NR\n 3 MgSO~4~ rt CH~2~Cl~2~ 24 NR\n 4 MgSO~4~ reflux CH~2~Cl~2~ 24 NR\n 5 Ti(OEt)~4~/Et~3~N rt CH~2~Cl~2~ 24 trace\n 6 Ti(OEt)~4~/Et~3~N reflux CH~2~Cl~2~ 24 trace\n 7 Ti(OEt)~4~/Et~3~N reflux toluene 24 10\n 8 Ti(OiPr)~4~/Et~3~N reflux CH~2~Cl~2~ 24 trace\n 9 TiCl~4~/Et~3~N rt CH~2~Cl~2~ 24 46\n 10 TiCl~4~/Et~3~N rt CH~2~Cl~2~ 12 47\n 11 TiCl~4~/Et~3~N rt CH~2~Cl~2~ 6 33\n 12 TiCl~4~/Et~3~N reflux CH~2~Cl~2~ 12 21\n 13 TiCl~4~/Et~3~N rt Et~2~O 12 20\n 14 TiCl~4~/Et~3~N rt THF 12 29\n 15 TiCl~4~/Et~3~N rt toluene 12 11\n 16 TiCl~4~/DIPEA rt CH~2~Cl~2~ 12 31\n ------------------------------------------- -------------------- ---------- ------------ ---------- --------------\n\n^a^Rearrangement conditions: Phosphinyl amide **1** (0.5 mmol), ketoester **2a** (1.0 mmol), solvent (3.0 mL); ^b^isolated yields.", "\n\nWith the optimized conditions in hand, we then used varieties of keto-esters **2** as starting materials for the preparation of chiral α-imino esters **3** ([Table 2](#T2){ref-type=\"table\"}). ", "As shown in [Table 2](#T2){ref-type=\"table\"}, modest yields were obtained (29--59%) for all the cases. ", "In general, electron-deficient substrates performed better and the best yield was found for the substrate with *para*-fluoro substituent ([Table 2](#T2){ref-type=\"table\"}, entry 4). ", "The substrate with *ortho*-substituent led to lower yield due to steric effects ([Table 2](#T2){ref-type=\"table\"}, entry 7). ", "Besides, the reaction with ethyl ester also worked well and resulted in a slightly lower yield ([Table 2](#T2){ref-type=\"table\"}, entry 11).", "\n\n###### \n\nSynthesis of *N*-phosphinyl-protected α-imino esters^a^.\n\n ------------------------------------------- ------------------- ---- --------- --------------\n ![](", "Beilstein_J_Org_Chem-10-653-i002.jpg) \n \n entry Ar R product yield (%)^b^\n \n 1 C~6~H~5~ Me **3a** 47\n 2 4-BrC~6~H~4~ Me **3b** 50\n 3 4-ClC~6~H~4~ Me **3c** 49\n 4 4-FC~6~H~4~ Me **3d** 59\n 5 3-FC~6~H~4~ Me **3e** 53\n 6 3-CH~3~C~6~H~4~ Me **3f** 40\n 7 2-CH~3~C~6~H~4~ Me **3g** 38\n 8 3,5-Cl~2~C~6~H~3~ Me **3h** 29\n 9 2-Naphthyl Me **3i** 26\n 10 4-Ph-C~6~H~4~ Me **3j** 35\n 11 C~6~H~5~ Et **3k** 43\n ------------------------------------------- ------------------- ---- --------- --------------\n\n^a^Reaction conditions: Phosphinyl amide **1** (0.5 mmol), ketoester **2** (1.0 mmol), titanium(IV) chloride (0.5 mmol), triethylamine (2.0 mmol), dichloromethane (4.0 mL), rt for 12 h; ^b^isolated yields.", "\n\nOptimization of the asymmetric reduction reaction conditions\n------------------------------------------------------------\n\nThen, the obtained chiral *N*-phosphinyl α-imino esters were used for the asymmetric synthesis of α-amino esters through reduction. ", "The reduction condition scan was firstly focused on the examination of reductants. ", "A number of reductants, including Hantzsch ester, silanes, organoaluminum and boranes were tested in the system. ", "Unfortunately, silanes failed to trigger the reduction ([Table 3](#T3){ref-type=\"table\"}, entries 2 and 3). ", "Hantzsch ester and DIBAL were also not suitable for this reduction, and almost no desired product was obtained ([Table 3](#T3){ref-type=\"table\"}, entries 1 and 5). ", "Lithium triethylborohydride ([Table 3](#T3){ref-type=\"table\"}, entry 4) and sodium borohydride ([Table 3](#T3){ref-type=\"table\"}, entry 6) were decent choices, giving modest yields and very poor diastereoselectivity. ", "Further screening of reductants found that L-Selectride and N-Selectride were good candidates, especially for L-Selectride, 92% yield and virtually complete controlled diastereoselectivity (99:1) were found ([Table 3](#T3){ref-type=\"table\"}, entry 7). ", "It did not matter at all when the reaction time was shortened to 8 h. However, the yield decreased when the time was further shortened to 6 h ([Table 3](#T3){ref-type=\"table\"}, entries 9 and 10). ", "The examination of solvents showed that polar solvents ([Table 3](#T3){ref-type=\"table\"}, entries 11 and 13) were superior to a non-polar one such as toluene ([Table 3](#T3){ref-type=\"table\"}, entry 12). ", "The temperature influenced the reaction obviously, and raising the temperature to −40 °C reduces the yield to 89% and the diastereoselectivity to 87:13 ([Table 3](#T3){ref-type=\"table\"}, entry 14).", "\n\n###### \n\nOptimization of asymmetric reduction of α-imino esters^a^.\n\n ------------------------------------------- ---------------- ---------- --------------- ---------- -------------- -------\n ![](", "Beilstein_J_Org_Chem-10-653-i003.jpg) \n \n entry reagent *T* (°C) solvent time (h) Yield (%)^b^ dr^c^\n \n 1 Hantzsch ester −78 THF 12 Trace ---\n 2 HSiCl~3~ −78 THF 12 NR ---\n 3 HSiEt~3~ −78 THF 12 NR ---\n 4 LiBHEt~3~ −78 THF 12 71 75:25\n 5 DIBAL −78 THF 12 Trace ---\n 6 NaBH~4~ −78 THF 12 48 66:34\n 7 L-Selectride −78 THF 12 92 99:1\n 8 N-Selectride −78 THF 12 90 90:10\n 9 L-Selectride −78 THF 8 92 99:1\n 10 L-Selectride −78 THF 6 85 99:1\n 11 L-Selectride −78 4-MeTHF 8 90 99:1\n 12 L-Selectride −78 toluene 8 47 96:4\n 13 L-Selectride −78 diethyl ether 8 82 99:1\n 14 L-Selectride −40 THF 8 89 87:13\n ------------------------------------------- ---------------- ---------- --------------- ---------- -------------- -------\n\n^a^Reaction conditions: α-imino ester **3a** (0.15 mmol), reduction reagent (0.30 mmol), solvent (5.0 mL); ^b^isolated yields; ^c^determined by ^31^P NMR of the crude reaction mixture.", "\n\nScope of the asymmetric reduction reaction\n------------------------------------------\n\nAfter getting the optimized reduction conditions, several chiral *N*-phosphinyl α-imino esters prepared above were subjected to this system to examine the reaction scope. ", "As shown in [Table 4](#T4){ref-type=\"table\"}, reduction of these chiral α-imino esters provided excellent yields (up to 98%) and diastereoselectivities (up to 99:1). ", "Almost all the reductions could achieve more than 90% yield, only for the case of *para*-phenyl-substituted substrate, a slightly lower yield was found (88%, [Table 4](#T4){ref-type=\"table\"}, entry 10). ", "The diastereoselectivities of the reactions were almost completely controlled, and most of them were 99:1. ", "Except for the 4-bromo-substituted case, a dr of 96:4 was observed ([Table 4](#T4){ref-type=\"table\"}, entry 2). ", "It is interesting that GAP (group-assisted purification) was introduced into the reaction \\[[@R49]--[@R51]\\]. ", "In five cases ([Table 4](#T4){ref-type=\"table\"}, entries 1, 3--5 and 11), the final purified products were obtained by just washing with hexane, and no column chromatography or recrystallization was needed.", "\n\n###### \n\nScope of novel phophinyl substituted α-amino esters.^a^\n\n ------------------------------------------- ------------------- ---- --------------- --------------------- -------------- -------\n ![](", "Beilstein_J_Org_Chem-10-653-i004.jpg) \n \n entry Ar R α-amino ester purification method yield (%)^b^ dr^c^\n \n 1 C~6~H~5~ Me **4a** GAP^d^ 92 99:1\n 2 4-BrC~6~H~4~ Me **4b** Column 90 96:4\n 3 4-ClC~6~H~4~ Me **4c** GAP^d^ 96 99:1\n 4 4-FC~6~H~4~ Me **4d** GAP^d^ 98 99:1\n 5 3-FC~6~H~4~ Me **4e** GAP^d^ 95 99:1\n 6 3-CH~3~C~6~H~4~ Me **4f** Column 95 99:1\n 7 2-CH~3~C~6~H~4~ Me **4g** Column 94 99:1\n 8 3,5-Cl~2~C~6~H~3~ Me **4h** Column 92 99:1\n 9 2-Naphthyl Me **4i** Column 93 99:1\n 10 4-Ph-C~6~H~4~ Me **4j** Column 88 99:1\n 11 C~6~H~5~ Et **4k** GAP^d^ 94 99:1\n ------------------------------------------- ------------------- ---- --------------- --------------------- -------------- -------\n\n^a^Reaction conditions: α-imino esters **3** (0.15 mmol), L-Selectride (0.30 mmol), THF (5.0 mL); ^b^isolated yields; ^c^ determined by ^31^P NMR; ^d^group-assisted purification.", "\n\nDetermination of the absolute configuration\n-------------------------------------------\n\nThe phosphinyl auxiliary could be easily cleaved by treating with concentrated hydrochloric acid in methanol. ", "After stirring of **4a** with acid overnight, the conversion was complete and the corresponding amino ester hydrochloride was obtained. ", "Then, the obtained free amino ester was directly converted into its *N*-Cbz-protected derivative **5a** by treating with CbzCl/Et~3~N ([Scheme 2](#C2){ref-type=\"fig\"}). ", "The absolute configuration of the newly formed chiral center was assigned as *S* by comparing the optical rotation with that of known sample \\[[@R57]\\]. ", "The stereochemical assignments of other products were made by analogy correspondingly.", "\n\n{#C2}\n\nConclusion\n==========\n\nIn conclusion, we have developed a method for the synthesis of chiral *N*-phophinyl α-imino esters for the first time, which have been used as precursors for asymmetric reductions with L-Selectride as reductant. ", "Varieties of α-amino esters were obtained in excellent chemical yields and almost completely controlled diastereoselectivities. ", "Furthermore, a part of the products could be purified without use of any column chromatography or recrystallization, which provides an alternative way for the synthesis of α-amino esters. ", "The auxiliary was easily removed by treatment with acid to result the free α-amino esters.", "\n\nExperimental\n============\n\n**General procedure for the asymmetric reduction of** ***N*** **-phophinyl α-imino esters:** A reaction vial under argon was charged with L-Selectride (0.3 mmol) with THF (2.5 mL). ", "The reaction mixture was then cooled to −78 °C for 10 min. ", "Meanwhile, α-imino ester **3** (0.15 mmol, dissolved in 2.5 mL of THF) was cooled to −78 °C for 10 min. ", "Then the α-imino ester **3** solution was transferred dropwise via a cannula at −78 °C and the reaction was kept at the same temperature for 8 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (4.0 mL) and the organic layer was extracted with dichloromethane. ", "The organic layers were dried over anhydrous Na~2~SO~4~, filtered and concentrated under reduced pressure. ", "The crude product was purified using the GAP method or flash column chromatography on silica gel using EtOAc/hexanes (2:1, v/v) as the eluent to afford protected α-amino ester **4**.", "\n\nSupporting Information\n======================\n\n###### \n\nExperimental details and spectral data.", "\n\nWe gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. ", "21102071). ", "The Jiangsu 333 program (for Pan) and Changzhou Jin-Feng-Huang program (for Han) are also acknowledged.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Being publicly-funded gives us a greater chance to continue providing you with high quality content. ", "Please support us!", "\n\nWhen animals happen to live in a place that humans are interested in, they are sadly in danger. ", "If humans can hurt each other over land and resources, they especially don’t take animals into consideration. ", "The city of Samarkand in Uzbekistan was recently poisoning stray dogs to clear the streets for a music festival. ", "The United States government culls and slaughters wild horses and burros. ", "The United Kingdom infamously culls badgers and grey squirrels. ", "In Australia, kangaroos have even been culled to make space for animal agriculture. ", "Now, Australia is also culling cats.", "\n\nThe Australian government plans to kill two million cats by 2020. ", "They’re shooting, poisoning, trapping and bounty-killing outdoor cats. ", "They even airdrop sausages laced with poison. ", "They claim that feral cats are the single biggest threat to Australia’s native species. ", "It was initially claimed that there were over 20 million cats on the continent, but further studies have found this to be untrue. ", "More recent studies put the number between 2.1 and 6.3 million which is significantly lower.", "\n\n\nIf the government really does believe that the cats are such a threat, why can’t they at least find a humane alternative? ", "They could instead use exclusionary fencing, invest more in trap/spay/neuter/return programs. ", "They could also work harder toward conserving threatened animals in sanctuaries. ", "Australia has been having an extinction crisis for a while and studies show the government has not done nearly enough as they should to help the animals at risk of extinction.", "\n\nIf they put as much effort into helping endangered animals as they have been toward culling cats, they might not have to blame cats for their extinction crisis.", "\n\nSign this petition to demand an end to this cruel cat culling!", "\n\nFor more Animal, Earth, Life, Vegan Food, Health, and Recipe content published daily, subscribe to the One Green Planet Newsletter! ", "Also, don’t forget to download the Food Monster App on iTunes — with over 15,000 delicious recipes it is the largest meatless, vegan and allergy-friendly recipe resource to help reduce your environmental footprint, save animals and get healthy!", "\n\n\nLastly, being publicly-funded gives us a greater chance to continue providing you with high quality content. ", "Please consider supporting us by donating!", "\n\nAdvertisement" ]

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[ "‘Game of Thrones’ Clue is a board game full of fun and terrors\n\nIf George R.R. Martin hasn’t packed enough death into your life, Clue and HBO just released an official Game of Thrones version of the classic board game.", "\n\nGame of Thrones Clue pairs the murder mystery game with the most murder-y series on television for a gloriously geeky round of whodunit.", "\n\nUSAopoly\n\nThe game features double-sided board set in Mereen and the Red Keep, each with their own mystery to solve. ", "It’s like getting two games for the price of one.", "\n\nIconic suspects like Colonel Mustard and Mrs. Peacock are replaced with some of the show’s characters, including Littlefinger, Cersei Lannister, and Missandei. ", "Because if Game of Thrones has taught us anything, it’s to watch out for the unassuming characters.", "\n\nA thousand years ago, when Iceland probably had a lot in common with Westeros, a Viking named Orm Storolfson picked up a log weighing 1,433 pounds and dragged it three steps. ", "On the third step, his back broke. ", "Ouch. ", "Nevertheless, Storolfson made it into Icelandic lore as a legendary strongman." ]

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[ "Has anyone read the August 15th edition of American Way? ", "If you flip to page 10, you’ll see Tom Horton’s column on “entertaining history”. ", "I actually found the article really interesting, especially the part about American’s 747 coach lounges.", "\n\nIn 1966, the airline ordered a slow of Boeing 747 Astroliners. ", "These were the biggest commercial airplanes in the sky at the time, and in 1966, air travel was growing, so the order made a lot of sense. ", "Unfortunately, by the time American received the new aircraft in 1970, the economy was in a recession and there was too much capacity in the industry to justify all these 303-seat jumbos. ", "The solution to this problem was at once simple and radical. ", "American pulled 50 seats off each 747 and used the free space to create a passenger lounge. ", "The airline then installed a Wurlitzer piano in each lounge. ", "Once again, American enlisted Sinatra to help promote its latest musical marketing ploy. ", "This time, Frank Sinatra Jr. performed on a packed red-eye flight from Los Angeles to New York. ", "In a time of depressed air-travel demand, the Skylounges – which typically featured well-known singers whose only compensation was free travel – helped generate lots of traffic. ", "Not surprisingly (and certainly not for the last time), other airlines borrowed this American idea. ", "Alas, the piano-lounge-in-the-sky era didn’t last long, in just a few months, the economy rebounded and American was able to return the 50 seats to the cabin.", "\n\nCourtesy of Airlines Past & Present:\n\nAny of our more seasoned readers get to experience the Coach Lounges?", "\n\nThe responses below are not provided or commissioned by the bank advertiser. ", "Responses have not been reviewed, approved or otherwise endorsed by the bank advertiser. ", "It is not the bank advertiser's responsibility to ensure all posts and/or questions are answered." ]

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[ "Hemispheric asymmetry in global/local processing: effects of stimulus position and spatial frequency.", "\nWe examined the neural mechanisms of functional asymmetry between hemispheres in the processing of global and local information of hierarchical stimuli by measuring hemodynamic responses with functional magnetic resonance imaging (fMRI). ", "In a selective attention task, subjects responded to targets at the global or local level of compound letters that were (1) broadband in spatial-frequency spectrum and presented at fixation; (2) broadband and presented randomly to the left or the right of fixation; or (3) contrast balanced (CB) to remove low spatial frequencies (SFs) and presented at fixation. ", "Central broadband stimuli induced stronger activation in the right middle occipital cortex under global relative to local attention conditions but in the left inferior occipital cortex, stronger activation was induced under local relative to global attention conditions. ", "The asymmetry over the occipital cortex was weakened by unilateral presentation and by contrast balancing. ", "The results indicate that the lateralization of global and local processing is modulated by the position and SF spectrum of the compound stimuli. ", "The global attention also produced stronger activation over the medial occipital cortex relative to the local attention under all the stimulus conditions. ", "The nature of these effects is discussed." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Q:\n\nSum a list of numbers until a number X is found\n\nIn my program I need to put a while function which sums this list until a particular number is found:\n[5,8,1,999,7,5]\n\nThe output is supposed to be 14, because it sums 5+8+1 and stops when it finds 999.", "\nMy idea looks like:\ndef mentre(llista):\n while llista !", "= 999:\n solution = sum(llista)\nreturn solution\n\nA:\n\nAn example of explicitly using a while loop would be as follows:\ndef sum_until_found(lst, num):\n index = 0\n res = 0\n if num in lst:\n while index < lst.index(num):\n res += lst[index]\n index += 1\n else:\n return \"The number is not in the list!\"", "\n return res\n\nAnother possible way is:\ndef sum_until_found(lst, num):\n index = 0\n res = 0\n found = False\n if num in lst:\n while not found:\n res += lst[index]\n index += 1\n if lst[index] == num:\n found = True\n else:\n return \"The number is not in the list!\"", "\n return res\n\nThere's many ways of doing this without using a while loop, one of which is using recursion:\ndef sum_until_found_3(lst, num, res=0):\n if num in lst:\n if lst[0] == num:\n return res\n else:\n return sum_until_found_3(lst[1:], num, res + lst[0])\n else:\n return \"The number is not in the list!\"", "\n\nFinally, an even simpler solution:\ndef sum_until_found(lst, num):\n if num in lst:\n return sum(lst[:lst.index(num)])\n else:\n return \"The number is not in the list!\"", "\n\n" ]

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[ "The epithelial layer in the gastrointestinal (GI) tract represents a fundamental line of defense against potential enteric pathogens. ", "Paneth cells contribute to this defense by producing antimicrobial molecules and by providing an epithelial niche for Lgr5^+^ ISCs that maintain the epithelium^2^. ISCs are critical for damage-induced intestinal regeneration^[@R5]^, but the mechanisms regulating ISC function and inducing epithelial regeneration after tissue damage remain poorly understood. ", "Furthermore, although epithelial barrier function is a core component of intestinal immunity, little is known about the role of the immune system in regulating the ISC compartment. ", "Group 3 ILCs (ILC3s) are critical for maintaining GI epithelial integrity and barrier function in multiple experimental models of intestinal injury^[@R3]^. Tissue-resident ILC3s are potent producers of IL-22 after damage, and expression of IL-22 is associated with reduced injury in colitis as well as several non-intestinal tissue damage models^[@R3],[@R4],[@R6]-[@R9]^. However, while the IL-22 receptor (IL-22R) is present in many epithelial tissues, the specific cellular targets and mechanisms of IL-22 inducing tissue recovery are largely unknown. ", "Utilizing an organoid model of *ex vivo* epithelial regeneration^[@R10]^, we examined if ILCs and IL-22 could regulate the ISC compartment.", "\n\nWe first sorted murine SI lamina propria lymphocytes (LPLs), which include both innate and adaptive lymphoid cells capable of producing IL-22^[@R4]^, and cultured them with freshly isolated murine SI crypts in standard organoid media containing EGF, Noggin, and R-spondin-1 (ENR). ", "An IL-23-based cytokine cocktail was included for IL-22 induction. ", "Two-dimensional perimeter tracing ([Extended data Fig. ", "1a](#F5){ref-type=\"fig\"}) indicated that co-culture with wild-type (WT) LPLs significantly increased organoid size ([Fig. ", "1a](#F1){ref-type=\"fig\"}). ", "In contrast, LPLs isolated from IL-22-deficient (*Il22^−/−^*) mice failed to augment organoid size ([Fig. ", "1a](#F1){ref-type=\"fig\"}). ", "To specifically evaluate the role of ILC3s in organoid growth, SI lamina propria CD45^+^CD3^−^RORγt^+^ ILC3s were isolated from RORγt-GFP reporter mice and cultured with SI crypts. ", "ILC3s significantly increased SI organoid size, and this was inhibited by an anti-IL-22 neutralizing antibody ([Fig. ", "1b](#F1){ref-type=\"fig\"}).", "\n\nGiven that IL-22 was essential for ILC-mediated augmentation of organoid size, we focused on studies with recombinant murine (rm)IL-22. ", "SI crypts cultured with rmIL-22 yielded substantially larger organoids in a concentration-dependent fashion ([Fig. ", "1c-d](#F1){ref-type=\"fig\"} and [Extended Data Fig.1b](#F5){ref-type=\"fig\"}). ", "While high concentrations of IL-22 reduced the efficiency of organoid generation from SI crypts, culture with 1-5 ng/ml rmIL-22 increased organoid size without affecting organoid formation ([Extended Data Fig. ", "1c](#F5){ref-type=\"fig\"}). ", "IL-22 also increased large intestine (LI) organoid size without affecting efficiency ([Fig. ", "1e](#F1){ref-type=\"fig\"} and [Extended Data Fig.1d](#F5){ref-type=\"fig\"}), and culture with IL-22 augmented crypt budding in both SI and LI organoids ([Fig. ", "1f](#F1){ref-type=\"fig\"}). ", "Furthermore, recombinant human (rh)IL-22 significantly increased the size of human intestinal organoids generated from primary duodenal tissue ([Fig. ", "1g](#F1){ref-type=\"fig\"} and [Extended Data Fig. ", "1e](#F5){ref-type=\"fig\"}).", "\n\nWnt/β-catenin signaling is essential for ISC maintenance and organoid function *ex vivo*^[@R10]^. However, we found no evidence of enhanced production of molecules in the Wnt/β-catenin pathway within SI organoids cultured with IL-22, including no difference in expression of Wnt3, β-catenin, or the downstream target Axin2 ([Extended Data Fig. ", "1f](#F5){ref-type=\"fig\"}). ", "Consistent with this, IL-22 could not replace R-spondin-1, an agonist of Wnt/β-catenin signaling, as its removal eliminated SI organoid growth even in the presence of IL-22 ([Extended Data Fig. ", "1g](#F5){ref-type=\"fig\"}). ", "Additionally, we found no IL-22-induced activation of gene expression in the Notch pathway, which is also critical for ISC maintenance, or for Slit2 or Robo1, although they can regulate ISC recovery from damage induced by chemotherapy and radiation^[@R11]^ ([Extended Data Fig. ", "1h](#F5){ref-type=\"fig\"}). ", "Consistently, there was also no increase in Wnt or Notch pathway gene expression in LI organoids ([Extended Data Fig. ", "1i](#F5){ref-type=\"fig\"}). ", "However, culture with IL-22 increased SI organoid mRNA for Reg3β and Reg3γ ([Extended Data Fig. ", "1j](#F5){ref-type=\"fig\"}), innate antimicrobial molecules whose expression is dependent on Stat3 signaling^[@R12]^.\n\nLittle is known about JAK/Stat signaling within ISCs, although it has been reported that Stat3 may be important for ISC maintenance^[@R13]^. We evaluated Stat3 signaling in SI organoids and found that IL-22 increased phosphorylation of Stat3 Y705 ([Extended Data Fig. ", "2a](#F6){ref-type=\"fig\"}). ", "Furthermore, treatment with the Stat3 inhibitor Stattic significantly impaired growth of SI organoids ([Fig 2a](#F2){ref-type=\"fig\"} and [Extended Data Fig. ", "2b](#F6){ref-type=\"fig\"}). ", "However, IL-22 can also promote epithelial Stat1 signaling^[@R14]^, which Stattic has inhibitory activity against^[@R15]^. Indeed, organoid Stat3 and Stat1 were both phosphorylated in response to IL-22 and inhibited by Stattic ([Fig. ", "2b](#F2){ref-type=\"fig\"}). ", "To determine their relative importance for IL-22-induced epithelial regeneration, we assessed the growth of organoids with genetic deletion of either *Stat1* or *Stat3*. ", "Despite the induction of phospho-(p)Stat1 by IL-22, SI crypts from *Stat1^−/−^* mice demonstrated intact organoid growth and response to IL-22 ([Fig. ", "2c](#F2){ref-type=\"fig\"} and [Extended Data Fig. ", "2c](#F6){ref-type=\"fig\"}). ", "As *Stat3^−/−^* mice are not viable, we next cultured SI crypt cells from *Stat3^fl/fl^* mice with adenoviral-Cre (adeno-Cre) to delete Stat3. ", "Crypt cells from WT mice demonstrated intact organoid growth and IL-22 response despite *in vitro* infection with adeno-Cre ([Fig. ", "2d](#F2){ref-type=\"fig\"}). ", "Additionally, uninfected *Stat3^fl/fl^* crypt cells demonstrated normal organoid growth and response to IL-22 ([Extended Data Fig. ", "2d-e](#F6){ref-type=\"fig\"}). ", "However, crypt cells from *Stat3^fl/fl^* mice failed to generate organoids after infection with adeno-Cre, and IL-22 failed to recover organoid growth or augment organoid size ([Fig. ", "2d](#F2){ref-type=\"fig\"}).", "\n\nLgr5^+^ ISCs can generate all cell types of mature intestinal epithelium *ex vivo* and *in vivo*^[@R1],[@R10]^. To evaluate if Stat3 was important for ISCs during tissue damage *in vivo*, we performed a gene set enrichment analysis (GSEA), assessing expression of a published Lgr5^+^ ISC gene signature (GEO dataset GSE33948)^[@R16]^ in another dataset of WT (*Stat3^fl/fl^*) vs. epithelial Stat3-deficient (*Stat3^fl/fl^;Villin-Cre*) mice with DSS colitis (GSE15955)^[@R12]^. Expression of the Lgr5^+^ ISC gene signature was significantly reduced in Stat3-deficient mice with colitis ([Fig. ", "2e](#F2){ref-type=\"fig\"}). ", "This was validated with a second independently established Lgr5^+^ ISC gene signature (GEO dataset GSE23672)^[@R16]^, while no significant changes were seen in a negative control Paneth cell gene signature (GEO dataset GSE39915)^[@R17]^ ([Extended Data Fig. ", "2f-g](#F6){ref-type=\"fig\"}). ", "Given the induction of pStat3 by IL-22 and the importance of Stat3 for ISC gene signature maintenance, we examined the effect of IL-22 during regeneration using purified ISCs. ", "We isolated Lgr5-GFP SI ISCs by fluorescence-activated cell sorting (FACS) and cultured single ISCs under standard conditions^[@R10]^ +/− IL-22. ", "IL-22 significantly increased budding of early organoids after just four days ([Fig. ", "2f](#F2){ref-type=\"fig\"}). ", "Furthermore, as with crypt-derived organoids, 1 ng/ml rmIL-22 augmented the size of organoids generated from purified ISCs without affecting the efficiency of organoid formation ([Fig. ", "2g](#F2){ref-type=\"fig\"} and [Extended Data Fig. ", "3a-b](#F7){ref-type=\"fig\"}).", "\n\nConsistent with increased size, IL-22 enhanced EdU incorporation in SI organoids, demonstrating increased proliferation ([Extended Data Fig. ", "4a-b](#F8){ref-type=\"fig\"}). ", "Hoechst staining revealed an IL-22-dependent increase in G2/M populations after two days in culture ([Fig. ", "2h](#F2){ref-type=\"fig\"}), and IL-22 treatment rapidly reduced key cell cycle checkpoint molecules Cdkn1a and Cdkn2d in both SI and LI organoids ([Extended Data Fig. ", "4c-d](#F8){ref-type=\"fig\"}). ", "Furthermore, IL-22 expanded Lgr5-GFP^high^ ISCs in SI organoids ([Fig. ", "2i](#F2){ref-type=\"fig\"}) and increased expansion of SI organoids over multiple passages in culture ([Fig. ", "2j](#F2){ref-type=\"fig\"}). ", "Next we evaluated the ISC compartment after radiation injury. ", "Pre-treatment with rmIL-22 increased the percentage of dissociated SI crypt cells that were viable in culture following *ex vivo* irradiation, as measured by MTT reduction ([Extended Data Fig. ", "5a](#F9){ref-type=\"fig\"}). ", "Consistent with this, IL-22 treatment increased the number of organoids that could grow from single cells two days after irradiation ([Extended Data Fig. ", "5b](#F9){ref-type=\"fig\"}). ", "This was more evident with increasing doses of irradiation, and protection was present even seven days after irradiation ([Extended Data Fig. ", "5c](#F9){ref-type=\"fig\"}). ", "Accordingly, irradiation was found to increase expression of IL-22R mRNA within intestinal crypts ([Extended Data Fig. ", "5d](#F9){ref-type=\"fig\"}).", "\n\nWe next evaluated the effect of IL-22 *in vivo* after tissue damage utilizing a clinically relevant murine GVHD model. ", "T cell-depleted (TCD) LP marrow was transplanted +/− purified LP T cells into lethally irradiated C57BL/6 (B6) recipients (H-2^b^**→**H-2^b^). ", "Mice receiving allogeneic T cells for GVHD induction were treated with 4μg rmIL-22 or PBS daily via intraperitoneal (IP) injection starting seven days post-BMT. ", "Treatment with IL-22 reduced histopathologic evidence of GVHD in SI and LI ([Fig. ", "3a](#F3){ref-type=\"fig\"}), including a reduction in apoptosis within crypt epithelium ([Extended Data Fig. ", "6a-b](#F10){ref-type=\"fig\"}). ", "GVHD pathology was reduced despite an intact alloimmune response, as evidenced by similar T cell subset distribution, activation markers, and gut homing molecules, as well as similar systemic and GI expression of inflammatory cytokines ([Extended Data Fig. ", "6c-d](#F10){ref-type=\"fig\"}). ", "However, IL-22 treatment did increase SI expression of Reg3β and Reg3γ mRNA ([Fig. ", "3b](#F3){ref-type=\"fig\"}). ", "Consistent with the findings of Eriguchi et al.^[@R18]^, we found that Reg3β was primarily expressed by enterocytes in allogeneic BMT recipients, including after treatment with IL-22 ([Extended Data Fig. ", "6e](#F10){ref-type=\"fig\"}).", "\n\nGVHD is associated with a loss of both ISCs^[@R19],[@R20]^ and niche-forming Paneth cells^[@R21],[@R22]^, and T cell-replete BMT led to a significant loss of Lgr5-LacZ^+^ SI ISCs three weeks post-transplant ([Fig. ", "3c](#F3){ref-type=\"fig\"}). ", "However, IL-22 treatment increased the recovery of Lgr5^+^ ISCs ([Fig. ", "3c](#F3){ref-type=\"fig\"}). ", "This was associated with increased regeneration as evidenced by increased crypt height, including the transit-amplifying (TA) compartment ([Fig. ", "3d](#F3){ref-type=\"fig\"}). ", "Paneth cells support Lgr5^+^ ISCs through delivery of Wnt, Notch ligand, and EGF signals^[@R2]^. Additionally, IL-22 is thought to regulate Paneth cell production of innate antimicrobial molecules. ", "We thus hypothesized that IL-22 could support ISC recovery post-BMT by improving the function of the stem cell niche. ", "Consistent with prior clinical and experimental studies^[@R21]-[@R23]^, minor antigen-mismatched BMT led to a reduction in Paneth cells three weeks post-transplant ([Fig. ", "3e](#F3){ref-type=\"fig\"}). ", "However, IL-22 administration did not increase recovery of Paneth cells ([Fig. ", "3e](#F3){ref-type=\"fig\"}), mRNA expression of Wnt3 or EGF ([Extended Data Fig. ", "6f-g](#F10){ref-type=\"fig\"}), or expression of Notch ligand target Hes1 ([Extended Data Fig. ", "6h](#F10){ref-type=\"fig\"}). ", "Furthermore, although stroma can support ISC Wnt signaling *in vivo* independent of Paneth cells^[@R24]^, we found no change in expression of stromal R-spondin-3 after IL-22 treatment post-BMT and no change in expression of Wnt pathway genes regardless of the upstream source. ([", "Extended Data Fig. ", "6i-k](#F10){ref-type=\"fig\"}).", "\n\nGiven that IL-22 treatment appeared to improve ISC numbers without improving niche function in BMT recipients, we sought to evaluate how IL-22 was targeting the ISC compartment. ", "Consistent with the *in vivo* findings, IL-22 had no effect on Paneth cell frequency or α-defensin-1 expression within SI organoids cultured *ex vivo* ([Extended Data Fig. ", "7a-b](#F11){ref-type=\"fig\"}). ", "Immunofluorescent staining for IL-22Rα1 and the Paneth cell marker lysozyme using SI sections from Lgr5-GFP reporter mice indicated substantial IL-22R staining within crypts and enterocytes at the villous base, but not on lysozyme^+^ Paneth cells ([Fig. ", "4a](#F4){ref-type=\"fig\"}). ", "Using flow cytometry, there was also little evidence for expression of IL-22R on Paneth cells at baseline or after radiation injury and no evidence of pStat3 in Paneth cells in response to IL-22 ([Extended Data Fig. ", "7c-e](#F11){ref-type=\"fig\"}). ", "In contrast, IL-22R was identified in the TA progenitor compartment and on Lgr5-GFP^+^ ISCs ([Fig. ", "4a](#F4){ref-type=\"fig\"}). ", "IL-22R expression in Lgr5^+^ cells was confirmed by qPCR after sorting for Lgr5-GFP^+^ cells ([Extended Data Fig. ", "8a-b](#F12){ref-type=\"fig\"}). ", "Furthermore, SI crypt cells from Lgr5-GFP reporter mice demonstrated increased Stat3 Y705 phosphorylation within GFP^+^ cells after incubation with IL-22, indicating functional IL-22R signaling in ISCs ([Fig. ", "4b-c](#F4){ref-type=\"fig\"}). ", "Stat3 phosphorylation was a specific response, as there was no effect of IL-22 on pStat1 in Lgr5^+^ cells ([Fig. ", "4c](#F4){ref-type=\"fig\"}).", "\n\nIL-22R expression and Stat3 phosphorylation suggested that IL-22 might promote regeneration via direct targeting of ISCs. ", "To further investigate the role of ISCs and Paneth cells in IL-22-mediated regeneration, we assessed organoid growth when either cell population was depleted. ", "Treatment of Lgr5-DTR mice with diphtheria toxin (DT) leads to a rapid deletion of Lgr5^+^ cells^[@R25]^. Deletion of Lgr5^+^ cells *ex vivo* by culturing Lgr5-DTR SI organoids with DT impaired epithelial regeneration as evidenced by a reduction in organoid size and efficiency ([Fig. ", "4d](#F4){ref-type=\"fig\"} and [Extended Data Fig. ", "9a](#F13){ref-type=\"fig\"}). ", "Although IL-22 increased the size of Lgr5-DTR organoids cultured without DT, IL-22 failed to increase the size or maintain the numbers of Lgr5-DTR organoids cultured with DT ([Fig. ", "4d](#F4){ref-type=\"fig\"} and [Extended Data Fig. ", "9a](#F13){ref-type=\"fig\"}), indicating that Lgr5^+^ cells are essential for IL-22-mediated epithelial regeneration.", "\n\nWe next investigated the functional importance of Paneth cells for IL-22-mediated regeneration by culturing organoids with IL-22 after inducible Paneth cell depletion. ", "Paneth cells were deleted *in vivo* following tamoxifen treatment of *Atoh1^fl/fl^;Villin-Cre^ERT2^* (*Atoh1^ΔIEC^*) mice^[@R26]^. IL-22 led to robust Stat3 phosphorylation within *Atoh1^ΔIEC^* SI organoids, confirming that Paneth cells were not essential for IL-22-mediated intracellular signaling, and *Atoh1^ΔIEC^* organoids demonstrated an intact growth response to IL-22 ([Fig. ", "4e-f](#F4){ref-type=\"fig\"} and [Extended Data Fig. ", "9b](#F13){ref-type=\"fig\"}). ", "Additionally, we found that IL-22 could augment the size of organoids cultured without EGF ([Extended Data Fig. ", "9c-d](#F13){ref-type=\"fig\"}). ", "These findings indicated that the Paneth cell niche was not required for IL-22-mediated epithelial regeneration, and IL-22 could promote the growth of organoids cultured without addition of the niche-derived growth factor EGF.", "\n\nRecent reports have suggested that T cell-derived IL-22 may contribute to GVHD, as might peritransplant administration of IL-22 to MHC-mismatched BMT recipients^[@R27],[@R28]^. However, IL-22-producing ILCs are eliminated in GVHD^[@R19]^, ILC deficiency is associated with increased clinical GVHD^[@R29]^, and GI damage may be central to the pathogenesis of systemic GVHD^[@R30]^. We thus hypothesized that stimulating regeneration with IL-22 after the initiation of GVHD-related tissue damage may be therapeutically beneficial. ", "Given the improved pharmacologic stability of Fc-fusion molecules, we evaluated the potential of F-652, a recombinant human (rh)IL-22-dimer/Fc-fusion protein, for treatment of systemic GVHD. ", "First, we found that F-652 had activity in murine epithelial regeneration, augmenting the growth of both SI and LI organoids without evidence of toxicity ([Extended Data Fig. ", "10a-d](#F14){ref-type=\"fig\"}). ", "Additionally, treatment of Lgr5-LacZ reporter mice with F-652 significantly protected SI Lgr5^+^ crypt cells from radiation injury *in vivo* ([Extended Data Fig. ", "10e-f](#F14){ref-type=\"fig\"}). ", "We next investigated an early intervention model for GVHD, treating allogeneic BMT recipients (LP**→**B6) with F-652 starting one week after transplant. ", "Mice treated with F-652 demonstrated reduced systemic signs of GVHD and GVHD-related mortality compared to PBS-treated controls ([Fig. ", "4g-h](#F4){ref-type=\"fig\"}).", "\n\nIn summary, we found that IL-22 links immunity to epithelial regeneration by acting directly on ISCs. ", "Purified ILCs enhanced organoid growth in an IL-22-dependent fashion, and IL-22 augmented ISC-mediated epithelial regeneration, promoting cell cycle progression, epithelial proliferation, and regeneration of the ISC pool. ", "IL-22 induced Stat3 phosphorylation in Lgr5^+^ ISCs, and while IL-22 may not be its sole regulator in ISCs, Stat3 was essential for organoid growth and IL-22-dependent epithelial regeneration. ", "Paneth cells, in contrast, were not required for IL-22-driven regeneration. ", "Given the activation of IL-22 production and the upregulation of crypt IL-22R expression after tissue damage, these findings indicate that IL-22 contributes to damage-induced regulation of the ISC compartment. ", "We conclude that in addition to the stromal and epithelial components of the ISC niche that are essential for normal epithelial maintenance, IL-22 provides evidence for an immunologic contribution to the ISC niche that is activated to restore the epithelium after tissue injury. ", "By acting directly on epithelial stem cells, the immune system is thus able to regulate intestinal regeneration and support the fundamental defense system provided by the structural integrity of the epithelial barrier.", "\n\nMethods {#S1}\n=======\n\nMice {#S2}\n----\n\nC57BL/6 (B6, H-2^b^) and LP (H-2^b^) mice were obtained from Jackson Laboratory (Bar Harbor, USA). ", "B6 Lgr5-LacZ and B6 lgr5-gfp-ires-CreERT2 (Lgr5-GFP) mice were kindly provided by H. Clevers^[@R1],[@R10]^. Mouse maintenance and procedures were done in accordance with the institutional protocol guideline of the Memorial Sloan Kettering Cancer Center (MSKCC) Institutional Animal Care and Use Committee. ", "Mice were housed in micro-isolator cages, five per cage, in MSKCC pathogen-free facilities and received standard chow and autoclaved sterile drinking water. ", "To adjust for differences in weight and intestinal flora among other factors, identical mice were purchased from Jackson and then randomly distributed over different cages and groups by a non-biased technician who had no insight or information about the purpose or details of the experiment. ", "The investigations assessing clinical outcome parameters were performed by non-biased technicians with no particular knowledge or information regarding the hypotheses of the experiments and no knowledge of the specifics of the individual groups.", "\n\nCrypt isolation and cell dissociation {#S3}\n-------------------------------------\n\nIsolation of intestinal crypts and the dissociation of cells for flow cytometry analysis were largely preformed as previously described^[@R10]^. Briefly, after euthanizing the mice with CO~2~ and harvesting small and large intestines, the organs were opened longitudinally and washed with PBS. ", "To dissociate the crypts, small intestine was incubated at 4°C in EDTA (10 mM) for 15 minutes and then in EDTA (5mM) for an additional 15 minutes. ", "Large intestine was incubated in Collagenase Type 4 (Worthington) for 30 minutes at 37°C to isolate the crypts. ", "To isolate single cells from small and large intestine crypts, the pellet was further incubated in 1x TrypLE express (Gibco, Life technologies) supplemented with 0.8KU/ml DNase1 (Roche).", "\n\nOrganoid culture {#S4}\n----------------\n\nFor mouse organoids, depending on the experiments, 200-400 crypts per well were suspended in Matrigel composed of 25% Advanced DMEM/F12 medium (Gibco) and 75% growth factor-reduced Matrigel (Corning). ", "After the Matrigel polymerized, complete EGF/Noggin/R-spondin-1 (ENR)-medium containing advanced DMEM/F12 (Sigma), 2mM Glutamax (Invitrogen), 10 mM HEPES (Sigma), 100 U/ml penicillin/100 μg/ml streptomycin (Sigma), 1 mM N-acetyl cysteine (Sigma), B27 supplement (Invitrogen), N2 supplement (Invitrogen), 50 ng/ml mEGF (Peprotech), 100 ng/ml mNoggin (Peprotech) and 10% human R-spondin-1 conditioned medium from R-spondin-1-transfected HEK 293T cells^[@R31]^ was added to small intestine crypt cultures^[@R10]^. For experiments evaluating organoid budding, the concentration of R-spondin was lowered to 1.25-5%. ", "For mouse large intestine, crypts were cultured in \"WENR\" medium containing 50% of Wnt3a-conditioned medium in addition to the aforementioned proteins and 1% BSA (Sigma) and supplemented with SB202190 (10uM, Sigma), ALK5 inhibitor A83-01(500nM, Tocris Bioscience) and Nicotinamide (10mM, Sigma). ", "Media was replaced every 2-3 days. ", "Along with medium changes, treatment wells received different concentrations of recombinant murine (rm)IL-22 (Genscript). ", "We also tested the effects of F-652, a recombinant human IL-22 dimer/Fc fusion molecule provided by Generon Corporation (Shanghai) Ltd, China. ", "In some experiments, organoids from crypts were cultured in the presence of Stattic (Tocris Bioscience). ", "For passaging of organoids, after 5-7 days of culture, organoids were passaged by mechanically disrupting with a seropipet and cold media to depolymerize the Matrigel and generate organoid fragments. ", "After washing away the old Matrigel by spinning down at 600 rpm, organoid fragments were replated in liquid Matrigel.", "\n\nIntestinal stem cells (ISCs) were isolated from Lgr5-GFP mice using a modified crypt isolation protocol with 20 minutes of 30 mM EDTA^[@R32],[@R33]^ followed by several strainer steps and a 5 minunte incubation with TrypLE and 0.8 KU/ml DNase1 under minute-to-minute vortexing to make a single cells suspension. ", "The Lgr5-GFP^high^ cells were isolated by fluorescence-activated cell sorting (FACS). ", "5000 ISCs were plated in 30uL Matrigel and cultured in WENR media containing Rho-kinase/ROCK inhibitor Y-27632 (10uM, Tocris Bioscience) and Jagged1 (1 μM, Anaspec). ", "Starting from day 4 ISC were cultured without Wnt.", "\n\nFor lymphocyte co-culture experiments, intestinal lymphoid cells were isolated from the small intestine lamina propria. ", "Washed small intestine fragments were incubated in EDTA/IEL solution \\[1xPBS with 5% FBS, 10mM Hepes Buffer, 1% Pen/strep (Corning), 1% L-glutamine (Gibco), 1mM EDTA and 1 mM DTT\\] in a 37°C shaker for 15 minutes. ", "The samples were strained (100uM) and put in a Collagenase solution \\[RPMI 1640, 5%FCS, 10mM Hepes, 1% PS, 1% Glutamine and 1 mg/ml Collagenase D (Roche) and 1u/ml DNAse 1 (Roche)\\] and incubated twice for 10 minutes in a 37 °C shaker. ", "Afterwards, the samples were centrifuged at 1500 rpm for 5 minutes and washed with RPMI solution without enzymes. ", "After several washes, the cell suspension was transferred into a 40% Percoll solution (Percoll in PBS), which is overlaid on an 80% Percoll solution. ", "After spinning the interface containing the lamina propria mononuclear cells was aspirated and washed in medium. ", "Then the cell suspension was stained with extracellular markers and Topro3 for viability. ", "Topro3^−^CD45^+^CD11b^−^CD11c^−^CD90^+^ lamina propria lymphocytes (LPLs) from B6 WT and *IL-22^−/−^* mice and Topro3^−^CD45^+^CD3^−^RORγt^+^ group 3 innate lymphoid cells (ILCs)^[@R34]^ from Rorc(γt)^+^ GFP mice (Jackson) were sorted for co-cultures with SI crypts. (", "For antibodies used, see [Supplementary Table 1](#SD2){ref-type=\"supplementary-material\"}.) ", "To activate and maintain LPLs and ILCs in culture, rmIL-2 (1000u/ml), rmIL-15 (10 ng/ml), rmIL-7 (50 ng/ml), and rmIL-23 (50 ng/ml) were added to the ENR medium in co-culture experiments. ", "We have also performed co-cultures with addition of only rmIL-23 (50 ng/ml) to ENR media. ", "LPLs and SI crypts were cultured in Matrigel with a 7:1 LPL:crypt ratio; ILCs and crypts were cultured in Matrigel with a 25:1 ILC:crypt ratio. ", "Co-cultures were compared to crypts cultured in ENR + cytokines without LPLs/ILCs present. ", "A neutralizing monoclonal antibody against IL-22 (8E11, Genentech)^[@R35]^ was used to abrogate IL-22-specific effects of ILCs.", "\n\nFor specific experiments, organoids were cultured from fresh crypts obtained from specific genetically modified mice, such as the *Stat1^−/−^* mice (129S6/SvEv-Stat1tm1Rds, Taconic) and *Stat3^fl/fl^* mice (Jackson). ", "Organoids from *Stat3^fl/fl^* mice that had been grown for 7 days were dissociated as single cells and incubated with Adenoviral-Cre (University of Iowa) to cause the deletion of *Stat3* from floxed organoid cells. ", "Frozen passaged organoids from *Lgr5^CreER^;Lgr5^DTR^* (Lgr5^GFP-DTR^)^[@R25]^ mice were used to culture organoids in which Lgr5^+^ stem cells could be depleted with daily administration of Diphtheria Toxin (DT, 1 ng/ul).", "\n\nFor Paneth cell-deficient organoid cultures, frozen crypts from *Atoh1^fl/fl^;Villin-Cre^ERT2^* mice^[@R36]^ depleted of Paneth cells were used to culture organoids. ", "As previously described^[@R36]^, *Atoh1^fl/fl^;Villin-Cre^ERT2^* mice (and littermate controls) were given an intraperitoneal (IP) injection of tamoxifen (1 mg/mouse, Sigma, dissolved in corn oil) for 5 consecutive days to achieve deletion of Atoh1 from intestinal epithelium. ", "Animals were sacrificed on day seven after the first injection and intestinal crypts were isolated and frozen in 10% DMSO and 90% FBS.", "\n\nTo investigate the effect of IL-22 on human small intestine, we generated human duodenal organoids from banked frozen organoids (\\>passage 7) that had been previously generated from biopsies obtained during duodenoscopy of three independent healthy human donors. ", "All human donors had been investigated for celiac disease, but turned out to have normal pathology. ", "All provided written informed consent to participate in this study according to a protocol reviewed and approved by the review board of the UMC Utrecht, the Netherlands (protocol STEM study, METC 10-402/K). ", "Human organoids were cultured in 10ul Matrigel drops in expansion medium containing WENR with 10nM SB202190, 500nM A83-01 and 10 mM Nicotinamide. ", "For IL-22 stimulation experiments, rhIL-22 10 ng/ml (Genscript) was added daily. ", "For the purpose of size measurements at D6, organoids were passaged as single cells.", "\n\nWhere applicable, organoid cultures were performed using conditioned media containing R-spondin-1 and Wnt3a produced by stably transfected cell lines. ", "R-spondin-1-transfected HEK293T cells^[@R31]^ were kindly provided by Calvin Kuo, Department of Medicine, Stanford University. ", "WNT3a-transfected HEK293T cells were kindly provided by Hans Clevers, Hubrecht Institute (patent WO2010090513A2). ", "Cell lines were tested for mycoplasma and confirmed to be negative.", "\n\nOrganoid measurement {#S5}\n--------------------\n\nFor size evaluation, the surface area of organoid horizontal cross sections was measured. ", "If all organoids in a well could not be measured, multiple random non-overlapping pictures were acquired from each well using a Zeiss Axio Observer Z1 inverted microscope and then analyzed using MetaMorph or ImageJ software. ", "Organoid perimeters for area measurements have been defined both manually and by automated determination using the Analyze Particle function of ImageJ software, with investigator verification of the automated determinations, as automated measurements allowed for unbiased analyses of increased numbers of organoids. ", "For automated size measurements, the threshold for organoid identification was set based on monochrome images. ", "The sizes of the largest and smallest organoids in the reference well were measured manually, and their area sizes were used as the reference values for setting the minimal and maximal particle sizes. ", "Organoids touching the edge of the images were excluded from the counting. ", "After five-to-seven days in culture, total organoid numbers per well were counted by light microscopy to evaluate growth efficiency. ", "All organoid numbers were counted manually in this fashion except for the organoid counts presented in Extended Data 5b, which were counted using automated ImageJ analysis, as these organoids were too numerous to count manually. ", "To compare organoid efficiency in different conditions, combining experiments with different organoid numbers, the percentage of organoids relative to the number of organoids in ENR-control (rmIL-22 0ng/ml) was calculated. ", "The efficiency from sorted ISCs was presented as the percentage of cells forming organoids per number of seeded cells.", "\n\nBone marrow transplantation (BMT) {#S6}\n---------------------------------\n\nBMT procedures were performed as previously described^[@R37]^. A minor histocompatibility antigen-mismatched BMT model (LP**→**B6, H-2^b^**→**H-2^b^) was utilized. ", "Female B6 WT mice were typically used as recipients for transplantation at an age of 8 to 10 weeks. ", "Recipient mice received 1100 cGy of split-dosed lethal irradiation (550 cGy x2) 3-4 hours apart to reduce gastrointestinal toxicity. ", "To obtain LP bone marrow cells from euthanized donor mice, the femurs and tibias were harvested aseptically and the bone marrow canals washed out with sterile media. ", "Bone marrow cells were depleted of T cells by incubation with anti-Thy 1.2 and low-TOX-M rabbit complement (Cedarlane Laboratories). ", "The T cell-depleted bone marrow (TCD BM) was analyzed for purity by quantification of the remaining T cell contamination using flow cytometry. ", "T cell contamination usually was about 0.2% of all leukocytes after a single round of complement depletion. ", "LP donor T cells were prepared by harvesting splenocytes aseptically from euthanized donor mice. ", "T cells were purified using positive selection with CD5 magnetic Microbeads with the MACS system (Miltenyi Biotec). ", "T cell purity was determined by flow cytometry and was routinely approximately 90%. ", "Recipients typically received 5×10^6^ TCD BM with or without 4 × 10^6^ T cells per mouse via tail vein injection.", "\n\nMice were monitored daily for survival and weekly for graft vs. host disease (GVHD) scores with an established clinical GVHD scoring system (including weight, posture, activity, fur ruffling, and skin integrity) as previously described^[@R38]^. A clinical GVHD index with a maximum possible score of ten was then generated. ", "Mice with a score of five or greater were considered moribund and euthanized by CO~2~ asphyxia.", "\n\n*In vivo* cytokine administration {#S7}\n---------------------------------\n\nRecombinant murine IL-22 was purchased from GenScript and reconstituted as described by the manufacturer to a concentration of 40μg/ml in phosphate-buffered saline (PBS). ", "Mice mere treated daily via IP injection with either 100μl PBS or with 100μl PBS containing 4μg rmIL-22. ", "IL-22 administration was started on day seven post-BMT. ", "This schedule was based on the results of rmIL-22 pharmacokinetics tested in untransplanted mice. ", "For *in vivo* F-652 administration, starting from day seven post-BMT, mice were injected subcutaneously every other day for ten consecutive weeks with PBS or 100μg/kg F-652.", "\n\nHistopathology analysis of GVHD target organs {#S8}\n---------------------------------------------\n\nMice were euthanized for organ analysis 21 days after BMT using CO~2~ asphyxiation. ", "For histopathologic analysis of GVHD, the small and large intestines were formalin-preserved, paraffin-embedded, sectioned, and stained with hematoxylin and eosin (H&E). ", "An expert in the field of GVHD pathology assessed the sections for markers of GVHD histopathology. ", "As described previously^[@R38]^, a semi-quantitative score consisting of 19 different parameters associated with GVHD was calculated.", "\n\nLacZ staining {#S9}\n-------------\n\nFor evaluation of stem cell numbers, small intestines from Lgr5-LacZ recipient mice that were transplanted with LP bone marrow (and T cells where applicable) were harvested. ", "β-galactosidase (LacZ) staining was preformed as previously described by Barker et al^[@R1]^. Washed 2.5 cm sized small intestine fragments were incubated with an ice-cold fixative, consisting of 1% formaldehyde, 0.2% NP40 and 0.2% gluteraldehyde. ", "After removing the fixative, organs were stained for the presence of LacZ according to manufacturer\\'s protocol (LacZ staining kit, Invivogen). ", "Then the organs were formalin-preserved, paraffin-embedded, sectioned, and counterstained with Nuclear Fast Red (Vector Labs).", "\n\nImmunohistochemistry (IHC) staining {#S10}\n-----------------------------------\n\nIHC detection of Reg3β was performed at the Molecular Cytology Core Facility of Memorial Sloan Kettering Cancer Center using a Discovery XT processor (Ventana Medical Systems). ", "Formalin-fixed tissue sections were deparaffinized with EZPrep buffer (Ventana Medical Systems), antigen retrieval was performed with CC1 buffer (Ventana Medical Systems) and sections were blocked for 30 minutes with Background Buster solution (Innovex). ", "Slides were incubated with anti-Reg3β antibodies (R&D Systems; cat\\# MAB5110; 1ug/ml) or isotype (5ug/ml) for six hours, followed by a 60 minute incubation with biotinylated goat anti-rat IgG (Vector labs, cat\\# PK-4004) at 1:200 dilution. ", "The detection was performed with DAB detection kit (Ventana Medical Systems) according to the manufacturer\\'s instructions. ", "Slides were counterstained with hematoxylin (Ventana Medical Systems) and coverslipped with Permount (Fisher Scientific). ", "Refer to [Supplementary Table 1](#SD2){ref-type=\"supplementary-material\"} for full description of antibodies used.", "\n\nImmunofluorescent (IF) staining and microscopic imaging {#S11}\n-------------------------------------------------------\n\nIF staining was performed at the Molecular Cytology Core Facility of Memorial Sloan Kettering Cancer Center using a Discovery XT processor (Ventana Medical Systems). ", "Formalin-fixed tissue sections were deparaffinized with EZPrep buffer (Ventana Medical Systems), antigen retrieval was performed with CC1 buffer (Ventana Medical Systems). ", "Sections were blocked for 30 minutes with Background Buster solution (Innovex) followed by avidin/biotin blocking for 12 minutes. ", "IL-22R antibodies (R&D Systems cat\\# MAB42, 0.1ug/ml) were applied and sections were incubated for five hours followed by 60 minutes incubation with biotinylated goat anti-rat IgG (Vector labs, cat\\# PK-4004) at 1:200 dilution. ", "The detection was performed with Streptavidin-HRP D (part of DABMap kit, Ventana Medical Systems), followed by incubation with Tyramide Alexa Fluor 488 (Invitrogen, cat\\# T20932) prepared according to manufacturer instruction with predetermined dilutions. ", "Next, Lysozyme antibodies (DAKO; cat\\# A099; 2ug/ml) were applied and sections were incubated for six hours followed by incubation with biotinylated goat anti-rabbit IgG (Vector labs, cat\\#PK6101) for 60 minutes. ", "The detection was performed with Streptavidin-HRP D (part of DABMap kit, Ventana Medical Systems), followed by incubation with Tyramide Alexa Fluor 594 (Invitrogen, cat\\# T20935) prepared according to manufacturer instruction with predetermined dilutions. ", "Finally, GFP antibodies were applied and sections were incubated for five hours followed by incubation with biotinylated goat anti-chicken IgG (Vector labs, cat\\# BA-9010) for 60 minutes. ", "The detection was performed with Streptavidin-HRP D (part of DABMap kit, Ventana Medical Systems), followed by incubation with Tyramide Alexa Fluor 647 (Invitrogen, cat\\# T20936) prepared according to manufacturer instruction with predetermined dilutions. ", "Slides were counterstained with DAPI (Sigma Aldrich, cat\\# D9542, 5 ug/ml) for 10 minutes and coverslipped with Mowiol. ", "For immunofluorescent and other microscopic imaging, including LacZ and IHC slides, contrast and white balance were set based on control slides for each experiment, and the same settings were used for all slides to maximize sharpness and contrast. ", "Refer to [Supplementary Table 1](#SD2){ref-type=\"supplementary-material\"} for full description of antibodies used.", "\n\nCytokine multiplex assay {#S12}\n------------------------\n\nSpleen and small intestine were harvested from euthanized BMT recipients, then organs were homogenized and spun down. ", "The supernatant was stored at −20°C until used for cytokine analysis. ", "The cytokine multiplex assays were performed on thawed samples with the mouse Th1/Th2/Th17/Th22 13plex (FlowCytomix Multiplex kit, eBioscience) and performed according to the manufacturer\\'s protocol.", "\n\nFlow cytometry {#S13}\n--------------\n\nFor *in vivo* experiments, lymphoid organs were harvested from euthanized mice and processed into single cell suspension. ", "Cells were stained with the appropriate mixture of antibodies. ", "For intracellular analysis, an eBioscience Fixation/Permeabilization kit was used per the manufacturer\\'s protocol. ", "After thorough washing, the cells were stained with intracellular and extracellular antibodies simultaneously. ", "Fluorochrome-labeled antibodies were purchased from BD Pharmingen (CD4, CD8, CD24, CD25, CD45, α4β7, and P-Stat3 Y705, P-Stat1 Y701), eBioscience (Foxp3), R&D (IL-22R), and Invitrogen (GFP). ", "DAPI and Fixable Live/Dead Cell Stain Kits (Invitrogen) were used for viability staining. ", "Paneth cells were identified based on bright CD24 staining and side scatter granularity as described by Sato et al^[@R2]^.\n\nFor flow cytometry of small intestine organoid cells, organoids were dissociated using TrypLE (37°C). ", "After vigorously pipetting through a p200 pipette causing mechanical disruption, the crypt suspension was washed with 10ml of DMEM/F12 medium containing 10% FBS and 0.8 KU/ml DNase1 and passaged through a cell strainer. ", "Where applicable, the cells were directly stained or first fixed (PFA4%) and permeabilized (methanol) depending on the extracellular or intracellular location of the target protein. ", "All stainings with live cells were performed in PBS without Mg^2+^ and Ca^2+^ with 0.5% BSA. ", "For 5-ethynyl-2'-deoxyuridine (EdU) incorporation experiments there was a 1 hour pre-incubation of EdU in the ENR medium of the intact organoid cultures before dissociating the cells with TrypLE. ", "Cells were stained using Click-it kits for imaging and flow cytometry (Life Technologies). ", "For cell cycle analysis, single cell suspensions obtained from dissociated organoids were fixed and stained with Hoechst 33342 (Life Technologies), then assessed with flow cytometry for DNA content and ploidy.", "\n\nFor intracellular phospho-Stat staining of organoids, organoids were mechanically disrupted into crypt fragments, stimulated for 20 minutes with 20 ng/ml IL-22 at 37°C, and then fixed with PFA4% (10 minutes at 37°C). ", "To assess Stat activation in Lgr5^+^ cells, after freshly isolating crypts from Lgr5GFP mice, single cell suspensions including Y-27632 (10uM) were stimulated with IL-22. ", "After obtaining a single cell suspension of stimulated and fixed cells, the samples were filtered (40uM) and permeabilized with ice-cold (−20°C) methanol. ", "Fixed and permeabilized cells were rehydrated with PBS and thoroughly washed with PBS before staining, then stained with anti-phospho-Stat3 and anti-phospho-Stat1, plus anti-GFP or cell surface markers, for 30 minutes at 4°C.", "\n\nAll flow cytometry was performed with an LSRII cytometer (BD Biosciences) using FACSDiva (BD Biosciences), and the data were analyzed with FlowJo software (Treestar). ", "Refer to [Supplementary Table 1](#SD2){ref-type=\"supplementary-material\"} for full description of antibodies used.", "\n\nImmunoblotting analysis {#S14}\n-----------------------\n\nWestern blot analysis was carried out on total protein extracts. ", "Free-floating crypts isolated from small intestine were treated in DMEM supplemented with Y-27632 ([10 ng/ml,]{.ul} Tocris) and IL-22 (5ng/ml, 30 minutes). ", "Vehicle (PBS) was added to control (CTRL) wells. ", "Crypts were then lysed in RIPA buffer containing a cocktail of protease and phosphatase inhibitors (Sigma). ", "After sonication, protein amount was determined using the bicinchoninic acid assay Kit (Pierce). ", "Loading 30 μg/lane of lysate, proteins were separated using electrophoresis in a 10% polyacrylamide gel and transferred to nitrocellulose. ", "Membranes were blocked for one hour at room temperature with 1% Blot-Qualified BSA (Promega, W384A) and 1% non-fat milk (LabScientific, M0841) and then incubated overnight at 4°c with the following primary antibodies: rabbit anti-phospho-Stat1 (7649P), rabbit anti-phospho-Stat3 (9131S), rabbit anti-Stat1 (9172P), and rabbit anti-Stat3 (4904P), all from Cell Signaling. ", "This was followed by incubation with the secondary antibody anti-rabbit HRP (7074P2) and visualization with the Pierce™ ECL Western Blotting Substrate (Thermo Scientific, 32106).", "\n\nMTT assay {#S15}\n---------\n\nCell viability in organoids was assessed with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) test, based on the identification of metabolically active cells. ", "The organoids were incubated with MTT (0.9 mg/ml final concentration, Sigma) for 2 hours at 37°C. ", "Matrigel and cells containing intracellular reduction end product formazan were solubilized with acidic isopropanol (isopropanol with HCl) and the reduction end formazan production was evaluated by spectrophotometry using the Infinite M1000 pro plate reader (Tecan).", "\n\nRT qPCR {#S16}\n-------\n\nFor quantitative (q)PCR, segments of small intestine or isolated crypts were harvested from euthanized mice and stored at −80°C. ", "Alternatively, RNA was isolated from organoids after *in vitro* culture. ", "Extracted RNA was also stored at −80°C. ", "RT-PCR was performed with a QuantiTect Reverse Transcription Kit (QIAGEN) or a High-Capacity RNA-to-cDNA Kit (Applied Biosystems). ", "qPCR was performed on a Step-One Plus or QuantStudio^®^ 7 Flex System (Applied Biosystems) using TaqMan Universal PCR Master Mix (Applied Biosystems). ", "Specific primers were obtained from Applied Biosystems: β-actin: Mm01205647_g1; Hprt: Mm00446968_m1; Reg3β: Mm00440616_g1; Reg3γ: Mm00441127_m1; WNT3: Mm00437336_m1 and EGF: Mm00438696_m1; Rspo3: Mm00661105_m1; Axin2: Mm00443610_m1; β-catenin: Mm00483039_m1. ", "DEFA1: Mm02524428_g1, IL-22Ra1: Mm01192943_m1. ", "Other primers were obtained from PrimerBank: Gapdh (ID 6679937a1), Cdnk1a/ P21 (ID 6671726a1); Cdnk2d/P19 (ID 31981844a1); WNT3a (ID 7106447a1); Axin2 (ID 31982733a1); Hes1 (ID 6680205a1) Dll4 (ID 9506547a1) Dll1 (ID 6681197a1), for which cDNAs were amplified with SYBR master mix (Applied Biosystems) in QuantStudio^®^ 7 Flex System (Applied Biosystems). ", "Relative amounts of mRNA were calculated by the comparative ΔC(t) method with β-Actin, Hprt or Gapdh as house keeping genes.", "\n\nFor *Il22Ra1* qPCR on Lgr5^+^ cells, dissociated crypt cells from Lgr5-GFP mice were stained and isolated using the following monoclonal antibodies/parameters: EpCAM-1 (G8.8; BD Bioscience); CD45 (30F11; Life Technologies); CD31 (390; BioLegend), Ter119 (Ter119; BioLegend); GFP expression; dead cells were excluded using 7AAD. ", "Cells were acquired on a BD ARIAIII and FACS-sorted. ", "Cells were sorted directly into RA-1/TCEP (Macherey-Nagel) lysis buffer and stored at −80°C until further analysis. ", "RNA of hematopoietic cells (composite of DC, ILC and B-cells) was used as negative control. ", "RNA was extracted using the NucleoSpin RNA XS kit (Machery Nagel) and cDNA was prepared with Ovation® Pico and PicoSL WTA Systems V2 (NuGen). ", "For quantitative PCR, a Neviti Thermal Cycler (Applied Biosystems) and DyNAmo Flash SYBR Green qPCR kit (Finnzymes) were used, with the addition of MgCl2 to a final concentration of 4 mM. All reactions were done in duplicate and normalized to *Gapdh*. ", "Relative expression was calculated by the cycling threshold (CT) method as 2-ΔCT. ", "The primer sequences were as follows: *Il22ra1* forward TCGGCTTGCTCTGTTATC; *il22ra1* reverse CCACTGAGGTCCAAGACA.", "\n\nGene set enrichment analysis (GSEA) {#S17}\n-----------------------------------\n\nTo explore the association of ISC gene signatures (GSE33948 and GSE23672)^[@R16]^ with Stat3-regulated genes, we performed GSEA in a Stat3ΔIEC murine DSS colitis dataset (GSE15955)^[@R12]^, comparing *Stat3^fl/fl^;Villin-Cre^−^* (WT) vs. *Stat3^fl/fl^;Villin-Cre^+^* (*Stat3^ΔIEC^*) mice with DSS colitis (GSEA2-2.2.0; <http://www.broadinstitute.org/gsea>)^[@R39],[@R40]^. A Paneth cell signature gene set was used as a negative control (DLL1^+^CD24^hi^, GSE39915)^[@R17]^. Nominal P-values are shown.", "\n\nStatistics and software {#S18}\n-----------------------\n\nTo detect an effect size of \\> 50% difference in means, with an assumed coefficient of variation of 30%, common in biological systems, we attempted to have at least five samples per group, particularly for *in vivo* studies. ", "All experiments were repeated at least once. ", "No mice were excluded from experiments. ", "Experiments that were technical failures, such as experiments *in vitro* where cultures did not grow or experiments *in vivo* where transplanted control mice (BM + T cells) did not develop GVHD, were not included for analysis. ", "Occasional individual mice that died post-transplant prior to analysis could not be included for tissue evaluation.", "\n\nAll bars and error bars represent the means + standard error of the mean (SEM) for the various groups. ", "Statistics are based on \"n\" biologic replicates. ", "All tests performed are two sided. ", "For the comparisons of two groups, a t-test or nonparametric test was performed. ", "Adjustments for multiple comparisons were made. ", "In most cases, non-parametric testing was performed if normal distribution could not be assumed. ", "RT qPCRs and ordinal outcome variables were tested non-parametrically. ", "All analyses of statistical significance were calculated and displayed vs. the reference control group unless otherwise stated.", "\n\nThere is large biologic variation in organoid size. ", "Statistical analyses of organoid sizes were thus based on all evaluable organoids (at least 25 organoids/group for all experiments). ", "Statistical analyses of organoid numbers/efficiency were based on individual wells. ", "To take into account intra-individual and intra-experimental variation as well, all *in vitro* experiments were performed at least twice with multiple wells per condition and sample material coming from at least two different mice. ", "Statistical analyses of stem cell numbers (Lgr5-LacZ mice) *in vivo* were performed on multiple independent sections from multiple mice. ", "Statistics were calculated and display graphs were generated using Graphpad Prism.", "\n\nExtended Data {#S19}\n=============\n\n{#F5}\n\n{#F6}\n\n{#F7}\n\n{#F8}\n\n{#F9}\n\n{#F10}\n\n{#F11}\n\n{#F12}\n\n{#F13}\n\n{#F14}\n\nSupplementary Material {#SM}\n======================\n\nWe gratefully acknowledge the technical assistance of the MSKCC Research Animal Resource Center and Molecular Cytology Core Facility. ", "We also thank Hans Clevers, Henner Farin, Sabine Middendorp, Caroline Wiegerinck, Johan van Es, Marc van de Wetering, Nobuo Sasaki, Joe Sun, and Ming Li for their advice and critical evaluation of our work. ", "This research was supported by National Institutes of Health award numbers K08-HL115355 (A.M.H.), R01-HL125571 (A.M.H.), R01-HL069929 (M.R.M.vdB.), R01-AI100288 (M.R.M.vdB.), R01-AI080455 (M.R.M.vdB.), R01-AI101406 (M.R.M.vdB.), P01-CA023766/Project 4 (Richard J. O\\'Reilly/M.R.M.vdB.), K99-CA176376 (J.A.D.), and P30-CA008748 (MSKCC Core Grant). ", "Support was also received from the U.S National Institute of Allergy and Infectious Diseases (NIAID Contract HHSN272200900059C), the European Union (award GC220918, C. Blackburn), The Experimental Therapeutics Center of MSKCC funded by Mr. William H. Goodwin and Mrs. Alice Goodwin, The Lymphoma Foundation, Alex\\'s Lemonade Stand, The Geoffrey Beene Cancer Research Center at MSKCC, The Susan and Peter Solomon Divisional Genomics Program, MSKCC Cycle for Survival, and The Lucille Castori Center for Microbes, Inflammation & Cancer. ", "T.C. was supported by Innovational Research Incentives Scheme Vidi grant \\#91710377 from the Netherlands Organization for Scientific Research (Zon-MW), and M.R. was supported by the People Programme (Marie Curie Actions) of the European Union\\'s Seventh Framework Programme FP7/2007-2013 under REA grant agreement no. ", "289720. ", "A.M.M. was supported by the Bio Medical Exchange Program of the Deutscher Akademischer Austauschdienst. ", "C.A.L. was supported by Dutch Cancer Society clinical fellowship grant \\#2013-5883 and by a mobility grant from the University Medical Center Utrecht. ", "J.A.D. was supported by a C.J. Martin fellowship from the Australian National Health and Medical Research Council, a Scholar Award from the American Society of Hematology, and the Mechtild Harf Research Grant from the DKMS Foundation for Giving Life. ", "A.M.H. was supported by a Scholar Award from the American Society of Hematology, a New Investigator Award from the American Society for Blood and Marrow Transplantation, and the Amy Strelzer Manasevit Research Program. ", "A provisional patent application has been filed on the use of IL-22 and F-652 as ISC growth factors (US 61/901,151) with A.M.H., C.A.L., and M.R.M.vdB. listed as inventors.", "\n\nAuthor Contributions\n\nC.A.L. and M.C. designed and performed organoid experiments. ", "A.M.M and M.H.O. performed and analyzed *in vivo* experiments. ", "J.A.D, R.R.J., and E.V. provided input and helped with various assays. ", "L.F.Y., O.M.S., and G.L. performed and monitored bone marrow transplants and maintained the mouse colonies. ", "J.A.I. assisted with organoid quantification. ", "YF analyzed crypt sizes and confocal microscopy. ", "S.T. assisted with ILC co-culture experiments. ", "G.H., M.L.M., and R.K. assisted with ISC isolation and *in vivo* ISC quantification experiments and provided reagents and expertise. ", "K.P.O. and L.D. assisted with adenoviral-Cre experiments and optimizing various assays. ", "Y.L. and N.F.S. assisted with Paneth cell deficiency experiments. ", "M.M. and E.E.N. performed the GSEA analyses and assisted with reagents and resources. ", "M.R.H. performed PCR analyses on purified stem cells and immune cells under the guidance of T.C., and C.L. analyzed intestinal histopathology. ", "M.R.M.vdB. and A.M.H. supervised the research. ", "All authors contributed to experimental design, interpretation, and manuscript editing.", "\n\nThe authors have no competing financial interests.", "\n\n{#F1}\n\n{ref-type=\"supplementary-material\"}.](nihms-739694-f0002){#F2}\n\n{#F3}\n\n{ref-type=\"supplementary-material\"}.](nihms-739694-f0004){#F4}\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Q:\n\nWord Frequency Analysis of Document Sets\n\nI'm doing some work trying to extract commonly occurring words from a set of human classified documents and had a couple questions for anyone who might know something about NLP or statistical analysis of text.", "\nWe have a set of a bunch of documents, and users have classified them as either good or bad. ", "What I'd like to do is figure out what words are common to the good documents, but not necessarily the other ones.", "\nI could, for example, use the (frequency within good documents / total frequency) which would essentially normalize the effect of a word being generally common. ", "This, unfortunately, gives very high precedence to words that occur in only a few good documents & not at all in the other documents. ", "I could add some kind of minimum threshold for # of occurrences in good docs before evaluating the total frequency, but it seems kind of hacky.", "\nDoes anyone know what the best practice equation or model to use in this case is? ", "I've done a lot of searching and found a lot of references to TF-IDF but that seems more applicable for assessing the value of a term on a single document against the whole set of docs. ", "Here I'm dealing with a set of docs that is a subset of the larger collection.", "\nIn other words, I'd like to identify which words are uniquely or more important to the class of good documents.", "\n\nA:\n\nThere are many algorithm to do classification: Naïve Bayes, logistic regression, SVM, decision tree..etc. ", "My suggestion is to try Naïve Bayes first by calculating below probabilities which a new document belongs to $class_{good}$ or $class_{bad}$. (https://web.stanford.edu/class/cs124/lec/naivebayes.pdf)\n$$\nP(Class_{good} \\vert document_{new}) = \\frac{P(document_{new} \\vert Class_{good}) \\cdot P(Class_{good}) }{P(document_{new})}\n$$\n$$\nP(Class_{bad} \\vert document_{new}) = \\frac{P(document_{new} \\vert Class_{bad}) \\cdot P(Class_{bad}) }{P(document_{new})}\n$$\nAnd generally, when we are doing text mining questions, we will do several preprocess on one document: \n\nTokenization(1-gram/bigram/...etc)\nremove stop words ('a', 'the' 'at', ... etc)\nStemming: transforms a word into its root form. (", "studied => study)\n\nMy suggestion is to do above preprocesses and try more features not just the words in one document, if there are some metadataes.", "\n\n" ]

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[ "Alex Martelli wrote:\n> It IS sort of nice to be able to name all predicates ending with '?',", "\n> all functions-which-modify-args ending with '!', ", "etc. ", "The price you\n> pay for that is that you have to put spaces in LOTS of spaces\n> where they are not needed in \"run-of-the-mill\" languages (such\n> as Python) that severely restrict the set of characters usable in\n> identifiers.", "\n> a+b this would be an identifiers, so\n> a + b is what you must write for addition\n> etc, etc. (", "LISP-ish syntax is different -- if no infix operators\n> exist, the space-around-operators issue of course disappears:-).", "\n>These required whitespaces (and the freedom in variable, procedure..\nnames) are also a feature in Tcl. ", "But I'm not much troubled by having to\nput in lots of spaces -- the space bar is so easy to hit with the\nthumb...\n--\nSchoene Gruesse/best regards, Richard Suchenwirth - +49-7531-86 2703\nRC DT2, Siemens Electrocom, Buecklestr. ", "1-5, D-78467 Konstanz,Germany\n-------------- http://purl.org/thecliff/tcl/wiki//Richard*Suchenwirth\nAL:The Analytical Engine worketh not! ", "CB:What version dost thou have?" ]

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[ "How to Enable Volume Press / Screen Touch to Capture on HTC One M8\n\n‬\n\n‬\n\nBy default, you need to press the shutter icon to capture images on HTC One M8, but you can also press the volume button or touch to capture as 2 easier alternatives. ", "To enable these 2 alternatives, do as follows:\n\n1. ", "Open Camera application2. ", "Tap the 3dot icon and then go to Camera Settings by tapping the Gear Icon3. ", "Scroll down and touch Volume button optionsand select \"Capture\" 4. ", "Now, go to Camera options and make sure to mark the \"Touch to capture\" option5. ", "From now on, you can either touch the shutter icon, touch the screen, or press the volume button to take pictures\n\nBy default, you need to press the shutter icon to capture images on HTC One M8, but you can also press the volume button or touch to capture as 2 ..." ]

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[ "With the League Two table as tight as it is, we’ve got a couple of vital games coming up over the next few days – we take on second-placed Wycombe at St James’s Park on Saturday before travelling to Port Vale on Tuesday.", "\n\nAs things stand, we’re four points, and the same number of places, behind Wycombe having played a game less. ", "So, if we can beat the Buckinghamshire side on Saturday we’ll move to within a point of them with a game in hand.", "\n\nClearly, that has to be the objective, but Gareth Ainsworth’s side are in great form, having won six of their last seven League Two fixtures, and we know we’re in for a real test. ", "If past form is anything to go by, Wycombe will look to hit their big man up front and get runners off him; they also tend to target set pieces, so we’ll be at pains not to concede too many in dangerous positions.", "\n\nRead More\n\nThat said, we came away from Adams Park in October with a creditable 0-0 draw and our home form has been excellent this season so we have to believe that if we perform to the best of our ability we’re capable of bagging all three points.", "\n\nTruth be told, all our attention right now is on the Wycombe game and we won’t begin to think about Port Vale until Saturday is out of the way. ", "While, Vale are one of the few sides to have beaten us at the Park this season [the Valiants won 1-0 in October], they’re without a win in their last six games and we’ll be looking to extend that sequence at Vale Park on Tuesday night.", "\n\nJordan Storey (Image: Pinnacle)\n\nI thought we did okay at league leaders Luton on Saturday – all the more so when you consider we went into the game with a number of key personnel sidelined. ", "Be that as it may, it was disappointing to come away with nothing and, while there was a bit of good fortune about the Hatters’ winning goal, it would be hard to deny the home side deserved their victory.", "\n\nNevertheless, there was at least one big positive to take from the game with Jordan Storey, who in the absence of the two Troys [Brown and Archibald-Henville], Jordan Moore-Taylor and Luke Croll, came in alongside Dan Seaborne in the centre of defence, enjoying an excellent full debut.", "\n\nRead More\n\nIt was unfortunate for Jordan that Luton’s winning goal came when Harry Cornick’s 38th-minute effort looped off him and past Christy Pym, but it could just as easily have been a great block. ", "In any case, he didn’t let it affect him and, up against one of the most potent attacks in League Two, I fought he had a fine game.", "\n\nJordan’s an old-fashioned centre-half, who isn’t afraid to get stuck in, and I can see him doing well at Exeter. ", "He barely put a foot wrong on Saturday and, while he may have to bide his time when the squad isn’t quite so depleted, I know from my own experience that Tis likes to give youngsters a chance and I’m sure he can look forward to more opportunities.", "\n\nWhile Luton enjoyed the majority of the play, we defended resolutely and thought we’d nicked a hard-earned equaliser when Liam McAlinden bundled the ball home late on. ", "Unfortunately, the referee ruled Robbie Simpson had fouled Luton keeper Marek Stetch and Liam’s effort was struck off. ", "To be honest, I didn’t have a great view from where I was, and haven’t yet seen a replay, but, certainly, I thought Simo had every right to go for it.", "\n\nIt was a bit different playing Wednesday-Saturday rather than Tuesday-Saturday, though, all said and done, I suppose it’s not much different from playing Saturday-Tuesday.", "\n\nHad we had an extra 24 hours, I reckon Pierce Sweeney might have overcome the dead leg which meant he started on the bench and the extra recovery time might also have heightened Troy A-H’s chances of being involved.", "\n\nRead More\n\nMoreover, Luton are a good footballing side, who move the ball quickly, and, with that in mind, an extra day to recover after the Forest Green game wouldn’t have gone amiss!", "\n\n(Image: Pinnacle)\n\nTransfer deadline day has become and bigger over the last few years and, like everyone else, I enjoy following last Wednesday’s events on Sky Sports and all the apps. ", "In years gone by, I think players sometimes got to hear what was going on before it became common knowledge, but these days the media is all over everything and I don’t suppose we know a whole lot more than the next man.", "\n\nMy only experience of being involved in a deadline day move came back in January 2011 when I moved from Derby to Crystal Palace. ", "I’d just signed a new contract at Pride Park and it all came out of the blue but the Rams needed the money. ", "Fortunately, it was all sorted very quickly and it turned out to be the best move I ever made.", "\n\nDougie Freedman’s side were struggling at the wrong end of the Championship when I joined them, but within 18 months we were promoted to the Premier League. ", "As you might imagine, it was a dream come true.", "\n\nKyle Edwards celebrates scoring for Exeter City under-23s against Hull City in the Premier League Cup (Image: Pinnacle)\n\nLess than 24 hours after the visit of Wycombe, there will be more action at the Park when our U23 side face their Sunderland counterparts in the Premier League Cup [2pm kick-off]. ", "With two games to go, our youngsters top a group which also includes Brighton and Hull U23s and victory on Sunday should ensure they progress to the next round of the competition.", "\n\nRead More\n\nThat would be a tremendous achievement and, with that in mind, I do hope that people will make every effort to get along to the game and lend the youngsters their support. ", "Of course, the rules permit you to field a number of over-age players so it’s not inconceivable a few of those on the road to recovery, or short of match practice, might also feature.", "\n\nIf you haven’t already seen them in action then, take it from me, the City side is likely to feature some extremely talented youngsters and the £5 admission charge [just £2 for U18s] promises to be money well spent. ", "Certainly, family commitments permitting, I’m looking forward to going along and cheering them to victory!" ]

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[ "836 F.2d 22\n101 A.L.R.Fed. ", "793\nCharles H. DESFOSSES, Plaintiff, Appellant,v.WALLACE ENERGY, INC., ", "Defendant, Appellee.", "\nNo. ", "87-1150.", "\nUnited States Court of Appeals,First Circuit.", "\nHeard Sept. 16, 1987.Decided Dec. 23, 1987.", "\n\n1\nJeffrey A. Gorlick with whom Law Offices of Robert E. Weiner, Boston, Mass., were on brief, for appellant.", "\n\n\n2\nStephen E. Weyl with whom Peter S. Cowan and Sheehan, Phinney, Bass & Green Professional Association, Manchester, N.H., were on brief, for appellee.", "\n\n\n3\nBefore BREYER and SELYA, Circuit Judges, and LAGUEUX,* District Judge.", "\n\n\n4\nLAGUEUX, District Judge.", "\n\n\n5\nAppellant Charles Desfosses (hereinafter \"Desfosses\" or \"plaintiff\") brought this action for damages against Appellee Wallace Energy, Inc. (hereinafter \"Wallace\") for claims arising out of the nonrenewal of a gasoline service station lease and franchise agreement. ", " Desfosses claimed that Wallace's failure to renew the franchise agreement violated the Petroleum Marketing Practices Act, 15 U.S.C. Secs. ", "2801-2841 (1982) (hereinafter \"PMPA\") and that Wallace misrepresented its state of mind at the time it entered into the franchise agreement and thus committed the tort of deceit under New Hampshire law.", "\n\n\n6\nThe District Judge heard the claims together; the deceit claim was tried to a jury while the PMPA claim was tried to the court. ", " At the close of plaintiff's case, the District Judge directed a verdict for Wallace on the deceit claim. ", " At the end of the trial, the District Court rendered decision for Wallace on the PMPA claim.", "\n\n\n7\nThe issue before this Court is whether the District Judge erred in making these two rulings. ", " For the reasons stated below, we hold that Wallace complied with the PMPA and that Desfosses failed to produce enough evidence to go to the jury on the deceit claim. ", " Accordingly, we affirm the District Court.", "\n\nI. BACKGROUND\n\n8\nDesfosses is a vigorous entrepreneur who has been successful in operating eleven motor vehicle service stations. ", " He owns several of these stations outright and has leased others from their respective owners. ", " Wallace is a distributor of motor vehicle and other fuels. ", " Wallace supplies service stations with fuel and, in two or three instances, has entered into lease arrangements for the operation of the service stations.", "\n\n\n9\nIn April, 1983 Paul LaBrecque, then general manager of Wallace, contacted Desfosses and persuaded him to visit a service station located at the Massabesic Traffic Circle in Manchester, New Hampshire (hereinafter \"Massabesic Mobil\" or \"the premises\"). ", " The premises were owned by the Morris Rachins Trust (Trust) and leased to Mutual Oil Company (Mutual).", "\n\n\n10\nAfter Desfosses consented to enter into an operation agreement with Wallace, LaBrecque negotiated an \"Indenture of Sublease\" with Mutual. ", " Under the sublease, Mutual granted Wallace a one-year tenancy of the premises from May 1, 1983 to April 30, 1984. ", " The sublease also gave Wallace the option to purchase the premises from Trust for $135,000 on condition that Wallace give written notice to Trust \"not less than sixty days prior to the termination of\" the leasehold.", "\n\n\n11\nOn April 28, 1983 Desfosses and Wallace entered into a \"Lease/Trial Franchise\" giving Desfosses tenancy of the premises for the same period afforded Wallace by Mutual. ", "This agreement contained a specific reference to the existence of the underlease:\n\n\n12\nThe term of this lease is subject to an underlying lease held by the Lessor, which lease expires on the 30th day of April, 1984. ", " This lease shall automatically terminate 30 days prior to the expiration of the Lessor's underlying lease.", "\n\n\n13\nExhibit 2 at Tr. ", "1-2.", "\n\n\n14\nOn March 20, 1984 LaBrecque obtained from Mutual an extension of the Wallace sublease for an additional year. ", " LaBrecque then orally advised Desfosses that he could remain in possession of the premises for an additional year under the same terms and conditions.", "\n\n\n15\nOn July 9, 1984 Wallace Energy summarily dismissed LaBrecque from its employment. ", " LaBrecque then contacted Mutual and Desfosses to express his interest in procuring an assignment of the Wallace sublease. ", " Although Mutual and Desfosses initially advised LaBrecque that they would have no objection, Desfosses thereafter changed his mind and contacted Wallace.", "\n\n\n16\nOn July 24, 1984, Desfosses met with representatives of Wallace to discuss the future of the franchise. ", " Desfosses told them that he was happy with the business but did not want LaBrecque to become his landlord in the place of Wallace. ", " The parties then entered into an oral franchise agreement whereby Wallace promised the following: (1) to exercise its option to purchase the premises; (2) to sell the premises to Desfosses at the cost of the price of the option plus the improvements at their depreciated value; and (3) to continue supplying Desfosses with gasoline after the closing of the sale unless and until Desfosses entered into a gasoline supply agreement with another dealer. ", " Desfosses agreed to the following: (1) to obtain the necessary financing to purchase the premises; (2) to notify Wallace of that fact; (3) to purchase the premises from Wallace at the agreed price; and (4) to continue purchasing gas from Wallace until he entered into an agreement with another supplier. ", " (App. ", "304).", "\n\n\n17\nAt trial the parties disputed whether Wallace's obligation to exercise the option was conditioned upon Desfosses's notifying Wallace that he had obtained financing to purchase the premises. ", " Wallace claimed that it was not obligated to exercise the option until Desfosses notified it that he had obtained the necessary financing. ", " Desfosses claimed that Wallace's obligation to exercise the option was absolute. ", " The District Court found, however, that \"[w]hen the parties separated, it was understood that plaintiff was to arrange his financing for the purchase of Massabesic Mobil and notify Wallace, and Wallace would then proceed to exercise the option.\" ", " (App. ", "304).", "\n\n\n18\nAt the July 24, 1984 meeting Wallace also gave Desfosses a copy of the agreements between Wallace, Mutual, and Trust setting forth the term of the underlying sublease and conditions upon which the option had to be exercised. ", " Id. The one page \"Extension of Sublease\" handed to Desfosses stated that Mutual agreed to extend the sublease with Wallace \"for a period of one year commencing May 1, 1984 and terminating on April 30, 1985\" subject to the same terms contained in the original \"Indenture of Sublease.\" ", " Exhibit 3B at Tr. ", "24.", "\n\n\n19\nThe \"Indenture of Sublease\" also handed to Desfosses on that day described the method of exercising the option:\n\n\n20\nLESSEE shall exercise said right and option by giving said Trustees notice by certified mail of its intention to exercise said right and option at any time not less than sixty (60) days prior to the termination of the term of this lease. ", " If such notice shall not be given by LESSEE to said Trustees within such time, such right and option shall thereupon cease and terminate.", "\n\n\n21\nExhibit 3A at Tr. ", "21. ", " At trial, plaintiff and his office manager testified that they had read and understood the terms of these agreements at the time. ", " Brief of Defendant-Appellee at 25 (citing Tr. ", "II at 25; Tr. ", "III at 85-86 (testimony of plaintiff's office manager, Jacqueline Trott)).", "\n\n\n22\nSubsequent to this meeting, LaBrecque contacted Wallace to obtain an assignment of the sublease of the premises. ", " Wallace advised LaBrecque that it intended to exercise its option and sell the premises to Desfosses and therefore could not assign the sublease to LaBrecque.", "\n\n\n23\nThroughout the following months, Wallace contacted Desfosses concerning his progress in obtaining financing to purchase the premises. ", " When it appeared that this financing would be delayed, Wallace made arrangements for a temporary loan from its own bank. ", " With these funds Wallace intended to exercise its option and then resell the premises to Desfosses when he obtained the necessary financing.", "\n\n\n24\nUnfortunately, Wallace failed to calendar or otherwise remind itself of the sixty-day notice requirement of the option to purchase. ", " Accordingly, on March 21, 1985, when Wallace advised its attorney to exercise the option, the attorney, after reviewing the necessary documents, advised Wallace that it was too late to comply with the sixty-day notice provision. ", " Nevertheless, Wallace directed its attorney to attempt to exercise the option. ", " The Trust, however, rejected the offer as untimely.", "\n\n\n25\nWallace notified Desfosses by telephone of its difficulty in exercising the option. ", " The company told Desfosses it would sue Mutual and Trust to enforce the option and that Desfosses need not worry. ", " On April 10, 1985 Wallace brought suit in New Hampshire Superior Court to enforce the option.1 On April 16, 1985, however, Wallace delivered to Desfosses a notice of the termination of the franchise. ", " The parties agreed that, pending the outcome of the action, Desfosses could remain at the premises under the same terms and conditions as then existed.", "\n\n\n26\nIn May 1985, while continuing to operate Massabesic Mobil, Desfosses leased a Getty motor vehicle service station across the same traffic circle. ", " Desfosses then raised the fuel prices of Massabesic Mobil above the prices at the Getty Station. ", " He also deposited property under repair on the premises of Massabesic Mobil.", "\n\n\n27\nOn June 13, 1985 the Federal District Court of New Hampshire held that Wallace no longer had the right to exercise its option. ", " Mutual requested that Wallace evict Desfosses so that Mutual could prepare for the summer travel season. ", " When Wallace asked Desfosses promptly to vacate the premises at Massabesic Mobil, he \"delayed and dissembled.\" ", " (App. ", "307). ", " It was not until July 24, 1985, that Wallace was able to enter upon and turn over the premises to Mutual. ", " Because of plaintiff's delay in vacating the premises, and the condition in which he left them, Mutual sued Wallace. ", " The resulting settlement required Wallace to pay substantial sums to Mutual. ", " Id.\n\nII. ", "THE PMPA CLAIM\n\n28\nTitle 1 of the PMPA establishes minimum federal standards governing the termination and nonrenewal of franchise relationships for the sale of motor fuel. ", " S.Rep. ", "No. ", "731, 95th Cong.2d Sess., ", "reprinted in 1978 U.S.Code Cong. & ", "Admin.", "News 873. ", " Congress, in enacting the PMPA, perceived a disparity in bargaining power between the large petroleum refiners and the small service station retailers. ", " The PMPA was therefore designed to protect the retailers from arbitrary or discriminatory termination or nonrenewal of their franchisees. ", " Id. However, Congress was also aware of the franchisors' need for adequate flexibility to respond to changing market conditions and consumer preferences. ", " Id. at 877. ", " See also Veracka v. Shell Oil Co., 655 F.2d 445, 448 (1st Cir.1981).", "\n\n\n29\nTo balance these distinct and often competing interests, the PMPA prohibits franchisors from terminating or not renewing the franchise agreement unless based on grounds described in sections 2802(b)(2) and 2802(c) and upon proper notice described in section 2804. ", " While \" 'the Act must be given a liberal construction consistent with its overriding purpose to protect franchisees,' Brach v. Amoco Oil, 677 F.2d 1213, 1221 (7th Cir.1982), we must also bear in mind that it constituted a diminution of prior rights of franchisors and thus should not be extended beyond the Act's language and purpose.\" ", " Russo v. Texaco, Inc., 630 F.Supp. ", "682, 687 (E.D.N.Y.), aff'd, 808 F.2d 221 (2nd Cir.1986).", "\n\n\n30\nDesfosses contends that Wallace violated the PMPA because it terminated him without complying with the requirements of sections 2802(b)(2)(C) and 2802(c)(4) or the notice requirements of section 2804.", "\n\n\n31\n1. ", "Compliance with Sections 2802(b)(2) and 2802(c)(4).", "\n\n\n32\nSection 2802(b)(2) describes several grounds for lawful termination of a franchise. ", " In terminating Desfosses's franchise Wallace relies on section 2802(b)(2)(C) which provides that termination is permissible if based upon:\n\n\n33\nThe occurrence of an event which is relevant to the franchise relationship and as a result of which termination of the franchise or nonrenewal of the franchise relationship is reasonable....\n\n\n34\n15 U.S.C. Sec. ", "2802(b)(2)(C).", "\n\n\n35\nIn section 2802, Congress provided an illustrative but non-exclusive list of events deemed to be relevant to the franchise relationship and as a result of which termination is reasonable within the meaning of section 2802(b)(2)(C). ", " If an event falls within the list, termination is conclusively presumed to be reasonable as a matter of law. ", " Russo v. Texaco, 808 F.2d 221, 225 (2nd Cir.1986). ", " The illustration that Wallace relies upon is set forth in section 2802(c)(4):\n\n\n36\n(4) loss of the franchisor's right to grant possession of the leased marketing premises through expiration of an underlying lease, if the franchisee was notified in writing, prior to the commencement of the term of the then existing franchise--\n\n\n37\n(A) of the duration of the underlying lease, and\n\n\n38\n(B) of the fact that such underlying lease might expire and not be renewed during the term of such franchise (in the case of termination) or at the end of such term (in the case of non-renewal).", "\n\n\n39\nDefosses claims that Wallace failed to comply with section 2802(c)(4) because, prior to the commencement of the July 24, 1984 franchise term, it failed to notify him in writing of the fact that the underlying lease might expire and not be renewed. ", " The District Court found that Desfosses had actual knowledge of the information provided by section 2802(c)(4), and held that requiring additional written notice \"would be an exercise in futility as it would merely equate with an elevation of form over substance.\" ", " (App. ", "314).", "\n\n\n40\nAs the District Court noted, courts have held that actual notice of the particulars protected by section 2802 will suffice if failure of written notice would elevate form over substance. ", " For example, in Amadeo v. Mobil Oil Caribe, Inc., 642 F.Supp. ", "962, 963 (D.P.R.1986), the court held that plaintiff's actual knowledge of the existence and the likely expiration of the underlying lease satisfied the notice of termination requirements of section 2802 even though notice was not reduced to writing. ", " See also Brown v. Magness Co., 617 F.Supp. ", "571, 574 (D.C.Tex.1985) (PMPA does not contemplate an elevation of form over substance where plaintiff has not been deprived of actual notification); Brown v. American Petrofina Mktg, 555 F.Supp. ", "1327, 1335 (M.D.Fla.1983), aff'd without opinion, 733 F.2d 906 (11th Cir.1984) (court could determine whether plaintiffs were actually aware of the information under section 2802(c)(4) and whether they were prejudiced by lack of written notice) (dicta). ", " But see Blankenship v. Atlantic Richfield Co., 478 F.Supp. ", "1016, 1018 (D.Or.1979) (compliance with notice provisions of section 2804(a)(2) is a mandatory prequisite to non-renewal and the court has no power either to cure or to waive a notice defect); Thompson v. Kerr-McGee Refining Corp., 660 F.2d 1380, 1388 (10th Cir.1981), cert. ", "denied, 455 U.S. 1019, 102 S.Ct. ", "1716, 72 L.E.2d 137 (1982) (expressly following Blankenship ).", "\n\n\n41\nBecause, as discussed below, Wallace delivered sufficient written notice to Defosses at the beginning of the franchise term, we need not address whether Desfosses's actual knowledge of the relevant facts satisfies sections 2802(b)(2) and 2802(c)(4) in the absence of any writing. ", " We do note, however, that under the proper circumstances a court could hold that actual notice may suffice to terminate or nonrenew a franchise because of the loss of the underlying lease. ", " Congress gave the courts the power to permit reasonable terminations and nonrenewals based on circumstances not squarely within the illustrations of section 2802(c). ", " The legislative history of the PMPA clearly states:\n\n\n42\nOther events satisfying the statutory standards set forth in section [2802](b)(2)(C), but not enumerated in subsection (c) of section [2802], may nevertheless serve as a ground for termination or nonrenewal under section [2802](b)(2)(C). ", " However, the enumerated list is intended to provide a measure of Congressional intent with respect to the meaning of this statutory standard. ", " For that reason the term \"includes such events as\" is utilized. ", " Thus, a judicial determination may be made that an event, other than one enumerated in the list, or an event similar but not identical to one enumerated in the list, constitutes an event which is relevant to the franchise relationship as a result of which termination or nonrenewal is reasonable. ", " However, events which are not enumerated in subsection (C) must be carefully scrutinized by the courts prior to a determination that the statutory standard set forth in section [2802](b)(2)(C) has been satisfied.", "\n\n\n43\nS.Rep. ", "731 at 37-38, reprinted in 1978 U.S.Code Cong. ", "and Admin.", "News at 896.", "\n\n\n44\nCourts have examined the reasonableness of a franchisor's termination or nonrenewal when based on grounds not specified in the enumerated list. ", " Lugar v. Texaco, Inc., 755 F.2d 53, 58 (3rd Cir.1985). ", " Compare Hifai v. Shell Oil Co., 704 F.2d 1425, 1430 (9th Cir.1983) (franchisor acted reasonably in recovering possession of premises so that it could avoid forfeiture of the improvements) with Brach v. Amoco Oil Co., 677 F.2d 1213, 1219-23 (7th Cir.1982) (nonrenewal because franchisee failed to purchase the marketing premises must be examined for materiality of real estate contract to franchise relationship, reasonableness of terms of the real estate contract, and whether the default was beyond the reasonable control of the franchisee). ", " Cf. ", "Kostantas v. Exxon Co., 663 F.2d 605 (5th Cir.1981) (franchisee's death justified termination), cert. ", "denied, 456 U.S. 1009, 102 S.Ct. ", "2302, 73 L.Ed.2d 1305 (1982).", "\n\n\n45\nThus, this Court could determine whether it was reasonable for Wallace not to renew the franchise where Desfosses had actual knowledge of the information required by section 2802(c)(4). ", " We do not, however, need to address this issue in order to resolve this case. ", " The record clearly indicates that on July 24, 1984 Wallace Energy gave Desfosses documents containing the information required by section 2802(c)(4). ", " The March 20, 1984 \"Extension of Sublease\" notified Desfosses of the existence and term of the underlying sublease commencing May 1, 1984 and terminating April 30, 1985. ", " The March 20, 1983 \"Indenture of Sublease\" notified him that the underlying sublease might expire at the end of the term unless Wallace exercised its option to purchase the premises by notifying the owner by certified mail at least sixty days prior to the end of the lease. ", " At trial Desfosses and his office manager both acknowledged that they had read and understood the terms of the Indenture of Sublease and the Extension of Sublease at that time. ", " Brief of Defendant-Appellee p. 25 (citing transcript II at 25; Tr. ", "III at 85-86). ", " These documents thus constitute sufficient written notice under section 2802(c)(4).", "\n\n\n46\nDesfosses argues that not only did Wallace fail to notify him in writing that the underlying lease might expire, but \"[t]o the contrary, Desfosses was promised orally, on July 24, 1984, by Wallace that his franchise would not be terminated and it would continue after April 30, 1985, if Desfosses would agree to purchase the premises from Wallace.\" ", " Brief of Plaintiff-Appellant at 28. ", " This argument assumes that section 2802(c)(4) requires a franchisor to promise or somehow assure the franchisee, prior to the commencement of the term, that the underlying lease will not expire. ", " Section 2802(c)(4), however, requires no such assurance. ", " The section allows termination if the franchisee is notified in writing \"of the fact that such underlying lease might expire.\" ", " 15 U.S.C. Sec. ", "2802(c)(4)(B) (emphasis added). ", " Not only was Desfosses aware that the underlying lease might expire from the numerous conversations with Wallace, but also from the documents handed to him on July 24, 1984. ", " Desfosses was on notice of the relevant facts and this constituted sufficient written notification under section 2802(c)(4).", "\n\n\n47\n2. ", "Compliance with Section 2804.", "\n\n\n48\nDesfosses also claims that Wallace failed to comply with the notice provisions of section 2804. ", " The general rule under section 2804(a) is that notice of termination must be given ninety days prior to the effective date of termination. ", " Section 2804(b)(1) provides, however, that less than ninety days notice is permitted if reasonable under the circumstances and if notice is given on the earliest date on which furnishing such notice is \"reasonably practicable.\"", "\n\n\n49\nIn holding that Wallace complied with the PMPA the District Judge implicitly found that it was reasonable for Wallace to give less than ninety days notice and that notice was furnished on the earliest date reasonably practicable. ", " We agree. ", " Under the circumstances of this case, it would not be reasonable to require Wallace to have furnished more.", "\n\n\n50\nWallace's lease with Mutual expired on May 1, 1985. ", " To comply with the 90 day requirement of section 2804(a), Wallace would have had to send the termination notice by February 1, 1985. ", " Wallace did not send the letter because as part of the July 24, 1984 franchise agreement, it had agreed to exercise the option and sell the premises to Desfosses after he notified Wallace he had arranged the required financing and to continue supplying gasoline to the station if he so desired. ", " (App. ", "304).", "\n\n\n51\nThe trial court found that Wallace relied on Desfosses to arrange this financing and to so notify Wallace. ", " (App. ", "313 fn. ", "14). ", " In the 219 days following their agreement, Desfosses failed to arrange the necessary financing. ", " By the time he notified Wallace that the financing had been arranged on March 21, 1985, Wallace's March 1st deadline to exercise the option had passed and so had the February 1st deadline for giving Desfosses 90 days notice under section 2804(a). ", " When it became clear after March 21, 1985 that Desfosses could not continue in possession of the premises after May 1, 1985, Wallace sent the termination letter. ", " Because Wallace had relied on Desfosses to arrange financing, it did not send such a letter before February 1, 1985. ", " Under these circumstances it was reasonable for Wallace to furnish less than 90 days notice under section 2804(b)(1).", "\n\n\n52\nDesfosses argues that section 2804(b)(1)(A) does not apply to this case. ", " In support plaintiff cites Wisser Co. v. Mobil Oil, 730 F.2d 54, 60 (2nd Cir.1984). ", " Wisser held that a franchisee failed to raise a serious question as to the reasonableness of termination under Section 2804(b)(1)(A) where franchisor had notified franchisee of termination \"effective immediately\" because of franchisee's misbranding of gasoline. ", " In determining which circumstances justify the application of section 2804(b)(1)(A), the Wisser court rejected as too restrictive the analysis in Escobar v. Mobil Oil Corp., 522 F.Supp. ", "593, 600 (D.Conn.1981). ", " Escobar held that section 2804(b)(1)(A) was intended to apply only to \"circumstances created by an outside agency, such as condemnation of the marketing premises.\" ", " Wisser, 730 F.2d at 60.", "\n\n\n53\nThe Wisser court found evidence of broader Congressional purpose for section 2804(b)(1)(A) in the legislative history: \"Legislative history and hearings ... indicate that Sec. ", "2804(b)(1)(A) was added to dispense with the lengthy notice requirement where, for example, a franchisee committed serious defaults of the franchise agreement, such as misbranding.\" ", " Id. (referring to S.Rep. ", "No. ", "120, 94th Cong., ", "1st Sess. ", "8 (1975)); Petroleum Marketing Practices: Hearing on H.R. 13000 ... and S. 323 before the Subcommittee on Energy and Power of the House Committee on Interstate and Foreign Commerce (94th Cong., ", "2d Sess. ", "334-36, 340-41 (1976)) Desfosses claims that Wallace was not entitled to raise section 2804(b)(1)(A) as a defense in this case because he did not commit any serious default of the franchise agreement or engage in wrongful conduct.", "\n\n\n54\nWe decline to restrict the application of section 2804(b)(1)(A) only to serious defaults of the franchise agreement or instances of \"wrongful conduct.\" ", " The language of section 2804(b)(1)(A) does not contain such a restriction. ", " Neither does the Senate report accompanying the Act. ", " That report simply states, \"Less than 90 days notice is permitted if reasonable under the circumstances.\" ", " S.Rep. ", "at No. ", "731 at 40, reprinted in 1978 U.S.Code Cong. ", "and Admin.", "News at 898. ", " Notably Wisser did not restrict the application of section 2804(b)(1)(A) to instances of wrongful conduct and serious default of the franchise agreement. ", " For the reasons discussed above, we hold that under the circumstances of this case it was reasonable to provide less than 90 days notice under section 2804(b)(1)(A).", "\n\n\n55\nDesfosses also argues that Wallace failed to comply with section 2804(b)(1)(A) because April 16, 1985 was not the earliest date reasonably practicable for Wallace to notify him of termination even if Wallace learned from its attorney that the option had already expired on March 21, 1985. ", " We do not agree. ", " Wallace was entitled to a reasonable time to evaluate the need for termination of the franchise after becoming aware of the expiration of the option. ", " Shortly after learning that the option had expired, Wallace nevertheless attempted to exercise the option. ", " When Trust rejected the attempt as untimely, Wallace brought suit against Trust and Mutual to enforce the option on April 10, 1985. ", " On April 16, 1985 Wallace sent the notification required by section 2804, apparently realizing that its efforts to enforce the option might be unsuccessful. ", " Under these circumstances, it cannot be said that the statute required Wallace to notify Desfosses of termination on an earlier date.", "\n\n\n56\nAs this Court stated in Avramidis v. Arco Petroleum Products Co., 798 F.2d 12, 17 (1st Cir.1986), \"The purpose of the PMPA's notice of termination requirements is to give the dealer sufficient advance warning of the impending termination so that he may make appropriate arrangements.\" ", " Here the parties allowed Desfosses to continue operating the station pending outcome of litigation to enforce the option. ", " Desfosses remained at the station for 100 days. ", " During this time he successfully negotiated and began operating a Getty service station franchise across the traffic circle. ", " Under the circumstances, Wallace complied with both the spirit and the letter of section 2804 when it notified Desfosses of termination.", "\n\n\n57\nDesfosses next argues that Wallace failed to comply with Section 2804(c)(3)(A) because Wallace failed to raise Desfosses's delay in securing financing and notification as a reason for termination in the termination letter. ", " Section 2804(c)(3)(A) provides that notice must contain \"a statement of intention to terminate the franchise together with the reasons therefor.\" ", " In Davy v. Murphy Oil, 488 F.Supp. ", "1013, 1015 (W.D.Mich.1980) the district court stated, \"[I]t is essential that the reasons for the non-renewal be specific and unambiguous, so that plaintiffs are able to determine if reasons are consistent with the [PMPA].\" ", " In Baldauf v. Amoco Oil Co, 553 F.Supp. ", "408, 416 (W.D.Mich.1981), aff'd, 700 F.2d 326 (6th Cir.1983), the district court stated that \"the notice should direct the franchisee to the section of the statute the franchisor relies upon so that the franchisor cannot conjure up another reason for termination after the fact.\" ", " Wallace's April 16, 1985 termination letter clearly met these requirements. ", " The letter stated:\n\n\n58\nOur relationship is being terminated because of the occurrence of an event which is relevant to the relationship between us and which is a reasonable ground for such termination, as allowed by 15 U.S.C. Sec. ", "2802(b)(2)(C). ", " Specifically, our relationship is being terminated because Wallace Energy Inc.'s (Wallace Energy) underlying leasehold of the premises leased to you is being terminated. ", " Therefore, Wallace Energy will no longer have the right to grant possession of the premises to you, so your tenancy must be terminated.", "\n\n\n59\nExhibit 4 at Tr. ", "25.", "\n\n\n60\nIn any event, Desfosses's conduct in securing financing was not the basis for nonrenewal. ", " Rather such events served only to explain why Wallace lost the right to exercise the option. ", " The District Judge stated, \"Plaintiff's dilatory action in procuring the necessary financing, combined with the dilatory action of Wallace in attempting to exercise its notice, I find to be the concurrent proximate causes of the loss of the option.\" ", " (App. ", "313-314). ", " The loss of the option made the termination of the franchise inevitable. ", " Yet loss of the underlying leasehold was the reason for the termination and that is all that need be referred to in the notice of termination.", "\n\n\n61\nReferring to the trial court's proximate cause language, Desfosses also claims that the District Court erroneously applied tort law to the present case. ", " Despite the District Court's unfortunate choice of language and its reference to New England Tel. & ", "Tel. ", "Co. v. Reed, 336 F.2d 90, 95 (1st Cir.1964), it is clear that the Court based its decision not on tort law but upon the PMPA and the relevant decisions. ", " In any event, we hold that Wallace properly terminated Desfosses under the PMPA.", "\n\nIII. ", "THE DIRECTED VERDICT\n\n62\nDesfosses also claims that the District Court erred in directing a verdict for Wallace in the pendent action for deceit. ", " In reviewing the grant of a directed verdict, this Court has followed the rule that \" '(w)hen the evidence is such that without weighing the credibility of the witnesses there can be but one reasonable conclusion as to the verdict,' a directed verdict is proper.\" ", " Liberty Leather Corp. v. Callum, 653 F.2d 694, 697 (1st Cir.1981). ", " (citations omitted) While the evidence of the nonmovant is to be believed and all justifiable inferences are to be drawn in his favor, we have emphasized that a \"scintilla of evidence is not enough to warrant submission of an issue to the jury.\" ", " Id. \"This is particularly true where ... the party seeking a directed verdict does not bear the burden of proof.\" ", " Id.\n\n\n63\nThe Supreme Court recently reaffirmed this standard in Anderson v. Liberty Lobby, Inc., 477 U.S. 242, 106 S.Ct. ", "2505, 91 L.Ed.2d 202 (1986). ", " Furthermore, in Anderson the Supreme Court held that the judge must consider the substantive evidentiary standards that apply to the case in determining whether plaintiff has produced sufficient evidence to warrant submission of the issue to the jury. ", " With this rule in mind, we now turn to New Hampshire law to determine the elements of an action in deceit and the applicable evidentiary standards.", "\n\n\n64\nUnder New Hampshire law, one who intentionally misrepresents his intention to perform an oral agreement to sell real estate to another is subject to liability for deceit. ", " Munson v. Raudonis, 118 N.H. 474, 387 A.2d 1174 (1978). ", " In Munson the Supreme Court of New Hampshire stated:\n\n\n65\n[A] promise to perform in the future carries with it an implied representation that the speaker has a present intent to fulfill his promise. ", " If the speaker makes a promise and at the same time intends not to perform, this operates as a misrepresentation of the speaker's state of mind and is a proper basis for an action in deceit.", "\n\n\n66\nId. 387 A.2d at 1176. ", " The court noted, however, that to prevail in a deceit action, plaintiff must prove that the decedent misrepresented her state of mind at the time the promise was made. ", " \"The mere breach of a promise is not enough by itself to establish an action in deceit.\" ", " Id. Moreover, under New Hampshire law, plaintiff must prove defendant made such a misrepresentation by clear and convincing evidence. ", " See Caledonia, Inc. v. Trainor, 123 N.H. 116, 459 A.2d 613, 617-18 (1983).", "\n\n\n67\nIn the present case, the District Court granted Wallace's motion for a directed verdict holding that the evidence, when viewed in the light most favorable to the plaintiff, showed nothing more than a failed oral promise.", "\n\n\n68\nDesfosses claims that he had presented sufficient evidence for the jury reasonably to infer that Wallace misrepresented its state of mind to plaintiff on July 24, 1984. ", " Specifically, Desfosses claims that \"[i]n light of Wallace's own inconsistent testimony as to whether its promise to Desfosses was absolute, conditioned upon Desfosses first obtaining financings, or subject to its decision on whether to exercise the option, and the concurrent competing dealings with Desfosses and Labrecque, the jury may have rationally found that Wallace had not formulated an actual intent to fulfill its promise to Desfosses or that Wallace was consciously indifferent as to whether it would fulfill its promise to exercise the option and in turn sell the premises to Desfosses.\" ", " Brief of Plaintiff-Appellant at 21.", "\n\n\n69\nWe affirm the decision of the District Court. ", " Plaintiff's version of the facts does not support a reasonable inference that Wallace entered into the July 24, 1984 agreement with the then present intention not to perform.", "\n\n\n70\nIn particular, LaBrecque's request that Wallace assign him the lease so that LaBrecque could exercise the option and purchase the premises himself is not probative of Wallace's lack of intent to sell the premises to Desfosses. ", " It is true that LaBrecque requested that Wallace assign the lease to him. ", " Yet Wallace clearly refused to assign the lease to LaBrecque. ", " Indeed, on September 12, 1984, Wallace's attorney notified Desfosses that \"there appears to be no deal which is acceptable both to the dealer at Massabesic [Desfosses] and to Wallace Energy by which the lease for the Massabesic station could be assigned to Paul LaBrecque.\" ", " Exhibit 6D at Tr. ", "43. ", " These negotiations simply do not establish that Wallace had an intent on July 24, 1984 not to convey the property to plaintiff.", "\n\n\n71\nIndeed the evidence on record establishes that on July 24, 1984 Wallace fully intended to perform its promises: (1) Wallace agreed to exercise the option and convey the premises to Desfosses at no profit to Wallace; (2) Wallace refused to assign any of its rights or obligations under the lease to LaBrecque; (3) Wallace sought to enforce the option through litigation against Trust and Mutual.", "\n\n\n72\nIt is true that Wallace attempted to exercise the option only after the expiration date. ", " Yet, even if we accept Desfosses's assertion that Wallace's promise to exercise its option was unconditional, Desfosses at most has established that Wallace breached an oral promise to convey real estate. ", " In short, the evidence, when viewed in its most favorable light to plaintiff, falls far short of establishing with \"convincing clarity\" that Wallace had no present intention of fulfilling its promises on July 24, 1984.", "\n\nIV. ", "CONCLUSION\n\n73\nWe conclude that the District Court correctly rendered decision for Wallace on the issue of compliance with the PMPA and correctly directed a verdict for Wallace on the deceit count. ", " Accordingly, the judgment below is AFFIRMED.", "\n\n\n\n*\n Of the District of Rhode Island, sitting by designation\n\n\n1\n Defendants Mutual and Trust thereafter removed the suit to the Federal District Court of New Hampshire\n\n\n" ]

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[ "Jessica Samuelsson of Sweden warms up prior to the FIFA Women's World Cup. ", "Photograph: Kevin C. Cox/Getty Images Scandal-plagued FIFA postponed the bidding for the right to host the 2026 World Cup......\n\nFormer international football player David Ginola. ", "Photograph: Jessica Hromas/Getty Images David Ginola's unlikely bid for the FIFA presidency appeared to end on Thursday when his campaign website......" ]

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[ "On this day January 30, 1994\n\nClint Black, Wynonna Judd, Travis Tritt and Tanya Tucker performed at the halftime show (billed as ) at Super Bowl XXVIII. ", "The finale featured a special appearance by Naomi Judd, who joined Wynonna in performing The Judds’ single “Love Can Build a Bridge” (their first major appearance together since their of 1991).", "\nSource: This Day in Country" ]

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[ "Geralmente, as maiores invenções são aquelas que ajudam a solucionar algum problema comum ao dia-a-dia de muitas pessoas. ", "E esse é certamente o caso do conjunto de utensílios de mesa EatWell, criado pela designer industrial Sha Yao para ajudar pacientes com Alzheimer a se alimentar mais facilmente.", "\n\nA ideia para o projeto surgiu quando a avó de Sha Yao foi diagnosticada com Alzheimer. ", "Desde então, a designer decidiu se tornar voluntária em um centro de atendimento ao idoso e passou a conviver com as dificuldades enfrentadas por pacientes que sofriam com a doença ou com deficiências cognitivas parecidas.", "\n\nA dificuldade de se alimentar sozinhos chamou a atenção de Sha Yao, que decidiu que poderia desenvolver utensílios que facilitassem o processo de alimentação para estas pessoas. ", "Com isso surgiu o Eatwell, um conjunto de pratos, copos e talheres pensado especificamente para quem sofre com estes problemas.", "\n\nTodos os aspectos do conjunto foram pensados para facilitar a alimentação: cores, formas e materiais foram de grande importância para melhorar a experiências dos pacientes ao se alimentar. ", "Os potes de comida possuem um ângulo de 90º no qual a colher se encaixa perfeitamente, permitindo mais facilidade na hora de comer. ", "Além disso, os copos e canecas ganharam reforço na parte inferior, o que evita que sejam derrubados com facilidade.", "\n\nOs produtos obtiveram financiamento coletivo através da plataforma Indiegogo, onde ainda é possível adquirir um kit através de um investimento mínimo de U$ 55 (R$ 190) para o kit de quatro peças. ", "Além de tudo, o conjunto conquistou o prêmio máximo de 2014 no Stanford Design Challenge.", "\n\nConfere só os detalhes do produto no vídeo abaixo (em inglês):\n\nThe Adobe Flash Player is required for video playback.", "\n\nGet the latest Flash Player or Watch this video on YouTube.", "\n\nFotos: Divulgação." ]

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[ "---\nabstract: 'The study of open quantum systems is important for fundamental issues of quantum physics as well as for technological applications such as quantum information processing. ", "Recent developments in this field have increased our basic understanding on how non-Markovian effects influence the dynamics of an open quantum system, paving the way to exploit memory effects for various quantum control tasks. ", "Most often, the environment of an open system is thought to act as a sink for the system information. ", "However, here we demonstrate experimentally that a photonic open system can exploit the information initially held by its environment. ", "Correlations in the environmental degrees of freedom induce nonlocal memory effects where the bipartite open system displays, counterintuitively, local Markovian and global non-Markovian character. ", "Our results also provide novel methods to protect and distribute entanglement, and to experimentally quantify correlations in photonic environments.'", "\nauthor:\n- 'Bi-Heng Liu'\n- 'Dong-Yang Cao'\n- 'Yun-Feng Huang'\n- 'Chuan-Feng Li'\n- 'Guang-Can Guo'\n- 'Elsi-Mari Laine'\n- 'Heinz-Peter Breuer'\n- Jyrki Piilo\ntitle: 'Photonic realization of nonlocal memory effects and non-Markovian quantum probes'\n---\n\nIntroduction {#introduction .unnumbered}\n============\n\nRealistic quantum systems interact and exchange information with their surroundings. ", "The engineering of the decoherence and the flow of information between an open quantum system and its environment has recently allowed, e.g., to drive quantum computation by dissipation [@Verstraete], to control entanglement and quantum phases in many-body systems [@Diehl; @Cho; @Krauter], to create an open system quantum simulator [@Barreiro], and to control the transition from Markovian dynamics to a regime with quantum memory effects [@Liu]. ", "Moreover, there has been recently rapid progress in understanding various fundamental issues on quantum non-Markovianity [@Piilo08; @Vacchini08; @Wolf; @Lidar2009; @BLP; @RHP; @Kossakowski2010].", "\n\nIn general, the power of quantum information processing is based on the presence of quantum correlations in multipartite systems. ", "However, as any realistic quantum system, those systems are vulnerable to the detrimental effects of the environment such as the loss of coherence and information. ", "Depending on its physical composition, an open multipartite system can interact either with a single common environment or each of the sub-parties can interact locally with their own reservoirs. ", "The latter case, which is in the focus of our paper, is a common scenario, e.g., in quantum information processing and entanglement dynamics [@Bellomo], and in energy transport in biological organisms [@Rebentrost].", "\n\nThe central question to be studied here is, can a composite open quantum system exploit during its time evolution the information carried initially by the environmental degrees of freedom, i.e., the information to which it does not have access initially? ", "On the basis of a recent theoretical prediction [@Laine11], we demonstrate experimentally that initial correlations between local parts of the environment lead to nonlocal memory effects and allow to protect and maintain genuine quantum properties of an open system. ", "We will show further that the non-Markovian dynamics of photonic open systems provides a diagnostic tool for characteristic features of their environments.", "\n\nResults {#results .unnumbered}\n=======\n\nThe physical system and experimental setup {#the-physical-system-and-experimental-setup .unnumbered}\n------------------------------------------\n\nOur experimental open system consists of the polarization degrees of freedom of a pair of entangled photons. ", "The photon pair is created by spontaneous parametric down-conversion after which the photons travel along different arms $i=1,2$ and move through different quartz plates of variable thickness (see Fig.", " 1). ", "The quartz plates act as birefringent media which lead to a local coupling between the polarization degrees of freedom of the photon in arm $i$ and its frequency (mode) degrees of freedom forming its local environment. ", "This local interaction can be described by a local unitary operator which is defined by $U_i(t_i)|\\lambda\\rangle\\otimes|\\omega_i\\rangle=e^{in_{\\lambda}\\omega_i t_i}\n|\\lambda\\rangle\\otimes|\\omega_i\\rangle$, where $|\\lambda \\rangle \\otimes |\\omega_i\\rangle$ denotes the state of the photon in arm $i$ with polarization $\\lambda = H,V$ (horizontal or vertical) and frequency $\\omega_i$. The refraction index for photons with polarization $\\lambda$ is denoted by $n_{\\lambda}$, and $t_i$ represents the interaction time.", "\n\n![", "\\[Fig:1\\] Experimental setup. ", "Maximally entangled photon pairs are generated by parametric down conversion (PDC) with an ultraviolet (UV) pump pulse whose spectral width can be controlled. ", "Then a series of quartz plates are added in arm $1$ and arm $2$ to realize the local dephasing channels. ", "The final two-photon polarization state is analyzed by state tomography. ", "Key to the components: NC – nonlinear crystal, FP – Fabry-Pérot cavity, DM – dispersion medium, HWP – half wave plate, QWP – quarter wave plate, IF – interference filter, QP – quartz plate, PBS – polarizing beamsplitter, and SPD – single photon detector.](fig1){width=\"40.00000%\"}\n\nAny pure initial state for the polarization degrees of freedom of the photon pair, which forms our bipartite open system, can be written as $\\ket{\\psi_{12}}=a \\ket{HH}+b\\ket{HV}+c\\ket{VH}+d\\ket{VV}$. The total system initial states are assumed to be product states $$\\label{total}\n \\ket{\\Psi(0)} = \\ket{\\psi_{12}} \\otimes \\int d\\omega_1 d\\omega_2 \\,\n g(\\omega_1,\\omega_2) \\ket{\\omega_1,\\omega_2}, \\nonumber$$ where $g(\\omega_1,\\omega_2)$ is the probability amplitude for the photon in arm $1$ to have frequency $\\omega_1$ and for the photon in arm $2$ to have frequency $\\omega_2$, with the corresponding joint probability distribution $P(\\omega_1,\\omega_2)=|g(\\omega_1,\\omega_2)|^2$.\n\nOpen system dynamics {#open-system-dynamics .unnumbered}\n--------------------\n\nThe time evolution of the open system can be represented by means of the dynamical map $\\Phi^t_{12}$ [@Breuer2007] which maps the initial polarization state $\\rho_{12}(0) = \\ket{\\psi_{12}}\\bra{\\psi_{12}}$ to the polarization state state $\\rho_{12}(t) = \\Phi^t_{12} \\big(\\rho_{12}(0)\\big)$ at time $t$. Calculating the total system time evolution and taking the trace over the environment yields [@Laine11] $$\\label{rho12}\n\\rho_{12}(t) =\\left(\\begin{array}{cccc}\n |a|^2 & a b^* \\kappa_2(t) & ac^* \\kappa_1(t)& ad^* \\kappa_{12}(t) \\\\\n b a^* \\kappa_2^*(t) & |b|^2 & b c^*\\Lambda_{12}(t) & b d^* \\kappa_1(t)\\\\\n c a^* \\kappa_1^*(t) & c b^* \\Lambda_{12}^*(t) & |c|^2 & c d^* \\kappa_2(t)\\\\\n d a^* \\kappa_{12}^*(t) & d b^* \\kappa_1^*(t) & d c^* \\kappa_2^*(t) & |d|^2\n\\end{array}\\right).$$ The dynamics represents a pure dephasing process whose decoherence functions can be expressed completely in terms of the Fourier transform of the joint probability distribution $$\\label{Gt1t2}\n G(t_1,t_2)=\\int d\\omega_1 d\\omega_2 P(\\omega_1,\\omega_2) \n e^{-i\\Delta n(\\omega_1t_1+\\omega_2t_2)}$$ as $\\kappa_1(t)=G(t_1,0)$, $\\kappa_2(t)=G(0,t_2)$, $\\kappa_{12}(t)=G(t_1,t_2)$ and $\\Lambda_{12}(t)=G(t_1,-t_2)$, where $\\Delta n = n_V - n_H$ denotes the birefringence. ", "The function $\\kappa_i(t)$ describes the decoherence of the polarization state of photon $i$ which is induced by the local coupling to its frequency environment caused by the quartz plate in arm $i$. This can be seen by taking the trace over the polarization state of photon 2 to obtain the polarization state of photon 1: $$\\rho_{1}(t)= \\left(\\begin{array}{cc}\n |a|^2+|b|^2 & (a c^*+b d^*) \\kappa_1(t) \\\\\n (c a^*+d b^*) \\kappa_1^*(t) & |c|^2+|d|^2.", "\n\\end{array}\\right),\\nonumber$$ or by tracing over photon 1 to find the state of photon 2: $$\\rho_{2}(t)=\\left(\\begin{array}{cc}\n |a|^2+|c|^2 & (a b^*+c d^*) \\kappa_2(t) \\\\\n (b a^*+d c^*) \\kappa_2^*(t) & |b|^2+|d|^2\n\\end{array}\\right).\\nonumber$$\n\nNonlocal dynamical map {#nonlocal-dynamical-map .unnumbered}\n----------------------\n\nThe nonlocal character of the dynamical map $\\Phi_{12}^t$ is controlled by the decoherence functions $\\kappa_{12}(t)$ and $\\Lambda_{12}(t)$ in Eq.", " (\\[rho12\\]). ", "As a matter of fact, the map $\\Phi_{12}^t$ is a product of local dynamical maps, i.e., $\\Phi_{12}^t=\\Phi_1^t\\otimes\\Phi_2^t$ if and only if $\\kappa_{12}(t)=\\kappa_1(t)\\kappa_2(t)$ and $\\Lambda_{12}(t)= \\kappa_1(t)\\kappa^*_2(t)$. In particular, this implies that frequency correlations in the initial state do not influence the local dynamics of each photon and cannot be detected by observing the local polarization states. ", "However, the evolution of the composite two-photon polarization state is determined by the frequency correlations in the environment which lead to memory effects and global non-Markovian dynamics. ", "This also means that, counterintuitively, by adding degrees of freedom to an open system one can change its dynamics from the Markovian to the non-Markovian regime.", "\n\nTrace distance dynamics {#trace-distance-dynamics .unnumbered}\n-----------------------\n\nTo quantify non-Markovianity we use the trace distance based measure [@BLP] which is defined by $\\mathcal{N}(\\Phi)\n=\\max_{\\rho_{A,B}(0)}\\int_{\\sigma>0}dt\\,\\sigma(t,\\rho_{ A,B}(0))$. Here, $\\sigma(t,\\rho_{A,B}(0))=\\frac{d}{dt}D(\\rho_A(t),\\rho_B(t))$ and the trace distance $D$ between two states $\\rho_A$ and $\\rho_B$ is given by $D(\\rho_A, \\rho_B) = \\frac{1}{2} \\textrm{tr}|\\rho_A-\\rho_B|$. The amount of non-Markovianity is therefore equal to the total increase of the trace distance during the time evolution and quantifies the total information flow from the environment to the system. ", "This measure has been used recently in several theoretical and experimental contexts, see, e.g. Refs.", " [@Rebentrost; @Liu; @Paternostro; @Tang].", "\n\n![", "\\[Fig:2\\] Trace distance dynamics for different values of the spectral width of the pump pulse. ", "The widths and the amounts of non-Markovianity are: (a) $\\delta=0.18\\,\\rm{nm}$, $\\mathcal{N} = 0.48$, (b) $\\delta=0.52\\,\\rm{nm}$, $\\mathcal{N} = 0.23$, (c) $\\delta=0.73\\,\\rm{nm}$, $\\mathcal{N} = 0.14$, (d) $\\delta=1.89\\,\\rm{nm}$, $\\mathcal{N} = 0.02$. The $x$-axis represents time measured by the total effective path difference between the horizontal and vertical photons caused by quartz plates in arms $1$ and $2$ ($\\lambda_0=780\\,\\rm{nm}$). ", "The $y$-axis is the trace distance between the time-evolved initial open system states $|\\psi_{12}^{+}\\rangle$ and $|\\psi_{12}^{-}\\rangle$. We first add quartz plates in arm 1. ", "When the total effective path difference between horizontal and vertical photons equals $199\\lambda_0$, we add quartz plates in arm 2. ", "The solid line shows the fit using the theoretical result of Eq.", " (\\[D\\]). ", "The error bars are due to the counting statistics. ", "See the Supplementary Information for more details on the counting statistics and the fitting of the theoretical curves.](fig2){width=\"50.00000%\"}\n\nFor anticorrelated frequencies $\\omega_i$ the pair of the Bell-states $|\\psi_{12}^{\\pm}\\rangle = \\left( |HH\\rangle \\pm |VV\\rangle\\right) / \\sqrt{2}$ maximizes the increase of the trace distance and thus determines the non-Markovianity measure $\\mathcal{N}$ [@Laine11]. ", "These states are created by using spontaneous parametric down conversion as is illustrated in Fig.", " 1. ", "A femtosecond pulse (the duration is about $150\\,\\rm{fs}$ and the operation wavelength is at $780\\,\\rm{nm}$, with a repetition rate of about $76\\,\\rm{MHz}$) generated from a Ti:sapphire laser is frequency doubled to pump two $1$mm-thick beamlike cut beta barium borate (BBO) crystals [@Niu] creating the two-photon entangled state. ", "With the help of QWP1 we can easily tune the entangled state between $\\ket{\\psi_{12}^{+}}$ (QWP1 is set at $0^{\\circ}$) and $\\ket{\\psi_{12}^{-}}$ (QWP1 is set at $90^{\\circ}$). ", "The size of the anticorrelations between the photon frequencies is controlled in the experiment by the spectrum of the UV pump pulse. ", "Since energy is conserved in the down conversion process, decreasing the spectral width of the pump pulse decreases the uncertainty of the sum of the frequencies of the photons, and hence increases the anticorrelation between the frequencies. ", "We use four different pulse widths as described in more detail in the Methods Section. ", "It is also worth noting that even though our experimental setup is based on downconversion, which is a commonly used tool to prepare specific two-photon states in quantum optical experiments, the physical phenomena that we describe and realize experimentally was theoretically predicted only very recently [@Laine11].", "\n\n![", "\\[Fig:3\\] Trace distance dynamics of the open system with different dispersions of the pump pulse. ", "The quartz plate on the path of the pump pulse has thickness (a) $0$ (b) $13.19\\,\\rm{mm}$ (c) $39.57\\,\\rm{mm}$. In all cases $K=-0.55$ and the measured values of non-Markovianity are $\\mathcal{N} = 0.14, 0.13, 0.13$. The trace distance dynamics remains the same irrespective of the character of the correlations. ", "See the Methods Section for further details.](fig3){width=\"50.00000%\"}\n\nAssuming a Gaussian joint frequency distribution $P(\\omega_1,\\omega_2)$ with identical single frequency variance $C$ and correlation coefficient $K$, the time evolution of the trace distance corresponding to the optimal Bell-state pair is found to be [@Laine11] $$\\label{D}\n D(t)= \\exp\\left[\n -\\frac{1}{2}\\Delta n^2C \\left( t_1^2 + t_2^2 - 2|K|t_1t_2 \\right) \\right].$$ For uncorrelated photon frequencies, i.e. for uncorrelated local environments we have $K=0$ and the trace distance decreases monotonically, corresponding to Markovian dynamics. ", "However, as soon as the frequencies are anticorrelated, $K<0$, the trace distance is non-monotonic which signifies quantum memory effects and non-Markovian behavior.", "\n\nConsecutive interactions with local environments {#consecutive-interactions-with-local-environments .unnumbered}\n------------------------------------------------\n\nIn our first experiment the local decoherence induced by the quartz plates in arm $1$ and arm $2$ act consecutively, and we change the size of the initial correlations between the local reservoirs by tuning the spectral width of the pump pulse. ", "The results for the open system’s trace distance dynamics are displayed in Fig.", " 2, which shows how the initial environmental correlations induce and influence the quantum non-Markovianity. ", "First, when only the quartz plate in arm $1$ is active, the trace distance decreases monotonically demonstrating that information flows continuously from the system to the environment. ", "When subsequently the quartz plate in arm $1$ becomes inactive and the quartz plate in arm $2$ active, the trace distance increases again highlighting non-Markovian behavior and a reversed flow of information from the environment back to the open system. ", "It is important to note that this increase of the trace distance implies a revival of the entanglement between the photon polarizations. ", "Whilst there exists earlier literature, e.g., on how the entanglement is transferred from the open system to the environment [@Lopez2008], or on entanglement dynamics when the qubits interact with local non-Markovian reservoirs [@Bellomo], our results are fundamentally different. ", "We demonstrate that the entanglement can revive due to the nonlocal character of the dynamical map despite of the fact that the local interaction of the qubits with their environments is completely Markovian. ", "A further important aspect of the experimental scheme is that it enables to measure the frequency correlation coefficient $K$ of the photon pairs by fitting the theoretical prediction of Eq.", " (\\[D\\]) to the experimental data. ", "The fits shown in Fig.", " 2 corresponding to panels (a)-(d) yield the values $K=-0.92$, $-0.66$, $-0.55$, and $-0.17$. Thus we see that the open system (polarization degrees of freedom) functions as a quantum probe which allows us to gain nontrivial information on the correlations in the environment (frequency degrees of freedom). ", "To the best of our knowledge, our results present the first quantitative measurement of the correlation coefficient without reconstructing the joint frequency distribution.", "\n\nClassical vs. quantum initial correlations between the local environments {#classical-vs.-quantum-initial-correlations-between-the-local-environments .unnumbered}\n-------------------------------------------------------------------------\n\nThe open system dynamics of Eq.", " (\\[rho12\\]) depends solely on the decoherence functions $\\kappa_1$, $\\kappa_2$, $\\kappa_{12}$ and $\\Lambda_{12}$ which in turn are completely determined by the Fourier transform of the joint frequency distribution $P(\\omega_1,\\omega_2)$. Therefore, also the dynamical map of the open system depends only on $P(\\omega_1,\\omega_2)$ and not on the probability amplitudes $g(\\omega_1,\\omega_2)$. This fact leads to the conclusion that the nonlocal memory effects, and the revival of entanglement observed above, do not depend on the specific phase relations between different frequency components, and consequently, whether the initial frequency correlations between the photons are of quantum or classical character. ", "To test experimentally whether the nature of the correlations plays a role in inducing the memory effects, we insert quartz plates also on the path of the pump pulse, thereby changing the dispersion relations of the pump pulse while keeping fixed the correlation coefficient $K$. The results in Fig.", " 3 show that the trace distance dynamics remains the same in this case and only depends on the correlation coefficient $K$ of the photon frequencies. ", "Thus we see that nonlocal memory effects and the revival of the entanglement between the polarization states of the photons can be induced by purely classical correlations between local environments of the open system.", "\n\n![", "\\[Fig:4\\] Trace distance dynamics for five different quartz plate configurations and a fixed correlation coefficient of $K=-0.92$. For all curves the maximal length of the quartz plates in both arms is $199\\lambda_0$, giving a maximal total effective path difference of $398\\lambda_0$. From top to bottom, the curves show the results for the cases, when we start to add quartz plates to arm $2$ when the length of the plate in arm $1$ has reached the length of $0, 75, 100, 150, 199\\lambda_0$ respectively, see the Methods Section for details. ", "Hence, in the top curve the quartz plates are added simultaneously to both arms while in the bottom curve they act consecutively. ", "The results demonstrate that the final state is the same while in terms of the information flow the behaviour is completely different. ", "For the top (red) curve information flows slowly out of the system with a small rate and, in fact, the decoherence would completely halt in the ideal ideal case of fully anticorrelated frequencies ($K=-1.0$). ", "In the other extreme, for the bottom (violet) curve information first flows out of the system with a high rate and later on returns back nearly completely indicating strong memory effects. ", "The solid lines are fits on the basis of Eq.", " (\\[D\\]), see the Methods Section for details](fig4){width=\"50.00000%\"}\n\nDifferent interaction configurations {#different-interaction-configurations .unnumbered}\n------------------------------------\n\nIn the previous experiments the local dephasing environments acted consecutively. ", "In our final experimental series we reposition the quartz plates in arm 2 so that eventually the dephasing is active simultaneously in both arms (see the Methods Section). ", "The results are shown in Fig.", " 4. ", "We observe that the final state of the open system is always the same when the total effective path difference is equal to $398\\lambda_0$. However, the amount of non-Markovianity and the flow of information from the environment to the open system decreases with increasing overlap of the action of the quartz plates. ", "This demonstrates that initial correlations between the local environments and the reordering of the quartz plates allow to engineer the information flow between local systems while keeping fixed the final state. ", "It is also important to note that when the local dephasing channels act simultaneously on our open bipartite system (the top red curve in Fig.", " 4), the initial correlations between the composite environments protect the entanglement between the qubits. ", "One can see this also from Eq.", " (\\[D\\]) which shows that for $t_1=t_2$ and $K=-1$ the trace distance remains constant and that there is thus no outflow of information from the system for the considered Bell-states.", "\n\nDiscussion {#discussion .unnumbered}\n==========\n\nWe have realized nonlocal quantum dynamical maps of a photonic system and demonstrated experimentally how initial quantum or even classical correlations between the local environments of a composite open system induce nonlocal memory effects. ", "While the global dynamics of the open system is non-Markovian, its local subsystems behave perfectly Markovian. ", "The observation of the open system dynamics yields also important information about the environment. ", "In fact, we have seen that a measurement of the non-Markovian evolution of the two-photon polarization state leads to a novel method for the determination of the correlation coefficient of the photon frequencies. ", "Thus, the open system dynamics can be viewed as a non-Markovian quantum probe which enables to extract nontrivial information on characteristic features of the environment. ", "This fact as well as our demonstration that initial correlations in the environment can protect the entanglement within an open system, could find important applications in quantum technologies and control strategies, and in the development of novel diagnostics tools for complex quantum systems.", "\n\nMethods {#methods .unnumbered}\n=======\n\nControlling the widths of the pump pulse {#controlling-the-widths-of-the-pump-pulse .unnumbered}\n----------------------------------------\n\nThe width of the pump spectrum controls the frequency anticorrelations between the pair of photons created in the down conversion process. ", "By using filters and fused silica plates, we can control the width of the pump pulses which are depicted in Fig.", " 5. ", "The laser source is filtered to $3\\,\\rm{nm}$ (FWHF) and then passes through the frequency doubler ($1.5\\,\\rm{mm}$ thick BiB$_3$O$_4$). ", "Hence, the bandwidth of the UV pulse is about $0.52\\,\\rm{nm}$ as shown in Fig.", " 5 (b). ", "To obtain a sharper spectrum, as shown in Fig.", " 5 (a), we insert a thin fused silica plate, which is $0.05\\,\\rm{mm}$ thick and coated with a partial reflecting coating on each side, with approximately $75$% at $390\\,\\rm{nm}$. For the spectra displayed in Fig.", " 5 (c) and (d), we have no filter before the doubler and no fused silica plate after the doubler, and for Fig.", " 5 (d) we also replace the doubler by a $0.3\\,\\rm{mm}$-thick BBO.", "\n\nCounting statistics {#counting-statistics .unnumbered}\n-------------------\n\nThe details of the counting statistics and pump power for the experimental results of Fig.", " 2 are as follows. ", "For Fig.", " 2 (a) the pump power is about $2.4\\,\\rm{mW}$ and the total coincident count rate on the basis vectors HH, HV, VH, VV is about $18,000$ in $10$ seconds, (b) $10\\,\\rm{mW}$ and the rate is about $35,000$ in $4$ seconds, (c) $20\\,\\rm{mW}$ and the rate is about $35,000$ in $2$ seconds, and (d) $20\\,\\rm{mW}$ and rate is about $36,000$ in $4$ seconds. ", "Please note that the coincident count rate always depends also on the bandwidth of UV pump source.", "\n\nFitting the experimental data {#fitting-the-experimental-data .unnumbered}\n-----------------------------\n\nEmploying Eq.", " (3), the theoretical fits of the experimental data presented in Figs.", " 2 and 3 have been carried out as follows. ", "We first use the function $f(x) = A\\exp\\left(-Bx^2\\right)$ to make a fit for the process when the quartz plates are added to arm 1. ", "From this process, we can find $A$ and $B$ which agree with the experimental data. ", "Then in the second part, when the quartz plate in arm 2 is active, we use the function $g(x)=A\\exp\\left[-B\\left(199^2+(x-199^2)-2|K|199 (x-199)\\right)\\right]$. Here, $199$ corresponds to the effective path difference after the first quartz plate. ", "Since $A$ and $B$ are determined by the first fit, we can easily determine $K$ from the second fit.", "\n\nFor Fig.", " 4, again keeping in mind Eq.", " (3), we can do the fitting in the following way. ", "First, we use the functions $f(x)$ and $g(x)$ mentioned above to make a fit of the lowest curve and determine $A_1$, $B_1$, and $K_1$. Then we use a function $G(x) = A\\exp\\left[ -B \\left( x^2/2 - |K| x^2/2\\right) \\right]$ to fit the top curve of the figure. ", "From here, we determine $A_2$, $B_2$, and $K_2$. Then we determine $A_0=(A_1+A_2)/2$, $B_0=(B_1+B_2)/2$, and $K_0=(K_1+K_2)/2$ which are then used to plot the functions $F(t_1,t_2)= A_0\\exp\\left[ -B_0 \\left(t_1^2 + t_2^2-2|K_0|t_1t_2\\right)\\right]$ in the figure.", "\n\nTrace distance dynamics with different dispersions of the pump pulse {#trace-distance-dynamics-with-different-dispersions-of-the-pump-pulse .unnumbered}\n--------------------------------------------------------------------\n\nFor the experimental results of Fig.", " 3, the FWHM of the pump pulse is about $0.73\\,\\rm{nm}$, the pump power is about $20\\,\\rm{mW}$, and the total coincident count rate on the basis vectors HH, HV, VH, VV is about $35,000$ in $2$ seconds.", "\n\n![", "\\[Fig:S1\\] The frequency spectra of the ultra-violet (UV) pump pulses used for the down conversion process. ", "Full widths at half maximum (FWHM) of the pulse spectra are (a) $\\delta=0.18\\,\\rm{nm}$, (c) $\\delta=0.52\\,\\rm{nm}$, (c) $\\delta=0.73\\,\\rm{nm}$, and (d) $\\delta=1.89\\,\\rm{nm}$. The solid lines represent Gaussian fits of the experimental data.](fig5){width=\"50.00000%\"}\n\nQuartz plate configurations {#quartz-plate-configurations .unnumbered}\n---------------------------\n\nFigure 6 shows the five different quartz plate configurations used for Fig.", " 4. ", "To obtain the data of Fig.", " 4, the FWHM of the UV pulse is about $0.18\\,\\rm{nm}$, the pump power is about $2.4\\,\\rm{mW}$, and the total coincident count rate on the basis vectors HH, HV, VH, VV is about $18,000$ in $10$ seconds.", "\n\n![", "\\[Fig:S2\\] The schematic view of the different quartz plate configurations. ", "The configurations from (a) to (e) correspond to the curves of Fig.", " 4 from top to bottom. ", "For all cases the maximal length of the quartz plates in both arms is $199\\lambda_0$, giving a maximal total effective path difference of $398\\lambda_0$. We start to add quartz plates to arm $2$ when the length of the plate in arm $1$ has reached the length of (a) $0$, (b) $75\\lambda_0$, (c) $100\\lambda_0$, (d) $150\\lambda_0$, and (e) $199\\lambda_0$. ](fig6)\n\nAcknowledgments {#acknowledgments .unnumbered}\n===============\n\nThis work was supported by the National Natural Science Foundation of China (Grant Nos.", " 10874162, 11074242, 11104261 and 60921091), the National Basic Research Program of China, the Foundation for the Author of National Excellent Doctoral Dissertation of PR China (Grant No.", " 200729), the Fundamental Research Funds for the Central Universities (Grant Nos.", " 2030020004 and 2030020007), the Anhui Provincial Natural Science Foundation (Grant No.", " 11040606Q47), the Academy of Finland (mobility from Finland 259827), the Magnus Ehrnrooth Foundation (Finland), the Jenny and Antti Wihuri Foundation (Finland), the Graduate School of Modern Optics and Photonics (Finland), and the German Academic Exchange Service (DAAD).", "\n\nAuthor Contributions {#author-contributions .unnumbered}\n====================\n\nB.-H.L., D.-Y.C, Y.-F.H., C.-F.L., and G.-C.G. planned, designed and implemented the experiments. 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