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Site Mobile Navigation Back to Work for ‘Mad Men’ The fourth season of “Mad Men” brings major changes for the characters, including those played by, from left, Jon Hamm, Christina Hendricks, Elisabeth Moss and January Jones.Credit Frank Ockenfels 3/AMC “WHO is Don Draper?” is the question that opens the premiere of the fourth season of “Mad Men.” And that’s an insider’s joke, a wink at viewers who have spent three years burrowing into the cryptic ad man’s buried secrets and damaged psyche. AMC’s drama about Manhattan’s advertising world in the early 1960s isn’t just a cult favorite anymore; “Mad Men” has become a cultural phenomenon much in the way “The Sopranos” once was. The two shows are mirror opposites of course. “The Sopranos” amused viewers with unexpected glimpses of bourgeois ordinariness — lawn mowing, school meetings, psychotherapy — inside the scary, alien world of organized crime. “Mad Men” offers a far more commonplace milieu — the rat race — and finds comedy in the distortions of a rear-view mirror. There lies the spectacle of people just like us doing things that today seem scary and alien, like smoking, drinking old-fashioneds at lunch, letting children play with dry-cleaner bags. Photo The “mad men” played by from left, Jared Harris, Robert Morse, Vincent Kartheiser, John Slattery and Jon Hamm.Credit Frank Ockenfels 3/AMC It’s a series set in the days of ice-cold martinis and cold war anxiety that has seduced contemporary fashion, advertising and even the English language. There are “Mad Men” Barbie and Ken dolls, a “Mad Men” clothing line at Banana Republic and pop culture books like “Mad Men and Philosophy: Nothing Is as It Seems.” The term “mad men” has become an adjective, a shorthand way to describe things that are louche, elegant and dissipated in an antediluvian way. And accordingly there is “Mad Men” overload in the air and, in some corners, even a backlash. Don’s angst at times grew tiresome, as did his marital woes. Viewers yearned to get away from the home front and back to the office skirmishes at his agency, Sterling Cooper. Fortunately the series’s creator, Matthew Weiner, has found a way to finesse “Mad Men” fatigue at the end of the third season by giving his story a mulligan. Sterling Cooper is starting over, as Sterling Cooper Draper Pryce, and so is Don. When the series began in 2007, its main characters were established, slightly jaded players in a field that was on top of its game in a nation still puffed up with postwar confidence and superpower brio. The advertising firm was so successful, despite its disreputable office parties, that it was practically white shoe. And its creative director, Don Draper (Jon Hamm), married to lovely Betty (January Jones) with two lovely children in a lovely suburb, had little to prove, except, perhaps his effortless prowess as an extramarital ladies’ man. But when Sterling Cooper’s British parent company was sold at the end of last season to an even bigger advertising behemoth, Don and his colleagues broke away and lost their complacency. Photo Mr. Hamm’s Don is no longer married to Betty, below, and he must find clients to replace those like Rachel Menken (Maggie Siff), pictured here.Credit Doug Hyun/AMC Suddenly they became small and scrappy without the huge accounts, vast office space and bottomless expenses of yesteryear. And that final episode, as Don banded his loyalists together to start a new firm, was the most exhilarating moment of the season. Now, at the beginning of Season 4, which begins next Sunday, it’s a year later, and the executives of Sterling Cooper Draper Pryce go on cattle calls to woo clients. Contracts melt away. The business is precarious and copywriters stoop to publicity stunts to gin up business. His personal life is just as altered. Betty is freshly embarked on a new marriage with Henry Francis (Christopher Stanley), an older man and an aide to Nelson Rockefeller. Henry, who has grown children from a previous marriage, promises Betty a better life — though this one comes with a scornful mother-in-law. And Don, who had women falling over themselves trying to get him into bed when he was married, finds himself alone in a dark Greenwich Village apartment, shining his own shoes and going out on blind dates. Being a bachelor back in those days, before the pill was widely used by single women and the arrival of “The Sensuous Woman,” did not automatically include swinging. Don tries to kiss a young woman in the back of a cab but can’t get any further. She won’t let him accompany her to the door to the Barbizon, then a women-only hotel, because, as she puts it coyly, “I know that trick.” Photo Betty, played by January Jones, is freshly embarked on a new marriage in Season 4.Credit Carin Baer/AMC “Mad Men” keeps confounding expectations — the ’60s fashion, mores and cultural landmarks keep getting more familiar, but the characters maintain an elusive weirdness. Betty looks like Grace Kelly, but she seems blandly prosaic — except when she picks up a BB gun and shoots the neighbor’s pigeons, a cigarette dangling from her perfectly curved lips. Pete Campbell (Vincent Kartheiser) would be just another irritating office brown-noser, a prep school Sammy Glick, except that he too has a screw loose and a mystical rapport with firearms. Peggy (Elisabeth Moss) should be an easily identified Rona Jaffe heroine — an unmarried career woman breaking the barriers of sexism — but she too is peculiar and enigmatic. Even Don and Betty’s forlorn daughter, Sally (Kiernan Shipka), is more strange than sad. “Mad Men” is a period piece that reverses the template. Historical dramas like “The Tudors” or “John Adams” sift through a remote, archaic culture to highlight the most familiar and contemporary concerns of historical characters. “Mad Men” wallows in the comfort of a recent and well-known past by way of characters who are always a little opaque and unknowable. The narrative snakes through a Life magazine timeline of political turmoil and social change — the John F. Kennedy assassination is a transforming event, and so are the poems of Frank O’Hara and the songs of Bob Dylan. In the season premiere, a character cites the killing of Andrew Goodman, the civil rights volunteer who was murdered with two co-workers in Mississippi. It’s a mention that marks the year as 1964 and the mood of the country as nearing a boiling point. Or as one character puts it, “The world is so dark right now.” Photo Elisabeth Moss is fighting sexism as Peggy.Credit Carin Baer/AMC But it isn’t always obvious to those living in it. Copywriters goof around at work. Peggy and a young colleague jokingly coo the names “Marsha” and “John” at each other, an oblique nod to Stan Freberg, an ad writer and comedian who had a huge hit in 1951 with a recorded single, “John & Marsha,” a soap opera parody in which actors intone the words “John” and “Marsha” over and over to organ music. Don has dinner at Jimmy’s La Grange, a Midtown restaurant favored by advertising executives where chicken à la Kiev is a specialty, and diners are given bibs to protect them from the splatter of butter. Those kinds of oblique references tether the fictional world of Sterling Cooper Draper Pryce to the real advertising world of those times. That’s partly professional pride on the part of the writers, who dread complaints from old ad executives. Emeritus “mad men” can be as finicky and exacting about the historical details of their bygone days as Civil War re-enactors are about the uniforms worn at Bull Run. But those cues also hold out the promise that the coming season will once again pivot the story on the workplace. It’s where “Mad Men” started and where it was best. A fresh start at the rat race is just what the series needs. Correction: July 25, 2010 An article last Sunday about the premiere of the fourth season of “Mad Men” misspelled part of the name of the advertising agency featured on the show. It is Sterling Cooper Draper Pryce, not Sterling Cooper Draper Bryce. The article also referred imprecisely to 1964 as “those days before the pill.” While birth-control pills were not widely available to single women until late in the decade, they were available on a limited basis in 1964, having been approved by the Food and Drug Administration in 1960.	{ "pile_set_name": "Pile-CC" }
Q: jQuery - if two classes - get the first one Example: Here we have <p class="tab1 current"></p> How can I get only the first class? var GetFirstClass = $('p').attr('class').filter(':first'); ?? Any help much appreciated. A: Use JavaScript's split function: $('p').attr('class').split(' ')[0] Demo A: $('p').attr('class').split(' ')[0]	{ "pile_set_name": "StackExchange" }
(The January 19 story corrects last paragraph to say coronation will be first in living memory for most Thais, but not all.) Slideshow ( 5 images ) BANGKOK (Reuters) - Rival groups held demonstrations in Thailand’s capital on Saturday, with hundreds of people demanding quick elections to end military rule and a much smaller group of pro-junta supporters saying it was too soon for a vote. The competing protests were tiny compared to those that paralyzed Bangkok in 2014 before the army seized power in the name of ending instability, but were an indication of the tensions in the run-up to a long-delayed ballot. No date has been set for an election which was first promised for 2015 and most recently postponed from Feb. 24. Hundreds joined a demonstration calling for elections on March 10. “We’re calling for elections as soon as possible,” activist Sirawith Seritiwa told the crowd. The junta has said the most recent election delay is because of scheduling difficulties with planning for the coronation of King Maha Vajiralongkorn in early May - although it has said it still wants the ballot held before those ceremonies. The Election Commission of Thailand has given March 10 or March 24 as possible polling dates, but no date has been set and a royal decree must be issued before it can be. Some 1 km (0.6 miles) from the demonstration calling for elections, around 30 counter-protesters gathered with placards at the Democracy Monument. They said they were not opposed to a ballot, but national unity must come first. “We can wait for elections,” the group’s leader, Jathurun Bunbenjara, told reporters. “We don’t agree with protests that create chaos... We want to see Thais come together and hold an auspicious and great coronation.” Thailand’s longstanding political divide is between strongly royalist and pro-military conservatives and “red shirt” populists linked to exiled former premier Thaksin Shinawatra who have won every election since 2001. Despite measures by the junta to entrench the ruling generals’ hold on power after any election, opinion polls have shown that Thaksin’s supporters remain politically strong. Activist Sirawith denied that the group intended to create chaos ahead of the coronation - saying that holding elections earlier would reduce that danger. For most people it will be the first Thai coronation in living memory. The king’s revered late father reigned for more than 70 years until his death in 2016.	{ "pile_set_name": "OpenWebText2" }
1. Field of the Invention The present invention relates to warming fluids, and in particular, to warming IV fluid solution bags for use in the medical field. The present invention uses a safe and unique apparatus to heat and store a plurality of IV bags at the locations where they are to be used. 2. Description of the Prior Art The availability of a reliable and convenient source of warm (105.degree. F./40.degree. C.) intravenous fluid solution is important in medical applications and more particularly in an operating environment where large quantities of IV fluids may be necessary. Systems found in the prior art often require depletion of the self-contained sterilized IV fluid bag/container to heat the fluid. Removal of the fluid introduces unnecessary risk (i.e., contamination) and fails to provide for a regulated supply which is simple to use and is a convenient source of warmed IV fluid solutions. These prior art systems often require large and complex devices requiring a circulation unit to withdraw the fluid from a bag or other storage container. The removed fluids are then distributed across or through a variety of heating sources and returned to a separate container. Examples of such prior art systems may be found in the following U.S. Pat. Nos. to Rosner (4,678,460), Ogawa (4,293,762), Le Boeuf (4,309,592), Kurucz (4,844,074), van Leerdam (4,906,816) and Jewett (4,464,563). Each of the above cited patents show systems where removing the fluid is essential for proper heating. Prior art references directed to heating a fluid without removal of the fluid are detailed below. Each of the references fail to provide for a configuration similar to that of the present invention. The U.S. Pat. No. to White (4,936,336) is an apparatus and method for the warming of intravenous equipment consisting of an insulated wrap material having a removable and reusable heat pack. This reference fails to provide for a regulated source of heat integrated within a cabinet structure. To provide for a reliable heating source requires strict attention to temperature changes and distribution thereof. The heating source of White is a heat pack which does not maintain a specified thermal transfer ratio throughout the heating cycle and must be reheated and replaced each time heating is to take place. White is also limited to, at the most, two intravenous bags and has no provisions for adding additional bags. This becomes a problem in the operating room environment where a large quantity of heated bags are needed. The U.S. Pat. Nos. to Nicholas Marchiani Chatelain et al. (4,874,033) and Auerbach (4,801,777) are directed to methods and apparatuses for heating blood products. Both of these references require the submerging of a blood bag in water which is then heated by some means. Applicant's invention is not directed to heating blood products and further requires no source of water to operate. The requirement of providing a water source limits these devices to locations to where an immediate source of water is available. Applicant's instant invention can be used anywhere. The invention also is more convenient as no fluids other than the fluid to be heated are introduced into the system. The U.S. Pat. No. to Coffey (4,657,004) is a mobile livestock intensive care unit having a temperature controlled fluid/medicine chamber. This reference fails to provide for applicant's specific heating cabinet structure and associated electronics.	{ "pile_set_name": "USPTO Backgrounds" }
See editorial on page 293. SummaryWe have identified 5 molecularly and clinically relevant subtypes of the CpG island methylator phenotype (CIMP) in colorectal cancer. We show that CIMP-high cancers segregate into distinct subgroups, which display different frequencies of BRAF and KRAS mutation. These CIMP subtypes are associated with important clinical and molecular features, are correlated with mutations in different epigenetic regulator genes, and show a marked relationship with patient age. Colorectal cancer is a heterogeneous disease characterized by distinct genetic and epigenetic changes that drive proliferative activity and inhibit apoptosis. The conventional pathway to colorectal cancer is distinguished by APC mutation and chromosomal instability, and accounts for approximately 75% of sporadic cancers.[@bib1], [@bib2] The remaining colorectal cancers arise from serrated polyps and have activating mutations in the BRAF proto-oncogene, frequent microsatellite instability (MSI), and the CpG island methylator phenotype (CIMP).[@bib2], [@bib3] The development of CIMP is critical in the progression of serrated neoplasia.[@bib3] It is well established that CIMP can result in the silencing of key genes important for tumor progression, including the tumor-suppressor gene CDKN2A and the DNA mismatch repair gene MLH1.[@bib4], [@bib5] Gene silencing mediated by MLH1 promoter hypermethylation impairs mismatch repair function, which leads to MSI.[@bib5] CIMP can be detected using a standardized marker panel to stratify tumors as CIMP-high, CIMP-low, or CIMP-negative.[@bib3] Activation of the mitogen-activated protein kinase signaling pathway as a result of the BRAF mutation is associated highly with CIMP-high. CIMP-high cancers frequently arise proximal to the splenic flexure and are more common in elderly female patients,[@bib2], [@bib3] whereas CIMP-low cancers have been associated with KRAS mutation.[@bib6], [@bib7] More recently, consensus molecular subtyping (CMS) was proposed for classifying colorectal cancers based on transcriptional signatures. Guinney et al[@bib8] identified 4 major molecular subtypes (CMS1--CMS4). CMS1, or MSI immune subtype, is characterized by MSI, BRAF mutation, and enhanced immunogenicity. CMS2 can be distinguished by chromosomal instability and WNT pathway perturbations. CMS3, or metabolic subtype, is characterized by KRAS mutation, CIMP-low status, and infrequent copy number alterations. CMS4, or mesenchymal subtype, shows high copy number aberrations, activation of the transforming growth factor-β signaling cascade, stromal infiltration, and the worst overall survival. The relationship between CIMP and CMS subtypes is currently unclear. Methylation is not a phenomenon distinct to neoplasia. Changes in the epigenome also occur with age and in response to environmental factors.[@bib9], [@bib10] We previously showed that the promoter region of certain genes becomes increasingly methylated in normal colonic mucosa with age.[@bib9] CIMP-high cancers are identified primarily in older patients,[@bib2] hence, age-related hypermethylation might prime the intestinal epigenome for serrated neoplasia-type colorectal cancers. Methylation also is critical in the progression of serrated pathway precursors to invasive cancer, primarily through methylation of MLH1 at the transition to dysplasia.[@bib11], [@bib12] Thus, the natural history of the cancer within the colorectum may dictate the methylation profile of the cancer once malignancy develops. DNA methylation alone can be insufficient to induce transcriptional repression.[@bib13] Gene repression also is associated with repressive histone marks such as the H3K27me3 mark,[@bib14] which is catalyzed by the polycomb-repressor-complex 2. Modification of histone tails is catalyzed by a series of enzymes including epigenetic readers, which scan for histone modifications; writers, which effect the addition of a modification; and erasers, which are responsible for the removal of histone marks. Mutations in genes encoding epigenetic enzymes have been shown to occur frequently in cancer.[@bib15] Although DNA methylation is associated classically with gene silencing, the relationship between DNA methylation and histone modifications has not been fully elucidated, and the role of somatic mutations in enzymes that catalyze these epigenetic processes has not been examined comprehensively. In this study, we define the extent and spectrum of DNA methylation changes occurring in colorectal cancers and relate this to key clinical and molecular events characteristic of defined pathways of tumor progression. We investigate the role of DNA methylation in the modulation of gene transcription, and assess mutation of genes encoding epigenetic regulatory proteins. Results {#sec1} ======= Clinical and Molecular Features of the Consecutive Cohort in Comparison With the Cancer Genome Atlas Cohort {#sec1.1} ----------------------------------------------------------------------------------------------------------- Genome-wide DNA methylation levels were assessed in 216 unselected colorectal cancers ([Table 1](#tbl1){ref-type="table"}). The mean age of patients at surgery was 67.9 years. Twenty-nine of 216 (13.4%) cancers had a BRAF V600E mutation, and 75 of 216 (34.7%) cancers were mutated at KRAS codons 12 or 13. Mutation of BRAF and KRAS were mutually exclusive. Patients with BRAF mutated cancers were significantly older than patients with BRAF wild-type cancers (mean age, 74.9 vs 66.9 y; P = .01). TP53 was mutated in 78 of 185 (42.2%) cancers. MSI was associated significantly with BRAF mutation (18 of 29 BRAF mutant vs 9 of 187 BRAF wild-type cancers; P \< .0001). By using the Weisenberger et al[@bib3] panel to determine CIMP status, 24 of 216 (11.1%) were CIMP-high, 44 of 216 (20.4%) were CIMP-low, and 148 of 216 (68.5%) were CIMP-negative. CIMP-high was associated significantly with BRAF mutation compared with BRAF wild-type cancers (19 of 29 vs 5 of 186; P \< .0001). CIMP-low was associated significantly with KRAS mutation compared with KRAS wild-type cancers (26 of 75 \[34.6%\] vs 18 of 141 \[12.8%\]; P \< .001).Table 1Clinicopathologic Details of the 216 Colorectal Adenocarcinomas as Stratified for Methylation-Based CIMP Clustering, Measured on Illumina HM450 Arrays, Using the 5000 Most Variable CpG Sites That Were Not Hypermethylated in Normal Mucosal TissuenCIMP-H1CIMP-H2CIMP-L1CIMP-L2CIMP-NegP valueTotal, n2162322526653Mean age, y67.975.273.470.166.861.9\<.0001Sex Male100 (46.4%)5 (21.7%)9 (40.9%)24 (46.2%)35 (53.0%)27 (50.9%).11 Female116 (53.7%)18 (78.3%)13 (59.1%)28 (53.8%)31 (47.0%)26 (49.1%)Site Proximal75/213 (35.2%)19 (82.6%)13 (59.1%)20 (39.2%)15 (23.4%)8 (15.1%)\<.0001 Distal96/213 (45.1%)4 (17.4%)6 (27.3%)21 (41.2%)32 (50.0%)33 (62.3%) Rectal42/213 (19.7%)03 (13.6%)10 (19.6%)17 (26.6%)12 (22.6%)CIMP status CIMP-high24 (11.1%)16 (69.6%)3 (13.6%)3 (5.8%)2 (3.0%)0\<.0001 CIMP-low44 (20.4%)6 (26.1%)13 (59.1%)16 (30.8%)8 (12.1%)1 (1.9%) CIMP-neg148 (68.5%)1 (4.3%)6 (27.3%)33 (63.5%)56 (84.8%)52 (98.1%)Mutation KRAS mutant75 (34.7%)4 (17.4%)12 (54.5%)34 (65.4%)19 (28.8%)7 (13.2%)\<.0001 BRAF mutant29 (13.4%)17 (73.9%)2 (9.1%)6 (11.5%)4 (6.0%)0 (0%)\<.0001 TP53 mutant77/185 (41.6%)12/21 (57.1%)6/21 (28.6%)18/45 (40.0%)22/54 (40.7%)19/44 (43.2%).45Microsatellite instability MSI26 (12.0%)11 (47.8%)1 (4.8%)8 (15.4%)6 (9.1%)0\<.0001 MSS190 (88.0%)12 (52.2%)21 (95.2%)44 (84.6%)60 (90.9%)0CMS CMS135 (16.2%)16 (69.6%)4 (18.2%)5 (9.6%)9 (13.6%)1 (1.9%)\<.0001 CMS268 (31.5%)04 (18.2%)10 (19.2%)30 (45.5%)24 (45.3%) CMS353 (24.5%)3 (13.0%)12 (54.5%)21 (40.4%)10 (15.2%)7 (13.2%) CMS460 (27.8%)4 (17.4%)2 (9.1%)16 (30.8%)17 (25.8%)21 (39.6%)Stage I30/1110/155/11 (45.5%)8/30 (26.7%)13/35 (37.1%)4/20 (20.0%).15 II33/1117/15 (46.7%)1/11 (9.1%)10/30 (33.3%)10/35 (28.6%)5/20 (25.0%) III34/1116/15 (40.0%)4/11 (36.4%)7/30 (23.3%)11/35 (31.4%)6/20 (30.0%) IV14/1112/15 (13.3%)1/11 (9.1%)5/30 (16.7%)1/35 (2.9%)5/20 (25.0%)LINE170.368.7568.9672.0570.4569.67.38[^1][^2] We collected a subset of 32 matched noncancerous mucosal samples from patients in the consecutive cohort. The mean age of patients within the cohort of matched normal samples was 68.9, and was not significantly different than the mean age of patients in the wider cohort (P = .71). Methylation-Based Clustering Shows 5 Subtypes of Colorectal Cancer With Distinct Clinical and Molecular Features {#sec1.2} ---------------------------------------------------------------------------------------------------------------- We examined the extent and spectrum of DNA methylation changes in these 216 colorectal cancers using Illumina HumanMethylation450 BeadChip arrays (Illumina Inc, San Diego, CA). Five clusters were identified by recursively partitioned mixed model (RPMM) clustering ([Figure 1](#fig1){ref-type="fig"}). These included 2 clusters with high levels of methylation that we have designated CIMP-H1 and CIMP-H2; 2 clusters with intermediate levels of methylation, CIMP-L1 and CIMP-L2; and a single cluster with low levels of methylation, CIMP-neg. There was a significant stepwise increase in age between clusters concordant with increasing genomic methylation (CIMP-neg, 61.9 y; CIMP-L2, 66.8 y; CIMP-L1, 70.1 y; CIMP-H2, 73.4 y; and CIMP-H1, 75.2 y; P \< .0001) ([Table 1](#tbl1){ref-type="table"}).Figure 1Methylation heatmap of unselected 216 colorectal cancers using the 5000 most variable β values in CpG sites that were not hypermethylated in normal mucosal tissue. Clustering was performed using the RPMM R package. Clustering showed 5 distinct clusters, termed CIMP-H1, CIMP-H2, CIMP-L1, CIMP-L2, and CIMP-Neg. This was faithfully recapitulated in TCGA. The CIMP-H1 subgroup comprised 23 of all 216 (10.6%) cancers and was enriched for female patients (18 of 23, 78.3%; P \< .0001) and for tumors located proximal to the splenic flexure (19 of 23, 82.6%; P \< .0001). We observed no differences in cancer stage at diagnosis and methylation cluster. The CIMP-H1 cluster was strikingly enriched for cancers with features characteristic of serrated neoplasia, including BRAF mutation (17 of 23, 73.9%; P \< .0001), CIMP-H status was determined using the Weisenberger et al[@bib3] marker panel (16 of 23, 69.6%; P \< .0001), MSI (11 of 23, 47.8%; P \< .0001), and consensus molecular subtype CMS1 (16 of 23, 69.6%; P \< .0001) ([Table 1](#tbl1){ref-type="table"}, [Figure 1](#fig1){ref-type="fig"}). TP53 was mutated in 12 of 21 (57.1%) CIMP-H1 cluster cancers. CIMP-H2 cluster cancers also frequently arose in the proximal colon (consecutive cohort, 13 of 22; 59.1%). CIMP-H2 cancers were KRAS mutant more often than CIMP-H1 cancers (54.5% vs 17.4%), and were less often TP53 mutant when compared with the rest of the cohort (28.6%). The incidence of MSI within these cancers was low (4.8%). The frequency of the metabolic CMS3 subtype was higher than in the other CIMP subtypes (54.5%). CIMP-H2 cancers were significantly less likely to be identified as CIMP-high using the Weisenberger et al[@bib3] MethyLight panel when compared with CIMP-H1 cancers (13.6% vs 69.6%; P \< .001). CIMP-L1 cancers were significantly enriched for KRAS mutation (65.4%; P \< .0001), and were identified equally in the distal and proximal colon. These cancers were rarely MSI (15.4%), and were often the CMS3 (40.4%) or CMS4 (30.8%) subtype. CIMP-L2 cancers mutate KRAS with relative infrequency when compared with CIMP-H2 and CIMP-L1 cancers (28.8%), and are significantly enriched for distal colonic and rectal locations (50% and 26.6%, for distal and rectal locations, respectively; P \< .0001). The proportion of CMS2 cancers was significantly higher in CIMP-L2 cancers when compared with CIMP-H1, CIMP-H2, and CIMP-L1 cancers (P \< .001). The frequency of distal colonic location was the highest among CIMP-neg cancers (62.3%) and were identified in patients with the youngest mean age (61.9 y). We did not identify a BRAF mutation in any CIMP-neg cancers. CMS2 and CMS4 were the most frequent CMS subtypes in CIMP-neg cancers (45.3% and 39.6%, respectively). The proportion of CMS4 was highest in CIMP-neg cancers when compared with other subtypes (P \< .001). We sequenced hotspots on exons 11 and 15 of BRAF, codon 61 in KRAS, and exon 18 in EGFR in CIMP-H1/H2 cancers that were wild-type at BRAF V600E and KRAS codons 12 and 13, however, we did not identify any mutations in these regions. Validation of the Association Between CIMP Subtype and Clinical and Molecular Features in The Cancer Genome Atlas {#sec1.3} ----------------------------------------------------------------------------------------------------------------- DNA methylation was previously measured using the HumanMethylation 450 array in 392 colorectal cancers from The Cancer Genome Atlas (TCGA) project.[@bib16] We observed several differences in the TCGA cohort when compared with the consecutive Royal Brisbane and Women\'s Hospital (RBWH) cohort. The mean age of patients at the time of diagnosis was significantly lower in the TCGA cohort when compared with the consecutive cohort (64.5 vs 67.9; P \< .01). Male sex was slightly over-represented (199 of 373; 53.4%). The distribution of cancers throughout the colon was significantly different in the TCGA cohort. Cancers in the TCGA were significantly enriched for proximal location in comparison with the RBWH cohort (47.0% vs 35.2%; P \< .01), and less likely to be located in the distal colon (40.3% vs 45.1%; P \< .01) or rectum (12.7% vs 19.7%; P \< .01). There were many similarities between the TCGA and RBWH cohorts. The frequency of BRAF mutations was 9.4%, and was not significantly different from the proportion observed in the RBWH cohort. Likewise, there was no significant difference in the frequency of KRAS mutations between the cohorts (40.1% vs 34.7%, for TCGA and RBWH cohorts, respectively). The proportion of microsatellite unstable cancers was not significantly different between the 2 cohorts (15.9% vs 12%; P = .1). Despite underlying differences in the clinical and molecular features of the cohorts, unsupervised clustering using the same methods as was used in the RBWH cohorts also resulted in the 5 distinct CIMP clusters identified in the TCGA series ([Table 2](#tbl2){ref-type="table"}, [Figure 1](#fig1){ref-type="fig"}). There was a similar, striking association between CIMP subtype and biological age (P \< .0001). In keeping with the RBWH cohort, increasing CIMP in the TCGA cohort was associated with proximal colonic location (P \< .0001), and was correlated inversely with distal and rectal locations (P \< .0001 and P \< .05, for distal and rectal locations, respectively). The distribution of KRAS mutations in CIMP subtypes followed a similar bell-shaped distribution, and were most common in CIMP-L1 cancers (48 of 81; 59.3%), and least common in CIMP-H1 (5 of 22; 26.3%) and CIMP-negative cancers (21 of 102; 20.6%). Notably, KRAS mutation was more common in CIMP-H2 cancers when compared with CIMP-H1 cancers in the TCGA cohort (43.6% vs 26.3%).Table 2Clinicopathologic and Molecular Details of 374 Colorectal Adenocarcinomas From TCGA Stratified for CIMP SubtypenCIMP-H1CIMP-H2CIMP-L1CIMP-L2CIMP-negP valueTotal, n37419 (5.1%)39(10.4%)81 (21.7%)133 (35.6%)102 (27.3%)Mean age, y64.572.267.866.564.557.1\<.0001Sex Male1997 (36.8%)21 (53.8%)47 (58.0%)74 (55.6%)50 (49.5%)NS Female17412 (63.2%)18 (46.2%)34 (42.0%)59 (44.4%)51 (50.5%)Site Proximal16717 (100%)28 (84.8%)53 (67.9%)53 (40.8%)16 (16.5%)\<.0001 Distal143f04 (12.1%)18 (23.1%)57 (43.8%)64 (65.9%) Rectal4501 (3.0%)7 (9.0%)20 (15.4%)17 (17.5%)Mutation BRAF3510 (52.6%)19 (48.7%)5 (6.2%)1 (0.8%)0\<.0001 KRAS1505 (26.3%)17 (43.6%)48 (59.3%)59 (44.4%)21 (20.6%)\<.0001 TP5323410 (52.6%)19 (48.7%)44 (54.3%)85 (63.9%)76 (74.5%).01Microsatellite instability MSI5110 (52.6%)17 (50%)11 (16.7%)7 (6.2%)6 (6.7%)\<.0001 MSS2699 (47.4%)17 (50%)55 (83.3%)105 (93.8%)83 (93.3%)CMS CMS14210 (58.8%)20 (69%)9 (14.3%)3 (2.8%)0 (0%)\<.0001 CMS21212 (11.8%)1 (3.4%)25 (39.7%)48 (45.3%)45 (51.1%) CMS3454 (23.5%)4 (13.8%)16 (25.4%)14 (13.2%)7 (8%) CMS4951 (5.9%)4 (13.8%)13 (20.6%)41 (38.7%)36 (40.9%)Stage I543 (15%)9 (23.7%)16 (20.8%)11 (8.7%)15 (16%)\<.01 II1339 (45%)18 (47.4%)32 (41.6%)50 (39.4%)24 (25.5%) III1195 (25%)11 (28.9%)20 (26%)46 (36.2%)37 (39.4%) IV503 (15%)0 (0%)9 (11.7%)20 (15.7%)18 (19.1%)[^3][^4] In both cohorts, CMS2 cancers were most frequent in CIMP-L2 (TCGA, 45.3%; RBWH, 45.5%) and CIMP-negative (TCGA, 51.1%; RBWH, 45.3%). Likewise, CIMP-neg cancers were strongly enriched for the CMS4 subtype in both cohorts (TCGA, 40.9%; RBWH, 39.6%) In contrast to the RBWH cohort, CIMP-H1 cancers were less frequent overall (TCGA, 5.1%; RBWH, 10.6%) and BRAF mutation was associated with CIMP-H1 and CIMP-H2 (CIMP-H1: TCGA, 52.6%; RBWH, 73.9%; CIMP-H2: TCGA, 48.7%; RBWH, 9.1%). Perhaps as a consequence of the increased frequency of BRAF mutations in TCGA CIMP-H2 cancers, MSI was significantly more enriched in CIMP-H2 cancers in the TCGA cohort (50%). Although we did not identify any association between stage and CIMP subtype in the RBWH cohort, late-stage disease was associated significantly with decreasing CIMP in the TCGA cohort (stage IV: CIMP-H1, 15%; CIMP-H2, 0%; CIMP-L1, 11.7%; CIMP-L2, 15.7%; and CIMP-neg, 19.1%; P \< .01). The Colorectal Cancer Methylome Is Altered in Comparison With Normal Mucosa {#sec1.4} --------------------------------------------------------------------------- We identified differentially methylated probes in each cluster compared with 32 normal mucosal samples that matched a subset of cancers in the unselected series ([Table 3](#tbl3){ref-type="table"}). In all 4 CIMP clusters (CIMP-H1, -H2, -L1, and -L2), the number of differentially hypermethylated CpG sites greatly exceeded those that were hypomethylated ([Table 3](#tbl3){ref-type="table"}). By contrast, in the single CIMP-negative cluster, hypomethylation was more common than hypermethylation. Probe hypermethylation was most frequent in the CIMP-H1 cluster, including 21,168 hypermethylated probes occurring within 5165 unique CpG islands. Of these, 4333 also were hypermethylated in CIMP-H2, whereas 832 were uniquely hypermethylated in CIMP-H1. An additional 523 CpG islands were uniquely hypermethylated in the CIMP-H2 cluster relative to CIMP-H1. The highest number of hypomethylation events was seen in the CIMP-H2 cluster compared with all other clusters (P \< .0001), with the majority occurring in open sea regions of the genome.Table 3Distribution of Differentially Hypermethylated Probes in Reference to CpG Islands Vs Normal Mucosal TissueCpG locationCIMP-H1CIMP-H2CIMP-L1CIMP-L2CIMP-neg+-+-+-+-+-Island21,01120419,65142611,2971185685127754162South Shore319658630031359125342651328478242North Shore4745890464118852095617911420184346South Shelf2297431811620835744933119238North Shelf2807382591660925915834235246Sea20568396172115,575647681229741891043428Total31,51711,55729,45322,52515,46791387513569311744662[^5][^6] Next, we examined the impact of our chosen β value change threshold on the number of differential methylation events we were able to detect. Shifting the β value change threshold to 0.3 substantially reduced the number of differentially methylated probes identified (to 47.1%, 47.8%, 24.9%, 13.4%, and 5.8% of the probes identified at 0.2 for CIMP-H1 to CIMP-neg, respectively). When we increased the threshold to 0.4 we saw a similar, and more drastic, reduction in our ability to identify differentially methylated probes (DMPs) (18.9%, 19.5%, 4.1%, 1.2%, 0.3% of probes identified at 0.2 for CIMP-H1 to CIMP-Neg, respectively). There was a significant relationship between CIMP subtype and the magnitude of the DMPs identified (P \< .0001). We compared the probes that were differentially hypermethylated (vs normal mucosa) in the RBWH cohort with those differentially hypermethylated in the TCGA cohort. There was a remarkable degree of overlap in differentially methylated loci. In CIMP-H1, 80.2% of differentially hypermethylated loci were detected in both the RBWH and TCGA cohorts. Of the remaining 7481 probes, 6009 were detected solely in the TCGA and 1472 in the RBWH cohorts. We hypothesized that the β cut-off value (\>0.2 mean β value difference vs normal) may have resulted in the filtering of many of the probes that were detected in 1 cohort only. Indeed, of the 7481 DMPs detected in 1 cohort only, the methylation level of 98.5% was statistically significantly different from normal colonic mucosa in the other cohort, but were filtered as a result of the difference in the β cut-off value. This was consistent across all CIMP subtypes. The events that were recognized in 2 independent cohorts are likely to be bona fide differential methylation events. These data indicated that the selection of an appropriate difference in the β cut-off value is critical and that applying stringent cut-off values may significantly increase the type II error rate when reporting differentially methylated events. CIMP Subtypes Are Associated With Different Stromal Immune Cell Composition {#sec1.5} --------------------------------------------------------------------------- We hypothesized that CIMP subtypes may differ in their stromal cell type composition. We used CIBERSORT to deconvolute the relative composition of immune cells in the tumor microenvironment.[@bib17] CIMP-H1 cancers were enriched for M1 macrophages in comparison with all other CIMP subtypes, with the exception of CIMP-L2 cancers (P \< .01 vs CIMP-H2, P = .02 vs CIMP-L1, and P = .01 vs CIMP-neg). CIMP-H2 cancers were enriched for resting CD4 T memory cells (P \< .01), and were depleted for M1 macrophages (P = .01). Mast cells were associated inversely with DNA methylation subtype, with mast cells contributing least to the immune microenvironment in CIMP-H1 cancers and increasing in a stepwise manner from CIMP-H1 to CIMP-neg (P = .01). Conversely, natural killer cells were associated with CIMP-H cancers (analysis of variance, P \< .05), but did not differ between CIMP-H1 and CIMP-H2. CIMP-H1 and CIMP-H2 Cancers Can Be Delineated by Expression Profiles {#sec1.6} -------------------------------------------------------------------- To examine the extent to which CIMP-H1 and CIMP-H2 are transcriptionally distinct, we analyzed differential expression for each cluster with respect to normal mucosa using Illumina HT-12 expression arrays. We then performed single-sample gene set enrichment analysis[@bib18] to evaluate enrichments in the Hallmark gene set[@bib19] in individual samples (false-discovery rate \[FDR\] corrected, P \< .05). We identified 10 gene sets significantly enriched in CIMP-H1 cancers, 7 of which were related to the immune response ([Figure 2](#fig2){ref-type="fig"}). The bile acid metabolism gene set was significantly enriched in CIMP-H2 cancers. In TCGA we did not identify any significant differences in immune response or bile acid metabolism. This may be owing to the increased frequency of BRAF mutant MSI cancers in CIMP-H2 cancers in TCGA.Figure 2Differentially regulated hallmark gene sets between CIMP-H1 and CIMP-H2 cancers as assessed by single-sample gene set enrichment analysis. IL, interleukin; ssGSEA, single sample gene set enrichment analysis. Relationship Between Promoter Hypermethylation and Gene Transcriptional Activity {#sec1.7} -------------------------------------------------------------------------------- To determine the frequency of which DNA hypermethylation in promoter regions controls transcription of downstream genes, we examined the transcript levels for genes where the promoter was hypermethylated relative normal mucosa. Although promoter methylation was most common in CIMP-H1 and CIMP-H2 clusters ([Figure 3](#fig3){ref-type="fig"}A), these subgroups had the lowest proportion of genes in which hypermethylation correlated with reduced transcript expression (13.9% and 15.6%, respectively). This inverse relationship continued for CIMP-L1 (18.9%), CIMP-L2 (19.9%), and with the CIMP-negative cancers, with reduced transcription in 22.7% of hypermethylated promoters (P \< .0001) ([Figure 3](#fig3){ref-type="fig"}B). We observed a similar relationship between gene transcription and promoter methylation in cancers in TCGA. In TCGA, the proportion of methylated genes that resulted in gene transcription repression did not differ between CIMP subtypes.Figure 3(A) Number of differentially methylated promoters in each CIMP cluster vs the cohort of normal mucosal samples. (B) The proportion of methylation events within each cluster that resulted in gene repression at the transcript level. We considered that loci that were methylated and repressed in multiple CIMP clusters may be genes that are important for cancer development. Strikingly, of the 1273 genes that were methylated and repressed in at least 1 CIMP cluster, 82.3% were methylated and repressed in 2 or more CIMP clusters, 16.9% silenced in 3 or more CIMP subtypes, and 8.0% in all 4 CIMP subtypes (excluding CIMP-negative). We identified 21 tumor-suppressor genes, as per the Network of Cancer Genes (NCG)6.0 database, that were recurrently methylated and silenced in 3 or more CIMP subtypes ([Table 4](#tbl4){ref-type="table"}).Table 4Tumor-Suppressor Genes That Were Recurrently Methylated and Repressed in More Than 3 CIMP SubtypesGene nameDescriptionPCDH9Protocadherin 9 (source: HGNC symbol; Acc: HGNC: 8661)CDO1Cysteine dioxygenase type 1 (source: HGNC symbol; Acc: HGNC: 1795)MALMal, T-cell differentiation protein (source: HGNC symbol; Acc: HGNC: 6817)EPB41L3Erythrocyte membrane protein band 4.1-like 3 (source: HGNC symbol; Acc: HGNC: 3380)AKAP12A-kinase anchoring protein 12 (source: HGNC symbol; Acc: HGNC: 370)NDRG4NDRG family member 4 (source: HGNC symbol; Acc: HGNC: 14466)LIFRLIF-receptor α (source: HGNC symbol; Acc: HGNC: 6597)SCUBE2Signal peptide, CUB domain, and EGF-like domain containing 2 (source: HGNC symbol; Acc: HGNC: 30425)TMEFF2Transmembrane protein with EGF-like and 2 follistatin-like domains 2 (source: HGNC symbol; Acc: HGNC: 11867)DUSP26Dual-specificity phosphatase 26 (source: HGNC symbol; Acc: HGNC: 28161)C2orf40Chromosome 2 open reading frame 40 (source: HGNC symbol; Acc: HGNC: 24642)SFRP1Secreted frizzled-related protein 1 (source: HGNC symbol; Acc: HGNC: 10776)UCHL1Ubiquitin C-terminal hydrolase L1 (source: HGNC symbol; Acc: HGNC: 12513)IKZF1IKAROS family zinc finger 1 (source: HGNC symbol; Acc: HGNC: 13176)CADM2Cell adhesion molecule 2 (source: HGNC symbol; Acc: HGNC: 29849)CXCL12C-X-C motif chemokine ligand 12 (source: HGNC symbol; Acc: HGNC: 10672)IRF4Interferon regulatory factor 4 (source: HGNC symbol; Acc: HGNC: 6119)ZBTB16Zinc finger and BTB domain containing 16 (source: HGNC symbol; Acc: HGNC: 12930)CHFRCheckpoint with forkhead and ring finger domains (source: HGNC symbol; Acc: HGNC: 20455)SLIT2Slit guidance ligand 2 (source: HGNC symbol; Acc: HGNC: 11086)ZFP82ZFP82 zinc finger protein (source: HGNC symbol; Acc: HGNC: 28682)[^7] Polycomb-Repressive Complex 2 Occupancy at Hypermethylated CpGs Is Correlated Inversely With Global Hypermethylation {#sec1.8} -------------------------------------------------------------------------------------------------------------------- Supressor Of Zeste 12 (SUZ12) occupancy is a surrogate for polycomb-repressor complex 2 occupancy and in embryonic stem cells this has been shown to associate with transcriptional repression of hypermethylated loci.[@bib6], [@bib20] Consistent with this, we observed an increase in the number of methylated CpG sites that overlap with SUZ12-occupied regions with increasing CIMP cluster (P \< .0001) ([Figure 4](#fig4){ref-type="fig"}A). Conversely, and in keeping with our findings with promoter methylation, an inverse association between the proportion of hypermethylated loci genes that overlapped with SUZ12-occupied sites with increasing CIMP cluster was observed (P \< .0001) ([Figure 4](#fig4){ref-type="fig"}B). This further supports our finding that although DNA hypermethylation occurs more frequently with increasing CIMP cluster, these methylation events are more likely to result in gene silencing in CIMP-negative cancers.Figure 4(A) Proportion of SUZ12-occupied regions in hESC1 cells that contained hypermethylated probes in respective CIMP clusters. (B) Proportion of differential hypermethylation events that overlapped with Polycomb Repressive Complex-2 (PRC2)-occupied regions. CIMP-H1 and CIMP-H2 Promoter Methylation Is Defined by the Enrichment of Distinct Transcription Factor Binding Sites {#sec1.9} -------------------------------------------------------------------------------------------------------------------- Transcription factor binding sites often contain CpG sequences and therefore are a target of DNA methylation, which may explain some of the effects of methylation on transcription. To explore whether DNA methylation is targeted to specific transcription factor binding sites we performed an enrichment analysis using the CentriMo[@bib21] tool to examine the 2-kb region immediately upstream of hypermethylated genes. There were 128 significantly enriched binding sites that overlapped in CIMP-H1 and CIMP-H2 cancers. An additional 323 sites were uniquely enriched in CIMP-H1 cancers and an additional 330 sites in CIMP-H2 cancers. SMAD4 and FOXP3 (adjusted P values = 1.2 × 10^-24^ and 4.1 × 10^-23^, respectively) were the most significantly enriched motifs in CIMP-H1 cancers. SPDEF, FLI1, and NKX6 (adjusted P values = 7.2 × 10^-30^, 1.1 × 10^-16^, and 3.5 × 10^-16^, respectively) were most significantly enriched in CIMP-H2 cancers. [Table 5](#tbl5){ref-type="table"} presents the top 10 enriched consensus binding sites that were exclusive to CIMP-H1 and CIMP-H2.Table 5Motifs That Were Most Significantly and Exclusively Enriched at Methylated Promoters in CIMP-H1 and CIMP-H2CIMP-H1CIMP-H2Motif nameMotifRaw P valueAdjusted P valueMotif nameMotifRaw P valueAdjusted P valueSmad4TGTCTRGM1.2E-211.2E-24SPDEF_DBD_2GTGGTCCCGGATTAT7.2E-337.2E-30FOXP3_DBDRTAAACA4.1E-204.1E-23UP00142_1VNTAATTAATTAABGSG2.4E-202.4E-17FOXP3RTAAACA4.1E-204.1E-23FLI1_full_2ACCGGAAATCCGGT1.1E-191.1E-16POU2F2_DBD_2HWTRMATATKCAWA4.5E-194.5E-22UP00200_1GVWAATTAATTAMYBBG3.5E-193.5E-16Zscan4_primaryDHNATGTGCACAYAHWN1.2E-181.3E-21NHLH1_DBDCGCAGCTGCS2.1E-182.1E-15HOXC10GTCRTAAAAH1.3E-181.3E-21ERG_full_2ACCGGAWATCCGGT4.8E-184.8E-15Bbx_secondaryHVWNNGTTAACASHNRV3.1E-163.1E-19MA0680.1TAATCGATTA8.7E-188.6E-15Foxc1_DBD_1GTAAAYAAACA1.3E-151.3E-18PAX7_DBDTAATYRATTA1.4E-161.4E-13 Gene Bodies of Wnt Pathway Antagonists Are Resistant to Methylation {#sec1.10} ------------------------------------------------------------------- We further explored gene bodies that were unmethylated but had more than 10 CpG island probes, and performed pathway analysis to identify pathways that were devoid of gene body methylation. There were 6 pathways that were significantly enriched among these genes, including the WNT signaling pathway ([Figure 5](#fig5){ref-type="fig"}). The WNT signaling pathway was most heavily enriched. PCDHA6, PCDHGA2, PCDHA7, and PCDHA2 contained 36, 15, 10, and 20 gene body CpG island probes, respectively, which were all unmethylated. These protocadherins have been implicated in the regulation of the WNT signal and may act as a tumor-suppressor gene. Likewise, AXIN1, a gene critical to the β-catenin destruction complex, contained 11 unmethylated intragenic CpG Island (CGI) probes. TCF3, a WNT pathway repressor, contained 19 unmethylated intragenic CGI probes. We considered whether gene body methylation within WNT antagonists could alter gene transcription, however, we did not observe any differences in expression profiles of these genes vs normal mucosa tissue, and they were not expressed in normal mucosa tissue. In the remaining WNT genes we did not identify any consistent expression changes.Figure 5Pathways significantly enriched for genes that contained CpG islands that were devoid of methylation in both CIMP-H clusters. VEGF, vascular endothelial growth factor. Oncogenes Are Significantly More Likely Than Tumor-Suppressor Genes to Undergo Gene Body Methylation in CIMP-H1 and CIMP-H2 Cancers {#sec1.11} ----------------------------------------------------------------------------------------------------------------------------------- Gene body methylation is correlated positively with gene expression.[@bib22] We examined hypermethylation in gene body CpG islands, defined as a minimum of 2 probes in the CpG island as hypermethylated relative to normal (P \< .01) and there was a mean absolute difference in β values vs normal of greater than 0.2 to evaluate whether gene body methylation was a phenomena enriched in oncogenes of CIMP-H--type cancers, or was driven more nonspecifically by CIMP itself. In total, 239 genes were annotated as known oncogenes, and 239 as known tumor-suppressor genes in the NCG6.0 cancer gene database.[@bib23] Of these, 121 tumor suppressors and 116 oncogenes had a CpG island within the gene body that was probed on the array. In CIMP-H1 cancers, 21.5% (20.2% in TCGA) of oncogenes had significant gene body methylation in reference to normal, by comparison, significantly fewer tumor-suppressor genes underwent gene body methylation (12.4% in the RBWH cohort, P \< .05; 8.1% in TCGA; P \< .001). Likewise, gene body methylation was significantly more likely to occur in oncogenes than tumor-suppressor genes in CIMP-H2 cancers (23.3% vs 11.6%; P = .01). The gene expression of 5 oncogenes in CIMP-H1 and CIMP-H2 differed significantly from normal mucosa (FEV, BCL2, and KIT were down-regulated and PAX3 and SND1 were up-regulated in CIMP-H1; LMO2 and CTNND2 were down-regulated and SND1, CNTTA2, and TLX1 were up-regulated in CIMP-H2). [Table 6](#tbl6){ref-type="table"} presents the oncogenes that had significantly higher gene body methylation in CIMP-H1 and CIMP-H2 cancers compared with normal colonic mucosa.Table 6Oncogenes With Significantly Higher Methylation Within the Body of the GeneCIMP-H1CIMP-H2GeneExpressionDescriptionGeneExpressionDescriptionFEVDown-regulatedFEV, ETS transcription factorLMO2Down-regulatedLIM domain only 2BCL2Down-regulatedBCL2, apoptosis regulatorCTNND2Down-regulatedCatenin Δ 2KITDown-regulatedKIT proto-oncogene receptor tyrosine kinaseSND1Up-regulatedStaphylococcal nuclease and tudor domain containing 1PAX3Up-regulatedPaired box 3CTNNA2Up-regulatedCatenin α2SND1Up-regulatedStaphylococcal nuclease and tudor domain containing 1TLX1Up-regulatedT-cell leukemia homeobox 1LMO2No differenceLIM domain only 2PREX2No differencePI-3,4,5-trisphosphate-dependent Rac exchange factor 2RSPO3No differenceR-spondin 3RSPO3No differenceR-spondin 3CTNND2No differenceCatenin delta 2RETNo differenceRet proto-oncogeneTLX3No differenceT-cell leukemia homeobox 3LMO1No differenceLIM domain only 1SIX1No differenceSIX homeobox 1FLT3No differenceFms-related tyrosine kinase 3HOXC13No differenceHomeobox C13CACNA1DNo differenceCalcium voltage-gated channel subunit α1 DLMO1No differenceLIM domain only 1WWTR1No differenceWW domain containing transcription regulator 1ZNF521No differenceZinc finger protein 521CHST11No differenceCarbohydrate sulfotransferase 11SALL4No differenceSpalt like transcription factor 4PAX3No differencePaired box 3ZEB1No differenceZinc finger E-box binding homeobox 1FLT4No differenceFms-related tyrosine kinase 4PREX2No differencePI-3,4,5-trisphosphate dependent Rac exchange factor 2CXCR4No differenceC-X-C motif chemokine receptor 4OLIG2No differenceOligodendrocyte transcription factor 2TLX3No differenceT-cell leukemia homeobox 3SMONo differenceSmoothened, frizzled class receptorTAL1No differenceTAL bHLH transcription factor 1, erythroid differentiation factorFLT3No differenceFms related tyrosine kinase 3SIX1No differenceSIX homeobox 1GATA2No differenceGATA binding protein 2HOXC11No differenceHomeobox C11TLX1No differenceT-cell leukemia homeobox 1OLIG2No differenceOligodendrocyte transcription factor 2TAL1No differenceTAL bHLH transcription factor 1, erythroid differentiation factorMYOD1No differenceMyogenic differentiation 1CACNA1DNo differenceCalcium voltage-gated channel subunit a1 DZEB1No differenceZinc finger E-box binding homeobox 1MYOD1No differenceMyogenic differentiation 1HOXC13No differenceHomeobox C13CTNNA2No differenceCatenin a2ZNF521No differenceZinc finger protein 521CHST11No differenceCarbohydrate sulfotransferase 11SMONo differenceSmoothened, frizzled class receptorNR4A3No differenceNuclear receptor subfamily 4 group A member 3GATA2No differenceGATA binding protein 2NR4A3No differenceNuclear receptor subfamily 4 group A member 3[^8] Loci Marked by the PRC2 Complex in Human Embryonic Stem Cells Are Prone to Gene Body Methylation During Cancer Development {#sec1.11a} -------------------------------------------------------------------------------------------------------------------------- Polycomb Repressive Complex-2 (PRC2) marking in human embryonic stem cells has been shown previously to overlap significantly with promoter hypermethylation in colorectal cancers.[@bib6] We hypothesized that a similar phenomenon would occur with regard to gene body hypermethylation. In CIMP-H1 and CIMP-H2 cancers, 30.59% and 31.04%, respectively, of loci marked with H3K27me3 in human embryonic stem cells developed significant gene body hypermethylation ([Table 7](#tbl7){ref-type="table"}) (P = 1.34 × 10^-280^ for CIMP-H1 and P = 2.5 × 10^-300^ for CIMP-H2 overlap). We observed a lesser, but still highly significant, overlap between H3K27me3 marked loci and gene body methylation in CIMP-L1 (13.1%; P = 6.11 × 10^-122^) and CIMP-L2 (8.5%; P = 1.6 × 10^-78^) cancers, but did not observe any correlation in CIMP-neg cancers, which likely is owing to the scarcity of which gene body methylation occurs in these cancers. We observed similar overlaps for embryonic ectoderm development (EED) targets, SUZ12 targets, and PRC2 targets.Table 7Overlap Between Genes Marked by the PRC2 Complex and H3K27Me3 in hEScells and Genes That Undergo Significant Gene Body Methylation in Colorectal Cancer DevelopmentGene set nameCIMP-H1CIMP-H2CIMP-L1CIMP-L2Overlap fractionFDR P valueOverlap fractionFDR P valueOverlap fractionFDR P valueOverlap fractionFDR P valueBENPORATH_ES_WITH_H3K27ME330.59%1.34E-28031.04%2.50E-30013.06%6.11E-1228.50%1.60E-78BENPORATH_EED_TARGETS30.70%3.91E-26731.07%1.12E-28412.81%8.75E-1128.66%8.47E-77BENPORATH_SUZ12_TARGETS30.92%5.05E-26430.73%9.67E-27312.91%1.29E-1108.48%2.02E-72BENPORATH_PRC2_TARGETS37.27%1.04E-21838.04%8.59E-23516.41%4.56E-9811.04%2.05E-66[^9] Epigenetic Regulator Gene Mutations Are Common in TCGA Cancers {#sec1.12} -------------------------------------------------------------- Mutations in epigenetic modifier genes have been shown previously to modulate transcriptional profiles in cancer.[@bib15] We assessed the mutational frequency of 719 epigenetic regulator genes in cancers from the TCGA colon adenocarcinoma and rectal adenocarcinoma projects using the CIMP subtypes identified earlier. For these analyses we included only mutations that were truncating in nature (nonsense or indels), were predicted to alter splicing, or were predicted to have a deleterious effect by PolyPhen.[@bib24] Overall, 92.8% of cancers had a deleterious mutation in an epigenetic regulator gene (347 of 374). There were 94.7% and 100% of CIMP-H1 and CIMP-H2 cancers that had at least 1 mutation in an epigenetic regulator. The proportion of CIMP-L1, CIMP-L2, and CIMP-negative cancers with deleterious mutations in these genes was slightly lower (93.8%, 89.5%, and 93.1%, respectively), however, these proportions were not significantly different from CIMP-H1 or CIMP-H2. Of the 719 genes we investigated, 95.7% were mutated in at least 1 cancer (688 of 719). [Figure 6](#fig6){ref-type="fig"} shows the most commonly mutated epigenetic regulators in each cluster. Mutations were least common in cancers classified as CIMP-neg, with increasing global methylation being associated with a concordant increase in epigenetic mutational load. However, when we examined epigenetic mutation frequency in relation to microsatellite instability, there was no significant relationship between CIMP cluster and epigenetic mutation frequency, indicating that the differences observed between CIMP clusters may be driven by the increasing frequency of microsatellite instability in CIMP clusters with higher genomic methylation.Figure 6High-impact mutations in epigenetic regulator genes are frequent in cancers with higher genomic methylation. Del, deletion; Ins, insertion. CIMP-H1 and H2 Subtypes Have Similar Mutational Patterns in Epigenetic Regulator Genes {#sec1.13} -------------------------------------------------------------------------------------- We examined the top 25 mutated epigenetic regulator genes in CIMP-H1 and CIMP-H2 to identify mutational targets that are common to CIMP-H and those that are exclusive to either the CIMP-H1 or CIMP-H2 subtypes. This was not influenced by MSI, which was equally represented in these cancer subtypes (53% CIMP-H1, 50% CIMP-H2). A total of 31.6% of these genes were identifiable in the top 25 epigenetic mutational targets in both CIMP-H1 and CIMP-H2. Such genes included 4 histone lysine methyltransferases (SETD1B, KMT2A, KMT2B, and KMT2D), the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex member ARID1A, and the chromohelicase domain gene CHD7. Thirteen genes were identified in the top 25 mutated epigenetic regulators in CIMP-H1, but not CIMP-H2, these included the DNA demethylases TET1 (mutated in 15.8% of CIMP-H1 cancers vs 10.3% of CIMP-H2 cancers) and TET3 (mutated in 26.3% of CIMP-H1 cancers vs 10.3% of CIMP-H2 cancers). Mutations in histone lysine demethylase KDM2B were enriched in CIMP-H1 cancers (mutated in 36.8% of CIMP-H1 cancers vs 7.7% of CIMP-H2 cancers; P = .01). In contrast, 13 genes were found in the top 25 mutated epigenetic regulators of CIMP-H2 but not CIMP-H1. The NCOR1 transcription factor was mutated in 20.5% of CIMP-H2 cancers compared with 5.3% of CIMP-H1 cancers, and the cohesin complex subunit NIPBL in 15.4% of CIMP-H2 cancers, despite not being identified as mutated in any CIMP-H1 cancer. Epigenetic Regulator Gene Mutation Exclusivity Supports the Dichotomization of CIMP-L Clusters {#sec1.14} ---------------------------------------------------------------------------------------------- We used a similar approach (top 25 epigenetic gene mutations) to investigate whether CIMP-L1 and CIMP-L2 subtype cancers also target similar epigenetic regulators for somatic mutation. Here, 11 epigenetic regulator genes were commonly mutated in both CIMP-L1 and CIMP-L2. The histone lysine methyltransferases KMT2B and KMT2C were among the top 25 mutated epigenetic regulators in both CIMP-L1 and CIMP-L2, however, the frequency of mutation in both KMT2B and KMT2C was lower in CIMP-L2 cancers (KMT2B CIMP-L1, 11.8%; CIMP-L2, 5.7%; KMT2C CIMP-L1, 10.5%; and CIMP-L2, 6.5%), but this was not statistically significant. There was a nonsignificant trend (P = .06) for increased ASH1L mutation in CIMP-L1 cancers (13.2%) vs CIMP-L2 cancers (4.9%). Fourteen genes were in the top 25 mutated epigenetic regulators of CIMP-L1 or CIMP-L2 alone. SETD1B, a histone lysine methyltransferase identified as a commonly mutated gene in CIMP-H cancers was mutated in 6 CIMP-L1 cancers, but was only mutated in a single CIMP-L2 cancer (P \< .01). Likewise, we identified recurrent ARID1A mutations in CIMP-L1 (9.2%), however, we identified significantly fewer in CIMP-L2 cancers (1.6%; P \< .01). The SWI/SNF Complex Is a Commonly Aberrantly Mutated Chromatin Remodeling Complex in CIMP-H1, CIMP-H2, and CIMP-L1 Cancers {#sec1.15} -------------------------------------------------------------------------------------------------------------------------- Next, we examined the SWI/SNF complex (MARCA2, ARID1A, ARID1B, ARID2, PBRM1, SMARCB1, and SMARCA4) for high-impact somatic mutations. Mutations in any of the SWI/SNF subunits occurred in 19.06% of cancers. An ARID1A mutation was the most frequent genetic alteration of the complex (6.7%). We observed a number of recurrently mutated positions in ARID1A, including 6 frameshift deletions at codon 2141, 4 deletions at codon 1850, and 3 deletions at codon 1072 ([Figure 7](#fig7){ref-type="fig"}). ARID2 was mutated in 6% of cancers, but unlike ARID1A we did not identify any recurrently mutated positions. The distribution of the mutations between CIMP subtypes was significantly skewed toward subtypes with higher overall methylation (P \< .0001). SWI/SNF mutations were observed in 50% of CIMP-H1 cancers, and 38.5% of CIMP-H2 cancers. A total of 26.3% of CIMP-L1 samples mutated a SWI/SNF member, and in contrast to CIMP-H1 and CIMP-H2, the most frequently mutated member of the complex was SMARCA4 (11%). The R885C mutation was observed in 3 cancers in CIMP-L1. Mutations in SWI/SNF subunits were similarly infrequent and significantly less prevalent in CIMP-L1 and CIMP-neg (10.6% and 11.6%, respectively; P \< .0001).Figure 7High impact mutations in ARID1A are common in colorectal adenocarcinomas. Del, deletion; Ins, insertion. Synthetic lethality in the SWI/SNF complex was established previously.[@bib25] CIMP-H1, CIMP-H2, and CIMP-L1 cancers may be more vulnerable to treatments targeting the other element of the SWI/SNF complex. To test whether 1 SWI/SNF mutation confers dependency on other SWI/SNF subunits in vitro, we correlated exome capture data from 15 cell lines[@bib26] with cell line--dependency data from Meyers et al.[@bib27] Five cell lines had an ARID1A truncating mutation and these were significantly more dependent on ARID1B expression for survival (0.31 vs 0.06; P \< .05). The Frequency of Genetic Perturbation of Chromodomain Helicase DNA Binding Genes Is Associated With DNA Methylation {#sec1.16} ------------------------------------------------------------------------------------------------------------------- CHD genes are members of another chromatin remodeling family. High-impact CHD family gene mutations were present in 22.4% of colorectal cancers in the TCGA. CHD mutations were markedly more common in CIMP-H1 and CIMP-H2 cancers. Family members were mutated in 50% and 51.3% of CIMP-H1 and CIMP-H2 cancers, respectively. CHD7 was the most frequently altered gene in CIMP-H1 (33% of cancers), and CHD8 in CIMP-L2 (22%). CHD mutations were less common, but still frequent, in CIMP-L1 cancers (19.7%). In these cancers, CHD4 was the most commonly mutated gene (8%). The frequency of CHD mutations continued to decline as concordant with DNA methylation. The frequency of CHD mutations in CIMP-L2 was 11.7%, and was lower than the frequency observed in CIMP-neg cancers (15%). We examined the CHD genes for recurrently mutated positions. At the CHD7 locus, which was mutated in 5.5% of cancers, we observed 5 frameshift deletions (D2988fs del 3) at the 3' end of the gene. This mutation has been observed in a number of colorectal cancer cell lines. For CHD3, CHD4, and CHD9 we observed 3 recurrently mutated positions at R540fs del 16, R975H, and F760fs del 16. Discussion {#sec2} ========== Remodeling of the epigenome is fundamental to colorectal cancer progression. One of the most common epigenetic phenomena altered throughout carcinogenesis is the DNA methylation landscape. Here, we aimed to better understand the extent and heterogeneity of aberrant DNA methylation in colorectal cancers, and characterize the interplay between DNA methylation, somatic variation in epigenetic regulator genes, and gene transcription. Through the genome-scale interrogation of the largest unselected and consecutive series of colorectal cancers to date, we identified 5 clinically and molecularly distinct DNA methylation subtypes. The 5 subtypes identified in this study are highly correlated with key clinical and molecular features, including patient age, tumor location, microsatellite instability, and oncogenic mitogen-activated protein kinase mutations. We show that cancers with high DNA methylation show an increased preponderance for mutating genes involved in epigenetic regulation, and namely those that are implicated in the chromatin remodeling process. Hinoue et al[@bib6] previously reported the presence of 4 colorectal cancer methylation subgroups by assessing 125 colorectal cancers using Illumina 27K DNA methylation arrays. In the present study, we have considerably increased the power to assess subgroups based on differential methylation by studying 216 unselected cancers using the Illumina 450K DNA methylation platform. The Illumina 450K DNA methylation platform is capable of assessing more than 10 times more CpG sites and thus can identify methylation subtypes more robustly. A major difference of our study was the identification of 2 discrete CIMP-high subtypes: CIMP-H1 and CIMP-H2. The dichotomization of these CIMP-H cancers identified a homogeneous subgroup of CIMP-H1 cancers with an average age of 75 years, striking over-representation of female sex, and BRAF mutant cancers arising in the proximal colon. The newly identified CIMP-H2 subtype encompasses more KRAS mutant cancers than CIMP-H1, and the majority of cancers in this subtype would be CIMP-low using the 5-marker CIMP panel proposed by Weisenberger et al.[@bib3] Our genome-scale analyses of both our cohort and the TCGA indicate this is not the case. Together, our CIMP-H1/H2 clusters represent 21% of our unselected cohort, and 16.3% of the TCGA cohort. Collectively, the current findings indicate that CIMP is more prevalent than previously thought, and classification of cancers using existing panels may not identify all CIMP-high colorectal cancers. We observed a consistent increase in patient age with CIMP cluster, from 62 years in CIMP-neg cancers to 75 years in CIMP-H1 cancers. This is in contrast to the Hinoue et al[@bib6] study. The variance in our assay was mostly contained in uniquely mapping probes that were not present in the Illumina HumanMethylation27 BeadChip array used by Hinoue et al.[@bib6] Numerous studies have shown age-related methylation in different tissues[@bib9], [@bib28], [@bib29] and we previously identified hypermethylated loci in the colons of patients even with no history of colonic disease.[@bib9] In the present study, we detected a significant correlation between methylation and patient age. After removal of all probes that were significantly hypermethylated in normal mucosal tissue, we still observed distinct, age-linked clustering. This association was faithfully reproduced in cancers from TCGA. The subtype with the highest degree of methylation (CIMP-H1) was strongly associated with mutations in the BRAF oncogene. BRAF mutations are a hallmark of the serrated neoplasia pathway, and indicate that these cancers probably arose in serrated precursor lesions. We previously showed that the colonoscopic incidence of sessile serrated adenomas does not differ between patients aged in their 30s and patients who are much older, whereas BRAF mutant cancers were restricted to older individuals,[@bib30] suggesting these BRAF mutant polyps may have limited malignant potential in young patients. We also reported a striking association between patient age and CIMP in sessile serrated adenomas.[@bib31] Here, we report that the vast majority of BRAF mutant cancers in both the RBWH and TCGA cohorts are CIMP-H and arise in older individuals. Collectively, these findings suggest that sessile serrated adenomas may be relatively benign in young patients. In older patients with more advanced DNA methylation changes in the colon, the risk of progression to cancer will be significantly greater. Recently, we recapitulated this process in a murine model for serrated neoplasia and showed that early onset Braf mutation leads to the temporal accumulation of DNA methylation and ultimately to malignancy.[@bib32] Additional studies are necessary to fully determine the natural history of BRAF mutant cancers, and elucidate the determinants of malignant potential to inform the development of patient-centric surveillance for young and older patients who present with sessile serrated adenomas. Differential CpG island and shore hypermethylation were the most frequently observed methylation events in the study. Probes on the north and south CpG shelves, as well as those in the open seas, frequently were hypomethylated across most cancers. The implications of hypomethylated CpG dinucleotides outside of CpG islands are unclear. We did not observe any relationship between hypomethylation and gene transcription, however, it is possible that hypomethylation of specific regions of the genome may affect chromatin accessibility elsewhere and hence may modulate transcription in a trans-acting manner. Open sea hypomethylation was also the most frequent methylation event in CIMP-neg cancers. These are predominately conventional pathway cancers with a high degree of chromosomal instability. One hypothesis that may explain this association is that hypomethylation outside of CpG islands may predispose to copy number changes in these cancers.[@bib33], [@bib34] Functional studies are necessary to explore the implications of shelf and open sea hypomethylation and whether this is relevant to the cancer development process for these cancers. There were marked differences in transcriptional deregulation of key cancer-related pathways between methylation clusters. CIMP-H1 cancers activated several immune pathways, including those involved in the interferon response, inflammatory response, and complement signaling, consistent with the over-representation of CMS1 cancers in this group. This likely is owing to the higher mutational burden in these cancers, largely driven by the increased incidence of epigenetically induced microsatellite instability. MSI cancers have been associated with greater immune infiltrate and hence some of this signaling may originate in the stromal immune cells, rather than from within the tumor itself.[@bib35] In the RBWH cohort, CIMP-H2 cancers were uniquely enriched for altered bile acid metabolism, consistent with the previously described relationship between silencing of the farnesoid X bile acid receptor in KRAS mutant cancers.[@bib36] Bile acids are more concentrated in the proximal colon and metabolism is influenced by the gut microbiome.[@bib37] The increased bile acid metabolism signaling in this group of cancers may identify a subset of cancers that have arisen owing to aberrant bile acid accumulation. We did not observe such an effect in the TCGA cohort. This may be owing to the increased frequency of BRAF mutant MSI cancers in CIMP-H2 in TCGA. A better understanding of the role of bile acid signaling in KRAS mutant cancers of the proximal colon may have therapeutic implications for this cancer subgroup. Paradoxically, despite observing less differential methylation, we observed an increase in gene silencing that correlated with promoter hypermethylation in the least methylated cancer clusters. This may indicate that promoter hypermethylation in CIMP-L1/2 and CIMP-neg cancers is more specifically selected based on a functional advantage in these cancers. Alternatively, the increased frequency of mutations in epigenetic regulators of CIMP-H1/2 cancers may result in a reduced capacity to induce gene repression at certain loci. This may be owing to the loss of a repressive histone-modifying enzyme, or mutation of locus-specific repressive transcription factors. Methylation alone may be insufficient to induce gene repression in certain instances. Instead, relevant chromatin remodeling and histone modifications, such as the addition of the repressive PRC2 mark, may be required in tandem with methylation changes to reduce gene expression. Indeed, we showed that PRC2 occupancy was most frequently related to transcriptionally repressed and methylated genes in the CIMP-neg subgroup. We also observed instances of promoter methylation that correlated with increased gene transcription. It is possible that some transcription factors preferentially bind methylated DNA,[@bib38] and that binding sites for these transcription factors become available after promoter methylation. These data may indicate that the genomic context of methylation is important for determining whether gene expression changes will occur. In TCGA, however, we were unable to discern any significant differences in the proportion of methylated and repressed genes vs all methylated genes between CIMP subtypes. This may be owing to technological differences between the array-based methods used to evaluate gene transcription in the current study and the RNA sequencing-based methods used in TCGA. Direct comparisons between the expression values derived from each of these studies is difficult and should be approached with caution. A major novel finding of the current study was the discovery that gene body methylation may be a major driver of serrated tumorigenesis, and that this may be mediated by H3K27me3 histone marks. Gene body hypermethylation recently was correlated with increased oncogene expression.[@bib22] Here, we identified many well-characterized oncogenes, such as BCL2 and ZEB1, with methylation of their gene bodies in CIMP-H1/2 cancers, and noted a significant preference for the methylation of gene bodies of oncogenes compared with tumor-suppressor genes. We also identified Wnt pathway antagonists that are resistant to gene body methylation. In the present study, we did not identify distinct transcriptional differences in these Wnt pathway antagonists. It is possible that gene body methylation affects other aspects of the transcriptional process that were not assessed in this study, such as splicing and isoform switching. Alternatively, this gene body methylation may be a stochastic result of the overall increase in aberrant DNA methylation in these cancers. The epigenome is regulated by proteins that interact with histones or DNA. We assessed the coding sequence of 719 epigenetic regulator genes in the TCGA data set. The chromodomain-helicase-DNA (CHD) binding protein family was a frequent mutational target in CIMP-H1 cancers. Recently, Fang et al[@bib39] showed that CHD8 operates in a transcriptional repression complex to direct methylation in the setting of BRAF mutation. In the current study we showed BRAF and CHD8 mutations were associated with CIMP-H1. Thus, these data suggest that CHD8 mutation may enhance repression complex activity in the setting of BRAF mutation, resulting in hypermethylation. Moreover, CHD8 has been associated with the CCCTC-binding factor (CTCF) protein, which is essential for promoter-enhancer looping and regional insulation. CHD8 mutations may influence CIMP by decreasing the ability of CTCF to insulate regions of the genome, and could encourage methylation spreading throughout the genome.[@bib40] Similarly, we report frequent mutations in different members of the CHD family. CHD7 was the most mutated CHD gene, and some positions in the CHD7 locus were recurrently mutated. Tahara et al[@bib41] identified mutations in CHD7 and CHD8 in 42% of CIMP1 colorectal cancers. The functional consequences of CHD7 mutations are unclear. In pancreatic duct adenocarcinoma, CHD7 expression has been shown to correlate with gemcitabine sensitivity.[@bib42] The most commonly mutated CHD gene in CIMP-L1 cancers was CHD4. Recently, Xia et al[@bib43] in 2017 proposed an oncogenic role for CHD4 through facilitating the hypermethylation of tumor-suppressor genes. In contrast, Li et al[@bib44] in 2018 showed that CHD4 mutations that promote protein degradation enhance stemness and contribute to the progression of endometrial cancers via the transforming growth factor-β signaling cascade. Indeed, we identified 3 mutations at the R975H hotspot of CHD4 that were studied by Li et al[@bib44] and a number of other mutations that were predicted to be damaging. It is not possible to conclude from our data whether these mutations promote the hypermethylation proposed by Xia et al,[@bib43] and therefore support the oncogenic role of the protein or whether the enhanced protein degradation and increased stemness proposed by Li et al[@bib44] is the predominant purpose of these mutations. Chromatin remodeling is an essential process whereby condensed euchromatin is modified in a context-specific manner to give rise to regions of heterochromatin that can be actively transcribed. Chromatin remodeling is driven by a series of complexes that are able to enzymatically catalyze reactions that modify histone tails and, in turn, modulate the accessibility of the chromatin. In mammalian cells, 5 key chromatin-modifying complexes predominate, the CHD binding complex, the INO80 complex, the SWI/SNF complex, Imitation SWItch (ISWI) complex, and the NuRD complex.[@bib45] Here, we have examined the frequency of mutations in the SWI/SNF complex, which has been shown previously to be perturbed in various cancers. Interestingly, half of CIMP-H1 and more than 25% of CIMP-H2 and CIMP-L1 cancers harbored somatic mutations in SWI/SNF members that were predicted to be deleterious. We hypothesized that mutation of 1 member of the subunit would increase the reliance of the cancer on other otherwise redundant subunits. To test this hypothesis we used public colorectal cancer cell line dependency data in conjunction with mutational data, and identified a strong dependency conferred upon ARID1B after genetic perturbation of ARID1A. These data support the investigation of SWI/SNF inhibitors to exploit synthetic lethality presented by SWI/SNF mutations in CIMP-L1 cancers. Although we have shown associations between genomic methylation and SWI/SNF mutations, and between mutations of SWI/SNF members and synthetic lethality, functional causation is difficult to infer from our study. Collectively, these data indicate a need for further functional experiments to elucidate the role of these mutations in the carcinogenic process of CIMP-H1, CIMP-H2, and CIMP-L1 cancers, and to determine whether the potential synthetic lethalities they create can be exploited. We leveraged the publicly available DNA methylation data from the TCGA project to validate findings in our consecutive cohort. Key findings, including relationships between CIMP subtype and age, proximal location, BRAF mutation, and KRAS mutation also were identified in an analysis of the TCGA data. In our unselected and consecutively collected series we observed a strong relationship between the BRAF mutation and CIMP-H1 and the KRAS mutation and CIMP-H2. Although BRAF was still enriched in the TCGA CIMP-H1 cancers, and KRAS among the CIMP-H2 cancers, we observed a higher proportion of BRAF mutant CIMP-H2 cancers in the TCGA cohort. The increased proportion of BRAF mutant/CIMP-H2 cancers skewed these cancers toward a preference for microsatellite instability, and the CMS1 subtype. It is notable that more than 40% of CIMP-H2 cancers in the validation cohort are KRAS mutant, and, of these, the majority are microsatellite stable and follow similar CMS patterns to that observed in our consecutive series. The discrepancies observed between the 2 cohorts may be owing to structural differences in each cohort. The mean age of patients in our study was 3.4 years older than those in the TCGA cohort. Cancers were identified most often in the distal colon of the patient, as is typical for colorectal cancers,[@bib46] however, in contrast, the TCGA consisted of a marked over-representation of proximal cancers (47.7%). It is important to recognize the limitations of our study. First, our samples were collected in a consecutive manner in which there was sufficient sample available for DNA and RNA analyses. This excluded very small cancers and those in patients in whom surgery was not possible. This presents a slight bias, however, this is standard practice and unavoidable in studies of this nature. As technologies improve and analyses are possible on smaller amounts of tissue it will be important to replicate the key findings of this study. Moreover, because we collected fresh tissue we were not able to make any assessments of tumor purity. One alternative would have been to perform analyses on formalin-fixed, paraffin-embedded samples, in which we could perform accurate histologic assessments of the purity of the samples. Although the Illumina HM450 platform and newer platforms such as the EPIC arrays are amenable to formalin-fixed, paraffin-embedded--derived DNA, co-extraction of high-quality RNA from formalin-fixed, paraffin-embedded remains challenging. We note that the findings of this study are largely correlative and as such we cannot draw causation from our data. In depth, mechanistic follow-up evaluation is necessary to fully examine many of the key associations we have identified in the present study. Another limitation of our study was the use of normal mucosal samples from patients with cancer. Field DNA methylation defects have been reported in colorectal cancer.[@bib47] Thus, we cannot exclude the possibility that field DNA defects impacted our analysis. In the current study, we performed all analyses on bulk tissue samples. As such, we have collected the DNA methylome and transcript profile of an aggregate of cells that includes epithelial cells, immune cells, and stromal cells. The interplay between these cell types is crucial and it is important to note that some of the expression and methylation differences observed here may be driven by any of the cells in the bulk cell sample. Conclusions {#sec3} =========== The past decade has heralded an era in which the importance of the cancer epigenome increasingly is recognized, in which treatments targeting different epigenetic modifications are entering the clinic and improving patient outcomes. Although early strategies targeting epigenetic modifications in colorectal cancers largely have proved ineffective, it has become apparent that a comprehensive understanding of the epigenetic drivers of cancer will be crucial in the rational design of clinical trials and the development of precision medicine strategies. Here, we have identified 5 clinically and molecularly distinct subgroups based on a comprehensive assessment of a large, unselected series of colorectal cancer methylomes. We have validated these subtypes in an additional cohort of 374 cancers from TCGA. In contrast to earlier studies, we identified 2 clinically and molecularly distinct CIMP-H clusters. We observed a striking association between genomic methylation and age, which further supports the investigation of the epigenetic clock in serrated neoplasia risk. We identified an association between gene body methylation CIMP-H cancers, which may be mediated by H3K27me3 histone marks. Our interrogation of the coding regions of epigenetic regulatory genes shows that they frequently are mutated in colorectal cancers and this may be partially influenced by the degree of genomic methylation. Our analyses have identified potentially druggable vulnerabilities in cancers of different methylation subtypes. Inhibitors targeting synthetic lethalities, such as SWI/SNF component inhibitors for those with ARID mutations, should be evaluated because these agents may be clinically beneficial to certain patient subsets. Methods {#sec4} ======= Patient Samples {#sec4.1} --------------- Colorectal cancer (N = 216) and matched normal (N = 32) samples were obtained from patients undergoing surgery at the Royal Brisbane and Women's Hospital in Brisbane, Australia, in a consecutive manner between 2009 and 2012. Tissue was snap-frozen in liquid nitrogen to preserve sample integrity. Written informed consent was obtained from each patient. The study protocol was approved by the Royal Brisbane and Women's Hospital and QIMR Berghofer Medical Research Institute Research Ethics Committees. TCGA colon adenocarcinoma exome and methylation data (N = 278) were used for independent validation.[@bib16] DNA and Messenger RNA Extractions {#sec4.2} --------------------------------- DNA and messenger RNA (mRNA) were extracted simultaneously from approximately 30 mg of homogenized tissue using the AllPrep DNA/RNA Kit (QIAGEN, Hilden, Germany) in accordance with the manufacturer's protocols. Double-stranded DNA concentration was assessed using the PicoGreen quantitation assay (Thermofisher Scientific, Waltham, MA). mRNA quality was measured using the Bioanalyzer 2100 platform (Agilent, Santa Clara, CA). Microarray analysis was performed on samples with a RNA integrity number greater than 7. Molecular Characterization of Cancer Samples {#sec4.3} -------------------------------------------- Cancer sample DNA was analyzed for the BRAF V600E mutation using allelic discrimination as previously reported.[@bib48] In addition, we assayed mutations in KRAS codons 12 and 13, and TP53 exons 4 to 8 using previously reported methods.[@bib49], [@bib50] We assessed CIMP status by methylation-specific polymerase chain reaction using the 5-marker panel (CACNA1G, IGF2, NEUROG1, RUNX1, and SOCS1) proposed by Weisenberger et al.[@bib3] Samples were considered CIMP-high if 3 or more markers were methylated, CIMP-low if 1 or 2 markers were methylated, and CIMP-negative if no markers were methylated. MSI was assessed using the criteria of Nagasaka et al[@bib51] in which instability in 1 or more mononucleotide markers, and 1 or more additional nonmononucleotide markers, using the marker set reported by Boland et al,[@bib52] was indicative of MSI, the remainder being microsatellite stable. LINE1 methylation was assessed using pyrosequencing as per Irahara et al.[@bib53] CIMP-high cancers that were both KRAS and BRAF wild-type at hotspot codons were Sanger sequenced for BRAF exons 11 and 15 (exon 11, forward: 5'-TTCCTGTATCCCTCTCAGGCA-3', reverse: 5'-AAAGGGGAATTCCTCCAGGTT-3'; exon 15, forward 5'-GGAAAGCATCTCACCTCATCCT-3', reverse 5'-TAGAAAGTCATTGAAGGTCTCAACT-3'), KRAS codon 61 (forward: 5'-TCCAGACTGTGTTTCTCCCTTC-3', reverse: 5'-TGAGATGGTGTCACTTTAACAGT-3'), and EGFR exon 18 (forward: 5'-ATGTCTGGCACTGCTTTCCA-3', reverse: 5'-ATTGACCTTGCCATGGGGTG-3'). DNA Methylation Microarray {#sec4.4} -------------------------- Genome-scale DNA methylation was measured using the HumanMethylation450 BeadChip array (Illumina). The BeadChip array interrogates cytosine methylation at more than 480,000 CpG sites. A total of 500 ng DNA was bisulfite-converted using the EZ-96 DNA Methylation Kit (Zymo Research, Irvine, CA) per the manufacturer's protocol. Whole-genome amplification and enzymatic fragmentation was performed on post-treatment DNA, which subsequently was hybridized to the array at 48°C for 16 hours. Arrays were scanned using the iScan System (Illumina). Gene Expression Microarray {#sec4.5} -------------------------- Gene expression levels for more than 47,000 transcripts were measured for all samples using the HumanHT-12 v3 Expression BeadChip array (Illumina). Total mRNA (500 ng) was reverse-transcribed, amplified, and biotinylated using the TotalPrep-96 RNA Amplification Kit (Illumina). The labeled complementary RNA (750 ng) was hybridized to the array followed by washing, blocking, and staining with streptavidin-Cy3. Arrays were scanned on the iScan System and the data were extracted using GenomeStudio Software (Illumina). Data Analysis {#sec4.6} ------------- Methylation microarray data were checked for quality against parameters provided by Illumina using the GenomeStudio Software package. IDAT files were read into the R environment using Limma.[@bib54] We used subset-within-array normalization to correct for biases resulting from type 1 and type 2 probes on the array. We used the BEclear R package to assess for probe-level batch effects and excluded probes that were significantly batch-affected (n = 1072) from downstream analysis. We filtered probes that had a detection of P \> .05 in more than 50% of samples, as well as probes that were on the X or Y chromosome, where the CpG site was within 10 bp of a single-nucleotide polymorphism, or where a probe mapped to the genome ambiguously. At the conclusion of filtering, 377,612 probes remained and were used for subsequent analyses. The RPMM clustering method[@bib55] was used for unsupervised clustering. To capture cancer-specific methylation we followed the methods used based on TCGA.[@bib56] DNA methylation drift with age has been characterized in a number of different normal and cancerous tissues.[@bib10] To limit confounding from methylation that occurs through age, probes with a mean β value greater than 0.3 in normal samples were excluded from clustering analysis. A total of 144,542 probes were unmethylated (mean β value, \<0.3) in normal mucosa, of these the 5000 probes with the greatest variance in tumor samples were selected for clustering. The RPMM clustering method is particularly suited to analysis of methylation data generated from the HumanMethylation450 array because output β values are between 0 and 1, and can be modeled using a β-like distribution.[@bib55] We accessed level 1 DNA methylation data from the TCGA project and performed an identical analysis as mentioned earlier for validation. For motif analysis, the CentriMo tool was used.[@bib21] CentriMo identifies over-represented motifs within sequences, correlating these with known DNA protein-binding motifs.[@bib21] β values were transformed to M values using the following formula: M = log~2~ (β/\[1 - β\]). For differential methylation analysis vs the subset of normal mucosal samples, a probe was considered to be differentially methylated in a comparison if the Benjamini--Hochberg[@bib57] adjusted P value for the comparison was less than 0.05 and had an average absolute Δβ ≥ 0.2 vs normal mucosal samples. For examination of methylation in oncogenes and tumor-suppressor genes we consulted the NCG6.0 cancer gene database.[@bib23] For these analyses we included only cancer genes that were annotated in NCG6.0 without ambiguity (were not annotated as both tumor-suppressor genes and oncogenes) and those that we probed on the array. Expression data were preprocessed and normalized using quantile normalization with the Limma R package. For between-group comparisons the empiric Bayes function was used, and adjusted for multiple testing using the Benjamini--Hochberg[@bib57] method to control for FDR and avoid type 1 errors. We examined gene expression in the TCGA by accessing level 3 expression data in Fragments Per Kilobase of transcript per Million reads (FPKM) format from Genome Data Commons.[@bib58] We used Limma to perform a voom transformation to correct for heteroscedasticity and examine differential expression against normal colonic mucosal samples using the same methods as used in the consecutive series. We considered 0.05 to be the FDR threshold for significance. For integrated expression and methylation data analysis, genes were considered to be methylated if 1 probe within 2 kb upstream of the gene transcription start site was methylated differentially by FDR and had an average Δβ ≥ 0.2 at that site. If a gene met this criterion, and had a significant FDR corrected P value for the cancer vs normal expression value, it was predicted to be influenced by methylation. Single-sample gene-set enrichment analysis was used for between-groups comparisons of transcriptomes.[@bib18] We used the CIBERSORT algorithm to compute the relative proportion of stromal cells within each subtype.[@bib17] The CMS classifier package was used to classify cancers into CMS as previously reported.[@bib8] To examine the mutational frequency of epigenetic regulators, level 3 somatic variant data were downloaded from the Genome Data Commons portal. Silent variants were discarded and variants in epigenetic regulator genes present in the EpiFactors database extracted for further analyses. We assessed the potential pathogenicity of missense mutations using the PolyPhen2 tool.[@bib59] PolyPhen2 predicts functional effects of missense mutations by examining how evolutionarily conserved the affected residue is, and computes the likelihood that the event will induce a structural change. Only variants that were predicted to be probably or possibly damaging were retained. Variants predicted to be benign were not included as part of these analyses PRC2 and Methylation Overlap Analysis {#sec4.7} ------------------------------------- Polycomb occupancy was inferred from SUZ12 Chromatin Immunoprecipitation (ChIP) sequencing data from hESC1 cells analyzed as part of the Encyclopedia of DNA Elements (ENCODE) ENCODE consortium.[@bib60] SUZ12 was chosen as a surrogate for PRC2 occupancy because previous studies have indicated that it is an essential subunit of the PRC2 complex.[@bib20], [@bib61] The overlap function within BedTools[@bib62] was used to overlap differentially methylated probes within each cluster vs normal with regions where SUZ12 was bound in hESC1 cells, producing a list of regions where methylation and PRC2 occupancy co-occurred. Synthetic Lethality Analysis {#sec4.8} ---------------------------- Cell line dependency data from Meyers et al[@bib27] was correlated with colorectal cancer cell line mutation data.[@bib26] Synthetic lethal relationships were inferred if a high-impact mutation (truncating mutations or those in splice sites) occurred in 1 subunit of a molecular complex, and the cell line had relatively higher dependence values on other subunits when compared with cell lines that lacked a mutation. Cell lines were grouped as having a mutation in a specific gene and those not having a mutation, and a Student t test was performed on dependence values in every other subunit within the complex. Statistical Analysis {#sec4.9} -------------------- For statistical analyses a combination of different types of software were used, including R and GraphPad Prism 7 (GraphPad Software, San Diego, CA). The Fisher exact test was used for hypothesis testing on 2 × 2 contingencies. The Pearson chi-squared test was used to compare contingencies larger than 2 × 2. The Student t test or the Wilcoxon rank-sum test was used to compare continuous variables where appropriate. One-way analysis of variance was used for continuous variable comparisons with more than 2 groups. Supplementary Material {#appsec1} ====================== Supplementary Material The authors are thankful for the insightful comments offered by the reviewers and for their contribution in greatly improving the manuscript. The microarray data have been deposited in the ArrayExpress database at EMBL-EBI ([www.ebi.ac.uk/arrayexpress](http://www.ebi.ac.uk/arrayexpress){#intref0010}) under accession number E-MTAB-8148 (expression) and E-MTAB-7036 (methylation). Author contributions Lochlan Fennell performed bioinformatic and statistical analyses on the data, was involved in the conceptualization aspects of the study, and prepared the manuscript; Troy Dumenil performed molecular and bioinformatic analyses and revised the manuscript for content; Gunter Hartel was involved in the statistical and bioinformatic analysis of the data; Katia Nones was involved in the bioinformatic analysis of methylation data and revised the manuscript for content; Catherine Bond performed molecular analyses and revised the manuscript for content; Diane McKeone was involved in molecular analyses; Lisa Bowdler processed the microarrays; Grant Montgomery processed the microarrays; Leesa Wockner was involved in bioinformatic analyses; Kerenaftali Klein was involved in bioinformatic analyses; Ann-Marie Patch was involved in bioinformatic analyses of The Cancer Genome Atlas exome data; Stephen Kazakoff was involved in bioinformatic analyses of The Cancer Genome Atlas exome data; John Pearson was involved in bioinformatic analyses of The Cancer Genome Atlas exome data; Nicola Waddell was involved in bioinformatic analyses of The Cancer Genome Atlas exome data; Pratyaksha Wirapati performed consensus molecular subtype analysis; Paul Lochhead performed Long Interspersed Nuclear Element-1 methylation assays and analysis; Yu Imamura performed Long Interspersed Nuclear Element-1 methylation assays and analysis; Shuji Ogino performed Long Interspersed Nuclear Element-1 methylation assays and analysis and provided supervision for this aspect of the study; Renfu Shao supervised the study and was involved in the conceptualization aspects of the study; Sabine Tejpar performed Consensus Molecular Subtype analysis and provided supervision for this aspect of the study; Barbara Leggett supervised the study, was involved in conceptualization aspects of the study, revised the manuscript for content, and secured funding for the study; Cheng Liu performed molecular analyses and revised the manuscript for content; Jennifer Borowsky performed molecular analyses and revised the manuscript for content; Isabell Hoffmann performed bioinformatic analysis and revised the manuscript for content; and Vicki Whitehall conceptualized the study, performed statistical analyses, revised the manuscript for content, secured funding for the study, and provided overarching supervision of the study. Conflicts of interest The authors disclose no conflicts. Funding This work was supported through funding from the National Health and Medical Research Council (1050455 and 1063105), the US National Institutes of Health (R01 CA151933 and R35 CA197735), and Pathology Queensland. Also supported by a Senior Research Fellowship from the Gastroenterological Society of Australia (V.W.); and by a Research Training Program Living Scholarship from the Australia Government and a Top-Up award from QIMR Berghofer and Australian Rotary Health (L.F.). [^1]: NOTE. P values reported were obtained using analysis of variance for continuous variables and chi-squared analysis for categoric variables. [^2]: MSS, microsatellite stable. [^3]: NOTE. P values reported were obtained using analysis of variance for continuous variables and chi-squared for categoric variables and represent the P value for an association between all subtypes and the feature in question. [^4]: MSS, microsatellite stable. [^5]: NOTE. Cancers were stratified for CIMP clustering. Differential methylation was deemed as an absolute β value change of more than 0.2 and an FDR corrected P value less than .01 compared with 32 normal colorectal mucosal samples. [^6]: +, differential hypermethylation; -, differential hypomethylation. [^7]: Acc, accession number; BTB, Broad-Complex, Tramtrack and Bric a brac; EGF, epidermal growth factor; HGNC, Human Genome Organisation Gene Nomenclature Committee; LIF, leukocyte inhibitory factor; NDRG, N-Myc downregulated gene. [^8]: BCL, B-cell lymphoma; bHLH, basic helix-loop-helix; ETS, E26 transformation specific; FEV, fifth ewing variant; PI, phosphatidylinositol; SIX, Sineoculis homeobox homolog; TAL, T-cell acute lymphocyctic. [^9]: NOTE. The overlap fraction represents the gene bodies that are methylated (k) divided by the number of genes marked by each respective mark in hES cells (K) (k/K). The FDR corrected P value was obtained through modeling a hypergeometric distribution (k-1, K, N-K, n; where k is the number of genes methylated in each cluster; K is the number of genes in the gene set; N is the number of genes in the human genome; and n is the number of genes in the query set) using the compute overlaps tool on the Gene Set Enrichment Analysis (GSEA) web portal using the Benporath gene sets, which were obtained though ChIP-on a Chip analysis of human embryonic stem cells.	{ "pile_set_name": "PubMed Central" }
Justin Brown, LC PRINCIPAL Justin received a Bachelor of Science in Industrial Design from the Rhode Island School of Design. His additional experience in metal work and fabrication have allowed him to specialize in custom fixture design as a lighting designer. He is the recipient of three IIDA Awards of Merit and proud father of two, and is currently rebuilding a 1953 Dodge M43 military ambulance.	{ "pile_set_name": "Pile-CC" }
A randomised controlled trial of patient information leaflets as a medication counselling aid. Medication counselling improves patient safety, adherence and satisfaction but is poorly done in clinical practice. Written aids further improve outcomes when used with verbal counselling. No studies have previously compared two types of written counselling aid. To compare the utility of a patient information leaflet (PIL) with a drug monograph as a medication counselling tool for patients starting a new medicine. A single-blinded randomised controlled trial of medical students counselling simulated patients during a clinical examination. The PIL was compared with the drug monographs as counselling aids by assessing information transfer and aid usage. A total of 96 students was recruited. The PIL was superior to the drug monograph for counselling relating to missed doses (P = 0.02), and non-inferior for other domains of information transfer. The aid was used more frequently in the PIL arm (91% vs 77%, P = 0.09) and for longer (4.6 min vs 2.9 min, P < 0.01). The PIL was non-inferior to the drug monograph for overall information transfer, but superior for contingency planning. Aid usage was greater in the PIL arm, which may reflect greater student satisfaction with the tool.	{ "pile_set_name": "PubMed Abstracts" }
/* * Copyright 2020 Google LLC * * Licensed under the Apache License, Version 2.0 (the "License"); * you may not use this file except in compliance with the License. * You may obtain a copy of the License at * * https://www.apache.org/licenses/LICENSE-2.0 * * Unless required by applicable law or agreed to in writing, software * distributed under the License is distributed on an "AS IS" BASIS, * WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied. * See the License for the specific language governing permissions and * limitations under the License. / /* * External dependencies / import { select } from '@storybook/addon-knobs'; import { action } from '@storybook/addon-actions'; /* * Internal dependencies */ import { VIEW_STYLE } from '../../../constants'; import ViewStyleBar from '..'; export default { title: 'Dashboard/Components/ViewStyleBar', component: ViewStyleBar, }; export const _default = () => { return ( <ViewStyleBar layoutStyle={select('layoutStyle', VIEW_STYLE, VIEW_STYLE.LIST)} onPress={action('on press clicked')} /> ); };	{ "pile_set_name": "Github" }
PCR-Based Assays for the Detection of Puccinia horiana on Chrysanthemums. Puccinia horiana, the causal agent of chrysanthemum white rust, is a pathogen of quarantine status in many countries where Chrysanthemum × morifolium cultivars are grown. Historically, identification protocols for white rust relied upon macroscopic symptom development and microscopic examination of infected leaves for teliospores. Symptoms become visible 7 to 10 days after initial infection under favorable conditions followed by the production of telia. Infected plants can therefore evade detection before symptoms and fruiting bodies are evident. Conventional and real-time polymerase chain reaction (PCR) assays were developed to detect P. horiana using primers designed to amplify portions of the internal transcribed spacer (ITS) regions of the nuclear ribosomal DNA (rDNA). The species-specific primers could detect the pathogen from 1 ng of DNA isolated from infected leaf tissue in conventional PCR assays and from 1 pg in real-time PCR assays. While both assays were capable of detecting P. horiana in symptomatic tissue, the greater sensitivity offered by the real-time PCR assay makes it more reliable for detecting the pathogen during the latent stage of infection. The P. horiana primers did not amplify the rDNA target using DNA isolated from leaf tissue infected with P. chrysanthemi.	{ "pile_set_name": "PubMed Abstracts" }
Chaotic Brillouin optical correlation-domain analysis. We propose and experimentally demonstrate a chaotic Brillouin optical correlation-domain analysis system for distributed fiber sensing. The utilization of a chaotic laser with a low coherence state ensures high spatial resolution. The experimental results demonstrate a 4 cm spatial resolution over a 906 m measurement range. The uncertainty in the measurement of the local Brillouin frequency shift is ±1.2 MHz. The analysis of the expected spatial resolution and signal-to-noise ratio is also given.	{ "pile_set_name": "PubMed Abstracts" }
0 0 You might be wondering what “Odds and Ends” means in the context of a SFX library. Let me soothe your worried mind with a short concise explanation: Odds and Ends is basically a general library, but smaller. Most general libraries total up to about 100gb or more, where as this is a lot of the same material, but aimed to supplement your already existing library. Along with the general sound effects, there are some pretty unique recordings that frankly can’t be developed into full libraries, due to budget constraints, or limited access. For example, submarine interior ambiences. Because I can’t cover multiple submarines effectively, there are approximately 8 recordings, and that’s most likely the number we’re going to stay at for the time being. One of the most extensive potions of the library is about 8gb of ambiences. Due to how much I’ve been moving around, I’ve covered quite a few locations, but haven’t been able to cover enough of any one subject matter that it would make sense to bundle them together. Take a look through the metadata sheet provided below, and give it a listen. Number of Files: 645 High Quality WAVS Size Unpacked: 20.7 GB Sample Rate: 16/48, 24/96, 24/192 Other Info: Meta-Tagged	{ "pile_set_name": "OpenWebText2" }
GENOME ANNOUNCEMENT {#s0} =================== Escherichia coli is a common commensal of the human and animal gut. E. coli strain WG5 is used as a host to detect somatic coliphages, proposed to be an indicator of human and animal fecal contamination of water, sediments, and sludge, as described in ISO method 10705-1 (2000) ([@B1]). This is an easily applicable and affordable method for water quality and contamination management in water treatment facilities ([@B2]). Other studies employ a similar method using strain WG5 as a host to detect temperate infectious phages from food ([@B3], [@B4]). The applicability of the method is based on the high sensitivity of the E. coli WG5 host to infection by somatic coliphages ([@B5]). E. coli WG5 ([@B6]) is a nalidixic acid-resistant mutant of E. coli C, also known as strain CN, and is publicly available in the ATCC (ATCC number 700078). E. coli strain WG5 possesses an attenuated host restriction-modification system and contains only the core part of the lipopolysaccharide (LPS), increasing susceptibility to phage infections ([@B5], [@B7]). Bacterial DNA was isolated using a DNeasy blood and tissue kit (Qiagen), according to the manufacturer's protocols. DNA libraries were prepared using a TruSeq Nano kit (Illumina) and sequenced on a MiSeq platform (2 × 300 bp). In parallel, genomic DNA was used to prepare barcoded DNA with Native barcoding kit 1D (product number EXP-NBD103; Oxford Nanopore Technologies), together with Ligation sequencing kit 1D (SQK-LSK108; Oxford Nanopore Technologies). DNA was sequenced using R9.4 chemistry (FLO-MIN106; Oxford Nanopore Technologies), and the raw signal was base called using Albacore 1.2.6. The sequences were assembled de novo into a single contig using the Unicycler hybrid assembler ([@B8]), with default settings. The WG5 strain has a circular complete genome of 4,592,887 bp. Genome annotation was acquired from NCBI Prokaryotic Genome Annotation Pipeline ([@B9]), which revealed 4,657 genes, 4,536 coding sequences, 22 rRNAs (5S, 16S, and 23S), 87 tRNAs, and 22 noncoding RNAs. Multilocus sequence types were identified using MSTL ([@B10]). No horizontally identified antibiotic resistance genes were detected by using ResFinder ([@B11]). The PHASTER prophage finder ([@B12]) identified three prophage regions, with two incomplete prophage regions and one questionable prophage region. Accession number(s). {#s1} -------------------- The genome sequences have been deposited in GenBank under the accession number [CP024090](http://www.ncbi.nlm.nih.gov/nuccore/CP024090). The version described in this paper is the first version. Citation Imamovic L, Misiakou M-A, van der Helm E, Panagiotou G, Muniesa M, Sommer MOA. 2018. Complete genome sequence of Escherichia coli strain WG5. Genome Announc 6:e01403-17. <https://doi.org/10.1128/genomeA.01403-17>. This research was funded by the EU H2020 ERC-20104-STG LimitMDR (grant 638902), the Danish Council for Independent Research Sapere Aude Program DFF-4004-00213, and the European Union Seventh Framework Programme (FP7-KBBE-2013-7-singlestage, no. 613745, Promys). M.O.A.S. acknowledges additional funding from the Novo Nordisk Foundation Center for Biosustainability and the Lundbeck Foundation. M.-A.M. acknowledges Spanish Ministerio de Innovación y Ciencia (AGL2016-75536-P), the Agencia Estatal de Investigación (AEI), and the European Regional Fund (ERF).	{ "pile_set_name": "PubMed Central" }
Electronic systems for tomorrow's power grids Electronic systems for tomorrow's power grids Germanys transition to a new energy economy requires more than simply switching to renewables. To meet the countrys goal of generating 80 per cent of its energy requirements from renewable sources by 2050, power grids must also be completely overhauled. Its not just a question of creating electricity highways to transmit power over long distances: the infrastructure also needs to be adapted. In the past, it consisted of a small number of large, centralised power plants, which generated electricity that was then distributed to all users. Now there are more and more small-scale generators connected to the grid, whose wind turbines, biogas plants, and solar panels feed in varying amounts of power at different times. To assure that power supply remains stable and reliable throughout the grid under these changed conditions, radical reengineering is called for to create a decentralised network. Two aspects are of particular importance. Firstly, the restructured grid must deliver power to users at all levels dependably, from private households to industry. And secondly, the efficiency of distribution grids must exceed its present level to enable optimal utilisation of the available resources. Ways of thinking are changing Changes will have to be made on numerous levels, from the major European power grids and the distribution networks to factories, homes, and electric vehicles, points out Professor Lothar Frey, director of Fraunhofer IISB. The potential for change is particularly high in homes and offices. When you think about it, the way we do things today is crazy, says Frey. Electricity is supplied by the grid at 230 volts and used to power electronic devices such as computers, printers, TVs, hi-fi systems and fluorescent lighting. Almost all of these devices have their own internal power supply unit (PSU) that converts 230-volt alternating current (AC) into the direct-current (DC) voltage required by the device. Since these PSUs are usually made of cheap components to minimise costs, their conversion efficiency is relatively low in other words, they transform part of the electricity into unwanted heat. This is a huge waste of energy. Electrical losses from connecting electronic devices to the AC grid supply via a PSU are 40 to 80 per cent higher than if they were connected directly to a DC supply. Moreover, the internal PSU makes the devices bigger, heavier, and more expensive. It would make more sense to convert the 230-volt AC grid supply into direct current at a central point inside the building and then provide DC power to specific circuits and types of load at, say, 24 or 380 volts. Furthermore, an increasing number of buildings are now equipped with solar panels, which natively generate DC. Rather than converting their output into AC, as it is now, it could be input directly to a DC network. The same applies to the DC output of solar storage batteries. The best place to start creating a DC network is in rooms that require little power, such as offices or living rooms, by installing an AC-to-DC converter in the wiring circuit serving those rooms. Researchers at Fraunhofer IISB have developed components to make this technically possible, including a converter the size of a pack of playing cards capable of serving all power outlets in a living room, and a DC network manager with a total capacity of 120 kilowatts, capable of serving an entire office building or several single-family homes. The converter has an efficiency of 98.5 per cent and its efficiency is far superior to that of the PSUs in use today. With conventional technology, the switchgear needed to control a domestic power supply of 20 kilowatts would fill an entire cabinet, explains Professor Frey. We can provide the same functions using efficient power electronics in a box no bigger than a telephone directory. In addition to its use in office and residential buildings, the new technology is also of interest to industrial and commercial users, whose refrigerators and cooling systems, variable-speed motors, and lighting systems can also be operated more efficiently, reliably, and at lower cost using DC power. As part of the SEEDs project funded by the Bavarian Ministry of Economic Affairs, Fraunhofer IISB is currently working on a holistic solution for its own institute building based on existing technologies and components. The aim is to reduce peak loads and energy losses and to integrate secondary sources of energy, such as waste heat, process cooling, and process gasses. In this way, the institute itself will serve as a research and demonstration platform for efficient energy management, and as a model that can be adapted to the more complex requirements of industrial plants. Reconfiguring the grid for the energy transition On a different scale, power electronics also plays an essential role in the German and European energy supply system. High-voltage DC (HVDC) transmission offers considerable advantages for long-distance power lines of the sort Germany needs to transport energy generated by offshore wind farms in the north of the country to electricity consumers in the south. An HVDC system basically consists of a transmission line with converter stations at each end. The first of these converts AC power from the conventional grid into DC, and the second converts the transmitted DC power back into AC. The advantage of this method is that energy losses are 30 to 50 per cent lower than in an AC transmission system. Modern DC transmission lines can be operated at voltages of up to several hundred thousand volts and the higher the voltage, the lower the transmission losses. The cables can be installed as overhead power lines on overland routes, or buried underground, or laid as submarine cables. Each end of the DC transmission line terminates in a substation containing up to several thousand inverter cells with semiconductor power switches. Each of these inverter cells weighs around 50 kilograms and stores a quantity of energy roughly equivalent to the explosive charge of a hand grenade. The Fraunhofer researchers have designed a fail-safe system that prevents the propagation of faults beyond a failed inverter cell, enabling the system as a whole to continue operating without interruption. Another advantage of this multi-level converter concept, according to Professor Martin Mrz, deputy director of the IISB and head of the Energy Electronics department, is that: The passive filters used to limit the impact of electrical disturbances in conventional systems require an area the size of an entire football pitch. The new technology makes it possible to construct systems that fit into a standard industrial building or mobile container. While Germany will certainly need its AC grids for a long time to come, in future they will co-exist with DC grids. Power electronics will be essential as a means of linking the two types of grid. In my view, says Professor Lothar Frey, the way we send power through the grid will soon resemble the way we transmit data over the Internet. Theres electronics at every web interface, and in future the same will be true of power grids. The different elements, such as long-distance transmission lines, local substation networks, decentralised energy storage units, the many new generators, and of course the end consumers, will be linked via a multiplicity of power electronic nodes. Together with intelligent control systems, this will have a stabilizing effect on the grid as a whole, affirms Frey. New components for electromobility Another power source that will be exploited by tomorrows power grid is the energy stored in the batteries of electric vehicles. But before that can happen, electromobility must address a number of technical issues and these can be solved with the aid of power electronics. In a typical high-voltage vehicle power-net, the battery delivers an output of about 400 volts to drive the electric motor. At the same time, the battery has to supply the lower voltages to operate the lighting, air conditioning, servo-assisted steering, car radio, windscreen wipers, and other essential vehicle functions. In most cases, these electrical loads require different voltages and currents. The necessary interfaces are provided by power electronic converters, which need to be very compact and reliable. Moreover, they have to comply with electromagnetic compatibility (EMC) requirements to ensure that they do not interfere with other electronic components or vehicle systems. To meet EMC requirements, and in order to save space and weight and reduce the need for costly wiring, the researchers chose to place individual power electronics components as close as possible to the functions they control, rather than grouping them in a central location. Martin Mrz refers to this approach as point-of-action-focused system integration. As a result, he and his researchers were able to reduce the number of connectors by two thirds and eliminate many heavy, expensive, thick high-voltage cables. This means the electronic inverter, which converts DC power from the vehicle power-net into AC power to drive the electric motor, can be mounted directly on the motor or integrated into the drive system, as in electric wheel hub motors. The power converter that generates the necessary low-voltage supply from the vehicle network is installed in the battery compartment, together with the charging device that allows the vehicles battery to be recharged at any charging station. We have developed an innovative fast charging solution based on a DC system that does not require an extra fast charger, which makes our solution particularly economical, says Mrz. To prove that these ideas also work in practice, the IISB researchers have already demonstrated their concept creating a hybrid version of an Audi TT. To do so, they completely developed all power-electronics systems along the energy chain, from the charging point to the wheels, including the charging device, the battery system, all monitoring functions, voltage converters, and the powertrain. The converters built by the researchers are extremely compact and yet do not require any extra cooling cycle. Redesigned from the materials through to the processes To reduce the size and increase the reliability of power converters, it is frequently necessary to adopt an entirely new approach when choosing materials, designing electronic components, packaging and systems, and manufacturing. Fraunhofer IISB conducts research in each of these areas. Its scientists have a special preference for silicon carbide (SiC) materials, because they can be used to produce electron devices with particularly low loss characteristics and high temperature resistance. To separate chips from SiC wafers, the IISB has developed a high-output method that is based on the concept of thermal laser separation (TLS). New technologies are also available to increase the reliability of bonded, soldered, and sintered joints, and for the polymer casting techniques frequently used to prevent flashover. Once they reach the prototype stage, the researchers integrate them in their demonstrators, where they are subjected to an exhaustive range of tests, including accelerated ageing, to determine their load and wear resistance. The most important parameters when testing power electronics are efficiency and power density. The IISB has set a number of benchmarks in this domain, for example in 2013 when its researchers set the record for the performance of an SiC power converter by reaching a power density of 100 kW per liter of volume. In 2014, they became the reference for the design of DC-DC converters by reaching a conversion efficiency of 99.3 % with gallium-nitride power switches.	{ "pile_set_name": "Pile-CC" }
Challenges Faced by Expatriate Workers in the Gulf Cooperation Council Countries Pranav Naithani Waljat Colleges of Applied Sciences Muscat, Oman pranavnaithani@gmail.com A.N. Jha Birla Institute of Technology Extension Centre, Lalpur, Ranchi, India anjha06@rediffmail.com Year: 2009 Challenges Faced by Expatriate Workers in the Gulf Cooperation Council Countries Pranav Naithani and A.N. Jha Abstract Over the last six decades, the reliance of the Gulf Cooperation Council (GCC) countries' economy on expatriate workforce has increased incessantly. The majority of the private sector workforce in the Gulf Cooperation Council (GCC) countries are expatriates. Recent attempts by governments in the GCC countries to localise the workforce, through their workforce nationalisation programmes, have offered limited results. Thus, dependence on expatriate workforce will continue in the near future and GCC countries, short of professionally and technically qualified local workers will need to employ a large number of expatriates to support their economic and social development plans. This calls for a systematic approach to understand the specific challenges faced by expatriates of different nationalities in GCC countries, so that these challenges can be addressed to enable GCC countries to become a preferred destination for technically and professionally qualified expatriate workers. This paper presents an overview of GCC countries; the reasons for their dependence on expatriate workforce; key current challenges faced by expatriates in GCC countries and suggestions for facilitating adjustment of expatriate workers in the GCC countries. Keywords: Expatriate adjustment, Migration, Foreign worker, Gulf Cooperation Council, GCC 1. Introduction Workers working in a foreign location for more than one year are considered to be expatriate workers. (Richardson & McKenna, 2003). Expatriates are temporary workers who work in a foreign location under contracts which are of limited duration (Ward, Bochner & Furnham, 2001 as cited by McGinley, 2008). These work contracts may be renewed multiple times, thus prolonging the stay of an expatriate worker in a foreign country (Shah, 2009). Increasing numbers of expatriate workers are now accompanied by their spouse and/or children (Haslberger & Brewster, 2008), thus necessitating the need of not only workplace adjustment but also social and cultural adjustment of self and family. A major section of the work force in GCC is expatriate population derived from different nationalities (Forstenlechner, 2008). This expatriate work force and accompanying family members face specific challenges during their stay in a foreign land. Before dwelling into the nature and reasons for such challenges, the following section first presents an overview of GCC countries. 2. Common economic features of the Gulf Cooperation Council (GCC) countries The Gulf Cooperation Council (GCC) came into existence in 1981, when Bahrain, Qatar, Saudi Arabia, UAE, Oman and Kuwait joined hands for regional collaboration. The GCC countries are a part of the Arab world and share a common cultural, religious and historical background (Kirk & Napier, 2008). Some common economic features amongst the GCC countries are: dependence on petroleum products, young and fast paced growth of the local labour population, and high dependence on expatriates in the private sector (Sturm, Strasky & Peschel, 2008). The sparsely populated region of GCC faces acute shortage of technically and professionally qualified nationals (MoEA, 2001). 3. Nationalisation of workforce in the GCC countries For many years GCC has been attempting to promote higher participation of the local population in the national workforce with workforce nationalization programs such as Bahrainization (Bahrain), Emiratization (UAE) and Omanization (Oman). This has been necessitated by the fact that about 60 per cent of the local population of the GCC is between the ages of 14 and 27 (Dollman, 2007) and is speedily adding to the increasing number of employment seeking adults. In the public sector workforce, higher participation of the local population has been achieved through lower knowledge and experience requirements for recruits (Al-Ali, 2008; Forstenlechner, 2008). Public sector employees are offered better salary, higher job security, lesser work hours, lesser work content and generous holidays (Al-Ali, 2008). This creates a privileged workforce segment of local nationals in the public sector with better compensation and less demanding work profile. 4. Growth of expatriate workforce in the GCC countries In GCC countries, nationals are a predominant component of government workforce where as expatriates are in the majority in the private sector (Forstenlechner, 2008; Keivani, Parsa & Younis, 2003 as cited by Malecki & Ewers, 2007). The number of migrant workers in the GCC has increased from just 9 million in 1990 to 13 million in 2005 (Dito, 2008). The popularity of expatriates in the private sector workforce is due to higher productivity and better discipline (Sadi & Henderson, 2005). Poor participation of the local population in the private sector has been due to various reasons such as long and irregular work hours and focus on employee performance (Al-Ali, 2008). Private sector organisations depend on expatriates, due to following economic reasons: Expatriates are a major source of technical and professionally qualified and experienced workforce. Lesser training and induction time as expatriates learn and adapt fast to the new environment. Expatriates are willing to work longer hours and have lower rates of absenteeism when compared to that of the local workforce. In comparison to local workforce, the productivity of expatriate workforce is higher. The majority of Asian expatriates working in the GCC countries is available at lower salaries when compared to that of the local workforce and expatriates from the advanced western world. Due to above mentioned reasons government supported programmes for higher nationalisation of the workforce in the GCC countries have not delivered the desired results in the private sector. Private sector organisations continue to depend on expatriate workforce for pure business reasons and will continue to do so in near future as well. 5. Gender differences in migration in the GCC countries Though expatriate population in the GCC has grown in the last six decades, yet participation of female in the migrating workforce to GCC is one of the least in the world with only 29 per cent of the migrants being females (Dito, 2008). A substantial number of Asian female migrants in GCC are engaged in the occupation of domestic servants (Malecki & Ewers, 2007). This highlights the fact that professional expatriate women have limited opportunities in the GCC. Orthodox social and cultural factors are responsible for lack of work opportunities for single women in GCC as some of the countries do not easily allow work permits for single expatriate females or married expatriate females not accompanied by a spouse. The majority of female expatriate professionals in the GCC are those who have accompanied working spouse or parents to the GCC on a family visa and have later managed a job opportunity. 6. Gender differences in salary in the GCC countries In the Arab world, women in the workplace suffer from bias with reference to severe differences in pay as well as a social attitude towards women in leadership position (Al-Ali, 2008) and the same applies to GCC. According to Haslberger and Brewster (2008), accompanying spouses of expatriates find it difficult to find a new job in a foreign location. With specific reference to female expatriate workers, as many of them originally accompany their working spouse under spouse sponsored family visa and with no confirmed job, they are more vulnerable to lower paying jobs. In many circumstances for the same job, with similar work content and responsibility, female expatriate workers agree to work for a lower salary in comparison to the salary paid to a male colleague, as they prefer to work for lower salary rather than to sit idle at home. 7. Social Division of labour in the GCC countries and social interaction between locals and expatriates While adjusting in an environment of a new country, expatriates face multiple social and cultural challenges (ORC, 2007). In the social hierarchy in GCC, local Arabs occupy the highest platform, followed by skilled westerners, Arabs from other countries and the lowest position is occupied by the Asians (Malecki & Ewers, 2007). Within Asians Indians are placed slightly higher than the Bangladeshis and Sri Lankans (Malecki & Ewers, 2007). Expatriates from different foreign locations are extended a different social treatment and Asian expatriates do not enjoy the same social status as their counterparts from western world do. This social division gets further enhanced by the fact that local and expatriate populations have lower social and cultural interaction with each other. Most expatriates in the Middle East live in housing compounds which are located separately from the housing facilities of the locals (Mesmer-Magnus & Viswesvaran, 2007). The social interactions of most of the expatriates in GCC with the local population are primarily limited to professional reasons. An exception to this may be a Muslim expatriate who may be relatively easily accepted by the local Muslims in GCC countries (Mamman, 1995) 8. Work visa requirements The majority of migrants in GCC can not gain citizenship (MoEA, 2001; Shah, 2004; Shah, 2009). Expatriates in GCC work on a short term work visa and permanent residency status for the expatriates are discouraged on account of social and cultural reasons. The work visa is generally issued until the age of 60 years (Al-Ali, 2008) and needs to be renewed after every two years. This creates a sense of uncertainty and job insecurity in the minds of expatriates as the present labour laws are skewed in the favour of the employer and the work contracts can be terminated any time by the employer (Al-Ali,2008). 9. Weak labour laws in the GCC countries and labour market liberalization The labour laws in GCC are weak. Following facts related to unskilled and semi-skilled expatriate workers highlight the poor compliance of existing labour laws by a large number of employers in GCC countries (ILO, 2009; Rajan & Prakash, 2009; Saif, 2009). Poor safety condition at workplace Forced daytime outdoor work when the temperature is very high Poor housing conditions Delay in payment of salary Forced overtime coupled with non payment for overtime work Forced surrender of passport For an expatriate to change a job from one employer to another, while remaining in the same country in the GCC, once required a NOC (no objection certificate) from the current employer. On account of international pressure on the GCC countries to reform its labour laws, such practices are being gradually abolished (Gulf Talent 2008), but still more worker friendly labour laws are the need of the hour. 10. Economic problems of expatriates in the GCC Countries According to Haslberger (2008) adjustment of an expatriate in a foreign location is also influenced by living cost, house rents and other expenses. High inflation in the last few years has become an important feature of GCC economy. Average inflation in GCC increased to above 6% in 2007 (Sturm et al., 2008) and further increased to double digit figures in 2008 (Saif, 2008). This directly influences the capacity of an expatriate to save and remit money to the parent country. 10.1 Rising house rents In GCC, residential rents contribute to inflation in a major way. Residential rents rose in different GCC nations in the range of 15 to 42 per cent during 2007-2008 (Gulf Talent, 2008). In UAE in 2008, 35 per cent of the income of an employee was being spent on paying residential rent, in Oman it was 28 per cent and in Bahrain 26 per cent (Gulf Talent, 2008). Rise in residential rents in most of the GCC countries has been attributed to the large inflow of expatriate workers, opening of real estate markets to foreign buyers and upgrading of housing facilities by the nationals (IMF, 2008). The current recession has had some impact on housing rents and the rents have declined in certain cities and regions such as Dubai (UAE) and Doha (Qatar) but still a large section of expatriate population has to pay a significant part of their monthly salary as house rent. 10.2 Rising other expenses The current economic slowdown has not had any impact on the cost of living of expatriates in GCC countries. Most of the cities in the GCC are witnessing higher costs of housing, transportation, food, clothing, household goods and entertainment. A recent survey conducted in March 2009 by global human resource consulting firm Mercer found Dubai rising from 52 nd rank to 20 th rank in the global list of most expensive cities (BI-ME, 2009). Other GCC cities also witnessed rise in ranks in the list of global most expensive cities. Abu Dhabi in UAE jumped 39 places, from 65th to 26th, Kuwait city rose from 94th to 77th, Manama in Bahrain rose from 112th to 82nd, Riyadh in Saudi Arabia rose from 119th to 90th rank (BIME, 2009). 10.3 Increasing gap between salary growth and inflation According to Bayt (2007) research report, the average increase in salary in GCC was 15 per cent but the average increase in the cost of living due to inflation and other related factors was 24 per cent. This rising gap between increase in salary and inflation resulted in reduced disposable income in the hands of expatriates. Similar findings were stated by Gulf Talent (2008) report, in which many expatriates reported a fall in net disposable income. For example in the UAE, 40 percent respondents reported lower savings due to inflation and poor growth in salary (Gulf Talent, 2008). 10.4 Salary gap within different expatriate communities For similar educational qualification, work experience and job responsibilities, expatriates from western advanced nations are paid a higher salary in GCC in comparison to expatriates from Asian countries. Arabian Business Salary Survey for the year 2009 highlighted the fact that British expatriates working in GCC countries are paid salaries, which amount to more than two times of the salaries paid to their Indian counterparts (Sambidge, 2009). Differences in salary combined with differences in social treatment of expatriates on the basis of different regions/ countries create two categories of expatriates. First is the preferred category of expatriates from the western advanced nations and the second is the general category of Asian expatriates. 11. Some solutions to challenges faced by expatriates in the GCC Countries Expatriates are in general perceived to be temporary worker, but in GCC a large number of expatriates have been living for a longer duration (Coffman, 2003). Further, a large number of expatriates in GCC want to stay back. According to a recent survey, 77 per cent of expatriates want to continue working in UAE, further, 54 per cent in Bahrain and 46 percent in Oman want to continue working (Gulf Talent, 2008). Above mentioned findings suggest that to a large extent expatriate workers in GCC countries have been able to overcome the hurdles they face while adjusting in a foreign land. Successful expatriate adjustment in the GCC countries is a joint effort in which the GCC governments, employer and expatriate themselves participate and jointly attempt to remove the roadblocks for expatriate adjustment. Expatriates do not get to socialise much with the local community and this brings a bonding amongst the expatriates of similar social status, common regional background, language, religion or profession (MoEA, 2001). Hundreds of expatriate cultural/ recreational associations / clubs are active throughout the GCC (MoEA, 2001) thereby providing a platform for the expatriate community to connect socially. Thus expatriates themselves successfully overcome the challenge of social isolation. Some GCC countries such as Bahrain and Kuwait are attempting to address the drawbacks of work visa requirements and are trying to simplify the procedures in favour of the expatriate workers. Bahrain is in the process of granting expatriate workers, some freedom of movement in the labour market by allowing them to transfer jobs without paying any penalty (Shaikh & Sinclair, 2009). But still more needs to be done by governments in the GCC to legally protect the work related interests of expatriates. Proactive governments of Bahrain, Kuwait and UAE are in the process of establishing a free labour market and in near future stronger laws to protect the interests of expatriate workers are expected. But till then the employers will continue to enjoy the higher bargaining power under the protection of present labour laws skewed in the favour of employers. Thus the GCC governments are attempting to ensure a more liberal and hassle free work visa system for the expatriates. Gaps between the salaries of expatriates of advanced western nations and Asian expatriates have narrowed in the recent past with specific reference to Indian expatriate workers. Indian expatriates are the single largest segment of the GCC workforce. The economic boom in the early years of the current century has resulted in growth in salaries in India, and this has put pressure on employers in GCC. They have two choices, either to stop / reduce recruitments from India or to increase salaries of Indian expatriates. According to Gulf Talent (2008) survey, Asian expatriates, the majority of whom are Indian expatriates, were recipients of the highest increase in salary during 2004-2008. This has resulted in narrowing of the salary gap between the Asian expatriates and Arab/ Western expatriates. But this reduction in salary gap is limited to highly qualified and technically skilled workers, and majority of Asian expatriates still suffers from the drawback of bias and gap in salary due to their origin. 12. Conclusion Though some of the solutions have been implemented in the recent past to facilitate expatriate adjustment in the GCC countries, yet a lot more is still required to be done by the governments and private sector organisations in the GCC countries. To become an attractive destination for qualified expatriate workforce, governments in the GCC countries need to immediately address the following issues: Introduction of more stringent labour laws to protect expatriate workers from forced overtime, poor living conditions, working under hazardous conditions. Introduction of more stringent laws to protect expatriate workers from arbitrary increase in house rents Simplification of work visa rules to enable an expatriate to freely change employer Joint initiatives with the private sector to reduce salary bias against Asian expatriates. To become an attractive destination for qualified expatriate workforce, governments in GCC countries also need to further promote participation of female expatriates in the workforce. To attract larger number of professionally qualified female workers, following initiatives by governments of the GCC countries are required: Reduction in gender differences in migration by simplifying work visa rules for female expatriates. Better enforcement of labour laws to protect the interests of female workers, especially unskilled and semiskilled female workers. Joint initiatives with the private sector to provide a work environment where female expatriate workers do not suffer from any work related bias, especially with reference to salary bias. While protecting their cultural heritage and sentiments, governments and private sector employers in GCC countries need to implement programmes for enhancing social and cultural interaction between expatriate and local population. The GCC governments also have to continue their efforts in improving the work-visa laws as well as labour laws to protect the interests of expatriate workers. Governments in the GCC countries in partnership with the private sector need to continue the initiatives for a free labour market and to systematically and gradually introduce stronger labour laws to protect expatriate workers from possible exploitation by the employer. Thus, the governments in GCC countries need to play a more effective role in creating a professional and social environment, which can attract better quality expatriate workers who can contribute better in the economic development of the region. Introduction of any policy, programme or law to protect the interests of expatriate workers will produce results only when the implementation and monitoring of such policy, programme or law is effective and proper care is taken that such policy, programme or law is adhered to by the employers. Implementation of labour laws and adherence by local employers is one of the major weaknesses in the work environment of GCC countries. Out of the three stages of policymaking, policy implementation and adherence to the policy, it is the third stage of adherence to the policy that needs to be given the top priority by the GCC governments. References Al-Ali, J. (2008). Emiratisation: drawing UAE nationals into their surging economy. International Journal of Sociology and Social Policy, 28(9-10), 365-379. Bayt. (2007). GCC Human Resource Overview: Salaries, cost of living and loyalty. [Online] Available: http://www.bayt.com/job/research-report-1641 (4th September, 2009). BI-ME. (2009). Cost of living rises highest for GCC expats in Abu Dhabi and Dubai, Business Intelligence: Middle East, 7th July 2009. [Online] Available: http://bime.com/main.php?id=38729&t=1&c=34&cg=4&mset (7th August2009). Coffman, J. (2003). Higher Education in the Gulf: Privatization and Americanization. International Higher Education,The Boston College Center for International Higher Education, 33, 17-19. Dito, Mhd. E. (2008). GCC Labour Migration Governance. Paper presented in the UN Expert Group Meeting onInternational Migration and Development in Asia and the Pacific, Bangkok, Thailand, 20-21 September 2008. Dollman, S. (2007). A model of American higher education in the Middle East. Educause Quarterly, 3, 59-62. Forstenlechner, I. (2008). Workforce nationalization in the UAE: image versus integration. Education, Business and Society: Contemporary Middle Eastern Issues, 1(2), 82-91. Gulf Talent. (2008). Gulf Compensation Trends 2008: Key Developments in Salaries and Employment Across UAE,KSA, Kuwait, Qatar, Bahrain and Oman. Gulf Talent. Haslberger, A. (2008). Expatriate Adjustment: A more nuanced view. In Dickmann, M., Brewster, C. & Sparrow, P.(Eds.), International H.R. Management: A European Perspective, (pp. 130-149). Routledge. Haslberger, A., & Brewster, C. (2008). The expatriate family: An international perspective. Journal of ManagerialPsychology, 23(3), 324-346. ILO. (2009). International labour migration and employment in the Arab region: Origins, consequences and the way forward, Thematic paper by ILO, Arab Employment Forum, Beirut, Lebanon, 19-21 October, 2009. IMF. (2008). Regional Economic Outlook Middle East and Central Asia. World Economic and Financial Surveys, International Monetary Fund. Keane, D., & McGeehan, N. (2008). Enforcing Migrant Workers' Rights in the UAE. International Journal on Minorityand Group Rights, 15, 81-115. Keivani, R., Parsa, A., & Younis, B. (2003). Development of the ICT sector and urban competitiveness: the case of Dubai. Journal of Urban Technology, 10, 19-46. Kirk, D., & Napier, D. (2008). The Transformation of Higher Education in the UAE: Issues, Implications and Intercultural Dimensions. In, Zajda, J., Daun, H., & Saha, L.J. (Eds.) Nation-Building, Identity and Citizenship Education: Cross Cultural Perspectives (pp. 131142). Springer. Malecki, E. J., & Ewers, M. C. (2007). Labor migration to world cities: with a research agenda for the Arab Gulf. Progress in Human Geography, 31(4), 467-484. Mamman, A. (1995). Expatriates' intercultural effectiveness by chance of birth. In Selmer, J. (Ed.) Expatriate Management: New ideas for international business (pp. 137-55). Quorum Books. McGinley, J. (2008). Expatriate adjustment within a social context: Examination of a sample in Russia. Journal of Social, Evolutionary, and cultural psychology, 2(2), 56-68. Mesmer-Magnus, J. R. & Viswesvaran, C. (2007). Expatriate Management: A review and directions for research in expatriate selection, training and repatriation. In Harris, M.M. (Ed.) Handbook of Research in International HRM, LEA's organization and management series (pp. 183-206). NY: Taylor & Francis Group/Lawrence Erlbaum. MoEA. (2001). Report of the high level committee on the Indian Diaspora (pp. 11-30). Ministry of External Affairs, Government of India. ORC. (2007). Expatriate Work-Life Balance Survey. ORC Worldwide. Rajan, S. I., & Prakash, B. A. (2009). Migration and development linkages re-examined in the context of the global economic crisis. Paper presented in the 3rd Global forum on migration and development, Athens, 2-3 November, 2009. Richardson, J., & McKenna, S. (2003). International experience and academic careers: What do academics have to say? Personnel Review, 32 (6), 774-795. Sadi, Mhd. A. & Henderson, J. C. (2005). Local versus Foreign Workers in the Hospitality and Tourism Industry: A Saudi Arabian Perspective. Cornell Hotel and Restaurant Administration Quarterly, 46 (2), 247-257. Saif, I. (2009). The oil boom in GCC countries, 2002-2008: Old challenges, changing dynamics. Carnegie paper No. 15, Carnegie Middle East Center. Saif, I. (2008). The Food Price Crisis in the Arab Countries: Short Term Responses to a Lasting Challenge. [Online] Available: http://www.carnegieendowment.org/files/saif_food_prices_final.pdf (24th July, 2009). Sambidge, A. (2009) Brit expats earn double that of Indian counterparts. [Online] Available: http://www.arabianbusiness.com/research/salary-survey-report-2009/feature/548493 (28th October, 2009). Shah, N. (2004). Gender and labour migration to the Gulf countries. Feminist Review, 77, 183-85. Shah, N. (2009). The management of irregular migration and its consequences for development: Gulf Cooperation Council. Working Paper No. 19, Regional Office for Asia and the Pacific, ILO. Shaikh, H., & Sinclair, Z. (2009). Saudi Seeks Naturalisation for Long-term Expatriates, Khaleej Times dated 14th July 2009. [Online] Available: http://www.khaleejtimes.com/DisplayArticle08.asp (19th July 2009). Sturm, M., Strasky, J., Adolf, P., & Peschel, D. (2008). The GCC Countries Economic structures, recent developments and role in the global economy. ECB Occasional Paper No. 92. Ward, C., Bochner, S., & Furnham, A. (2001). The Psychology of Culture Shock. (2nd ed.). New York: Routledge.	{ "pile_set_name": "PhilPapers" }
Jason Janes really loves to barbecue. He can be found behind one of the three outside grills at his home in the Humber Valley on Newfoundland's west coast a few times a week, and he keeps things sizzling all year long. "I love things that are low and slow," he said, describing his favourite dish — pulled pork with smoked macaroni and cheese. Janes says grooves will naturally form over time to match people's barbecue grates. (JuniperBBQScraper/Facebook) So when Janes saw stories in the news about the dangers of wire bristles from barbecue brushes becoming embedded in people's throats, he hit the hardware store. Janes said he didn't have much luck finding a safer alternative, and the cedar shakes he was using to scrape the grill in the meantime were wearing out too quickly. "I said, 'Geez, this is a bit of a nuisance,' so I called up my dad and said, 'Do you have a piece of juniper?'" Jason Janes started the scraper business in spring of 2017, and his wife Jackie and parents Lynn and Bern all help run it. (JuniperBBQScraper.com) That's when he hit upon what just might become a million-dollar idea. Janes knew juniper is hard and durable and lasts a long time in the wood stove, so he carved a piece into a scraper. He was so impressed with his invention he posted a picture on social media to see if anyone else would want one, and then went on vacation for a couple of weeks. When he got back there were hundreds of replies. The former tech entrepreneur now manufactures scrapers from his home garage, selling 5,000 in the first six months. Truly home grown The choice of tamarack, which is commonly referred to as juniper in Newfoundland and Labrador, is key. "It's just so beautiful. Every single piece is unique. It's like a piece of art," he said. "And because it has a very high heat resistance it doesn't burn as fast on the barbecue and will last longer than cedar … Also there's no such thing as Newfoundland cedar — it doesn't exist here. This is a local product. If it's cedar it's imported." Janes works in advance with the local harvesters who supply the pulp and paper mill in Corner Brook, and buys the juniper by the tractor trailer load. A small load of juniper fresh out of the kiln is destined to become scrapers. (JuniperBBQScrapers/Facebook) Janes said any splinters from his scraper, unlike wire bristles or pieces of bamboo that get caught on the grill and stuck in the food, will simply burn up. "If a splinter comes off this thing it just burns. It becomes smoke and flavour to the food." All in the family The budding business — which started with the first prototype in May 2017 — is a family affair. Janes's wife Jackie helps with shipping. His dad, Bern, pitches in on production when it's busy, and his mother, Lynn, hand-cut and sewed the straps for the first 1,000 units from old thrift-store leather jackets. "We've well outgrown that," said Janes. The scrapers are now available in 60 retail outlets throughout Newfoundland and Labrador, and a national distribution with a big chain is in the works. Janes also sells from his website and has shipped scrapers across Canada and the U.S., as well as to the Caribbean and the U.K. "We can feel it. It's here. I've been involved in a lot of startups over the years, and the ones that take off you can start to feel something when it's about to happen. You can sense it," he said. Janes says he is still using the prototype scraper he carved in May 2017. (JuniperBBQScraper/Facebook) "It was a hobby and now it's starting to feel like a business. I feel that we're right on the verge of that. That's the part that I love."	{ "pile_set_name": "OpenWebText2" }
In vitro and in vivo expression of endothelial von Willebrand factor and leukocyte accumulation after fractionated irradiation. Previous investigations have demonstrated an increased release of von Willebrand factor (VWF; also known as vWF) in endothelial cells after high single-dose irradiation in vitro. We have also found increased levels of Vwf protein in mouse glomeruli after a high single dose of renal irradiation in vivo. In addition, increased numbers of leukocytes were observed in the renal cortex after irradiation in vivo. The aim of the present study was to investigate and quantify these biological processes after clinically relevant fractionated irradiation and to relate them to changes in renal function. A significantly greater increase in release of VWF was observed in cultured human umbilical vein endothelial cells (HUVECs) after fractionated irradiation (20 x 1.0 Gy) than after a single dose of 20 Gy (147% compared to 115% of control, respectively, P < 0.0005). In contrast with the in vitro observations, glomerular Vwf staining was lower after fractionated irradiation in vivo (20 x 2.0 Gy or 10 x 1.6 Gy +/- re-irradiation) than after a single dose of 16 Gy. The number of leukocytes accumulating in the renal cortex was also lower after fractionated in vivo irradiation than after a single radiation dose. The onset of these events preceded renal functional and histopathological changes by approximately 10 weeks. These data indicate that radiation-induced changes in endothelial VWF expression after in vivo irradiation may be distinct from the in vitro observations. Increased VWF expression may reflect pivotal processes in the pathogenesis of late radiation nephropathy and provide a clue to appropriate timing of pharmacological intervention.	{ "pile_set_name": "PubMed Abstracts" }
In case anyone wonders, this batch is the same as the last batch. I've mentioned some changes we're making to the circuit design, but that's going to be in the next round, and won't be ready for several months. In case anyone wonders, this batch is the same as the last batch. I've mentioned some changes we're making to the circuit design, but that's going to be in the next round, and won't be ready for several months. Click to expand... Can you elaborate on the circuit design changes? And what that means functionally for us? In case anyone wonders, this batch is the same as the last batch. I've mentioned some changes we're making to the circuit design, but that's going to be in the next round, and won't be ready for several months. Click to expand... Will this be the last batch with the OTA design? If so, then this will be a collectable soon! Yes, the OTA chip we were using is now discontinued, so rather than hunting for inventory around the world, or using a less ideal chip, we are going to scrap the OTA and go optical. We have two definite design goals: --Make it sound and act just like the existing model. --Give it a better input level control. One person has asked for separate attack and release time controls, but I'm not sure I want to sacrifice the tone knob, or use a stacked pot (expensive and maybe fragile) for that. Definitely open to requests and feedback though. One person has asked for separate attack and release time controls, but I'm not sure I want to sacrifice the tone knob Click to expand... FWIW, I really like the current control arrangement, and it's one of the reasons, (in addition to the great tone), that I bought it. I love tweaking knobs as much as anyone, but in a live application when switching between basses or adjusting for a different sound on a given tune, it's nice to be able to dial in what I want quickly without worrying about whether I have 1ms too much or too little of attack or release. Get it done, and get going; because the band leader rarely give me enough time to change basses, let alone my compressor settings. (Oh yeah, the Tone knob rules too.) I love the Smoothie--I think everybody would dig it, but it's especially great for people like me who have sort of a remedial understanding of compression and need to make quick, effective changes on the fly on a dark stage. Having the attack and release on one knob and the ratio and threshold on another really makes it a breeze. Add in the tone and wet/dry controls...man, don't change a thing! I love the Smoothie--I think everybody would dig it, but it's especially great for people like me who have sort of a remedial understanding of compression and need to make quick, effective changes on the fly on a dark stage. Having the attack and release on one knob and the ratio and threshold on another really makes it a breeze. Add in the tone and wet/dry controls...man, don't change a thing! Click to expand... Agreed. Its pretty much idiot proof and I say that as a full fledged idiot Suave and tough? Does the tough version respond with a faster attack than the suave version or am I misinterpretting. I like slow attack to let my initial attack through before being compressed. Please advise. It's a bit hard to describe. That's the main thing that held me up from listing them for sale over the last few days--trying to figure out the most accurate and useful way to describe the difference. Your interpretation is pretty close: the tough version responds faster, and stronger, which works faster to knock down the note attack, when both pedals are set to the same settings. But both versions have a wide-ranging attack control, so the tough one will also let initial peaks though as you wish. The suave one is a bit more transparent in its action, the tough one a bit more rubbery.	{ "pile_set_name": "Pile-CC" }
STATE OF MICHIGAN COURT OF APPEALS LASAN BELLAMY, UNPUBLISHED March 20, 2018 Petitioner-Appellant, v No. 336584 Ingham Circuit Court DEPARTMENT OF CORRECTIONS and LC No. 16-000017-AW PAROLE BOARD, Respondents-Appellees. Before: SAWYER, P.J., and BORRELLO and SERVITTO, JJ. PER CURIAM. Petitioner, Lasan Bellamy, appeals by right the trial court’s opinion and order denying his petition for mandamus, motion for summary disposition, motion for temporary restraining order, and request for a preliminary injunction, all of which were directed at respondents Michigan Department of Corrections (MDOC) and the Michigan Parole Board (the Parole Board) (collectively “respondents”). We affirm the trial court’s order. I. BASIC FACTS In March 1996, petitioner was sentenced to 12 to 30 years in prison for first-degree criminal sexual conduct. His earliest release date was October 1, 2006. Petitioner was released on parole on October 3, 2013. A condition of his parole was that petitioner reside at the Kalamazoo Probation Enhancement Program (“KPEP”) facility in Benton Harbor Michigan, a “residential sex offender placement facility.” On January 22, 2014, petitioner absconded parole, leaving KPEP without permission and removing his electronic monitoring device. After three months, petitioner turned himself in. He was re-incarcerated and pleaded guilty to eight counts of parole violation. His parole status was subsequently revoked and continued to be revoked. Petitioner filed a petition for mandamus seeking, among other things, reinstatement of his parole and an order that respondents be prohibited from conditioning future parole on a requirement that he reside in a facility such as KPEP. Respondents filed a brief arguing that the trial court lacked subject matter jurisdiction because petitioner’s petition was not in accordance with the Michigan Prison Litigation Reform Act (PLRA), MCL 600.5501 et seq. The trial court agreed with respondents and dismissed petitioner’s petition. Petitioner appealed the dismissal, and in lieu of granting leave to appeal, this Court reversed and remanded because petitioner was not required to comply with the requirements of the PLRA since his petition was not a civil -1- action concerning prison conditions. Bellamy v Dep’t of Corrections, unpublished order of the Court of Appeals, entered July 1, 2016 (Docket No. 332250), citing Hayes v Parole Bd, 312 Mich App 774, 781-782; 886 NW2d 725 (2015). Before the trial court could reinstate petitioner’s case, he submitted a motion for summary disposition and various other filings. He also requested a temporary restraining order and a preliminary injunction. The court denied petitioner’s petition for mandamus, his motion for summary disposition, and his motion for temporary restraining order and preliminary injunction. II. MANDAMUS Petitioner first argues that the trial court erred in denying his petition for mandamus. We review the denial of a writ of mandamus for an abuse of discretion. Rhode v Dep’t of Corrections, 227 Mich App 174, 178; 578 NW2d 320 (1997). Whether a defendant has a clear legal duty to perform and whether a plaintiff has a clear legal right to performance of a duty are questions of law that we review de novo. Id. We also review the proper interpretation and application of statutes de novo. Hayes v Parole Bd, 312 Mich App 774, 778; 886 NW2d 725 (2015). Petitioner argues that KPEP falls under the definition of a “community residential home” and therefore, when the Parole Board required that he reside there as a condition of his parole, it exceeded its legal authority. He argues that this entitles him to a writ of mandamus to compel respondents to reinstate his parole and alter future parole conditions. We disagree. “Mandamus is an extraordinary remedy, and its issuance is discretionary with the court.” Lee v Macomb Co Bd of Comm’rs, 235 Mich App 323, 331; 597 NW2d 545 (1999), rev’d on other grounds 464 Mich 727 (2001). “The primary purpose of the writ of mandamus is to enforce duties created by law, where the law has established no specific remedy and where, in justice and good government, there should be one.” State Bd of Ed v Houghton Lake Community Sch, 430 Mich 658, 667; 425 NW2d 80 (1988) (citation omitted). In order to obtain a writ of mandamus, the plaintiff bears the burden of showing that (1) the plaintiff has a clear legal right to the performance of a specific duty; (2) the defendant has the clear legal duty to perform the specific duty; (3) the act is ministerial; and (4) the plaintiff is without any other adequate legal or equitable remedies. Barrow v Detroit, 301 Mich App 404, 412; 836 NW2d 498 (2013). The Parole Board has authority to grant parole to qualified inmates. In re Parole of Bivings, 242 Mich App 363, 372; 619 NW2d 163 (2000). Parole is a conditional release where the paroled prisoner remains in the custody of the Department of Corrections, but is permitted to leave the confinement of prison.1 People v Clark (On Remand), 315 Mich App 219, 229; 888 1 We note that the trial court erroneously found that petitioner was not an “incarcerated individual” at the time of his parole. Parolees are still prisoners under the custody of the Department of Corrections until they are released into the community at large. MCL 791.238(1); People v Armisted, 295 Mich App 32, 39; 811 NW2d 47 (2011). -2- NW2d 309 (2016). “The purpose of a parole is to keep the prisoner in legal custody while permitting him to live beyond the prison [enclosure] so that he may have the opportunity to show that he can refrain from committing crime.” People v Holder, 483 Mich 168, 174; 767 NW2d 423 (2009). Pursuant to MCL 791.236(4), the Parole Board has the authority to impose conditions of parole and must “specifically provide proper means of supervision of the paroled prisoner.” The Parole Board may condition a parolee’s release on his or her supervised residence at a “community corrections center” or in a “community residential home.” MCL 791.236(11). But, “[a] prisoner who is convicted of a crime of violence or any assaultive crime, and whose minimum sentence imposed for the crime is 10 years or more, shall not be placed in a community residential home during any portion of his or her sentence.” MCL 791.265a(8). When interpreting a statute this Court must “discern and give effect to the Legislature’s intent.” Hayes, 312 Mich App at 778. When statutory language is unambiguous, it is presumed that the Legislature’s intent is clearly expressed and no further judicial construction is required or permitted. Id. “Further, courts must give effect to every word, phrase, and clause in a statute and avoid an interpretation that would render any part of the statute surplusage or nugatory.” Id. at 779 (internal quotation marks omitted). This Court considers statutes in their entire context so that statutory schemes are consistent and harmonious. Id. “Statutes that address the same subject matter or share a common purpose are in pari materia and must be read collectively as one law, even when there is no reference to one another.” Id. Only limited definitions are provided for the terms “community corrections center” and “community residential home.” The statute describes a community residential home as “a location where electronic monitoring of prisoner presence is provided by the department 7 days per week, 24 hours per day.” MCL 791.265a(9)(b). This Court found in People v Sheets, 223 Mich App 651, 659-660; 567 NW2d 478 (1997), that a parolee’s residence in his wife’s apartment on 24-hour electronic monitoring “clearly” fell under the definition of a community residential home; the Court said “private residence[s]” are community residential homes under the statute. Id. at 660. In contrast, the statute defines a community corrections center as “a facility either contracted for or operated by the department in which a security staff is on duty 7 days per week, 24 hours per day.” MCL 791.256a(9)(a). In Sheets, the Court said that community corrections centers are “state correctional facilities” because they are owned or leased by the department of corrections. 223 Mich App at 660. Similarly, in People v Armisted, 295 Mich App 32, 39; 811 NW2d 47 (2011), although interpreting a different statute, this Court considered a “residential parolee reentry program” to be a community corrections center, and therefore, a “corrections facility,” because it was “designed to involuntarily restrain or confine persons committed to its jurisdiction while those persons receive certain remedial services designed to help them transition to the community at large.” 295 Mich App at 43-44. We conclude that KPEP is a “community corrections center” and not a “community residential home” as petitioner attempts to categorize it. KPEP is not a private residence. As it was described in petitioner’s order of parole, it is a “residential sex offender placement facility.” In petitioner’s own filings he described that he was “ordered to reside” there and that while there he was “without the privilege to leave or seek employment.” It is a staffed facility that is under the control, at least indirectly, by the department of corrections. MCL 791.265a(9)(a). Further, -3- it offers services and programming for parolees to prepare them to transition into the community. Armisted, 295 Mich App at 43-44. Petitioner seizes on the language “electronic monitoring,” found in the definition of community residential home but not in the definition of community corrections center, to argue that KPEP was a community residential home because he was placed on electronic tether. However, there is nothing that suggests that electronic monitoring in addition to on-site security changes the nature of a community corrections center. MCL 791.256a(9)(a). Accordingly, KPEP is properly characterized as a community corrections center. Petitioner next argues that he does not meet the “community status” criteria pursuant to MCL 791.265h, and that his placement in community residential homes and community corrections centers was therefore forbidden. Accordingly, he argues that his placement at KPEP was in error. Under MCL 791.265h(1), (1) A prisoner who does not meet the community status criteria shall not be placed in a community corrections center or community residential home. The community status criteria include all of the following requirements: * * * (c) The prisoner is not serving a sentence for conviction of a criminal sexual conduct offense [including first-degree criminal sexual conduct, MCL 750.520b.] (d) The prisoner is not classified as a very high assault risk according to the departments risk screening criteria. However, a prisoner may also obtain community status under MCL 791.265h(1)(g) [i]f the prisoner is serving a sentence for conviction of a crime of violence or an assaultive crime, as defined by rules of the department, the prisoner has less than 180 days remaining on his or her minimum sentence, and otherwise meets the community placement requirements of section 65a (citation omitted). The “community placement requirements of section 65a” state that the director of the Parole Board “may extend the limits of confinement of a prisoner when there is reasonable assurance, after consideration of all facts and circumstances, that the prisoner will not become a menace to society or to the public safety.” MCL 791.265a(1). Although subject to legislative restraints, the Parole Board has broad discretion in determining whether to grant a prisoner parole. Hopkins v Mich Parole Bd, 237 Mich App 629, 643; 604 NW2d 686 (1999). Here, petitioner was granted parole in accordance with the Parole Board’s discretion and within the confines of the legislative restraints imposed by MCL 791.265h and MCL 791.265a. First, the requirements of MCL 791.265h(1) were met. Although petitioner was serving a sentence for an assaultive crime, he had less than 180 days remaining on his minimum sentence. Next, pursuant to MCL 791.265h(1)(g), he met the requirements of MCL 265a(1), because the Parole Board’s decision to parole him stated that “[r]easonable -4- assurances exist that the prisoner will not become a menace to society or to the public safety.” Therefore, because petitioner fit the statutory criteria, and in the Parole Board’s discretion he was deemed not to be a menace to society or pose a threat to public safety, his release into a community corrections center did not violate MCL 791.265h. Finally, petitioner argues that MCL 769.2a(1)(a) supports the proposition that his placement at KPEP was erroneous. This statute mandates that a prisoner serving a sentence for first-degree criminal sexual conduct, among other listed crimes, “shall not be eligible for custodial incarceration outside a state correctional facility or county jail.” MCL 796.2a(1). However, this statute explicitly excludes “community corrections center” from the prohibition. MCL 769.2a(2). Petitioner fails to identify any statute that would prohibit the Parole Board from mandating that he reside in a community corrections center. The first requirement that must be satisfied in seeking a writ of mandamus is establishing that the petitioner “has a clear legal right to the performance of the duty sought.” Id. at 411. There is no legal right to parole in Michigan. Morales v Mich Parole Bd, 260 Mich App 29, 39; 676 NW2d 221 (2003). However, if the Parole Board, in its discretion, does grant parole it may impose conditions on that parole. MCL 791.236(4). Here, the Parole Board was within its discretion to condition petitioner’s parole on the requirement that he reside at KPEP. Accordingly, petitioner has not shown that he has a legal right to be granted parole or not to be ordered to reside at KPEP as a condition of that parole. Therefore, he cannot show that a writ of mandamus is an appropriate remedy and the trial court did not abuse its discretion in denying his petition. III. SUMMARY DISPOSITION Petitioner next argues that the trial court erred in denying his motion for summary disposition. “This Court reviews the grant or denial of summary disposition de novo to determine if the moving party is entitled to judgment as a matter of law.” Maiden v Rozwood, 461 Mich 109, 118; 597 NW2d 817 (1999). Petitioner argues that summary disposition should have been granted under MCR 2.116(C)(10) because respondents did not address his argument that KPEP was a community residential home. Summary disposition motions are appropriately granted under MCR 2.116(C)(10) when “there is no genuine issue as to any material fact.” “A genuine issue of material fact exists when the record, giving the benefit of reasonable doubt to the opposing party, leaves open an issue upon which reasonable minds might differ.” West v Gen Motors, 469 Mich 177, 183; 665 NW2d 468 (2003). A court must consider the evidence in the light most favorable to the moving party. Joseph v Auto Club Ass’n, 491 Mich 200, 206; 815 NW2d 412 (2012). In respondents’ reply brief to petitioner’s motion for summary disposition, they did not specifically address whether KPEP constituted a community residential home or a community corrections center. Instead, respondents’ argument focused on the fact that petitioner did not have a clear legal right to compel the Parole Board to change conditions of his parole or reinstate his parole. Evidence of a clear legal right and a clear legal duty are requirements for a plaintiff to receive a writ of mandamus. Barrow, 301 Mich App at 412. Accordingly, petitioner was not -5- entitled to judgment as a matter of law and summary disposition for petitioner would have been inappropriate under MCR 2.116(C)(10). Second, petitioner argues that summary disposition was appropriate under MCR 2.116(C)(9) because respondents “failed to state a valid claim.” Presumably, plaintiff means they failed to state a valid defense. Petitioner appears to mean that there was no defense stated because respondents never answered the petition. Summary disposition under MCR 2.116(C)(9) is appropriate where “[t]he opposing party has failed to state a valid defense to the claim asserted against him or her.” MCR 2.116(C)(9); Domako v Rowe, 184 Mich App 137, 142; 457 NW2d 107 (1990), aff’d 438 Mich 347 (1991). However, respondents’ reply brief was the first responsive pleading filed following this Court’s reversal and remand to the trial court. Respondents were not required to state a defense before filing this response. Summary disposition would therefore not have been appropriate under MCR 2.116(C)(9). IV. FRAUD ON THE COURT Respondent also argues that the trial court erred by failing to hold a hearing on his allegations of fraud on the court. We review a trial court’s decision to hold an evidentiary hearing to determine whether there has been a fraud perpetrated on the court for an abuse of discretion. Williams v Williams, 214 Mich App 391, 399; 542 NW2d 892 (1995). Petitioner asserts that because respondents argued that the PLRA precluded his suit, they perpetrated a fraud on the court. Fraud is “a knowing misrepresentation” or “knowing concealment of a material fact” made to induce another to his or her detriment. Black’s Law Dictionary (10th ed). “A fraud is perpetrated on the court when some material fact is concealed from the court or some material misrepresentation is made to the court.” Matley v Matley (On Remand), 242 Mich App 101, 102; 617 NW2d 718 (2000). In reversing and remanding petitioner’s case to the trial court, this Court cited Hayes, 312 Mich App at 781-782, which holds that the Michigan PLRA does not exclude prisoners from seeking mandamus to force the Parole Board to consider a prisoner for parole. In Hayes, decided in 2015, the prisoner was seeking mandamus relief because the Parole Board was refusing to consider the prisoner for parole upon the completion of his minimum sentence. Id. at 782. However, petitioner is seeking mandamus for a reinstatement of parole and a change of his parole conditions. Respondents made a similar but not the same argument as the respondents did in Hayes, asserting that the PLRA precluded petitioner’s requested relief. Petitioner failed to explain how respondents made a material misrepresentation or concealed a material fact and accordingly, the court did not abuse its discretion in failing to hold a hearing to explore petitioner’s allegations of fraud on the court. V. DUE PROCESS AND FRAUDULENT MISREPRESENTATION Petitioner argues that respondents made a fraudulent material misrepresentation and violated his due process rights when they conditioned his parole on his residence at KPEP. These claims are unpreserved. Fast Air, Inc v Knight, 235 Mich App 541, 549; 599 NW2d 489 (1999). -6- We review the proper interpretation and application of statutes de novo. Hayes, 312 Mich App at 778. Similarly, constitutional issues are reviewed de novo as a matter of law. Thomas v Pogats, 249 Mich App 718, 724; 644 NW2d 59 (2002). However, we review unpreserved claims of error for plain error affecting substantial rights. People v Carines, 460 Mich 750, 763-764; 597 NW2d 130 (1999). The thrust of petitioner’s argument stems from his assertion that the parole condition requiring him to reside at KPEP was a “fraudulent material representation” and a violation of due process. “To prove a claim of fraudulent misrepresentation, or common-law fraud, a plaintiff must establish that: (1) the defendant made a material representation; (2) the representation was false; (3) when the representation was made, the defendant knew that it was false, or made it recklessly, without knowledge of its truth, and as a positive assertion; (4) the defendant made it with the intention that the plaintiff should act upon it; (5) the plaintiff acted in reliance upon the representation; and (6) the plaintiff thereby suffered injury.” Robert v Saffell, 280 Mich App 397, 403; 760 NW2d 715 (2008). The Parole Board has the authority to impose conditions on a prisoner’s parole. MCL 791.236. One of petitioner’s conditions was that he reside at KPEP. There is nothing false or misleading regarding this valid parole condition. Accordingly, petitioner’s argument must fail because respondents did not make any fraudulent misrepresentations. Next, petitioner argues that respondent’s “fraudulent material representations” forced him to waive his rights, be treated by a psychologist, be placed in a psychiatric treatment program, and relinquish his rights to confidentiality, therefore making his order of parole null and void. However, petitioner fails to explain how any of these conditions of prison or parole constitute fraudulent misrepresentations. This Court is not under the obligation to rationalize a petitioner’s position. Cheesman v Williams, 311 Mich App 147, 161; 874 NW2d 385 (2015) (“An appellant may not merely announce a position then leave it to this Court to discover and rationalize the basis for the appellant’s claims; nor may an appellant give an issue only cursory treatment with little or no citation of authority.”). Petitioner next asserts that he has a liberty interest protected by due process not to be subjected to “involuntary treatment that has stigmatizing consequences and mandatory behavior modifications.” Both the Michigan and the United States Constitutions guarantee that a person may not be deprived of life, liberty, or property, without the due process of law. US Const, Am XIV; Const 1963, art 1, § 17. “Whether the due process guarantee is applicable depends initially on the presence of a protected property or liberty interest.” Hanlon v Civil Serv Comm, 253 Mich App 710, 723; 660 NW2d 74 (2002) (quotation marks omitted). However, “prisoners do not shed all constitutional rights at the prison gate but lawful incarceration brings about the necessary withdrawal or limitation of many privileges and rights.” Martin v Stine, 214 Mich App 403, 419; 542 NW2d 884 (1995) (quotation marks omitted), quoting Sandin v Conner, 515 US 472; 115 S Ct 2293; 132 L Ed 2d 418 (1995). Further, the possibility of parole is not an interest protected by due process, and accordingly, placing its imposition on certain conditions does not implicate due process protection. Glover v Parole Bd., 460 Mich 511, 520; 596 NW2d 598, 603 (1999) (explaining that the possibility of parole is a “mere hope” and not a benefit protected by due process). Parole is granted at the discretion of the Parole Board, and is not a -7- right. Morales, 260 Mich App at 39. Therefore, petitioner has no “right” to have his parole reinstated and his due process claims must fail because he has not shown deprivation of any constitutionally protected liberty interest. VI. ENFORCEMENT OF COURT RULES Next, petitioner asserts that the trial court violated numerous court rules in order to prejudice him. “The interpretation and application of court rules . . . presents a question of law that is reviewed de novo.” McAuley v General Motors Corp, 457 Mich 513, 518; 578 NW2d 282 (1998). We find no error. First, petitioner asserts that the trial court acted in a biased manner against him. “A trial judge is presumed to be impartial and the party who asserts partiality has a heavy burden of overcoming the presumption.” Cain v Dep’t of Corrections, 451 Mich 470, 497; 548 NW2d 210 (1996). Petitioner’s bare assertion that the trial judge’s actions were a “bias tactic in favor” of respondents does not overcome the heavy burden needed to surmount the presumption of impartiality. Second, petitioner argues that the trial court allowed respondents two extra days to file a response to his petition for mandamus in order to prejudice him. Under MCR 2.108(A)(2), a respondent who is served by registered mail “must serve and file an answer or take other action permitted by law or these rules within 28 days after service.” Here, it is true that respondents filed their reply to petitioner’s petition for mandamus beyond the time limit provided by the court rules; however, it is also true that they served the filing on petitioner within the prescribed time limit and filed the reply with the court before petitioner complained of the late filing. A trial court has the “inherent power to control the movement of cases on its docket,” Banta v Serban, 370 Mich 367, 368; 121 NW2d 854 (1963), and “[t]his Court will not disturb a trial court’s exercise of that inherent power unless a party shows a clear abuse of discretion.” Persichini v Beaumont Hosp, 238 Mich App 626, 642; 607 NW2d 100 (1999). Allowing respondents an extra two days to file a response was not an abuse of the court’s discretion. Importantly, the law favors the determination of claims on the merits, Alken-Ziegler, Inc v Waterbury Headers Corp, 461 Mich 219, 229; 600 NW2d 638 (1999), and the court rules “‘must be construed to prevent absurd results, injustice, or prejudice to the public interest.’” Hill v City of Warren, 276 Mich App 299, 305; 740 NW2d 706 (2007), quoting Rafferty v Markovitz, 461 Mich 265, 270; 602 NW2d 367 (1999). Mandamus is an “extraordinary remedy” and writs are issued in the trial court’s discretion. Lee, 235 Mich App at 331. Accordingly, it is logical that the trial court would choose to receive argument from both petitioner and respondents before making a ruling. Additionally, “absent a showing of prejudice resulting from noncompliance with the rules, any error is harmless.” Baker v DEC Int’l, 218 Mich App 248, 262; 553 NW2d 667 (1996), rev’d in part on other grounds 458 Mich 247, 580 NW2d 894 (1998). Petitioner fails to show how a two-day delay of filing, especially when he was in possession of the reply, prejudiced him. Third, petitioner argues that respondents failed to meet the requirements of MCR 2.111(C) and (E) because they did not number their paragraphs as petitioner did in his petition. -8- However, MCR 2.111(C) applies to responsive pleadings to complaints, not to petitions for mandamus. Fourth, petitioner argues that he submitted a motion for reconsideration that was never entered and that every letter he sends to the court’s clerk is ignored. Beyond bald assertions in his brief and affidavits filed by petitioner, there is no record of any such filing and no evidence in the Register of Actions. Furthermore, petitioner appealed the order he was seeking reconsideration on and had his case reversed and remanded. Similarly, petitioner argues that he submitted a petition for a personal protection order that was never entered; however, again he submits no proof of such an action and no evidence appears in the record. Fifth, petitioner argues that the trial court erred by not holding a hearing on his motion for a temporary restraining order. A temporary restraining order may only be entered if “it clearly appears from specific facts shown by affidavit or by a verified complaint that immediate and irreparable injury, loss, or damage will result to the applicant from the delay.” MCR 3.310(B)(1)(a). There is no requirement that the court hold a hearing on the matter. MCR 3.310. Sixth, petitioner argues that respondents did not comply with the trial court’s order to respond to his motion for summary disposition and motion for temporary restraining order and preliminary injunction within 30 days. However, the record shows that respondents filed their brief within the ordered 30 days. Furthermore, petitioner takes issue with the fact that respondents also responded to his petition for mandamus in their response, arguing that they did not have a right to do so under MCR 2.118(A)(2). However, MCR 2.118(A)(2) relates to amended pleadings; respondent’s answer to petitioner’s motion for summary disposition was not an amended pleading and therefore this rule does not apply. Finally, petitioner argues that he filed a motion for appointment of counsel, which was never entered and that he was forced to file his motion for summary disposition twice because of the court’s refusal to acknowledge his filings. However, the record shows that petitioner’s motion for appointment of counsel was entered. Similarly, petitioner’s motion for summary disposition was originally filed on July 18, 2016, and again on October 13, 2016. This double filing appears to be based on petitioner’s general unhappiness with the lack of immediate response from the trial court, not on any wrongdoing by the lower court. VII. MOTION FOR TEMPORARY RESTRAINING ORDER Petitioner argues that the trial court’s denial of his motion for a temporary restraining order was in error. We review a trial court’s decision to grant injunctive relief for an abuse of discretion. Head v Phillips Camper Sales & Rental, Inc, 234 Mich App 94, 110; 593 NW2d 595 (1999). A court abuses its discretion if its decision is “outside the range of reasonable and principled outcomes.” Barrow v Detroit Election Comm’n, 305 Mich App 649, 662; 854 NW2d 489 (2014). “The interpretation and application of court rules . . . presents a question of law that is reviewed de novo.” McAuley, 457 Mich at 518. “Injunctive relief is an extraordinary remedy that issues only when justice requires, there is no adequate remedy at law, and there exists a real and imminent danger of irreparable injury.” Jeffrey v Clinton Twp, 195 Mich App 260, 263-264; 489 NW2d 211 (1992). Under the court -9- rules, a temporary restraining order may be granted, “only if it clearly appears from specific facts shown by affidavit or by a verified complaint that immediate and irreparable injury, loss, or damage will result . . . .” MCR 3.310(B)(1)(a). This is separate from the four-part analysis required to issue a preliminary injunction. State Employees Ass’n v Dep’t of Mental Health, 421 Mich 152, 157-158; 365 NW2d 93 (1984). Petitioner first argues that he was entitled to an interview or a hearing before his motion was denied pursuant to MCR 3.705. However, MCR 3.705 applies to personal protection orders, not temporary restraining orders. MCR 3.705. Personal protection orders are granted in accordance with MCL 600.2950 and MCL 600.2950a. MCL 600.2950 applies to domestic personal protection orders, and MCL 600.2950a(31) specifically states that “[a] court shall not issue a personal protection order . . . if the petitioner is a prisoner.” Furthermore, there is no requirement that the court hold a hearing on a motion for a temporary restraining order. MCR 3.310. After review of petitioner’s motion for temporary restraining order, it is apparent that the trial court did not abuse its discretion in denying him relief. Petitioner’s “irreparable harm” arguments were based on his arguments, dismissed above as meritless, that his parole was illegally conditioned on his residence at KPEP and his completion of sex offender programming. Other irreparable harm was based on alleged harassment during sex offender programming and “stalking” by psychologists who were “verbally attacking” him and “stating [that he thought] he kn[ew] everything.” Further, he asserted that being required to participate in sex offender programming and psychiatric treatment in order to reobtain his previous parole status was coercion and causing him emotional distress. Finally, he argued that he was facing irreparable harm because being detained in prison “creates emotional distress and is a threat to [his] life.” Despite being unhappy with his prison conditions and his mental health treatment, petitioner did not articulate how he was suffering a real or imminent danger of irreparable injury. MCR 3.310(B)(1)(a). Accordingly, the trial court did not abuse its discretion in denying petitioner’s motion for a temporary restraining order. VIII. DAMAGES Petitioner argues that he is entitled to damages. However, because he has been denied all other relief, damages are not appropriate. IX. CONCLUSION Petitioner was not entitled to mandamus relief, summary disposition, or a temporary restraining order or preliminary injunction. We affirm the trial court’s order. /s/ David H. Sawyer /s/ Stephen L. Borrello /s/ Deborah A. Servitto -10-	{ "pile_set_name": "FreeLaw" }
var streamUrl = "https://streamer.cryptocompare.com/"; var fsym = "BTC"; var tsym = "USD"; var currentSubs; var currentSubsText = ""; var dataUrl = "https://min-api.cryptocompare.com/data/subs?fsym=" + fsym + "&tsyms=" + tsym; var socket = io(streamUrl); $.getJSON(dataUrl, function(data) { currentSubs = data['USD']['TRADES']; console.log(currentSubs); for (var i = 0; i < currentSubs.length; i++) { currentSubsText += currentSubs[i] + ", "; } $('#sub-exchanges').text(currentSubsText); socket.emit('SubAdd', { subs: currentSubs }); }); socket.on('m', function(currentData) { var tradeField = currentData.substr(0, currentData.indexOf("~")); if (tradeField == CCC.STATIC.TYPE.TRADE) { transformData(currentData); } }); var transformData = function(data) { var coinfsym = CCC.STATIC.CURRENCY.getSymbol(fsym); var cointsym = CCC.STATIC.CURRENCY.getSymbol(tsym) var incomingTrade = CCC.TRADE.unpack(data); console.log(incomingTrade); var newTrade = { Market: incomingTrade['M'], Type: incomingTrade['T'], ID: incomingTrade['ID'], Price: CCC.convertValueToDisplay(cointsym, incomingTrade['P']), Quantity: CCC.convertValueToDisplay(coinfsym, incomingTrade['Q']), Total: CCC.convertValueToDisplay(cointsym, incomingTrade['TOTAL']) }; if (incomingTrade['F'] & 1) { newTrade['Type'] = "SELL"; } else if (incomingTrade['F'] & 2) { newTrade['Type'] = "BUY"; } else { newTrade['Type'] = "UNKNOWN"; } displayData(newTrade); }; var displayData = function(dataUnpacked) { var maxTableSize = 30; var length = $('table tr').length; $('#trades').after( "<tr class=" + dataUnpacked.Type + "><th>" + dataUnpacked.Market + "</th><th>" + dataUnpacked.Type + "</th><th>" + dataUnpacked.ID + "</th><th>" + dataUnpacked.Price + "</th><th>" + dataUnpacked.Quantity + "</th><th>" + dataUnpacked.Total + "</th></tr>" ); if (length >= (maxTableSize)) { $('table tr:last').remove(); } }; $('#unsubscribe').click(function() { console.log('Unsubscribing to streamers'); $('#subscribe').removeClass('subon'); $(this).addClass('subon'); $('#stream-text').text('Stream stopped'); socket.emit('SubRemove', { subs: currentSubs }); $('#sub-exchanges').text(""); }); $('#subscribe').click(function() { console.log('Subscribing to streamers') $('#unsubscribe').removeClass('subon'); $(this).addClass('subon'); $('#stream-text').text("Streaming..."); socket.emit('SubAdd', { subs: currentSubs }); $('#sub-exchanges').text(currentSubsText); });	{ "pile_set_name": "Github" }
Transgenic mouse model integrating siRNA targeting the foot and mouth disease virus. We have constructed 2 small interfering RNAs (siRNAs) specifically targeting homogenous 3D and 2B1 regions of 7 serotypes of the foot and mouth disease virus (FMDV) and tested the ability of siRNAs to inhibit virus replication in baby hamster kidney (BHK-21) cells and suckling mice. In this study, we generated transgenic mouse models integrating short hairpin RNA (shRNA) targeting microinfected FMDV. When examined at the 7th passage in transgenic mice, the target gene was still found by PCR to be integrated in the genome. Compared to the control mice, the transgenic mice showed only slightly abnormal pathology when they were infected with the FMDV serotype Asia 1. The number of viruses in the tissues of the transgenic mouse was very low and in some tissues no virus could be detected by immunohistochemistry.	{ "pile_set_name": "PubMed Abstracts" }
Introduction {#s1} ============ Research comparing abstract words (e.g., effect) and concrete words (e.g., table) has been abundant. The concreteness effect is often revealed, whereby people perform better with concrete words than with abstract words on a variety of tasks such as memory recall, lexical decision, sentence processing, and translation [@pone.0114421-Kounios1]--[@pone.0114421-West1]. In recent years, another semantic feature, emotionality, has received much attention. Studies have shown that emotionally arousing words demonstrate processing advantage over neutral words [@pone.0114421-Citron1]. Research on concept representation offers perspective on the distinctions between abstract, concrete and emotion words. A concrete concept, such as table or television, usually has a core referent, whereas an abstract concept, such as effect or consultation, is usually represented as a situation or a scenario with a number of key elements [@pone.0114421-Barsalou1]. Among these elements, subjective experience, i.e., what one thinks and how one feels in a certain situation, is essential for the representation of abstract concepts [@pone.0114421-WiemerHastings1]. For example, the representation of consultation should involve an agent with a motive of seeking information, and possibly also a feeling of eagerness. Therefore, one\'s own experience, direct or indirect, with such situation as well as one\'s understanding about this experience must be an integral part of forming and developing the proper concept. Just as Barsalou pointed out, introspection plays an important role in the representation of abstract concepts [@pone.0114421-Barsalou2]. In this regard, emotion concepts (e.g., joy, guilt, sadness, and excitement) may be considered an extreme case, the formation and development of which rely primarily on introspective effort. People reliably differ in their levels of self-insight, i.e., awareness and understanding of one\'s subjective experiences including cognitive or affective states and processes [@pone.0114421-Grant1]. Consider the aforementioned representational differences between concrete concepts and abstract concepts, including emotion concepts as the special case in the abstract domain, individual variations in self-insight might be reflected as differences in semantic knowledge about abstract words in general and emotion words in particular. Specifically, a high level of self-insight should be reflected as rich semantic knowledge about words that denote abstract concepts involving cognitive or affective experiences and particularly about words that denote complex emotions, which may eventually translate into speedy and effortless processing of these words. Intuitively, introspective clarity or insight may not be as relevant to the processing of concrete words. However, concept formation or word learning in general requires reflecting upon one\'s own perception, memory, and thought processes. For example, car is an obvious concrete word, but driving experience must be part of our knowledge about cars. In addition, the process of learning to read, to write, and to understand the meaning of this word is also an experience subjective to introspection. Consequently, efficient processing of concrete words might also relate to one\'s level of insight. It thus can be speculated that self-insight is relevant to word processing in general, but the extent to which it is relevant may vary across different word categories, depending on how much introspective knowledge is involved in acquiring the concept. The present study utilized the ERP technique to examine the effect of self-insight on semantic processing for three categories of words: abstract neutral words (e.g., logic and effect), concrete neutral words (e.g., teapot and table), and emotion words (e.g., despair and guilt). It was expected to reveal individual differences in word processing, which were associated with different levels of self-insight. After an extensive review of the literature about emotional words, Citron indicated that research on individual differences, particularly among healthy population, has been lacking [@pone.0114421-Citron1]. In fact, individual differences in semantic processing in general are very much in need of investigation. This is especially true when it comes to words denoting abstract entities or events. This study was therefore expected to contribute to the literature along these lines. Furthermore, through examination of the relations between self-insight and ERP responses to different word categories, findings of this study may reveal potential electrophysiological evidence for representational differences across word categories. Structural and functional differences between the male brain and the female brain, including the sexually dimorphic nature of the amygdala, have been well documented [@pone.0114421-Cahill1]. Gender thus appears particularly relevant to the aim of the present study to examine individual differences across and within different word categories, including emotion words. In particular, converging evidence has clearly shown that women experience more self-conscious emotions such as guilt relative to men [@pone.0114421-ElseQuest1], which indicates that women and men may differ in their levels of introspective knowledge regarding at least some aspects of their affective experiences. Gender is one of the few individual differences variables that have been investigated for semantic processing. However, research on gender differences along the time course of word processing is limited. Wirth et al. analyzed participants\' N400 responses in a word priming task [@pone.0114421-Wirth1]. Female participants were found to always engage in more elaborative processing of semantic information than did male participants. Daltrozzo et al. obtained the same results in the N400 time window, but reported a lack of significant gender difference in P300 [@pone.0114421-Daltrozzo1]. The reason for the lack of evidence for gender variation at the early stage could be due to possible insensitivity of the early ERP component. Alternatively, it could be due to the specific word samples chosen by the studies. As Daltrozzo et al. pointed out, men and women responded to different categories of words differently [@pone.0114421-Daltrozzo1]. To achieve a certain level of balance across different semantic categories, their study incorporated various types of words including a small portion of abstract words and erotic words. Similarly, the study by Wirth et al. included 50% abstract words and 50% concrete words [@pone.0114421-Wirth1]. However, neither study conducted gender comparison within each of the different word categories. A study by Sass et al. examined gender differences in early ERP components in response to pleasant words, threat words, and neutral words [@pone.0114421-Sass1]. They found that men showed preferential processing of threat words at about 100 ms post word onset, while women showed preferential processing of threat words not until 300 ms post word onset. Extending from these earlier studies, the present study incorporated gender as another individual differences variable along with level of self-insight to investigate their effects on early processing of emotion words, abstract neutral words, and concrete neutral words. With these different word categories, the study was expected to extend the knowledge about the timing of gender variation in semantic processing across word categories and potential gender contrast in the relationship between self-insight and semantic knowledge. In sum, this study aimed to examine the effects of gender and self-insight on the early stage of word processing with abstract neutral words, concrete neutral words, and emotion words. The study utilized a paradigm to obtain an early ERP component, the Recognition Potential (RP), which is considered an index for semantic activation, peaking between 200 and 250 ms [@pone.0114421-MartnLoeches1], [@pone.0114421-Rudell1]. With a mixed word sample, gender difference in processing level has been shown emerging in the N400 time window [@pone.0114421-Wirth1], [@pone.0114421-Daltrozzo1]. With emotionally arousing words, research found gender difference before 300 ms post stimuli [@pone.0114421-Sass1]. It was therefore predicted that the RP would reveal gender difference in early processing of emotion words. However, Rudell and Hua showed that the RP was sensitive to individual differences in reading ability [@pone.0114421-Rudell2]. Therefore, should gender difference exist in early word processing in general, not just in the processing of emotion words, the RP would also reveal gender variation in response to abstract and concrete neutral words. In such case, women were expected to show a greater processing level relative to men [@pone.0114421-Wirth1], [@pone.0114421-Daltrozzo1]. The investigation of the relationship between level of self-insight and word processing was exploratory in nature. Based on the above discussion that representations of abstract words and emotion words contain essentially introspective knowledge relative to that of concrete words, a tentative prediction was that level of self-insight would show stronger association with the processing of abstract words and emotion words than with the processing of concrete words. Gender variation might exist with regard to the relation between self-insight and word processing, particularly for emotion words given that women and men showed differential responses to this type of words at early processing stage and different levels of introspective knowledge about this type of concepts [@pone.0114421-ElseQuest1], [@pone.0114421-Sass1]. As for RP differences across word categories, based on past research [@pone.0114421-MartnLoeches2], [@pone.0114421-MartnLoeches3], it was predicted that concrete neutral words would elicit greater RP than abstract neutral words. In addition, in one study with similar experimental paradigm, Hinojosa et al. found in the 225--300 ms time window greater negativity for some words with emotional significance relative to neutral words [@pone.0114421-Hinojosa1]. It was therefore predicted that emotion words might lead to greater RP than abstract and concrete neutral words. Finally, one thing needed to be pointed out is that many studies on the effect of emotionality in word processing intermixed emotion words (e.g., despair, guilt, joy, sadness) that denote emotion states or processes with emotional words (e.g., success, hostility, flower, and enemy) that denote non-emotion concepts but evoke emotional responses [@pone.0114421-Citron1]. Because emotional words can vary in abstractness, these studies often employed the factorial design to examine both abstractness and emotionality, and often reveal complex, yet inconsistent, interactions between the two factors [@pone.0114421-Kaltwasser1]--[@pone.0114421-Palazova1]. Acknowledging complexity of the interplay between abstractness and emotionality in word processing, for the specific purpose of this research, the experiment described below utilized only emotion words in order to detect potential individual differences in the representation and processing of emotion concepts relative to abstract and concrete neutral concepts. As indicated by prior research on emotion words, they are abstract in nature [@pone.0114421-Altarriba1], [@pone.0114421-Altarriba2]. Therefore, the present study employed a one-way design to compare the three types of words. Method {#s2} ====== Ethics Statement {#s2a} ---------------- This study was approved by the Institutional Review Board of the Imaging Center for Brain Research of Beijing Normal University. All participants gave written informed consent prior to the experiment and were paid for their participation. Participants {#s2b} ------------ Fifty-five college students were recruited for the experiment. The final analysis excluded five participants with signals from electrodes of interest interfered by unknown noise, another participant with a response accuracy rate lower than 75%, and yet another participant with no accurate responses due to misunderstanding of task instruction. This resulted in 48 participants (25 females) with an average age of 22.06 (SD = 1.82) ranging from 19 to 26. They were all native speakers of Chinese, right-handed, with normal or corrected to normal vision. As one of the recruitment criteria, right-handedness was determined based on participant report, and further verified by the experimenter through observation during the course of the experiment. Experimental Stimuli {#s2c} -------------------- Following the paradigm described by earlier studies of RP [@pone.0114421-MartnLoeches2], the experimental stimuli included real words, non-words, and background stimuli. There were three types of real Chinese two-character words (all nouns): 48 abstract words, 48 concrete words, and 48 emotion words (28 negative words and 20 positive words). These real words were sampled from a database that contained 715 Chinese two-character words with normative information on frequency, part of speech, number of strokes, and emotionality ratings. The emotionality was assessed using a 5.0 scale (0 = "neutral" and 4 = "high emotional value"). For the purpose of this study, abstractness ratings were collected using a 6.0 scale (1 = "highly concrete" and 6 = "highly abstract") from a group of 21 Chinese native speakers who did not participate in the main experiment. Considering that this rating process can be sometimes difficult, an even number (6.0) was chosen for this bipolar scale (highly concrete versus highly abstract) in order to prevent potentially a large number of convenient responses by selecting the mid-point of the scale (e.g., 4 on a 7.0 scale). The properties of the sampled abstract, concrete and emotion words are displayed in [Table 1](#pone-0114421-t001){ref-type="table"}. The three types of words were matched on frequency (F\<1) and number of strokes (F = 2.30, p\>.10). Abstract words and concrete words were also matched on emotionality ratings (p\>.45), both rated lower than emotion words (both ps\<.001). Abstract words and emotion words were matched on abstractness ratings (p\>.27), both rated higher than concrete words (both ps\<.001). In addition, to constitute a semantic judgment task, 48 animal words were collected with their numbers of strokes matched with the three types of real words. 10.1371/journal.pone.0114421.t001 ###### Properties of the three types of real words. ![](pone.0114421.t001){#pone-0114421-t001-1} Property Word Type Mean SD --------------------- ---------------- ------- ------ frequency (log) abstract words 3.03 1.50 concrete words 2.84 1.24 emotion words 3.02 1.20 number of strokes abstract words 16.75 3.39 concrete words 17.98 4.23 emotion words 18.42 4.18 emotionality rating abstract words 0.16 0.11 concrete words 0.10 0.11 emotion words 2.40 0.36 abstractness rating abstract words 4.07 0.56 concrete words 1.46 0.31 emotion words 4.20 0.23 There were 48 non-words. A non-word was created by cutting two Chinese characters each into half and then re-arranging the four pieces. As a result, these non-words appeared to resemble real two-character words, but were devoid of meaning. There were 240 background stimuli. A background stimulus was created by cutting a pair of two Chinese characters into 32 pieces and re-arranging them randomly to form an image without word-like characteristics or meanings. Exemplars for each type of stimuli are listed in the [S1 Appendix](#pone.0114421.s001){ref-type="supplementary-material"}. Measure for Level of Self-insight {#s2d} --------------------------------- The Self-Reflection and Insight Scale (SRIS) [@pone.0114421-Grant1] served to assess individual differences in self-insight. It contains 20 statements. Respondents indicate how much each statement describes their own characteristics by rating on a 6.0 scale. The SRIS consists of two subscales, self-reflection (SRIS-SR) and insight (SRIS-IN). SRIS-SR was designed to measure "the inspection and evaluation of one\'s thoughts, feelings, and behaviors," while the SRIS-IN was intended to measure "the clarity of understanding of one\'s thoughts, feelings, and behaviors" [@pone.0114421-Grant1]. Grant et al. indicated that scores from SRIS-SR were not always positively associated with, and thus not reflective of, the level of insight [@pone.0114421-Grant1]. Therefore, for the purpose of this study, only the summation score collected from SRIS-IN was used to assess individual differences in self-insight. In this study, participants\' insight scores ranged from 15 to 45, with a mean of 32.17 (SD = 6.07). There was not a significant difference between men (M = 33.17, SD = 6.56) and women (M = 31.24, SD = 5.56), p\>.27. Procedure {#s2e} --------- All participants signed a written informed consent form prior to the experiment. The experiment was carried out in a soft-lighted and soundproof recording room. All stimuli were presented white-on-black, 3.5 cm high and 6.6 cm wide, in the middle of the computer screen. Participants sat about 100 cm from the screen. The Rapid Stream Stimulation paradigm [@pone.0114421-Hinojosa2], [@pone.0114421-Rudell3] was employed with a stimulus onset asynchrony (SOA) of 250 ms. The screen refresh rate was set at 60 Hz, and each stimulus was presented for 250 ms. The experiment included three sessions. Each session contained 16 abstract words, 16 concrete words, 16 emotion words, 16 animal words, 16 non-words, and 80 background images. Each session began with a string of asterisks (\\\\\\), where participants were instructed that they could blink as much as they needed, and that they could begin the presentation of the stimuli by pressing a key when they were ready. Then, there were eight sequences in a session. Each sequence contained ten test stimuli, including two abstract words, two concrete words, two emotion words, two animal words, and two non-words presented in random order. Each word or non-word was preceded by four to six background stimuli. The presentation order of the sequences within each session was randomized, so was the presentation order of the sessions. Participants were instructed to press a key as quickly and accurately as possible whenever they detected an animal word. All stimuli were presented only once. During the experiment, there were two breaks, with duration determined by the participants. To ensure that the participants understood the task, they practiced with a different set of stimuli before the experiment. After the experiment, they filled out the Self-Reflection and Insight Scale [@pone.0114421-Grant1]. The whole experiment lasted about 1.5 hours. EEG Recording and Data Analysis {#s2f} ------------------------------- Participants\' electroencephalograms (EEG) were recorded from a 32-channel Quik-cap (NeuroScan, Inc.) with the right mastoid as reference. Vertical eye movements were recorded by two electrodes symmetrically placed above and below the left eye. Horizontal eye movements were monitored by two electrodes placed on the left and right outer canthi. Impedances of all electrodes were kept below 5 kΩ. The sample rate was 500 Hz with a band-pass of 0.05--100 Hz. The data were re-referenced offline using the global average reference method, which was proved to be the best way to obtain the RP [@pone.0114421-MartnLoeches2]. The continuous data were segmented from 100 ms pre-stimulus to 600 ms post-stimulus for abstract words, concrete words, emotion words, and non-words. Data were filtered offline with a low pass of 30 Hz (24 dB). The mean voltage of the 100 ms pre-stimulus interval acted as the baseline for ERP measurement. Wrong trials and trials contaminated by eye blinks, eye movements, or muscle potentials exceeding ±100 µV at any scalp electrode were excluded from analysis. Thus, about 6.66% of trials were excluded. The segmented data were then averaged for each word type within each participant. Data extraction and analyses focused on average recordings from P7, P8, O1, and O2 electrodes, the areas where RP was found most evident [@pone.0114421-MartnLoeches2], [@pone.0114421-Hinojosa2], [@pone.0114421-Iglesias1]--[@pone.0114421-Zhang1]. The peak latency and peak amplitude value of RP were measured in the 150--400 ms time window that covered the presentation time of one stimulus and included the most negative peak of RP [@pone.0114421-Rudell2], [@pone.0114421-MartnLoeches2]. More specifically, for each participant, a peak value and the corresponding peak latency were extracted from the most negative peak within the time window under each word condition at each of the four electrode sites. To examine gender difference in RP peak latency across different word conditions, a mixed 4×2 ANOVA with word condition (abstract, concrete, emotion, and non-word) and gender as factors was conducted on RP latency at each of the four electrode sites of interest: P7, P8, O1, and O2. The same analysis was applied to examine gender difference in RP peak amplitude. For the above analyses, the Geisser-Greenhouse correction for non-sphericity was applied when appropriate, with unadjusted degrees of freedom presented. To examine the relationship between insight level and the RP, correlational analysis was first performed. Regression analysis then further examined the role of self-insight in semantic activation of real words by partialing out individual variation in response to non-words. Results {#s3} ======= Gender Differences {#s3a} ------------------ ### Latency {#s3a1} [Fig. 1](#pone-0114421-g001){ref-type="fig"} presents the RP at the four chosen electrode sites. The mixed 4×2 ANOVA with word condition and gender as factors revealed a significant word condition effect only at P8, F (3, 138) = 7.42, p\<.001. The same effect seemed to approach significance at P7 and O2, both ps = .07. Bonferroni t-tests showed that, at P8, abstract words (M = 225 ms) and emotion words (M = 220 ms), but not concrete words, elicited shorter RP latency than did non-words (M = 234 ms), both ps\<.04. In addition, emotion words (M = 220 ms) had shorter RP latency than concrete words (M = 227 ms), p = .02. No gender effect or gender by word interaction approached significance at any sites. ![Grand mean RP waveforms in response to abstract words, concrete words, emotion words, and non-words at four electrode sites.](pone.0114421.g001){#pone-0114421-g001} ### Peak amplitude {#s3a2} To examine potential gender difference in level of processing, the 4×2 mixed ANOVA with word condition and gender as factors was applied to RP peak amplitude at P7, P8, O1, and O2, respectively. [Fig. 2](#pone-0114421-g002){ref-type="fig"} contrasts the RP between two gender groups. At O2, female participants (M = −7.63 µV) showed significantly greater RP than male participants (M = −6.04 µV), F (1, 46) = 4.72, p = .035. The absence of gender by word interaction indicated that this difference was consistent for all real word conditions and the non-word condition, which may suggest that, compared to men, women engage in deeper processing in response to both written words and word-like visual stimuli. ![Grand mean RP waveforms of male and female participants in response to abstract words, concrete words, emotion words, and non-words at four electrode sites.](pone.0114421.g002){#pone-0114421-g002} The ANOVA also revealed a significant main effect of word condition at P7, F (3, 138) = 12.06, p\<.0000005. Bonferroni t-tests showed that all three real word conditions (M = −7.22 µV for abstract words, M = −7.39 µV for concrete words, and M = −7.55 µV for emotion words) led to significantly greater RP than did the non-word condition (M = −6.55 µV), all ps\<.005, which indicated that semantic activation was evident at P7. No other effects appeared significant at this or other sites. Level of Self-insight {#s3b} --------------------- To reveal potential gender contrast in the relationship between self-insight and word processing, correlational analysis was first performed for each gender group. For the male group, insight scores appeared negatively related to RP latency at all sites, but most evidently at P7 for abstract words, r (23) = −.478, p = .021, and concrete words, r (23) = −.441, p = .035. Higher insight scores were associated with shorter latency for both types of words ([Fig. 3](#pone-0114421-g003){ref-type="fig"}). For the female group, insight scores showed a significant positive correlation with RP peak amplitude at O2 for abstract words, r (25) = .461, p = .020, and emotion words, r (25) = .482, p = .015. Lower insight scores were associated with greater RP for both types of words ([Fig. 4](#pone-0114421-g004){ref-type="fig"}). ![Correlation of insight scores and male RP peak latency at P7 in response to abstract words and concrete words.](pone.0114421.g003){#pone-0114421-g003} ![Correlation of insight scores and female RP peak amplitude at O2 in response to abstract words and emotion words.](pone.0114421.g004){#pone-0114421-g004} To test whether insight level accounts for variation in semantic activation instead of simply variation in RP responses to word and non-word stimuli in general, regression analysis was applied to further examine the effect of insight scores on RP responses to the real words identified in the above correlational analysis. Specifically, for the male group, RP latency at P7 in response to abstract and concrete words was regressed upon insight score after partialing out variation in RP latency in response to non-words at this electrode site. After controlling for RP latency of non-words, insight scores no longer accounted for a significant amount of variation in RP latency for abstract words (ΔR^2^ = .07, F (1, 20) = 3.14, p = .09) or concrete words (ΔR^2^ = .05, F (1, 20) = 2.21, p = .15). For the female group, RP peak amplitude at O2 in response to abstract and emotion words was regressed upon insight score after partialing out variation in RP peak amplitude in response to non-words at O2. After controlling for variation in non-words, insight scores still accounted for a significant amount of variation in RP peak amplitude for abstract words (ΔR^2^ = .07, F (1, 22) = 8.34, p = .009), and for emotion words (ΔR^2^ = .10, F (1, 22) = 7.17, p = .014). Discussion {#s4} ========== Through examining the RP, an early ERP component, during a semantic judgment task, this study investigated the effects of two individual differences variables, gender and level of self-insight, on early semantic processing. The experiment utilized emotion words, abstract neutral words, and concrete neutral words. Results indicated that women showed a greater level of processing, as assessed by RP amplitude, in response to real word and word-like stimuli than did men. Level of self-insight demonstrated differential relations with RP responses of men versus women. For men, the effect of self-insight manifested as difference in speed of processing, whereas for women, the effect manifested as difference in level of processing. Most notably, for women, level of self-insight accounted for a significant amount of variation in semantic activation for abstract neutral words and emotion words. Individual Differences {#s4a} ---------------------- Early research has shown that women tend to engage in more elaborative semantic processing [@pone.0114421-Wirth1], [@pone.0114421-Daltrozzo1], [@pone.0114421-MeyersLevy1]. However, with a mixed word sample, gender difference did not become evident until the N400 time window [@pone.0114421-Daltrozzo1]. This study found that, as early as 200--250 ms post stimuli, female participants showed greater electrophysiological activities than male participants in response to real word and word-like visual stimuli. Further, gender difference did not just manifest at the early stage of processing for semantically salient emotion words, as shown by Sass et al. [@pone.0114421-Sass1]. It was evident across three word categories. The RP is considered an index representing the process of analyzing visual form to gain semantic access [@pone.0114421-MartnLoeches1]. Therefore, gender difference revealed here in both real words and non-words suggests that women start to engage in deeper processing than men not only before semantic integration as indexed by N400 in previous studies, but also before actual semantic access is attained. In the literature, the time course and mechanism of verbal processing by which the male brain and the female brain differ have not been fully investigated [@pone.0114421-Wirth1]. The findings of this study add to the literature with regard to the timing of gender differences in semantic processing. It awaits future research to further investigate whether such early gender variations manifest specifically in response to word-like visual stimuli, and what characteristics of visual stimuli trigger such differential reactions. Gender differences were further evidenced in the relationship between level of self-insight and semantic processing. This finding was astonishing in that the two gender groups were qualitatively different in terms of how level of self-insight influenced the RP waveform. To better depict this contrast between the female and the male participants, within each gender group, a median split based on their insight scores divided participants further into two groups, the high insight group and the low insight group. [Fig. 5](#pone-0114421-g005){ref-type="fig"} displays RP responses by the high and low insight groups for male versus female participants. ![Differential relations between insight and RP waveforms for male versus female participants.](pone.0114421.g005){#pone-0114421-g005} For the female group, at the electrode site O2, higher level of self-insight was found significantly associated with smaller RP amplitude in response to abstract words (e.g., logic, feature, and tradition) and emotion words (e.g., despair, sadness, and gratitude). This was true even after controlling for individual variation in response to non-word visual stimuli. That is, level of self-insight can explain a significant amount of variation in the level of semantic activation for abstract and emotion words. Individuals who reported lower levels of self-insight showed enhanced activation to these two types of words, whereas those who reported higher levels of self-insight showed relatively reduced activation to these words. Statistically, this relationship did not hold for the processing of concrete words (e.g., teapot, window, and vehicle). The differential relationship of insight to the processing of different categories of words may be a reflection that the level of introspective knowledge involved in word processing varies as a function of these word categories. As discussed earlier, research has indicated that subjective experiences are an integral part of the representation of abstract concepts [@pone.0114421-WiemerHastings1]. Intuitively, this seems particularly the case for the representation of emotion concepts, whereas the representation of concrete concepts may rely to a much lesser degree on introspective knowledge about one\'s subjective experiences. Recent research [@pone.0114421-Kousta1], [@pone.0114421-Vigliocco1] on abstract concepts seems to offer even further explanation for the parallel between abstract and emotion words revealed by the present study. These studies have shown that one\'s emotional experiences play a crucial role in the representation of abstract concepts. That is, involvement of emotional experiences, rather than other types of subjective experiences, in the representations of abstract and emotion words could be the primary reason why processing both types of words were found closely related to self-insight. The finding that insight appeared more relevant to the activation of abstract words and emotion words relative to concrete words therefore may be considered further evidence for the representational differences across word categories. However, it is not clear why this was only reflected in the RP of female participants. It might be possible that the greater RP of this gender group rendered the relationship between insight and processing level more detectable. This certainly requires further research to be addressed. The revealed association of insight with the processing of abstract and emotion words among women was correlational in nature, and it needs future research to explore potential causality. On one hand, it is possible that an inherent self-perception of uncertainty about one\'s own subjective experiences results in more extensive activation of introspective knowledge during processing of these words, and hence an augmented level of electrophysiological reaction. On the other hand, it is also possible that a predisposed tendency to engage in enhanced electrophysiological reactions to words that evoke introspective knowledge leads to a self-perception of uncertainty about relevant experiences. More likely the two factors are intertwined during the course of mental development. Research on the relationship between these factors may have implications for intervention with cognitive and affective disorders. For the male group, the relationship between insight level and RP responses to word processing appeared less conclusive. In contrast to the female group, a higher level of self-insight was found associated with shorter RP latency, particularly evident in response to abstract and concrete words at the electrode site P7. However, insight scores did not account for latency variation in response to these real words above and beyond individual variation in response to non-word visual stimuli. This may indicate that level of self-insight is not a reliable predictor for latency of semantic activation. Alternatively, this may be partially due to the fact that insight scores among male participants appeared negatively skewed. While the majority of the male participants\' scores were well above the mid-point of the insight scale, three participants reported substantially lower insight scores ([Fig. 3](#pone-0114421-g003){ref-type="fig"}), which may or may not be an unbiased reflection of their actual insight levels. Analysis excluding these three participants revealed even stronger correlation between insight and RP latencies for these words. While subjectivity is inherent to self-report measures, a larger sample may help elucidate the relationship of insight and processing speed among male participants in future research. For male participants, the finding that higher insight tended to be associated with shorter latency in response to word stimuli (Pearson\'s rs ranging from.33 to.48 for emotion, concrete, and abstract words) may prompt one to ponder whether language proficiency, particularly vocabulary knowledge, is the underlying factor for the relationship between insight and the speed of semantic judgment. Rudell and Hua indeed reported an association between RP and language proficiency as assessed by GRE verbal test [@pone.0114421-Rudell2]. Their participants in the fourth quartile of GRE verbal scores generated the longest RP latency and the smallest RP amplitude. This association appeared to hold for both men and women. However, in the present study, low insight scores were associated with longer RP latency only for the male group. For the female group, low insight scores were associated with greater RP amplitude. This contrast suggests that verbal proficiency and insight are two factors that, though possibly partially overlapping, differ in the mechanisms by which they influence the RP waveform. Future research is needed to investigate the mechanism through which insight, gender, and verbal proficiency interact in the process of language processing. Different Word Categories {#s4b} ------------------------- This study found that the three real word categories elicited comparable levels of RP. The lack of difference between abstract words and concrete words was in contrast to Martin-Loeches et al. [@pone.0114421-MartnLoeches2], which utilized the same experimental paradigm and revealed that concrete words elicited greater RP than abstract words. The following might have contributed to this discrepancy. First, the present study included emotion words as a separate category of comparison, and excluded emotion words from the abstract word category, which resulted in a word sample with different semantic features from that of the earlier study. Further, to distance abstract and concrete words from emotion words, the emotionality ratings of these two categories of words were designed to fall on the lower end of the scale. Under this constraint, matching emotionality, frequency, and stroke number between abstract and concrete conditions further restricted word sampling. As a result, the contrast in abstractness ratings between the two conditions was relatively limited compared with the rating contrast in the earlier study. A numerical comparison of rating difference between the two studies showed that this was indeed the case. Second, the fact that the two studies were conducted in two different languages, Spanish and Mandarin, might also have been a factor. Specifically, non-words in the present study contained recognizable radicals and thus, to a large degree, preserved word-like visual features. A more careful control for visual form similarity between abstract words and concrete words relative to non-words may help to detect semantic processing differences between these two real word conditions. Further research is necessary to investigate RP amplitude in response to the processing of different semantic features as well as the application of RP paradigm to research in different languages. Finally, emotion words did not elicit greater RP than did abstract and concrete words. In the literature about word emotionality, more studies have been done through examining another early ERP component, the early posterior negativity (EPN). Some studies reported that the EPN was amplified by emotionally significant words around 250 ms post word onset [@pone.0114421-Hinojosa1], [@pone.0114421-Palazova1], [@pone.0114421-Kissler1]. However, other studies using emotional words did not find the EPN [@pone.0114421-Kaltwasser1], [@pone.0114421-Kanske1]. The EPN has been thought to signify allocation of attentional resources [@pone.0114421-Potts1], [@pone.0114421-Schacht1], and functionally linked to the RP [@pone.0114421-Kissler2]. Therefore, the lack of difference between emotion words and neutral words in the present study could be due to the semantic judgment task, which might to some extent have diverted attention away from word emotionality. Further, the fact that the present study utilized only emotion words (not emotionally significant words) might also have been a factor. Unfortunately, there does not seem to be research looking into processing differences between words that denote specific emotion states or processes and words that have general emotional connotations. A follow up study seems appropriate to address this issue. Limitations {#s4c} ----------- As emphasized earlier, the RP is an early ERP component indexing early stage of word processing. The findings of this study likely reflect mainly the automatic and implicit stage of semantic processing. To gain a more comprehensive understanding about processing differences across various word categories and individual differences in word processing, later ERP components certainly need to be investigated. The Rapid Stream Stimulation (RSS) paradigm in this study is generally utilized to enhance the RP [@pone.0114421-Rudell3]. A different design is needed to obtain more standard later ERP components, which will be adopted in future research to examine the more controlled and explicit stage of semantic processing. This study employed a semantic judgment task with animal words serving as the target words to be responded to by participants. There might be a possibility that this design could have distorted the differences between abstract, concrete, and emotion words. More specifically, animal words denote a type of concrete concept that might share greater conceptual similarities with concepts denoted by concrete words than those denoted by abstract words or emotion words. Consequently, word processing during the experiment might have been biased toward concrete words, but away from abstract and emotion words. It is not clear how much difference this could make at the early stage of word processing. However, for future research, a design to induce more balanced processing across word categories would be helpful. Lastly, the primary goal of this study was to explore individual differences in word processing. Although emotion words were included as one of the word categories for investigation, valence was not taken into consideration. Roughly half positive words (e.g., joy and excitement) and half negative words (e.g., guilt and despair) constituted the category of emotion words. In the literature of word emotionality, valence has been shown a complex factor as evidenced by inconsistent reports with regard to its modulations of emotionally sensitive ERP components such as the EPN and the late positive component [@pone.0114421-Hinojosa1]--[@pone.0114421-Palazova1]. Therefore, it should be acknowledged that separate investigations of positive emotion words and negative emotion words would help to enhance our understanding about processing differences across word categories, and possibly to reveal further individual variations. Conclusions {#s5} =========== This study found gender difference in the level of early stage semantic processing. In addition, level of self-insight exhibited a differential relationship with word processing for men versus women. Generally speaking, for men, high insight appeared to be associated with a greater processing speed. For women, low insight appeared to be associated with a greater processing level. These relations were found to vary as a function of word categories with different semantic features, e.g., concreteness and emotionality, which may reflect representational differences across these word categories. Although many questions remain to be answered about the mechanism by which gender, self-insight, and semantic knowledge interact in word processing, the individual variations revealed in this study highlight the need to take into consideration subject variables when utilizing electrophysiological measures in related research. Acknowledgments {#s6} =============== The authors would like to thank Wuwei Fan, Jie Lin, and Haoyun Zhang for their assistance with data collection. We also sincerely thank Kathy Brode and Christopher Twilley for proofreading this manuscript. Supporting Information {#s7} ====================== ###### Exemplar words for each type of experimental stimuli. The abstract word shown here means logic in English, the concrete word teapot, the emotion word despair, and the animal word frog. (TIF) ###### Click here for additional data file. [^1]: Competing Interests:The authors have declared that no competing interests exist. [^2]: Conceived and designed the experiments: XX TG. Performed the experiments: CK. Analyzed the data: XX CK TG. Contributed reagents/materials/analysis tools: XX CK TG. Wrote the paper: XX CK TG.	{ "pile_set_name": "PubMed Central" }
s picked without replacement from {q: 1, a: 3, z: 1, m: 1, c: 1}? 1/21 What is prob of picking 1 a and 1 z when two letters picked without replacement from zkzkkkaklaskaklkk? 3/68 Four letters picked without replacement from {r: 10, l: 10}. What is prob of picking 3 l and 1 r? 80/323 What is prob of picking 2 m and 2 w when four letters picked without replacement from {w: 2, r: 5, m: 5}? 2/99 Calculate prob of picking 1 q and 1 e when two letters picked without replacement from oeqeeeeek. 1/6 Two letters picked without replacement from hdrhrrdhhrddhhrrh. Give prob of picking 1 r and 1 h. 21/68 Three letters picked without replacement from {o: 2, r: 2, x: 8, l: 3}. What is prob of picking 3 x? 8/65 Calculate prob of picking 1 c and 1 l when two letters picked without replacement from {l: 3, c: 1}. 1/2 Two letters picked without replacement from mszjsmjossooszjmos. What is prob of picking 1 s and 1 j? 2/17 Two letters picked without replacement from {q: 2, y: 2, w: 5}. What is prob of picking 2 w? 5/18 What is prob of picking 2 e when two letters picked without replacement from {y: 5, a: 5, e: 3}? 1/26 Two letters picked without replacement from {l: 3, h: 9}. Give prob of picking 2 h. 6/11 What is prob of picking 3 o and 1 h when four letters picked without replacement from {b: 2, z: 8, h: 7, o: 3}? 7/4845 What is prob of picking 2 w when two letters picked without replacement from fffww? 1/10 Three letters picked without replacement from {v: 4, z: 2, t: 5, c: 2}. Give prob of picking 1 v, 1 t, and 1 c. 20/143 Calculate prob of picking 2 m when two letters picked without replacement from fmmmmmfmmmfmmmmmmmff. 21/38 Calculate prob of picking 4 p when four letters picked without replacement from ppppppppp. 1 Four letters picked without replacement from {c: 5, t: 3, p: 1}. What is prob of picking 1 p and 3 t? 1/126 What is prob of picking 2 a, 1 z, and 1 w when four letters picked without replacement from awazzzzadazaaa? 15/143 Two letters picked without replacement from {i: 1, j: 1, o: 2}. Give prob of picking 1 i and 1 o. 1/3 Two letters picked without replacement from {k: 5, l: 4, n: 1, w: 3}. What is prob of picking 1 l and 1 w? 2/13 Two letters picked without replacement from nnwnnnnnunnnnnnn. What is prob of picking 2 n? 91/120 Calculate prob of picking 2 a when two letters picked without replacement from {a: 4, f: 2, y: 10, b: 1}. 3/68 Two letters picked without replacement from aaayycay. What is prob of picking 1 y and 1 a? 3/7 Calculate prob of picking 1 i and 1 s when two letters picked without replacement from suyyysiyyyyyyy. 2/91 Three letters picked without replacement from {e: 6, y: 4}. Give prob of picking 1 y and 2 e. 1/2 Four letters picked without replacement from xjaaajjpraaaj. Give prob of picking 1 j, 1 x, 1 p, and 1 a. 24/715 Four letters picked without replacement from {m: 1, x: 4, h: 3, j: 2}. What is prob of picking 1 h and 3 x? 2/35 Three letters picked without replacement from yabia. What is prob of picking 1 y, 1 i, and 1 b? 1/10 What is prob of picking 4 u when four letters picked without replacement from uujiuujuijiui? 3/143 Two letters picked without replacement from {g: 2, w: 6, d: 1, z: 2, t: 1, u: 5}. Give prob of picking 1 w and 1 g. 3/34 Calculate prob of picking 2 a when two letters picked without replacement from aapaaopboapop. 5/39 Three letters picked without replacement from {z: 7, g: 9}. Give prob of picking 3 g. 3/20 Two letters picked without replacement from rrrrhrhr. Give prob of picking 2 r. 15/28 Calculate prob of picking 3 d when three letters picked without replacement from ffddpfpffdfpdddff. 1/34 Three letters picked without replacement from {g: 2, y: 1, p: 1, c: 1, a: 1, i: 2}. What is prob of picking 1 a, 1 y, and 1 p? 1/56 Calculate prob of picking 2 d when two letters picked without replacement from {d: 2, v: 4, a: 4, r: 1}. 1/55 Two letters picked without replacement from {i: 4, o: 2, z: 1, u: 2, j: 5}. Give prob of picking 1 z and 1 j. 5/91 Calculate prob of picking 1 w, 1 t, and 1 c when three letters picked without replacement from {c: 4, t: 6, w: 7}. 21/85 What is prob of picking 1 f and 2 i when three letters picked without replacement from csfisiicsfs? 2/55 What is prob of picking 1 j, 1 w, 1 u, and 1 x when four letters picked without replacement from uwkjknx? 1/35 What is prob of picking 2 e and 1 h when three letters picked without replacement from hhehhee? 12/35 What is prob of picking 1 r and 1 l when two letters picked without replacement from {g: 1, r: 4, l: 10, c: 2}? 5/17 What is prob of picking 1 d and 1 h when two letters picked without replacement from dhhlhzz? 1/7 Calculate prob of picking 2 e when two letters picked without replacement from {e: 11, z: 4, d: 3}. 55/153 What is prob of picking 1 v and 3 a when four letters picked without replacement from vvavvvvvaav? 4/165 What is prob of picking 1 s and 3 w when four letters picked without replacement from mwismsimiwmiiwiiii? 1/1530 Calculate prob of picking 2 r when two letters picked without replacement from {r: 7, p: 1}. 3/4 Calculate prob of picking 1 s and 1 k when two letters picked without replacement from {k: 2, s: 2, a: 5}. 1/9 Three letters picked without replacement from ybyykpbbcbpb. What is prob of picking 1 p and 2 y? 3/110 What is prob of picking 1 r, 1 h, and 1 f when three letters picked without replacement from ffhqrfrfqqh? 16/165 Three letters picked without replacement from ocnpb. What is prob of picking 1 c, 1 o, and 1 b? 1/10 Calculate prob of picking 1 k, 1 m, and 1 q when three letters picked without replacement from {i: 1, k: 1, q: 3, d: 5, p: 4, m: 1}. 3/455 Four letters picked without replacement from {g: 2, w: 6}. What is prob of picking 2 w and 2 g? 3/14 Calculate prob of picking 2 j and 1 w when three letters picked without replacement from {w: 1, j: 2, i: 1, b: 1}. 1/10 What is prob of picking 2 y when two letters picked without replacement from zzyzyzzzz? 1/36 What is prob of picking 1 f and 1 e when two letters picked without replacement from feejcfn? 4/21 What is prob of picking 1 c and 1 x when two letters picked without replacement from xceec? 1/5 Two letters picked without replacement from llallfillliffflali. Give prob of picking 2 l. 4/17 Four letters picked without replacement from {q: 5}. What is prob of picking 4 q? 1 What is prob of picking 2 z, 1 d, and 1 e when four letters picked without replacement from dedpddzzo? 2/63 Calculate prob of picking 2 u when two letters picked without replacement from {q: 4, u: 2, t: 3, f: 3, n: 2, k: 2}. 1/120 Three letters picked without replacement from xyyx. Give prob of picking 1 y and 2 x. 1/2 Two letters picked without replacement from {u: 17, j: 3}. Give prob of picking 1 j and 1 u. 51/190 Two letters picked without replacement from {z: 10, v: 4}. Give prob of picking 2 v. 6/91 Four letters picked without replacement from {y: 8, v: 3, f: 2, b: 6}. What is prob of picking 1 b, 2 f, and 1 v? 3/646 What is prob of picking 1 x and 1 n when two letters picked without replacement from xcxcxxxxnltctt? 6/91 What is prob of picking 1 v and 1 h when two letters picked without replacement from pwwpwhpwpfwvwprrv? 1/68 Four letters picked without replacement from {c: 6, d: 6}. What is prob of picking 1 c and 3 d? 8/33 Two letters picked without replacement from {l: 3, e: 1, x: 3}. Give prob of picking 1 e and 1 x. 1/7 Four letters picked without replacement from eevyekeeygky. What is prob of picking 1 y and 3 e? 2/33 Four letters picked without replacement from {n: 4, p: 14}. Give prob of picking 3 p and 1 n. 364/765 Two letters picked without replacement from wwawwaawawwaaawaaw. What is prob of picking 2 w? 4/17 Three letters picked without replacement from qqqqpqiqqqpqpqiigqpp. What is prob of picking 1 q, 1 p, and 1 g? 11/228 Calculate prob of picking 1 i and 3 c when four letters picked without replacement from {b: 1, w: 2, i: 1, c: 9}. 84/715 Two letters picked without replacement from {g: 1, s: 2, c: 3, o: 1}. What is prob of picking 2 s? 1/21 What is prob of picking 1 g and 2 l when three letters picked without replacement from llorollolooglllo? 1/20 What is prob of picking 2 t and 1 r when three letters picked without replacement from {s: 1, r	{ "pile_set_name": "DM Mathematics" }
Digital Realty, a leading global provider of data center, colocation, and interconnection solutions, has entered into definitive agreements with affiliates of Mapletree Investments Pte Ltd (MIPL) and Mapletree Industrial Trust for the sale of a portfolio of 10 Powered Base Building data centers. The deal also includes the establishment of a joint venture on three existing Turn-Key Flex hyper-scale data centers. The total consideration for both transactions will be approximately $1.4 billion. The company informed that proceeds from the transactions would initially be used to pay down debt. It will ultimately be used to fund future investment activity. "These transactions represent an important step towards our goal of self-funding our growth and diversifying our sources of equity capital while shrinking our asset base and setting the stage for accelerating growth as the proceeds are redeployed into accretive investment opportunities," said A. William Stein, Chief Executive Officer, Digital Realty in a statement in the company press release. Headquartered in Singapore, MIPL is a leading real estate development, investment, capital, and property management company. MIPL currently manages four Singapore-listed REIT and six private equity real estate funds with assets located across Asia Pacific, Europe, UK, and US markets. Mapletree Industrial Trust, another real estate investment trust, has a portfolio of 87 industrial properties in Singapore and 14 data centers in the United States. MIPL and Mapletree Industrial Trust will acquire the Powered Base Building portfolio from Digital Realty for a total purchase price of approximately $557 million. These 10 fully-leased properties are expected to generate 2020 cash net operating income of approximately $37 million, representing a 6.6% cap rate. "We have deepened our presence in the fast-growing data center sector with our second portfolio acquisition in North America. These transactions add high-quality properties in key data center markets underpinned by global cloud and colocation players," said Hiew Yoon Khong, Group Chief Executive Officer of Mapletree Investments in a statement. As per the agreement, an entity jointly owned by Mapletree Investments and Mapletree Industrial Trust will purchase an 80% interest, and Digital Realty will retain a 20% interest, in a joint venture on three fully stabilized hyper-scale facilities located in Ashburn, Virginia. They will acquire its 80% stake for approximately $811 million, valuing these three assets at approximately $1.0 billion. These three facilities are fully leased. They are expected to generate 2020 cash net operating income of approximately $61 million, representing a 6.0% cap rate. Digital Realty said that it would continue to operate and manage these facilities. The data center provider expects the transactions to close in late 2019 or early 2020, subject to customary closing conditions. More than 2,000 firms rely on Digital Realty's secure, network-rich portfolio of data centers located throughout North America, Europe, Latin America, Asia, and Australia. The company has more than 200 data centers to its credit in five continents. Author Bart Dorst • Datacenter and Cloud consultant providing tactical solutions for businesses for over 9 years.	{ "pile_set_name": "Pile-CC" }
Photo : AP Cars have been around for more than a century now. We take it for granted that we have names like ‘automobile’ and ‘car’ to describe these four-wheeled beasts we love so much; they’re the only names we’ve ever known. But, friends, it could have been worse. It could have been so much worse. What started out as a quest to explore the rise and fall of some of America’s original auto manufacturers turned into a realization that, dear God, just about everyone who put an engine on some wheels had a different name for their creation. I mean, it makes sense; I’m sure the cavemen who invented clothing all had a different name for what they were covering their bodies with. It makes sense that cars wouldn’t have always been ‘cars’. See, what we consider our norm today pissed off a lot of people back in the day. In an August 1897 issue, The New York Times reported that “the new mechanical wagon with the awful name automobile has come to stay”. Wait, what? Awful? If that was so awful, then what were our other options? Let’s Talk Patents In 1792, Oliver Evans applied for a US patent in Philadelphia for what was, at the time, essentially a prototype of what we’d consider a car today. Its name? Oruktor Amphibolos. We’ve written a whole article about this legendary creation, but it was basically designed to dredge Philadelphia’s dockyards. It was the first self-propelled vehicle in America at the time, but it couldn’t actually dredge much of anything because Evans was mostly just excited to build an engine. It’s probably good that this thing didn’t stick around. Then came George Selden, a patent attorney from New York. In 1879, he patented something he called a “road machine” (which is slightly more agreeable than the Oruktor). He hadn’t actually, y’know, built anything yet, but he kept expanding the patent throughout the years as automotive technology advanced because it meant he could collect royalties from American car manufacturers. Good ol’ Henry Ford was rightfully annoyed that this guy who hadn’t even made anything could reap the benefits of all the hard work automakers were putting in. He took Selden to court in 1904, where the judge decided that Selden would have to build a road machine from his own patent. Selden couldn’t do it. In 1911, the patent was overturned, giving manufacturers the freedom to build cars at a lower cost, since they didn’t have to shell out big bucks to a guy whose claim to fame was some words on a page, not an automobile. While the Selden drama was playing out, brothers Charles and Frank Duryea decided they wanted to expand their bicycle making business to include cars as well. They patented their “motor wagons” in 1895, and they had a pretty interesting history. Frank Duryea drove one of their cars to the win America’s first automobile race, averaging a whopping speed of 7.3 mph. The press they received meant they were able to sell the first commercial vehicle in the US, which was then promptly involved in America’s first recorded car accident. Nice. Motor wagons did not catch on. And then, we had Henry Ford. Drawing his inspiration from the bicycle, Ford submitted a patent in 1896 for what he was calling a “Quadricycle”. It was a name that, thankfully, didn’t stick around for very long. Thanks, Media Early media references to cars utilized a wide variety of fun and creative names. There wasn’t any standardization yet as far as names or even designs went. For journalists and authors, it was basically a creative exercise to describe something they’d never seen before. A fine selection of their choices include: Autobaine Autokenetic Autometon Automotor horse Buggyaut Diamote Horseless carriage Mocole Motor carriage Motorig Motor-vique Oleo locomotive Truckle So Where Did Today’s Names Come From? ‘Automobile’ was just one of the many words being thrown around back in the day. We’re not really sure how it came to be our standard, but its use in The New York Times was a key factor in its widespread adoption. The name first originated with an Italian painter and engineer back in the 1300s. His name was Martini, and he, like Selden, never actually built a car. He did draw up plans for a four-wheeled man-powered carriage, though, and called it the automobile by combining the Greek word auto (‘self’) and the Latin word mobils (‘moving’). Or, a self-moving vehicle. Easy. Plus, it sounded a whole lot nicer than something like ‘autobaine’. Yeesh. “Car” had been around for a while. Derived from the Celtic word carrus (‘cart’ or ‘wagon’), it had been another name for horse-drawn carriages. It was a pretty easy transfer, given what some of the first vehicles looked like. All I gotta say is, we got pretty lucky when it came to names.	{ "pile_set_name": "OpenWebText2" }
Q: Check if user is logged in first time How can i check if user is logged in for the first time on site? If it is, i want to show him a message... Can someone help me? Thank you! A: UPDATE As suggested by oknate, using hook_user_login: function hook_user_login(&$edit, $account) { if(!$account->access) { drupal_set_message(t('This is your first login. Welcome!')); } } Original less optimal method You can use hook_init() in D7, and check if they have a value for last access: function hook_init() { global $user; $first_login = db_query('SELECT 1 FROM {users} WHERE uid = :uid AND access = 0', array(':uid' => $user->uid))->fetchField(); if($first_login) { drupal_set_message(t('This is your first login. Welcome!')); } } A: In both Drupal 7 and 8, there is hook_user_login, where you can can check whether the current user has accessed the site before, but the parameters are slightly different. Drupal 7 version: function mymodule_user_login(&$edit, $account) { if ($account->access == 0) { drupal_set_message(t('This is your first login. Welcome!')); } } Drupal 8 version: function mymodule_user_login($account) { if (!$account->getLastAccessedTime()) { drupal_set_message(t('This is your first login. Welcome!')); } } hook_user_login in Drupal 8.	{ "pile_set_name": "StackExchange" }
Boots of Hell Boots of Hell is an EP from Ghoultown, released in 1999 on Angry Planet Records. In 2001, the EP was remastered and re-released with two rare tracks added. Track listing "Boots of Hell" - 5:06 "After 2" - 3:42 "Killer in Texas" - 4:22 "Pale Skin Diva" - 1:38 "Southern Witch" - 3:16 References External links CD Baby: GHOULTOWN: Boots of Hell Ghoultown : Boots of Hell-Listen, Review and Buy at ARTISTdirect Category:1999 EPs Category:Ghoultown albums	{ "pile_set_name": "Wikipedia (en)" }
Verbena officinalis essential oil and its component citral as apoptotic-inducing agent in chronic lymphocytic leukemia. We evaluated the pro-apoptotic activity of Verbena officinalis essential oil and of its main component citral, on lymphocytes collected from normal blood donors and patients with chronic lymphocytic leukemia (CLL). The number of apoptotic cells was greater in CLL patients than in healthy subjects at all different times of incubation (4, 8 and 24 hours) for samples treated with Verbena officinalis essential oil (A) and citral (B) as well vs controls at different concentrations (0.1% and 0.01%). The greater pro-apoptotic ability was shown by both essential oil of Verbena officinalis and citral at lower concentrations (after 4 h A 0.1%: 17.8% vs 37.1%; A 0.01%: 15.8% vs 52%; B 0.1%: 18.4% vs 46.4%; B 0.01%: 15.8% vs 54.2%; after 8 h A 0.1%: 23% vs 38%; A 0.01%: 22.2% vs 55%; B 0.1%: 32% vs 42.2%; B 0.01%: 22% vs 54.3%; after 24 h A 0.1%: 5% vs 20.7%; A 0.01%: 25.8% vs 47.2%; B 0.1%: 18.4% vs 46.4%; B 0.01%: 15.8% vs 54.2%). Patients carrying deletion 17p13 (p53 mutation) showed a reduced ability to undergo apoptosis with respect to patients with other genomic aberrations or normal karyotype. The proapoptotic activity of Verbena officinalis essential oil and citral is thought to be due to a direct procaspase 3 activation. These data further support evidence that indicate natural compounds as a possible lead structure to develop new therapeutic agents.	{ "pile_set_name": "PubMed Abstracts" }
Dr Ž. Malek This page has been moved. You are being redirected. Summary Žiga’s main research interests are changes to the land systems and the associated consequences in terms of risk and changes to ecosystem services provisioning. Specific interests of his range from spatial analysis and modeling carried out using remote sensing, geographic information systems and environmental simulation, to identifying driving forces of environmental change and development of future socio-economic scenarios through participatory modelling. He is interested in regions in socio-economic transition and areas particularly vulnerable to environmental changes, such as mountainous and Mediterranean regions. Before joining the environmental geography group, Žiga worked as a researcher in Austria at the International Institute for Applied Systems Analysis (IIASA) and the University of Vienna. There, he worked on the potential effects of land systems changes on future hydro-meteorological risks. Dr. Malek studied landscape architecture at the Biotechnical Faculty of the University of Ljubljana in Slovenia. He holds a doctorate in Physical Geography from the University of Vienna. Selected publications Malek, Ž. & Boerboom, L. (2015). Participatory Scenario Development to Address Potential Impacts of Land Use Change: An Example from the Italian Alps. Mountain Research and Development, 35(2), 126–138. DOI: 10.1659/MRD-JOURNAL-D-14-00082.1	{ "pile_set_name": "Pile-CC" }
Tom Pollard Tom Pollard (28 April 1857 – 30 August 1922) was a New Zealand comic opera producer and manager. He was born in Launceston, Tasmania, Australia in 1857. References Category:1857 births Category:1922 deaths Category:People from Launceston, Tasmania Category:New Zealand musicians Category:Australian emigrants to New Zealand	{ "pile_set_name": "Wikipedia (en)" }
HBO “Real Time” host Bill Maher blasted special counsel Robert Mueller for following Justice Department guidelines and not indicting President Donald Trump. “New rule, just because you have a stone face doesn’t mean you belong on Mount Rushmore,” Maher said, with a picture of Mueller. “For over two years, America has had a crazy person in the White House, and for over two years the Democrats have done fck-all about it because they were waiting for Mueller,” he said. ADVERTISEMENT “We all sat around waiting for prosecutor Jesus to turn in his big report,” he continued. “And he came back with, ‘ask someone else.'” “We needed Superman and we got Clark Can’t,” Maher said. “I get it, Mueller’s a Boy Scout, a straight arrow, he played it by the book, but you may have noticed for the last three years, we’ve kind of been off book,” he said. “Greatness sometimes means not doing everything by the book.” “All he had to do is what people in the justice system do every day, use the law to come to justice,” he explained. “Not be so restricted by technicalities that the bad guys win.” Mueller had particular contempt for one line in the report, where it was written that Donald Trump, Jr. “declined to be voluntarily interviewed.” ADVERTISEMENT “So make him,” Maher argued. “Was he too busy? You couldn’t work around his tweeting schedule?” he wondered. “It’s one feckless punt after another,” he said. “You can’t indict a sitting president? It’s not in the Constitution, it’s not even a law,” Maher noted. “It’s a guideline, like drinking white wine with fish or not fcking your cousin.” ADVERTISEMENT “It’s a f*cking memo,” Maher said. Watch: ADVERTISEMENT Mueller from Bob Brigham on Vimeo.	{ "pile_set_name": "OpenWebText2" }
1. Field of the Invention This invention relates to the art of manufacturing clarifiers or settling tanks and particularly deals with travelling bridge clarifiers easily and quickly assembled at the use site on a concrete basin from pre-fabricated components and sub-assemblies forming compact bundles fitting on a conventional size truck for over the road shipment to the use site. 2. Prior Art Travelling bridge clarifiers or settling tanks are generally too large to be shipped in assembled form and have been erected at the use site requiring services of skilled builders for a prolonged time period frequently under unsatisfactory weather conditions all contributing to large expense and delays. Travelling bridge clarifiers of the type disclosed and claimed in our U.S. Pat. No. 4,193,871 issued Mar. 18, 1980 may be 15 to 25 feet in width, 40 to 75 feet in length, and 6 to 10 feet in depth, thus preventing over the road shipment of complete assembled units. Further the metal tank of the clarifier required heavy steel sheets and beams adding to shipment costs and installation problems. It would, therefore, be an improvement in the art to produce clarifiers with concrete basins which are poured at the use site and pre-fabricated sub-assemblies and interfitting components small enough to be compactly packed and shipped on a conventional size flat bed truck and then easily and quickly assembled on top of the concrete basin.	{ "pile_set_name": "USPTO Backgrounds" }
using System; using System.Windows.Input; namespace Samples.ViewModels { public class CommandViewModel { public string Text { get; set; } public ICommand Command { get; set; } } }	{ "pile_set_name": "Github" }
Introduction {#sec1_1} ============ The resistance arteries (\<300 μm in internal diameter) are essential for mediating the autoregulation of flow and the stabilization of capillary pressure. An important component of this protective mechanism, called the myogenic response, allows these vessels to change diameter in response to alterations in intraluminar pressure. Besides resulting in enhanced myogenicity of the resistance arteries \[[@B1]\], sustained high blood pressure is associated with changes in cardiovascular structure. Resistance vessels develop a narrowed lumen and a thickened vascular wall, but without an apparent increase in cross-sectional area. This process, known as inward eutrophic remodeling, occurs as a response to prolonged (myogenic) constriction in order to protect the downstream vasculature, and it is thought to be an energetically favored mechanism to preserve a reduced lumen diameter for long periods. Such a structural adaptation involves a migratory process, whereby vascular smooth-muscle cells (VSMCs) reposition in the vascular wall \[[@B2]\], and it can be observed in most forms of hypertension including onset and milder hypertensive states. When hypertrophy is observed, the rise in blood pressure is often fulminant and severe. Autoregulatory mechanisms are then inadequate to normalize wall stress. Recently, it has been reported that the development of small-artery hypertrophy is an adverse prognostic sign \[[@B3]\]. The integrin/extracellular-matrix (ECM) axis transfers tensile forces exerted by blood pressure across the cell membrane. Integrins are cell surface ECM receptors that can heterodimerize in a noncovalent fashion to form 24 different αβ receptors which recognize a wide variety of cellular and ECM components present in the arterial extracellular space including collagen, fibronectin and laminin \[[@B4]\]. In resistance arteries, specific integrin subtypes are initially utilized for the mechanotransduction of pressure \[[@B5]\], while others mediate the migration of VSMCs towards a narrowed lumen \[[@B6],[@B7]\]. Engagement of integrins upon migration activates intracellular signaling complexes found at focal adhesion (FA) sites \[[@B8]\]. To date, there has been no conclusive evidence that FA sites, which contain active tyrosine kinases (e.g. focal adhesion kinase, FAK) and other cytoskeletal associated phosphoproteins observed in migrating cells in vitro \[[@B9]\], exist in vivo in arterial VSMCs. However, it is clear that the migratory process of arterial VSMCs in vivo is more subtle and is limited to the elongation of tapered cells and an increase in cell overlap \[[@B2]\] compared with the more pronounced movement of cells in vitro. Eutrophic remodeling is a relatively rapid process that is followed by the fixation of cells within the vascular ECM scaffold and it requires active transglutaminases \[[@B10]\]. Recently, we described a key role for αVβ3 integrin in eutrophic remodeling and other studies have described its function in myogenic constriction \[[@B6]\]. There is increasing evidence that FAK is an important mediator for cell attachment and mechanosensing \[[@B11]\]. The Src family kinases are also regarded as key components of mechanotransduction to special domains via the cytoskeleton when force is applied to fibronectin-binding integrins such as αVβ3 \[[@B12]\]. Moreover, FAK/Src association with specific integrin subunits seems to regulate particular cellular functions: for example, α5β1 appears to regulate the L-type calcium current, which mediates myogenic constriction via Src and FAK signaling \[[@B13]\], whereas the association of FAK/Src with β3 integrin subunits seems to be important for cell migration \[[@B14]\]. In addition, evidence is accumulating for the initiation of FAK phosphorylation in the growth response of arteries exposed to elevated intraluminal pressure \[[@B15]\]. We wished to test the hypothesis that FAK/Src signaling is crucial in mechanotransduction and the eutrophic inward remodeling of resistance arteries as a response to elevated pressure. This study examined the activation levels of FAK/Src in arteries exposed to elevated pressure in vitro and ex vivo, and we report differential FAK Y397 phosphorylation levels present at the integrin β subunits of resistance arteries from hypertensive TGR(mRen2)27 rats as pressure rises and eutrophic inward remodeling occurs. Ex vivo pressurization of arterial segments which exhibit myogenic tone confirmed that FAK Y397 phosphorylation is increased as a response to elevated pressure. Methods {#sec1_2} ======= Animals {#sec2_1} ------- The TGR(mRen2)27 rat carries a DBA/2J Ren2 transgene and develops hypertension with vascular structural changes from eutrophic inward remodeling \[[@B6],[@B16]\]. These animals, together with Sprague-Dawley (SD) normotensive control animals, were studied by immunohistochemistry and Western blot at 4 and 5 weeks of age. Ex vivo studies were performed on arteries harvested from SD rats at 5 weeks of age. On the day of study, rats were sacrificed by stunning and cervical dislocation. All animal procedures were performed in accordance with the UK Home Office Regulated Procedures on Living Animals (Scientific Procedures) Act 1986. Blood Pressure Measurement {#sec2_2} -------------------------- Blood pressure measurements of TGR(mRen2)27 and SD control animals were performed using tail-cuff plethysmography under light fluothane anesthesia. Vessel Morphology and Integrin Antagonism {#sec2_3} ----------------------------------------- We performed studies on the small arteries harvested from animals sacrificed at 5 weeks of age, because hypertension-induced eutrophic remodeling takes place from the age of 4 weeks and is completed by week 5, as described previously \[[@B6]\]. Segments of 2nd-order arteries (approx. 200 µm) were isolated from the proximal region of the mesenteric bed, mounted on a wire myograph and held in physiological salt solution (PSS; 119 mM NaCl, 4.7 mM KCl, 25 mM NaHCO~3~, 1.17 mM KH~2~PO~4~, 1.17 mM MgSO~4~, 0.026 mM EDTA, 1.6 mM CaCl~2~ and 5.5 mM glucose) at 37°C and gassed with 5% CO~2~ and 95% O~2~ to maintain a pH of 7.4. Subsequent morphological parameters of live vessels such as the media-to-lumen ratio, growth and remodeling indices were then measured and calculated, as previously described \[[@B17]\]. In order to study the effects of integrin αV antagonism, TGR(mRen2)27 rats were injected intraperitoneally at the age of 4 weeks with cRGDfV or cRADfV peptide (10 mg/kg; Calbiochem) twice daily for 5 days before sacrifice \[[@B6]\]. These act as an αV integrin-specific inhibitory peptide, thereby inhibiting integrin functions or inactive control peptide, respectively \[[@B18],[@B19],[@B20]\]. Arteries were then harvested for morphological measurements using wire myography. Phosphorylated FAK Y397 Western Blot Analysis {#sec2_4} --------------------------------------------- Western blot analysis was performed according to the methodology described by Laemmli \[[@B21]\]. Vessels were dissected and protein extracted on ice in radioimmunoprecipitation assay buffer containing phosphatase and protease inhibitors to prevent changes in the phosphorylation status of the proteins under investigation. Anti-phosphorylated (p)FAK Y397 antibody (1:1,000, 0.5 μg/ml; AB4803, Abcam, Nottingham, UK), with a total (pan)-FAK antibody as a control for loading (1:1,000, 1.0 µg/ml; AB1311, Abcam), was used to detect expression in 25 µg of total protein. pFAK Y397 expression levels were corrected for the amount of total (pan)-FAK. Densitometric analysis was performed on a BioRad-GS690 scanner. Integrin αV Immunoprecipitation {#sec2_5} ------------------------------- An amount of 5 μg of each antibody was used to precipitate integrin subunits from 250 μg of total resistance artery radioimmunoprecipitation assay extract. The antibodies used for immunoprecipitation were: β1 (AB1952), β3 (AB1932) and α5 (aba5b) integrin antibodies (Chemi-Con, Moses Lake, Wash., USA). Agarose IgG/protein A (Sigma-Aldrich, UK) was used to bind and identify coprecipitated complexes. Subsequent Western blot analysis was performed using FAK Y397 (1:1,000) antibody and Src Y418 (1:500, 0.5 μg/ml; Abcam). Protein A-HRP was used for chemiluminescent detection of coprecipitated proteins \[[@B22]\]. Ex vivo Pressure Arteriography {#sec2_6} ------------------------------ Arterial segments from the proximal region of the cremasteric artery from SD animals were dissected and mounted between two glass microcannulae in physiological salt solution in a pressure myograph (Living Systems Instrumentation, Burlington, Vt., USA). Experiments were carried out at 32°C. PP2 and PP3, i.e. a potent inhibitor of c-Src and an inactive analog (negative control) of PP2, respectively \[[@B23],[@B24]\], were used at 1 μM (Calbiochem, Cambridge, UK). Only arteries that exhibited pressure-mediated constriction were included in the study. After pressurization at either 60 or 120 mm Hg for 1 h, arteries were quickly fixed in ice-cold 4% paraformaldehyde solution, left overnight, washed in 70% ethanol and prepared for histology/immunofluorescence. Immunohistochemical preparations of arteries ex vivo and in vitro were the same. Immunofluorescence Localization {#sec2_7} ------------------------------- Vessels for immunofluorescence were dissected on ice and snap-fixed in ice-cold 4% paraformaldehyde. Paraffin-embedded arteries were sliced at 4 μm, dewaxed and rehydrated. The pFAK Y397 integrin (1:100; AB4803, Abcam) and a nonimmune control IgG antibody were used separately, followed by donkey anti-rabbit antibody with conjugated TRITC (1:200, 1 μg/ml; Jackson ImmunResearch Laboratories, West Grove, Pa., USA). Diamidino-2-phenylindole (DAPI, 1 pg/ml) (Jackson ImmunoResearch Laboratories) was used as a blue fluorescent nuclear stain. A Leica DM6000 epifluorescence microscope was used at ×1,000 magnification in conjunction with Leica FW4000 software for image capture and analysis. Superimposing fluorescence and phase-contrast microscopy images allowed the visualization of the VSMC membrane and the internal elastic lamina which indicates the smooth-muscle/endothelium boundary. Statistical Analysis {#sec2_8} -------------------- Statistical analysis was performed using MS Excel. Values are expressed as mean ± standard deviation. Differences between data were tested using the two-tailed unpaired homoscedastic Student t test. p \< 0.05 was considered statistically significant. Results {#sec1_3} ======= Blood Pressure {#sec2_9} -------------- Between 4 and 5 weeks of age, mean systolic blood pressure in TGR(mRen2)27 rats was significantly increased from 121 ± 7.9 to 148 ± 3.0 mm Hg (n ≥ 6, p \< 0.02). SD control rats showed no age-dependent increase in blood pressure which ranged from 80.9 ± 8.8 to 93.4 ± 8.1 mm Hg. Pressures in TGR(mRen2)27 rats were significantly higher than those in SD rats at both time points (p \< 0.0001). The administration of cRGDfV and cRADfV peptides had no effect on the blood pressure rise seen in TGR(mRen2)27 rats (data not shown). Vascular Morphology {#sec2_10} ------------------- The cross-sectional area of TGR(mRen2)27 rat arteries at 5 weeks was unchanged compared with at 4 weeks of age, with a remodeling index of 97% indicating the development of eutrophic inward remodeling due to the media-to-lumen ratio being significantly increased (p \< 0.01). The structural parameters of SD rat arteries did not change over 7 days. cRGDfV treatment reduced the remodeling index to 9% and there was evidence of hypertrophic growth, with a calculated growth index of 17%. Treatment with cRADfV had no effect on remodeling, as predicted (data not shown). Western Blot {#sec2_11} ------------ Western blot analysis of pFAK Y397 showed significant rises in autophosphorylation levels in resistance arteries from TGR(mRen2)27 animals treated with cRADfV control peptide (approx. 1.4-fold, p \< 0.05), compared with vessels from SD normotensive control animals (fig. [1a, b](#F1){ref-type="fig"}). Surprisingly, an increase in pFAK of approximately 2-fold was observed in TGR(mRen2)27 rat arteries treated with the active cRGDfV peptide (p \< 0.01) compared with vessels from normotensive animals treated with the same peptide (n ≥ 4). Relative pFAK Y397 levels, established by densitometry, were corrected by comparison to total (pan)-FAK (fig. [1a, b](#F1){ref-type="fig"}). Immunofluorescence {#sec2_12} ------------------ Phospho-FAK Y397 immunofluorescent staining of the arteries from normotensive SD animals was faint but present throughout the medial smooth-muscle cells (n ≥3; fig. [2b, d](#F2){ref-type="fig"}). The level of pFAK Y397 was observed to be increased in the VSMCs of TGR(mRen2)27 rat (n ≥ 3) resistance arteries (fig. [2a](#F2){ref-type="fig"}). Superimposing phase-contrast images onto fluorescent signals allowed the visualization of the VSMC medial layer, the internal elastic lamina and intense fluorescent pFAK Y397 regions of staining present in TGR(mRen2)27 rat VSMCs (fig. [2c](#F2){ref-type="fig"}). This is in contrast with fluorescence of total (nonphosphorylated) FAK (fig. [3a--d](#F3){ref-type="fig"}), which is expressed diffusely throughout the VSMCs of the medial layer (fig. [3c](#F3){ref-type="fig"}). FAK was localized to FA sites as identified by coimmunohistochemistry for FAK Y397 and vinculin, a membrane protein found associated with the FA sites of the elastic lamina (fig. [4](#F4){ref-type="fig"}). Control incubations with nonimmune IgG did not result in any detectable signal (fig. [2](#F2){ref-type="fig"}, [3](#F3){ref-type="fig"}, [4](#F4){ref-type="fig"}). The treatment of animals with the cRGDfV peptide (10 mg/kg) showed localization of pFAK within the medial layer of VSMCs and more intense staining in the treated TGR(mRen)27 rat arteries than in those from SD rats (n ≥ 3; fig. [5a](#F5){ref-type="fig"}) and more diffuse than in untreated arteries (fig. [2a](#F2){ref-type="fig"}), thereby supporting quantified data from our observations from Western blot analysis (fig. [1](#F1){ref-type="fig"}). Figure [5](#F5){ref-type="fig"} a, c clearly shows intense Y397 staining is throughout the medial layer of arteries. In contrast, cRGDfV treatment of normotensive SD animals did not have any effect on pFAK Y397 levels (fig. [5b, d](#F5){ref-type="fig"}). Inspection of arterial segments undergoing FAK Y397 phosphorylation staining, which were pressurized at 120 mm Hg for 1 h (and then developed myogenic-tone ex vivo) exhibited increases in FAK Y397 phosphorylation compared with vessels pressurized at 60 mm Hg (n ≥ 5). No passive morphological alterations of vessels to pressure were observed at this stage (data not shown). Phosphorylation of FAK Y397 at 120 mm Hg was abrogated when arteries were coincubated with 1 μM of PP2. In contrast, coincubation of PP3 did not have any effect (fig. [6](#F6){ref-type="fig"}). Integrin Coimmunoprecipitation {#sec2_13} ------------------------------ pFAK Y397 was coprecipitated with integrin β3 and, to a lesser extent, with integrin α5β1 (fig. [7a](#F7){ref-type="fig"}) from the protein extracts of SD rat arteries. However, no FAK was coprecipitated with the general subpopulation of β1 integrins (fig. [7a](#F7){ref-type="fig"}). In contrast to the protein extracts of normotensive SD resistance arteries, pFAK Y397 coprecipitation with all the integrins, i.e. β1, β3 and α5β1, was observed in the arteries of TGR(mRen2)27 animals (fig. [7b](#F7){ref-type="fig"}). Coimmunoprecipitation of the protein extracts from resistance arteries of 5-week-old cRGDfV-treated TGR(mRen2)27 animals (which inhibited eutrophic inward remodeling but showed hypertrophy) did not show pFAK cobinding with β3 or α5β1 integrins, but interacted solely with other subpopulations of β1 integrins (fig. [7c](#F7){ref-type="fig"}). In conjunction with FAK, c-Src was prominently coprecipitated with integrin α5β1 and, to a lesser extent, with integrin β3 (fig. [8a](#F8){ref-type="fig"}). In contrast, c-Src is not coprecipitated with the α5β1 integrins of resistance arteries of hypertensive TGR(mRen2)27 animals, but with integrins β1 and β3 (fig. [8b](#F8){ref-type="fig"}). c-Src, however is not recruited to the β3 cytoplasmic domain when αVβ3 binding to the ECM with the cRGDfV peptide is inhibited (fig. [8c](#F8){ref-type="fig"}). Discussion {#sec1_4} ========== Previously, we showed that the hypertension-mediated inward eutrophic remodeling of TGR(mRen2)27 rat resistance arteries commenced at 4 weeks of age and was complete at 5 weeks \[[@B6]\]. This process was dependent on the integrin αVβ3 (the only VSMC β3 integrin) because administration of cRGDfV peptide, which preferentially interferes with the binding of this integrin-heterodimer to the ECM \[[@B18],[@B19],[@B20],[@B25]\], prevented the remodeling process but enhanced hypertrophy. We also investigated the localization of FAK and its activation status in the smooth-muscle cells of TGR(mRen2)27 rat resistance arteries and determined its association with β1 or β3 integrin subunits. We established that low basal levels of FAK Y397 phosphorylation in normotensive SD rat mesenteric arteries are predominantly associated with the β3 integrin subunit and that active c-Src associates with integrin α5β1. FAK Y397 phosphorylation was significantly increased in hypertensive TGR(mRen2)27 resistance arteries and recruited to FA sites after blood pressure rose and once eutrophic inward remodeling was complete. In addition, both pFAK Y397 and active c-Src associated with β1 and β3 integrins in the resistance arteries of TGR(mRen2)27 animals. However, the inhibition of remodeling by the administration of cRGDfV peptides resulted in the hypertrophy of VSMCs and a further increase of FAK Y397 phosphorylation. This process was associated with integrins containing the β1 subunit only. We can conclude from these data that FAK phosphorylated at tyrosine position 397 (the autophosphorylation site) is present at both the integrin β1 and β3 cytoplasmic sites in the resistance arteries of hypertensive TGR(mRen2)27 animals, in contrast to SD controls, which exhibit relatively low pFAK Y397 levels only associated with the integrin β3 subunit. We cannot rule out the possible involvement of FAK Y397 phosphorylation in subsequent length/autoregulation processes during the hypertension remodeling processes downstream of the integrin β3 subunit. However, it is now thought that the initial role, in the light of the FAK Y397 phosphorylation observed, is in mechanotransduction, as cRGDfV peptides not only inhibited eutrophic remodeling but also encouraged further FAK Y397 phosphorylation during the onset of hypertension in this model. Therefore, the increase of FAK Y397 phosphorylation observed is more likely to occur as a consequence of increases in wall tension, rather than acting as a direct intermediate of eutrophic inward remodeling. Besides aiding adhesion and migration \[[@B26]\], β1 and β3 integrins are both responsible for the intracellular transfer of these forces in the VSMCs of resistance arteries \[[@B27],[@B28]\]. This conclusion is strengthened further by how the arterial segments of the cremaster muscle, at a high pressure (120 mm Hg), exhibit a prompt induction of FAK Y397 phosphorylation (\<1 h) when compared with vessels pressurized at much lower levels and completely independent of neurohumoral influences \[[@B29]\]. There is the possibility that the increase of FAK Y397 phosphorylation observed in the resistance arteries of the young TGR(mRen2)27 hypertensive animals was induced by enhanced activity of the renin-angiotensin system (RAS; reviewed in \[[@B30]\]). However, this seems unlikely because at 5 weeks of age the resistance arteries of these animals have eutrophically remodeled without evidence of hypertrophy \[[@B6]\], similar to the morphological adaptations observed in a low-renin model of hypertension \[[@B31]\] and the BMH-2 mouse model which develops hypertension independently of the RAS \[[@B32]\]. The hallmark of a locally activated vascular RAS in older animals is vascular hypertrophy \[[@B30],[@B33]\]. Again, ex vivo pressurization has determined that FAK Y397 phosphorylation is likely to be associated with an increase in pressure, in an Src-dependent manner, without the possible interference of neurohumoral influences. However, we cannot completely rule out the contribution of RAS activity to FAK Y397 phosphorylation in the TGR(mRen2)27 resistance arteries \[[@B34],[@B35]\]. Various studies have reported the association of FAK with different β integrin subunits; β1, β3 and β5 cytoplasmic domains all contain sufficient information to trigger FAK phosphorylation and these specific regions have been identified \[[@B36]\]. Different cellular systems in vitro utilize different integrins for FAK activation, e.g. β3-but not β1-integrin engagement in cultured cardiomyocytes and VSMCs is accompanied by FAK activation in FAs \[[@B14],[@B37]\]. In contrast, fibroblasts cultured on collagen employ β1 integrins only for FAK activation \[[@B38]\]. In response to the hepatocyte growth factor, VSMCs are known to utilize both β1 and β3 integrins for FAK activation and subsequent migration \[[@B39]\]. In this study, using the TGR(mRen2)27 rat model \[[@B16]\], it became apparent that both β1 and β3 integrins are involved in VSMC FAK recruitment/signaling when pressure becomes elevated, in contrast to normotensive controls. However, the FAK Y397 phosphorylation observed which is associated with β-integrin subunits in response to elevated pressure is not exclusively increased when eutrophic remodeling processes take place, but is already apparent at the initial stages when pressure becomes elevated. Clinical Perspectives {#sec1_5} ===================== It has been established that both β1 and β3 integrin subtypes are required not only in the adhesion of VSMCs to the ECM of the vascular wall but also for pressure-mediated signaling, resulting in vascular myogenic constriction and remodeling in hypertension \[[@B6],[@B27]\] (summarized in fig. [9](#F9){ref-type="fig"}). In this study, we identified FAK Y397 phosphorylation as an early event as a result of elevated pressure in vivo and ex vivo. The identification of FAK Y397 phosphorylation in an Src-dependent manner is an important first step in resolving the complex signaling cascades that underlie integrin-mediated vascular adaptations of resistance arteries in hypertension. The relevance of unraveling molecular components in specific signaling events, in the context of pressure mechanotransduction in hypertension, will enlighten the design of pharmacological agents to prevent hypertension-mediated target-organ damage. Recent data have suggested that the morphological changes in the arterial wall of small blood vessels are associated with cardiovascular prognosis. The normal response to untreated hypertension is eutrophic inward remodeling, i.e. a rearrangement of the vascular wall architecture without any evidence of growth \[[@B17]\]. When hypertrophy supervenes, this heralds the breakdown of normal homeostatic mechanisms such as autoregulation and, as such, there is clear evidence that this is the structural alteration associated with an adverse prognosis \[[@B3]\]. This study was funded by the Wellcome Trust. We thank Mrs. Maureen Speed for her expert secretarial assistance. ![FAK Y397 phosphorylation in the resistance arteries of TGR(mRen2)27 rats treated with cRGDfV. a Representative Western blot of pFAK Y397 and total FAK (125 kDa) using 25 μg of protein from resistance artery extracts. b Levels of pFAK Y397 analyzed by densitometric scans and corrected for total FAK (n ≥ 4, \* p \< 0.05, \\ p \< 0.01).](jvr-0051-0305-g01){#F1} ![Basal levels of pFAK Y397 immunofluorescence in resistance mesenteric arteries. a, c TGR(mRen2)27 rat mesenteric artery and the prominent localization of pFAK Y397 to VSMCs. b, d pFAK Y397 localization in SD rat resistance arteries is loosely distributed throughout the cells in contrast with TGR(mRen2)27 rat arteries. ×1,000. Scale bar: 25 µm.](jvr-0051-0305-g02){#F2} ![Total FAK (nonphosphorylated) immunofluorescence in resistance arteries. a, c The localization of total FAK throughout the VSMCs of TGR(mRen2)27 rat mesenteric artery. b, d Similarly, total FAK is present throughout the VSMCs of SD rat mesenteric arteries. ×1,000. Scale bar: 25 μm.](jvr-0051-0305-g03){#F3} ![Localization of FAK Y397 at FA sites in SD rat resistance arteries. a DAPI staining for nuclei of within the resistance artery. FAK Y397 (b), vinculin staining (c) and phase-contrast images of the elastic lamina (d) demonstrate colocalization of FAK Y397 to FA sites within the medial layer of the artery (e). f A blank control.](jvr-0051-0305-g04){#F4} ![pFAK Y397 immunofluorescence of rat mesenteric arteries following α5 antagonism by cRGDfV treatment (10 mg/kg, intraperitoneal injection twice daily for 5 days). a, c pFAK Y397 staining is increased and present throughout the VSMC medial layer of TGR(mRen2)27 rat resistance arteries. b, d In contrast, cRGDfV treatment has no effect on pFAK Y397 levels in SD rat mesenteric arteries. ×1,000. Scale bar: 25 μm.](jvr-0051-0305-g05){#F5} ![Immunofluorescence localization of phosphorylated FAK Y397 after ex vivo pressurization (60 and 120 mm Hg) of cremaster arteries. a, b PP3 coincubation has no effect on pressure-induced myogenic constriction or phosphorylation levels of FAK Y397. a Arteries at 60 mm Hg only present minimal phosphorylation of FAK Y397. b Arteries pressurized at 120 mm Hg exhibit prominent phosphorylation levels of FAK Y397. c Phosphorylation of FAK Y397 was abrogated when arteries were incubated with 1 µM PP2. Scale bar: 25 µm.](jvr-0051-0305-g06){#F6} ![Integrin immunoprecipitation: coprecipitation of pFAK Y397. a pFAK Y397 is coprecipitated with β3 and α5β1 integrins in SD rat arteries. b In contrast, pFAK Y397 is coprecipitated with all the integrins tested in TGR(mRen2)27 rat arteries. c Inhibition of remodeling with cRGDfV peptides results in coprecipitation of pFAK Y397 only with β1 integrins. Immunoprecipitations shown are representative of at least 3 experiments.](jvr-0051-0305-g07){#F7} ![Integrin immunoprecipitation: coprecipitation of pSrc Y418. a pFAK pSrc Y418 is coprecipitated with β3 and α5β1 integrins in SD rat arteries. b In TGR(mRen2)27 rats, pSrc Y418 is coprecipitated with β1 and β3 integrins. c In contrast, cRGDfV treatment results in coprecipitation of pSrc Y418 with β1 integrins only. Immunoprecipitations shown are representative of at least 3 experiments.](jvr-0051-0305-g08){#F8} ![Schematic representation of the role of β integrins in mediating FAK Y397 autophosphorylation of the resistance arteries. a Normotenisve: integrin α5β1 (involved in calcium influx) and β3 integrin subunits are mechanically activated resulting in FAK Y397/Src Y418 phosphorylation, and are probably required for normal vascular integrity during normotensive pressure fluctuations. Relatively little change in FAK Y397 and Scr Y418 phosphorylation is required for normal vascular adaptations to minor changes in pressure. Signaling of FAK/Src via 'general' ECM-anchoring β1 integrins is minimal. b Hypertensive inward remodeling with cRADfV: during hypertensive remodeling, an increase in phosphorylation of the mechanosensitive FAK Y397/Src Y418 signaling complex is mediated via β1 and β3 integrins (but not the pSrc Y418 component of α5β1), suggesting a role of β1 and β3 integrin subunits to maintain vascular integrity in response to an increase in pressure. c Hypertrophic remodeling: abrogation of αVβ3 signaling with cRGDfV results in hypertrophy in response to pressure and mechanosignaling exclusively through β1 integrins. The majority of the β1 integrins are thought to be important in 'anchoring' VSMCs within the matrix of the vascular wall. Exclusive mechanosensing of FAK Y397 via β1 integrins through this rigid scaffold is thought to be central to these structural adaptations in hypertension.](jvr-0051-0305-g09){#F9}	{ "pile_set_name": "PubMed Central" }
Q: Android Studio - Gradle assemble task I'm currently struggling with a build process in gradle. My goal is to not have a specific java class in the final .apk for a specific flavor. The logic goes like this: 1.) before compiling my project delete MyClass.java and copy it to a temp folder 2.) after assembling the apk copy back MyClass.java to my original folder 3.) delete the temp folder This happens only if I build a specific flavor, so it doesn't happen for all build variants. My code works perfectly when I build only one flavor and one build variant e.g. assembleFlavorRelease, but if I wan't to make my code work for multiple build types; if I run assembleFlavor it should build flavorDebug the same way it does flavorRelease. However my logic goes trough only the first time and after that it stops, so flavorDebug is build with MyClass and it shouldn't be, while flavorRelease doesn't include MyClass in the .apk because my code runs the first time. Here is what the code looks like: task copyResource << { copy { from 'src/main/java/MyClass.java' into 'src/temp' } } task deleteResource << { delete { 'src/main/java/MyClass.java' } } task deleteTemp << { delete { 'src/temp' } } task copyBackToSource << { copy { from 'src/temp/MyClass.java' into 'src/main/java' } deleteTemp.execute() } android.applicationVariants.all { variant -> if (variant.name.contains('flavor')) { deleteResource.dependsOn copyResource variant.javaCompile.dependsOn deleteResource variant.assemble.doLast { copyBackToSource.execute() } } } I think that the directories which I use in my code are somehow locked when trying to execute the whole process the second time? A: I feel that you are approaching the problem in the wrong way. Instead of thinking Put the java file in src/main/java and remove it from flavorX You should instead be approaching it as Add an extra source directory to the source sets for flavorY and flavorZ Once you approach the problem like this it becomes much easier If you only want the file in one flavor, you can put the file in the flavor specific source folder using the built in conventions (ie src/flavorX/java) If you want the file in more than one flavor you could put MyClass.java in src/common/java and do something like android { productFlavors { flavor1 { } flavor2 { } flavor3 { } } } sourceSets { flavor1.java = ['src/flavor1/java','src/common/java'] flavor2.java = ['src/flavor2/java','src/common/java'] }	{ "pile_set_name": "StackExchange" }
Kindly Share This Story: Neimeth, Cornerstone Insurance and Chams, emerged as the best performing equities on the Nigerian Stock Exchange (NSE) in the month of November. Data obtained by the News Agency of Nigeria (NAN) show that Neimeth led eight others to emerge as the best-performing stocks in percentage terms during the period under review. Also read: A breakdown of the data showed that Neimeth, which opened trading for the month at 0.39k, rose by 87.18 per cent to close at 73k per share. It was followed by another penny stock, Cornerstone Insurance, which inched by 75.55 per cent, while Chams notched 59.09 per cent rise. Others are Jaiz Bank which rose by 46.67 per cent, Law Union Insurance 44.44 per cent and Dangote Sugar 33.33 per cent. UACN also inched by 33.33 per cent, University Press 32.75 per cent, Guinness 29.98 per cent and AG Leventis 28.57 per cent. Mr Ambrose Omordion, the Chief Operating Officer, InvestData Ltd., said the stocks rallied on the strength of low prices and market sentiment. Conversely, Unilever was the worst performer in percentage terms, dropping by 39.70 per share to close at N16.10 per share. It was followed by International Breweries with 25.30 per cent price drop, Total 9.98 per cent, C&I Leasing Services 9.89 per cent, MRS 9.73 per cent and Okomu Oil 9.65 per cent. Others were ABC Transport 6.82 per cent, NPF Micro Finance Bank 6.72 per cent, UACN Property 6.54 per cent and Fidson Healthcare 6.26 per cent. NAN reports that the All-Share Index rose during the period by 642.80 points to close at 27,002.15 from the 26,355.35 achieved in October. Also, the market capitalisation, which opened at N12.829 trillion, rose by N204 billion to close at N13.033 trillion. Commenting on the market performance, Omordion attributed the growth recorded to rekindled interest by market players driven by the crash in money market rates. He said that the rebound experienced during the period was due to the decision of the Central Bank of Nigeria (CBN) to restrict individuals and local firms from investing in it’s Open Market Operations (OMO) auctions impacted positively on the market. Omordion said that the restriction contributed to investors’ renewed interest in the stock market during the period. Vanguard Kindly Share This Story:	{ "pile_set_name": "OpenWebText2" }
Zaļenieki Manor Zaļenieki Manor, also called Zaļā Manor because of the German word Grünhof, is a manor house in the historical region of Zemgale, in Latvia. Surrounded by a 27-hectare landscape park with ponds and lakes, it was one of the oldest properties of the Livonian Order in Zemgale. Its architecture enables the manor to be evaluated as the first and greatest early classical model in Courland. History After the collapse of the Livonian Order in 1562, the manor became property and a popular hunting spot for Gotthard Kettler, first Duke of Courland and Semigallia. In 1766, Duke Ernst Johann von Biron signed the first order for the construction of the new manor. The initial architectural design is supposed to have been the work of Italian-born Russian architect Bartolomeo Rastrelli, who died in 1771 before completion of the project. Construction began in 1768 and finished in 1775 under the supervision of Rastrelli's Danish-born assistant Severin Jensen, which explains the influence of both Late Baroque and Classicism architecture in the completed manor house. In 1795, when the Duchy of Courland and Semigallia was incorporated into the Russian Empire, the Russian Emperor Paul I gave Zaļenieki Manor and all the estate to his brother-in-law Alexander of Württemberg. In 1850 his sons sold the property to the landlord of Bornsminde Manor Alexis von Scheping. His wife Aleksandra Lieven of Mežotne, after her husband's death, passed the estate over to the hands of the Baltic-German Count Karl Theodor von Medem of Eleja at the end of the nineteenth century. After the Latvian agrarian reforms in 1920, the building was nationalized and turned into a vocational secondary school, which continues in operation as of today. Restoration work under the new stucco layers in the hall and several other rooms on the second floor revealed wall paintings. The facade of the Zaļenieki Manor has not undergone any major changes since the eighteenth century. However, the interior of the manor was redesigned and refitted from 1866 to 1868. The complex used to consist of more than 30 buildings, including stables and accommodation for the servants. See also List of palaces and manor houses in Latvia References External links Category:Manor houses in Latvia Category:Bartolomeo Rastrelli buildings Category:Jelgava Municipality	{ "pile_set_name": "Wikipedia (en)" }
Glucose uptake by muscle and fat tissue is a primary mechanism for energy storage and represents a main control mechanism for glucose concentration in the circulation. A detailed understanding of the intracellular signaling system that mediates insulin-triggered translocation of the glucose transporter (GLUT4) will likely provide new findings for attacking diseases such as diabetes and obesity. The main goal of the proposal is to develop a kinetic screen to identify adipocyte regulatory proteins that control dynamic parameters for PIP3 signaling and for GLUT4 translocation and endocytosis. We will establish a wide-field TIRF system to measure the translocation and endocytosis rates of GLUT4 transporters, as well as the generation and degradation rate of PI3P lipids, in individual cells under 12 different perturbation conditions in parallel. We will create an RNAi library to target the approximately 800 adipocyte signaling/secretory proteins and a library of 800 expressed dominant negative and constitutively active expression constructs for complementary pertubation studies. In contrast to earlier approaches in which screens were based on end-point assays in fixed cells, the live-cell strategy proposed here focuses instead on the identification of adipocyte signaling and secretory proteins that control important kinetic parameters in insulin triggered PIP3 signaling as well as in GLUT4 translocation. In the second part, we will execute, analyze and interpret a screen of the insulin-PIP3-GLUT4 signaling network with this new approach and will also perform a screen of cross-talk between insulin and TNF-alpha signaling. These screens will be used to identify new players in the insulin-GLUT4 signaling network and to gain a better understanding of kinetic control mechanisms. The project will also provide a test case for a kinetic screening strategy and a test case for a combined screen using RNAi, as well as DN and CA expression constructs.	{ "pile_set_name": "NIH ExPorter" }
How To Erase Deodorant Marks With Dry Cleaning Hangers We shunned wire hangers years ago for a variety of reasons: they’re damaging on clothes, not functional, and call us snotty, but we just don’t think they deserve a place in a sophisticated, well-organized closet. Pro clutter cleaner Lili Pettit agrees with us. However, the Huffington Post just gave us a new reason to save a few after our next dry-cleaning pick up: they’re excellent at removing deodorant marks on clothing. Follow the link below to see how.	{ "pile_set_name": "Pile-CC" }
Postnatal management and outcome for neural tube defects including spina bifida and encephalocoeles. The incidence of neural tube defects (NTDs) has declined in recent decades, however myelomeningocele and encephalocele still represent one of the commoner prenatally diagnosed congenital malformations. Improved perinatal and post natal care mean that the mortality associated with these conditions has also fallen. Advances in the multidisciplinary management of children with myelomeningocele have led to significant improvements in functional outcome for many with this condition. However, there remains a substantial population of patients born with NTDs whose life expectancy is substantially reduced and who suffer significant cognitive and physical disability remaining wholly or partially dependant on the care of others into adult life. This article aims to outline the contemporary early management of these conditions and examine the prospects for functional outcome where possible, attempting to show how early anatomical features of these conditions can help predict where, along the wide spectrum of outcome, a given individual may lie.	{ "pile_set_name": "PubMed Abstracts" }
Yesterday, the wifie was supposed to go out with her mom and sisters “for a few hours” starting at around 10:00 am. Those of you who know my dear, sweet in-laws know that “for a few hours” is code for “we won’t be home until midnight, if then”. Since yesterday was the start of spring break, it meant that daddy would have all day with his daughters. Now to be honest, this isn’t always a slam dunk. I’m great with kids – older kids. High schoolish kids. I’m not so great with little kids. My patience isn’t what it needs to be. I’m too demanding (or so I’ve been told). I get irritated far too easily. My sarcasm is lost on the audience. You get the gist of it… Anyway, the day started off in a bad way. I told the girls that before we could have fun, we had to pick up the house a little bit – before play, the work must get done. Its a noble lesson every parent should teach their kids. But it doesn’t feel so noble when the whining starts immediately. “But Daddy – we are supposed to have FUN today,” whinedReagan. “Sobs,” from Riley, who is now laying face down on the couch. My tolerance already tested, I have a discussion with them about the importance of work and how if they don’t learn to work now, how can they ever hope to be successful in life. Yes, it might have been a bit over their heads. Reagan angrily pronounced, “Daddy Day is never fun when you make us slave away in the house!” Well, they did work… and they grumbled the whole time. After about an hour, I told them I would take them out for lunch. I asked them to pick a place to eat. Again, mistake on my part. Reagan immediately chose Arby’s, and Riley wanted McDonald’s. Then Reagan decided on Applebee’s, and Riley went with Buffalo Wild Wings. I said those cost too much (“You’re so cheap, daddy!” Reagan informed me). Finally, I had a winning idea. They girls both love Pizza Hut lunch buffet, so I told them to get in the car – we’re going to Pizza Hut!!! Both girls gave me a look as if I was crazy. “I hate the pizza there!” Reagan shook her fist. “I want tasty wild wings,” cried Riley, tears welling up all over again. What’s a dad to do? Forge ahead with his plan, of course. “Pizza Hut it is!!!” I declared, despite the wailing of the natives. On the way to Pizza Hut, I caught my first break. There was a bad accident on the road, and the girls instantly forgot their disappointment with pizza. “Look at that smashed up car!” “I hope they’re in heaven!” “No, Riley, they’re not in heaven! They’re in front of the ambulance right there!” “Oh yeah! Well, I hope if they had any dogs in the car that they are alright.” “That car isn’t alright, that’s for sure! Look at its smashed front end! I bet they were going fast, huh Daddy?” Nothing like a little destruction to turn a day around. Pizza Hut helped me to continue my comeback. The accident had caused total memory loss, and the girls tore into endless pizza and breadsticks. Daddy cleverly managed to drop the lid of the marinara dipping sauce pot into the pot itself at the buffet, leading to endless giggles from the girls as daddy tried to fish it out. Daddy also was talking to the girls while walking back to the buffet, and ran right into a small boy that was carrying a plate full of pizza. Another eruption of giggles. Our next journey was to the reptile shop. I have had it in my mind for quite some time now that we need a pet tortoise. Wifie is adamantly opposed. The girls side with me on this one. So we made our way to Stinger’s Exotics, the best reptile shop in our part of town. Unfortunately, it was closed for Good Friday. They must be the devout kind of snake handlers. The true problem – my momentum was lost. The girls were angered by the shopkeeper’s display of piety. There was a real danger that tears would soon erupt anew. Sometimes pressure brings out the best in me. What hadn’t I done with the girls in a long, long time? Gone to a movie! Hmmm… was there a movie out right now that mama didn’t want them to see because it would be too scary, but daddy could take them whilst mama spent money with reckless abandon? The new Wizard of Oz movie! Aww yeah! After our eyes readjusted to the light of day, we decided to go home and ride bikes. However, plans sometimes change – especially when the killer squirrel of Plymouth is on the loose. As we drove up, I saw my arch nemesis bounding across the front yard. Oh, how I hate that creature. I sent the girls inside to get the Nerf bow and arrows while I treed the attack squirrel. He is not afraid of me. He climbed the tree to about the height of my head, and then turned and started chittering away. He bared his teeth at me too! Oh, it was on! Luckily, I had my two sidekicks there to help me! Reagan handed me the bow, and Riley the Nerf arrow. I took careful aim, and targeted the nasty little tree rodent. I released. Boom! Direct hit to the face! The girls cackled in delight! Then they took their turns. While neither hit him, I had won the moment. The day with Daddy was quickly turning into a winner! After battles, warriors need to quench the fire in their bellies with cookies and a drink – so off to Panera. The girls couldn’t stop talking about all that had happened – the car wreck, daddy smacking the boy in Pizza Hut, Oz, the showdown with the squirrel… I felt like a champ. One last activity awaited us – spring weather meant time for our first bike ride of the year. We rode over to the campus where I teach. For the uninitiated, the school(s) where I teach consists of three separate high schools, all connected by paths and roads. Its truly a huge high school – over 6,600 students, and a huge amount of land. We road over bridges, onto trails, between the schools, over curbs, and raced along the back road. We discovered a tipi built in the woods. Finally, as we made our way home, we discovered a dead squirrel in the gravel on the side of the final path. It seemed a solemn moment – as if the enemy that had bound us together several hours before had been ultimately defeated. We dismounted and gathered around for a moment of silence. Then, the girls reached a decision. “We need to bury him, daddy,” Reagan told me. “Yes, the poor thing never had a chance,” Riley said, dabbing at a tear. I explained that, without a shovel, we wouldn’t be able to bury him – they would need to find a likely spot for his resting place. They poked around a bit and saw a tree uprooted about 5 feet into the woods. Underneath the tree appeared to be a puddle. They felt that the puddle would wash away the horrors of death, if I would but tenderly place the squirrel there. I found a large stick, and used it to pick up the squirrel. He was freshly dead – not even stiff yet. We walked him to the spot, single file, paying our respects by observing the proper decorum. We wished him farewell, and I tossed him into the puddle. Except that it wasn’t a puddle. Since the uprooted tree was deep in the shadows, the puddle was still ice. The squirrel landed with a loud, wet thump and went skidding across the surface. I turned to the girls, worried about how they might react. They were already bent over, howling with laughter! “Did you hear that wet smack?” “I know – daddy broke a dead squirrel!!!” We ran back to our bikes, and rode off into the dusk. I’ll always remember Riley’s feet pumping furiously and Reagan’s pony tail flowing out behind her as they laughed the last few minutes of the day away.	{ "pile_set_name": "OpenWebText2" }
Ray Horton, ex-secondary coach for the Pittsburgh Steelers and new defensive coordinator for the Arizona Cardinals, did a pretty generous thing recently: he sold his 1999 Mercedes-Benz SL 500 to a long-time cafeteria worker that served the coaches and staff for just $20. The car is worth closer to $17,000 on the open market, so even though it's almost 13 years old and has 64,000 miles on the clock, it's a rather generous parting gift from Horton. As for Maurice "Mo" Matthews, the worker that received the car, he can barely believe his luck. According to ThePostGame, the transfer occurred as Horton stopped by the facility to say goodbye on his way out of town, headed to Arizona. Horton asked Matthews how much money he had on him, and when Matthews replied that he had $20, Horton said, "Sold for $20!" and promptly gave Matthews the keys. Title and paperwork were handled the next morning. The Mercedes-Benz SL-Class recently made some news of its own, with the V-12-powered models quietly slipping from the sales roster as the 2013 redesign looms. [ThePostGame]	{ "pile_set_name": "OpenWebText2" }
We are unable to complete a "prelim" profit or loss statement because of computer coding complications between enpower and portcalc. Two of the I.T. managers are working on it and think that they can complete their "fix" Saturday. They will call me at home with a report on their hopeful success. I will leave you and John L. a voice mail regarding same if it is not completed by Monday.	{ "pile_set_name": "Enron Emails" }
region1description=''The'' center of Chicago for work and play with major corporate headquarters, skyscrapers, shopping, big theaters, parks, beaches, museums and the city's most famous travel sights \| + region1description=''The'' center of Chicago and the entire Midwest for work and play with major corporate headquarters, skyscrapers, shopping, big theaters, parks, beaches, museums, and the city's most famous travel sights \| region2name=North Side \| region2name=North Side \| Revision as of 17:44, 7 April 2014 Chicago is a huge city with several district articles containing sightseeing, restaurant, nightlife and accommodation listings — have a look at each of them. Chicago's skyline viewed from Millennium Park Chicago is located in the Midwest. It is the third largest city in the United States. Chicago is a huge vibrant city and sprawling metropolitan area. It is the home of the blues and the truth of jazz, the heart of comedy and the first builder of the skyscraper. Here, the age of railroads found its center, and airplanes followed. It is one of the world's great cities, and yet the metropolitan luxuries of theater, shopping, and fine dining have barely put a dent in real Midwestern friendliness. It's a city with a swagger, but without the surliness or even the fake smiles that can be found in other cities. As the hub of the Midwest, Chicago is easy to find —its picturesque skyline calls across the waters of huge Lake Michigan, a first impression that soon reveals world-class museums of art and science, miles of sandy beaches, huge parks and public art, and perhaps the finest downtown collection of architecture in the world. With a wealth of iconic sights and neighborhoods to explore, there's enough to fill a visit of weeks or even months without ever seeing the end. Prepare to cover a lot of ground: the meaning of Chicago is only found in movement, through its subways and archaic elevated tracks, and eyes raised to the sky. Districts Many visitors never make it past the attractions in Chicago's large central area, but there are also many attractions to be found in the city's other districts. The city consists of three large Sides (the North Side, the South Side, and the West Side) each named according to its direction from the downtown area, or the Loop as it is called. Each Side contains numerous neighborhoods. Chicagoans tend to identify strongly with their neighborhood within the city, reflecting a real place of home and culture. Districts of Chicago Downtown (The Loop, Near North, Near South)The center of Chicago and the entire Midwest for work and play with major corporate headquarters, skyscrapers, shopping, big theaters, parks, beaches, museums, and the city's most famous travel sights North Side (Lakeview, Boystown, Lincoln Park, Old Town)Upscale neighborhoods with entertainment aplenty in storefront theaters and the Friendly Confines of Wrigley Field, along with a ton of bars and clubs, and one of the largest LGBT communities in the nation Far Southwest Side (Beverly, Mount Greenwood)Ireland in Chicago: authentic Irish pubs, brogues, galleries, and the odd haunted castle, all extremely far from the city center Understand Chicago was known as a fine place to find a wild onion if you were a member of the Potawatomi tribe, who lived in this area of Illinois before European settlers arrived. It was mostly swamps, prairie and mud long past the establishment of Fort Dearborn in 1803 and incorporation as a town in 1833. It could be argued that nature never intended for there to be a city here; brutal winters aside, it took civil engineering projects of unprecedented scale to establish working sewers, reverse the flow of the river to keep it out of the city's drinking supply, and stop buildings from sinking back into the swamps — and that was just the first few decades. By 1871, the reckless growth of the city was a sight to behold, full of noise, Gothic lunacy, and bustling commerce. But on October 8th, Mrs. O'Leary's cow reportedly knocked over a lantern in the crowded immigrant quarters in the West Side, and the Great Chicago Fire began. It quickly spread through the dry prairie, killing 300 and destroying virtually the entire city. The stone Water Tower in the Near North is the most famous surviving structure. But the city seized this destruction as an opportunity to rebuild bigger than before, giving canvas for several architects and urban planners who would go on to become legends of modern architecture. At the pinnacle of its rebirth and the height of its newfound powers, Chicago was known as The White City. Cultures from around the world were summoned to the 1893 World's Columbian Exposition, to bear witness to the work of Louis Sullivan, Daniel Burnham, and the future itself. Cream of Wheat, soft drinks, street lights and safe electricity, the fax machine, and the Ferris Wheel bespoke the colossus now resident on the shores of Lake Michigan. As every road had once led to Rome, every train led to Chicago. Carl Sandburg called Chicago the Hog Butcher for the World for its cattle stockyards and place on the nation's dinner plate. Sandburg also called it the City of the Big Shoulders, noting the tall buildings in the birthplace of the skyscraper — and the city's "lifted head singing so proud to be alive and coarse and strong and cunning." But Chicago is a city in no short supply of nicknames. Fred Fisher's 1922 song (best known in Frank Sinatra's rendition) calls it That Toddlin' Town, where "on State Street, that great street, they do things they don't do on Broadway." It's also referenced by countless blues standards like Sweet Home Chicago. Chicago is also known as The Second City, which refers to its rebuilding after the fire — the current city is literally the second Chicago, after the one that nearly burned down in 1871. The moniker has stuck as Chicago had long-held the position of the nation's second-largest city. And many know the nickname from Chicago's great comedy theater Second City located in Old Town which has supplied countless talent to television's Saturday Night Live and many sitcoms. During the Prohibition era, Chicago's criminal world, emblemized by names like Al Capone, Baby Face Nelson, and later Sam Giancana, practically ran the city. The local political world had scarcely more legitimacy in a town where voter turnout was highest among the dead and their pets, and precinct captains spread the word to "vote early, vote often." Even Sandburg acknowledged the relentless current of vice that ran under the surface of the optimistic city. Chicago is also known as The Windy City. Walking around town, you might suspect that this nickname came from the winds off Lake Michigan which can, on occassion, make for some windy days. Truth be told, Chicago is far from being excessively windy. In fact, according to the United States National Climatic Data Center, Chicago does not rank high on the list of windy cities. The origin of the saying Windy City comes from politics; some saying it may have been coined by rivals like New York City as a derogatory reference; at the time the two cities were battling for the 1893 World's Fair, which Chicago ultimatley won. Others say that the term originated from the city's strong political climate. Finally, the city is also known as the The City That Works as promoted by longtime Mayor Richard M. Daley, which refers to Chicago's labor tradition and its willingness to tackle grand civic projects. Daley and his father, former Mayor Richard J. Daley, ruled the city for decades in what can only be described as a benevolent dictatorship; as other manufacturing cities like Cleveland and Detroit went into decline, Chicago thrived, transforming from a city of factories to a financial giant; which now including the world's largest future exchanges (the Chicago Mercantile Exchange) no less. With Richard M. Daley deciding not to run for mayor again due to his ailing wife, and former White House Chief of Staff Rahm Emanuel resigning from that post to become mayor of Chicago, the city elected its first Daley-less administration with Emanuel since Mayor Richard M. Daley was in office from April 1989 to May 2011. While the city has many great attractions in its huge central/downtown area, lots of Chicagoans live and play outside of the central business district as well. To understand more of Chicago, travelers can venture away from the Loop and Michigan Avenue and out into the vibrant neighborhoods to soak up the local nightlife, sample the wide range of fantastic dining, and see other sights that are also important to Chicagoans. Thanks to the city's massive public transit system, all parts of Chicago are indeed accessible. As far as Chicago's weather goes, well let's just say that Chicago is a huge city so things tend to get blown out of porportion more than they would in other locales, that includes the weather. The city doesn't have weather like Honolulu - then again, what other city does? The winters in Chicago are indeed cold, but then again, so is most of the United States from Maine to Utah, with the exception of the extreme south. A fact; Chicago receives less precipitation (snow and rain) in the winter than East Coast cities like New York City or Boston receive. Chicago's summers are not much hotter than the East Coast, and definitely not as hot as the southern U.S. where there is a nonstop heatwave throughout the summer. There is a good time to be had in any season in Chicago, and the summer offers an array of parades, festivals, and events. The winter months from December to March will see cold temperatures with cold wind chill factors. Snow is usually limited to a handful of heavy storms per season, with a few light dustings in-between and a little more along the lakefront —in the local parlance, that's "lake effect snow". Chicago is a city that's well-accustomed to winter season, so city services and public transportation are highly unlikely to ever shut down. A little-known fact: there are more days with a maximum temperature of 80-84°F (27-29°C) than any other five-degree range, this includes winter months. Chicago's summer days can feel as warm as Honolulu or as humid and sticky as Miami. During any random summer, temperatures in July or August may go above the normal average of 83°F and become hot and humid with dewpoints that can be similar to those found closer to the Gulf of Mexico. However, these heatwaves are not for the entire duration of the summer, but usually in patches of days. Summer nights are usually reasonable and you'll get a few degrees' respite along the lakefront — in the local parlance again, that's "cooler by the lake." Chicago does have several months of nice weather. June and September are very pleasant; April and May are quite fine, although thunderstorms can occur suddenly. July and August are okay as long as a heatwave hasn't hit the entire country. Although there may be a slight chill in the air, October rarely calls for more than a light coat and some days that's not even necessary. And in some years, prolonged mild summer-like temperatures overlap into November. Literature Chicago literature found its roots in the city's tradition of lucid, direct journalism, lending to a strong tradition of social realism. Consequently, most notable Chicago fiction focuses on the city itself, with social criticism keeping exultation in check. Here is a selection of Chicago's most famous works about itself: Karen Abbott's Sin in the Second City is a recent best-seller about Chicago's vice district, the Levee, and some of the personalities involved: gangsters, corrupt politicians, and two sisters who ran the most elite brothel in town. Nelson Algren's Chicago: City on the Make is a prose poem about the alleys, the El tracks, the neon and the dive bars, the beauty and cruelty of Chicago. It's best saved for after a trip, when at least twenty lines will have you enraptured in recognition. Saul Bellow's Adventures of Augie March charts the long drifting life of a Jewish Chicagoan and his myriad eccentric acquaintances throughout the early 20th century: growing up in the then Polish neighborhood of Humboldt Park, cavorting with heiresses on the Gold Coast, studying at the University of Chicago, fleeing union thugs in the Loop, and taking the odd detour to hang out with Trotsky in Mexico while eagle-hunting giant iguanas on horseback. This book has legitimate claim to be the Chicago epic (for practical purposes, that means you won't finish it on the plane). Gwendolyn Brooks' A Street in Bronzeville was the collection of poems that launched the career of the famous Chicago poetess, focused on the aspirations, disappointments, and daily life of those who lived in 1940s Bronzeville. It is long out of print, so you'll likely need to read these poems in a broader collection, such as her Selected Poems. Sandra Cisneros' The House on Mango Street is a Mexican-American coming-of-age novel, dealing with a young Latina girl, Esperanza Cordero, growing up in the Chicago Chicano ghetto. Theodore Dreiser's Sister Carrie is a cornerstone of the turn of the 20th century Chicago Literary Renaissance, a tale of a country girl in the big immoral city, rags-to-riches and back again. Stuart Dybek's The Coast of Chicago is a collection of fourteen marvelous short stories about growing up in Chicago (largely in Pilsen and Little Village) in a style blending the gritty with the dreamlike. John Guzlowski's Lightning and Ashes chronicles the author's experiences growing up in the immigrant and DP neighborhoods around Humboldt Park in Chicago, talking about Jewish hardware store clerks with Auschwitz tattoos on their wrists, Polish cavalry officers who still mourned for their dead horses, and women who walked from Siberia to Iran to escape the Russians. Erik Larson's Devil in the White City is a best-selling pop history about the 1893 Colombian Exposition; it's also about the serial killer who was stalking the city at the same time. For a straight history of the Exposition and also the workers' paradise in Pullman, try James Gilbert's excellent Perfect Cities: Chicago's Utopias of 1893. Audrey Niffenegger's The Time-Traveler's Wife is a recent love story set in Chicago nightclubs, museums, and libraries. Mike Royko's Boss is the definitive biography of Mayor Richard J. Daley and politics in Chicago, written by the beloved late Tribune columnist. American Pharaoh (Cohen and Taylor) is a good scholarly treatment of the same subject. Carl Sandburg's Chicago Poems is without a doubt the most famous collection of poems about Chicago by its own "bard of the working class." Upton Sinclair's The Jungle sits among the canon of both Chicago literature and US labor history for its muckraking-style depiction of the desolation experienced by Lithuanian immigrants working in the Union Stockyards on Chicago's Southwest Side. Richard Wright's Native Son is a classic Chicago neighborhood novel set in Bronzeville and Hyde Park about a young, poor, black boy hopelessly warped by the racism entrenched in American society at the time. Movies Union Station. This train station is used in a scene in the film The Untouchables. Hold on to your baby carriages! Chicago is America's third most prolific movie industry after Los Angeles and New York, and there have been scores upon scores of films amd television series filmed here. Here is a very small list of some very Chicago-centric movies that have been produced in the city. These are just a few: Ferris Bueller's Day Off (John Hughes, 1986). The dream of the northern suburbs: to be young, clever, and loose for a day in Chicago. Ferris and friends romp through the old Loop theater district, catch a game at Wrigley Field, and enjoy the sense of invincibility that Chicago shares with its favorite sons when all is well. Adventures in Babysitting (Chris Columbus, 1987). The flip side of Ferris Bueller — the dangers that await the suburbanite in the Loop at night, including memorable trips to lower Michigan Avenue and up close with the Chicago skyline. The Blues Brothers (John Landis, 1980). Probably Chicago's favorite movie about itself: blues music, white men in black suits, a mission from God, the conscience that every Chicago hustler carries without question, and almost certainly the biggest car chase ever filmed. The Untouchables (Brian De Palma, 1987). With a square-jawed screenplay by David Mamet, this is a retelling of Chicago's central fable of good vs. evil: Eliot Ness and the legendary takedown of Al Capone. No film (except perhaps The Blues Brothers) has made a better use of so many Chicago locations, especially Union Station (the baby carriage), the Chicago Cultural Center (the rooftop fight), and the LaSalle Street canyon. High Fidelity (Stephen Frears, 2000). John Cusack reviews failed relationships from high school at Lane Tech to college in Lincoln Park and muses over them in trips through Uptown, River North, all over the city on the CTA, his record store in the rock snob environs of Wicker Park, and returning at last to his record-swamped apartment in Rogers Park. Batman Begins (Christopher Nolan, 2005) and its sequel The Dark Knight (2008). Making spectacular use of the 'L', the Chicago Board of Trade Building, Chicago skyscrapers, the Loop at night, and lower Wacker Drive, the revived action series finally sets the imposing power and intractable corruption of Gotham City where it belongs, in Chicago. Some others include Harrison Ford vs. the one-armed man in The Fugitive, the CTA vs. true love in While You Were Sleeping, Autobots vs. Decepticons in Transformers 3, the greatest Patrick Swayze hillbilly ninja vs. Italian mob film of all time, Next of Kin, and the humble John Candy film Only The Lonely which captures the south side Irish mentality, the love and comfort of neighborhood dive bars, as well as the Chicago working class, and political power, theme with the repeated line "Sometimes it's good to be a cop". Smoking Smoking is prohibited by state law at all restaurants, bars, nightclubs, workplaces, and public buildings. It's also banned within fifteen feet of any entrance, window, or exit to a public place, and at CTA train stations. The fine for violating the ban can range from $100 to $250. Tourist Information Chicago Water Works Visitor Information Center, 163 E Pearson Ave, ☎+1 877 244-2246, [1]. M-Th 8AM-7PM, F 8AM-6PM, Sa 9AM-6PM, Su 10AM-6PM (closed 1 Jan, 4th Th of Nov (Thanksgiving), 25 Dec). The city's main visitor information center is located on the Magnificent Mile in the historic Pumping Station, across the street from the Water Tower. In addition to extensive free visitor materials, there is a small cafe and a Hot Tix window for discount theater tickets. Get in By plane Chicago (IATA: CHI for all airports) is served by two major airports: O'Hare International Airport[60] and Midway Airport[61]. There are plenty of taxis both to and from the city center, but they are quite expensive, especially during rush hours. Expect upwards of $40 for O'Hare and $30 for Midway. CTA trains provide direct service to both larger airports for $2.25 from anywhere in the city — faster than a taxi during rush hour and a lot less expensive. Many large hotels offer complimentary shuttle vans to one or both airports, or can arrange one for a charge ($15-25) with advance notice. O'Hare O'Hare International Airport (IATA: ORD, ICAO: KORD) is 17 miles (27 km) northwest of downtown and serves many international and domestic carriers. United Airlines[62] has the largest presence here (about 50%) followed by American Airlines[63] with about 40%. Most connecting flights for smaller cities in the Midwest run through O'Hare. It's one of the biggest airports in the world, and it has always been notorious for delays and cancellations. Unfortunately, it's too far northwest for most travelers who get stuck overnight to head into the city. As a result, there are plenty of hotels in the O'Hare area. See the O'Hare article for listings. The CTA Blue Line runs between the Loop and O'Hare every 15 minutes, 24 hours a day and 7 days a week. A lot of repair work has been completed on the Blue line and the trip from O'Hare to the Loop now takes 35-50 minutes. The O'Hare station is the end of the line and is essentially in the basement of O'Hare airport. Walking from the platform to the ticket counters should take 5-10 minutes for Terminals 2 or 3, slightly more for Terminal 1, and a great deal longer for the International Terminal 5 (It is necessary to take the free people mover for transfer). Midway Midway International Airport (IATA: MDW, ICAO: KMDW) is 10 miles (16 km) southwest of downtown. If it's an option for your trip, Midway is more compact, less crowded, has fewer delays, and usually cheaper. And, of course, it's significantly closer to downtown. The CTA Orange Line train runs between the Loop and Midway in around 25 minutes. Keep in mind that the CTA Midway Station is at the end of the Orange Line. There is an enclosed tunnel that links the station and airport but it takes approximately 10-15 minutes to walk from one to the other. There are a number of hotels clustered around Midway, too — see the Southwest Side article for listings. Others Chicago Executive Airport (IATA: PWK, ICAO: KPWK) is nine miles north of O'Hare, serves the general and business aviation sector, and is the third busiest airport in Illinois. Approximately three hundred aircraft are based on the field and approximately 200,000 take-offs and landings occur annually. Air taxi and air charter companies such as Jetset Charter[64] fly a variety of private charter aircraft and jets, from charter luxury Gulfstream's down to economical piston twins for small groups and individuals. Milwaukee's General Mitchell International Airport[65] (IATA: MKE, ICAO: KMKE) is served by 7 Amtrak trains per day (6 on Sunday), and the Hiawatha Service has a 95% on-time rating. The trip from Chicago Union Station to Mitchell Airport Station is about one hour and 15 minutes. There are also buses from Mitchell Airport to Chicago O'Hare Airport. By bus Greyhound, 630 W Harrison St, ☎+1 312 408-5800, [4]. 24 hours. Very frequent service to destinations throughout the Midwest with connections to most of the US, Canada and Mexico. The main terminal is near the southwestern corner of the Loop. There are secondary terminals at the 95th/Dan Ryan red line station and the Cumberland blue line station. Indian Trails, (at the Greyhound Station), [5]. Frequent service to East Lansing, Grand Rapids with onward destinations availible. Daily service to Michigan's Upper Peninsula connecting via Greyhound in Milwaukee. Wifi and power outlets onboard. By train Three-level streets in the Loop Chicago is historically the rail hub of the entire United States. Today, Amtrak[66], ☎ +1 800 872-7245, uses the magisterial Union Station (Canal St and Jackson Blvd) as the hub of its Midwestern routes, making Chicago one of the most convenient U.S. cities to visit by train, serving the majority of the passenger rail company's long-distance routes, with options from virtually every major U.S. city. With its massive main hall, venerable history, and cinematic steps, Union Station is worth a visit even if you're not coming in by train. Most (but not all) Metra suburban trains run from Union Station and nearby Ogilvie/Northwestern Station (Canal St and Madison St), which are west of the Loop. Some southern lines run from stations on the east side of the Loop. The suburban trains run as far as Kenosha, Aurora, and Joliet, while the South Shore line runs through Indiana as far as South Bend. Several CTA buses converge upon the two stations, and the Loop CTA trains are within walking distance. By car Chicagoans refer to some expressways by their names, not the numbers used to identify them on the signs you'll see posted on the U.S. interstate highway system. So you'll have to commit both name and number to memory. I-55 (the Stevenson Expressway) will take you from the southwest city and the southwest suburbs to downtown Chicago. I-90/94 (called The Dan Ryan south of downtown) comes in from Indiana to the east (via the Chicago Skyway - I-90 and Bishop Ford Freeway - I-94) and from central Illinois (via I-57). I-90 (called The Kennedy north of downtown) comes in from the northwest city and northwest suburbs. I-94 (called the Edens Expressway) comes in from the North Side and the northern suburbs to downtown. I-80 runs south of the city in an east-west direction, linking with several north-south expressways. The Illinois tollway, which in addition to I-90, consists of I-88 which serves the west suburbs, I-355 which connects Joliet with Schaumburg, and I-294 - The Tri-State which runs from the South Side to the far Northwest Side and passes next to O'Hare Airport. Be prepared for toll booths off to the right hand side of the tollway which will cost about $1.50 per booth, a much lower cost than you will find on tolls in New York City or the Los Angeles area. When traveling the tollway, always have a few dollars in cash and coins to pay at the booths, which are staffed on mainline toll plazas. If arriving downtown from the south on I-94 or I-90, or from the north on I-90/94, great views can be seen as you approach the downtown skyline. If arriving on I-55 from the southwest, or on I-290 (the Eisenhower Expressway, formerly and sometimes still called The Congress Expressway) from the west, the skyline is also visible. If arriving from north or south on Lake Shore Drive (U.S. Highway 41) a scenic introduction will be provided, day or night, on what has to be the most beautiful thoroughfare in the world. Get around CTA trains route map Navigating Chicago is easy. Block numbers are consistent across the whole city. Standard blocks, of 100 addresses each, are roughly 1/8th of a mile long. (Hence, a mile is equivalent to a street number difference of 800.) Each street is assigned a number based on its distance from the zero point of the address system, the intersection of State Street and Madison Street. A street with a W (west) or E (east) number runs north-south (indicating how many blocks East or West of State St. it falls), while a street with a N (north) or S (south) number runs east-west (indicating how many blocks North or South of Madison St. it falls). A street's number is usually written on street signs at intersections, below the street name. Major thoroughfares are at each mile (multiples of 800) and secondary arteries at the half-mile marks. Thus, Western Ave at 2400 W (3 miles west of State Street) is a north-south major thoroughfare, while Montrose Ave at 4400 N is an east-west secondary artery. In general, "avenues" run north-south and "streets" run east-west, but there are numerous exceptions. (e.g., 48th Street may then be followed by 48th Place). In conversation, however, Chicagoans rarely distinguish between streets, avenues, boulevards, etc. Several streets follow diagonal or meandering paths through the city such as Clark St, Broadway, Milwaukee Ave, Archer Ave, Vincennes Ave, and South Chicago Ave to name a few. Interestingly, many of the angled streets in Chicago (including Archer Ave., Clark Street and Lincoln Ave.) were originally Native American trails established long before Chicago was a city. By public transit The best way to see Chicago is by public transit. It is cheap (basically), efficient (at times), and safe (for the most part). The Regional Transportation Authority (RTA)[67] oversees the various public transit agencies in the Chicagoland area. You can plan trips online with the RTA trip planner[68] or get assistance by calling 836-7000 in any local area code between 5AM-1AM. The RTA also has an official partnership with Google Maps, which can provide routes with public transit. CTA The Chicago Transit Authority (CTA)[69] operates trains and buses in the city of Chicago and some of the suburbs. Put simply, the CTA is Chicago. It is a marvel and a beast, convenient and irreplaceable. Even if you have the option of driving while you're in town, no experience of Chicago is complete without a trip on the CTA. Fares are paid with transit cards, which can be purchased and re-filled at kiosks in the lobby of every CTA station. All accept cash, and some accept credit cards. Many locals use the Chicago Card, which cannot be purchased at stations, but can be ordered online [70] and also purchased at grocery stores and currency exchanges. Visitor passes are sold for unlimited travel on the CTA and Pace: 1 Day (24 hours) for $10; 3 Days for $20; 7 Days for $28 and 30 Days for $100. These passes are on sale at certain train stations (notably, the O'Hare Blue Line station), currency exchanges and some convenience stores, and online [71]. Transit cards for single rides or larger increments can also be purchased online. Unlike many cities' rail system that are set up on zone fares, Chicago's L network, regardless of how many miles you're traveling, only cost $2.25. At many stations, you can transfer to another L line at no additional cost. If you have exited the turnstiles, entering another CTA station or boarding a CTA bus costs an additional $0.25 with your transit card, and transferring a third time is free provided it is still within two hours of when you started the trip. Locals refer to Chicago's public train system as the "L". (Most lines run on el-evated tracks — get it?) All train lines radiate from the Loop to every corner of the city. The "Loop" name originally referred to a surface-level streetcar loop, which pre-dated the elevated tracks. A CTA bus - note the number/destination and symbol for wheelchair accessibility CTA train lines are divided by colors: Red, Green, Brown, Blue, Purple, Yellow, Orange and Pink. All lines lead to the Loop except the Yellow Line, which is a nonstop shuttle between the suburb of Skokie and the northern border of Chicago. The Red and Blue lines run 24/7, making Chicago and New York City the two American cities that offer 24-hour rail service running throughout their city limits. Hours for the other lines vary somewhat by the day, but as a general rule run from about 4:30AM -1:00AM. Before you travel, find out the name of the train station closest to your destination, and the color of the train line on which it is located. Once you're on-board, you'll find route maps in each train car, above the door. The same map is also available online [72]. The name signs on platforms often have the station's location in the street grid, e.g. "5900 N, 1200 W" for Thorndale. There should be an attendant on duty at every train station. They cannot provide change or deal with money, but they can help you figure out where you need to go and guide you through using the machines. A CTA bus stop: note the symbols for wheelchair accessibility and late-night hours. Buses run on nearly every major street throughout the entire city, and in many cases, every four blocks apart. Look for the blue and white bus stop sign, which should show the route that the bus will take. Once inside, watch the front of the bus, a red LED display will list the names of the streets as they pass by, making it easy to know that your stop is approcahing if you're unfamiliar with the city. Rides of any length cost $2 with a transit card or Chicago Card or $2.25 in cash. Chicago has a large and comprehensive bus system, and buses typically run frequently. This allows Chicagoans to go to bus stops and wait for the bus without even looking at bus schedules, as buses usually run every few minutes apart. The major bus routes run every 7-15 minutes apart during the morning and afternoon hours. In the evening, these same routes run about every 15-20 minutes apart. The less traveled bus routes may run about 15-20 minutes apart during the day. There are many bus routes that run 24 hours a day; these are called OWL routes and the bus stop sign usually has a picture of an owl to belabor that point. Overnight OWL service is approximately every 30 minutes. (See individual district articles for major bus routes through different parts of the city.) If you have a web-enabled mobile device, the CTA runs a little godsend called the CTA Bus Tracker[73], which uses GPS to provide reliable, real-time tracking information for almost all bus routes. CTA buses accept transit cards but do not sell them. They also accept cash but do not provide change. Like any bus system, you pay exact fare or forfeit your change. In compliance with the Americans With Disabilities Act, all CTA buses and some train stations are accessible to wheelchairs. Wheelchair-accessible 'L' stations are indicated by the international wheelchair symbol and have elevators or are at ground level. If you are trying to get to a place with a non-accessible station, there will be alternate routes by bus so contact the CTA for more information. Crime on the CTA is low, but as with any major urban area, travelers should be aware of their surroundings, especially when traveling in the wee hours of the night. Some L cars have a button and speaker for emergency communication with the driver, located in the center aisle of the car on the wall next to the door. This is for emergencies only: do not press this just to ask questions, as the driver is required to halt the train until the situation has been confirmed as resolved, and your fellow passengers will not be amused. On Monday, March 24, 2014, a CTA Blue line train heading to the O'Hare Station derailed from its tracks and crashed into the O'Hare Blue Line station. The train landed on an escalator in the station and injured more than 30 people. As CTA officials continue their investigation, they have come to the conclusion that the train was not speeding but the CTA employee in charge of the trains controls may have fallen asleep. Metra and South Shore Metra train on the way to the Loop Metra system map Metra[74], ☎ +1 312 322-6777, runs commuter trains for the suburbs, providing service within Illinois, to Kenosha, Wisconsin, out west, and to the South Shore railroad, which provides service to South Bend, Indiana. Metra trains are fast, clean, and punctual, but unpleasantly crowded during rush hour. Generally, every car or every other car on the train has a bathroom. Metra's Electric Line provides service to the convention center (McCormick Place), Hyde Park (Museum of Science and Industry, University of Chicago), and the Far Southeast Side's Pullman Historic District and Rainbow Beach. The Electric Line is fast, taking at most 15 minutes to reach Hyde Park from the Loop. Unfortunately, service outside of rush hours is infrequent (about once/hour), so be sure to check the schedules while planning your trip. Although there are plans to change this in the future, none of the commuter trains currently accept CTA transit cards as payment. The fare to McCormick Place and Hyde Park, however, is only $2. Buy your tickets before boarding the train at a window or one of the automated vending machines. You can buy a ticket on the train, but that comes with an extra $3/ticket surcharge if the station you're leaving from had an open ticket window or an operational ticket machine. Ten-ride, weekly, and monthly passes are available. If you have a group of four or more people, it may be cheaper to purchase a ten-ride card and have all of your fares punched from that one card. If using Metra on Saturday and/or Sunday, you can purchase an unlimited ride weekend pass for just $7. Keep in mind that Metra only accepts cash at this time. Pace Pace[75] runs buses in the suburbs, although some routes do cross into the city, particularly in Rogers Park at the Howard (Red/Purple/Yellow Line) CTA station and the Far Northwest Side at the Jefferson Park (Blue Line) CTA station. Pace provides paratransit services should you need to go somewhere inconvenient via CTA. By car Avoid driving in downtown Chicago if at all possible. Traffic is heavy and garages in the Loop can cost as much as $35 per day. Free websites like ParkWhiz.com [76] and ParkingPanda.com [77]let you book off-street parking in advance after searching by location and price, which is often discounted. Other sites like ChiParking.com [78] provide tips about where to park in different parts of the city. Although downtown streets are laid out on the grid, some streets have multiple levels which can confuse even the most hardened city driver. Even outside of the city center, street parking may not be readily available. If you do find a spot, check street signs to make sure that a) no residential permit is required to park, and b) parking is not disallowed during certain hours for street cleaning, rush hour or something along those lines. Parking restrictions are swiftly enforced in the form of tickets and towing — be especially wary during snowy weather. On-street parking is handled by one-per-block kiosks, which will issue a slip for you to put in your front window. The kiosks will accept cash or credit cards. If the kiosk fails for any reason (such as the printer running out of paper), there should be a phone number to call to report it and ensure you don't receive a ticket. Be advised: talking on a handheld cell phone while driving is illegal, and the police will write you a much-deserved ticket as this action puts many people's lives in danger. If you need to take or make a call, use a hands-free headset — or better yet, pull over. Drivers on the city expressways can be very aggressive. For those used to driving on expressways in the Northeast US or Southern California, this may simply be a reminder of home. For everyone else, though, it may be intimidating. By taxi Your Name Here As in most cities, "naming rights" are all the rage. While official city tourism guides rush to comply, using the new names will earn an eye roll or an oblivious look from most Chicagoans (and cab drivers). A few of the worst offenders: Sears Tower — 36 years after it was built, the Western Hemisphere's tallest building was redubbed the Willis Tower. For most Chicagoans, however, it is still and will always be the Sears Tower. Comiskey Park — Winning the city's first World Series in nearly a century helped earn some acceptance for the "U.S. Cellular Field" moniker (nicknamed "the Cell"), but it's still regarded as profanity by the old-timers in Bridgeport, where the first Comiskey Park was built in 1910. Hollywood Beach — The favorite beach of Chicago's gay and lesbian community was renamed Kathy Osterman Beach for one of the mayor's Edgewater-based political friends who died of cancer. But more than a decade later only city signage knows it by that name; everyone else still calls it by its original name, Hollywood Beach. Chicago has some of the least expensive taxi fares in the U.S. for a major city. Taxis can be hailed from the street throughout the entire city, and are most plentiful in the tourist areas. Rates are regulated by the city; fares are standard and the initial charge ("flag pull") is $2.25 for the first 1/9 mile, then $0.20 for each additional 1/9 mile or $0.20 for each elapsed 36 seconds. There is a $1.00 fuel surcharge added to the initial charge. There is also a flat $1.00 charge for the second passenger, and then a $0.50 charge for each additional passenger after that (for example, if four people take a taxi together, there will be $2.00 in additional flat fees). Rides from O'Hare and Midway to outer suburbs cost an additional 50% over the metered fee. Give the driver the nearest major intersection to which you are heading (if you know it) and then the specific address. There is no additional charge for baggage or credit card use, although some drivers discourage credit card payments if the distance traveled is short. If you are outside of Downtown, North Side, Near West, or Near South neighborhoods, it may be mless easy to find cabs from the street and easier just to call one. Taxis typically take 10-15 min from the time you call to arrive. The principal companies are: The above applies only to Chicago taxis. Suburban taxi cabs have their own fares and rates, depending on the laws and regulations of the town in which they are based. By bicycle Chicago has a bike path along the shores of Lake Michigan, making north-south travel very convenient as long as the weather is favorable by the lake. Most major city streets have bike lanes, and the biking culture is established enough that cars tend to accommodate and (grudgingly) yield to bicycles. Bike trips can also be combined with rides on the CTA. See the bicycling section below for more details. By water taxi In the summer, water taxis are sometimes more convenient than the CTA, if you are traveling around the fringes of downtown. They are also a relatively cheap way to take in some offshore views. Two private companies operate water taxi services around the Loop. Museums Penguin triumphant, Lincoln Park Zoo Chicago's set of museums and cultural institutions are among the best in the world. Three of them are located within a short walk of each other in the Near South, on what is known as the Museum Campus, in a beautiful spot along the lake: the Adler Planetarium, with all sorts of cool hands-on space exhibits and astronomy shows; the Field Museum of Natural History, which features SUE, the giant Tyrannosaurus Rex skeleton, and a plethora of Egyptian treasures; and the Shedd Aquarium, with dolphins, whales, sharks, and the best collection of marine life east of California. A short distance away, in Hyde Park, is the most fun of them all, the Museum of Science and Industry — or, as generations of Chicago-area grammar school students know it, the best field trip ever. In the Loop, the Art Institute of Chicago has a handful of iconic household names among an unrivaled collection of Impressionism, modern and classical art, and tons of historical artifacts. And in Lincoln Park, a short trip from the Loop, the cheerful (and free) Lincoln Park Zoo welcomes visitors every day of the week, with plentiful highlights like the Regenstein Center for African Apes. Also, Chicago has some knockout less well-known museums scattered throughout the city like the International Museum of Surgical Science and the Loyola University Museum of Art in Gold Coast, Chicago History Museum in Lincoln Park, DuSable Museum of African American History in Washington Park, National Museum of Mexican Art in Pilsen, the Polish Museum of America in Wicker Park, the Museum of Photography in the Loop, and the Driehaus Museum in Near North. The University of Chicago, in Hyde Park, has several cool (and free) museums that are open to all visitors, showcasing a spectacular collection of antiquities and modern/contemporary art. Discount packages like the Chicago CityPASS[83] can be purchased before you arrive in town. They cover admission to some museums and other tourist attractions, allowing you to cut to the front of lines, and may include discounts for restaurants and shopping. Also, programs such as Bank of America's Museums to Go offer free admission at multiple Chicago museums for designated times which can save you a small fortune on admission fees. Architecture From the sternly classical to the space-age, from the Gothic to the coolly modern, Chicago is a place with an embarrassment of architectural riches. Frank Lloyd Wright fans will swoon to see his earliest buildings in Chicago, where he began his professional career and established the Prairie School architectural style, with numerous homes in Hyde Park/Kenwood, Oak Park, and Rogers Park — over 100 buildings in the Chicago metropolitan area! Frank Lloyd Wright learned his craft at the foot of the lieber meister, Louis Sullivan, whose ornate, awe-inspiring designs were once the jewels of the Loop, and whose few surviving buildings (Auditorium Theater, Carson Pirie Scott Building, one in the Ukrainian Village) still stand apart. The 1871 Chicago Fire forced the city to rebuild. The ingenuity and ambition of Sullivan, his teacher William Le Baron Jenney (Manhattan Building), and contemporaries like Burnham & Root (Monadnock, Rookery) and Holabird & Roche/Root (Chicago Board of Trade) made Chicago the definitive city of their era. The world's first skyscrapers were built in the Loop as those architects received ever more demanding commissions. It was here that steel-frame construction was invented, allowing buildings to rise above the limits of load-bearing walls. Later, Mies van der Rohe would adapt Sullivan's ethos with landmark buildings in Bronzeville (Illinois Institute of Technology) and the Loop (Chicago Federal Center). Unfortunately, Chicago's world-class architectural heritage is almost evenly matched by the world-class recklessness with which the city has treated it, and the list is long of masterpieces that have been needlessly demolished for bland new structures. Today, Chicago boasts three out of America's five tallest buildings: the Sears Tower (1st), the Trump Tower (2nd), and the Aon Center (5th) (although the local favorite is actually #6: the John Hancock Center). For years, the Sears Tower was the tallest building in the world, but it has since lost the title. Various developers insist they're bringing the title back with proposed skyscrapers. Until they do, Chicago will have to settle for having the tallest building in the Western Hemisphere with the Sears Tower, although the Hancock has a better view and is quite frankly better-looking. Chicago is particularly noted for its vast array of sacred architecture, as diverse theologically as it is artistically. There were more than two thousand churches in Chicago at the opening of the twenty-first century. Of particular note are the so-called Polish Cathedrals like St. Mary of the Angels in Bucktown and St. Hyacinth Basilica in Avondale, as well as several treasures in Ukrainian Village — beautifully crafted buildings with old world flourishes recognized for their unusually large size and impressive scope. Architectural tours cover the landmarks on foot and by popular river boat tours, or by just standing awestruck on a downtown bridge over the Chicago River; see individual district articles for details. For a tour on the cheap, the short trip around the elevated Loop train circuit (Brown/Purple Lines) may be worth every penny of the $2 fare. African-American history Chicago's African-American history begins with the city's African-American founder, Jean Baptiste Pointe du Sable. Born to a Haitian slave and a French pirate, he married a woman from the Potawatomi tribe, and built a house and trading post on the Chicago River on the spot of today's Pioneer Court (the square just south of the Tribune Tower in the Near North). Du Sable lived on the Chicago River with his family from the 1770s to 1800, when he sold his house to John Kinzie, whose family and friends would later claim to have founded the city. Relative to other northern cities, African-Americans constituted a fairly large part of Chicago's early population because of Illinois' more tolerant culture, which was inherited from fervent anti-slavery Mormon settlers. As a non-slave state generally lacking official segregation laws, Illinois was an attractive place to live for black freedmen and fugitive slaves. By the 1920s, Chicago had a thriving middle class African-American community based in the Bronzeville neighborhood, which at the time became known as "The Black Metropolis," home to a cultural renaissance comparable to the Harlem Renaissance of New York. African-American literature of the time was represented by famous and local poetess Gwendolyn Brooks and the novelist Richard Wright, most famous for his Native Son, nearly all of which takes place in Chicago's Bronzeville and Hyde Park/Kenwood. The Chicago school of African-American literature distinguished itself from the East Coast by its focus on the new realities of urban African-American life. Chicago became a major center of African-American jazz, and the home for the blues. Jazz great Louis Armstrong got his start there; other famous black Chicagoans of the day included Bessie Coleman — the world's first licensed black pilot, the hugely influential African-American and women's civil rights activist Ida B. Wells, the great pitcher/manager/executive of Negro League Baseball Andrew "Rube" Foster, and many more. Helping to fuel Chicago's black renaissance was one of the single most influential parts of African-American history: the Great Migration. African-Americans from the South moved to the industrial cities of the North (particularly Chicago) due to the post-WWI shortage of immigrant industrial labor, and to escape the Jim Crow Laws and racial violence of the South. The massive wave of migrants increased Chicago's black population alone by more than 500,000. With it came southern food, Mississippi blues, and the challenges of establishing adequate housing for so many recent arrivals. Black Chicago's renaissance was halted momentarily, as was the entire world, by the Great Depression. In 1937 came the creation of the Chicago Housing Authority which sought to build affordable public housing for the city. However well-intentioned, the results were not well. The largest housing projects by far were the 1940 Ida B. Wells projects; the Cabrini Green projects, which developed a reputation as the most violent housing projects in the nation , and the massive 1962 Robert Taylor Homes which stretched for several miles. In the beginning, the housing projects were indeed decent. As the years past, unsavory people and less maintenance proved to be the downfall of the projects. The Black Metropolis was unable to cope with this development and surrounding neighborhoods fell with it. Today, the city has torn down most of these structures and replaced them with lower rise, mixed used buildings; which has shown to have more success than the previous dwellings. Further damaging to Chicago's black population was the phenomenon of "white flight" that took place across the nation. Unwilling to live beside black neighbors, many white Chicagoans fled desegregation to the suburbs. This trend was accelerated by the practice of "blockbusting," where unsavory real estate agents would fan racist fears in order to buy homes on the cheap. As a result, most of Chicago neighborhoods never truly integrated at that time, and the social, educational, and economic networks that incoming non-whites had hoped to join disintegrated in the wake of fleeing white citizens. Today, integration has come a long way and integration exists in many Chicago neighborhoods including the communities on the entire eastern half of the North Side that border the lakefront, as well as communities such as Hyde Park/Kenwood, Logan Square, Little Italy, Auburn Gresham, Beverly, and Hegewisch. However, there are still parts of the city that are predominantly composed of one race. In 1966, Dr. Martin Luther King, Jr. decided to come north and chose Chicago as his first destination. However, from the moment of his arrival on the Southwest Side, King was utterly confounded. The death threats that followed his march through Marquette Park were challenge enough, but nowhere in the South was there a more expert player of politics than Chicago's Mayor Richard J. Daley. King left town frustrated and exhausted, but Rev. Jesse Jackson continued civil rights efforts in Chicago through his Operation PUSH. The 1983 election of Mayor Harold Washington, the first black mayor of Chicago, was a watershed event for Chicago's African-American population, and although long battles with obstructionist and racist white politicians lay ahead, it marked the moment when Black elected officials became major, independent forces in Chicago. Today, comprising well over a third of the city, Chicago's black population is the country's second largest in overall numbers, after New York City. However, blacks make up a larger percentage of Chicago than they do of New York City. The large South Side is the cultural center of Chicago's black community. The South Side along with the adjoining south suburbs constitutes the largest single Black region in the entire country, and boasts the country's greatest concentration of black-owned businesses. Some Chicagoans and outsiders from other parts of the country who are ignorant of this area may tell you that it is dangerous. North Siders in general do not think much of the West Side or the South Side (similar to the way Manhattanites in New York City do not think much of the other four boroughs of that city). Although the West Side of Chicago does contain many economically challenged neighborhoods, the reality of the South Side is more complex. On the South Side there are affluent, middle class, and economically challenged neighborhoods. Affluent and upper-middle class areas on the South Side include the South Loop, Hyde Park/Kenwood, upper Bronzeville, Chatham, South Shore, Beverly, Mount Greenwood, West Lawn, and western Morgan Park. Chicago is a very large city and the South Side is large, thus, many people outside the South Side may not be familiar with these affluent/upper-middle class areas on the South Side. The local newscasts also have a bad habit: When a crime happens on the North Side, the commentator will put emphasis on the neighborhood in which it happened, as to not give the entire North Side a bad image. However, when a crime happens on the South Side, the emphasis is put on South Side, thus giving the entire South Side a bad image. For those interested in African-American history, Bronzeville is a top destination. The Kenwood area also boasts interesting recent history, as it has been (or is) home to championship boxer Muhammad Ali, Nation of Islam leaders Elijah Muhammad and Louis Farrakhan, and President Barack Obama. No one should miss the DuSable Museum of African-American History in Bronzeville, adjancent to Hyde Park, the first museum of African-American history in the United States. And if your interest is more precisely in African-American culture than history, head down to Chatham and South Shore to enter the heart of Chicago's black community. Ethnic neighborhoods Wentworth Ave, Chinatown's main street Chicago is among the most diverse cities in America, and many neighborhoods reflect the character and culture of the immigrants who established them. Some, however, do more than just reflect: they absorb you in a place that, for several blocks at a time, may as well be a chunk of another country, picked up and dropped near the shores of Lake Michigan. The best of Chicago's ethnic neighborhoods are completely uncompromised, and that makes them a real highlight for visitors. Chicago's Chinatown is among the most active Chinatowns in the world. It even has its own stop on the CTA Red Line. It's on the South Side near Bridgeport, birthplace of the Irish political power-brokers who have run Chicago government for most of the last century. More Irish communities exist on the Far Southwest Side, where they even have an Irish castle to seal the deal. The Southwest Side houses enormous populations of Polish Highlanders and Mexicans, as well as reduced Lithuanian and Bohemian communities. No serious Chicago gourmand would eat Indian food that didn't come from a restaurant on Devon Avenue in Rogers Park. It's paradise for spices, saris, and the latest Bollywood flicks. Lawrence Avenue in Albany Park is sometimes called Seoul Drive for the Korean community there, and the Persian food on Kedzie Avenue nearby is simply astonishing. At the Argyle Red Line stop, by the intersection of Argyle and Broadway in Uptown, you'd be forgiven for wondering if you were still in America; Vietnamese, Thais, and Laotians share space on a few blocks of restaurants, grocery stores, and even dentists. Neither the Swedish settlers who built Andersonville or the Germans from Lincoln Square are the dominant presence in those neighborhoods any more, but their identity is still present in restaurants, cultural centers, and other small discoveries to be made. Likewise, Little Italy and Greektown on the Near West Side survive only as restaurant strips. A more contemporary experience awaits in Pilsen and Little Village, two neighborhoods on the Lower West Side where the Spanish signage outnumbers the English; in fact, Chicago has the second largest Mexican and Puerto Rican populations outside of their respective home countries. Pilsen and its arts scene is an especially an exciting place to visit. It's hard to imagine displacement being a concern for the Polish community on the city's Far Northwest and Southwest sides. The Belmont-Central business district is what you might consider the epicenter of Polish activity,. Bars, restaurants, and dozens of other types of Polish businesses thrive on this strip, and on a smaller section of Milwaukee Avenue (between Roscoe and Diversey) in the vicinity of St. Hyacinth Basilica which bears the Polish name of Jackowo- Chicago's Polish Village. Polish Highlanders, or Górals, on the other hand dominate the city's Southwest Side with a cuisine and culture that is decidedly Balkan. A host of restaurants and cultural institutions visibly display the rustic touch of their Carpathian craft such as the Polish Highlanders Alliance of North America at Archer Avenue just northeast of its intersection with Pulaski Road.Taste of Polonia, held over Labor Day weekend on the grounds of the Copernicus Foundation at the historic Gateway Theatre, draws an annual attendance of about 50,000 people and is touted as the city's largest ethnic fest. Do Shedd Aquarium (Shedd Aquarium), 1200 S. Lake Shore Dr. Chicago, IL 60605, ☎(312) 939-2438, [8]. 9 am - 5pm. Chicago's Shedd Aquarium is the city's premier location for aquatic life and family fun! With over 32,000 creatures, ranging from fish to crustaceans and everything in between, Shedd is the perfect place for children to learn and inspire curiosity about oceanic and aquatic life! Various exhibits include Aquatic Shows, Amazon Rising, Caribbean Reef, Jellies, Abbott Oceanarium, Polar Play Zone, Waters Of The World, Wild Reef, and A Holiday Fantasea. Come see us today!Adults - $8, Children - $6. (41.8676° N,87.6140° W) Beaches The five Great Lakes together form the largest mass of freshwater on Earth, containing 21% of the world's surface fresh water alone, and Chicagoans enjoy flocking to the beaches of Lake Michigan. Chicago has great beaches and anyone can show up and swim. There are no admission fees on the city's miles upon miles of beaches, and nearly the entire waterfront is open as public beach and parkland; what amounts to terrific planning by the city. The water is quite warm in the summer and early fall (check with the NOAA for temperatures [84]). The Chicago shore has been called the second cleanest urban waterfront in the world, and that's really saying something for a metropolitan area of nearly 10 million people. Bacteria levels in the water do force occasional closures, but they are very rare. Lifeguards will be posted when the beach is officially open. Oak Street Beach and North Avenue Beach (in the Near North and Lincoln Park) are the fashionable places to sun-tan and be seen and are usually crowded due to their proximity to downtown and area hotels. Rogers Park, Edgewater, and 35th Street Beach allow visitors more individual space and an enjoyable vibe as well. Hyde Park's Promontory Point is beautiful, and offers skyline views from its submerged beach by the rocks, although a swim there is technically against city rules. Hollywood Beach in Edgewater is the main gay beach. Montrose Beach in Uptown is the city's largest beach and hosts a large dog beach and a full service, outdoor restaurant in addition to July 3 fireworks and a variety of live music events. A large bird sanctuary and one of the few hills in Chicago are also located near Montrose Beach. Volleyball tournaments are occassionally held at Chicago beaches. The city has 33 beaches of various sizes within the city limits alone. There are additional beaches in the northern suburbs as well. Parks The Osaka Garden on Jackson Park's Wooded Isle Where there are beaches, there are waterfront parks. During the summer months, the parks are a destination for organized and impromptu volleyball and soccer games, chess matches, and plenty more, with tennis and basketball courts dotted along the way. There are also terrific parks goin inland. In the Loop, Grant Park hosts music festivals throughout the year, and Millennium Park is a fun destination for all ages, especially during the summer. In Hyde Park, Midway Park offers skating, and summer and winter gardens in the shadow of the academic giant, the University of Chicago, and Jackson Park has golf, more gardens and the legacy of the city's shining moment, the 1893 World's Colombian Exposition. In Bronzeville, Washington Park is one of the city's best places for community sports. And that's just a brief overview. Almost every neighborhood in Chicago has a beloved park. Chicago is also in the development stages of creating the Bloomingdale Trail. This is a linear park in the sky. This elevated greenway, created from railroad right-of-ways and its viaducts, will be nearly 3 miles long, running through several Chicago neighborhoods, and complete with walking paths, bike lanes, benches, flowers and plants. This linear park over former rail lines will be the third such type in the entire world, after a nearly 3 mile long version in Paris, and a 1 mile long version in New York City. Events & Festivals If you're absolutely determined and you plan carefully, you may be able to visit Chicago during a festival-less week. It's a challenge, though. Most neighborhoods, parishes, and service groups host their own annual festivals throughout the spring, summer, and fall [85]. And the city has several in the winter. There are a few can't-miss city-wide events, though. In the Loop, Grant Park hosts Taste of Chicago in July, the largest outdoor food festival in the world; and there are four major music festivals: Blues Fest and Gospel Fest in June, Lollapalooza in August, and Jazz Fest in September. All but Lollapalooza are free. The Chicago-based music website Pitchfork Media also hosts their own annual three day festival of rock, rap, and more in the summer at Union Park on the Near West Side. Sports With entries in every major professional sports league and several universities in the area, Chicago sports fans have a lot to keep them occupied. The Chicago Bears play football at Soldier Field in the Near South from warm September to frigid January. Since the baseball teams split the city in half, nothing seizes the Chicago sports consciousness like a playoff run from the Bears. Aspiring fans will be expected to be able to quote a minimum of two verses of the Super Bowl Shuffle from memory, tear up at the mention of Walter Payton, and provide arguments as to how Butkus, Singletary, and Urlacher represent stages in the evolution of the linebacker, with supporting evidence in the form of grunts, yells, and fists slammed on tables. The Chicago Bulls play basketball at the United Center on the Near West Side. They are an exciting team to watch, led by star Derrick Rose. The Chicago Blackhawks share quarters with the Bulls. As one of the "Original Six" teams in professional hockey, the Blackhawks have a long history in their sport, and the team is experiencing a renaissance after capturing the Stanley Cup in 2010 for the first time in 49 years and winning their second championship in four seasons in 2013. Home games for both teams tend to sell out, but tickets can usually be found if you check around. Both the Bulls and the Blackhawks play from the end of October to the beginning of April. It's baseball, though, in which the tribal fury of Chicago sports is best expressed. The Chicago Cubs play at Wrigley Field ( It is the oldest National League ballpark and the second oldest active major league ballpark) on the North Side, in Lakeview, and the Chicago White Sox play at U.S. Cellular Field (Comiskey Park, underneath the corporate naming rights) on the South Side, in Bridgeport. Both franchises have more than a century's worth of history, and both teams play 81 home games from April to the beginning of October. Everything else is a matter of fiercely held opinion. The two three-game series when the teams play each other are the hottest sports tickets in Chicago during any given year. If someone offers you tickets to a game, pounce. There are plenty of smaller leagues in the city as well, although some play their games in the suburbs. The Chicago Fire (Major League Soccer) and Chicago Red Stars (Women's Professional Soccer) play soccer in the suburb of Bridgeview, the Chicago Sky play women's professional basketball at the UIC Pavilion on the Near West Side, and the Windy City Rollers skate flat-track roller derby in neighboring Cicero. Minor league baseball teams dot the suburbs as well. While college athletics are not one of Chicago's strong points, Northwestern football (in Evanston) and DePaul basketball (off-campus in Rosemont) show occasional signs of life. If you find yourself in Hyde Park, ask someone how the University of Chicago football team is doing — it's a surefire conversation starter. Theater The Gateway Theatre in Jefferson Park, seat of the Copernicus Foundation. The theater's Baroque spire is a replica of the Royal Castle in Warsaw. Modern American comedy — the good parts, at least — was born when a group of young actors from Hyde Park formed The Compass Players, fusing intelligence and a commitment to character with an improvisational spark. One strand of their topical, hyper-literate comedy led, directly or indirectly, to Shelly Berman, Mike Nichols & Elaine May, Lenny Bruce, MAS*H and The Mary Tyler Moore Show; another strand, namely The Second City, led to Saturday Night Live and a pretty huge percentage of the funny movies and television of the last thirty years. Still in Chicago's Old Town (and few other places as well), still smart and still funny, Second City does two-act sketch revues followed by one act of improv. If you only see one show while you're in Chicago, Second City is a good choice. Improvisational comedy as a performance art form is a big part of the Chicago theater scene. At Lakeview and Uptown theaters like The Annoyance Theater, I.O., and The Playground, young actors take classes and perform shows that range from ragged to inspired throughout the week. Some are fueled by the dream of making the cast of SNL or Tina Fey's latest project, and some just enjoy doing good work on-stage, whether or not they're getting paid for it (and most aren't). There's no guarantee that you'll see something great on any given night, but improv tends to be cheaper than anything else in town, and it can definitely be worth the risk. Another popular theater experience is the comedy/drama hybrid Too Much Light Makes The Baby Go Blind, offering 30 plays in 60 minutes every weekend in Andersonville. Steppenwolf, in Lincoln Park, is Chicago's other landmark theater. Founded in 1976, they have a history of taking risks onstage, and they have the ensemble to back it up, with heavyweights like Joan Allen, John Malkovich, and Gary Sinise. Steppenwolf isn't cheap any more, but they mix good, young actors with their veteran ensemble and still choose interesting, emotionally-charged scripts. It's the best place in town to see modern, cutting-edge theater with a bit of "I went to..." name-drop value for the folks back home. Most of the prestige theaters, including the Broadway in Chicago outlets, are located in the Loop or the Near North. Tickets are expensive and can be tough to get, but shows destined for Broadway like The Producers often make their debut here. For the cost-conscious, the League of Chicago Theatres operates Hot Tix[86], which offers short-notice half-price tickets to many Chicago shows. One theater to see, regardless of the production, is The Auditorium in the Loop. It's a masterpiece of architecture and of performance space. Designed by Dankmar Adler and Louis Sullivan, who were on a commission from syndicate of local business magnates to bring some culture to the heathen city, it was the tallest building in Chicago and one of the tallest in the world at the time of its opening in 1889, and it's still an impressive sight, inside and out. Bicycles Chicago has a strong, passionate bicycle culture, and riding opportunities abound. Pedaling your way around the city is one of the best ways to get to know Chicago. And the terrain is mostly flat — a boon for easy-going cyclists! If you don't have a bike, that's no problem. Bobby's Bike Hike[87] has the official city concession, with a central bike rental location near Navy Pier, at the old North Pier at 465 N. McClurg Court. In June 2013, the Divvy bikeshare system [88] launched in Chicago. Tourists can buy a 24-hour pass that includes an unlimited number of 30-minute rides for $7. The scenic Lakefront Trail runs for 18 continuous miles along the city's beautiful shoreline, from Hollywood Beach in Edgewater to the magnificent South Shore Cultural Center. Even while riding at a moderate pace, traveling downtown along the lakefront can be faster than driving or taking the CTA! If you're starting from downtown, you'll be at the approximate midpoint of the trail. Head south if you want a speed workout with fewer crowds, or north to see more of the locals at play. Further inland, many streets have bike lanes, and signs direct riders to major bike routes. The City of Chicago maintains helpful bicycle resources online[89], including major civic bike events and (slow) interactive maps of major streets with bike lanes. Bicyclists have to follow the same "rules of the road" as automobiles (stop at red lights and stop signs, etc). Bicycle riding is not allowed on sidewalks (except for children under age 12). This rule is strictly enforced in higher density neighborhoods, mostly areas near the lake, and is considered a criminal misdemeanor offense. You must walk your bike on the sidewalk. CTA buses are all equipped with front bike racks, which carry up to two bicycles, and 'L' trains permit two bicycles per car except during rush hour (roughly 7-9:30AM and 3:30-6:30PM weekdays, excluding major holidays on which the CTA is running on a Sunday schedule). With the buses, inspect the rack closely for wear or damage and be absolutely certain that the bike is secured before you go, lest it fall off in traffic (and be immediately flattened by the bus). The CTA will fight tooth and nail to avoid reimbursing you for the loss, and the driver might not stop to let you retrieve it. Bikes may be rented from the North Avenue Beach House (Lincoln Park), Navy Pier, (Near North), the Millennium Park bike station (Loop), and from several bike shops in the city. Another option is to contact the terrific Working Bikes Cooperative[90], an all-volunteer group of bike lovers that collects and refurbishes bikes, and then sells a few in Chicago to support their larger project of shipping bikes to Africa and South America. You could buy a cheap bike and donate it back when you're done, or even spend a day or two working as a volunteer. For an opportunity to connect with the local bike community and take a memorable trip through the city, don't miss the Critical Mass[91] rides on the last Friday of every month, starting from Daley Plaza in the Loop (5:30PM). With numbers on their side, the hundreds or even thousands of bike riders wind up taking over entire streets along the way, with themed routes that are voted upon at the outset of the trip. Anyone is free to join or fall away wherever they like. Police are generally cooperative — take cues from more experienced riders. Learn Several major and minor universities call Chicago home. The University of Chicago and Northwestern University are undoubtedly the most prestigious among them. The University of Chicago's Gothic campus is in Hyde Park, which is, famously, "home to more Nobel Prizes per square kilometer than any other neighborhood on Earth." Further north, in the Bronzeville area, is the Illinois Institute of Technology, which has notable programs in engineering and architecture. Northwestern University has its main campus in Evanston, just north of Chicago, but it also has campuses in the Near North off Michigan Ave, including its medical, law, and business schools. On the North Side, there are two major Catholic universities with over a hundred years in Chicago: DePaul University, in Lincoln Park, and Loyola University, in Rogers Park. Both schools also have campuses in the Loop. Rush University Medical School, on the Near West Side, traces its roots back even further, to 1837. Dating back to 1891, North Park University serves as another fine private liberal arts university in Albany Park on the Northwest Side. A handful of schools in the Loop attract students in the creative arts. Columbia College has an enviable location on Michigan Avenue, and its programs in film are continually noted as one of the top in the nation, along with its programs in creative writing and photography which are also are well-regarded. The School of the Art Institute is generally regarded as one of the top three art and design schools in the country and is one of the few art schools that does not require its students to declare majors. The Illinois Institute of Art specializes in different fields of art and design, with a top-notch culinary program. The main campus of Roosevelt University, former home to Chicago heavyweights like Harold Washington and Ramsey Lewis, is in the Auditorium Theatre building. To the west of the Loop, built over the remains of Little Italy and Maxwell Street neighborhoods is the brutalist Near West Side campus of the University of Illinois at Chicago (UIC), the second-largest member of the Illinois state university system. Work Chicago still loves Carl Sandburg and his poems, but the city shucked off the hog butcher's apron a long time ago. In terms of industry, there's little that distinguishes Chicago from any other major city in America, save for size. The Chicago Board of Trade[93] and Chicago Mercantile Exchange[94] are among the biggest employers, with stables of traders and stock wizards. Boeing[95] moved its headquarters to Chicago amid much fanfare a few years ago; United Airlines[96], Abbott Laboratories[97], and AbbVie[98] are other international companies with headquarters in town. The Big Five consulting firms all have one or more offices in the Loop. And there's always construction work in the city; the city has a strong union presence. For younger workers, the museums in the downtown area are always looking for high-enthusiasm guides, and the retail outlets on the Magnificent Mile and State Street are also good options. And with so many colleges and universities in the city, study abroad opportunities abound. Buy Whatever you need, you can buy it in Chicago, on a budget or in luxury. The most famous shopping street in Chicago is a stretch of Michigan Avenue known as The Magnificent Mile, in the Near North area. It includes many designer boutiques, and several multi-story malls anchored by large department stores like 900 N Michigan and Water Tower Place. Additional brands are available from off-strip shops to the south and west of Michigan. State Street used to be a great street for department stores in the Loop, but it's now a shadow of its former self, with Carson Pirie Scott's landmark Louis Sullivan-designed building now a Target store, and invading forces from New York holding the former Marshall Field's building hostage under the name Macy's (Most locals still insist that it is "Marshall Field's"). Even Filene's Basement, the famous discount location, is now closed, though a few other discount shops persist. For a classic Chicago souvenir, pick up a box of Frango Mints, much-loved mint chocolates that were originally offered by Marshall Field's and are still available at Macy's stores. Although no longer made in the thirteenth-floor kitchen of the State Street store, the original recipe appears to still be in use, which pleases the loyal crowds fond of the flavor — and too bad for anyone looking to avoid trans-fats. However, for a more unique shopping experience, check out the fun, eclectic stores in Lincoln Square, or the cutting-edge shops in Bucktown and Wicker Park, which is also the place to go for music fiends — although there are also key vinyl drops in other parts of the city as well. Southport in Lakeview and Armitage in Lincoln Park also have browser-friendly fashion boutiques. For art or designer home goods, River North is the place to go. Centered between the Merchandise Mart and the Chicago Avenue Brown Line "L" stop in the Near North, River North's gallery district boasts the largest arts and design district in North America outside of Manhattan. The entire area is walkable and makes for fun window-shopping. Goods from around the world are available at the import stores in Chicago's many ethnic neighborhoods; check See for descriptions and district articles for directions. If you are the type that loves to browse through independent bookstores, Hyde Park has a stunning assortment of dusty used bookstores selling beat-up-paperbacks to rare 17th century originals, and the world's largest academic bookstore. Printer's Row in the Near South is also a great stop for book lovers. Groceries and other basics The major supermarket chains in Chicago are Jewel, Mariano's, Food 4 Less, Aldi, Whole Foods Market, and Trader Joe's. In addition the nation's three largest discount store chains Walmart, Target, and Kmart have several stores in Chicago as well. 7-Eleven convenience stores are usually found every couple of blocks and are always open 24-7, but have limited selection and high prices. The Walgreens drug store chain which is based in the city are also ubiquitous throughout Chicago with many locations open twenty four hours a day. Due to its huge expat and immigrant population, Chicago also features a large variety of ethnic grocery stores, including Indian, Pakistani, Chinese, Korean, Vietnamese, Polish, and Mexican. Eat Chicago's love affair with Polish sausages runs deep. As Hyde Park is to academics, and Near North is to department stores, so Avondale is to Polish sausages. Cavernous delis line the streets here, particularly up Milwaukee Avenue Chicago is one of the great restaurant towns in America. If you're looking for a specific kind of cuisine, check out the neighborhoods. Greektown, the Devon Ave Indian corridor, Chinatown, and Chatham's soul food and barbecue are just the tip of the iceberg. Other areas are more eclectic: Lincoln Square and Albany Park have unrivaled Middle Eastern, German, and Korean food, while Uptown offers nearly the whole Southeast Asian continent with Ghanaian, Nigerian, contemporary American, stylish Japanese, and down-home Swedish a few blocks away. If you're interested in celebrity chefs and unique creations, Lincoln Park and Wicker Park have plenty of award-winners. River North has several good upscale restaurants, but don't waste your time on tourist traps like Rainforest Cafe, Cheesecake Factory, or the Hard Rock Cafe. In fact, you should never submit to standing in line — there are always equally good restaurants nearby. No matter what you enjoy, you'll have a chance to eat well in Chicago, and you won't need to spend a lot of money doing it — unless you want to, of course. But while Chicago has a world class dining scene downtown, it is the low-end where it truly distinguishes itself. No other city on earth takes fast food so seriously; for those who don't concern themselves with calorie counting, Chicago is cheap, greasy heaven. Head northwest and you'll find sausage shops and old-style Polish restaurants that carry on as if health food and celebrity chefs never happened in Jackowo- Chicago's Polish Village, as well as at Belmont-Central- an Eastern European culinary heaven. The suburb of Des Plaines on the northwest side of the city near O'Hare is where you can find the world's first McDonalds, or as locals like to say: The Birth of American Obesity. Quite a few other local "culinary specialties" in particular deserve further description. Chicago pizza Chicago's deep dish pizza is incredible Chicago's most prominent contribution to world cuisine might be the deep dish pizza. Delivery chains as far away as Kyoto market "Chicago-style pizza," but the only place to be sure you're getting the real thing is in Chicago. To make a deep dish pizza, a thin layer of dough is laid into a deep round pan and pulled up the sides, and then meats and vegetables — Italian sausage, onions, bell peppers, mozzarella cheese, and more — are lined on the crust. At last, tomato sauce goes on top, and the pizza is baked. It's gooey, messy, not recommended by doctors, and delicious. When you dine on deep dish pizza, don't wear anything you were hoping to wear again soon. Some nationally-known deep dish pizza hubs are Pizzeria UNO and DUE, Gino's East, Giordano's, and Lou Malnati's, but plenty of local favorites exist. Ask around — people won't be shy about giving you their opinion. But deep dish is not the end of the line in a city that takes its pizza so seriously. Chicago also prides itself on its distinctive thin-crust pizza and stuffed pizzas. The Chicago thin crust has a thin, cracker-like, crunchy crust, which somehow remains soft and doughy on the top side. Toppings and a lot of a thin, spiced Italian tomato sauce go under the mozzarella cheese, and the pizza is sliced into squares. If you are incredulous that Chicago's pizza preeminence extends into the realm of the thin crust, head south of Midway to Vito and Nick's, which is widely regarded among local gourmands as the standard bearer for the city. The stuffed pizza is a monster, enough to make an onlooker faint. Start with the idea of a deep dish, but then find a much deeper dish and stuff a lot more toppings under the cheese. Think deep-dish apple pie, but pizza. Allow 45 minutes to an hour for pizza places to make one of these and allow 3-4 extra notches on your belt for the ensuing weight gain. Arguably the best stuffed pizza in town is at Bella Bacino's in the Loop, which somehow is not greasy, but other excellent vendors include Giordano's, Gino's, and Edwardo's. The Chicago hot dog A charred Chicago-style hot dog with all the trappings This may come as a surprise to New Yorkers, but the Chicago hot dog is the king of all hot dogs — indeed, it is considered the perfect hot dog. Perhaps due to the city's history of Polish and German immigration, Chicago takes its dogs way more seriously than the rest of the country. A Chicago hot dog is always all-beef (usually Vienna beef), always served on a poppy-seed bun, and topped with what looks like a full salad of mustard, diced tomatoes, a dill pickle spear, sport (chili) peppers, a generous sprinkling of celery salt, diced onion, and a sweet-pickle relish endemic-to-Chicago that is dyed an odd, vibrant bright-green color. It's a full meal, folks. Ketchup is regarded as an abomination on a proper Chicago-style hot dog. Self-respecting establishments will refuse orders to put the ketchup on the dog, and many have signs indicating that they don't serve it; truly serious hot dog joints don't even allow the condiment on the premises. The reason for Chicago's ketchup aversion is simple — ketchup contains sugar, which overwhelms the taste of the beef and prevents its proper enjoyment. Hence, ketchup's replacement with diced tomatoes. Similarly, Chicagoans eschew fancy mustards that would overwhelm the flavor of the meat in favor of simple yellow mustard. And for the hungry visiting New Yorkers, the same goes for sugary sauerkraut — just no. At most hot dog places, you will have the option to try a Maxwell Street Polish instead. Born on the eponymous street of the Near West Side, the Polish is an all-beef sausage on a bun, with fewer condiments than the Chicago hot dog: usually just grilled onions, mustard, and a few chili peppers. In a tragic, bizarre twist of fate, the areas of Chicago most visited by tourists (i.e., the Loop) lack proper Chicago hot dog establishments. If you are downtown and want to experience a Chicago hot dog done right, the nearest safe bet is Portillo's. Although, if you're up for a little hot dog adventure, you can eat one right at the source, at the Vienna Beef Factory deli. Sadly, both baseball parks botch their dogs, although the 2011 return of Vienna Beef as the official hot dog of Wrigley Field is a step in the right direction. Italian Beef The Italian Beef sandwich completes the Chicago triumvirate of tasty greasy treats. The main focus of the sandwich is the beef, and serious vendors will serve meat of a surprisingly good quality, which is slow-roasted, and thinly shaved before being loaded generously onto chewy, white, Italian-style bread. Two sets of options will come flying at you, so prepare yourself: sweet peppers or hot, and dipped or not. The "sweet" peppers are sautéed bell peppers, while the hots are a mixed Chicago giardiniera. The dip, of course, is a sort of French dip of the sandwich back into the beef broth. (Warning: dipped Italian Beefs are sloppy!) If you are in the mood, you may be able to get an Italian Beef with cheese melted over the beef, although travelers looking for the "authentic Italian Beef" perhaps should not stray so far from tradition. The Italian Beef probably was invented by Italian-American immigrants working in the Union Stockyards on the Southwest Side, who could only afford to take home the tough, lowest-quality meat and therefore had a need to slow-roast it, shave it into thin slices, and dip it just to get it in chewable form. But today the sandwich has found a lucrative home downtown, where it clogs the arteries and delights the taste buds of the Chicago workforce during lunch break. Some of the city's favorite downtown vendors include Luke's Italian Beef in the Loop and Mr. Beef in the Near North, while the Portillo's chain is another solid option. Four fried chickens and a coke... With the Great Migration came much of what was best about the South: blues, jazz, barbecue — but following a legendary meal at which a young, hungry Harold Pierce saw the last piece of bird flee his grasp into the mouth of the local preacher, Harold made it his mission to add fried chicken to that prestigious list, and to ensure that no South Side Chicagoan ever run out. Harold's Chicken Shack, a.k.a. the Fried Chicken King, is a South Side institution like no other. The Chicago-style fried chicken is considered by many connoisseurs to be some of the nation's best (certainly in the North), and it is fried in a home-style mix of beef tallow and vegetable oil, then covered with sauce (hot or mild). Crucially, it is always cooked to order — ensuring that essential layer of grease between the skin and the meat. A half chicken meal can come as cheap as $4 and includes coleslaw, white bread, and sauce-drenched fries — make like a local and wrap the fries in the bread. Initially, the fried chicken chain spread throughout black neighborhoods, which were ignored by other fast food chains, but in later years the franchise has extended its greasy fingers to the West and North Sides, as well as downtown. While chances are you will not find better fried chicken outside of Harold's walls, the quality, pricing, and character vary between individual locations. Your safest bets are on the South Side — if you are served through bullet-proof glass under signs bearing a chef chasing a chicken with a hatchet, rest assured you are getting the best. Drink Chicago is a drinking town, and you can find bars and pubs in every part of the city. It is believed that Chicago has the second highest bars-per-capita in the U.S. (after San Francisco). Unlike many other big cities where the hottest clubs are sought after, Chicago locals much prefer the dive bars and many don't seem to particularly like staying in one place. Most areas that thrive on the bar culture do so for the variety, and bar hopping is the norm. Grab a drink or two, then try the place next door. It is all about variety. Be prepared to be asked for identification to verify your age, even at neighborhood dive bars. Smoking is banned in Chicago bars (and restaurants). The best places to drink for drinking's sake are Wicker Park and neighboring Logan Square and Bucktown, which have a world-class stock of quality dive bars and local craft breweries, although these two areas can be difficult to reach via public transportation. These two areas are where the majority of Chicago's Hipsters live, with the effect that most of the bars are considered Hipster Bars. North Center and Roscoe Village are also a great (and underrated) destination for the art of the beer garden. Just to the West of the Addison CTA Red Line stop and near Wrigley Field in Lakeview is the Wrigleyville area with bars that are popular with twenty-somethings. These bars are crowded on weekends and whenever the Cubs are playing. One block to the East of the Addison stop on Halsted Street, is the center of Chicago's Gay community, known as Boystown. Boystown centers around Halsted street and stretches from Belmont in the South to Irving Park in the North. This area is filled with trendy shops, bars, clubs, and restaurants. Boystown can is busy most nights of the week and is surprisingly lively on Sundays. Just to the south, Lincoln Park has bars and beer gardens to indulge those who miss college, and some trendy clubs for the neighborhood's notorious high-spending Trixies. Ill-informed tourists converge upon the nightclubs of Rush and Division St. The city's best DJs spin elsewhere, the best drinks are served elsewhere, and the cheapest beers are served elsewhere; the hottest of-the-moment clubs and in-the-know celebrities are usually elsewhere, too. For the last few years the West Loop's warehouse bars were the place to be, but more recently the River North neighborhood has been making a comeback. Still, the Rush/Division bars do huge business. This area includes the "Viagra Triangle," where Chicago's wealthy older men hang out with women in their early 20s. Streeterville, immediately adjacent, exchanges the dance floors for high-priced hotel bars and piano lounges. Although good dance music can be found in Wicker Park and the surrounding area, the best places to dance in the city are the expensive see and be seen clubs in River North and the open-to-all (except perhaps bachelorette parties) clubs in gay-friendly Boystown, which are a lot of fun for people of any sexual orientation, Halsted St in boystown has many LGBT bars and nightclubs, for every age and type of music, take the redline train and get off at belmont station. Jazz and Blues See The Jazz Track for a wealth of information about current and historic jazz clubs in Chicago. The Lower Mississippi River Valley is known for its music; New Orleans has jazz, and Memphis has blues. Chicago, though located far away from the valley, has both. Former New Orleans and Memphis residents brought jazz and blues to Chicago as they came north for a variety of reasons: the World's Columbian Exposition of 1893 brought a lot of itinerant musicians to town, and the city's booming economy kept them coming through the Great Migration. Chicago was the undisputed capital of early jazz between 1917-1928, wih masters like Joe King Oliver, Louis Armstrong, Jimmie Noone, Johnny Dodds, Earl Hines, and Jelly Roll Morton. Most of Chicago's historic jazz clubs are on the South Side, particularly in Bronzeville, but the North Side has the can't-miss Green Mill in Uptown. The blues were in Chicago long before the car chase and the mission from God, but The Blues Brothers sealed Chicago as the home of the blues in the popular consciousness. Fortunately, the city has the chops to back that up. Maxwell Street[99] (Near West Side) was the heart and soul of Chicago blues, but the wrecking ball, driven by the University of Illinois at Chicago, has taken a brutal toll. Residents have been fighting to save what remains. For blues history, it doesn't get much better than Willie Dixon's Blues Heaven Foundation (Near South), and Bronzeville, the former "Black Metropolis," is a key stop as well. Performance venues run the gamut from tiny, cheap blues bars all over the city to big, expensive places like Buddy Guy's Legends (Loop) and the original House of Blues (Near North). But don't let yourself get too wrapped up in the past, because Chicago blues is anything but. No other city in the world can compete with Chicago's long list of blues-soaked neighborhood dives and lounges. The North Side's blues clubs favor tradition in their music, and are usually the most accessible to visitors, but offer a slightly watered down experience from the funkier, more authentic blues bars on the South and Far West Sides, where most of Chicago's blues musicians live and hang. If one club could claim to be the home of the real Chicago blues, Lee's Unleaded Blues in Chatham-South Shore would probably win the title. But there are scores of worthy blues joints all around the city (many of which are a lot easier to visit via public transport). A visit to one of these off-the-beaten-path blues dives is considerably more adventurous than a visit to the touristy House of Blues, but the experiences born of such adventures have been known to reward visitors with a life-long passion for the blues. Although playing second fiddle to the blues in the city's collective consciousness, jazz thrives in Chicago, too, thanks in no small part to members of the Association for the Advancement of Creative Musicians (AACM) and their residencies at clubs like The Velvet Lounge and The Jazz Showcase (both of which see regular national acts) (Near South), The New Apartment Lounge (Chatham-South Shore) and The Hideout (Bucktown), with more expensive national touring acts downtown at The Chicago Theater (Loop). If you are staying downtown, the Velvet Lounge will be your best bet, as it is an easy cab ride, and its high-profile performances will rarely disappoint. Fans should time their visits to coincide with Blues Fest in June, and Jazz Fest over Labor Day Weekend. Both take place in Grant Park (Loop). Concerts Wicker Park and Bucktown are the main place to go for indie rock shows: the Double Door and the Empty Bottle are the best-known venues, but there are plenty of smaller ones as well. In Lakeview, the Metro is a beloved concert hole, with Schubas, Lincoln Hall, The Vic, and the Abbey Pub nearby (the latter on the Far Northwest Side). Other mid-sized rock, hip-hop and R&B shows take place at the Riviera and the awesome Aragon Ballroom in Uptown. The Near South has become an underrated destination for great shows as well. The legendary Chicago Theater The Park West in Lincoln Park has light jazz, light rock, and other shows you'd sit down for; so does Navy Pier (Near North), particularly in the summer. The venerable Chicago Theater in the Loop is better-known for its sign than for anything else, but it has rock, jazz, gospel, and spoken-word performances by authors like David Sedaris. The world-renowned Chicago Symphony Orchestra (CSO) is the main bulwark in the city for classical and classy jazz, with occasional curve-balls like Björk. You'll find musicians from the CSO doing outreach all over the city, along with their counterparts at the Lyric Opera. Both are in the Loop. A few big concerts are held at the UIC Pavilion, the Congress Theater, and the United Center on the Near West Side every year, and some huge concerts have taken place at Soldier Field (Near South). The Petrillo Bandshell in Grant Park and the Pritzker Pavilion in Millennium Park, both in the Loop, tend to host big, eclectic shows and festivals in the summer, which are sometimes free. Otherwise, most big shows are out in the suburbs, primarily at the Allstate Arena and the Rosemont Theater in Rosemont, the Sears Centre in Hoffman Estates, the First Midwest Bank Amphitheatre in Tinley Park, Star Plaza in Indiana, and the Alpine Valley Music Theater over the Wisconsin border in Elkhorn. You'll also have to head out to the suburbs for Ravinia, which features upscale classical, jazz, and blues outdoors throughout the summer. See Chicagoland for details on suburban venues. Sleep Chicago hosts many major conventions each year and has plenty of places to stay. The majority are either at O'Hare Airport or downtown in the Loop and the Near North (near the Magnificent Mile). If you want to explore the city, aim for downtown — a hotel near O'Hare is good for visiting one thing and one thing only, and that's O'Hare (although the CTA Blue Line is walking distance from most of them, so access to the city is easy, aside from 30 minutes). However, if you have a specific interest in mind, there are hotels throughout the city, and getting away from downtown will give you more of a sense of other neighborhoods. You'll appreciate that if you're in town for more than a couple of days. Make sure that where you're staying is within your comfort level before committing to stay there, though. More far flung transient hotels will be suitable for those seeking to relive Jack Kerouac's seedy adventures around the country, but may alarm and disgust the average traveler. Budget-priced places are usually pretty far from the Loop, so when you're booking, remember that Chicago is vast. Travelers on a budget should consider accommodations away from the city center which can be easily reached via any of the several CTA train lines. There is a hostel in the Loop and three others near the universities in Lincoln Park,Rogers Park and in Wicker Park, all of which are interesting neighborhoods in their own right, and close to the L for access to the rest of the city. For deals on mid-range hotels, there are good options far out from the center by Midway and in North Lincoln. Wyndham Grand Chicago Riverfront',71 East Wacker Drive, Chicago, IL, 60601, phone 1-312-346-7100, Formaly Hotel 71, this hotel is located near the intersection of Michgan Avenue and Wacker Drive. Near The Loop and the Magnificent Mile. On site restaurant and an event room that can seat 250 people. Rates $129 and above. Courtyard Chicago Downtown Magnificent Mile, 165 E Ontario Street, ☎312-573-0800, [20]. checkin: 3pm; checkout: 12pm. With spectacular shopping, world-class museums, dynamic corporations and breathtaking architecture, the Windy City has it all and this hotel is located right in the heart of everything! Stay safe Chicago is a big city with big city problems. The majority of the city's violent crimes occur within in localized pockets, mostly in the West and South Sides, and most are restricted to gang violence. Nonetheless, the city's level of crime means that tourists should exercise caution, especially in the most affected areas. In general, common sense will keep you safe: know where you go every time you set out, avoid unfamiliar side streets (especially at night), stick to busy routes, and keep a $20 bill hidden for cab fare if you are stuck or feel unsafe. Beggars or homeless persons almost never pose any kind of problem. Most are either holding up a sign asking for some type of assistance or actively solicit you for spare change. If you ignore them, they will ignore you. Some sell a local newspaper called Streetwise to make a living. These people will be wearing a badge of some kind to indicate they sell the newspaper and they get to keep a portion of the profits that they make. If you feel generous, those selling Streetwise are your best bet. Dress appropriately for the weather. Chicago's winter is famously windy and cold, so cover exposed skin and wear layers in the winter, but heat exhaustion is an equal risk in the summer months, especially July and August. Stay off the road during a snowstorm. Chicago's streets and sanitation department generally does a good job clearing the major roads in the center of the city, but the neighborhoods can take longer, and the construction-littered expressways are anyone's guess. Respect Chicago has a reputation of being a segregated city, yet this image has finally started to erode somewhat. In many ways, it is like any other city: What may be okay behavior on one side of the city may get you into trouble on another side of the city. Homosexuality, accepted through downtown and the North Side, and parts of the South Side, may not be as well received elsewhere. There are many neighborhoods in Chicago where various races live in harmony, and race isn't an issue whatsoever. There are also neighborhoods that are mainly white, black, or latino and outsiders may be looked at with a curious eye. Chicagoans in general, however, are not social people, especially with strangers, and trying to interact with them can get you in trouble, especially in the middle and far suburbs of the metropolitan area. Contact Internet The first Internet cafe in the United States was opened in Chicago, but they never really caught on here. There are still a few, though; check individual district articles. If you have a computer with you, free wireless Internet access is now standard-issue at coffee shops throughout the city including major ones like Starbucks. Most hotels above the transient level offer free Wi-Fi, too. The good news is that all branches of the Chicago Public Library system offer free internet access, via public terminals and free, password-free, public wireless. If you do not have a Chicago library card, but you have a photo ID that shows you do not live in Chicago, you can get a temporary permit from the library information desk. (If you are from Chicago and don't have a library card, though, all you can get is a stern look and a brief lecture on how Chicagoans need to support the library system.) The most centrally located branch is the giant Harold Washington Library in the Loop, but there are branch libraries in every part of the city — again, see individual district articles. Only Harold Washington and the two regional libraries (Sulzer and Woodson) are open on Sundays. Telephones 312 was the area code for all of Chicago for a long time; it's still the code of choice for the Loop, and most of the Near North and Near South. 773 surrounds the center, covering everything else within city limits. Cope Publications The Chicago Tribune (The Trib), [21]. The Tribune is Chicago's oldest daily, recently converted into a tabloid format for newsstand purchases. New ownership has shed much of the Trib's former prestige with a debt-leveraged purchase and forced bankruptcy, widespread staff layoffs, and an ill-advised redesign. The Chicago Sun-Times, [22]. The Sun-Times is Chicago's other "major" newspaper. It has a long-standing reputation for aggressive (some might say "sensationalist") investigative journalism. It has also been teetering on the verge of oblivion for some time. The Redeye, [23]. Redeye is a free weekdays-only newspaper produced by the Tribune. Although its covers appear to report from some parallel universe where topics like sandwiches and being tired at work are the top stories of the day, it does have basic news coverage inside along with entertainment gossip. The Chicago Defender, [24]. The Defender is Chicago's biggest African-American daily, and it played a major role in the city's African-American history. Its distribution network today is comparatively small, though. The Chicago Reader, [26]. The Reader is a free weekly newspaper distributed throughout the city each Wednesday. It includes extensive listings of arts, music, and events. Nobody knows more about Chicago than the Reader, but it's definitely oriented toward locals. Crain's Chicago Business, [27]. Crain's is a long-standing weekly newspaper covering the Chicago area business community, with a dash of politics and lifestyle — definitely worth a look if you're in town on business. New City, [28]. New City is a free weekly alternative arts and entertainment magazine, distributed every Wednesday. Event listings and local content are skimpy, but it is free. Time Out Chicago, [29]. Time Out produces a weekly magazine available at most newsstands and bookstores. Its listings for events, bars, and restaurants are by far the most comprehensive and easiest to use for visitors to the city. The Daily Herald. The Daily Herald is wide serving suburban newspaper based in Arlington Heights, a Chicago suburb. Religious services The spectacular Bahá'í Temple There are places of worship all over the city; the front desk of your hotel will almost certainly be able to direct you to one nearby. If not, though, the following are centrally located in either the Loop or the Near North, unless otherwise noted. For churches of specific Orthodoxies, check in neighborhoods that feature communities with ties to that region. There's a majestic Orthodox church in Ukrainian Village, for example. Evangelical Christian ministries are mostly on the South Side, with some historic churches in Bronzeville. For the Baha'i faith, visit the Baha'i Temple in Wilmette, easily accessible by the CTA Purple Line. Holy Name Cathedral, 735 N State St (Chicago Red Line), [40]. Open for private prayer or reflection from 5:30AM-7PM. Flagship of the Roman Catholic Archdiocese of Chicago. Sunday Masses at 7AM, 8:15AM, 9:30AM (incl. sign language), 11AM, 12:30PM, and 5:15 PM. See website for Saturday, weekdays, and Holy Days schedules, as well as other sacraments. Get out Chicago Suburbs Forest preserves are prevelant on the far north, northwest, and southwest sides, and into the nearby Chicagoland suburbs. They are excellent for biking, jogging, picnics, and various outdoor activities. Toyota Park in Bridgeview, IL is an outdoor stadium that hosts several sporting events and concerts including the Chicago Fire of Major League Soccer. It is located on Harlem Avenue south of the Stevenson Expressway/Interstate 55. An express bus runs from the Midway station on the CTA Orange Line on event days. The Brookfield Zoo, which is Chicagoland's other world-class zoo, is loacted in nearby Brookfield, IL. Though not accessible via the CTA, the Hollywood station on METRA's Burlington Northern line is 2 blocks away. It is located on 31st Street close to the Eisenhower Expressway/Interstate 290. Evanston is over the northern border of Chicago. In addition to Northwestern University, the city has a vibrant downtown area, some historical homes scattered about, and a lovely lakefront. Just beyond that is Wilmette, with the fascinating Baha'i Temple. Both suburbs are accessible via the CTA Purple Line. The Chicago Botanic Garden in Glencoe, IL is a 385 acre garden featuring 25 display gardens, four natural habitats, and 2.5 million plants. Though not accessible by the CTA, the Braeside station along METRA's Union Pacific North line is nearby. It is located on Lake Cook Road near the Edens Expressway/Interstate 94 and US Route 41. In the same category as the Chicago Botanic Garden is the Morton Arboretum in western suburb of Lisle, IL. It hosts over 186,000 catalogued plants, the largest restored Prairie in Chicagoland, 16 miles (26 km) of hiking trails and nine miles (14 km) of roadways for driving/bicycling on 1700 acres. The Lisle station on METRA's Burlington Northern line is about 2 miles away. It is located on IL Route 53 near the Reagan Tollway/Interstate 88. Naperville has a wonderful and trendy downtown area. It boasts numerous restaurants, shops, and a riverwalk. It is located on The Reagan Tollway/Instertate 88 or near the Naperville Station on METRA's Burlington Northern line. Oak Park was the home of architecture legend Frank Lloyd Wright. The village boasts many houses that were designed by him and his home and studio are now a museum. Walking tours to see his designs are a must for anyone who appreciates architecture. The museum and beautiful downtown Oak Park are loacted near the Oak Park CTA Green Line station or not too far from the Eisenhower Expressway/Interstate 290. Ravinia is the summer home of the Chicago Symphony Orchestra. The arts and crafts style architecture coupled with a dazzling array of acts make this a classic summer destination for Chicagoans and tourists. Bring food, a blanket, wine, and a citronella candle; buy anything you forgot on-site. The Ravinia Park station on METRA's Union Pacific North line stops at the park gates and a return train waits for late-ending concerts. It is located on Half-Day Road about a mile from the Edens Expressway/Interstate 94 and US Route 41. Elsewhere in Illinois Six Flags Great America has the biggest and wildest roller coasters in Illinois. It is located off of Interstate 94 in Gurnee. Historic Galena, is great for hiking, sightseeing, and antiquing. Drive here in just over 3 hours via Interstate 90 and US Route 20. Peoria is in some ways a miniature Chicago. It is located about about 3 hours southwest of Chicago via Interstates 55 and 74. Springfield is the Illinois state capital and a city closely tied to Abraham Lincoln. This final resting place of the 16th president of the United States is located about 3 1/2 hours south of Downtown Chicago on Interstate 55. Starved Rock State Park, defined by its numerous canyons and waterfalls, sits on over 2600 acres. It is located near the junction of Interstates 39 and 80, about 2 hours southwest of Downtown Chicago. The Quad Cities bridge the Mississippi River forming a unique metropolitan area on the border of Iowa and Illinois. They sit about 3 hours west of Downtown Chicago on Interstates 80 and 88. Indiana The Indiana Dunes are a moderate drive away, and are also accessible via the South Shore commuter rail. If you've enjoyed the beaches in Chicago, you owe the Indiana Dunes a stop — that's where all the sand came from. Taking the Skyway/Interstate 90 to the Indiana Toll Road is the easiest way to visit. Gary is just over the border on the Skyway, with a skyline that rivals Chicago's for strength of effect — industrial monstrosity, in this case — with casinos, urban ruins, and a few entries by Prairie School architects Frank Lloyd Wright and George Maher. You can drive to Gary on the Indiana Toll Road/Interstates 80/90. South Bend is about a two hour drive to the east or a simple ride on the South Shore from Millennium Station. It is most famous as the home of the University of Notre Dame but also has a history as the location of former automobile manufacturer Studebaker. Another half an hour drive east to Elkhart County will land you in Northern Indiana Amish country. Both are accessible via the Indiana Toll Road/Interstates 80/90. The South Shore terminates at the South Bend Airport. Indianapolis is about a three hour drive southeast of Chicago and is worth a visit if you have time. Just follow Interstate 94 to Interstate 65. Also just over the Skyway (before you reach Gary) is East Chicago's bizarre 19th century planned community, Marktown, which looks like a small English village totally incongruous with the gigantic steel mills and the world's largest oil refinery which surround it. Michigan Further along the lake from the Indiana Dunes are Michigan's dunes and summer resorts in Harbor Country. Keep your eyes open because notables such as former Mayor Richard M. Daley, University of Chicago President Robert Zimmer, and others summer here. This region, well-known for its wineries and fresh fruit, is about an hour and a half drive from Chicago on Interstate 94. Saint Joseph & Benton Harbor are two towns about 2 hours northeast of Chicago. St. Joseph sits on a bluff that overlooks Silver Beach State Park and Lake Michigan. The view will knock your socks off - especially at sunset. St. Joseph has numerous shops and various festivals throughout the summer. It is easily accessible via Interstate 94. Detroit has many of Chicago's most hated sports rivals. Although it has fallen on hard times, it has a musical and architectural heritage comparable to the Windy City. It is a little over 4 hours away on, you guessed it, Interstate 94. Wisconsin Lake Geneva, across the Wisconsin border, is the other big summer getaway. Nearby are the Kettle Moraine state parks, with good mountain biking. Madison is located about two and half hours from Chicago on I-90 and via Van Galder buses. It is a vibrant city home to the giant University of Wisconsin and is known for its lively downtown, thriving culture, and beautiful scenery. Milwaukee and its venerable breweries are less than two hours from Chicago on I-94, via Amtrak, and by intercity bus services. Spring Green is an easy weekend trip from Chicago, about three and a half hours from town on I-90. It's the home of two unique architectural wonders: Frank Lloyd Wright's magnificent estate Taliesin, and Alex Jordan's mysterious museum The House on the Rock. The Wisconsin Dells are another (wet) summer fun destination, just three hours north of the city by car (I-90/94), also accessible by Amtrak train. Cedarburg is a popular festival town with a charming downtown featured on the National Register of Historic Places. It is located 20 miles north of downtown Milwaukee. Take 1-94 to Milwaukee and continue north on I-43.	{ "pile_set_name": "Pile-CC" }
Lock Locksmiths Ansonia, CT – Ansonia CT Locksmith Store Although people might think that the role of lock locksmiths is exaggerated, it is a different story altogether, in reality. The importance of locks and locksmiths in our life are many fold. Just imagine whether you will ever leave cash or valuables in open places, or leave for work with your front door unlocked, or keep your safe open. It is no perfect world without crimes; we are living in practical times. Incidents of theft and burglary are only on the rise. Locks are no doubt the primary line of security to protect valuables and lock locksmiths are the vital persons who manage your locks and lock-related issues. Choosing lock locksmiths: Given the importance of locks in protecting premises and properties, the technicians who are employed to handling them must naturally be diligently picked. They need to be qualified, have experience and skill in efficiently repairing, replacing, or installing locks. Ansonia CT Locksmith Store has acquired a select team of expert locksmiths who are capable of ensuring that clients’ security needs are never compromised. Having hands-on experience and know-how, they are able to handle any type of locks and resolve client issues at the shortest time possible. What our lock locksmiths can do? Fix any lock: Replacing the dysfunctional lock with a new one instantly is the easiest choice in locksmithing. Real challenge is in locating the problem in the lock and correcting it. It requires extensive experience and profound knowledge which our Ansonia CT Locksmith Store technicians are rich in. They bring almost any faulty lock back to working condition. Offer security advice: There is no ‘one model fits all’ in locks. You need to choose locks according to your needs. Trying to protect a warehouse using simple deadbolt or using a padlock for securing your residence will not pay. It is one of the responsibilities of expert locksmiths to suggest and install the right kind of locks as per client requirement. Unlock service: Many a times, people get themselves locked out of their own premises and vehicles inadvertently. No need to fret – Ansonia CT Locksmith Store can handle the devices and get them unlocked quickly with no damage done. Hire our locksmiths: We have been serving the Ansonia, CT community with round the clock lock-related services since more than a decade. We are able to offer instant solutions through mobile vans. When you are faced with any lock or key-related issue, just call 203-403-0849 to avail our efficient service!	{ "pile_set_name": "Pile-CC" }
A novel cell-to-cell interaction between mast cells and other cell types. Time-lapse cinephotomicrography and transmission electron microscopy (TEM) have been used to study the interactions between rat mast cells and different cell monolayers in culture (fibroblasts, vascular endothelial cells and cardiac muscle cells). This report documents a novel form of behavior between mast cells and certain other cell types. We have tentatively termed this cellular behavior 'transgranulation', which involves sequential changes not seen in control cells, including: (1) formation of a granule-containing mast cell pseudopod that becomes closely applied to an adjacent cell; (2) development of specialized plasma membrane interrelationships between apposing cells; (3) alteration of granules and perigranular membranes within the mast cell pseudopod; (4) occasional transfer of exocytosed mast cell granules to the cytoplasm of the adjacent cell; (5) presence of a specialized inclusion body in the mast cell; and finally, (6) either withdrawal of the pseudopod by the mast cell, or casting-off of the pseudopod from the mast cell, leaving it on the surface of the adjacent cell (pseudopod translocation). These mast cell interactions occur specifically with fibroblasts and endothelial cells in vitro and are never observed with cardiac muscle cells or non-cellular substrates. Our investigations of rat mesenteries in situ confirm that these cell-cell interactions also occur in vivo. We suggest it represents a form of cell-to-cell communication involving secretion from a mast cell pseudopod to another cell type. The significance of specialized contacts between mast cells and other cell types in vivo is discussed.	{ "pile_set_name": "PubMed Abstracts" }
Q: Submitting one value of the Hidden input in the current row clicked How to pass one value of the current row of multiple hidden input in PHP. I have the following code: foreach($portfolio as $portfolio){ echo "<tr class ='table-comments'>"; echo "<td>".$portfolio['portfolio_title']."</td>"; echo "<td class = 'comment-content'>".$portfolio['portfolio_client']."</td>"; echo "<td><a target = '_blank' href = ".$portfolio['portfolio_link'].">".$portfolio['portfolio_link']."</a></td>"; echo "<td>"; echo "<input type='hidden' name='portfolio_id' value='" . $portfolio['portfolio_id'] . "' />"; echo "<input type = 'submit' value = 'Edit'>"; echo "<input type = 'submit' value = 'Move to Trash' class = 'action-button'>"; echo "</td>"; echo "</tr>"; } I also have submit button each row that triggers the form. When I click the submit button, it submits all the value of the row of the hidden input. I only want the clicked button row value. URL is like this: /portfolio?portfolio_id=1&portfolio_id=2&portfolio_id=3&portfolio_id=4 and so on I only want /portfolio?portfolio_id=3 A: Have a new form for each row... <form method="get"> </form> Like this: foreach($portfolio as $portfolio){ echo "<tr class ='table-comments'>"; echo "<td>".$portfolio['portfolio_title']."</td>"; echo "<td class = 'comment-content'>".$portfolio['portfolio_client']."</td>"; echo "<td><a target = '_blank' href = ".$portfolio['portfolio_link'].">".$portfolio['portfolio_link']."</a></td>"; echo "<td>"; echo '<form method="get">'; echo "<input type='hidden' name='portfolio_id' value='" . $portfolio['portfolio_id'] . "' />"; echo "<input type = 'submit' value = 'Edit'>"; echo "<input type = 'submit' value = 'Move to Trash' class = 'action-button'>"; echo "</form>"; echo "</td>"; echo "</tr>"; }	{ "pile_set_name": "StackExchange" }
"As far as the buyout, that has not been broached," Paxson said. "I would say this: In this type of scenario, it would have to benefit us. Dwyane was a great pro last year, and he's been around a lot of different situations. He was in Miami when they had a couple of rebuilding years as well. So right now we're operating under assumption that he'll be here."	{ "pile_set_name": "OpenWebText2" }
Q: How to grep a string after a specified line number? I have a large text file, I want to see the lines containing "time spent" in this text file, I use: grep -in "time spent" myfile.txt But I'm interested only in the lines after 50000. In the output I want to see lines after 50000 and that contain "time spent". Is there a way to do this? A: You can tail it, then grep: tail -n +50000 myfile.txt \| grep -in "time spent" A: Alternatively you can use sed. sed can be used to mimic grep like this: sed -n 's/pattern/&/p' By default sed prints every line even if no substitution occurs. The combinations of -n and /p makes sed print only the lines where a substitution has occured. Finally, we replace pattern by & which means replace pattern by itself. Result: we just mimicked grep. Now sed can take a range of lines on which to act. In your case: sed -n '50000,$s/time spent/&/p' myfile.txt The format to specify the range is as follow: start,end We just instruct sed to work from line 50000 to $ which means last line. A: Answer for grepping between any 2 line numbers: Using sed and grep: sed -n '1,50000p' someFile \| grep < your_string >	{ "pile_set_name": "StackExchange" }
[Pyrazinamide monoresistant Mycobacterium tuberculosis in Manisa region, Turkey]. Pyrazinamide (PZA) is a primary antituberculous drug. BACTEC 460TB is the recommended reference method for the detection of PZA resistance in Mycobacterium tuberculosis. This method is more expensive than the conventional susceptibility methods and therefore, it is recommended that each laboratory should establish their own protocol for the inclusion of PZA in the panel of primary drugs tested. One of the most important factors that help this decision is the prevalence of PZA resistance, particularly PZA monoresistance in the related community. The aim of the present study was to determine the extent of PZA monoresistance in M. tuberculosis complex (MTBC) isolates in our region. In this study, PZA susceptibility testing of 109 MTBC strains (susceptible to isoniazid, rifampicin, ethambutol and streptomycin) isolated from Manisa province in the Aegean region of Turkey was performed by using the BACTEC 460TB radiometric system (Becton Dickinson, MD). Two (1.8%) of the 109 isolates which were susceptible to all primary drugs revealed monoresistance against PZA. One of the PZA-monoresistant isolates has been identified as M. bovis and the other as M. tuberculosis by molecular method (Genotype MTBC, Hain Lifescience, Germany). The results of our study indicated that since the rate of PZA monoresistance was low, susceptibility testing of a panel of primary drugs without PZA may be an economical alternative in our region.	{ "pile_set_name": "PubMed Abstracts" }
E3 2013: Mario Kart 8 Coming to Wii U in Early 2014 Instead of having a physical presence at E3 this year, Nintendo decided to get all futuristic on us and broadcast a live look at what it has in store for us this year. During the livestreamed Nintendo Direct event, the big N dropped some deets about the future of Mario and friends. Nintendo gave us a first look at the next installment in its popular racing franchise, Mario Kart, announcing that Mario Kart 8 will be available on the Wii U in Spring 2014. Mario Kart 8 looks like its predecessors, both graphics and game play wise. Of course, the Wii U shots look smoother and brighter than the Wii version, and still hold true to Nintendo’s quite cartoony character design and style. There are some gameplay additions, with carts turning into hovercraft like vehicles and a 3D world that goes upside down, inside out and all over the place. Air gliding, underwater racing and driving up vertical walls are all now normal occurrences while shooting a red turtle shell at that dude in the first place slot.	{ "pile_set_name": "Pile-CC" }
Q: C# Webbrowser navigating links in order I'm trying to teach myself C# and to start I'm trying to convert a program I originally wrote in Autoit. I'm using a Windows Application Form and the program is suppose to take one or two links as input. Navigate to those to pages, grab some links from a table, then visit each of those pages to grab some content. If only one link is entered it seems to go to that page and grab the links from a table like it is suppose to. If two links are entered it seems to only grab the links from the second table. So if two links are passed this method private void getPageURLList(string site1, string site2) { getPageURLList(site1); getPageURLList(site2); } Calls the same method that gets called when there is only one link private void getPageURLList(string site) { webBrowser.DocumentCompleted += createList; webBrowser.Navigate(site); } I'm pretty sure the issue is "Navigate" is getting called a second time before createList even starts the first time. The reason I am using WebBrowser is because these pages use Javascript to sort the links in the table so HTTPRequests and the HTMLAgilityPack don't seem to be able to grab those links. So I guess my question is: How can I keep my WebBrowser from navigating to a new page until after I finish what I'm doing on the current page? A: You have to make a bool variable to know when the first proccess has completed. And then start the other. Application.DoEvents() will help you. Note that all this events run in the main thread.	{ "pile_set_name": "StackExchange" }
Q: Where is "to do a magical turn" used to describe an illegal U-turn? There's this expression in Spanish, "hacer una pirula", used to describe a U-turn in a zone not designed to do so. While reading a thread on WordReference to determine the English equivalent, I found the following post: in the US I once heard someone say "to do a magical turn", which in my opinion is what best suits "hacer una pirula" in a driving context. The poster wasn't a native speaker, as per their profile. I haven't been able to find any evidence of the expression "doing a magical turn", so I'm skeptical. Is "to do a magical turn" used in any region of the United States to describe a prohibited U-turn? A: In AmE, performing a U-turn where it is not permitted is simply called an illegal U-turn there is nothing "magical" about it, unless the police "magically" appear and hand you a driving violation.	{ "pile_set_name": "StackExchange" }
Ideas, information and industry news for collegiate retailers Which Faculty Have the Greatest Impact on Campus Store Business? An Illustrated Guide Excellent campus store faculty relations start with understanding your audience. You need to know as much as you can about the context in which teachers are most likely to receive your communication. Part IV of our Campus Store Faculty Communication Guide includes an illustrated guide to the academic teaching environment, a reference you can use to increase the effectiveness of your faculty message. Which faculty have the most contact with students? For most campus stores, serving students is the No. 1 priority. If students top your agenda of concerns, the typical academic system can seem upside down. The teachers with the most direct impact on the academy’s tuition-paying customers — i.e. students — often have the lowest status. Despite fewer scholarly laurels, teachers with heavy course loads have an impact on the day to day business of a college store. They often place their own adoptions and teach large introductory classes. This brings them into direct contact with greater numbers of undergraduates — especially first-year students —than just about any other campus employee. Campus stores must reach teachers working in different contexts Reaching out to college and university teachers presents challenges. Professors, assistant professors, associates, instructors, lecturers, adjuncts: each of these groups has different obligations, expectations and a distinct effect on the daily lives of students. Adjuncts teach more than half the college and university courses in the country, working primarily on per term contracts. However, they are not usually included in a school’s official faculty numbers. They have little contact with administrators and tenured professors. But they encounter hundreds of undergraduates weekly. Even though adjuncts are not technically “faculty,” it’s likely that their actions and views affect campus store business. Adjuncts often select and adopt course materials and design their own syllabus. Because they teach an abundance of first-year courses, young students often seek them out for counsel — including advice about where to buy books and whether the purchases are worthwhile. Many departments must hire adjuncts late in the term — after budget and enrollment numbers finalize. If the adjuncts have freedom to select course materials, late adoptions are inevitable. The different worlds within the campus faculty hierarchy This graphic depicts differences among faculty members in terms of income, job security, expectations — and student contact. As teachers ascend the academic ladder, they often have less contact with students, especially undergraduates. They teach fewer courses, interact with fewer university newcomers and adopt fewer course materials. As you review the data, bear in mind that academia is not standardized. This infographic presents a generalized map of the system. It shows common features of the academic hierarchy that can vary on different campuses. Most popular posts Most popular topics Contact MBS Customer Service800-325-0530cserv@mbsbooks.com Order Processing800-325-0577 Stay Connected With Us As MBS’ signature publication, Foreword Online is dedicated to offering daily industry insight and cutting-edge news that keep college retailers ahead of the curve. Follow us on social media. Contact us with ideas and feedback. Subscribe for regular updates.	{ "pile_set_name": "Pile-CC" }
India says demand for Headley, Rana extradition stands Source : Last Updated: Thu, Jan 31, 2013 15:30 hrs New Delhi, Jan 31 (IANS) India said Thursday that its demand for extradition of 26/11 plotter David Headley and his accomplice Tahawwur Hussain Rana "continues to stand" and it would work with the US "in taking the legal processes forward" in the Mumbai attack cases. "We have received good cooperation from the US in the 26/11 cases. We intend to work closely with the US in taking the legal processes forward. Our demand for extradition of Rana and Headley continues to stand," said the external affairs ministry spokesperson here. The spokesperson also said that India would seek access to Rana, who has been sentenced by a US court, for his involvement in the 26/11 attack. "We have not been able to question Rana given his rights as an accused under US law. Now that he is a sentenced person, we will seek US government support for access to him and for further access to Headley," the spokesperson added. Rana, 52, was on Jan 17 sentenced to 14 years in jail by a Chicago court for providing material support to Pakistan-based LeT and for backing a "dastardly" plot to attack a Danish newspaper. Headley on Jan 24 was handed a 35-year prison sentence for his role in plotting the 2008 Mumbai terrorist attacks that killed 166 people and for a foiled plot in Denmark. India had said after Headley's sentencing that the LeT operative should have got a "harsher" punishment for his role in plotting the attacks. External Affairs Minister Salman Khurshid had said that though the US legal system does not have provision to extradite Headley, India will continue to try and get him tried in India. The spokesperson said Thursday that bringing to justice the perpetrators of the 2008 Mumbai attacks is a "work in progress and we will take it to its logical conclusion". He also said that India intends to continue to work with the US to seek access to "others who may be of interest and would use all existing bilateral mechanisms" for that. "We wish to continue to work the US to help us to seek access to others who are chargesheeted to be placed before the National Investigation Agency (NIA) court." Headley had entered into a plea deal with the US under which US prosecutors "had agreed not to seek the death penalty against him and to not extradite him to Pakistan, India or Denmark for the offences to which he pleaded guilty".	{ "pile_set_name": "Pile-CC" }
Zammad::Application.routes.draw do # shorter version match '/ical', to: 'calendar_subscriptions#all', via: :get match '/ical/:object', to: 'calendar_subscriptions#object', via: :get match '/ical/:object/:method', to: 'calendar_subscriptions#object', via: :get # wording version match '/calendar_subscriptions', to: 'calendar_subscriptions#all', via: :get match '/calendar_subscriptions/:object', to: 'calendar_subscriptions#object', via: :get match '/calendar_subscriptions/:object/:method', to: 'calendar_subscriptions#object', via: :get end	{ "pile_set_name": "Github" }
Francisco FUENTES Researcher and Professor at Faculty of Agronomy and Forestry, Pontifical Catholic University of Chile. His prior working experience includes Researcher at Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University, USA; International Quinoa Expert, Administration of Foreign Expert of Jilin Province, P. R. China; and FAO (Food and Agriculture Organization of the United Nations) consultant in Chile. He obtained his PhD in Agroforestry and Veterinary Sciences, Molecular Genetics at University of Chile in 2007 and B.S. in Agronomy and Crop Science at Concepcion University, Chile in 2001. He has completed Technical Internship in Genetics Advances for Horticultural Crops and Internship Research in the following topics: Sequencing and Phylogenetic Analysis of Chloroplast bar code of Chenopodium genus, Developing Multiplex Fluorescent Microsatellite Markers for Genetic Diversity Assessment in Quinoa and Molecular Marker Screening to assess Genetic Diversity in Quinoa. He received awards including Postdoctoral Fellowship funded by the National Commission for Science and Technology (CONICYT), Chile (2012-2014) and Doctoral Fellowship funded by the National Commission for Science and Technology (CONICYT), Chile (2004-2007). He has also received number of research grants as Principal Investigator, Associate Investigator and International Research Collaborator, publishing +40 research articles in refereed journals. He serves as Editor-in-chief of “Journal of Agronomy” and as editorial board member in international journals, including “Notulae Botanicae Horti Agrobotanici Cluj-Napoca” and “Notulae Scientia Biologicae”. Celebration and scientific conference - 40 Years of Horticulture Education in Cluj-Napoca - September 27, 2017. Accepted contributions have been published in a special issue of Notulae Botanicae Horti Agrobotanici Cluj-Napoca.	{ "pile_set_name": "Pile-CC" }
Client Area Artwork Setup Guidelines Download our guidelines for the supply of print ready artwork Applications Preferred file format Adobe Illustrator CS5 ai, eps Adobe Photoshop CS5 psd, tiff, eps, jpeg* Adobe InDesign CS5 indd - version 6 QuarkXPress qxd - version 5 - 8 Adobe Acrobat PDF** When supplying artwork to us setup in ‘InDesign/QuarkXPress’ please ensure all fonts and images are collected and included in the file. Artwork set up in Adobe Illustrator ensure all fonts are vectored/outlined, also include with all files a low res PDF of the final artwork, this way there will be a quicker and faster turnaround of the end result. JPEG - We accept this format but only if used to compress a file for ease of sending, the original artwork should have been created high resolution - 300dpi or vector eps to print at the best possible quality. *PDF - These are print files only and can not be altered to fit different sizes, artwork must be set up at the correct proportion and at print ready quality. Make sure images are saved at high resolution (300dpi). Image resolution (dpi) To get the best results before going to print, images should be set up to the following spec:	{ "pile_set_name": "Pile-CC" }
Let r = t - 0.7. Let m = -3 + 3.3. What is the third biggest value in r, -2/3, m? -2/3 Let s = -6.237 + -0.063. Let p = 0.7 - s. Let c = 6.5 - p. What is the third smallest value in 4/5, c, -5? 4/5 Let p = -21 - -19. Which is the third smallest value? (a) 2 (b) -2/19 (c) p a Suppose 2i - 10i = -32. What is the second smallest value in -2, -0.09, i? -0.09 Let r = 55.4 - 51. Let u = r + -0.4. Which is the second smallest value? (a) 5/6 (b) -3 (c) u a Let f = -0.5 - -0.1. Let q = 6.84 - -0.16. Let p = q + -6.8. What is the second biggest value in p, f, -3/5? f Let b = -22 + 27. Suppose 2i + 18 = -4m + 5m, 0 = -m - 5i - 17. What is the smallest value in -2/5, b, m? -2/5 Let c = 1 - 1. Suppose -2u - 4a + 20 = c, a - 64 = -5u - 2a. Let b be u/(-40) + 2/(-8). What is the biggest value in b, 5/2, -5? 5/2 Let d = -3 - -2. Which is the second smallest value? (a) -2/7 (b) 0.4 (c) d a Let r = -3 + 3. Let p = 5 - 4. What is the third biggest value in -1, p, r? -1 Let w = 4 - 6. Let p = -1.5 - w. Let x = 2 - 6. What is the biggest value in x, p, 1/6? p Let s = 2.5 - 2.2. Which is the smallest value? (a) 8 (b) s (c) -5 c Suppose 159 + 114 = -3i. Let g = -453/5 - i. Which is the smallest value? (a) 4/5 (b) -1/2 (c) g b Let t(q) = q + 1. Let k be t(-5). Which is the second smallest value? (a) 0.4 (b) -1/12 (c) k b Let z(g) = g3 + 7g*2 + 3g. Let q be z(-5). Let d be ((-28)/q)/(2/5). What is the second biggest value in -1, d, -2/11? -1 Let w = 2.1 + -13.1. Let d = w + 16. What is the third biggest value in d, 2/21, 2? 2/21 Let o = 3.4 - -0.8. Let n = -0.2 + o. Which is the second smallest value? (a) 1/6 (b) 1/5 (c) n b Let z = -145 - -142. What is the second smallest value in -7, 4, z? z Suppose 5x - 111 = 3p, -2p + 6p = -5x + 97. Let a be (-4)/(-14)x/(-27). What is the second biggest value in 2, a, 1? 1 Suppose -m - 10 = -6m. Suppose 0 = -0q - mq - 2. Which is the third smallest value? (a) q (b) -1/9 (c) 0.2 c Let k = 8.9 - 9.2. Which is the fourth biggest value? (a) 1 (b) -2 (c) k (d) -4 d Let d = -11 + 6. Which is the second biggest value? (a) d (b) 2 (c) -2 c Suppose -24 + 2 = v - 2p, -25 = v - p. Let i be (4/v)/(12/(-14)). Which is the third biggest value? (a) 1 (b) i (c) -2/5 c Let z = 1.15 + -0.05. Let f = z - 1.6. Which is the third smallest value? (a) -0.4 (b) 4/5 (c) f b Let q = 60 - 63. Which is the second biggest value? (a) q (b) -7 (c) 1/4 a Let u = 3.1 - 3. Let l = -3.1 + u. Let v = 4 - -1. Which is the second smallest value? (a) l (b) v (c) 0.3 c Suppose 6x + 59 = -7. What is the biggest value in -0.4, 5, x? 5 Let z = 3.7 - 3.2. Let x = -2/455 + 473/4095. Let r = -11 + 7. Which is the smallest value? (a) r (b) z (c) x a Let l = 214 + -219. Suppose -u - 3u - 12 = 0. Which is the third biggest value? (a) u (b) 1 (c) l c Let b = 84.1 + -84. What is the smallest value in 1, -0.3, b, 7? -0.3 Let s = 0.17 + -10.17. Let i = s - -6. What is the smallest value in i, -0.4, 0.5? i Let l = 34 + -135/4. What is the fourth biggest value in l, 19, 0.5, -2? -2 Let n = 0.08 + -5.08. Let b = 2 + n. What is the third biggest value in 4, -1, b? b Let p(z) = -z + 12. Let n be p(7). Which is the smallest value? (a) -1 (b) n (c) -0.2 a Let v(m) = 9m - 22. Let p be v(2). What is the smallest value in -0.7, p, -1? p Let d(q) = q3 + 3q*2 + q + 4. Let s be d(-6). Let p be 4/s1-5. Which is the biggest value? (a) -1 (b) -0.2 (c) p c Let u = 23.6 - 27. Let p = 1.4 + u. Let t = -4 - -14/3. What is the third biggest value in t, -5, p? -5 Let j = -4 + 4.1. Let a = 0.1 - j. Let u = 4 - a. What is the biggest value in 2/5, 5, u? 5 Let u = -18 - -20. Let h be u/10 - (-57)/15. Which is the second biggest value? (a) 3/2 (b) h (c) 0.2 a Let h = 3.55 - -2.69. Let y = h + -6. Let l = -0.04 + y. What is the third biggest value in l, 4, 1/9? 1/9 Let h = -0.57 + 0.27. Which is the third smallest value? (a) h (b) 5/7 (c) 3/2 c Let f = 1019/2496 - 13/64. Let b = -196/195 + f. What is the third biggest value in -4, b, -3? -4 Let m be -4 + 4 - 1 - -3. Let v = 7 + -3. Which is the smallest value? (a) m (b) v (c) -2/3 c Let k = -144 + 143. What is the fourth smallest value in 2/3, k, 1/5, -0.3? 2/3 Let j be 1/((-3)/(-4)) - 1. Let r = 1135 + -5699/5. Let i = 62/15 + r. What is the biggest value in j, 3, i? 3 Let d = 5.5 + 1.5. Let h = -3 + d. Let j = h + -4.4. Which is the smallest value? (a) -3 (b) 2/7 (c) j a Let w = 6 + -5.94. Let h = 10 - 10. What is the biggest value in -4, w, h? w Let y = -3 + 5. What is the second biggest value in 0, -5, y? 0 Let f be 9 - 31/3. Let x = 12 - f. Suppose -3g + 3y + 0y = 0, -xg + 2y = 0. Which is the third smallest value? (a) 2/7 (b) -4 (c) g a Let g = -3 + 3.2. Suppose z = 5u + 139, -4z + u = -0u - 518. Let l = z + -1159/9. Which is the smallest value? (a) l (b) g (c) -5 c Let n = 0.5 + 0. Let f = 2.4 - 5.4. What is the second smallest value in n, f, -0.1? -0.1 Suppose 0 = -5u - 3s - 40, -u + 5s = 3u + 32. Let l be 30/(-45)(-3)/u. Which is the second smallest value? (a) l (b) -3 (c) 1 a Let m = -1 + -2. Which is the smallest value? (a) m (b) 4 (c) 1/4 a Let i = 5 - 6. Which is the third biggest value? (a) 4 (b) 5 (c) i c Let n = 668/5 + -134. What is the biggest value in n, -20, -1/2? n Let h = 0.1 + 0. Let u = -8 - -12. Which is the smallest value? (a) 0.2 (b) h (c) u b Let b = -0.1 + -0.9. Let i = -5.3 + 0.3. Let w = 2 + -1. What is the third biggest value in i, w, b? i Let l = 49 - 44. Let n be (2/3)/(1 + 4). Which is the second biggest value? (a) n (b) -1 (c) l a Let q be (-6)/10 + 104/240 + 1. Which is the biggest value? (a) -1/2 (b) q (c) -4/3 b Let y = -11 + 8. Let f = 280.2 + -280. Which is the biggest value? (a) f (b) y (c) -2/9 a Let k be -1(3 - 3 - -1)7. Which is the third biggest value? (a) k (b) -2/3 (c) 0 a Let t be (-5)/(-5) - 35/25. What is the second smallest value in t, -1, -5? -1 Let d = 17.1 - 17. Let h(k) = k3 - 9k*2 - 2k + 13. Let x be h(9). What is the biggest value in x, -4/3, d? d Let x = -93/13 + 7. What is the second biggest value in 0, x, 0.1, 5/4? 0.1 Let u be 3/604 - 22/60. What is the third biggest value in u, -0.5, -19? -19 Let o = -94 + 90.05. Let m = -0.05 + o. What is the second biggest value in 0.2, -1/11, m? -1/11 Suppose 10c + 2c + 24 = 0. What is the third smallest value in -1, 0.4, c? 0.4 Let n = 21/50 + 2/25. Let f = 9 - 9. What is the second smallest value in f, -0.5, n? f Let t = -53/168 + 4/21. Let j be -12(-4)/63 + -3. Let s = 18/7 + j. What is the biggest value in 1/5, t, s? s Suppose 4i - i + 126 = 0. Let r be (-1)/(-14) + (-18)/i. What is the second biggest value in -4, r, 0.4? 0.4 Let z = 6 + -3. Suppose 3g + g = 3k - 5, zk = -5g - 13. What is the second biggest value in g, 5, 1/2? 1/2 Let x be (-116)/203 - (-4)/(-14). Let l(w) = w + 1. Let v be l(-1). Which is the second smallest value? (a) x (b) 1 (c) v c Suppose i + 2c - 5 = 0, 5c - 13 = -3. Let v(f) = 6f - 1. Let r be v(i). Let o = 0.1 + 0. What is the third biggest value in 0.4, r, o? o Let x = -64.5 - -64. What is the fourth biggest value in 2/11, x, 0, 3? x Let i(x) = 12x - 1. Let s(o) = -o2 + 6o - 1. Let l be s(6). Let g be i(l). Let r = 9 + g. What is the biggest value in -3, -1/4, r? -1/4 Let b = -99 - -395/4. What is the third biggest value in -1, b, -1/8, -2/7? -2/7 Let c = -1.6 + 1.6. What is the second smallest value in 0.5, -5, c? c Let r = 318/299 + -28/23. Which is the second biggest value? (a) r (b) 2/5 (c) 2 b Let k = -7.9 - -0.9. Let a = 6.6 + k. What is the third biggest value in a, -2/9, 2/7? a Let m = -4 + 4.4. Let j = 0 + m. Let q = 148.1 - 148. Which is the second biggest value? (a) j (b) q (c) 1/6 c Let i = 0.1 + -2.1. Let m = i - -1.9. Which is the smallest value? (a) -2 (b) 3 (c) m a Let z = -0.28 - 4.72. What is the smallest value in 1, z, 6? z Let i = 40 + -39.5. Which is the third biggest value? (a) 0.1 (b) i (c) -0.01 c Let y = -0.5 + -2.5. Which is the smallest value? (a) y (b) -1/2 (c) -4 c Let m = 0.5 - 0.1. Let v be (-5)/110*-4 + (-36)/77. Let t = 116 - 810/7. What is the third biggest value in t, m, v? v Let r = 12 + -17. Let b = 22.1 -	{ "pile_set_name": "DM Mathematics" }
When the magician Jocelyn Brandon Hope died he bequeathed Melstone House to his grandson Andrew. He also left his ‘field of care’: an area of strangeness surrounding the land around the house, whose boundary Andrew must walk in order to preserve its power. When the magician Jocelyn Brandon died he bequeathed Melstone House to his grandson Andrew Hope. He also left his ‘field of care’: an area of strangeness surrounding the land around the house, whose boundary Andrew must walk in order to preserve its power.	{ "pile_set_name": "Pile-CC" }
Account Manager salaries at TIG Global can range from $76,431-$83,213. This estimate is based upon 1 TIG Global Account Manager salary report(s) provided by employees or estimated based upon statistical methods. See all Account Manager salaries to learn how this stacks up in the market.	{ "pile_set_name": "Pile-CC" }
Complimentary and alternative medicines (CAM) are amongst the most commonly used therapies worldwide and in the US for chronic liver diseases. Silymarin, the active ingredient of the milk thistle, Silybum marianum, is one of the commonest used herbal medications but its efficacy in chronic liver disease is unproven. Liver disease secondary to both hepatitis C (HCV) and non-alcoholic steatohepatitis (NASH) represent 2 of the commonest liver diseases in the US and there is a need for the study of silymarin in these diseases in a controlled clinical trial. We are proposing three collaborative clinical trials to evaluate silymarin versus placebo in HCV patients who have never received treatment, in HCV patients who have failed treatment and in patients with NASH. These will be double blind, placebo controlled phase l/ll trials focusing on dose finding, safety and efficacy of silymarin. The endpoints of the trials will include histological improvement in liver disease and multiple secondary surrogate markers to understand both how silymarin works and to get a preliminary idea of the endpoints to be utilized in larger Phase 3 trials. We also intend to evaluate important secondary factors such as expectations of patients on CAM and effect of silymarin on quality of life. The goal of these studies is to determine whether there is a rationale for larger Phase 3 studies of silymarin in patients with chronic liver disease.	{ "pile_set_name": "NIH ExPorter" }
Poor families in El Salvador, Guatemala and Honduras are fleeing drought, food insecurity and gang violence BOGOTA, Sept 17 (Thomson Reuters Foundation) - Food shortages and cuts in farming jobs caused by a prolonged drought are driving thousands of people living in parts of Central America to leave their homes, according to new academic research. The International Organisation of Migration (IOM) and the United Nations World Food Programme (WFP) said in a study that worsening hunger, combined with high levels of crime and gang violence, are driving poor families in El Salvador, Guatemala and Honduras to migrate. Those affected are moving within their own country, often from rural to urban areas in search of a better life and jobs, or to other countries in the region or the United States, the study said. "Migration has always been linked to income disparities between countries, socio-economic instability, and population pressures; however, this is the first time food insecurity has been specifically singled out as a trigger for migration," Miguel Barreto, WFP's regional director for Latin America and the Caribbean, said in a statement on Thursday. "This exploratory study is important because it underscores the need to invest in food security to prevent migration." Hardest hit are subsistence farmers in Central America's "dry corridor" running through parts of Guatemala, El Salvador and Honduras, where growing numbers of women and children have migrated in recent years, the study said. Low rainfall for two consecutive years has caused widespread and severe drought, leading to poor harvests of staple crops like beans and maize and leaving more than one million people in the corridor facing a shortage of food and rising food prices, the study said. "This has negatively affected many of the most vulnerable segments of society that are largely dependent on one harvest per year and compounded by declining labour opportunities," the study, supported by the Organisation of American States, said. Last year 'a significant percentage of households' affected by the drought reported at least one family member migrating in search of a job, according to a WFP study. The Central American Agricultural Council - headed by agriculture ministers of the subregion - declared a state of alert after hundreds of thousands of subsistence farmers lost part or all their crops planted for the main May-September season, the U.N. Food and Agriculture Organisation said earlier this week. Food harvests in Central America have fallen this year by as much as 60 percent for maize and 80 percent for beans due to prolonged dry spells linked to the El Nino weather phenomenon, according to the FAO. Rampant gang violence is also forcing people to leave their homes, especially in Guatemala and Honduras, and is linked with the shortage of food, the study said. "A relationship exists, especially between food security and migration, and migration and violence, and to a lesser degree also between food security and violence," the study said. It said more research was needed to better understand the correlation between violence, hunger and migration and the current evidence 'is not conclusive'. The El Nino weather pattern could last until early 2016, the study said. (Reporting By Anastasia Moloney, Editing by Tim Pearce.Please credit the Thomson Reuters Foundation, the charitable arm of Thomson Reuters, that covers humanitarian news, women's rights, trafficking, corruption and climate change. Visit www.trust.org) Our Standards: The Thomson Reuters Trust Principles.	{ "pile_set_name": "OpenWebText2" }
Tumi Koto Tumi Koto (born 19 November 1994) is a South African cricketer. He made his first-class debut for Northerns in the 2016–17 Sunfoil 3-Day Cup on 9 February 2017. He made his List A debut for Northerns in the 2017–18 CSA Provincial One-Day Challenge on 7 January 2018. In September 2018, he was named in Mpumalanga's squad for the 2018 Africa T20 Cup. He made his Twenty20 debut for Mpumalanga in the 2018 Africa T20 Cup on 14 September 2018. References External links Category:1994 births Category:Living people Category:South African cricketers Category:Mpumalanga cricketers Category:Northerns cricketers Category:Place of birth missing (living people)	{ "pile_set_name": "Wikipedia (en)" }
Q: CSS z-index property Really hoping someone can help a z-index novice. I'm trying to position a div on top of everything else on my page: http://www.designbyantony.com/bipf/index.html The div (you can probably see the problem) is the roun blue circle with 'March 6-8 2015'. I'd like it to sit on top of everything else properly - ie: run over the nav bar a bit and chip over the area which has the repeating 'arch' design. I've tried using z-index but I'm obviously going wrong somewhere. CSS is at http://www.designbyantony.com/bipf/styles.css Can anyone help me? A: Change into your CSS like that.Remove the both position:relative from CSS #page_content { width: 970px; margin: auto; height: auto; padding-top: 15px; padding-left: 5px; padding-right: 5px; /* position: relative; / background-color: #FFFFFF; overflow: hidden; / position: relative; */ z-index: 2; } and again change your CSS of #dates.remove left position left:1046;top: 171px; and put there right:0 #dates { position: absolute; left: 1046px; top: 171px; z-index: 10000; height: 140px; width: 140px; display: block; background-color: none; } A: Remove overflow: hidden in the #page_content in styles.css at Line 245: #page_content {overflow: visible;} Or if you would like to have clearing after the #page_content, you can use something like this: #page_content:after {display: block; clear: both; content: " ";} Reason: The parent of #dates is been cropped by #page_content, which has overflow: hidden, that doesn't allow contents to be hanging.	{ "pile_set_name": "StackExchange" }
p 257 Since the early twentieth century in Japan and for the past two decades in the west, the Zen master Dōgen (1200-1253), founder of the Sōtō lineage, has attracted widespread attention and acclaim both as a philosopher and as a literary master. Dōgen 's primary work, the Shōbōgenzō, written and compiled serially during the last two decades of his life, is now regarded as one of the greatest expressions of truth in the Buddhist tradition. The title itself, The Eye and Treasury of True Dharma, [1]shows that the overall aim of the work is to disclose truth. The text purports to penetrate to the very essence of Buddhist experience by disclosing its truth (bo) properly or correctly (sho). Invariably dedicated to the truth of the matter at hand, Dōgen works his way through the vast spectrum of traditional Buddhist thought and practices, skillfully appropriating, criticizing, and redefining the meaning of Buddhist experience. Yet nowhere in this quest for truth does the Shōbōgenzō systematically address the question of the nature of truth as such. We are not told what understanding of truth supports the claim, for example, that a certain doctrine is true, or that the practice of zazen authenticates the truth of doctrine. The aim of this study of the Shōbōgenzō will be to clarify its implicit concept of truth, and to show how such clarification can shed light on the meaning of the text as a whole. This task is complicated, however, by the fact that the Shōbōgenzō deals with two kinds of truth, yet never makes their difference explicit. On the other hand, true Dharma signifies "correct doctrine," p 257 and many chapters in the Shōbōgenzō take this as their primary concern. "True followers of the way" are sharply distinguished from "non-believers," and "right transmission" of Buddhism is opposed to "false doctrine." Here the Shōbōgenzō's task is to clarify the difference between true and false doctrinal positions and to encourage correct belief. In this case, "truth" implies a straightforward correspondence between doctrine and the reality that it represents. According to a second understanding, however, truth is manifest beyond the distinction between correct and incorrect correspondence. This view overturns the centrality of doctrine in the sense that true Dharma does not contrast with false Dharma, but rather, includes it. Hence, truth can encompass equally the oppositions between belief and doubt, enlightened and ignorant, samsara and nirvana. This understanding of truth goes beyond truth as correspondence, yet includes subtle traces of it. True Dharma in these references is that in which one resides, or the essence that all beings embody, but in no instance is it a conceptual possession of certain individuals. On the contrary, all beings are possessed by it whether they realize it or not. As we shall see, both of these understandings of truth can be found throughout the Shōbōgenzō. Truth as Correct Dharma and Right Understanding Dōgen initiates a significant change of course in the Zen tradition when, from within that tradition, he opposes the radically anti-doctrinal posture of Zen's paradigmatic figures such as Bodhidharma, Hui-neng, Lin-chi, and Ta-hui. Even today, Dōgen 's writings are unique in the Zen tradition for the extent to which they take seriously such traditional matters as doctrine, language, scripture, and faith. In chapter after chapter of the Shōbōgenzō, an adamant stand is taken: sutras are not just "names and forms" that must be rejected in order to attain authentic practice and enlightenment. On the contrary, to reject the sutras is to reject the Buddha's proclamation of Dharma. For Dōgen, the spoken Dharma is as essential as the "wordless Dharma" and, in fact, is inseparable from it. Similarly, for Dōgen, the practice of zazen is not, as some of the great Chinese Ch'an masters had been teaching, a ritualized behavior that one must leave behind in the quest for enlightened spontaneity. Failure to practice zazen is failure to practice the Buddha Way. Zazen is not an ordinary activity; it is handed down from Buddhas and Patriarchs as the right way to practice enlightenment. p 258 The Shōbōgenzō expresses immense respect for the Buddhist sutras, for the historical Buddha who initiated their transmission, and for the transmitted tradition as a whole, and on this basis, takes a strong stand in doctrinal matters. A master of critique, with an uncanny sense and awareness of language, Dōgen works his way through the vast repertoire of Buddhist doctrines and practices, alternately praising, criticizing, and reinterpreting them. In the process, Dōgen makes it perfectly clear: belief or disbelief is not an indifferent matter. On the contrary, correct doctrinal belief is essential to the Buddhist way. Dōgen is persistent in his efforts to expose "false views" and to present the "correct viewpoint." Ability to "discriminate the true from the false" is for Dōgen essential to enlightenment (1977:78/1972:188). [3] "Trainees should learn this: It is imperative that we can discern true from false" (1983a:109;1972:450). "Mistaken belief," "evil belief," "distorted ideas and opinions" are to be rooted out, and replaced by the "correct viewpoint," "truth without error." References to "non-believers" — those doctrinally "outside the Way" — are found throughout the Shōbōgenzō, and Dōgen warns of the dangers of associating with them (1983a:83;1972:75). Various versions of "distorted teaching" stand in clear opposition to the true, which should not be subjected to doubt (1983b:16;1972:345). "When you hear the true teaching believe it without any doubt" (1975:95;1970:294-5). "Do not have any doubt about it" (1977: 164; 1970:332). Which particular doctrines and viewpoint are taken to be "correct" is not of concern here. But one example will illustrate how the case is made for right understanding in doctrinal matters. In the ]inshin Inga chapter, where Dōgen defends the principle of "causality," the text reads: "To harbor doubts regarding the law of causality as many monks do, is a clear denial of this law's very existence. Truly it is regrettable that the Way of the Buddhas and Patriarchs has declined in this way.... We should not doubt this [teaching]" (1983a:97;1972:432). Correct belief on this issue distinguishes true Buddhists from the unorthodox, those "outside the Way" (gedo). "A man may take ordination, he may wear a monk's robe, but if he subscribes to this mistaken view, he is not a disciple of the Buddha, for, as already stated, this is the doctrine of non-believers"p 260 (1983a:98-99;1972:450). Dōgen is adamant that unless one believes and understands correctly on this matter, there can be no progress on the Buddhist path. "It is imperative that trainees clarify the principle of causality first, otherwise they will remain susceptible to false views, their practice decline, and finally they will cease from doing good altogether. The principle of causality is straightforward; those who do wrong fall into hell; those who do good attain enlightenment" (1983a:101;1972:437). Quoting a Zen poem that says that "causality is as true and unchangeable as pure refined gold" (1983a:100;1972:436), Dōgen makes this point clearly: the principle of causality is permanent and knowable. When one understands properly and holds the correct viewpoint on this matter, then one's understanding corresponds with the way things truly are, and the consequences of such correct belief are ultimately beneficial. On the other hand, "spreading false doctrine is a most serious crime" (1983a:106;1972:447). "The principle of causality means that those who practice well realize enlightenment — it's as straightforward as that" (1983a:98;1972:433). To justify this doctrinal claim to truth, Dōgen appeals to tradition. "It is apparent that the Patriarchs never denied the chain of causality....Do not teach that causality does not exist; this is untrue and conflicts with the Law transmitted by the Buddhas and Patriarchs. Only those ignorant of the true teaching support such views" (1983a:97;1972:432-33). Several times the appeal is made to one particular patriarch, Nagarjuna, who, ironically enough, in his "causality" based claim that all doctrines are empty (sunya), initiated the historical sequence that led to the denial of causality that Dōgen so dreaded. So Dōgen invokes Nagarjuna to set things straight. "As Patriarch Nagarjuna said, "to deny, as non-Buddhists do, the principle of causality, is not only a denial of the existence of the present and future worlds, but also the existence of the three treasures, the Four Noble Truths, and the various stages of arhathood" (1983a:98; 1972:434). The authority of tradition, and of Nagarjuna in particular, is so powerful that Dōgen can simply sum up the matter by saying: "The preceding are the compassionate teachings of the Patriarch Nagarjuna, We should gratefully accept and heed these words" (1983a:98; 1972:434). This example shows the Shōbōgenzō's position on the nature and importance of correct doctrinal belief by focusing on a doctrine that is fundamental to most Buddhist thought. The same essential attitude, however, is presented on many matters of correct belief and practice, from the doctrine of karma to the details of monastic practice. There is a right way of belief and practice in all matters that is knowable and verifiable as true and efficacious. How can one correctly distinguish p 261 the true from the false? [4] The Shōbōgenzō's answer to this question in the above example is a pattern that appears throughout the text. Tradition, "the Buddhas and Patriarchs," supplies the standard by which to judge the truth of doctrine. "Anyone who wishes to determine if a teaching is correct or not should use the standards of the Buddhas and Patriarchs. They are the true masters of the wheel of the Law whom we should consult" (1977:23;1970:392). A doctrine can be verified as correct if it can be found to be the teaching of Buddhas and Patriarchs. Furthermore, the Shōbōgenzō holds that the content of correct belief and practice has been accurately transmitted from the Buddhas through centuries of tradition. [5] "I also learned (from a sutra) that the Patriarchs transmit the Dharma free of error" (1983b:100;1972:400). That the Patriarchs' transmission can be trusted Dōgen claims to have learned from a sutra. The tradition apparently verifies itself. Furthermore, because the transmission of doctrine is unbroken, the Buddhist Dharma has been able to escape the vicissitudes of history: " ... it is not difficult to authenticate a doctrine even if removed by centuries from the Buddhas and Patriarchs" (1983b:72). Dōgen is aware of at least some of the historical and hermeneutical problems that arise when the truth of historically transmitted doctrine is based upon the word or confession of that same transmission. The divergence and plurality of belief is an often mentioned and much lamented fact in the Shōbōgenzō. But Dōgen 's response is simply that the others have received it incorrectly, and that the truth runs like a single unbroken thread down through the centuries. "Shakyamuni's Eye and Treasury of the true Law and supreme enlightenment was only rightly transmitted to Mahakasyapa, and no one else. The right transmission surely passed to Mahakasyapa" (1977:23;1970:392). But in spite of the continuity of tradition, there are those who hold "mistaken and distorted views." "Unfortunately many masters have proclaimed the teaching based on their own limited mistaken views... They distorted the teachings to conform to their own misguided interpretation which they contested to be true Buddhism" (1983b: 16; 1972:345). Although these people think they possess the p 262 truth, they are caught in an illusory perspective that can only be exposed by showing them the correct interpretation of the teachings. "Inferior monks remain ignorant and do not know that their teaching is twisted. It is a pity that they are trapped in illusion. Such people have not experienced the Dharma and do not know how to think properly" (1983a:83;1972:76). Apparently those who hold a correct viewpoint and those who adhere to incorrect doctrine both believe that their view is true, and both verify that view by reference to the tradition. Yet nothing in the Shōbōgenzō indicates how one might adjudicate the conflict of interpretations. The circularity of an appeal to tradition as a means to verify an interpretation of tradition is not raised to the status of an issue. Therefore, even the pivotal principle itself can be stated in circular terms: "This is the Buddhist teaching of right transmission — only those with right transmission can correctly calculate right transmission" (1983a:68;1972:38). As Dōgen seems to sense, the whole procedure seems to rest on one crucial belief: "belief in right transmission" (1977: 181). But even if there is difficulty in grounding correct belief, it nevertheless remains a central theme throughout the Shōbōgenzō that the truth or falsity of one's doctrine and practice is a matter of great significance. In contrast to much of the Zen tradition that precedes it, the Shōbōgenzō is adamant that doctrine does make a difference. To bring the significance of this position into focus, one might contrast Dōgen’s relentless critique of false views with Nagarjuna's famous "critique of all views." For Dōgen, not all views obstruct realization, only those "outside the way" (gedo). Others, sanctioned by Buddhas and Patriarchs, are to be cultivated. It is significant that the Shōbōgenzō commonly refers to the Lotus Siitra as the highest standard for truth, because this text can clearly be seen to support Dōgen's emphasis on correctness and truth of belief. But this same sutra also expresses a concern for universality and all-inclusiveness. It probes toward a position that, rather than simply contradicting other positions, attempts to take them all in, including them in one universal Dharma. This is also Dōgen 's concern, a concern which derives from a second approach to the question of truth. Truth as the Embodiment of Dharmata Some sections of the Shōbōgenzō take a different position on the question of truth. Rather than focusing on conceptual or propositional truth, they maintain that truth is neither graspable in concepts nor expressable in propositions. Although nowhere in the Shōbōgenzō is a systematic theory of knowledge articulated, it is not difficult to p 263 sense, in many chapters, that the Buddhist concepts of impermanence and emptiness (as well as Dōgen’s own practice) stand behind his view that truth, dharmata, is not graspable in conceptual knowledge. Many passages demonstrate a profound insight into the Mahayana understanding of "ungraspability," "unattainability," "incomprehensibility." Two such passages read: "When you have complete understanding then even the ideas of the wisdom of enlightenment or the status of detachment will be seen for what they are — tentative and delusive"(1975:70;1970:260). "We cannot say that there is; or is not, practice and enlightenment — it cannot be comprehended or attained. Again the great meaning is beyond attainment or comprehension. We cannot say that there are no holy truths, practice or enlightenment, nor can we say that there are holy truths, etc. Nothing can be attained, nothing can be comprehended" (1977:5;1970:307)." On this basis, it would be inappropriate to hold, with unquestioning certainty, any view. Such holding is a kind of grasping that prevents attainment of the way. This second understanding of truth appears to stand in sharp contrast to the first which advocates "correct views" and which seeks to expose heresy (gedo). Some sections of the text even go so far as to proclaim the impossibility of propositional correctness and its inadequacy as the goal of praxis. Even in its most anti-heresy passages, the Shōbōgenzō never comes close to saying that enlightenment consists in absolute knowledge or correct understanding. Clearly, realization does not consist in transcending human limitations; it entails instead an awareness of them and the "unattainability" of perfect knowledge. Thus the Genjokoan chapter maintains that, "when the Dharma is completely present, there is a realization of one's insufficiencies" (1975:2;1970:37). Dharma or truth, therefore, must include those insufficiencies along with an understanding of them. One of the Shobogetizo's most famous passages says, "To have great enlightenment about illusion is to be a Buddha" (1975:1;1970:35). This radical grasp of illusion characterizing a "Buddha" is contrasted with the "great illusions about enlightenment" which characterize sentient beings. One has "great illusions about enlightenment" when one takes it to be the perfect possession of knowledge rather than the humble practice of "no-mind." One who truly practices the way, realizes the "insufficiencies" of all views and is, therefore, less inclined to engage in the self-centered struggle to have one's own view prevail. In matters of thought, it is more fruitful to seek the strength or the truth of all views. In this vein Dōgen can say, "Never take your own viewpoint to be definitive, alternative interpretations must be studied to develop unified understanding" (1983b:49;1970:130). The attitude appropriate to this kind of p 264 truth is detachment. Such truth becomes manifest only when all self-centered grasping for it is set aside and replaced by a mode of being characterized by openness. Thus the Shōbōgenzō occasionally interrupts meditation on an idea to remind the reader that the text's message can only be understood in a released state of mind. "If there is no detachment, there can be no attainment of this observation" (1975:20;1970:85). No matter how subtle and open a discussion is, the conceptual process inevitably tends toward abstraction, objectification and attachment. "Remember though, that real Buddha mind is detached even from these statements" (1975:20;1970:85). On this basis Dōgen concludes that ordinary thinking is inadequate to this highest form oftruth. Our rational thought processes only attain the perspectives and opinions criticized above; by their very nature they cannot grasp "the true nature of all dharmas" (dharmata / hossho). On the other hand, a simple negation of thinking gets one no closer to realization. Because non-thinking is a willful, active, and mediated relation to immediate experience it shares essential features with its supposed opposite, thinking. Both thinking and non-thinking express the subject's own effort to determine and "frame" experience in a particular way. Dōgen sets out to show that there is a fundamentally different kind of "thinking" (experience) which he calls "thinking without thinking." [6] "Without thinking" (hishiryo) is not "non-thinking" (fushiryo) just as Buddhist "no-mind" is not mindlessness. Rather, it is the foundation of mind that encompasses mindfulness and mindlessness — all forms of mind — and thus actualizes mind in its entirety. Dōgen puts it this way: "After we develop the mind of practice through enlightenment, we will realize that the source of all these forms of mind is "no-mind." "No-mind" is the true Buddhist mind undivided, beyond discrimination of opposites — and contains no analysis. To comprehend the true way we need "thinking without thinking" (1975:9;1970:74-75). "Without thinking," according to Dōgen, is the fundamental state of mind; it precedes all discrimination, analysis, and subject/object separation. This prereflective "pure experience" is the basis of all positive and negative reflection. All experiential, linguistic, and conceptual structures arise out of it. This level of experience is prereflective — it precedes thought — both in the sense that it comes first and in the sense that it grounds all reflection. All conceptualized experience has a basis in and is elicited by the world that appears to us preconceptually. The one who does the thinking — the individual subject or self — makes his/her appearance in p 265 the course of time, [7] gradually, and in different ways, but does so, according to the Shōbōgenzō, on the basis of a prior unity. Although forgotten or obscured, this unity is nevertheless always present; without it neither subject nor object would appear. Dharmata (Hossho), "the true nature of all dharmas" is not, therefore, the subject's correct experience of objective dharmas — it is the "presence of things as they are" (genjokoan) prior to the reflective separation between subject and object. Therefore, very often, when Dōgen (and others in his tradition of language practice) speak of mind (shin), they signify neither the subject's reflection, nor the mechanism of reflection, but the total, unbroken process whereby the world comes to manifestation through the subject. In the deepest sense, mind is the unity of experience: "This is the stage of pre-thought beyond egocentric cognition. If you reach this state of pre-thought you will realize the true luminous nature of mind — prethought must become the eye through which you view phenomena" (1975:10;1970:75).[8] Reflective, second and third order experience, "enforms" and "enframes" this prereflective presence in particular ways. Pattern, structure, and a framework order experience in various ways that are meaningful, suggestive, and useful. But for Dōgen, this thoughtfulness loses track of its character and its basis. The forms and structures of conceptuality are taken to be "the true nature of things" — a closure that fails to see other structures and perspectives, as well as the experiential basis of all subsequent structuring. Fundamentally, mind is open and undetermined. Structural closure is a static and narrowing focus. For this reason, "without thinking" (pre-thought) is characterized in terms of openness and receptivity. Hence Dōgen exhorts his listeners and readers to look at things from different angles and perspectives, to pry open the rigidity of frameworks, and thus, perhaps, to work back through them to their foundation — the pre-reflective, unframed presence of things as they are. This is the function of zazen, for Dōgen, the practice of things as they are and the occasion for things to be as they are. In true zazen, the practitioner penetrates beneath the structures and norms of conceptualization, beneath even subjectivity and objectivity, to the pure becoming present of dharmas — what is in truth. This truth is transcendent, unlike the truth of propositional correspondence, because it is not conceptually constructed, nor is it graspable in that form. "It completely goes beyond ideas of difference and identity, separation and unity, between this phenomenal world and dharmata" p 266 (1977:64). Its transcendence, however, is its depth and proximity rather than its distance from us. As what is most fundamental and deeply rooted (hon), the truth of dharmata lies so close to us and is so all-pervasive that, immersed in it, we cannot grasp it as something at hand. [9] The fact that this truth encompasses all beings, whether they know it or not, allows Dōgen, in ecstatic language, to play with the meaning of enlightenment and the dichotomy between enlightenment and illusion. "Priests of the present day think that there are two distinct states: unenlightenment and enlightenment. They think that unenlightenment becomes enlightenment and it is attained from somewhere or someone else. But even that idea is nothing but great enlightenment. ... Consequently, everything, right now, is the eternal present in great enlightenment. This is great enlightenment, this is great enlightenment" (1975:38;1970:24). All views, including the enlightened and unenlightened, derive from what is most primordial and, therefore, common to all beings. Great enlightenment encompasses everything; it is the "true nature of all dharmas" and is experienced in pre-reflective immediate presence. Therefore, it cannot properly be contrasted with an opposite — unenlightenment. Thus the text says: "We should not study enlightenment as something that occurs when unenlightened people are awakened to great enlightenment. Both people in illusion and enlightened people have great enlightenment; unenlightened people and those who are not in illusion also have great enlightenment" (1977:55;1972:21). Truth in this second sense of dharma does not stand in contrast to an opposite such as untruth, falsity or ignorance: "Wisdom and ignorance appear to be in opposition like the sun to the moon but ultimately they transcend this opposition" (1975:62). Rather, untruth or ignorance is simply another form that dharma takes. The Shōbōgenzō continually plays with this paradox: "Turning one's back or opposing truth is malicious. However, truth can even be found in those actions. Who can fathom the relation between maliciousness and truth?" (1975:52;1972:154). Furthermore, this level of truth is indifferent to the distinction between doubt and belief so important to the first meaning of truth discussed. "Even if we doubt it, still Buddha-nature has emerged in us" (1983b:123;1970:48). Dharmata, the true nature of all dharmas, is all-inclusive and inescapable. Neither illusion, doubt, nor everyday mindlessness puts one outside of its scope. Dōgen shows this conclusively in one of the p 267 Shōbōgenzō's most beautifully crafted sections by appealing to the Zen master Baso: "Zen master Baso said, 'Sentient beings have never left the state of dharmatta samadhi throughout myriads of kalpas. They are always in a state of dharmatta samadhi, putting on their clothes, eating rice, greeting their visitors, and using the six sense organs. All their actions are the function of dharmata" (1977:64;1972:84). Truth in the sense of dharmatta is not something that anyone lacks; not is it, therefore, the legitimate goal or aim of anyone's quest. We already reside within it in an undivided and unqualified way. But what, then, is Dōgen’s Zen about, if not just such a quest? What is the meaning of the Buddhist way of practice if we are already possessed by its goal? According to the traditional story of Dōgen’s life, this very question set Dōgen himself out on his way (from the Buddhist establishment at Hieizan), forcing him to probe beneath the objectifications of Buddhist doctrine toward the experience that initially generated them. For Dōgen, the question was answered and its problematic character dissolved, when, through his own practice and the guidance of his teacher, he discovered that practice is ill-conceived when it is taken, as it had been traditionally in Buddhism, to be a means to the goal of enlightenment. Dōgen’s realization was that practice is the goal; the goal is to practice (that is, to undertake and perform in all one's actions and at all times) enlightenment. [10] The relationship between practice (shu) and realization (sho) is not to be conceived as a relationship between means and end where one practices in order to attain what one lacks. Rather, in practice, one authenticates the prior presence of Buddha-nature; and Buddha-nature shows its fundamental presence in any act or moment of practice. [11] Practice (exemplified in, but not limited to, zazen) is simply openness to the pre-reflective immediacy that is already present, although hidden beneath conceptual structures and reified ways of framing experience. On this account, practice is not abandoned when realization is attained, it is heightened and becomes more thoroughgoing as the presence of the Buddha-nature is revealed more and more concretely. Therefore, Dōgen says: "Even after attainment of the way, they neither relax nor abandon their practice. Their essence cannot be measured; their essence is their bearing and manner, and this manner is their attain- p 268 ment of the Way" (1977:87). Attainment of the way of practice manifests its results, we see in this passage from Dōgen, in a transformation of one's "bearing" or "manner". This bearing or manner is described as "continuous practice and study of the Way" (1983a:2;1970:166). To practice in this way is to "reside in the truth" (Yokoi: 176) at all times including "daily action, drinking tea and eating rice" (1983a:11;1970:181). In Dōgen’s view, this all-inclusive and very subtle understanding of practice is the most adequate because it mitigates against dualistic conceptions of practice, which separate it from realization. Therefore, Dōgen calls for practice without expectation of enlightenment, because in this view, such practice is enlightenment. Thus Dōgen exhorts his followers: "Concentrate on practice. Do not expect great enlightenment; great enlightenment is daily action, drinking tea and eating rice" (1983a:11;1970:181). Throughout this discussion, however, another more subtle distinction emerges: that between those who are engaged in authentic practice and those who are not. Yet how can this distinction be maintained against Dōgen’s claim that all sentient beings are always in the enlightened state of dharmata and that the distinction between enlightened mind and ordinary mind is false? "All minds are mindfullness. The minds of fools and saints, grass and trees" (1977:76; 1972: 184). The crucial distinction that remains and that Dōgen’s Zen must presuppose is that while dharmata expresses an ontological identity (all experience has its ground in pre-reflective unity), one must still acknowledge that some beings recognize and live in accordance with that realization and some do not. Although all acts are practice and all beings are Buddha-nature, not all beings live in awareness of that fundamental identity. Therefore, in traditional Mahayana terms, while the bodhisattva experiences the identity and emptiness of all beings, as this experience matures in practice, it becomes more and more obvious that most other beings do not recognize the reality in which they live. This difference comes to be experienced as crucial and gives rise to the bodhisattva's compassion. This important distinction can be seen throughout the Shōbōgenzō. In the following passage Dōgen says that doubt and belief are both forms of truth, but whether one realizes this or not makes all the difference: "Even doubts about the dharma are true form. Those who possess the Buddha's wisdom realize this, for they experience a peaceful existence" (1983b:114). Or as the following passage expresses it in paradoxical form, neither enlightenment nor illusion exist, yet to recognize that is enlightenment and not to do so is illusion: "We should p 269 know that neither enlightenment nor illusion exist. Those who are aware of this have attained enlightenment of absolute truth and are called Buddhas" (1983a:129 — my emphasis). In the Gyoji chapter of the Shōbōgenzō, Dōgen encourages his followers to engage in the "ceaseless practice of the present" (1983a:2;1970:166). But then, further down the page, he says something that could be taken to undercut any basis for encouragement: that all actions already are ceaseless practice (1983a:2; 1970: 166). If all actions already are ceaseless practice, why should one strive to practice ceaselessly? Dōgen’s point here is clearly that one's relation to practice makes all the difference. Although everyone always practices, that is, acts out their destiny in "daily life, eating rice, and drinking tea," most human beings tend to live in a narrowly conceived world of representations that limit and determine the openness and depth of life. To most people daily life is ordinary and dull, while the Buddha-nature they seek is exalted and otherworldly. But to Dōgen, for one who realizes it and practices it, daily life is the life of the Buddha. There is no difference between the acts of the enlightened and unenlightened: both eat rice and drink tea. The difference is manifest only in one's awareness of the activity. For the unenlightened, daily life is that with which one is occupied when one is not practicing. For the enlightened, daily life is practice, and what one practices is openness to the continual manifestation of what is present beyond the subject's own interests, concerns, and projections — indeed, beyond the self's individuated existence. The second meaning of truth in the Shōbōgenzō, truth as dharmata, goes beyond propositional correctness and correspondence. The "truth" is simply what is — what comes to be — beyond any partial and perspectival grasp that I have on it. This truth grounds all of us, enlightened and unenlightened; we are immersed in it; we speak, think, and act out of it. Still, Dōgen exhorts his listeners/readers: "Look into zazen for the truth" (1977:44;1970:448). Zazen in this passage is the "place" where one can most readily find the truth that already resides within and around one. "Truth" refers both to dharmata and to the awareness of dharmata. The former is nondualistic; dharmata is all that is. But the latter is distinct from its opposite, the absence of such awareness. This distinction between awareness and unawareness of truth generates the difference in "bearing" or "manner" that distinguishes "attainment of the Way" from non-attainment. Such "enlightened bearing" is the mode of being of one whose primary activity is "ceaseless practice of the present" and whose experience, therefore, reflects the "presence of things as they are." p 270 Doctrine and the Unity/Diversity of Truth In "pure experience" (junsui keikan), a contemporary way of referring to Dōgen’s pre-thinking mode of zazen, no reflective distinctions obtain. All that is, before thought, is the "presence of things as they are" (genjokoan). Nevertheless, as we have seen, the bodhisattva, immersed in this "emptiness", experiences an acute difference among living beings — that some are aware of pure experience and some are not. This experience gives rise to the bodhisattva's compassion and the call to activity. Dōgen’s reflections on this aspect of the tradition, and his own' experience of it, acknowledge the tension between the open receptivity of "pure experience" and the bodhisattva's calling to act and to "make a difference" for other beings. In classical Mahayana language, this is the tension between the experience of emptiness and compassion. Thus Dōgen says that even though doubt is itself the truth of dharmata, still we should enlighten and transform all doubt: "Even though disbelief is itself true form, still we should enlighten the true lotus flower and thus clarify the eternal existence of Buddha" (1983b:116). Although "pure experience" is empty and doctrineless, doctrine and teaching are not irrelevant to the bodhisattva's practice. On the contrary, Dōgen claims that teaching and thought are important aspects of the practice, and that these are inevitably doctrinal matters. Dōgen is relentless in his critique of the "wordless dharma," the view, widespread in the Zen tradition, that since ultimate truth is beyond language, any form of linguistic or doctrinal teaching is misleading or irrelevant (1977:188-9;1972:261). According to Dōgen, this position is naive about what really takes place in the tradition. "Those who think they know that words are just names and forms do not know that Shakyamuni's words are not bound by letters and forms. Those people are not liberated from ordinary mind. The Buddhas and Patriarchs who have totally cast off body and mind use words to proclaim the Dharma and turn the wheel of law and many benefit from seeing and hearing it. Those who have faith and follow the Dharma will be influenced by both the spoken and wordless Buddhist teachings" (1977:60;1972:57). The text appears to say that doctrine is one means by which one comes to experience the emptiness of doctrine. That doctrine is empty is itself a doctrine that must be appropriated in practice. Thus Dōgen radically reinterprets the role of language and doctrine in the Zen tradition. On this basis he says that the Zen admonition to "'Abandon profound and marvelous speech' is just another form of profound and marvelous speech" (1977:53;1972: 19). But the specific status of such "profound and marvelous speech" or doctrinal teaching is as ambiguous a matter as it is important. p 271 Several different possibilities are suggested throughout the text. There are passages that seem to imply that, although doctrine is not ultimately true itself, it can function as a means to the experience of truth. Thus the first meaning of truth as correct doctrine would stand in an instrumental relation to the second, truth as dharmata. In this light Dōgen can say, "Such an enlightened understanding must be developed by continuous practice and study of the Way" (1977:59;1972:56; Yokoi: 169). [12] But this view is explicitly and rigorously denied by other passages. One of the clearest themes in the Shōbōgenzō is that practice — including doctrinal practice, religious thinking — is not to be conceived as a means to the goal of realization. On the contrary, practice is based on enlightenment and issues from it. Practice in order to enlighten oneself is inauthentic practice, while a single instance of authentic practice actualizes enlightened "bearing." The unity of practice and realization (shusho-ittot / shushoichinyo) applies for thinking and doctrinal understanding in the same way that it does for zazen. Therefore, authentic understanding of the doctrine of genjokoan (the presence of things as they are), for example, is based upon the presence of things as they are, but no amount of thinking about the doctrine of genjokoan puts one in the presence of things as they are. Pure pre-reflective experience, the Buddha-nature that grounds all beings, is the basis for all thought; reflection (and all activities of the subject) has its point of departure in the unity of subject and object that is pre-reflective. But, human beings differ in the extent to which "pure experience" is obscured or manifested in daily life. Thus, one's thought or doctrinal understanding reflects the state of one's practice and realization. What one thinks and says (or does, writes, paints, etc.) corresponds to, and therefore reveals, one's mental state and depth of realization. Thought both arises out of and reveals the extent to which one practices and realizes the truth of dharmata in "pure experience." [13] In the Shōbōgenzō, the conventional means/end relation between practice and realization is inverted: practice is based on realization. This understanding leads Dōgen beyond the view that correct belief or doctrine is a prerequisite for realization. Instead, the text typically asserts that realization — the presence of things as they are in pre-reflective experience — authenticates doctrine. Doctrine is authenticated (sho) in pure experience in the sense that one comes to understand it for the first time. Prior to this transformation of experience, p 272 one's understanding was superficial and grounded more in subjectivity than in the unity of the situation. In the experience, however, seeing and believing are the same activity. To experience deeply the impermanence of all things is to understand the doctrine of impermanence. To be in "the presence of things as they are" (genjokoan) is to know finally what genjokoan means, thus authenticating a doctrine that before was only superficially believed. While this theme is crucial for understanding the relation between doctrine and realization in the Shōbōgenzō, it is still incomplete. Even if realization authenticates doctrine, we can still ask: How is doctrine itself significant? Authentic practice — which is realization — is the heart of the matter for Dōgen. That doctrine is authenticated in the process seems almost beside the point until we can see what significance it might have in itself. Indeed, the text's insistence that doctrine not be considered a means to the goal of realization, raises the question: Why does Dōgen bother with doctrine at all? An adequate answer to this question requires a brief clarification of the apparent opposition between Dōgen’s terms "thinking" (shiryo) and "without-thinking" (hishiryo). If realization isho) is truly "without thinking" (pre-reflective), and if thought does not function as a means to realization, then doctrine would seem to have no role to play in Dōgen’s Zen. But realization is not a negation of thinking (jushiryo), and the Shōbōgenzō is Dōgen’s finest doctrinal expression. For Dōgen, to ground oneself in pre-reflective experience (hishiruo) is not to abandon thought. On the contrary, such experience gives rise to thought of the purest kind, thought that reflects perfectly the "presence of things as they are." "To think without thinking" is to have so thoroughly set aside one's own will, desire, and subjectivity that one's thought reflects the occasion or situation at hand and not one's own design on it. Thought responds to the situation that evokes it by taking its bearings primarily from what is present, both here and now. Ordinary thinking (shiryo) is the subject's own creation. It accords more with the subject's desire or habits than with the situation at hand. The failure of ordinary thought is that it pre-forms all experience; it simply cannot allow what is to be present as it is. "Thinking without thinking" requires that the subject let go of its own plans and devices, and attend to what is as it comes to presence. Rather than eliminating thought, this simply realigns thought with reality, beyond the subject's own will to enframe it. On some occasions, it is sufficient to be aware of the situation at hand directly, without thinking. More complex situations call for more elaborate and systematic reflection. Both extremes, however, are grounded in the situation rather than in the subject, and both call for an openness that is uncharacteristic of p 273 anything we typically regard as thinking. Pure experience then, gives rise to thought of its own accord, and Dōgen’s religious thought is one form that this thinking can take. This understanding has far reaching consequences for the status of doctrine. If the situations to which thought conforms are impermanent, always turning into new situations, then doctrine would have to change along with them. Dōgen does not shy away from this conclusion: the teachings are impermanent: "Therefore, teaching, clarifying impermanence, and practice are by their nature impermanent. Kanzeon proclaims the Dharma by manifesting himself in a form best suited to save sentients. This is Buddha-nature. Sometimes they use a long form to proclaim a long Dharma, sometimes a short form for a short Dharma. Impermanence itself is Buddha-nature" (1983b:128; 1970:54). What this means is that there cannot be one permanent body of correct doctrine because the reality to which it would have to conform is itself variable and in transformation. As the text says clearly, "circumstances are constantly changing the form of suchness" (1975:130;1972:252). Religious thinking that originates in pure experience does correspond to the reality of the situation, but it is also empty (Ku) in the sense that it originates dependent upon the particularities of the given situation. As an expression (dotoku) of a given occasion (jisetsu), it is neither permanent nor universally applicable. On this account therefore, the Shōbōgenzō should be read as a series of such expressions occasioned or elicited by various and changing circumstances in Dōgen’s world between 1231 and the year of his death in 1253. If so then Dōgen’s Zen would appear to be ultimately baseless, without any kind of stable and enduring foundation. Again, the text, (Immo chapter) radically confirms our reservations: Suchness is the real form of truth as it appears throughout the world — it is fluid and differs from any static substance. Our body is not really ours. Our life is easily changed by life and circumstances and never remains static. Countless things pass and we will never see them again. Our mind is also continually changing. Some people wonder: If this is true on what can we rely? But others who have the resolve to seek enlightenment, use this constant flux to deepen their enlightenment (1975: 58). Dōgen’s position is simply that doctrine's ultimate baselessness is nothing to fear. In fact, that baseless quality of impermanence is the Buddha-nature towards which all authentic doctrine should direct us. But once again a qualification is required. Authentic thinking is not completely baseless. There is something concretely given to which it p 274 must correspond. That is the given situation itself, which comes into being in its own unique form and structure. All thought and action must take their bearings from this situation, responding to it in accordance with the situation's own requirements. Doctrine is authentic to the extent that it is such an open response and to the extent that it includes within it some recognition of its own impermanence/emptiness. If authentic Zen thinking is a spontaneous response to the situation arising out of "pure experience," it requires no justification in terms of function. As such, it simply belongs to the situation itself, as does the person, whose role is simply to be open to and to respond to "things as they are." Thus Dōgen can suggest (in Mujo-seppo) that his dharma discourse is not so much his as the dharma's own discourse, speaking through him as it does through all kinds of beings (1983a:68). But the Shōbōgenzō implies further that this thoughtful response to the given situation is extremely important. For Dōgen, as for the Mahayana tradition generally, doctrinal expressions correspond to the suffering and ignorance of the world. Buddhist thought suits the occasion whenever it alleviates suffering and enlightens ignorance. Since authentic doctrine expresses the "bearing" and "manner" of pure experience, it may function as an inspiration, an enabling power, or an opening toward the experience from which it derives for anyone who is in a position to appropriate it. Doctrinal expressions also make experience explicit; they bring a pre-reflective mode of being to conscious reflection. The Shōbōgenzō implies in numerous places that this process of thematic understanding is not a supplement to realization. Rather, it seems to be a necessary part of the development of enlightened awareness. Thus the paradoxical phrase "thinking without thinking" appears to express a reciprocal relation between thought and "without thinking." Dōgen formulates the relation in this way: "Priest Hoen once stated: 'Practice cannot go beyond thought; thought cannot exceed practice.' This expression is important. Think about it day and night, practice it morning and evening." (1983a:lO;1970:179). From this perspective, we necessarily practice what we understand, while, at the same time, understanding is based on practice. Similarly a reciprocal relation can be seen between realization (actualization of pure experience) and practice. Practice is based upon realization. As realization deepens, practice is transformed. One no longer sits zazen in the same way as before nor does one act and conduct daily life in the same way. But the reverse of this must also be true. As practice deepens so does realization, since in the final analyses they are one and the same. Thus, for Dōgen , thinking should be a spontaneous response to "things as they are" in themselves. As such, it is encompassed by p 275enlightened awareness, for its role is to bring the true situation to conscious awareness. Yet, doctrinal thought has no final status, since it is relative to a given situation. The impermanence of Buddhanature requires doctrinal impermanence. Enlightened awareness takes its cue from impermanence itself and embodies a responsive relation in it. This awareness is expressed most appropriately in doctrines that show their own impermanence/emptiness. These conclusions prompt one final question: To what extent does the Shōbōgenzō itself manifest this understanding of its own status as an open and thoughtful response to an impermanent situation? This is an extremely complex question to which only a preliminary response is possible here. Dōgen is well-known for his creative reinterpretations of traditional Buddhist texts and doctrines. Occasionally he ignores the standard grammar and syntax of a traditional text in order to draw a deeper meaning out of a passage. [14] Clearly, his account of truth overcomes the traditional requirement that all interpretation merely duplicate the earlier tradition. Nevertheless, the Shōbōgenzō usually presents these creative reinterpretations as "correct" (sho) in the sense that they reproduce the original meaning. Occasionally Dōgen will say: "We should possess the same thought as Shakyamuni at that time" (1977:79-80; 1972: 190). Such passages appear to reflect a more static and a historical position that neglects the prominence of impermanence in other sections of the text. Do these passages follow traditional patterns of thought that exempt aspects of the Buddhist tradition from the emptying process of time? Or do these statements, like others, reflect the demands of the situation and occasion to which each section of the Shōbōgenzō was a response? One further passage sheds light on this question: "The essence of the Dharma proclaimed by all Buddhas of the three worlds is the same, yet the actual words used depend on the time and circumstances" (1977:173-4;1970:360). This could mean that realization is transhistorical in the sense that it is simply openness to what is as it comes to be in its various and impermanent forms. Time and circumstances transform the doctrine, but its basis — pure, pre-reflective experience — remains the same. This interpretation depends on identifying "the essence of Dharma" as "pure experience," an easily supportable identification but one obviously open to other readings. For the word "dharma" itself has multiple traditional meanings. Two of those meanings correspond with the Shōbōgenzō's two forms of truth. Dharma can mean the teachings themselves (particular doctrines, concepts, and practices), or it can mean their referent, that to p 276 which the teachings themselves point (enlightened awareness). Where "dharma" means the teachings, Shōbō (correct dharma) can mean the correct way to interpret the traditional texts, their proper doctrinal meaning. Where "dharma" is that to which the teachings refer, then truth can mean "the presence of things as they are" in enlightened awareness. The Shōbōgenzō uses this ambiguity fruitfully, and this helps explain both the text's brilliance as a treatise guiding practice at various levels (discourse suited to the situation) and its difficulty as a systematic expression of thought. But the unity of these two kinds of truth is implied in a number of ways, converging in the act of practical application where the particularity of the situation reigns. Notice, finally, how the following passage works between the two: "There are many interpretations and explanations of this koan, but few have understood it correctly. Most people are just groping in the dark. If we look at this koan with a pre-thinking mind we can attain the same real free samadhi as Kyogen, and if we sit zazen like Kyogen we can grasp the meaning of this koan before he even speaks" (1975:114;1972:203-4).[15] Here, to understand "correctly" is not to grasp a universal doctrine or a concept, but to be immersed in the "presence of things as they are" where one "thinks without thinking" and where thought (doctrine) is evoked and thereby authenticated.!"[16] Notes 1 The Shōbōgenzō is widely regarded as one of the most difficult of all Buddhist texts to translate. What that really means, of course, is that the text is simply difficult to read. The text is deeply rhetorical, resists univocal meaning, and frequently shifts in mood and style. Translation perplexities begin with the title itself. David Shaner translates the title, with equal justification, Treasury of the Correct Dharma-eye. Several other possibilities could also be suggested. What they all indicate, however, is the text's focus on the matter of truth. 2 This correspondence is complicated, however, by the role of tradition as mediator between doctrine and reality and as the standard and guarantor oftruth. Section I below clarifies this relation. 3 References to the Shōbōgenzō will be made first to the Nishiyama translation, followed by the Terada version of the Japanese text. The Nishiyama translation is used here for consistency, in spite of its problems, because it is currently the only complete translation. Wherever difficulties affect passages quoted in this paper, revision will be made and noted. Readers are referred to numerous other translations of sections of the Shōbōgenzō, especially to the Abe/Waddell translations in The Eastern Buddhist and to Cook (1978). For a listing and review of Dōgen translations, see Kasulis (1978). 4 I have found no explicit epistemological discussion, in our modern sense of the term, in the Shōbōgenzō, Yet there are reflections concerning how the correspondence between doctrine and reality are grounded and justified. Tradition and contemplative experience that is authenticated by tradition are the two primary sources ofjustification. 5 Japanese scholars have noticed that the earlier sections of the Shōbōgenzō are more generous in specifying where that correct transmission can be found. Sections written after Dōgen's move to Echizen in 1243 are more sectarian and sometimes very critical of the Rinzai tradition of Zen. Various historical factors could account for this shift in position, but one commonly suggested is that Dōgen's audience changes to become strictly monastic and removed from the pluralistic world of Kyoto. 6 For an exceptionally clear and insightful interpretation of this particular pattern of thought, see T. P. Kasulis (1981). 7 For an account of Dōgen's understanding of temporality (and its relation to Heidegger) and a translation of the Vji (Being-time) text of Dōgen, see Heine. 8 Translation revised. 9 This non-dualistic "proximity" is expressed in another way by Shaner; the truth of dharmata is phenomenologically described as "first-order bodymind awareness." 10 An excellent essay highlighting the unity of practice and enlightenment in Dōgen is Cook (1983). 11 Buddha-nature signifies for Dōgen the ever-changing presence of "things as they are." Masao Abe's essay generated a great deal of the contemporary Western interest in Dōgen, and remains the seminal work on that important topic. Hee-Jin Kim's chapter on the Buddha-nature does an excellent job of showing the relationship between this understanding of Buddha-nature and other themes in Dōgen. 12 Yokoi stipulates "correct belief' as an aspect of the way to realization. 13 For a very helpful discussion of Dōgen's understanding of "expression" see Kim, chapter 3. 14 A classic example of this hermeneutic strategy is described very well by Kodera. 15 Translation revised 16 Earlier versions of this paper were presented to the Twenty Ninth International Congress of Orientalists in Tokyo, Japan (May 1984) and to the Western Regional Meeting of the American Academy of Religion (Los Angeles, 1985). References Abe, Masao, 1971,"Dōgen on Budda Nature." Eastern Buddist 4/1:28-71. Cook, Francis, 1978, How to Raise an Ox. Los Angeles: Center Publications. __________, 1983, "Enlightenment in Dōgen 's Zen."The Journal of the International Association of Buddist Studies 6/1:7--30. Heine, Steven, 1985, Existential and Ontological Dimensions of Time in Heidigger and Degen. Albany: State University of New York Press. Kasulis, T. P., 1978, "The Zen philosopher: A review article on Dōgen scholarship in English." Philosophy East and West, (July):353-373 __________, 1981, Zen Action Zen Person. Honolulu: University Press of Hawaii Kim, Hee Jin, 1975, Dōgen Kigen-Mystical Realist. Tuscon: University of Arizona Press. Kodera, Takashi James, 1977, "The Budda-nature in Dōgen's Shōbōgenzō" Japanese Journal of Religious Studies 4/4 (December):267-292 Nishiyama, Kosen and John Stevens, trans., 1975, Shōbōgenzō: The Eye and Treasury ofthe True Law. Vol. 1. Sendai, Japan: Daihokkaikaku Publishing Company __________, 1977, Shōbōgenzō. Vol 2. __________, 1983a, Shōbōgenzō. Vol 3. __________, 1983b, Shōbōgenzō. Vol. 4. Shaner, David, 1985, "The Bodymind Experience in Dōgen's Shōbōgenzō: A phenomenological Perspective." Philosophy East and West (January): 17-35 Terada, To-oru and Mizuno Yaoko, eds., 1970 Shōbōgenzō. Vol. 1. Tokyo: Iwanami Shoten. __________, 1972 Shōbōgenzō,. Vol. 2. Yokoi, Yuko, 1976, Zen Master Degen; An Introduction with Selected Writings, New York: John Weatherhill	{ "pile_set_name": "OpenWebText2" }
Salomea Deszner Salomea Deszner, née Teschner, Teszner (1759-20 March 1806), was a Polish stage actress, opera singer and theater director, active 1777-1806. Her father Adam Teschnerów was employed in the household of the Branicki family, and she was noticed by the king and engaged at his theater. She was employed at the National Theatre, Warsaw in 1777-85 and 1789–96, and in the theater in Vilnius in 1785-89 and 1796-1801. She was the director of the theater in Grodno from 1802 until 1806, and as such had authority over the theatrical policy in the entire district. As an actor, she was regarded as belonging to the elite in Poland, and she was active in tragedy, comedy and opera, was famed in breeches roles, and particularly known for the part of Minna von Barnhelm. She participated in the first opera buffa in Poland, Dla miłości zmyślone szaleństwo (1779). References Źródło: Słownik Biograficzny Teatru Polskiego 1765-1965, PWN Warszawa 1973 Category:19th-century Polish actresses Category:1759 births Category:1806 deaths Category:Polish opera singers Category:Polish theatre directors Category:18th-century Polish actresses Category:18th-century opera singers Category:19th-century opera singers	{ "pile_set_name": "Wikipedia (en)" }
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White House Warned of healthcare.gov Risks in March: Report http://archive.newsleader.com/VideoNetwork/2851720397001/White-House-Warned-of-healthcare-gov-Risks-in-March-Reporthttp://cdn.newslook.com/0d/0dfbd413ca7f696938ba8286c91cb956/mp4_low/0dfbd413ca7f696938ba8286c91cb956-mp4_low.mp4http://archive.newsleader.com/VideoNetwork/2851720397001/White-House-Warned-of-healthcare-gov-Risks-in-March-Reporthttp://cdn.newslook.com/0d/0dfbd413ca7f696938ba8286c91cb956/images/frame_0014.jpgWhite House Warned of healthcare.gov Risks in March: ReportA private consulting firm warned the Obama administration six months before Healthcare.gov's launch the website would have major problems.technologyBarack ObamanewslookusHealth02:00	{ "pile_set_name": "Pile-CC" }
Imagine picking your 5-year-old child up from school and having her show you her new hoop earrings. Real earrings. On her little 5-year-old ears that, when you dropped her off in the morning, were not pierced. Uh, yeah. That’s what happened to Eloise Cardenas when she picked up her daughter, Mia, from Dallas-based Marquita KinderCare earlier this week. Mia had apparently been complaining to her teacher that her ears hurt. Cardenas figured she was coming down with an ear infection ’til she took a closer look and saw her child was wearing earrings. “Who pierced your ears?” she asked incredulously. The little girl told her a teacher in a different class had done the piercings, which left her earlobes sore and red, reports The Star-Telegram. Needless to say, Cardenas was outraged. Can you blame her? You drop your child off at daycare expecting her to interact with friends, have a snack or two, build a tower, maybe play dress-up. Body piercings isn’t exactly up there on the list. Not that the issue is even about piercing. The Star-Telegram reports that Mia had previously had each ear double-pierced but had stopped wearing earrings two years ago, causing the holes to close. It’s more about this teacher – one who is responsible for the well-being of many little children – to use such more judgment. I mean, what was she thinking?! It gets worse. Cardenas confronted the teacher, who responded, “Mia had said it was okay.” That’s right, she trusted the judgment of a 5-year-old. “She’s a kid. You’re an adult. You should have known better,” Cardenas told her. I’d say! [tagbox tag=”daycare”] There’s also the whole safety issue to consider, too. That’s what would freak me out the most. As in, did this brilliant teacher bother to sterilize the needle before using it (and what was she doing with needles, anyway)? Or maybe she didn’t even use a needle or gun but rather an actual earring, which is even more cringe-worthy. KinderCare spokesperson Colleen Moran said the teacher has been “disciplined” (meaning she’s been written up, but that’s it). Cardenas and her husband also filed a report with Forth Worth police. “I don’t blame the day care,” Cardenas said. “I blame her.” (Photo: Anastasiya Igolkina/Shutterstock)	{ "pile_set_name": "OpenWebText2" }
Have you wondered what is like to be a Chef or Cook? Are you trying to find the best knives or place to take your loved one? Come with me and you will find kitchen stories, and products a cook trusts.	{ "pile_set_name": "OpenWebText2" }
Suprarenal abscess in a newborn. A case report of a new born with unilateral suprarenal abscess extending in to the right kidney is represented. Both the adrenal gland and the kidney had to be surgically removed. Early diagnosis is important, so the surgical intervention, the only successful therapy, can be kept as conservative as possible.	{ "pile_set_name": "PubMed Abstracts" }
Q: Unable to get good example of using memcached from Java boot I am using java boot for my development. For now I have used 'EhCache' for caching , it is directly supported from Java boot. This is "in-process" cache, i.e., becomes part of your process. It is okay for now. But my server will run on multiple nodes in near future. Hence want to switch to 'Memcached' as common caching layer. After spending good amount of time, I could not get good sample of using Memcached from java boot. I have looked at 'Simple Spring Memcached' which comes close to my requirement. But still it gives example using XML configuration in Spring way. Java boot does not use such XML configuration as far as possible. At least I could not map the example quickly to java boot world. I want to use Memcahed ( directly or via cache-abstraction-layer) from java boot. If anybody points me to a relevant java boot example, it will save a lot of time for me. A: You can find some materials how to configure SSM using Java configuration instead of XML files here and here. Basically you have to move definitions of all beans from XML to Java.	{ "pile_set_name": "StackExchange" }
// Copyright Aleksey Gurtovoy 2000-2004 // // Distributed under the Boost Software License, Version 1.0. // (See accompanying file LICENSE_1_0.txt or copy at // http://www.boost.org/LICENSE_1_0.txt) // // Preprocessed version of "boost/mpl/set_c.hpp" header // -- DO NOT modify by hand! namespace boost { namespace mpl { template< typename T, long C0 = LONG_MAX, long C1 = LONG_MAX, long C2 = LONG_MAX , long C3 = LONG_MAX, long C4 = LONG_MAX, long C5 = LONG_MAX , long C6 = LONG_MAX, long C7 = LONG_MAX, long C8 = LONG_MAX , long C9 = LONG_MAX, long C10 = LONG_MAX, long C11 = LONG_MAX , long C12 = LONG_MAX, long C13 = LONG_MAX, long C14 = LONG_MAX , long C15 = LONG_MAX, long C16 = LONG_MAX, long C17 = LONG_MAX , long C18 = LONG_MAX, long C19 = LONG_MAX > struct set_c; template< typename T > struct set_c< T, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX > : set0_c<T> { typedef typename set0_c<T>::type type; }; template< typename T, long C0 > struct set_c< T, C0, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX > : set1_c< T,C0 > { typedef typename set1_c< T,C0 >::type type; }; template< typename T, long C0, long C1 > struct set_c< T, C0, C1, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX > : set2_c< T,C0,C1 > { typedef typename set2_c< T,C0,C1 >::type type; }; template< typename T, long C0, long C1, long C2 > struct set_c< T, C0, C1, C2, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX > : set3_c< T,C0,C1,C2 > { typedef typename set3_c< T,C0,C1,C2 >::type type; }; template< typename T, long C0, long C1, long C2, long C3 > struct set_c< T, C0, C1, C2, C3, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX > : set4_c< T,C0,C1,C2,C3 > { typedef typename set4_c< T,C0,C1,C2,C3 >::type type; }; template< typename T, long C0, long C1, long C2, long C3, long C4 > struct set_c< T, C0, C1, C2, C3, C4, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX > : set5_c< T,C0,C1,C2,C3,C4 > { typedef typename set5_c< T,C0,C1,C2,C3,C4 >::type type; }; template< typename T, long C0, long C1, long C2, long C3, long C4, long C5 > struct set_c< T, C0, C1, C2, C3, C4, C5, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX > : set6_c< T,C0,C1,C2,C3,C4,C5 > { typedef typename set6_c< T,C0,C1,C2,C3,C4,C5 >::type type; }; template< typename T, long C0, long C1, long C2, long C3, long C4, long C5 , long C6 > struct set_c< T, C0, C1, C2, C3, C4, C5, C6, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX > : set7_c< T,C0,C1,C2,C3,C4,C5,C6 > { typedef typename set7_c< T,C0,C1,C2,C3,C4,C5,C6 >::type type; }; template< typename T, long C0, long C1, long C2, long C3, long C4, long C5 , long C6, long C7 > struct set_c< T, C0, C1, C2, C3, C4, C5, C6, C7, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX > : set8_c< T,C0,C1,C2,C3,C4,C5,C6,C7 > { typedef typename set8_c< T,C0,C1,C2,C3,C4,C5,C6,C7 >::type type; }; template< typename T, long C0, long C1, long C2, long C3, long C4, long C5 , long C6, long C7, long C8 > struct set_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX > : set9_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8 > { typedef typename set9_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8 >::type type; }; template< typename T, long C0, long C1, long C2, long C3, long C4, long C5 , long C6, long C7, long C8, long C9 > struct set_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX , LONG_MAX > : set10_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8,C9 > { typedef typename set10_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8,C9 >::type type; }; template< typename T, long C0, long C1, long C2, long C3, long C4, long C5 , long C6, long C7, long C8, long C9, long C10 > struct set_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, LONG_MAX, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX > : set11_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8,C9,C10 > { typedef typename set11_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8,C9,C10 >::type type; }; template< typename T, long C0, long C1, long C2, long C3, long C4, long C5 , long C6, long C7, long C8, long C9, long C10, long C11 > struct set_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX > : set12_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8,C9,C10,C11 > { typedef typename set12_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8,C9,C10,C11 >::type type; }; template< typename T, long C0, long C1, long C2, long C3, long C4, long C5 , long C6, long C7, long C8, long C9, long C10, long C11, long C12 > struct set_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, LONG_MAX , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX > : set13_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8,C9,C10,C11,C12 > { typedef typename set13_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8,C9,C10,C11,C12 >::type type; }; template< typename T, long C0, long C1, long C2, long C3, long C4, long C5 , long C6, long C7, long C8, long C9, long C10, long C11, long C12 , long C13 > struct set_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX > : set14_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 > { typedef typename set14_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8,C9,C10,C11,C12,C13 >::type type; }; template< typename T, long C0, long C1, long C2, long C3, long C4, long C5 , long C6, long C7, long C8, long C9, long C10, long C11, long C12 , long C13, long C14 > struct set_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 , LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX > : set15_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 > { typedef typename set15_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8,C9,C10,C11,C12,C13,C14 >::type type; }; template< typename T, long C0, long C1, long C2, long C3, long C4, long C5 , long C6, long C7, long C8, long C9, long C10, long C11, long C12 , long C13, long C14, long C15 > struct set_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 , C15, LONG_MAX, LONG_MAX, LONG_MAX, LONG_MAX > : set16_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 , C15 > { typedef typename set16_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8,C9,C10,C11,C12,C13,C14,C15 >::type type; }; template< typename T, long C0, long C1, long C2, long C3, long C4, long C5 , long C6, long C7, long C8, long C9, long C10, long C11, long C12 , long C13, long C14, long C15, long C16 > struct set_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 , C15, C16, LONG_MAX, LONG_MAX, LONG_MAX > : set17_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 , C15, C16 > { typedef typename set17_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8,C9,C10,C11,C12,C13,C14,C15,C16 >::type type; }; template< typename T, long C0, long C1, long C2, long C3, long C4, long C5 , long C6, long C7, long C8, long C9, long C10, long C11, long C12 , long C13, long C14, long C15, long C16, long C17 > struct set_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 , C15, C16, C17, LONG_MAX, LONG_MAX > : set18_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 , C15, C16, C17 > { typedef typename set18_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8,C9,C10,C11,C12,C13,C14,C15,C16,C17 >::type type; }; template< typename T, long C0, long C1, long C2, long C3, long C4, long C5 , long C6, long C7, long C8, long C9, long C10, long C11, long C12 , long C13, long C14, long C15, long C16, long C17, long C18 > struct set_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 , C15, C16, C17, C18, LONG_MAX > : set19_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 , C15, C16, C17, C18 > { typedef typename set19_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8,C9,C10,C11,C12,C13,C14,C15,C16,C17,C18 >::type type; }; /// primary template (not a specialization!) template< typename T, long C0, long C1, long C2, long C3, long C4, long C5 , long C6, long C7, long C8, long C9, long C10, long C11, long C12 , long C13, long C14, long C15, long C16, long C17, long C18, long C19 > struct set_c : set20_c< T, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 , C15, C16, C17, C18, C19 > { typedef typename set20_c< T,C0,C1,C2,C3,C4,C5,C6,C7,C8,C9,C10,C11,C12,C13,C14,C15,C16,C17,C18,C19 >::type type; }; }}	{ "pile_set_name": "Github" }
Q: Options basics: How to realize profit from a long call position I'm studying the basics of options trading and just read a 'crash course' book where the author states the following: ...you won't walk away from a call option with cash in hand. The profit we are talking about in this case is "intrinsic value". You can now take that stock and write a buy contract on it, selling it on and making that tangible profit in the process. ... as an options trader, you're not looking to keep hold of a stock portfolio. You're purchasing stocks through contracts to turn around and sell for a profit. So I have a fundamental question about long call options. Is the author here alluding to a requisite purchase of the underlying shares before a "buy contract" can be written against them? Surely, this is implied, because without executing the contract, you would have nothing to sell, right? My confusion is compounded by a statements just a couple of paragraphs prior Buying calls also allows you to consider shares that would ordinarily be out of your price range. ... Buying options on those stocks is a whole lot less expensive than buying the stocks themselves, ... This is call "leverage": the ability to control thousands of dollars in stock for just hundreds of dollars in premium. Here again I'm lost - if you have to execute the position in order to profit, then you need the full amount of the contract to ultimately purchase those shares, right? Lastly, if I have a long call that becomes valuable, whereby the strike price + premium is less than the current price of the stock, I then need to execute the option, buy buying the stock, before I can actually sell those shares (immediately after purchase) for a profit, right? Or is there some other way to realize the profit without actually purchasing the stock? A: It's no wonder that you're confused. The first paragraph that you quoted is a disaster. In clearer words: If a call appreciates in price and you sell it, you walk away with cash in hand and a profit That profit can be from intrinsic or extrinsic premium (the call's price must simply appreciate) There is no such thing as writing a buy contract. Writing is synonymous with selling to open (STO). If you were to sell a call against the original long call, you would be creating a spread (vertical, calendar, diagonal). There are two reasons to exercise an ITM call: 1) You want to own the stock. 2) If a call is ITM and it trades for less than parity (bid is less than intrinsic value) or as you wrote, the "strike price + premium is less than the current price of the stock", you can try for some price improvement with your STC order but there is no incentive for the market maker or anyone else to give you the full intrinsic value. While waiting for a better fill, the price of XYZ could drop and you could give back some of your call's gain. To avoid this haircut, you can perform perform the same Discount Arbitrage that a market maker would. If you have the margin to cover a short sell, short the stock and then exercise the call. That locks in the intrinsic value and avoids the haircut (short the stock first to avoid possible underlying price slippage). If you don't have the margin then you're going to have to work the order and take whatever you can get. If you need an example, ask away.	{ "pile_set_name": "StackExchange" }
ve ay - f + 21 - n = 0, 10 = -4y - 3f for y. -4 Let p(l) = 9l - 79. Let s be p(7). Let z(v) = 4v + 89. Let d be z(s). Solve i + 15 = -2i - m, 4m = -5i - d for i. -5 Let a = 18973 + -18972. Solve -2r - 6 = 10y - 6y, 0 = -y + a for r. -5 Suppose -864 = 11f - 919. Solve u = fk - 17, -2k + 1 + 5 = 0 for u. -2 Suppose 0 = 4u - 5r - 25, 6r + 20 = 2u + 2r. Let m = 12 - 8. Suppose -mq = 2q - uq. Solve -2f + 4k - k - 6 = q, -4f - 2k = -4 for f. 0 Suppose 2p + 3b - 29 = 0, 3b + 9 = -p + 31. Let c = -4 + 6. Solve -2 = 5x - p, -c = -m - 5x for m. -3 Suppose 0 = -2y, 5a + 500 = 3a + 4y. Let g = a + 253. Solve -2t - gl = 10, -2t - 25 = 3t + 3l for t. -5 Let m be (-3)/(-1)40/6. Let w be (14 + -19)-324/15. Let v = w - m. Solve 21 - 5 = -vf, 2r = -2f - 6 for r. 1 Suppose 4 = -2d - 5l, -139d + 135d + 44 = -3l. Let z = -7 - -11. Let r be 2/(-9) - 94/(-18). Solve 3m - n - z = -rn, -d = 5m + 3n for m. -4 Let j(b) = -b3 - 8b*2 + 14b + 48. Let q be j(-9). Let v be (-65)/26(-8)/10. Suppose -p = p - v. Solve -20 = -f - 4m, 5f - p = qm - 16 for f. 0 Let u(g) = 48g + 1010. Let x be u(-21). Solve 4c = -11p + 8p - 22, -4c - 20 = xp for p. -2 Suppose -59 = -5d - g, 2d + 8g - 38 = 4g. Let y be 6(-9)/81 - d/(-3). Solve u = -o + 3 - 0, o + 2u = y for o. 3 Let r be (-2 - -31/(-6))-2. Suppose -3b = -rd - 0b + 405, 287 = 4d + 5b. Let w = 81 - d. Solve -10 - 3 = -2c + 3f, -wf - 15 = 0 for c. -1 Let o be -2 + (2 + -1)5. Suppose -15d + 9030 = -0d. Let k = 607 - d. Solve -of + 4f - 8 = kb, f - 2b = 5 for f. 3 Let a(g) = 60g*2 + 663g + 35. Let d be a(-11). Solve 2b + 12 = -0n - dn, 5b + 29 = -4n for b. -5 Let i(j) be the second derivative of -j4/12 - 23j*3/6 - 19j*2/2 - 44j. Let z be i(-22). Solve 4h + zr = 0, -h - r = -2h for h. 0 Suppose -31c + 12 = 4g - 27c, 5c = 2g + 1. Solve 0 = 2k + t + 2, 4k - 5 = 3k - gt for k. -3 Let c = 13 + -9. Suppose 4y - l = 4l + 17, -y + 5l = 7. Let q(i) = i2 - 6i - 12. Let o be q(y). Solve 0 = ok - 2x + 4x - 2, -4 = -4k - cx for k. 0 Suppose z - 2 = 2. Let j = -33740 + 33742. Solve 0 = -2h + b - 2, zb + 5 = -jh - 3h for h. -1 Suppose -r + n = 13, 3r + 5n - 2n + 69 = 0. Let x be 6 + -1 - (r - -19). Solve p + 1 + 0 = -l, 0 = 3l + xp + 3 for l. -1 Suppose -4c - 418 = -942. Let k be c + -131 - (1 - 0)/(-1). Solve -3f - 2f + 4t = -1, -2t = -3f - k for f. -3 Let v = -2 - 2. Let n be v/(-14) + (-4)/14. Suppose -14 = -2i, -877j + 875j = -3i + 13. Solve 0 = d, jd + n - 6 = 2b for b. -3 Suppose -b + 5b - 12 = 0. Let l be 4 + -172 + (1 - (-15)/(-3)). Let m = l - -172. Solve -3s + 15 = bi, ms - 4s + 12 = 0 for i. 2 Let o = -2777 - -2781. Solve -3x = -x + ok - 6, 0 = 3k - 3 for x. 1 Let r be ((-1)/2 + (-40)/(-48))/(1/54). Solve 2b = i + 4, 19b = i + rb for i. 4 Let n = -5417 + 5457. Solve 5g - n = 5x, 2x + 30 - 2 = 4g for g. 6 Let n = -3 - -21. Suppose 8 - 26 = -nk. Solve -2y = 4s + 6, 3y = s - k + 13 for y. 3 Let q = -37 + 52. Suppose 6p - 7p = 3d - q, 5p - 31 = -4d. Solve -2w + ph = h + 12, 14 = -4w - h for w. -4 Let j(v) = 3v*2 + 6v - 9. Let u be j(2). Suppose -a + 11 = 4t, -a = -ut + 13t + 1. Solve 2w - 3q = -20, -2q + 8 = -aw - 3q for w. -4 Let t(i) = -i - 3. Let o be ((-19)/(-38))/((-2)/24). Let r be t(o). Solve rn + 17 = 2f - 5, 5f - 17 = -2n for n. -4 Suppose -7g - 3 = -8g, 0 = -3v - 5g + 33. Solve 2j + v = -4o, 5o + 3j = 1 - 7 for o. -3 Suppose 208 + 16 = 112k. Solve 3w = n - 0 - k, 2w - n + 1 = 0 for w. -1 Let b = -163 - -187. Suppose -6o + 0 + b = 0. Solve 2i + 8 = -3h + i, -5h = -oi - 15 for h. -1 Suppose -5 = 3o - 11. Suppose 51d = -15d + 156 + 108. Solve -ow - 26 = 4z + 3w, dz - 2w = -12 for z. -4 Let t be -1 + (-6)/(-6) + 4. Suppose -a = -2c - 5, 0 = ta - 0a - 2c - 14. Solve -z - 3 = -ax, 6z = 3z + x - 9 for z. -3 Let z(r) = -33r*2 - 4r + 24. Let x be z(0). Solve -2y = 2p + 18 - x, 0 = -3y - 2p + 6 for y. 0 Suppose -3r + 12 = -a + 23, 4r + 8 = 0. Solve 22l = 21l + 7, al - 34 = -x for x. -1 Let u be -12((-8)/10)/(66/110). Solve 2f + 1 = -h, h + u = f + 12 for h. -3 Suppose 0 = -144w + 9289 + 4535. Solve 3z + v + 113 - w = 0, 5z = 4v for z. -4 Let n = -1849 - -1851. Solve 5d - 4o = 2, o + n = d + d for d. 2 Suppose 367 + 1983 = 94t. Solve 0 = 27l - tl - 10, -l - 5 = 2m for m. -5 Let m(u) = -5u + 24. Suppose 17k = 12k + 10. Let c be m(k). Solve -4w - 3r - 1 + c = 0, -11 = -5w - 2r for w. 1 Suppose 0 = -w - 2 - 6. Let x be (-4 + (-5 - w))/(1/(-1)). Suppose -4z = -2q - 8, 7 + x = 4z - q. Solve -2k + 35 = 3k + 2y, zk - 3y + 5 = 0 for k. 5 Let m be (-6)/(-4) + 385/70. Suppose 4s = ms - 111. Solve -3g + 21 = 3t, -5g - 14 + s = t for t. 3 Suppose -4 = -2l - 0. Suppose -lr = 3r - 95. Let o(u) = -2u + 42. Let f be o(r). Solve 3y + 4 = 4h, y = -0y + fh - 4 for y. 0 Suppose -5u + 0u + 5 = 0. Suppose -2k = 3d + 9, 5k - 149 = -d - 152. Let b be -4 + u + 21 + d. Solve 0 = -5o - 15, 3f - o - 2o = b for f. 2 Let h be ((-85)/3 - -9)/(2/(-3)). Solve 3w - 3t - 29 = -32, w - h = -5t for w. 4 Let u be 37/6 + -2 - (-644)/(-552). Solve 10 = -2f, -uf - 21 = -2v - 0f for v. 3 Let c = 2 - 0. Suppose -t + 263 = 3g - 5t, -g = 4t - 77. Let q = 87 - g. Solve -ci = -2v - 0i, 0 = -qi + 6 for v. 3 Suppose -204h + 208h - 21 = -5f, -2f + 5h + 15 = 0. Solve 24 = fz + 4g, -44 + 35 = -z - 5g for z. 4 Suppose -120 = 11926c - 11930c. Let a(t) = t - 3. Let s be a(8). Solve -4x + v + 10 = c, 0 = -x - sv - 5 for x. -5 Let v = 71 - 67. Suppose -19k = -17k + i - 56, -vi = k - 28. Solve -s - m - 6 = 0, 5s + 0m + k = -3m for s. -5 Let d be (-216)/(-81)(-54)/(-4). Suppose -12u + du = 0. Solve uw - 2w + 12 = 5x, -8 = -3x - w for x. 4 Let x(o) = -o*3 + 44o*2 + 50o - 225. Let i be x(45). Solve i = -4c + 2q - 6, -5c + 15 = -6c - 4q for c. -3 Let r = 159 - 157. Let y(h) = -5h + 3 + h*3 + 0h + 4h. Let a be y(0). Solve -5 = -5p - rf + af, f = -4p + 4 for p. 1 Let q be 1 + (108/(-108))/(0 - -1). Solve q = -3j + 5m, 12 = j + 5m - 8 for j. 5 Let d = -8000 + 8008. Solve 0 = 5l - 9l - d, 0 = -3p + 3l + 21 for p. 5 Suppose 0u + 49 = -5a + u, 3a = 4u - 43. Let n(w) = -2w - 9. Let m be n(a). Let h(d) = -3d + 40. Let g be h(m). Solve 7k - g = 3k - 5v, 20 = 4v for k. -3 Let z be ((-9)/6)/((-33)/24 + 1). Let y be 7 + z/(-2) + 0. Let t(j) = -j*3 - 5j*2 + 5j - 2. Let c be t(-6). Solve 1 = cb - p + y, 0 = -b + p - 1 for b. -1 Let l(s) = 3s*2 + 3s*2 + 9 + 12s - 8s2 - 5s. Let k be l(4). Solve -17 = ky - 4g, -y - 5g + 14 = -0y for y. -1 Suppose -3243d + 3219d + 27 = -21. Solve 2t - 5w - 28 = 0, -w + 2 - 14 = -dt for t. 4 Suppose 5t + y = 9, -34t + 13 = -29t - 3y. Solve 20 = 2n + tn - 2l, 0 = 2n - 4l - 22 for n. 3 Let x = 3934 + -3917. Solve 0 = 2t - 3w - 9 + x, 0 = 2t + 4w - 6 for t. -1 Let r(z) = z*3 + 6z*2 + 13z + 22. Let s be r(-4). Solve -4f - 17 = 5w, -5f - 118 = -sw - 138 for w. -5 Let s(o) = o*3 - 66o*2 + 64o + 70. Let g be s(65). Solve -5w + 4y + 23 = 0, w - 53y + g = -57y for w. 3 Let g be (-8)/(-3)48/32. Suppose -s - 1 - 4 = z, -gz - 5s = 23. Let u be -10(z + (0 + 2)/2). Solve -2k + u = -4x + 38, 2x = 10 for k. -4 Suppose -26v + 7 = -45. Solve t = vh - 3, 9t + 4h = 7t - 6 for t. -3 Suppose 75n - 12n = -n + 384. Solve w - 6 = -4q, 141w = 139w - 5q + n for w. -2 Let j = -396 - -409. Suppose 0f + j = -f - 4u, -20 = 5u. Solve 0i + fi + 35 = -5p, 4i + 16 = p for p. -4 Suppose 0w + w + 55 = 2t, 4t = 3w + 105. Suppose tq = 20q + 40. Let s(l) = 3l*2 - 1. Let z be s(1). Solve -qp = -c - 17, -5c - p = zp + 16 for c. -5 Let d = -4455 + 4460. Solve w + 13 = ds, -9 + 8 = -s + w for s. 3 Let s = -283 + 303. Let j(v) = v - 14. Let h be j(s). Solve 0 = p + y + h, -2y + 3y = 3p + 2 for p. -2 Let d be 3630/429 - 6/13. Solve 3k + p + 18 = 0, 67p + d = -5k + 69p for k. -4 Let k = -42510 + 42535. Let h(i) = -i*3 - 6i*2. Let l be h(-6). Solve 0 = -m - 5u - k, -9 = m - lm + u for m. -5 Suppose 6b = 1244 + 208. Let d = 244 - b. Solve 2*z + 8 = q, -z - 2 - d = 0 for q. 0 Suppose 5	{ "pile_set_name": "DM Mathematics" }
<?xml version='1.0' encoding='UTF-8'?> <host xmlns="urn:jboss:domain:14.0" name="master"> <extensions> <?EXTENSIONS?> </extensions> <management> <security-realms> <security-realm name="ManagementRealm"> <authentication> <local default-user="$local" skip-group-loading="true"/> <properties path="mgmt-users.properties" relative-to="jboss.domain.config.dir"/> </authentication> <authorization map-groups-to-roles="false"> <properties path="mgmt-groups.properties" relative-to="jboss.domain.config.dir"/> </authorization> </security-realm> <security-realm name="ApplicationRealm"> <server-identities> <ssl> <keystore path="application.keystore" relative-to="jboss.domain.config.dir" keystore-password="password" alias="server" key-password="password" generate-self-signed-certificate-host="localhost"/> </ssl> </server-identities> <authentication> <local default-user="$local" allowed-users="*" skip-group-loading="true"/> <properties path="application-users.properties" relative-to="jboss.domain.config.dir"/> </authentication> <authorization> <properties path="application-roles.properties" relative-to="jboss.domain.config.dir"/> </authorization> </security-realm> </security-realms> <audit-log> <formatters> <json-formatter name="json-formatter"/> </formatters> <handlers> <file-handler name="host-file" formatter="json-formatter" path="audit-log.log" relative-to="jboss.domain.data.dir"/> <file-handler name="server-file" formatter="json-formatter" path="audit-log.log" relative-to="jboss.server.data.dir"/> </handlers> <logger log-boot="true" log-read-only="false" enabled="false"> <handlers> <handler name="host-file"/> </handlers> </logger> <server-logger log-boot="true" log-read-only="false" enabled="false"> <handlers> <handler name="server-file"/> </handlers> </server-logger> </audit-log> <management-interfaces> <http-interface security-realm="ManagementRealm"> <http-upgrade enabled="true"/> <socket interface="management" port="${jboss.management.http.port:9990}"/> </http-interface> </management-interfaces> </management> <domain-controller> <local/> </domain-controller> <interfaces> <interface name="management"> <inet-address value="${jboss.bind.address.management:127.0.0.1}"/> </interface> </interfaces> <jvms> <jvm name="default"> <heap size="64m" max-size="256m"/> <jvm-options> <option value="-server"/> <option value="-XX:MetaspaceSize=96m"/> <option value="-XX:MaxMetaspaceSize=256m"/> </jvm-options> </jvm> </jvms> <profile> <?SUBSYSTEMS socket-binding-group="standard-sockets"?> </profile> </host>	{ "pile_set_name": "Github" }
Usage Notes on Subject Areas This topic provides information about date and time subject areas, and quota periods. Date and Time Subject Areas Periods in your reports might be based on your company's fiscal calendar, which might differ from a standard calendar. For example, your company's fiscal year might begin on 1 June of each calendar year. If your company has recently changed its fiscal calendar year method in Oracle CRM On Demand, then review carefully historical analyses if they span multiple years. Data in reports based on your previous fiscal calendar method cannot be aligned with data using a new fiscal calendar method. Quota Periods Reports that include quota information by year use the closing month of the year. Whereas on the Quota screen, the year shows the starting month of the quota period, which is different from reports. For example, if the quota period runs from November 2009 to January 2010, then the Quota screen shows the year as 2009, but the reports show the year as 2010.	{ "pile_set_name": "Pile-CC" }
Related Tags: ST. LOUIS (AP) - St. Louis will apparently be host two big annual music festivals starting in 2015. Aldermen on Monday voted 21-4 to approve a bill granting the Los Angeles talent agency ICM and Summer Rocks LLC exclusive access to the Gateway Mall over Memorial Day and Labor Day weekends. ICM Partners has said it will host a country music festival in St. Louis every Memorial Day weekend, and a big rock festival every Labor Day weekend. Mayor Francis Slay still needs to the sign the bill, but he has publicly supported it. The city says it could earn as much as $1.5 million for each festival in ticket fees. But some local musicians worry that the new festivals could damage smaller events such as LouFest and Bluesweek.	{ "pile_set_name": "Pile-CC" }
Q: ASP.NET MVC 4 Intranet Template - Show Users Full Name I am using the Intranet template for MVC 4 under the VS 2012 RC. The top right hand corner shows domain\username, and I want it to show full name instead. I was able to get this working in _Layout.cshtml. I included the following helper in the body - @helper AccountName() { using (var context = new System.DirectoryServices.AccountManagement.PrincipalContext(System.DirectoryServices.AccountManagement.ContextType.Domain)) { try { var principal = System.DirectoryServices.AccountManagement.UserPrincipal.FindByIdentity(context, User.Identity.Name); @String.Concat(principal.GivenName, " ", principal.Surname) } catch { } } } (I also had to include System.DirectoryServices.AccountManagement in the References) I could then use the helper in the greeting code as follows - <section id="login"> Hello, <span class="username">@AccountName()</span>! </section> This works ok, but I don't like having the code in the _Layout.cshtml. I tried to put the helper in a seperate file under a Helpers directory, but @AccountName() no longer resolved then. Ideally the code should really be in a straight CS file. Can anyone suggest a better way to set this up? A: You can certainly put the code in a regular C# file, e.g. AccountUtil.AccountName() In that case, you need to include the namespace your helpers are in by placing @using My.App.Helpers @* Change to your own namespace *@ at the top of any view that wants to reference that code. Alternatively, you can make that namespace available to all views by editing the web.config file in the Views directory (not the one at the project level) <system.web.webPages.razor> <host factoryType="System.Web.Mvc.MvcWebRazorHostFactory, System.Web.Mvc, Version=4.0.0.0, Culture=neutral, PublicKeyToken=31BF3856AD364E35" /> <pages pageBaseType="System.Web.Mvc.WebViewPage"> <namespaces> <!-- Don't edit out the stuff that's already here! --> <add namespace="My.App.Helpers" /> <!-- Add your own namespace here --> </namespaces> </pages> </system.web.webPages.razor>	{ "pile_set_name": "StackExchange" }
Q: Flutter : PageView keep Stay in previous Screen I use PageView in my screen to Navigate to another screen. I have 3 screen Home,History and History Detail. Everything is fine i can move to history screen. Until i redirect to History Detail from History Screen and i back with Navigator.of(context).pop , I redirect to Home Screen. I want after Back from History Detail i keep stay in History Screen. I already initialize initialPage is 0 , and change the initialPage with onPageChanged but nothing happens, i still redirect to Home Screen. How can i do for my case? It's My Source Code. PageController _pageController; int currentPage = 0; @override void initState() { _pageController = PageController(initialPage: currentPage); super.initState(); } Widget build(BuildContext context) { final GlobalKey<ScaffoldState> _scaffoldKey = GlobalKey<ScaffoldState>(); double mqHeight = MediaQuery.of(context).size.height; return Scaffold( key: _scaffoldKey, body: FutureBuilder( future: Hive.openBox("debt_box"), builder: (ctx, snapshot) { if (snapshot.connectionState == ConnectionState.done) { if (snapshot.hasError) return Text(snapshot.error.toString()); else return Scaffold( body: PageView( scrollDirection: Axis.vertical, onPageChanged: (index) { currentPage = index; print(currentPage); }, physics: NeverScrollableScrollPhysics(), controller: _pageController, children: <Widget>[ CustomScrollView( slivers: <Widget>[ SliverAppBarHome(), SliverListHome(_scaffoldKey), ], ), HistoryDebt(), ], ), ); } else { return Center(child: CircularProgressIndicator()); } }, ), bottomNavigationBar: BottomAppBar( shape: CircularNotchedRectangle(), child: Container( height: mqHeight * 0.08, child: Row( mainAxisSize: MainAxisSize.max, mainAxisAlignment: MainAxisAlignment.spaceEvenly, children: <Widget>[ IconButton( icon: Icon(Icons.home), onPressed: () => functionHelper.previousButtonPageView(_pageController), ), IconButton( icon: Icon(Icons.insert_chart), onPressed: () => functionHelper.nextButtonPageView(_pageController), ), ], ), ), ), } A: I found the issue. When you press back button it re-builds your main widget. In the build method you have FutureBuilder which also gets rebuild. So it will show you CircularProgressIndicator. Since Hive.openBox("debt_box") gives the result instantaneously, you are not able to see it. While showing CircularProgressIndicator your PageView got deactivated (removed from widget tree). So _pageController loses its client. After the CircularProgressIndicator, a new PageView gets created. That is why it showed Home page Solution: As per the document we should not directly assign future: Hive.openBox("debt_box") during the build. Instead create a Future variable and initialize it in the initState, then pass that variable to future property of FutureBuilder PageController _pageController; int currentPage = 0; Future _openBox; @override void initState() { _pageController = PageController(initialPage: currentPage); _openBox = Hive.openBox("debt_box"); //initialize here super.initState(); } Widget build(BuildContext context) { final GlobalKey<ScaffoldState> _scaffoldKey = GlobalKey<ScaffoldState>(); double mqHeight = MediaQuery.of(context).size.height; return Scaffold( key: _scaffoldKey, body: FutureBuilder( future: _openBox, //pass the future variable here builder: (ctx, snapshot) { ...	{ "pile_set_name": "StackExchange" }
Prevalence of anti-endothelial cell antibodies in patients with autoimmune diseases. The prevalence of anti-endothelial cell antibodies (AECA) of IgA, IgG and IgM classes was studied by means of enzyme-linked immunosorbent assays (ELISA) in 466 patients with autoimmune/inflammatory disorders. The reference limits in the ELISAs for the AECA were determined from a random population sample of 249 subjects. The frequency of AECA was highest in patients with SLE (n = 42), 14.6% mainly of IgG class, and the presence of AECA correlated with disease activity in these patients. In the RA patient group (n = 200), 9.5% had AECA, mostly of IgA type. We found no association between the presence of AECA and extra-articular manifestations of RA or survival rate. In patients with undefined connective tissue disease (n = 57), ankylosing spondylitis (n = 109), and psoriatic arthritis (n = 58), the frequency of AECA corresponded to that of the random population sample. In a cohort of samples sent to the laboratory for determination of anti-nuclear antibodies (ANA) there was a correlation between the presence of ANA and AECA. Our findings indicate that RA patients are characterized by IgA class AECA, whereas SLE patients have IgG class AECA also correlating to disease activity.	{ "pile_set_name": "PubMed Abstracts" }
This comparison shows that Samsung I9500 Galaxy S4 is better than Samsung SM-N930FD Galaxy Note 7 Dous for business, music and entertainment, while Samsung SM-N930FD Galaxy Note 7 Dous is better than Samsung I9500 Galaxy S4 for photography, and they are nearly equivalent for appearance.	{ "pile_set_name": "Pile-CC" }
Gettext PO syntax highlighting for Vim The Gettext PO format is used by translators to translate free software. The Vim Gettext PO syntax highlighter enhances the current Vim PO file highlighter. These enhancements include the inclusion of KDE-specific highlighting, error detection, and highlighting of new features of the PO format, including pluralisation.	{ "pile_set_name": "Pile-CC" }
Varlık Vergisi Varlık Vergisi ("wealth tax" or "capital tax") was a Turkish tax levied on citizens of Turkey in 1942, with the stated aim of raising funds for the country's defense in case of an eventual entry into World War II. However, it is accepted that the underlying reason for the tax was to inflict financial ruin on the minority non-Muslim citizens of the country, terminate their prominence in the country's economy and move the assets of non-Muslims into the hands of the Muslim bourgeoisie. It can be defined as the last application to date of the jizya (cizye) tax on non-Muslims in Turkish history, and the only such application after the establishment of the constitutionally secular Turkish Republic in 1923; breaching the articles regarding secularism and citizen equality in the Turkish Constitution. Background The bill for the one-off tax was proposed by the Şükrü Saracoğlu government, and the act was adopted by the Turkish parliament on November 11, 1942. It was imposed on the fixed assets, such as landed estates, building owners, real estate brokers, businesses, and industrial enterprises of all citizens, but especially targeted the minorities. Those who suffered most severely were non-Muslims like the Jews, Greeks, Armenians, and Levantines, who controlled a large portion of the economy, though it was the Armenians who were most heavily taxed. The tax was supposed to be paid by all citizens of Turkey, but inordinately higher rates were imposed on the country's non-Muslim inhabitants, in an arbitrary and predatory way. Because those forced to pay the bulk of the taxes were exclusively non-Muslims, the law was perceived by the public as a "jizya - gavur tax" against them. These taxes led to the destruction of the remaining non-Muslim merchant class in Turkey, the lives and finances of many non-Muslim families were ruined. In addition, the law was also applied to the many poor non-Muslims such as drivers, workers and even beggars, whereas their Muslim counterparts were not obliged to pay any tax. The Varlık Vergisi resulted in a number of suicides of ethnic minority citizens in Istanbul. During World War II, Turkey remained neutral until February 1945. Officially, the tax was devised to fill the state treasury that would have been needed had Nazi Germany or the Soviet Union invaded the country. However, the main reason for the tax was to nationalize the Turkish economy by reducing minority populations' influence and control over the country's trade, finance, and industries. The tax could not be challenged in court. Non-Muslims had to pay their taxes within 15 days in cash. Many people who could not pay the taxes borrowed money from relatives and friends, also sold their properties at public auctions or sold their businesses to gather some money to pay. People who were unable to pay were sent to labor camps in eastern Anatolia. Workers were paid for their service but half of their wages were set-off for their debts. Because of the hard plowing work elder obligors conspired with young villagers from Aşkale to make them work instead and they paid villagers daily wages in return. Five thousand were sent there and all were non-Muslims, since the Muslim taxpayers who failed to pay received lighter sentences. Also, there were easiness for payments and tax discounts for the Muslims taxpayers. Although the law stipulated that people over fifty-five years old were exempt from labor service, elderly men, even sick people were sent there. Twenty-one of the people who were sent to the labor camps died there and the Turkish government usurped their wealth and sold it to Turkish Muslims at extremely low prices, paving the way to the creation of some of the contemporary Turkish conglomerates. The state also confiscated the property of the taxed person's close relatives (including parents, parents-in-law, children, and siblings) and sold it to settle the tax amount, even if the person had been forced into labor service. Foreign-passport residents in Turkey who gave in a tax return or owned a business were forced to pay a huge capital levy on supposed wealth too. However, none of them were ruined or committed suicide. The tax was not based on any reality, but just on a whim of the authorities. This provoked the intervention of foreign embassies and consulates on behalf of their nationals. Taxpayers were classified into four separate lists, the "M" list, for Muslims, the "G", for non-Muslims (Gayrimuslim), the "E", for Foreigners (Ecnebi) and the "D" for converts (Dönme). The rigidly-enforced, discriminatory law did not yield the results the government had hoped for. Companies increased the prices of their products sharply to recoup their losses, creating a spiral of inflation that ruined low-income consumers. However, according to official information, the Turkish government collected 324 million liras (at a time when 1 US dollar was equivalent to 1.20 Turkish lira) through the confiscation of non-Muslim assets. This amount would be equivalent to more than $4 billion today. During this incident, the Turkish press allegedly had "anti-minority" articles and reports. According to T.C. Resmi Gazete, the official journal of Turkey that publishes the new legislation and other official announcements, the Varlık Vergisi (Law #4305) was not applied to any particular ethnic or religious communities. Tax tariffs were determined one by one for every business sector. According to the T.C. Resmi Gazete, the tax tariff of 4.94% was for the large-scale farmers, and not limited to any particular religious community. It was also indicated that the tariff for the large-scale farmers could not exceed 5%. Repeal and aftermath The law could not sustain relentless international criticism. Under pressure from the United Kingdom and the United States, it was repealed on 15 March 1944. After the abolition of the law, the minority citizens who were at the labour camps were sent back to their homes. The Turkish government promised to give back the paid taxes to non-Muslims, but this did not happen. The opposition Democratic Party (DP) capitalized on its unpopularity in the general election of 1950, which was the first democratic general election in the Turkish Republic, thereby achieving a landslide victory against the Republican People's Party (CHP). These taxes brought about a permanent demographic change within the minority population. Many people of the minorities, especially the Greek minority, felt that there was no future for them in Turkey and they left their ancestral homes and became refugees in Greece. On the other hand, some, especially from the Jewish community had managed to secrete assets abroad and they were able to restart a reduced and hesitant life in Turkey. The tax also resulted in state confiscation of much minority property in Istanbul, "Turkifying" not only the economy but also the landscape. The 1935 Census records non-Muslims as 1.98% of the population; by 1945, this had fallen to 1.54%. In addition, the Varlık Vergisi once more demonstrated that being Muslim constituted a significant part of the definition of citizenship in Turkey. The Varlık Vergisi in the way it was dealt with by the Turkish Press exemplifies the close relations between the Executive and the Press, in Turkey. Years after the introduction of the Varlık Vergisi, the political elite of Turkey had difficulties coming to terms with the subject. The historical novel Salkım Hanım'ın Taneleri (variously translated as Mrs. Salkım's Diamonds/Pearls/Beads/Necklace), written by Turkish author Yilmaz Karakoyunlu, recounts stories and witnesses of the non-Muslims during the Varlık Vergisi. The novel was soon turned into a film of the same name, Mrs. Salkım's Diamonds. Members of parliament, such as Ahmet Çakar (MHP), were outraged at the screening. See also Taxation of the Jews in Europe for other types of taxes imposed on the Jews Jizya Dhimmi Confiscated Armenian properties in Turkey Istanbul pogrom (1955) Mrs. Salkım's Diamonds (movie) Racism in Turkey The Twenty Classes İbrahim Süreyya Yiğit References Further reading Category:Anti-Armenianism in Turkey Category:Antisemitism in Turkey Category:Discrimination in Turkey Category:Greeks in Turkey Category:History of the Republic of Turkey Category:Taxation in Turkey Category:Turkish words and phrases Category:1942 in Turkey Category:Economic history of Turkey Category:Persecution of Christians in Turkey	{ "pile_set_name": "Wikipedia (en)" }
We've heard two requests from our community over and over again: make it easier to get LBC, and let users subscribe to their favorite creators. With that in mind, the newest LBRY update should be a crowd-pleaser! Channel subscriptions are live, and we've integrated ShapeShift to allow users to easily convert popular cryptos into LBC without leaving the app. You'll find all this (and a lot more) in LBRY v0.19 - get it here and check out the full release notes below. Release Notes Added Subscriptions. File and channel pages now show a subscribe button. A new "Subscriptions" tab appears on the homepage shows the most recent content from subscribed channels. LBC acquisition widget. Convert other popular cryptos into LBC via a ShapeShift integration. Flow static type checking. This is a dev-only feature but will make development faster, less error-prone, and better for newcomers. Changed The first run process for new users has changed substantially. New users can now easily receive one credit. The wallet area has been re-organized. Send and Receive are now on the same page. A new page, "Get Credits", explains how users can add LBRY credits to the app. Significant structural changes to code organization, packaging, and building. The app now follows a typical electron folder structure. All 3 package.json files have been reduced to a single file. Redux related code was moved into its own subfolder. The macOS docking icon has been improved. The prompt for an insufficient balance is much more user-friendly. The credit balance displayed in the main app navigation displays two decimal places instead of one. Video download error messages are now more understandable. Windows path to the daemon/CLI executables changed to: C:\Program Files (x86)\LBRY\resources\static\daemon Deprecated We previously had two separate models for insufficient credits. These have been combined. Fixed	{ "pile_set_name": "OpenWebText2" }
1/10/2017 So, 2016 certainly was... a year. But disregarding all the absolute shit that happened, in terms of video games, it was a good year. We got some great games... and somedisappointments. But I'm counting down my favorite games of the year. Of course, this is all subject to change in the future, and only games I've actually played.	{ "pile_set_name": "Pile-CC" }
import React, { memo } from 'react'; import PropTypes from 'prop-types'; import { NavLink } from 'react-router-dom'; import Icon from './Icon'; function LeftMenuLink({ children, to }) { return ( <NavLink to={to}> <Icon /> <p>{children}</p> </NavLink> ); } LeftMenuLink.defaultProps = { children: null, }; LeftMenuLink.propTypes = { children: PropTypes.node, to: PropTypes.string.isRequired, }; export default memo(LeftMenuLink); export { LeftMenuLink };	{ "pile_set_name": "Github" }
Q: smtplib - No connection could be made because the target machine actively refused it although I can find a lot of similar questions regarding this failure, the suggestions/answers dont help my case so I am looking for some help. I have the following function which works perfectly fine on my development machine(Windows 7) but when I try to run it on another machine which is running a Windows Server 2012 R2 Standard OS, I get the "Errno 10061 - No connection could be made because the target machine actively refused it" failure. I have tried disabling the firewall on the machine but that didnt help. I know the port and SMTP server are correctly listening as the same code on my development machine works. How do I go about resolving this? Any help is appreciated def send_email(user, pwd, recipient, subject, body): gmail_user = user gmail_pwd = pwd FROM = user TO = recipient if type(recipient) is list else [recipient] SUBJECT = subject TEXT = body message = """From: %s\nTo: %s\nSubject: %s\n\n%s """ % (FROM, ", ".join(TO), SUBJECT, TEXT) try: server_ssl = smtplib.SMTP_SSL("smtp.gmail.com", 465) server_ssl.ehlo() # server_ssl.starttls() server_ssl.login(gmail_user, gmail_pwd) server_ssl.sendmail(FROM, TO, message) server_ssl.close() print 'successfully sent the mail' except: print "failed to send mail" A: the problem was the firewall blocking the connection. Once that was removed the script works	{ "pile_set_name": "StackExchange" }
Effectiveness of aromatherapy massage on the stress of the surgical center nursing team: a pilot study. To verify the effectiveness of aromatherapy with essential oils of lavender (Lavandula angustifolia) and geranium (Pelargonium graveolens) associated with massage for stress relief of a nursing staff of the surgical center through evaluation of biophysiological and psychological parameters. Pilot study, controlled and randomized clinical trial performed with the nursing team of a surgical center of a teaching hospital in the interior of the state of São Paulo. The intervention comprised six aromatherapy massages with essential oils diluted in neutral cream at concentration 1% each. Heart rate and blood pressure levels were measured before and after each massage session. The Work Stress Scale (WSS) and the List of Stress Symptoms (LSS) were applied before and at the end of the intervention. Statistical analysis was performed with the paired t-test and chi-square test, 95% confidence interval and p <0.05. There was a statistically significant reduction in heart rate and blood pressure levels after massage sessions. The use of aromatherapy has demonstrated effectiveness for lowering biophysiological parameters of the surgical center nursing staff. Brazilian Registry of Clinical Trials: RBR-6mgqn3.	{ "pile_set_name": "PubMed Abstracts" }
An investigation of the effects of late-onset dietary restriction on prostate cancer development in the TRAMP mouse. In our previous work we showed that dietary restriction initiated at puberty reduced prostate cancer development in the TRAMP mouse model. The current study was conducted to ascertain whether a dietary restriction regime would similarly reduce lesion development if imposed once tumor development was well established. Male TRAMP mice were maintained on an ad libitum diet until 20 weeks of age when proliferative prostate lesions are clearly evident. Mice were then subjected to a 20% restriction in dietary calories compared to matched controls, which were continued on ad libitum feeding. Mice were sacrificed at 20, 24, 32, and 39 weeks of age and proliferative epithelial lesions of the prostate were assessed using an established grading scheme. In this study, although dietary restriction reduced mean sex pluck weight (prostate and seminal vesicles), and mean grade of epithelial proliferative lesions in the dorsal and lateral lobes of the prostate, the effect was not as pronounced as was the case with dietary restriction from puberty. There was no relationship between serum insulin like growth factor (IGF-1) and prostate lesion grade. Additionally, we also report the relationship between lobe specific lesion development and SV40 immunostaining and, the occurance of neuroendocrine tumors (NETs) in the ventral prostate and urethra of the TRAMP mouse. NETs stained with high specificity and sensitivity for the neuroendocrine markers, synaptophysin and neuron-specific enolase (NSE), less for serotonin, but not for chromogranin A. NETs did not stain for cyclo-oxygenase-2 (COX-2) nor androgen receptor (AR). SV40 positive tubulo-acinar tumors seen occasionally in the kidney, did not stain for synaptophysin nor NSE.	{ "pile_set_name": "PubMed Abstracts" }
Q: Why should one study English in India? I'm a teacher teaching English in a village school.I need a concrete reason to continue to do so.I am looking for opinions,facts,references & even specific expertise. A: English is one of the two official languages of India, the second being Hindi. If any of your students want a job in any official government post, or a job where they have to deal with the government, speaking English will be a huge advantage to them. Being able to speak any other language is good for ones job prospects, and is in any case a fulfilling enterprise which broadens the mind. English is widely used across the world as a lingua franca. So being able to speak English enables you to communicate with people from many different parts of the world, including many other people for whom English isn't their first language.	{ "pile_set_name": "StackExchange" }
package com.fourlastor.dante.html; import android.content.res.Resources; import android.graphics.Bitmap; import android.graphics.drawable.BitmapDrawable; import android.graphics.drawable.Drawable; import androidx.annotation.NonNull; public interface ImgLoader { Drawable loadImage(@NonNull String src); abstract class BitmapLoader implements ImgLoader { private final Resources resources; protected BitmapLoader(Resources resources) { this.resources = resources; } @Override public Drawable loadImage(@NonNull String src) { Bitmap bitmap = loadBitmap(src); BitmapDrawable bitmapDrawable = new BitmapDrawable(resources, bitmap); bitmapDrawable.setBounds(0, 0, bitmap.getWidth(), bitmap.getHeight()); return bitmapDrawable; } protected abstract Bitmap loadBitmap(String src); } }	{ "pile_set_name": "Github" }
While the omnibus spending bill was a huge loss for President Trump's supporters, it was a huge win for the Israel lobby. The $1.3 trillion, 2,232 page bill which not one congressman read before passing gives Israel billions of dollars and defunds the Palestinian Authority. The bill had the full support of both the Republican and Democratic establishments. The bill also hits Russia, a key ally of Iran which is Israel's number one enemy, with a host of sanctions. Though America only got $1.6 billion for a few dozen miles of fencing, the countries surrounding Israel got $1.8 billion to secure their borders. It sure would be nice if there was a lobbying group for American citizens which was as powerful as AIPAC is for Israel. Follow InformationLiberation on Twitter, Facebook and Gab.	{ "pile_set_name": "OpenWebText2" }
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Arms smuggler arrested from Munger in Bihar Munger: An alleged arms smuggler was arrested with 24 automatic pistols in his possession from Jamalpur police station area in the district today. The police acted on a tip off and Mohammad Monu was arrested from the taxi stand area, Superintendent of Police Varun Kumar said. Two dozen automatic pistols, an ATM card and a driving license were recovered from Monu, a resident of Hazratganj locality of Munger town. During questioning, Monu said he had been working as an arms carrier for one Mohammad Mahtab, a resident of Maksudpur in the district, who has set up a factory in Malda district of West Bengal for manufacturing arms illegally, the SP said.	{ "pile_set_name": "Pile-CC" }
[Methods for intravenous injection and blood collection in the guinea pig via veins of the forelimb without anesthesia (author's transl)]. Methods for intravenous injection and blood collection by way of the forelimb in guinea pigs without anesthesia were investigated, with the results as follows: 1) Both the accessory cephalic and cephalic veins were found available for injection as well as for drawing blood samples. Venipuncture was accomplished with greater ease by using the accessory cephalic vein. 2) The following procedure has proven practical. (i) Clip the hair over the site. (ii) Restrain the animal to immobilize the foreleg in slight extension by grasping it at the elbow joint with the thumb and forefinger over its dorsal and ventral aspects, respectively. (iii) After disinfecting the skin surface with alcohol, perform injection using an appropriate syringe with a 27 (1/4) or 25 (1/3) gauge intravenous needle, or puncture the vein with a 23 (1/2) gauge i. v. needle to collect the blood that drips out.	{ "pile_set_name": "PubMed Abstracts" }
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Menu Apartments Serviced apartments in Mayfair are in great demand these days and most of the visitors prefer these apartments in comparison to the hotel rooms and such other alternatives like guest houses and resorts. There are multiple reasons for this. While the privacy and flexibilities offered are one of the major considerations; no less significant is the savings that one makes when he or she chooses to stay in one of the apartments. But for the purpose of getting the best apartments one requires the right provider who will cater to all the requirements of the prospective client. Attributes of the Best Provider The best provider of the serviced apartments in Mayfair will offer the clients with multiple options for choosing the serviced apartment according to his or her requirements and budget. The serviced apartments provided by quality provider will take care to ensure that the apartment has all the amenities that are available in at least the 4-star hotels. At the same time the apartment should be strategically located so that all the required facilities are within the reach of the prospective clients. In addition; the apartments will have adequate space for the occupiers to work and enjoy the facilities conveniently. Most important of all; the quality provider will keep the entire process transparent and will not charge the client exorbitantly so as to make the process financially non-viable for him or her. Short of Long; it is Always the Best Another important aspect of hiring the right service provider is that whether long or short, the apartments provided is always the best for the client befitting his or her requirements and budget. Whether it is short stay or longer residence purpose for which the serviced apartments in Mayfair are required, the quality provider will always give the best to the client. Finding the provider won’t be difficult as a little homework will lead one to the right service provider easily.	{ "pile_set_name": "Pile-CC" }
Paraneoplastic syndromes associated with small cell lung cancer. Small cell lung cancer (SCLC) is the most frequent cancer histology associated with paraneoplastic syndromes. These syndromes are typically caused by ectopic hormone production or immune-mediated tissue destruction caused by neural antigen expression from cancer cells. This antigen expression induces the production of antibodies that cross-react with neural tissue. This article discusses the most common ectopic hormone and neurologic paraneoplastic syndromes and emphasizes the relationships among antigens, clinical syndromes, and outcomes. Although ectopic hormone production has been associated with extensive-stage disease and a poorer outcome, the antibody-mediated paraneoplastic syndromes are prognostic factors associated with more favorable outcomes. Both have the potential for improvement with cancer treatment.	{ "pile_set_name": "PubMed Abstracts" }
Marty Lurie Posted in Uncategorized by Flavor on March 14, 2016 He threw out a tweet yesterday and I gave it the quickest, snarkiest response possible. I would probably change it to “no. 16. 7th inning stretch”. I love the 7th inning stretch. It’s just the perfection of baseball encapsulated into one minute. And I’m all about “take me out to the ballgame” not that silly “God Bless America” nonsense that started after 9/11. Anyway, how would you guys answer Lurie’s tweet? Share this: Like this: Related 42 Responses regarding Madness, everyone seems to think Pac 12 is underrated but all I saw was a bunch of teams losing on the road all year. Assuming none of them have a home game in the tourney, and I haven’t actually checked to see if any of them get a game at home, then aren’t they all pretty much a bet against to do anything other than get out of the first round? With a couple of exceptions — Oklahoma in OKC, Carolina in Raleigh — everyone else is on the road, too. Oregon gets first two in Spokane, though it’s in the middle of nowhere, I can see their fans making that trip. I’m pretty sure my co-worker Maryland fan, who was considering going to the Terps’ early games, won’t be going out there. And Utah is in Denver. I guess the big test will be Arizona in Providence and USC in Raleigh. for me, it’s not about just the fans in the seats. It’s the venue, the floor, the depth of the rim to the seats behind, stuff like that. There seems to be something about pac 12 teams this year excelling on their home court. But, small sample size I guess. we’ll see. I still like Utah a lot so if I send them through I probably should send Cal through a couple of rounds, too. Or, I might just play nothing but DFS players and skip the brackets. There is a LOT of money being offered in DFS for Madness this year. I think Williamson/Parker will be a leftfield platoon by the All-Star break. Williamson probably starts the season at AAA. I think Heston will get about 15 starts. A favorite baseball tradition is the arrival of the season preview magazines in stores. As we all know the G’s aren’t gonna eat Pagan’s 10mil.So until he gets hurt Mac stays in Sac unfortunately.Just hope they don’t let him play the “I lol be ok with a few days rest BS with a lingering injury and weaken the roster with a open space needed. My OF right now would be Span,Pence,Blanco,Parker&Williamson, but that won’t happen until Pagan craters.. I am not one for tradition..yeah I’m the conservative here. So I actually don’t care about 7th inning stretch nor God Bless America. In fact, I think playing the national anthem at every god dammed sporting event including high school sports is too much and lessens the actual value and impact of the anthem. I actually intentionally quietly protest the 7th inning stretch by sitting and refusing to sung any refrain of take me out the ballpark…. To badly paraphrase the comedian Greg Proops who said one day on his podcast that growing up in the Bay Area gave him a a massive dose of intense cynicism…. I think CLEAN MAC needs to start the season on sactown playing every day. I like Parker as the fifth OF. If CLEAN MAC starts on a tear and Parker and or Pagan falter or an injury pipes up then CLEAN MAC coming up June firstish makes sense. Heston I would expect gets all of Cain’s starts….let’s hope for the sake of Cain’s health that is not more than 6 starts unless they decide to give Kid Stratton a shot so they can keep Heston and his potential more adept arm in long relief. My Madness picks hinges on Kansas losing…so I have Cal or UCONN coming out of that bracket. If that is wrong, I’m f’d…UNC over OK as my more conservative pick with UCONN-UVA in the Final Four and Michigan State over Cal in my other entry with UK and A&M the other final four teams.. I think Williamson could hit a dozen dingers this spring and he still starts in Sac. I believe he botched a deep fly to LF the game I saw, after coming in for Pagan; his glove may be a bit like Burrell’s– maybe somebody has his fielding stats. Anyway, the OF options look broader this year, finally. Pagan and Blanco are almost certainly gone next season, so it’s good there look to be some internal candidates. Neither Williamson nor Parker are spring chickens — they need to come up soon and prove they are worthy or not good enough… No. 19 I like the sometimes-seen tradition where if a guy takes a big rip on the first pitch of the game, he gets the next pitch thrown at his chin. I saw Dravecky do this live to Steve Sax many years ago at Dodger Stadium. Might have even been opening day. Sax homered on the first pitch in the bottom of the 1st. Next time he came up, I started yelling that he was going to get knocked on his ass. And he did. My Final Four: Oklahoma (They impressed me big time earlier in the year and I like Lon Kruger) Arizona (brutal bracket. I hate the “Cats, but they always have talent and Miller can coach) Michigan State North Carolina (far and away the easiest path IMO) Hey SD–how your season turn out? Take a deep breath and relax after it’s over or did it end too soon? Those are good picks but AZ doesn’t have near talent they usually do. I like Maryland to take that bracket. Guy on KNBR Krueger went off this morning over Williamson, saying he’s the best they have for LF right now and should get the everyday ABs with big Giants over Pagan and Blanco instead of at Sacto. Curry’s inside finishes amaze me. Lot of guys can make nice moves to get there and then throw up a stupid shot and can’t finish. He blows by people with hesitation move/cross over and then gets to the rim and scores with variety of bank shots with English. hard to f-ing believe but Bogut just swished a 3. He was standing on top looking to pass while Warriors were standing around trying to get out off screens, shot clock hit 1 so he launched it. Then blocks a shot at other end which eventually leads to a 3 by Thompson for 18 pt lead. Um, Kings fans, pls tell me what happened to get Cousins suspended. What was the yelling with Karl about? I notice they lost to Utah with him back in LU. Is this relationship over? Who goes? Agree Chuck, It’s a meaningless ST game,and they should of immediately taken Cueto out. But as usual are crack medical staff who are incompetent leaves him in, then he goes under concussion protocol after the game?? WTF Why don’t major league teams hire a full time medical doctor like the NFL does?? @Willie: Season turned out pretty good (9-5), our best season in my 3 years at the helm. Just had our banquet tonight and hell yes, I’m taking a breath after going through the grind of another season of bus rides. Next year I may well be the varsity coach which will be another level of commitment, but I’m (mostly) ready for it. I like your Maryland pick, but I still think Zona has some nice talent on the roster. As for Kings, I’m ready to blow it up. Fire Karl, he was a lousy hire with nothing left in the tank. Trade Cousins for 50 cents on the dollar and let Rondo walk. Yeah, we’d probably go 12-70 in a brand new building if we did that, but I’m ready for it. The Kings kind of remind me of the Giants back in the 80’s before Al Rosen came in and blew shit up. Let’s put together a scrappy team that plays hard and represents the city with class. It still ABSOLUTELY KILLS me to see the Warriors become a legendary team after so many years of taking comfort in the fact that they sucked just as bad as the Kings did. At least some far left radicals hate the singing during the 7th inning stretch. Also the anthem, that ridiculous ritual. Although now that I’m a senior citizen I’m not so willing to say eff off to some young yahoo who tells me to take my hat off. So I’m often busy getting a beer then. But occasionally confrontations do occur. Tell it Trump, a-hole. I’m diggin’ those who think the national anthem sucks. It does. The tune is an old english pub driniking tune. The lyrics are about the beginning of the War of 1812, a war nobody gave much of a damn about then, or since. If you are going to sing anything ritually, use “America the Beautiful”. Good tune, easy to sing, lyrics are about the country, the people, not some dumbass war song. And, can the “God Bless America” stuff in the 7th inning. What’s next — we all have to sign a loyalty oath and pledge to the 700 Club to get a beer?…	{ "pile_set_name": "Pile-CC" }

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