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tomekkorbak

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[ "Bulls knockout RailRiders in 11th inning\n\nFans at the DBAP got just the type of game expected when the top two teams in the league meet.", "\n\nDurham and Scranton/Wilkes-Barre had a heavyweight fight in front of the 9,470 fans, going extra innings for the second straight night. ", "Johnny Field made it worth the wait, scoring the only run of the game to give the Bulls a 1-0 victory.", "\n\nThe walk-off by Field was the third this season for Durham. ", "On a night when hits were hard to come by, the first (and only) one for Field was the one that set off the wild celebration. ", "With Kean Wong on third, Field hit a line drive to lead the Bulls (72-45) to a huge win over the league leading RailRiders.", "\n\n“We had a couple of bases open so I didn’t really expect him to give me a fastball,” Field said.", "\n\nHelp us deliver journalism that makes a difference in our community.", "\n\nOur journalism takes a lot of time, effort, and hard work to produce. ", "If you read and enjoy our journalism, please consider subscribing today.", "\n\nWith a 2-1 count, Joe Mantiply threw a curveball that Field jumped on and sent it to left field.", "\n\n“It was right down the line,” Field said.", "\n\nDurham had a chance to get on the board early in the game. ", "In the bottom of the third the Bulls had two runners on with one out, but a double-play ended any hopes of a run. ", "Scranton/Wilkes-Barre (75-42) wasn’t so lucky. ", "The RailRiders only got two hits through the first nine innings, never getting more than one runner on base. ", "Scranton/Wilkes-Barre only got four batters up to bat three times in nine innings, as Durham’s defense was spectacular. ", "The offense, however, struggled against RailRiders’ pitcher Domingo German, who gave up just three hits in his six innings of work.", "\n\n“That was a hard fought game,” Field said. “", "Both teams pitched their (tails) off. ", "We couldn’t get anything going offensively and our pitchers went out there and dominated.”", "\n\nMike Broadway, who arrived in Durham from Montgomery sometime Wednesday night, got the start, going two innings, striking out three. ", "Diego Castillo (2.0IP, 1H, 3K) got the win. ", "On a bullpen night, Durham manager Jared Sandberg tipped his hat to his staff and the job they did, holding the RailRiders to three hits.", "\n\n“The pitchers were outstanding today to say the least,” Sandberg said. “", "When they are all in short stints like that it helps them pitched their game. ", "They were all did an incredible job.”", "\n\nThe two teams continue their four-game series Friday at 7:05 p.m. Ryan Yarbrough (12-5) starts for the Bulls, while Chance Adams (8-3) gets the start for the the RailRiders." ]

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[ "Computational analysis of the role of the hippocampus in memory.", "\nThe authors draw together the results of a series of detailed computational studies and show how they are contributing to the development of a theory of hippocampal function. ", "A new part of the theory introduced here is a quantitative analysis of how backprojections from the hippocampus to the neocortex could lead to the recall of recent memories. ", "The theory is then compared with other theories of hippocampal function. ", "First, what is computed by the hippocampus is considered. ", "The hypothesis the authors advocate, on the basis of the effects of damage to the hippocampus and neuronal activity recorded in it, is that it is involved in the formation of new memories by acting as an intermediate-term buffer store for information about episodes, particularly for spatial, but probably also for some nonspatial, information. ", "The authors analyze how the hippocampus could perform this function, by producing a computational theory of how it operates, based on neuroanatomical and neurophysiological information about the different neuronal systems contained within the hippocampus. ", "Key hypotheses are that the CA3 pyramidal cells operate as a single autoassociation network to store new episodic information as it arrives via a number of specialized preprocessing stages from many association areas of the cerebral cortex, and that the dentate granule cell/mossy fiber system is important, particularly during learning, to help to produce a new pattern of firing in the CA3 cells for each episode. ", "The computational analysis shows how many memories could be stored in the hippocampus and how quickly the CA3 autoassociation system would operate during recall. ", "The analysis is then extended to show how the CA3 system could be used to recall a whole episodic memory when only a fragment of it is presented. ", "It is shown how this recall could operate using modified synapses in backprojection pathways from the hippocampus to the cerebral neocortex, resulting in reinstatement of neuronal activity in association areas of the cerebral neocortex similar to that present during the original episode. ", "The recalled information in the cerebral neocortex could then be used by the neocortex in the formation of long-term memories." ]

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[ "#include <malloc.h>\n#include <string.h>\n#include <stdlib.h>\n#include <stdbool.h>\n\n#include \"utils.h\"\n\n#define MAX_LEN 8192\n#define MAX_OFFSET 16\n#define MIN_REDZONE 128\n#define BUFLEN (MAX_LEN+MAX_OFFSET+2*MIN_REDZONE)\n#define POISON 0xa5\n\nunsigned long COPY_LOOP(void *to, const void *from, unsigned long size);\n\nstatic void do_one(char *src, char *dst, unsigned long src_off,\n\t\t unsigned long dst_off, unsigned long len, void *redzone,\n\t\t void *fill)\n{\n\tchar *srcp, *dstp;\n\tunsigned long ret;\n\tunsigned long i;\n\n\tsrcp = src + MIN_REDZONE + src_off;\n\tdstp = dst + MIN_REDZONE + dst_off;\n\n\tmemset(src, POISON, BUFLEN);\n\tmemset(dst, POISON, BUFLEN);\n\tmemcpy(srcp, fill, len);\n\n\tret = COPY_LOOP(dstp, srcp, len);\n\tif (ret && ret !", "= (unsigned long)dstp) {\n\t\tprintf(\"(%p,%p,%ld) returned %ld\\n\", dstp, srcp, len, ret);\n\t\tabort();\n\t}\n\n\tif (memcmp(dstp, srcp, len)) {\n\t\tprintf(\"(%p,%p,%ld) miscompare\\n\", dstp, srcp, len);\n\t\tprintf(\"src: \");\n\t\tfor (i = 0; i < len; i++)\n\t\t\tprintf(\"%02x \", srcp[i]);\n\t\tprintf(\"\\ndst: \");\n\t\tfor (i = 0; i < len; i++)\n\t\t\tprintf(\"%02x \", dstp[i]);\n\t\tprintf(\"\\n\");\n\t\tabort();\n\t}\n\n\tif (memcmp(dst, redzone, dstp - dst)) {\n\t\tprintf(\"(%p,%p,%ld) redzone before corrupted\\n\",\n\t\t dstp, srcp, len);\n\t\tabort();\n\t}\n\n\tif (memcmp(dstp+len, redzone, dst+BUFLEN-(dstp+len))) {\n\t\tprintf(\"(%p,%p,%ld) redzone after corrupted\\n\",\n\t\t dstp, srcp, len);\n\t\tabort();\n\t}\n}\n\nint test_copy_loop(void)\n{\n\tchar *src, *dst, *redzone, *fill;\n\tunsigned long len, src_off, dst_off;\n\tunsigned long i;\n\n\tsrc = memalign(BUFLEN, BUFLEN);\n\tdst = memalign(BUFLEN, BUFLEN);\n\tredzone = malloc(BUFLEN);\n\tfill = malloc(BUFLEN);\n\n\tif (!", "src || !", "dst || !", "redzone || !", "fill) {\n\t\tfprintf(stderr, \"malloc failed\\n\");\n\t\texit(1);\n\t}\n\n\tmemset(redzone, POISON, BUFLEN);\n\n\t/* Fill with sequential bytes */\n\tfor (i = 0; i < BUFLEN; i++)\n\t\tfill[i] = i & 0xff;\n\n\tfor (len = 1; len < MAX_LEN; len++) {\n\t\tfor (src_off = 0; src_off < MAX_OFFSET; src_off++) {\n\t\t\tfor (dst_off = 0; dst_off < MAX_OFFSET; dst_off++) {\n\t\t\t\tdo_one(src, dst, src_off, dst_off, len,\n\t\t\t\t redzone, fill);\n\t\t\t}\n\t\t}\n\t}\n\n\treturn 0;\n}\n\nint main(void)\n{\n\treturn test_harness(test_copy_loop, str(COPY_LOOP));\n}\n" ]

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[ "The role of memory in awareness of memory deficits in Alzheimer's disease, schizophrenia, and brain injury.", "\nPatients with neuropsychiatric disorders such as Alzheimer's disease (AD), schizophrenia (Sz), and brain injury (BI) often show memory deficits and lack of awareness of those deficits. ", "This study aimed to investigate the role of memory in awareness of memory deficits and illness in multiple patient groups. ", "Comparison of awareness profiles between groups can reveal common or distinct patterns of awareness and predictors, which may inform theories about the structure of awareness. ", "Using the same standardized measures, AD (N = 27) Sz (N = 31), and BI (N = 26) patients were compared on memory functioning, awareness of illness, and awareness of memory deficits-measured by discrepancy of pretest estimate and actual test scores. ", "All groups were poor at pretest estimation of memory functioning, particularly the AD and BI groups. ", "In AD, patients with the lowest memory functioning rated their performance highest. ", "The BI group and to a lesser extent the AD group showed improved estimations of performance following the memory test. ", "Those with the poorest memory showed the greatest improvement in ratings accuracy post test. ", "The relationship between memory and awareness of memory was stronger than the association between memory and awareness of illness. ", "There was a double dissociation between awareness of memory and awareness of illness across patient groups. ", "The study shows that awareness of memory is linked to memory functioning, while memory is only modestly related to awareness of illness. ", "Dissociations in the role of memory in different domains of awareness and \"online\" awareness of performance provide information to refine cognitive models of awareness. ", "However, the results should be interpreted with caution given the heterogeneous nature of the sample." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Can you guess the Price this ‘barn-find’ 1960 Mercedes 190SL is going for?", "\n\nA 1960 Mercedes-Benz 190SL restoration project is coming up for auction with H&H Classics at its Duxford sale on July 26. ", "The car is being offered with no reserve, although the auction house estimates that it is likely to sell for £50,000.", "\n\nBack-View of the Benz 190SL\n\nThe 57-year-old classic convertible was discovered in an old garage in Solihull by Mark Bryan of H&H Classics’ motorcycle department while he was valuing bikes for sale.", "\n\nHe said: “What a great find. ", "Never in a million years did I expect to see this, an original UK-registered, right-hand-drive 190SL in dire need of restoration.", "\n\n“It just goes to show that you never know what is lurking in that old lock-up.”", "\n\nIf the car was in good condition it would fetch about £150,000 - the record price for a 190SL sold at auction is $209,000 (£164,000), a price achieved in 2015.", "\n\nDesigned as a more affordable version of the famed Mercedes-Benz 300SL supercar, dubbed the Gullwing due to its upward-opening doors, the 190SL was produced from 1955 to 1963 and was only available as an open roadster. ", "Unlike its more illustrious sibling, it had a conventional monocoque chassis, although it had the same suspension.", "\n\nInterior of the Convertible Benz 190SL\n\nThe 190SL’s 1.9-litre, four-cylinder engine (essentially two-thirds of the 300SL’s bellowing straight-six) developed 120bhp, giving a top speed of 109mph and 0-62mph acceleration in 11sec. ", "As examples of the 300SL now fetch in excess of £1 million, the 190SL is considered an affordable way to experience open-top Mercedes motoring at its finest." ]

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[ "Shalgam\n\nShalgam is a traditional salad from Kazakhstan and Kyrgyzstan. ", "It is made from radishes (shalgam), sweet Bulgarian bell pepper, carrots, onions, garlic and spices.", "\n\nSee also\n Kazakh cuisine\n Kyrgyz cuisine\n List of salads\n Şalgam (a Turkish beverage)\n\nReferences\n\nCategory:Kazakhstani cuisine\nCategory:Kyrgyz cuisine\nCategory:National dishes\nCategory:Salads" ]

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

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[ "ILEAS Foundation Partners with First Tactical to Offer Discounts on Equipment and Clothing\n\nILEAS has been asked by the ILEAS Foundation to announce that the Foundation is partnering with First Tactical to offer an introductory discount of 20%from any item purchased on their website catalog. ", "In addition to the discount, First Tactical is donating 7% of the sale to the ILEAS Foundation. ", "For more information on how you can get the discount, please follow this link to the ILEAS Foundation home page." ]

{ "pile_set_name": "Pile-CC" }

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[ "INTRODUCTION {#S5}\n============\n\nAntibiotics are the most common medications prescribed for infants in the neonatal intensive care unit (NICU) ([@R1]). ", "Although the incidence of culture-confirmed early-onset sepsis (EOS) in term infants is relatively low (\\~0.5-0.8 cases/1000 live births), both the incidence of disease (15-19 cases/1000) and EOS-attributable mortality (3.5% vs 35%) are substantially higher among very low birth weight, preterm infants ([@R2]). ", "Given the high mortality associated with EOS, presence of maternal and neonatal risk factors, and time required for pathogens to be isolated in culture, empirical antibiotics targeting EOS are administered to large proportions of infants in the NICU ([@R3],[@R4]).", "\n\nIn 2009, the *Eunice Kennedy Shriver* National Institute of Child Health and Human Development Neonatal Research Network (NRN) reported data from 1998-2001 suggesting that prolonged duration of antibiotics administered soon after birth to extremely low birth weight (ELBW, birth weight \\<1000 g) infants was associated with increased risk of death, necrotizing enterocolitis (NEC), and the composite measure of NEC or death ([@R5]). ", "In that study, 53% of 4039 infants surviving \\>5 days were administered antibiotics beginning at birth and extending ≥5 days in the absence of culture-confirmed infection. ", "These findings were consistent with other smaller studies ([@R6],[@R7]). ", "It is unclear to what degree neonatal clinicians have changed antibiotic practice over the ensuing 20 years and the impact on infant outcomes. ", "A recent study including 40,534 very low birth weight (VLBW, \\<1500 g) infants born at 297 primarily nonteaching centers found a small but significant decrease in the rate of prolonged early antibiotic administration among VLBW infants, but no change among the subgroup of 14,923 ELBW infants ([@R8]). ", "The purpose of this study was to 1) describe changes over time in the provision of prolonged early antibiotic therapy without culture-confirmed infection or intraabdominal inflammatory process, and 2) describe associations of such prolonged early antibiotic therapy with adverse outcomes among a more contemporary cohort of extremely premature infants cared for at academic centers of the NRN.", "\n\nMATERIALS AND METHODS {#S6}\n=====================\n\nSubjects {#S7}\n--------\n\nThis was a retrospective analysis of data entered into a registry of high-risk preterm infants maintained by the NRN. ", "Study infants were born between January 1, 2008, and December 31, 2014. ", "The registry contains maternal and neonatal information from the intrapartum period until infant discharge home, transfer from the primary center, death, or 120 days after birth. ", "Limited demographic, clinical, and outcome data, including whether or not infants were started on antibiotics before and continued beyond the first 5 postnatal days, were collected by trained research staff utilizing a standardized manual of operations. ", "Site participation differed over the study period, and we included data from the 13 centers that participated in the NRN for the entire study period (denoted with an asterisk in the Acknowledgments). ", "Infants were included in the study if they had a birth weight of 401-1000 g and gestational age of 22 0/7 -- 28 6/7 weeks. ", "Exclusion criteria were: death \\<5 days after birth; blood or cerebrospinal fluid culture obtained within the first 5 postnatal days growing pathogenic bacterial or fungal species; NEC or spontaneous intestinal perforation (SIP) diagnosed ≤5 days after birth; or major birth defect. ", "The institutional review board at each center approved participation in the registry.", "\n\nDefinitions {#S8}\n-----------\n\nProlonged early antibiotic therapy was defined as ≥5 days of antibiotic administration initiated at ≤72 hours of age. ", "Comparator infants may have had antibiotics initiated within 72 hours of age and discontinued before 5 days, or may not have had antibiotics initiated within 72 hours of age. ", "Small for gestational age (SGA) was defined as birth weight \\<10^th^ percentile for sex and gestational age using percentiles reported by Alexander et al ([@R9]). ", "Late-onset sepsis (LOS) was defined as a blood and/or cerebrospinal fluid culture obtained at \\>72 hours of age and growing a recognized bacterial or fungal pathogen if the infant was administered antibiotics for ≥5 days or until death. ", "NEC was defined as modified Bell's stage ≥IIA ([@R10],[@R11]).", "\n\nStatistical analysis {#S9}\n--------------------\n\nPrior to excluding infants who died at \\<5 days or who had a positive culture, NEC, or SIP in the first 5 days, we determined the proportion of infants with EOS by center. ", "After exclusions, we determined the proportion of infants who received prolonged early antibiotics overall and by center over time. ", "We compared infant demographic and maternal characteristics between infants who received prolonged early antibiotics and those who did not using Student's t-test for continuous variables and Wald chi-square test for categorical variables. ", "P-values were 2-tailed with values ≤0.05 considered statistically significant. ", "Analyses were conducted using SAS 9.4 (SAS Institute, Cary, NC).", "\n\nSeparate logistic regression models were used to evaluate associations between birth year, center, and receipt of prolonged early antibiotics; and between prolonged early antibiotics and outcomes, including all-cause mortality after 5 days of life, NEC, LOS, LOS due to organisms other than coagulase-negative staphylococci (non-CoNS LOS), and LOS due to one or more fungal organisms (fungal LOS). ", "We examined death and composite outcomes of death/morbidity for all infants; NEC and LOS were examined in survivors to discharge to reduce potential bias due to different at-risk periods, particularly for infants with short survival times. ", "All models included birth year (categorical), study center, infant characteristics (gestational age, SGA, sex, and 5-minute Apgar score \\<5), and maternal characteristics (black race, multiple birth, rupture of membranes \\>24 hours, receipt of antenatal steroids, perinatal antibiotic therapy, hypertension, antepartum hemorrhage, and cesarean section).", "\n\nBecause prolonged early antibiotics may be administered to more severely ill infants at greater risk for adverse outcomes, we also included an indicator in our models aimed at identifying severity of illness. ", "We defined this indicator as initiation of any mechanical ventilation on the day of birth and continued use for all of the first 7 days after birth, or for all days until death if death occurred before 7 days (continuous mechanical ventilation \\[cMV\\]). ", "We examined whether associations between prolonged early antibiotics and adverse outcomes were different among infants with and without this indicator by including the interaction between prolonged early antibiotics and cMV in our models. ", "Results are shown separately for the cMV and non-cMV groups if this interaction was significant at p≤0.10. ", "Otherwise, results shown are based on models that did not include the cMV interaction.", "\n\nRESULTS {#S10}\n=======\n\nThe NRN registry enrolled 14,212 infants from 2008-2014. ", "Of these, 5730 met all study inclusion and exclusion criteria ([Supplemental Digital Content S1](#SD1){ref-type=\"supplementary-material\"}). ", "Prolonged early antibiotics were administered to 2526/5730 (44%) infants. ", "Multiple maternal and neonatal characteristics differed significantly between infants who did or did not receive prolonged early antibiotics ([Table 1](#T1){ref-type=\"table\"}). ", "Overall, infants who received prolonged early antibiotics were younger and smaller, had lower 5-minute Apgar scores, were less likely to have been born via cesarean section, were more likely to have been born to a mother with prolonged rupture of membranes or who was treated with antenatal antibiotics, and were more likely treated with cMV ([Table 1](#T1){ref-type=\"table\"}).", "\n\nFactors associated with receipt of prolonged early antibiotics {#S11}\n--------------------------------------------------------------\n\nThe overall percentage of infants treated with prolonged early antibiotics decreased from 49% in 2008 to 35% in 2014 (adjusted odds ratio \\[aOR\\] 0.44 \\[95% CI, 0.35-0.56\\], p\\<0.001) ([Supplemental Digital Content S2](#SD1){ref-type=\"supplementary-material\"}, [Table 2](#T2){ref-type=\"table\"}). ", "The percentage of infants treated varied by center, ranging from 30-69% ([Figure 1](#F1){ref-type=\"fig\"}). ", "The center-specific incidence of EOS ranged from 0.3-3.6%. ", "The center-specific rate of prolonged early antibiotic administration decreased over the study period at 8 of the 13 centers. ", "Compared to the center with the lowest rate, infants cared for at 11 of the 12 remaining centers were significantly more likely to receive prolonged early antibiotics ([Table 2](#T2){ref-type=\"table\"}).", "\n\nRelationship of prolonged early antibiotics with outcomes {#S12}\n---------------------------------------------------------\n\nInfants who received prolonged early antibiotics had marginally but not significantly higher odds of death compared to those who did not receive prolonged early antibiotics (19% vs 13%, aOR 1.17 \\[95% CI, 0.99-1.40\\], p=0.07). ", "Prolonged early antibiotics were not significantly associated with the composite outcomes of death or specific morbidities ([Table 3](#T3){ref-type=\"table\"}), nor with specific morbidities among survivors to discharge. ", "These findings were not different among infants who did or did not receive cMV, with one exception: the relationship of prolonged early antibiotics with LOS caused by fungal organisms varied by cMV group (interaction p\\<0.001) ([Table 3](#T3){ref-type=\"table\"}). ", "Among infants not treated with cMV, prolonged early antibiotic administration was associated with increased odds of fungal LOS (2% vs 0.4%, aOR 4.95 \\[95% CI, 1.93-12.69\\], p\\<0.001) ([Table 3](#T3){ref-type=\"table\"}).", "\n\nDISCUSSION {#S13}\n==========\n\nWe observed a significant decline in the overall use of prolonged early antibiotics among ELBW infants cared for in 13 NRN centers over a 7-year period. ", "The overall use of prolonged early antibiotic therapy during this study was lower (44% vs 53%) than that reported in our prior study of early antibiotic use in infants born 1998-2001. ", "However, we observed persistent significant center-specific antibiotic practice variation. ", "The proportion of infants treated with prolonged early antibiotics differed between centers, and reduction in prolonged therapy was only observed at 8 of the 13 centers. ", "The rates of prolonged antibiotic administration remained 10-to-100-fold higher than the rates of culture-confirmed EOS, even with the observed decrease in prolonged therapy. ", "In contrast to our prior NRN study, we found no statistically significant association between prolonged early antibiotics and risk of death. ", "Our study raises several issues to be considered as neonatal caregivers work to identify the best approaches to use of antibiotics for medically fragile, extremely premature infants in the first postnatal days.", "\n\nOur findings reflect slowly evolving views of the role of antibiotics in neonatal care. ", "Multiple national organizations recommend comprehensive approaches to antimicrobial stewardship ([@R12]), and neonatal providers are actively pursuing approaches to optimize antibiotic use among NICU patients ([@R13]). ", "In a study using the Pediatric Health Information System database, antibiotic utilization decreased \\~5% per year from 2004 to 2012 among hospitals without mandatory public reporting requirements for central line-associated bloodstream infection ([@R14]); similar secular trends in NICU antibiotic use were observed among hospitals subject to such reporting requirements. ", "Neonatal antimicrobial stewardship programs at individual centers and collaboratives also report success in safely decreasing overall NICU antibiotic utilization ([@R15]-[@R17]). ", "However, NICUs care for infants across a wide spectrum of gestational ages and morbidities, and studies focused specifically on VLBW and ELBW infants report mixed outcomes. ", "The Premier Perspective Database study measured quarterly rates of antibiotic initiation and duration among 40,364 VLBW infants cared for in 297 centers across the United States from 2009-2015 ([@R8]). ", "No significant trends were observed for antibiotic initiation, but declines were noted for prolonged early antibiotics among VLBW (but not ELBW) infants. ", "The Canadian Neonatal Network (CNN) reported decreased antibiotic use in VLBW infants between 2010 and 2014, a finding that coincided with decreased rates of LOS ([@R18]). ", "Despite this decline, the study still found an overall 20% antibiotic utilization rate among VLBW infants in the absence of culture-confirmed infection or NEC. ", "Single-site studies further illustrate the challenges of antibiotic optimization among premature infants. ", "Guidelines for use of antibiotics targeting highly antibiotic-resistant pathogens (e.g., meropenem, vancomycin) resulted in more appropriate antibiotic use in one Canadian NICU, but improvements were not seen among VLBW infants ([@R19]). ", "A comprehensive antibiotic stewardship program in a large American NICU did not significantly decrease overall antibiotic utilization, although some changes were observed in the use of specific antibiotics such as ampicillin and vancomycin ([@R20]). ", "Viewed from the perspective of the many challenges in optimizing neonatal antibiotic administration, the decline in prolonged early antibiotic administration we observed in the current study (14% absolute change, 28% relative change) among ELBW infants without a corresponding statistically significant rise in subsequent mortality, LOS, or NEC is clinically significant.", "\n\nOne important issue raised by our study is whether there is a critical level, duration, or timing of antibiotic exposure at which antibiotics administered in the absence of proven infection begin to cause harm. ", "In contrast to prior findings from the NRN and other centers ([@R6],[@R21]), we found no significant association between prolonged early antibiotics and NEC. ", "Multiple practice differences over the past 20 years may have contributed to this finding, including changes in the use of mothers' own milk, human donor milk, and probiotic supplements, and we did not collect detailed information on those factors. ", "Our findings do suggest, however, that the association of empiric antibiotic use and risk of NEC has declined as overall antibiotic use has declined. ", "The multicenter CNN study also suggests that the magnitude of antibiotic exposure may be associated with the magnitude of antibiotic-related harm ([@R18]). ", "Increased exposure to antibiotics over an infant's entire hospital stay was associated with increased adjusted odds of a composite outcome of mortality and major morbidities, with the greatest risk associated with the highest quartile of antibiotic exposure. ", "The prior NRN study noted increased odds of death per day of antibiotic therapy (OR=1.16 \\[95% CI, 1.08-1.24\\]), and a substantial proportion of infants received therapy for ≥10 days ([@R5]). ", "In the current study, neither duration of antibiotics nor daily antibiotic exposure data were recorded, and it is possible that our findings reflect an even larger magnitude of decreased antibiotic use than we have measured.", "\n\nWe continue to find substantial center variation in the use of prolonged early antibiotics (range of 30-69% from 2008-2014 compared to 27-85% in 1998-2001). ", "This variation appeared to be unrelated to the incidence of EOS at each site. ", "It is unlikely to be due to a corresponding variation in severity of illness, as each NRN site is an academic, tertiary care center caring for relatively large numbers of extremely premature infants. ", "Schulman and colleagues also found wide variation in California NICU antibiotic use unexplained by variation in proven infection, NEC, surgical volume, or mortality ([@R22]). ", "We speculate that center variation in this early postnatal clinical practice represents true elective practice differences that reflect provider uncertainty regarding the risks and benefits of antibiotics administered in the absence of proven infection. ", "In our cohort, simply being born at one academic center instead of another could increase an infant's odds of receiving prolonged early antibiotics sevenfold, even after adjustment for demographic and clinical factors. ", "Our findings underscore an imperative for individual centers to track antibiotic utilization and to compare such data with other institutions. ", "Robust mechanisms for sharing and receiving such data, including membership in voluntary neonatal networks, will facilitate efforts to improve local practices.", "\n\nPotentially unjustified variation may matter. ", "While not statistically significant, receipt of prolonged early antibiotics was associated with marginally increased odds of death in our cohort of infants (aOR 1.17 \\[95% CI, 0.99-1.40\\]). ", "An OR \\>1.0 is consistent with the previous NRN report, which showed an aOR of 1.46 (95% CI, 1.19-1.78) for prolonged therapy ([@R5]). ", "Although our analysis cannot fully account for differences in severity of illness among infants who do and do not receive prolonged early antibiotics, the potential for mediating harm remains of concern. ", "The association between prolonged early antibiotics and fungal LOS in survivors to discharge may be an example of harm rather than confounding by indication. ", "In this instance, relative harm was associated with prolonged early antibiotic administration to infants who were clearly *less* severely ill (those whose caregivers did not decide to use cMV) compared to those who were more severely ill (those who were treated with cMV). ", "Broad-spectrum antibiotic use has been previously associated with invasive candidiasis in premature infants ([@R23],[@R24]), although why such use might differentially affect those of less illness severity, defined by available data describing degree of respiratory support, remains unclear. ", "We speculate that less severely ill infants had fewer risk factors for fungal LOS and thus risk was increased significantly due to the use of prolonged antibiotics; more severely ill infants may have already had maximized risk of fungal LOS due to other factors. ", "Increased perinatal and postnatal exposure to antibiotics in premature infants has been associated with alterations in the gut microbiome, and may provide some insight into the biologic mechanisms by which prolonged antibiotic administration may be harmful in the absence of confirmed infection ([@R25],[@R26]). ", "It is possible that dysbiosis leads to proliferation of potential pathogens and predisposition to later infection, with resulting increases in morbidity and mortality ([@R27]). ", "In addition, antibiotic exposure has been associated with a reduction in gastric bacterial colonization, which could increase risk for infection and increase feeding intolerance ([@R28]). ", "Regardless of the potential mechanisms of harm or magnitude of harm, our findings support ongoing efforts to limit empiric antibiotic administration to ELBW infants at highest risk of infection and to spare those who may be at lowest risk of EOS, such as those born by cesarean section, without labor or maternal chorioamnionitis ([@R29]).", "\n\nThe strengths of our study include the large sample size of extremely preterm infants, uniform definitions and data collection over time, and observation of trends over time and across multiple regions in the United States. ", "The retrospective analysis limits our ability to measure variables other than those routinely collected in the NRN database. ", "We attempted to account for clinical severity by adjusting for mechanical ventilation, but we were unable to calculate validated severity scores such as the CRIB II or SNAPPE-II ([@R30],[@R31]). ", "While we excluded infants with culture-confirmed sepsis in the first 5 postnatal days, we were unable to identify infants who may have had other true infections, such as neonatal pneumonia. ", "We did not have data regarding the type or timing of quality improvement interventions or antibiotic stewardship programs at participating centers. ", "Finally, while our study was similar to the previous NRN study, several differences limit comparisons between the two reports. ", "The previous study included infants diagnosed with NEC or SIP in the first 5 days after birth, while we excluded these infants ([Supplemental Digital Content S1](#SD1){ref-type=\"supplementary-material\"}). ", "Our rationale was that antibiotic administration to those infants is not discretionary, and infants with NEC and SIP are likely to justifiably receive prolonged early antibiotics and have increased likelihood of mortality and morbidity. ", "The previous NRN study included expanded data collection that detailed the exact days of exposure and the type of antibiotics prescribed on each day. ", "This level of detail was not available to the current study. ", "In the earlier NRN study, even 4 days of early antibiotics was associated with NEC, death, as well as the composite outcome; but in the current study, we were unable to examine the effect of antibiotics administered for \\>48 hours but \\<5 days, and the risk of this practice remains unclear. ", "We also do not know what proportion of infants had no antibiotics given in the first 72 hours after birth (\\~2-3% had none given in the prior study) ([@R5]), and we do not know what proportion of infants were administered cephalosporins, antibiotics that are associated with higher mortality and *Candida* infections ([@R24],[@R32]).", "\n\nCONCLUSION {#S14}\n==========\n\nIn this study of 5730 infants across 13 NRN centers, the proportion of infants who received prolonged early antibiotics in the absence of EOS, NEC, or SIP decreased significantly between 2008 and 2014. ", "Overall prolonged antibiotic use also declined in comparison to a prior NRN study that included infants born between 1998 and 2001. ", "Prolonged early antibiotic exposure continues to vary widely across NRN centers. ", "Our findings support ongoing efforts to promote neonatal antibiotic stewardship, as supported by the Centers for Disease Control and Prevention ([@R33]). ", "Such efforts must include robust means of identifying those infants who will derive maximum benefit and minimum harm from antibiotic treatments that will be acceptable across different sites of neonatal care.", "\n\nSupplementary Material {#SM1}\n======================\n\nThe National Institutes of Health and the *Eunice Kennedy Shriver* National Institute of Child Health and Human Development (NICHD) provided grant support for the Neonatal Research Network's Generic Database Study (high risk registry) through cooperative agreements. ", "While NICHD staff did have input into the study design, conduct, analysis, and manuscript drafting, the comments and views of the authors do not necessarily represent the views of the NICHD.", "\n\nData collected at participating sites of the NICHD Neonatal Research Network (NRN) were transmitted to RTI International, the data coordinating center (DCC) for the network, which stored, managed, and analyzed the data for this study. ", "On behalf of the NRN, Dr. Abhik Das (DCC Principal Investigator) and Ms. Dhuly Chowdhury and Ms. Nellie Hansen (DCC Statisticians) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. ", "The sites with data included in this study are denoted with an asterisk.", "\n\nWe are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. ", "The following investigators, in addition to those listed as authors, participated in this study:\n\nNRN Steering Committee Chair: Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine; Richard A. Polin, MD, Division of Neonatology, College of Physicians and Surgeons, Columbia University (2011-present).", "\n\n\\*Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904) -- Abbot R. Laptook, MD; Martin Keszler, MD; Angelita M. Hensman, MS RNC-NIC; Kristin M. Basso, MaT RN; Elisa Vieira, RN BSN; Emily Little, BSN RN.", "\n\n\\*Case Western Reserve University, Rainbow Babies & Children\\'s Hospital (U10 HD21364, M01 RR80) -- Michele C. Walsh, MD MS; Avroy A. Fanaroff, MD; Anna Marie Hibbs, MD; Nancy S. Newman, BA RN; Bonnie S. Siner, RN.", "\n\nChildren\\'s Mercy Hospital, University of Missouri Kansas City School of Medicine (U10 HD68284) -- William E. Truog, MD; Howard W. Kilbride, MD; Eugenia K. Pallotto, MD MSCE; Cheri Gauldin, RN BSN CCRC; Anne Holmes RN MSN MBA-HCM CCRC; Kathy Johnson RN, CCRC; Allison Knutson, BSN RNC-NIC.", "\n\n\\*Cincinnati Children\\'s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, M01 RR8084) -- Brenda B. Poindexter, MD MS; Kurt Schibler, MD; Barbara Alexander, RN; Cathy Grisby, BSN CCRC; Lenora D. Jackson, CRC; Kristin Kirker, CRC; Greg Muthig, BS.", "\n\n\\*Duke University School of Medicine, University Hospital, University of North Carolina, and Duke Regional Hospital (U10 HD40492, M01 RR30, UL1 TR83) -- Ronald N. Goldberg, MD; Kimberley A. Fisher, PhD FNP-BC IBCLC; Sandra Grimes, RN BSN; Joanne Finkle, RN JD; Matthew M. Laughon, MD MPH; Carl L. Bose, MD; Janice Bernhardt, MS RN; Gennie Bose, RN.", "\n\n\\*Emory University, Children's Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, UL1 TR454) -- David P. Carlton, MD; Ellen C. Hale, RN BS CCRC; Ann Blackwelder, RN MSN; Yvonne C. Loggins, RN BSN; Diane I. Bottcher, RN MSN.", "\n\n*Eunice Kennedy Shriver* National Institute of Child Health and Human Development -- Stephanie Wilson Archer, MA.", "\n\n\\*Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856, M01 RR750, UL1 TR6) -- Brenda B. Poindexter, MD MS; Gregory M. Sokol, MD; Leslie Dawn Wilson, BSN CCRC; Dianne E. Herron, RN CCRC.", "\n\n\\*McGovern Medical School at The University of Texas Health Science Center at Houston, Children\\'s Memorial Hermann Hospital (U10 HD21373) -- Kathleen A. Kennedy, MD MPH; Jon E. Tyson, MD MPH; Julie Arldt-McAlister, MSN APRN; Katrina Burson, RN BSN; Carmen Garcia, RN BSN CCRP; Beverly Foley Harris, RN BSN; Karen Martin, RN; Sara C. Martin, RN BSN; Georgia E. McDavid, RN; Shawna Rodgers, RN BSN; Patti L. Pierce Tate, RCP; Sharon L. Wright, MT (ASCP).", "\n\nNationwide Children's Hospital and the Ohio State University Medical Center (U10 HD68278) -- Leif D. Nelin, MD; Sudarshan R. Jadcherla, MD; Patricia Luzader, RN; Christine A. Fortney, PhD RN; Gail E. Besner; Nehal A. Parikh, MD.", "\n\nRTI International (U10 HD36790) -- Dennis Wallace, PhD; Marie G. Gantz, PhD; Jeanette O'Donnell Auman, BS; Margaret M. Crawford, BS CCRP; Jenna Gabrio, MPH CCRP; Carolyn M. Petrie Huitema, MS CCRP; Kristin M. Zaterka-Baxter, RN BSN CCRP.", "\n\n\\*Stanford University, Dominican Hospital, El Camino Hospital, and Lucile Packard Children\\'s Hospital (U10 HD27880, M01 RR70, UL1 TR93) -- Krisa P. Van Meurs, MD; Marian M. Adams, MD; David K. Stevenson, MD; M. Bethany Ball, BS CCRC; Andrew W. Palmquist, RN BSN; Melinda S. Proud, RCP.", "\n\nTufts Medical Center, Floating Hospital for Children (U10 HD53119, M01 RR54) -- Ivan D. Frantz III, MD; John M. Fiascone, MD; Brenda L. MacKinnon, RNC; Ellen Nylen, RN BSN.", "\n\n\\*University of Alabama at Birmingham Health System and Children's Hospital of Alabama (U10 HD34216, M01 RR32) -- Waldemar A. Carlo, MD; Namasivayam Ambalavanan, MD; Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN.", "\n\nUniversity of California - Los Angeles, Mattel Children\\'s Hospital, Santa Monica Hospital, Los Robles Hospital and Medical Center, and Olive View Medical Center (U10 HD68270) -- Uday Devaskar, MD; Meena Garg, MD; Teresa Chanlaw, MPH; Rachel Geller, RN BSN.", "\n\n\\*University of Iowa and Mercy Medical Center (U10 HD53109, M01 RR59) -- Edward F. Bell, MD; Dan L. Ellsbury, MD; John A. Widness, MD; Tarah T. Colaizy, MD MPH; Karen J. Johnson, RN BSN; Donia B. Campbell, RNC-NIC; Jacky R. Walker, RN.", "\n\n\\*University of New Mexico Health Sciences Center (U10 HD53089, UL1 TR41) -- Kristi L. Watterberg, MD; Robin K. Ohls, MD; Conra Backstrom Lacy, RN; Rebecca A. Tomson, BSN RNC; Carol Hartenberger, BSN MPH; Sandra Sundquist Beauman, MSN RNC-NIC.", "\n\nUniversity of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, and Children\\'s Hospital of Philadelphia (U10 HD68244) -- Barbara Schmidt, MD MSc; Haresh Kirpalani, MB MSc; Sara B. DeMauro, MD MSCE; Kevin C. Dysart, MD; Aasma S. Chaudhary, BS RRT; Soraya Abbasi, MD; Toni Mancini, RN BSN CCRC; Dara M. Cucinotta, RN; Erik A. Jensen, MD MSCE.", "\n\nUniversity of Rochester Medical Center, Golisano Children\\'s Hospital, and the University of Buffalo Women\\'s and Children\\'s Hospital of Buffalo (U10 HD68263, M01 RR44, UL1 TR42) -- Carl T. D'Angio, MD; Ronnie Guillet, MD PhD; Satyan Lakshminrusimha, MD; Anne Marie Reynolds, MD, MPH; Linda J. Reubens, RN CCRC; Rosemary Jensen; Deana Maffett, RN; Holly I.M. Wadkins, MA; Michael G. Sacilowski, MAT; Ashley Williams, MS Ed; Stephanie Guilford, BS; Mary Rowan, RN; Diane M.\n\nPrinzing, AAS; Julianne Hunn, BS; Ann Marie Scorsone, MS CCRC; Karen Wynn, RN; Melissa Bowman, RN; Dale L. Phelps, MD; Aimee Horan, LPN.", "\n\n\\*University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children\\'s Medical Center Dallas (U10 HD40689, M01 RR633) -- Myra H. Wyckoff, MD; Pablo J. Sanchez, MD; Luc P. Brion, MD; Lijun Chen, PhD RN; Alicia Guzman; Janet S. Morgan, RN; Lara Pavageau, MD; Diana M. Vasil, MSN BSN RNC-NIC; Lizette E. Torres, RN.", "\n\nUniversity of Utah University Hospital, Intermountain Medical Center, LDS Hospital, and Primary Children\\'s Medical Center (U10 HD53124, M01 RR64, UL1 TR105) -- Roger G. Faix, MD; Bradley A. Yoder, MD; Karen A. Osborne, RN BSN CCRC; Karie Bird, RN BSN; Jill Burnett, RNC BSN; Jennifer J. Jensen, RN BSN; Cynthia Spencer, RNC BSN; Kimberlee Weaver-Lewis, RN MS; Karen Zanetti, RN.", "\n\n\\*Wayne State University, University of Michigan, Hutzel Women's Hospital, and Children's Hospital of Michigan (U10 HD21385) -- Seetha Shankaran, MD; John Barks, MD; Rebecca Bara, RN BSN; Mary Johnson, RN BSN; Mary Christensen, RT; Stephanie Wiggins, MS.", "\n\nYale University, Yale-New Haven Children's Hospital, and Bridgeport Hospital (U10 HD27871, UL1 TR142) -- Richard A. Ehrenkranz, MD; Harris Jacobs, MD; Patricia Cervone, RN; Monica Konstantino, RN BSN; JoAnn Poulsen, RN; Janet Taft, RN BSN.", "\n\n**Funding source:** NIH Funding Grants - U10 HD27904, U10 HD21364, M01 RR80, U10 HD68284, U10 HD27853, M01 RR8084, U10 HD40492, M01 RR30, UL1 TR83, U10 HD27851, UL1 TR454, U10 HD27856, M01 RR750, UL1 TR6, U10 HD68278, U10 HD36790, U10 HD27880, M01 RR70, UL1 TR93, U10 HD53119, M01 RR54, U10 HD34216, M01 RR32, U10 HD68270, U10 HD53109, M01 RR59, U10 HD53089, UL1 TR41, U10 HD68244, U10 HD68263, M01 RR44, UL1 TR42, U10 HD21373, U10 HD40689, M01 RR633, U10 HD53124, M01 RR64, UL1 TR105, U10 HD21385, U10 HD27871, UL1 TR142\n\n**Disclosure statement:** The authors have no conflicts of interest relevant to this article to disclose.", "\n\n**Access to data statement:**Ms. ", "Chowdhury, Ms. Hansen, and Dr. Das had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.", "\n\n**Clinical trial registration:** [ClinicalTrials.gov](http://ClinicalTrials.gov) NCT00063063 <https://clinicaltrials.gov/ct2/show/NCT00063063>\n\n**Statement of financial support:** Please see [acknowledgement](#S15){ref-type=\"sec\"} for full funding information.", "\n\n**Category of study:** Clinical research article\n\n{#F1}\n\n###### \n\nDemographics and clinical characteristics^[a](#TFN2){ref-type=\"table-fn\"}^\n\n --------------------------------------------------------------------------------------------------------------------------------\n Prolonged\\ No prolonged\\ P-value\n early\\ early\\ \n antibiotics\\ antibiotics\\ \n (N=2526) (N=3204) \n ------------------------------------------------------------------------------------ ---------------- ---------------- ---------\n **Infant characteristics** \n\n  Birth weight, g (median, IQR) 730 (615, 850) 790 (670, 890) \\<0.001\n\n  Gestational age, weeks (median, IQR) 25 (24, 26) 26 (25, 27) \\<0.001\n\n  By gestational age week \\<0.001\n\n   22 1% 1% \n\n   23 11% 6% \n\n   24 23% 15% \n\n   25 24% 21% \n\n   26 20% 23% \n\n   27 13% 21% \n\n   28 7% 14% \n\n  Small for gestational age 11% 11% 0.48\n\n  Male 51% 46% \\<0.001\n\n  5-minute Apgar \\<5 24% 17% \\<0.001\n\n  Mechanically ventilated for first 7 days of life^[b](#TFN3){ref-type=\"table-fn\"}^ 55% 33% \\<0.001\n\n **Maternal characteristics** \n\n  Race/ethnicity^[c](#TFN4){ref-type=\"table-fn\"}^ 0.19\n\n   Black 45% 43% \n\n   White 36% 38% \n\n   Hispanic 13% 14% \n\n   Other 6% 5% \n\n  Multiple birth 23% 26% 0.01\n\n  Hypertension 26% 37% \\<0.001\n\n  Antenatal steroids 89% 91% 0.05\n\n  Antenatal antibiotics 76% 71% \\<0.001\n\n  Rupture of membranes \\>24 hours 28% 18% \\<0.001\n\n  Antepartum hemorrhage 19% 18% 0.84\n\n  Cesarean section 64% 73% \\<0.001\n --------------------------------------------------------------------------------------------------------------------------------\n\nIQR=interquartile range\n\nInformation was missing as follows: maternal race/ethnicity, 16 infants; maternal hypertension, 8 infants; antepartum hemorrhage, 5 infants; antenatal steroids, 12 infants; antenatal antibiotics, 34 infants; timing of rupture of membranes, 159 infants; cesarean delivery, 3 infants; 5-minute Apgar score, 14 infants; mechanical ventilation, 1 infant.", "\n\nThis group includes 40 infants who were intubated continuously until death before day 7.", "\n\nMaternal race/ethnicity was defined as non-Hispanic white, non-Hispanic black, Hispanic (both white and black), and other race (Asian/Pacific Islander, American Indian / Alaska native, more than one race, other not specified). ", "Those of white or black race with missing ethnicity information (5.3% of blacks, 0.9% of whites) were classified as non-Hispanic.", "\n\n###### \n\nDifferences in receipt of prolonged early antibiotic therapy by birth year and center adjusting for neonatal and maternal characteristics\n\n ------------------------------------------------------------------------------------------------\n Adjusted odds ratio\\ P-value\n (95% confidence interval) \n ---------------------------------------------------------- --------------------------- ---------\n **Birth year (reference: 2008)** \n\n  2009 0.89 (0.72-1.10) 0.29\n\n  2010 1.02 (0.82-1.27) 0.83\n\n  2011 0.79 (0.63-0.98) 0.03\n\n  2012 0.58 (0.47-0.72) \\<0.001\n\n  2013 0.58 (0.47-0.73) \\<0.001\n\n  2014 0.44 (0.35-0.56) \\<0.001\n\n **Center (reference: Center 1)** \n\n  2 1.16 (0.90-1.50) 0.26\n\n  3 1.42 (1.10-1.83) 0.008\n\n  4 1.78 (1.33-2.39) \\<0.001\n\n  5 1.61 (1.14-2.27) 0.007\n\n  6 2.24 (1.53-3.28) \\<0.001\n\n  7 1.61 (1.20-2.16) 0.002\n\n  8 1.81 (1.34-2.43) \\<0.001\n\n  9 2.17 (1.67-2.82) \\<0.001\n\n  10 2.97 (2.20-4.01) \\<0.001\n\n  11 3.07 (2.26-4.17) \\<0.001\n\n  12 5.46 (4.03-7.39) \\<0.001\n\n  13 7.36 (5.18-10.46) \\<0.001\n\n **Infant characteristics** \n\n  Gestational age, weeks (reference: 28) \n\n   22 1.81 (0.96-3.41) 0.07\n\n   23 2.54 (1.86-3.47) \\<0.001\n\n   24 1.98 (1.54-2.55) \\<0.001\n\n   25 1.74 (1.38-2.20) \\<0.001\n\n   26 1.40 (1.11-1.76) 0.004\n\n   27 1.06 (0.83-1.34) 0.66\n\n  Small for gestational age 1.65 (1.35-2.01) \\<0.001\n\n  Male 1.15 (1.03-1.29) 0.02\n\n  5-minute Apgar \\<5 1.38 (1.19-1.61) \\<0.001\n\n  Mechanically ventilated for entire first 7 days of life 1.79 (1.57-2.05) \\<0.001\n\n **Maternal characteristics** \n\n  Black race 1.24 (1.08-1.41) 0.002\n\n  Multiple birth 0.90 (0.78-1.04) 0.16\n\n  Hypertension 0.78 (0.67-0.91) 0.001\n\n  Antenatal steroids 0.82 (0.66-1.02) 0.07\n\n  Antenatal antibiotics 1.18 (1.01-1.37) 0.03\n\n  Rupture of membranes \\>24 hours 1.84 (1.59-2.14) \\<0.001\n\n  Antepartum hemorrhage 0.83 (0.71-0.97) 0.02\n\n  Cesarean section 0.84 (0.73-0.97) 0.02\n ------------------------------------------------------------------------------------------------\n\n###### \n\nOutcomes for infants who received prolonged early antibiotic therapy versus those who did not\n\n -----------------------------------------------------------------------------------------------------------\n Outcome, n (column %) Prolonged\\ No prolonged\\ Adjusted OR for\\ P-value\n early\\ early\\ outcome (95% CI)\\ \n antibiotics antibiotics prolonged early\\ \n antibiotics vs no\\ \n prolonged early\\ \n antibiotics \n ---------------------------------------------- ------------- --------------- -------------------- ---------\n **All infants who survived ≥5 days** **2526** **3204** \n\n  Death before discharge 466 (19) 409 (13) 1.17 (0.99-1.40) 0.07\n\n  Death or NEC 623 (25) 635 (20) 1.08 (0.93-1.25) 0.34\n\n  Death or LOS 1008 (40) 1082 (34) 0.98 (0.86-1.12) 0.76\n\n  Death or non-CoNS LOS 662 (26) 677 (21) 1.01 (0.87-1.17) 0.89\n\n  Death, NEC, or LOS 1086 (43) 1204 (38) 0.97 (0.86-1.11) 0.66\n\n **Infants who survived to discharge** **2055** **2787** \n\n  NEC 157 (8) 225 (8) 0.91 (0.72-1.15) 0.43\n\n  LOS 540 (26) 670 (24) 0.90 (0.77-1.05) 0.18\n\n  Non-CoNS LOS 195 (10) 268 (10) 0.84 (0.67-1.04) 0.11\n\n  Fungal LOS^[a](#TFN6){ref-type=\"table-fn\"}^ \n\n   cMV group 23 (2) 22 (3) 0.64 (0.33-1.23) 0.18\n\n   Non-cMV group 21 (2) 8 (0.4) 4.95 (1.93-12.69) \\<0.001\n -----------------------------------------------------------------------------------------------------------\n\nOR=odds ratio; CI=confidence interva; NEC=necrotizing enterocolitis; LOS=late-onset sepsis; CoNS=Coagulase-negative *Staphylococcus*; cMV=continuous mechanical ventilation for first 7 days.", "\n\nThe interaction between prolonged early antibiotics and the continuous mechanical ventilation group was significant at p\\<0.001, and therefore the adjusted ORs are reported separately.", "\n\n[^1]: Author contributions:\n\n Dr. Greenberg conceptualized and designed the study, drafted the initial manuscript, interpreted the data analyses, and reviewed and revised the manuscript.", "\n\n Ms. Chowdhury, Ms. Hansen, and Dr. Das carried out the data analysis, assisted with interpretation of the data analyses, and reviewed and revised the manuscript for important intellectual content.", "\n\n Dr. Cotten assisted with acquisition of the data, interpreted the data analyses, reviewed and revised the manuscript for important intellectual content, and obtained funding to support the study.", "\n\n Dr. Stoll assisted with acquisition of data and critical revision of the manuscript for important intellectual content.", "\n\n Dr. Higgins conceptualized and designed the study, assisted with data analysis and interpretation, and provided critical revision of the manuscript for intellectual content.", "\n\n Dr. Smith, Dr. Puopolo, and Dr. Mukhopadhyay provided analysis and interpretation of the data and critical revision of the manuscript for important intellectual content.", "\n\n Dr. Sanchez conceptualized and designed the study, assisted with acquisition of data, provided analysis and interpretation of the data, and obtained funding for support of the study.", "\n\n All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.", "\n" ]

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[ "A judge has ruled in favor of the State in a civil court case against Edwin Pace of Indianola. ", "Pace an insurance agent was on trial for selling fraudulent investments in customer-owned coin-operated telephones commonly referred to as \"COCOTs\"." ]

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[ "KNCO-FM\n\nKNCO-FM (94.1 FM, \"Star 94 FM\") is a radio station broadcasting an adult contemporary music format. ", "Licensed to Grass Valley, California, United States, it serves the Marysville/Yuba City and the Grass Valley/Nevada City area. ", "The station is currently owned by Nevada County Broadcasters, Inc. and features programming from Citadel Media.", "\n\nReferences\n\nExternal links\n \n \n\nNCO-FM\nCategory:Adult contemporary radio stations in the United States\nCategory:Grass Valley, California" ]

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[ "I have been “mistaken,” “misled,” “misrepresented,” and been “unaccountably in error,”\nand am sorry if you have been offended\n\nThursday, December 28, 2006\n\nTalk about Them Old Times: the New Administrative Reforms Minister and His Father\n\nMuch has been made of Shinzo Abe's desire, or need, to complete the unfulfilled legacy of his father Shintaro Abe, who came this close to becoming prime minister when he succumbed in 1991 to cancer. ", "The elder Abe was not alone in suffering that fate though. ", "Four years later, a heart attack also silenced his contemporary and once-rival Michio Watanabe.", "\n\nMr. Watanabe had begun having health problems around the time the elder Abe died, and the LDP had gone into temporary decline during the Hosokawa and Murayama administrations. ", "Thus, the political prospects of the septuagenarian were no longer looking so rosy in 1995 when he departed for that Great Big Diet in the Sky. ", "But in the dry winter of 1985, between cabinet jobs, when he visited Brazil for a fortnight, he was in the prime of his health. ", "It was then that I traveled with him and his entourage as embassy watchdog/gofer/interpreter. (", "I had been in Brazil for five months then.)", "\n\nThis was definitely not one of those Diet-in-recess \"survey missions\" that seem to have little effect on subsequent political deliberations. ", "Nor was Mr. Watanabe there, as was the wont of many a politician who visited Brazil and other parts of Latin America, to curry favor with the local Japanese immigrant community from his electoral district (more broadly the prefecture-based kenjinkai). ", "No: for his more or less annual, decidedly private trips usually avoided Sao Paulo and Rio neighborhood, where the bulk of the Japanese immigrant and business communities lived. ", "Instead he would typically make a beeline to Brasilia, look up a couple political figures, then take a four-hour drive on a dusty road to the little town of Paracatu, in whose neighborhood a small, predominantly Japanese agricultural community prospered, and spent a couple of days mixing with the locals. ", "He looked more like the Don back in his hometown of Corleone than anything else. ", "And in a very real way, he was the Godfather of that community. ", "This trip was not much of an exception; he would be making the rounds of a couple of Japanese-Brazilian joint ventures, but the last leg of the trip would definitely be the beloved immigrant community of Paracatu.", "\n\nMr. Watanabe's connection with Brazil that led to his ties to that little Japanese immigrant community in Paracatu began when he became Agriculture, Forestry and Fisheries Mnister in 1978. ", "He took a serious interest in the Cerrado Development Project, which used development loans, grants and other official development assistance from Japan for an irrigation and agricultural project of immense proportions. (", "Note: The project itself was a success, but the overall Brazilian public and external debt grew to enormous, ultimately unsustainable proportions, and the project did not escape the fallout.) ", "Adjacent to the Cerrado Project site but not part of the project proper, Japanese agricultural cooperatives cleared a much small patch of land and settled several hundred Japanese immigrant farmers there. ", "But this smaller, private-sector project went through some rough patches in its early years, threatening its viability. ", "So, to make a long story short, the farmers contacted Mr. Watanabe, who had become Finance Minster in the meantime, a loan came through from a Japanese agency, and the project was saved and was firmly on its feet by the time I had arrived in Brasilia in March 1985. ", "Mr. Watanabe never made a big deal about this, and no wonder; he stood to gain little from immigrant feedback to his particular home electoral constituency. ", "But he seemed to have fallen in love with those immigrants, and they with him.", "\n\nGoing back to my travels with Mr. Watanabe, I had never met the man, but he had a well-deserved reputation as a hothead, as quick with his brawn as with his brains, a man with a big ideas and a bigger mouth that sometimes got him into trouble. ", "Compared to the suave, impeccably pedigreed Abe the elder, he was a noisy, gauche upstart. ", "Or so we thought. ", "What I saw up close was a very different side of the man.", "\n\nTrue, his legendary ability to work a crowd was in full view when he took on the immigrant crowd. ", "The middle-aged ladies and the elderly in particular all but drooled over him. ", "But up close, one on one, he was retiring, almost shy at times, especially with young women, when he had to really force himself hard to make a stab at small talk. ", "In unguarded moments during our travels, he would let on that what we saw was what we really got, he was definitely not the glad-handing type and that he had a hard time remembering names and faces. ", "He did not go out of his way to thank us at every turn, but he never lorded it over us either. ", "In fact, although he never said much about it, he always seemed quietly appreciative of the ways we all tried to anticipate accommodate his wishes. ", "Two incidents stand out in this respect.", "\n\nAt one of our stops, we took more than an hour to check of our hotel, and the schedule had to be knocked back accordingly. ", "Now politicians can be, if anything, an impatient, sometimes impetuous breed who believe that the Sun revolves around them and them only. ", "He is not unusual the politician who would have bawled out the hotel management, his entourage and the government flack of the moment, on this occasion and not necessarily in that order. ", "So imagine my relief when Mr. Watanabe merely mumbled to his secretaries, \"Don't let this happen the next time around\", and that was the end of it. ", "But this paled in comparison to the next incident.", "\n\nThe four-hour drive to Paracatu is not a particularly scenic or, for Mr. Watanabe, an unfamiliar one. ", "Moreover, this was the last leg of the trip, and we had been all over the huge Brazilian map. ", "Thus, Mr. Watanabe had chartered a small twin-engine plane to fly him and his two secretaries there, and I would join them, presumably as the embassy dignitary-cum-interpreter. ", "The rest of the entourage would drive ahead of the plane, and wait for the plane at the Parcatu airport. ", "Now, with us at the time was the widow of a Paracatu community leader who had recently met his death on the road from Paracatu to Brazil and whose gave we were going to visit. ", "I, in all sincerity, gave up my seat to the widow, and vaguely remember feeling good about myself for doing so.", "\n\nThe Paracatu airport turned out to be little more than a large clearing exposing the red, porous Cerrado soil, a gateless fence separating the airstrip from the dirt road that had taken us there, and a cabana-like bar that doubled as the airport terminal of sorts. ", "We did not have to wait very long for the plane to arrive; first the sound of the propellers, then the plane itself coming into sight. ", "As the plane neared to make its landing, I was distracted and looked away, so I did not see the plane as it was about to touch down. ", "Then all of a sudden, there was a noisy rattle; I look around in surprise, to see the plane going up and away, while everybody else made a commotion. ", "The plane soon returned, this time to land safely. ", "When the plane stopped, we approached; and the visibly shaken secretaries were the first to emerge, then the widow, then finally, Mr. Watanabe himself, subdued, but clearly the most calm and collected of all. ", "One good look at the plane, and we saw a slender protrusion from the fuselage had been bent; worse, one of the propellers had been bent at a sharp angle. ", "A inch or two, one way or other, and the plane would surely have flipped and tumbled all over that dirt patch, at best horribly injuring the occupants and likely worse. ", "The first time around, the pilot had tried to land without lowering the landing gear. ", "He claimed that everything had indicated that the landing gear had been released the first time around. ", "Mr. Watanabe was not amused. ", "He told his secretaries to get to the bottom of this. ", "But that was that for the moment. ", "We continued on with our schedule, Mr. Watanabe acting as if nothing untoward had happened, duly visiting the grave of the community leader, enjoyed an evening cookout at one of the immigrant farmhouses, then retired to another farmhouse where a young recent immigrant couple close to the Watanabe family lived.", "\n\nSo, a couple of days later, we are back in Brasilia, and it nearing the time for Mr. Watanabe and his entourage to leave, their kokoro no sentaku (laundry of the heart) over. ", "It is then that they are talking about the Paracatu accident and I overhear Mr. Watanbe say, \"Harattoite yare (Pay them the charter fee)\".", "\n\nBless you, Mr. Watanabe, wherever you are.", "\n\nMost of you reading this blog will know that Mr. Watanabe's son is Yoshimi Watanabe, who replaced the ill-fated Genichiro Sada as Administrative Reforms Minister today. ", "And yes, he was a member of that entourage. ", "He handled the logistics jointly as one of two secretaries to Mr. Watanabe. ", "The other secretary was on leave from the insurance company where he was regularly employed; as far as I could gather, he and the younger Watanabe seemed to have been college buddies. ", "The younger Watanabe was in his early thirties then, but still had the unformed feel of someone not long out of college. ", "His buddy/co-secretary appeared to be the slightly dominant figure in this friendship. ", "Easy-going and good-natured, the unspoiled and youthful bachelor at the time did not display the Seisaku Shinjinrui (Policy-Wonk New Breed) gift of the gab of his later, Diet years. ", "The younger Watanbe and I had dinner once in 1988, together with other members of the embassy who returned to Japan that year, but I haven't talked to him since.", "\n\nSo, this time, it's Mr. Watanabe's chance to see if he can catch lightning in a bottle. ", "That will be difficult, if not impossible. ", "He doesn't have an abductees issue to grab (or the issue to grab him, if you prefer to put it that way), a Koizumi to push him to the front of the line, or that Abe charm that felt so cool in small doses. ", "That's a lot of strikes already. ", "And, unlike Mr. Abe's previous Cabinet Chief post, the Administrative Reform portfolio will bring to bear great pressure on him to show real and meaningful progress.", "\n\n(Note: I recall accompanying the Watanabes on another trip in 1986, likely after yet another of those annual cabinet shuffles that were the de rigeur of the times. ", "I was making myself useful, I suppose. ", "Thus, I may have conflating events from two trips.)", "\n\n日本語ブログ\n\nAbout Me\n\nAfter graduation, Jun Okumura promptly entered what is now the Ministry of Economy, Trade and Industry and stayed in in its ecosystem most of his “adult” life. ", "Along the way, he had pleasant stops in an assortment of Japanese quangos (Japangos?), ", "overseas assignments and government agencies. ", "After thirty years, though, it dawned on him that he had no aptitude whatsoever for administration and/or management. ", "Armed with this epiphany, he went to the authorities and arranged an amicable separation; to come out, as it were. ", "He is completely on his own IYKWIAS, but he and the METI folks remain “good friends.” ", "He currently holds the titles of “visiting researcher” at the Meiji Institute for Global Affairs (no, that MIGA) and counselor at a risk analysis firm that dares not speak its name. ", "This gives him plenty of time to blog or make money on his own. ", "His bank account says that he does too much of the first, and insists that he do more of what he calls “intellectual odd jobs”. ", "He wants to be paid to write fulltime, or better, talk—where the easy money is—but that distinction has largely escaped him. ", "He really should not be referring to himself in the third person; he is not that famous." ]

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[ "Human cytomegalovirus open reading frame UL11 encodes a highly polymorphic protein expressed on the infected cell surface.", "\nHuman cytomegalovirus (HCMV) open reading frame (ORF) UL11 locates within a polymorphic region of the viral genome identified previously by a restriction-fragment-length-polymorphism. ", "We report here that ORF UL11 encodes a polymorphic protein expressed on the surface of HCMV-infected cells. ", "First, we determined the nucleotide sequence of ORF UL11 from ten strains and compared it among the strains. ", "Out of 205 amino acids consisting of the predicted N-terminal region beside the putative transmembrane stretch in strain AD169, 88 residues were divergent on more than one strain. ", "In contrast, the predicted C-terminal side including the putative transmembrane domain was identical at the amino acid sequence level. ", "In addition, the number and location of predicted cysteine residues were also conserved. ", "Next, we screened a cDNA library from HCMV-infected cells and obtained a cDNA clone containing the full-length ORF UL11. ", "Finally, we identified the gene product of UL11 on the surface of HCMV-infected cells by FACS analysis with polyclonal antibodies generated against a glutathione S-transferase/UL11 fusion protein. ", "The fusion protein contained a region within the N-terminal side next to the predicted transmembrane stretch. ", "These results indicate that the N-terminal side of UL11 protein containing variable amino acid residues protrudes from the infected cell surface." ]

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[ "Disposition of the anti-ulcer medications ranitidine, cimetidine, and omeprazole following administration of multiple doses to exercised Thoroughbred horses.", "\nThe use of anti-ulcer medications, such as cimetidine, ranitidine, and omeprazole, is common in performance horses. ", "The use of these drugs is regulated in performance horses, and as such a withdrawal time is necessary prior to competition to avoid a medication violation. ", "To the authors' knowledge, there are no reports in the literature describing repeated oral administrations of these drugs in the horse to determine a regulatory threshold and related withdrawal time recommendations. ", "Therefore, the objective of the current study was to describe the disposition and elimination pharmacokinetics of these anti-ulcer medications following oral administration to provide data upon which appropriate regulatory recommendations can be established. ", "Nine exercised Thoroughbred horses were administered 20 mg/kg BID of cimetidine or 8 mg/kg BID of ranitidine, both for seven doses or 2.28 g of omeprazole SID for four doses. ", "Blood samples were collected, serum drug concentrations were determined, and elimination pharmacokinetic parameters were calculated. ", "The serum elimination half-life was 7.05 ± 1.02, 7.43 ± 0.851 and 3.94 ± 1.04 h for cimetidine, ranitidine, and omeprazole, respectively. ", "Serum cimetidine and ranitidine concentrations were above the LOQ and omeprazole and omeprazole sulfide below the LOQ in all horses studied upon termination of sample collection." ]

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[ "\n\n\nAERO DFW V. SWANSON\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nCOURT OF APPEALS\n\nSECOND DISTRICT OF TEXAS\n\nFORT WORTH\n\n\n\n\n\nNO. ", "2-06-179-CV\n\n\n\n\n\nAERO DFW, LP\tAPPELLANT\n\n\n\nV.\n\n\n\nTERRY SWANSON D/B/A\tAPPELLEE\n\nSWANSON FARM SERVICES\n\n\n\n------------\n\n\n\nFROM THE 236TH DISTRICT COURT OF TARRANT COUNTY\n\n\n\n------------\n\n\n\nMEMORANDUM OPINION\n(footnote: 1)\n\n\n------------\n\nAppellant Aero DFW, LP appeals the judgment of the district court refusing to grant attorneys’ fees based on the doctrine of excessive demand. ", " Appellant complains that the trial court erred by denying attorneys’ fees, challenging the legal and factual sufficiency of the trial court’s findings of fact and the correctness of its conclusion of law in support of its ruling. ", " We affirm.", "\n\n\n\nBackground Facts\n\nAppellant and appellee Terry Swanson d/b/a Swanson Farm Services executed a lease on September 24, 2002 for commercial property located at the Dallas/Fort Worth International Airport. ", " The lease stated that the term would begin on October 1, 2002, terminate on September 30, 2004, and require monthly payments of $1,254.", "\n(footnote: 2)\n\tAppellee paid a security deposit and rent for the first two months but abandoned the leased property in late November 2002 and discontinued paying rent. ", " Appellant sent appellee two letters—the first dated January 14, 2003 and the second dated January 23, 2003—notifying appellee that he was in default under the lease and informing him that $2,716 was “immediately due” for December 2002 and January 2003 rent. ", " The $2,716 did not include any late fees. ", " On March 31, 2003, appellant’s general counsel sent appellee a demand letter, which read as follows:\n\nIt is my understanding that you have vacated the above-referenced property and discontinued paying rent. ", " This matter has been turned over to me for collection. ", " The following amounts are due under the lease dated September 24, 2002 (“Lease”):\n\n\n\nBase Rent (12/1/02–9/30/04)\t$27,588.00\n\nLate Fees\t\t\t\t\t\n  $1,931.00\n\n\n\nTotal\t\t\t\t\t$29,519.00\n\n\n\nIn addition to the above, there may be additional amounts due under the Lease. ", " However, unless we receive the outstanding amount due of $29,519.00 within the next three (3) business days, this matter will be turned over to our local attorneys for collection at your cost.", "\n\n\n\nOn April 10, 2003, five months after appellee vacated the premises and seventeen days after the March 31 demand letter, appellant and D&M Distributors executed a lease for the same property to begin on May 1, 2003. ", "This lease provided for a monthly payment of $1,300 and terminated April 30, 2006.", "\n\nAppellant filed suit on May 23, 2003 requesting damages and attorneys’ fees for appellee’s breach of the lease. ", " During discovery, appellant made several different assertions of the amount due. ", " On October 21, 2003, in its response to appellee’s request for disclosures, appellant claimed that appellee owed $30,000. ", " On the same day, in its response to interrogatories, appellant claimed that appellee owed $300,000. ", " In June 2004, appellant also claimed that appellee owed $300,000 in a supplemental response to appellee’s request for disclosures.", "\n(footnote: 3)  In May and August 2005, appellant again responded to appellee’s request for disclosures, claiming that appellee owed $51,776.10\n.", "\n\nIn September 2005, appellee offered to settle for $6,270; however, appellant rejected the offer and responded with a counteroffer of $18,000. ", "Appellee did not accept the offer, and appellant submitted another offer for the same amount. ", " Appellant later modified its response to the request for disclosures, claiming that appellee owed only $6,708.86\n in damages.", "\n\nAfter a bench trial, the trial court found that appellant was entitled to damages in the amount of $5,860.32 but also found that appellant’s demands for payment were unreasonable and, accordingly, denied appellant’s attorneys’ fees claim based on the doctrine of excessive demand.", "\n\nIssues Presented\n\nIn its first issue, appellant contends generally that the trial court erred by denying it attorneys’ fees for appellee’s breach of the lease. ", " In its second through fifth issues, appellant contends that the evidence is legally and factually insufficient to support the trial court’s findings that appellant’s demands were unreasonable, that it made an excessive demand on appellee, that its demands sought amounts to which it was not entitled, and that appellee is not liable to appellant for attorneys’ fees due to appellant’s excessive demands. ", " Also in its fifth issue, appellant challenges the correctness of the trial court’s conclusion that due to appellant’s excessive demand, appellee is not liable to appellant for attorneys’ fees. ", " Appellant briefs these five issues together, and for ease of discussion, we will address them together.", "\n\nStandard of Review\n\nFindings of fact entered in a case tried to the court have the same force and dignity as a jury\n’\ns answers to jury questions. ", " \nAnderson v. City of Seven Points\n, 806 S.W.2d 791, 794 (Tex. ", "1991). ", " The trial court\n’s findings of fact are reviewable for legal and factual sufficiency of the evidence to support them by the same standards that are applied in reviewing evidence supporting a jury\n’\ns answer. ", " \nOrtiz v. Jones,\n 917 S.W.2d 770, 772 (Tex. ", "1996); \nCatalina v. Blasdel,\n 881 S.W.2d 295, 297 (Tex. ", "1994).", "\n\nA legal sufficiency challenge may only be sustained when:  (1) the record discloses a complete absence of evidence of a vital fact; (2) the court is barred by rules of law or of evidence from giving weight to the only evidence offered to prove a vital fact; (3) the evidence offered to prove a vital fact is no more than a mere scintilla; or (4) the evidence establishes conclusively the opposite of a vital fact. ", " \nUniroyal Goodrich Tire Co. v. Martinez\n, 977 S.W.2d 328, 334 (Tex. ", "1998),\n cert. ", "denied\n, 526 U.S. 1040 (1999);\n Robert W. Calvert, \n\"No Evidence\"\n \nand \"Insufficient Evidence\" Points of Error\n, 38 T\nEX\n. ", "L. R\nEV\n. ", "361, 362-63 (1960)\n. ", " In determining whether there is legally sufficient evidence to support the finding under review, we must consider evidence favorable to the finding if a reasonable factfinder could, and disregard evidence contrary to the finding unless a reasonable factfinder could not.", "\n  \nCity of Keller v. Wilson\n, \n168 S.W.3d 802, 827\n (Tex. ", "2005).", "\n\nAn assertion that the evidence is factually insufficient to support a fact finding means that the evidence supporting the finding is so weak or the evidence to the contrary is so overwhelming that the answer should be set aside and a new trial ordered. ", " \nGarza v. Alviar\n, 395 S.W.2d 821, 823 (Tex. ", "1965). ", " We are required to consider all of the evidence in the case in making this determination, not just the evidence that supports the finding. ", " \nMar. Overseas Corp. v. Ellis\n, 971 S.W.2d 402, 406-07 (Tex.), ", "\ncert. ", "denied\n, 525 U.S. 1017 (1998).", "\n\nConclusions of law may not be challenged for factual sufficiency, but they may be reviewed to determine their correctness based upon the facts. ", " \nCitizens Nat’l Bank v. City of Rhome\n, 201 S.W.3d 254, 256 (Tex. ", "App.—Fort Worth 2006, no pet.); ", "\nDominey v. Unknown Heirs and Legal Representatives of Lokomski\n, 172 S.W.3d 67, 71 (Tex. ", "App.—Fort Worth 2005, no pet.).", "\n\nApplicable Law\n\nA creditor who makes an excessive demand on a debtor is not entitled to attorneys’ fees for litigation required to recover the debt. ", " \nFindlay v. Cave\n, 611 S.W.2d 57, 58 (Tex. ", "1981); \nHernandez v.  Lautensack\n, 201 S.W.3d 771, 777 (Tex. ", "App.—Fort Worth 2006, pet. ", "denied)\n. ", " A demand is not excessive simply because it is greater than what the fact-finder later determines is actually due. ", " \nHernandez\n, 201 S.W.3d at 777; \nPratt v. Trinity Projects, Inc\n., ", "26 S.W.3d 767, 769 (Tex. ", "App.—Beaumont 2000, pet. ", "denied). ", " That a creditor’s demand is greater than the amount the fact-finder eventually determines is due may be evidence of an excessive demand, but “it cannot be the only criterion . . ., ", "especially where the amount due is unliquidated.” ", " \nFindlay\n, 611 S.W.2d at 58. ", " \n\tThe dispositive inquiry for determining whether a demand is excessive is whether the creditor acted unreasonably or in bad faith. ", " \nHernandez\n, 201 S.W.3d at 777\n; \nPratt\n, 26 S.W.3d at 769\n. ", " Application of this rule is limited to situations in which the creditor refuses a tender of the amount actually due or indicates clearly to the debtor that such a tender would be refused. ", " \nFindlay\n, 611 S.W.2d at 58; \nHernandez\n, 201 S.W.3d at 777.", "\n\nIn the absence of bad faith, a demand can be found excessive if it seeks an unreasonable amount from the debtor. ", " \nPennington v. Jerry F. Gurkoff, D.O., P.A.\n, 899 S.W.2d 767, 772 (Tex. ", " App.—Fort Worth 1995, writ denied).", "\n \n If a creditor demands monies to which he is not entitled, that demand is unreasonable and, consequently, excessive. ", " \nWayne v. A.V.A. Vending, Inc\n., ", "52 S.W.3d 412, 418 (Tex. ", "App.—Corpus Christi 2001, pet. ", "denied); \nsee  Ingham v. Harrison\n, 148 Tex. ", "380, 224 S.W.2d 1019, 1022 (1949).", "\n\nAnalysis\n\nOn March 31, 2003, \nappellant demanded that appellee pay $27,588, which represented the rent due from December 2004 (the date of the initial breach) through September 2004 (the date the lease was to originally terminate), plus late fees for the same time period totaling $1,931; this amount is approximately five times the amount ultimately awarded by the trial court.", "\n\nThe lease provided that if appellee defaulted, appellant could “elect not to terminate [the] Lease but to (i) recover . . ., ", "in advance, the present value of the future Rent.” ", " It also provided that “[e]ach Rent payment not received by the fifth of the month shall bear a late charge of two percent per month from the due date plus a one-time bookkeeping charge of five percent of the amount due.” ", " However, as of March 31, 2003, the date of the demand letter, only four of the monthly rent payments were late, so appellee owed only a small part of the $1,931 in late fees rather than the full amount claimed by appellant. ", " Moreover, the remedies provision of the lease did not allow for collection of such late fees in advance.", "\n\nAt the time of the March 31 demand letter, although appellant had a statutory duty to mitigate its damages,\n(footnote: 4) there is no evidence that it had yet agreed to the terms of the lease with D&M Distributors, Inc.  Therefore, the only evidence that this demand was excessive is with respect to the late fees due. ", " However, it is undisputed that appellee did not owe appellant $1,931 in late fees, either on March 31 or at trial. ", " Accordingly, there is evidence supporting the trial court’s findings that appellant demanded \npayment for amounts to which it was not entitled and which were, therefore, unreasonable. ", " Furthermore, the demand letter indicated that appellee could owe “additional amounts” under the lease.", "\n\nAdditionally, appellant’s demand letter stated that the collection would be turned over to attorneys if the \nfull\n amount of $29,519 was not paid within three days. ", " Accordingly, appellant’s letter indicates a refusal to accept a tender of any amount less than $29,519, an amount greater than what it was owed.", "\n  The Fourteenth Court of Appeals has held that a demand letter stating that the company would accept no less than full payment indicated a refusal to accept tender of any amount less than what was demanded. ", "\nWarrior Constructors, Inc.  v. Small Bus. ", " Inv. ", " Co.  of Houston\n, 536 S.W.2d 382, 386 (Tex. ", "Civ. ", "App.—Houston [14th Dist.] ", "1976, no writ).", "\n  \nWe agree and hold that appellant’s March 31 demand letter indicates a refusal to accept a tender of any amount less than $29,519.", "\n\nMoreover, even after filing suit and reletting the leased premises for a monthly rental amount greater than the monthly rental amount due under its lease with appellee, appellant continued to maintain that appellee owed rent for the full amount of the lease term without any credit for the rent subsequently paid by the new tenant. ", " Appellant’s counsel admitted at trial that appellant’s discovery responses initially did not provide for any such offset in the amount claimed because he was researching a legal theory to support an argument that appellant was not required to make such an offset. ", " According to counsel, only after he had concluded that such an argument was not sustainable were the discovery responses amended to include such an offset in the amount claimed. ", " This is further evidence of appellant’s indication to appellee that it would not accept a tender of a lesser amount than what it claimed appellee owed. ", " \nCf. ", "Ingham\n, 224 S.W.2d at 1022 (holding that appellee’s refusal to close loan without dropping claims for “extras” for which trial court later determined he was not owed, and without allowing offset that trial court later determined was proper, constituted an “unjust demand” and was in effect as if appellants had offered a tender at that time). ", " Accordingly, we conclude and hold that there is sufficient evidence to support the trial court’s findings of fact and that the trial court’s conclusion of law is correct. ", " We overrule appellant’s five issues.", "\n\nConclusion\n\nHaving overruled appellant’s five issues, we affirm the trial court’s judgment.", "\n\n\n\n\n\nTERRIE LIVINGSTON\n\nJUSTICE\n\n\n\nPANEL B:\tLIVINGSTON, DAUPHINOT, and HOLMAN, JJ.", "\n\n\n\nDELIVERED: March 8, 2007\n\nFOOTNOTES\n1:See\n \nTex. ", "R. App. ", "P.\n 47.4.", "\n\n\n2:The first two months’ rent payments were only $896 per month.", "\n\n\n3:Appellant maintained at trial, and the trial court appeared to accept, that this amount was a typographical error.", "\n\n\n4:Section 91.006 of the Texas Property Code requires a landlord to mitigate his damages after the breach of a lease and declares void any lease provision to the contrary. ", " \nSee\n \nTex. ", "Prop. ", "Code Ann\n. § ", "91.006 (Vernon Supp. ", "2006); \nLunsford Consulting Group, Inc. v. Crescent Real Estate Funding VIII, L.P\n., ", "77 S.W.3d 473, 476 (Tex. ", "App.—Houston [1st Dist.] ", "2002, no pet.); ", "\nsee also\n \nAustin Hill Country Realty, Inc. v. Palisades Plaza, Inc\n., ", "948 S.W.2d 293, 299-300 (Tex. ", "1997), \nabrogated in part by\n \nTex. ", "Prop. ", "Code Ann\n. § ", "91.006. ", "\n\n\n" ]

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[ "So What Happens Now?", "\n\nBy: Guest Authors\n\nBy: Craig Chamberlain\n\nBarack Obama is now the President Elect. ", "That means that a person of African descent will be living at 1600 Pennsylvania Ave. ", "So now that the historic has happened can we please stop saying that America is an inherently racist country as if it were gospel truth. ", "I mean a black man has been elected President in a country where blacks are a minority, that has never happened before. ", "Has a black ever been elected Prime Minister of Great Britain, or an Arab President of France? ", "Yet somehow I doubt that the left will let the myth of Amerikkka die.", "\n\nI didn’t vote for Obama, and while I’m sure in the eyes of his supporters this is an automatic guilty verdict in making me a racist, I wish him well. ", "Good luck to him, he has to put the campaign rhetoric aside and make decisions. ", "That’s something that he has had trouble with in the past as all those “present” vote should attest to. ", "As John McCain rightly pointed out, that’s not something he can do as President. ", "He’ll have to make a decision. ", "And being a leftist I doubt he’ll make good ones.", "\n\nWe already know what his domestic policy is: higher taxes, more spending, cutting back the military, withdrawing our troops from Iraq, imposing the “fairness doctrine” to eliminate the first amendment rights of his critics, card check instead of secret ballots so that his union allies can intimidate workers into signing onto form a union(a bigger union means more money for the union which they will spend to help the Democrats, no wonder the Democrats are so in favor of it) leftists judges who are more interested in empathy and international law than they are in the constitution, and absolutely no restrictions on abortion. ", "The ban on partial birth abortion will probably be repealed, as will the Hyde Amendment along with the Mexico City Policy. ", "The next four or eight years will not be friendly ones for those who are pro life.", "\n\nDespite his claims of being post racial and post partisan I think people should be skeptical. ", "He’s done nothing to show that he is actually willing to work with the Republicans. ", "In fact it is very likely that we will see the most hyper partisan presidency in history(so much for post partisan) and anyone who disagrees with our new President will be called a racist(so much for post racial). ", "Hardly a way to build bridges, heal wounds and get things done.", "\n\nWhile his domestic agenda is troubling, it’s nothing America hasn’t seen before. ", "These same stale, tired, and useless ideas are what inspired LBJ’s Great Society, and FDR’s New Deal. ", "Been there done that, it doesn’t work. ", "But it seems that a new generation of Americans is going to have to have that drilled into their heads before they learn that old lesson. ", "Until we do we can get used to inflation, higher unemployment, higher taxes and a return to the welfare society. ", "While all of this is bothersome it can be dealt with later.", "\n\nWhere America is likely in real danger is in foreign affairs. ", "Obama has promised to meet and talk with hostile and terrorits leaders without preconditions. ", "That hardly projects and image of strength. ", "America has not been attacked be terrorists since 9-11, and that has been because of the measures taken by President Bush. ", "It is unlikely that President Obama is going to be so agressive.", "\n\nIs he going to cave to the Russians over the missile shield in Poland? ", "Is he going to do anything to make sure that Iran does not acquire nuclear weapons? ", "Will he do anything to counter Hugo Chavez’s poisonous influence throughout South America? ", "These are problems that face all Americans. ", "Terrorism is a threat to all, not just to those who didn’t vote for Obama. ", "He’s now going to be the President of the United States, not just the “blue states” let’s hope he puts the country’s needs and problems above the interests of his own ideology and party.", "\n\nIf he truly wants to heal wounds and move past party then he needs to put the country’s needs over his party’s and over his own ideology." ]

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[ "Q:\n\nCan Intellisense recognize javascript prototype functions?", "\n\nI'm using VS Code and I would like Intellisense to recognize javascript prototype functions. ", " Is there a way to configure it to do so?", "\nfunction MyObject() {}\n\nMyObject.prototype.foo = function() {};\nMyObject.prototype.bar = function() {};\n\nvar myObj = new MyObject();\n\nmyObj. ", " //I want Intellisense to show me the foo and bar functions here\n\nA:\n\nThis is supported in the latest versions of VS Code.", "\nhttps://github.com/Microsoft/TypeScript/wiki/Salsa\n\n" ]

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[ "Q:\n\nPattern matching and constructors\n\nWhy do i get errors when I write this kind of pattern matching :\ntype t = A of int | B of float\n\nlet f = function\n | (A i | B f) -> true\n | _ -> false\n\nor\nlet f = function\n | A i | B f -> true\n | _ -> false\n\nError: Variable f must occur on both sides of this | pattern\n\nlet f = function\n | (A i | B i) -> true\n | _ -> false\n\nor\nlet f = function\n | A i | B i -> true\n | _ -> false\n\nError: This pattern matches values of type ints of type float\nbut a pattern was expected which matches value\n\nA:\n\nIf you provide a single right-hand side for multiple patterns (as you do), OCaml requires that the patterns consistently bind to pattern variables.", "\nIn the first situation,\nmatch ... with\n | A i | B f -> ...\n ...\n\nthe patterns don't agree on the variables they bind to: the first pattern binds to i, while the second binds to f.\nIn the second situation,\nmatch ... with\n | A i | B i -> ...\n ...\n\nthe patterns don't agree on the type of values to bind to their variables: the first pattern binds a value of type int to i, while the second binds a value of type float to i.\nThe only way in which these two pattern can consistently bind to variables is not to bind to any variables at all:\nmatch ... with\n | A _ | B _ -> ...\n ...\n\nThe complete example then becomes\ntype t = A of int | B of float\n\nlet f = function\n | A _ | B _ -> true\n | _ -> false\n\n(But note that the last arm of the pattern match is superfluous as the first two pattern already exhaustively match all values of your type t. Hence, we get:\nlet f = function\n | A _ | B _ -> true\n\nThis of course is equivalent to writing let f _ = true.)", "\n\nA:\n\nIn Or pattern (| pattern), you lose track of which constructors you are in. ", "Therefore, you need to bind the same set of variables to work without referring to constructors. ", "\nAnd OCaml is strongly-typed; a value i cannot have both type int and type float. ", "\nIf type t has more than two cases, you should write:\nlet f = function\n | A _ | B _ -> true\n | _ -> false\n\notherwise:\nlet f = function\n | A _ | B _ -> true\n\nis enough since pattern matching is already exhaustive.", "\nI agree that Or pattern is quite restrictive, but sometimes it is helpful when you have symmetric cases in your function:\ntype num = \n | Int of int\n | Float of float\n\nlet add s1 s2 = \n match s1, s2 with\n | Int i1, Int i2 -> Int (i1 + i2)\n | Int i, Float f | Float f, Int i -> Float (float i +. ", "f)\n | Float f1, Float f2 -> Float (f1 +. ", "f2)\n\n" ]

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[ "Long-distance control of nodulation: molecules and models.", "\nLegume plants develop root nodules to recruit nitrogen-fixing bacteria called rhizobia. ", "This symbiotic relationship allows the host plants to grow even under nitrogen limiting environment. ", "Since nodule development is an energetically expensive process, the number of nodules should be tightly controlled by the host plants. ", "For this purpose, legume plants utilize a long-distance signaling known as autoregulation of nodulation (AON). ", "AON signaling in legumes has been extensively studied over decades but the underlying molecular mechanism had been largely unclear until recently. ", "With the advent of the model legumes, L. japonicus and M. truncatula, we have been seeing a great progress including isolation of the AON-associated receptor kinase. ", "Here, we summarize recent studies on AON and discuss an updated view of the long-distance control of nodulation." ]

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[ "2017 Lollapalooza Signed & Numbered Poster\n\nChicago is a city that loves its parades. ", "St. Patrick's Day to Thanksgiving, presidential inaugurations to baseball championships, and Helenic Heritage to Pride - there are plenty of opportunities to hit the streets and fly your freak flag. ", "For the 2017 Lollapalooza poster, street artist Pixelpancho played on that tradition and imagined Lollapalooza as an old-timey street fair complete with marching band. ", "His version gets a surrealist spin with the musicians as robots, one of his signature motifs, powered not by gears but by the greenery of Grant Park. ", "While the execution is vintage in style, they march forward to today, when Lollapalooza will once again fill Chicago's streets with music. ", "We've reproduced the art in two very special editions. ", "As with all of our posters, we only print one run and once sold out will not be re-issued.", "\n\nSigned & Numbered Edition $175 - Silkscreened with 13 colors on heavyweight, 100% cotton rag paper. ", "This version does not include the band lineup. ", "Printed in a numbered edition of 325 that is also signed by both Pixelpancho and Lollapalooza/Jane's Addiction founder Perry Farrell. ", "24\"x 30\" IMPORTANT INFORMATION: All posters will begin shipping in July.", "\n\nAbout the Artist_Born in Turin in 1984, Pixelpancho was introduced to color and form by his grandfather, who painted occasionally. ", "With time, his passion for art and design led him to the Albertina Academy of Fine Arts followed by the Academy of Fine Arts in Valencia, Spain, where he obtained his degree. ", "It was in Spain that he became familiar with the graffiti and street art scenes and began working on outdoor surfaces with spray cans and markers. ", "Traveling between Turin and Valencia, Pixelpancho took every opportunity to be noticed on the streets, using different mediums such as tiles, wall painting and sticker/poster art, eventually expanding across Europe.", "\n\nPixelpancho's work is drawn from several diverse influences. ", "Traces of Joaquin Sorolla, Salvador Dali and the political painter group 'El Equipo Cronica' to the more modern Ron English, and Takashi Murakami can be seen in his works. ", "Traveling extensively for graffiti jams and gallery exhibitions has allowed his style to evolve from a simple robot character to the more complex compositions in his work today. ", "The narrative in Pixelpancho's work is driven by a forgotten world that sits under a blanket of dust. ", "In it, broken and dented robots are found decaying into the ground, their iron and rusted copper bodies falling and laying as if discarded into oblivion. ", "Although the scale of his work ranges, the surreal realm is a constant thread, piercing through contemporary and historical references that add a sense relevance within our place and time. ", "The strength of physical and gestural references that humanize these robots results in the artist's unmistakable mark. ", "Found on the walls of abandoned buildings in cities throughout Europe, the U.S. and Mexico, Pixelpancho's work is an interconnected structure of stories. ", "The murals, the paintings, the sculptures in the end are only a small part of something greater, another story within the ever-growing realm.", "\n\nUS$175.00\n\nQuantity:\n\nShare:\n\nRecommended Products\n\n2017 Lollapalooza Signed & Numbered Poster\n\nUS$175.00\n\nQuantity:\n\nRainbow Lineup Tee\n\nUS$30.00\n\nSize:\n\nQuantity:\n\n2017 Line-Up Ringer Tee by Aviator Nation\n\nUS$55.00\n\nSize:\n\nQuantity:\n\nLolla Bandana\n\nUS$10.00\n\nQuantity:\n\nCustom Text Field 7 - Full Width Bottom Banner - t30_07_banner\n\nJoin Our Mailing List\n\nFor the latest in merchandise specials and promotions, please join this email list. ", "You will only receive offers related to this artist. ", "We never sell or give our mailing lists to anyone." ]

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[ "Festival-centric website FestivalNews.co.uk has reported the leaked line-up for this summer's Glastonbury Festival.", "\n\nTo our eyes, though, there appear to be too many 'big' names here, too many potential headliners. ", "Unless Glastonbury is running eight or nine large stages at the same time, we're struggling to imagine how this not-so-little lot will fit in. ", "But, here's what we've heard, anyway..." ]

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[ "Introduction {#s1}\n============\n\nUntil the midst of the 20^th^ century psychologists and psychophysicists viewed perception as a primarily active process: perception is what emerges when an organism equipped with a brain interacts with its environment ([@bib87]; [@bib104]; [@bib114]; [@bib122]; [@bib173]). ", "Indeed, behavioral studies revealed that although mammals can perceive events or objects while being passive, most of the time mammalian individuals seek for objects and perceive the world via active body and sensor movements ([@bib2]; [@bib48]; [@bib56]; [@bib75]; [@bib99]; [@bib105]; [@bib109]; [@bib111]; [@bib126]; [@bib157]; [@bib161]). ", "Investigating perception at the neuronal level, however, proved to be extremely challenging and neuroscientists have adopted a series of reductionist methods in which various components of the process have been eliminated. ", "One critical such component has been sensor motion -- neuroscientists have been investing enormous efforts in precluding sensor movements as these movements, naturally, interfere with systematic characterizations of neuronal responses. ", "This passive paradigm indeed yielded invaluable descriptions of neuronal circuits and pathways that can convey sensory information and suggested how these pathways might process sensory information. ", "Crucially, however, passive paradigms cannot reveal how sensory information is actually processed during active perception ([@bib2]; [@bib52]; [@bib117]). ", "For that, a unified analysis of the motor and sensory components engaging brains with their environments is required.", "\n\nExperimental data are usually examined in light of, and reflect on, implicit or explicit hypotheses. ", "One salient outcome of the passive reductionist approach has been the over emphasis of open-loop schemes of perception. ", "The elimination of motor components from the experimental scheme yielded a parallel elimination of motor variables from the corresponding theoretical schemes, leaving models of perception as sensory-only open-loop schemes (e.g., [@bib36]; [@bib51]; [@bib118]; [@bib141]). ", "In agreement with previous suggestions ([@bib2]; [@bib45]; [@bib58]; [@bib96]; [@bib145]), we claim that such a reductionist paradigm should ultimately fail to elucidate neural mechanisms of natural perception. ", "This is not to say that any reduction would fail, but to emphasize that an appropriate reductionist paradigm should leave the motor-object-sensory interactions intact. ", "The current paper describes an attempt to bring the motor variables back to the theoretical modeling of perception, by proposing a motor-sensory closed-loop scheme for the perception of the external environment. ", "The paper makes use of ideas previously developed in various dynamic theories ([@bib10]; [@bib13]; [@bib96]; [@bib136]; [@bib145]; [@bib147]; [@bib182]) and, in general, refers to the perception of external objects as a process of acquiring information about presently-existing external objects, whether consciously or not. ", "The paper addresses perceptual acquisition - mechanisms of perceptual reports and their interactions with perceptual acquisition are not addressed here. ", "It is noted, however, that a comprehensive understanding of perception depends on the understanding of report mechanisms as well. ", "For simplicity, the term \"brain\" is often used in this article in an extended form that includes the sensory organs and their affiliated nerves and muscles.", "\n\nThe open loop perception (OLP) doctrine {#s1-1}\n---------------------------------------\n\nClosed loops are systems in which every signal eventually affects its source; open loops are systems in which signals cannot affect their sources. ", "Clearly, brains contain closed-loops at all levels, some of which have been implicated in relation to perceptual processing ([@bib5]; [@bib51]; [@bib119]; [@bib143]). ", "Yet, whether perceptual acquisition is considered an open-loop or closed-loop process does not depend on the existence of closed loops within the chain of processing, but on whether the entire chain of processing is closed (as a loop) or open. ", "Thus, a perceptual process that starts at the sensory organ and ends somewhere in the brain, whether containing local loops or not, is termed here an open-loop perceptual (OLP) process ([Figure 1A](#fig1){ref-type=\"fig\"}), whereas a perceptual process that includes the sensory organ but has no starting nor ending point, is termed a closed-loop perceptual (CLP) process ([Figure 1B](#fig1){ref-type=\"fig\"}).10.7554/eLife.12830.003Figure 1.Possible perceptual schemes.(**A**) An open-loop scheme (in the motor-sensory sense) -- perception begins with an interaction (uni- or bi-directional) between the object and the sensory organ (an eye in this illustration) and ends somewhere in the brain where a relevant neuronal representation (NR) is formed.", " (**B**) A closed-loop scheme (in the motor-sensory sense) -- perception is a circular process, with no starting or ending points, which contains the sensory organ.**DOI:** [http://dx.doi.org/10.7554/eLife.12830.003](10.7554/eLife.12830.003)\n\nThe OLP doctrine holds that external objects and features are perceived in an open-loop manner, in the motor-sensory sense ([@bib15]; [@bib42]; [@bib82]; [@bib155]; [@bib172]; [@bib175]). ", "Thus, for example, an apple activates retinal receptors, which in turn initiate a stream of activations in the brain, some of which may depend on internal loops, i.e., loops that do not include the sensory organ. ", "An activity pattern that is repeatedly evoked in a given neuronal network in response to a presentation of the apple, and/or when such an apple is perceived, is often termed a neuronal correlate or neuronal representation (NR) of that apple. ", "NRs are representations that are not necessarily consistent or unique, i.e., they may appear in only some of the cases in which the apple is presented or perceived, and may appear also when other objects are presented or perceived. ", "If a specific NR is evoked in a given brain for each and every perceived appearance of the apple, is invariant to changes in internal and environmental conditions, and is unique to the apple, it can be termed \"the\" invariant representation (IvR) of the apple in that specific brain. ", "Assuming OLP, IvRs should be invariant to the acquisition mode. ", "Visual IvRs of the apple, for example, should be the same in passive and active acquisition modes, i.e., when the eye is stationary and the object moves or flashes (passive mode) and when the object is stationary and the eye moves (active mode).", "\n\nThe search of NRs that are also IvRs, during the last 6--7 decades, yielded several key findings. ", "Among those is the characterization of NRs of various external features along the relevant sensory streams. ", "For example, NRs of brief presentations of visual elements, such as dots and bars, were characterized among retinal, thalamic and cortical neurons ([@bib77]; [@bib85]). ", "NRs of more complex visual patterns were characterized in various cortical areas ([@bib38]; [@bib62]; [@bib121]). ", "Crucially, however, although partial invariance had been demonstrated for portions of the proposed NRs in some of the cases, none of these NRs was shown so far to be \"the\" IvR of a specific external object or feature, namely an NR that is (at least substantially) invariant to changes in the most relevant conditions of perception. ", "Moreover, none of these studies provides information that can discriminate between OLP and alternative hypotheses. ", "Consider, for example, studies exhibiting single neurons that increase their firing rate significantly and selectively for a given object (e.g., a face) out of several presented objects, and for several variations of that object ([@bib121]; [@bib150]; [@bib177]). ", "The critical factor here is that such a neuron cannot be considered as describing the IvR of that object, neither as describing a reliable projection of the IvR. Based on combinatorial considerations and response variations the assumption in such cases is that the elevated firing rate of such a neuron is a (tiny) component of the relevant NR, and not the NR itself. ", "The question is, then, would the assumed NR be invariant to a sufficiently large portion of all relevant variations of object presentation and context. ", "Given that these neurons are not completely invariant even to the limited sample of variations presented to them (as is evident from the substantial trial-by-trial variability of their responses) and their tiny contribution to the actual NR, it is impossible to infer the level of invariance of the actual NR out of the firing patterns measured from these neurons.", "\n\nStudying the passive mode of sensation also revealed various forms of internal transformations between NRs, such as, for example, transformation from NRs of static dots to NRs of static bars ([@bib84]; [@bib154]), from temporal-code based NRs to rate-code based NRs ([@bib9]) or from rate-code based NRs to temporal-code based NRs ([@bib34]). ", "Clearly, these mechanisms can function within both OLP and CLP schemes of perception. ", "Passive-mode experiments were also instrumental in describing the minimal exposure times required for generating meaningful perceptual reports. ", "Across a large set of stimuli it was found that, depending on practice, exposure times as short as a few tens of milliseconds already allow a categorization of the presented stimulus, at least in a binary manner. ", "As will be shown below, these findings are consistent with both OLP and CLP schemes.", "\n\nChallenges to the OLP doctrine {#s1-2}\n------------------------------\n\nAs described above, the OLP doctrine allowed an invaluable characterization of various components of the perceptual systems of mammals, using a set of reductionist steps. ", "In order to verify that these specific reductions of the perceptual process are scientifically valid, one has to reconstruct perception by combining back the individual identified components. ", "Succeeding in doing so will not only validate the specific reductionist approaches used, but, more importantly, show that OLP can be considered as a valid (i.e., self-consistent) theory of perception. ", "At this stage we can ask whether OLP is consistent with the data collected so far. ", "We describe here several major findings that appear to be inconsistent with OLP and thus significantly challenge the validity of OLP as a mechanism for natural perception in mammals.", "\n\n### Sensation is normally active {#s1-2-1}\n\nMammalian sensory organs usually acquire information via movements ([@bib2]; [@bib31]; [@bib48]; [@bib99]; [@bib105]; [@bib109]; [@bib111]; [@bib148]; [@bib157]; [@bib161]). ", "The strategies employed by sensory systems are often similar. ", "Visual and tactile systems, for example, employ movements of sensory organs that contain two-dimensional arrays of receptors. ", "The movements serve several functions. ", "Larger movements (e.g., ocular saccades and head or arm movements) quickly move the array of receptors from one region of interest to another. ", "Smaller (and slower) movements (e.g., fixational drifts and finger or vibrissal scanning) scan the region of interest at fine resolution ([@bib2]). ", "This move-dwell-move pattern is typical for perceptual exploration across a large range of temporal scales, from minutes to less than a second ([Figure 2](#fig2){ref-type=\"fig\"}). ", "Olfaction and taste are probably as active as touch and vision ([@bib75]; [@bib97]; [@bib109]; [@bib181]). ", "The extent of action in hearing is less clear - while cochlear amplification is considered active ([@bib41]; [@bib132]), whether auditory sensation is typically obtained via sensor activation is still not known (see *Perceptual systems are organized as motor-sensory-motor (MSM) loops* and *Contrasting OLP and CLP -- discriminatory testable predictions* below). ", "Cross-modal effects between body and sensor movements, which are not discussed in this paper, are likely to play a significant role in perception as well ([@bib14]; [@bib57]; [@bib71]; [@bib95]; [@bib125]; [@bib129]). ", "During sensor scanning, activations of individual (e.g., photo- or mechano-) receptors are functions of the interactions between the moving sensor and the physical features of external objects ([@bib3]; [@bib10]; [@bib16]; [@bib24]; [@bib61]; [@bib2]; [@bib64]; [@bib81]; [@bib83]; [@bib88]; [@bib107]; [@bib109]; [@bib136]; [@bib139]; [@bib151]; [@bib152]; [@bib158]; [@bib159]; [@bib160]; [@bib164]). ", "These dependencies are termed here in general motor-sensory contingencies (MS-contingencies); they form one class of the sensorimotor contingencies described by O'Regan and Noe ([@bib136]).10.7554/eLife.12830.004Figure 2.Active sensing.(**A**) Ocular scanning of a scene.", "The trajectory of a human subject's gaze (of one eye) during free viewing of an image presented on a computer screen is depicted. \"", "Drift\" points to the slow eye movements scanning a region of interest during a fixational pause. \"", "Saccade\" points to a rapid saccadic eye movement moving the gaze from one fixational pause to another. ", "Section duration: 60 s; sampling: 240 Hz. ", "Courtesy of Moshe Fried and Amos Arieli.", " (**B**) Manual scanning of a surface. ", "The trajectory of a human subject's hand, while palpating a virtual surface with a varying density of elevated dots (black), is depicted. ", "The surface was mimicked via a tactile computer mouse system (VTPlayer; VirTouch, Jerusalem) whose two 4x4 pin arrays, which were touched constantly with the index and middle fingers of the right hand, reflected the spatial details of the virtual surface according to mouse location. ", "Section duration: 152 s; sampling: 125 Hz. ", "Courtesy of Avraham Saig and Amos Arieli.", " (**C**) Facial scanning of an arena. ", "The trajectory of the snout of a rat, exploring an arena using sniffing and touch, is depicted. ", "Section duration: 828 s; sampling: 25 Hz. ", "Courtesy of Ben Mitchinson, Chris J. Martin, Robyn A. Grant and Tony. ", "J. Prescott; see ([@bib124]).", " (**D**) Local vibrissal scanning. ", "The trajectory of a point near the middle of whisker C1 of a rat, exploring a region of an arena, is depicted. ", "All whiskers except row C were trimmed on both sides of the snout. ", "Section duration: 1.5 s; sampling: 500 Hz. ", "Courtesy of Tess Oram, Noy Barak and Dudi Deutsch.", " (**E**) Sensory granularity. ", "Left, a sample of retinal photoreceptors array of the human foveal area (from [@bib40]). ", "Middle, a schematic illustration of the organization of one type of mechanoreceptor (rapidly adapting) under the skin of the human fingertip. ", "Right, whiskers array: left, the array of whiskers across the right snout of a rat, courtesy of Sebastian Haidarliu; right, a schematic illustration of a whisker's follicle containing hundreds of mechanoreceptors, courtesy of Satomi Ebara.**DOI:** [http://dx.doi.org/10.7554/eLife.12830.004](10.7554/eLife.12830.004)\n\nThe fact that mammalian sensation is active significantly challenges the OLP doctrine. ", "First, it turns out that the common reductionist approach in which stimuli are flashed on passive sensory organs cannot be extended back to natural conditions. ", "This is because in such experiments no information is obtained about the dependency of sensory signals on natural active interactions with the object, interactions that cannot be mimicked with passive sensors. ", "In vibrissal touch, for example, a crucial sensory variable is the whisker curvature ([@bib16]; [@bib24]; [@bib151]), which cannot be physically mimicked with only external forces ([@bib16]). ", "In vision, while the conditions accompanying an ocular drift can be mimicked, in principle, by drifting the entire visual field, the conditions accompanying ocular saccades cannot be mimicked with passive eyes. ", "Ocular saccades are accompanied by peri-saccadic suppression during which, unlike with flashed stimuli, activity along the visual sensory pathway is significantly suppressed ([@bib76]). ", "Also, saccades are always ending with additional eye movements, such as overshoots, corrections and drifts, which are lacking in passive-eye experiments. ", "In general, it seems that the conditions introduced when stimuli are flashed on passive sensors mimic a small set of naturally-occurring states such as lightning at night or a sudden wind blowing over the rat's whiskers. ", "It is thus not surprising that, when compared, the characteristics of NRs revealed with passive sensors are substantially different from those revealed with active sensors (e.g., [@bib91]).", "\n\nOLP assumes that the presentation of an object retrieves the NR that represents it, i.e., its neuronal IvR. When this assumption was tested computationally at the presence of simulated eye movements it was found that such a retrieval is possible with a very simple environment (one stimulus) and a limited number of possible NRs (two), in which case the knowledge of the statistics of sensor motion (e.g., eye movements) can provide unique, unambiguous solutions ([@bib140]). ", "However, it is not clear if a similar mechanism can work with more crowded environments, even when the movement trajectory of the eye is tracked by the perceiver ([@bib28]). ", "The major challenge with IvR retrieval in OLP, even when the sensor trajectory is known (e.g., [@bib7]), is the instability of the sensory input. ", "With spike-based representations and finite firing rates this instability is devastating -- by the time required to construct a reliable representation the sensor may have already moved away and provide new inputs. ", "With representations of fine visual details it had been shown that this is indeed the case ([@bib3]).", "\n\nThe realization that the visual system codes external objects differently in passive and active modes sets another major challenge to OLP. ", "This difference can be attributed to the fact that while a passive eye that is stimulated by a flashed image can only use spatial coding to represent the image, a moving eye can use both spatial and temporal coding schemes. ", "In fact, the temporal code appears to be much more accurate, and of higher spatial resolution, than the spatial code ([@bib3]; [@bib17]; [@bib153]). ", "Thus an OLP theory assuming that the same IvR is retrieved with or without sensor motion must also assume that perception is based on the less accurate spatially-coded information and ignores (or corrects for) the more accurate temporally-coded information - clearly an inefficient strategy. ", "As we will see below (in *Contrasting OLP and CLP -- discriminatory testable predictions*), a more efficient OLP scheme, which is based on active sensing and can exploit its advantages, is also possible.", "\n\n### Sensory signals convey ambiguous information {#s1-2-2}\n\nSensory signals may often be ambiguous if processed without the motor signals that yielded them. ", "One example is the curvature signal generated at the base of a whisker upon its contact with an object. ", "The same curvature can be generated when contacting objects at different locations, an ambiguity that is resolved if the angle by which the whisker is rotated is taken into account ([@bib16]) ([Figure 3](#fig3){ref-type=\"fig\"}). ", "Similarly, temporal delays between two whiskers or two photoreceptors code spatial offsets ambiguously if sensor velocity is not considered ([@bib2], [@bib3]; [@bib100]). ", "Consistently, in vivo recordings from the primate retina ruled out pure sensory processing, such as lateral inhibition, as a basis for edge detection while supporting motor-sensory processes involving eye movements ([@bib52]). ", "These pieces of evidence join a substantial list of evidence for the ambiguity of sensory signals and the unambiguity of MS-contingencies ([@bib20]; [@bib136]). ", "For vision this is further supported by a series of experiments and analyses indicating that retinal information depends on the nature and trajectory of miniature eye movements ([@bib4]; [@bib102]; [@bib107]; [@bib137]; [@bib157]; [@bib166]).10.7554/eLife.12830.005Figure 3.An example of MS-Contingency in vibrissal touch.", "A schematic illustration of morphological coding of object location ([@bib16]) is depicted. ", "The motor-sensory phase plane describes the combinations of values of a motor (θ~p~: push angle, maximal change in whisker angle from contact onset) and sensory (k, whisker base curvature) variables when a whisker actively contacts an object at various locations. ", "The locations are defined by their coordinates in the horizontal plane (inset): three azimuth coordinates (L~θ~ = \\[p1, p2, p3\\]) and three radial coordinates (L~r~ = \\[60%, 75%, 90%\\] of whisker length) are depicted and coded by colors. ", "Note that neither of the two variables provide unambiguous coding of object location by itself; for example, k around .02 mm^-1^ codes for both \\~\\[p2, 60%\\] and \\~\\[p1, 90%\\]. ", "In contrast, the contingency between the motor and sensory variables provides unique coding of both L~r~ and L~θ~ (see equations).**DOI:** [http://dx.doi.org/10.7554/eLife.12830.005](10.7554/eLife.12830.005)\n\nNote that this challenge cannot be alleviated by adding efference copy information to open-loop perceptual processing -- efference copies are not accurate enough to account for perceptual accuracy ([@bib7]; [@bib140]; [@bib163]). ", "For example, perception of object location in rats ([@bib100]) depends on the details of the motor trajectory at a resolution corresponding to movements induced by individual motor spikes ([@bib79]; [@bib163]), a resolution that is likely not available in internal efference copies ([@bib54]; [@bib80]). ", "Similarly, the accuracy of visual efference copies is two orders of magnitude lower than the size of fine eye movements ([@bib140]).", "\n\n### Perceptual systems are organized as motor-sensory-motor (MSM) loops {#s1-2-3}\n\nSensory organs (eyes, hands, whiskers) are associated with muscles whose activations move the sensory organ and induce sensory signals ([@bib163]). ", "The neuronal motor and sensory systems that are associated with a given sensory organ are connected via an intricate system of loops that does not allow an isolated operation of either (see illustration of the vibrissal system in [Figure 4A](#fig4){ref-type=\"fig\"}). ", "When motor efferents of a specific sensory organ are activated, sensory signals are inevitably generated ([@bib78]; [@bib88]; [@bib90]; [@bib95]; [@bib146]) and when sensory signals are generated, motor efferents to the same sensory organ are naturally affected ([@bib21]; [@bib65]; [@bib102]; [@bib109]; [@bib128]). ", "One needs to anesthetize the brain, eliminate specific pathways, or prevent the movements of the relevant sensory organs in order to 'open' this motor-to-sensory-to-motor loop.10.7554/eLife.12830.006Figure 4.Anatomy and perceptual schemes of a sensory modality.(**A**) Closed-loop motor-sensory-motor (MSM) connections of the vibrissal system.", "A schematic diagram of the most relevant connections, through which sensory activities feed motor circuits at various levels, is depicted; efference copies are not explicitly depicted. ", "Oval circles indicate brain regions \\[BPN, brainstem premotor nuclei (arbitrarily divided into two oval circles); BG, basal ganglia; Cer, cerebellum; FN, facial nucleus; MCx, motor cortex; POm, posteromedial thalamic nucleus; RN, red nucleus; SC, superior colliculus; SI, primary somatosensory cortex; SII, secondary somatosensory cortex; TG, trigeminal ganglion; TN, trigeminal brainstem nuclei; VL, ventrolateral thalamic nucleus; VPM, ventroposteromedial thalamic nucleus; ZI, zona incerta\\]. ", "Black curves connecting brain regions indicate anatomical connections. ", "Arrows indicate the direction of information flow between brain regions. ", "Connections not labeled with arrows are reciprocal (for more details see [@bib23]; [@bib48]; [@bib99]). ", "Three examples of individual MSM-loops are illustrated by green (a brainstem loop), blue (a thalamic loop) and red (a cortical loop); the primary efferents (FN to muscles) and afferents (follicle to TN) may or may not be common to different pathways. ", "Modified from ([@bib6]; [@bib8]). ", "Inset, top view of the head and whiskers of a rat performing a bilateral localization task.", " (**B**) An MSM-loop (left) activates and senses the same organ. ", "Sensory-motor arcs (right), which sense one organ and activate another, are not discussed in this paper.", " (**C**) Inclusion in an MSM-loop. ", "Re-afferent loops (green) are always closed and thus can be considered as constantly 'perceiving' their organs. ", "Ex-afferent loops (magenta) are normally open (dotted). ", "An ex-afferent loop is closed (solid) only when the sensory organ interacts with the object (right); neither object presence alone (left) nor sensor movement alone (middle) close the loop.**DOI:** [http://dx.doi.org/10.7554/eLife.12830.006](10.7554/eLife.12830.006)\n\nBrain loops that include the relevant sensory organ for a given perception ([@bib3]; [@bib5]; [@bib10]; [@bib48]; [@bib99]; [@bib159]) are termed here motor-sensory-motor loops, or briefly *MSM-loops*. ", "For example, vibrissal MSM-loops include loops running via brainstem stations, thalamic stations and cortical stations, all sharing the same sensory organ ([Figure 4A](#fig4){ref-type=\"fig\"}; colored arcs). ", "Finger-touch MSM-loops include loops that are similar to those of the vibrissal system, running through homologous stations ([@bib8]). ", "Existing anatomical descriptions of Visual MSM-loops are less detailed, although it is known that they also follow a multi-pathway architecture ([@bib19]; [@bib29]; [@bib47]; [@bib110]; [@bib127]; [@bib180]), with sensory information feeding back onto oculomotor pathways at virtually all brain levels ([@bib46]; [@bib60]; [@bib72]; [@bib73]; [@bib106]; [@bib116]). ", "Likewise, sniffing and tasting are likely to be controlled via modality specific MSM-loops as well ([@bib93]; [@bib98]; [@bib125]). ", "As for the auditory system, relevant MSM-loops are likely those whose motor efferents activate the outer hair cells in the cochlea, which in turn change the tuning of the basilar membrane ([@bib74]; [@bib89]), those which activate the muscles of the middle ear ([@bib103]) and those which control the direction of the pinnae. ", "MSM-loops that control head movements can be shared by all cranial senses.", "\n\nThroughout this paper, when we refer to MSM-loops we refer both to their anatomy and function. ", "We use the term\"motor-sensory-motor\" instead of the common term \"sensory-motor\" in order to emphasize the fact that the loops that we refer to are those controlling a single sensory organ, and in which the flow of information is from the sensory organ to itself, via the brain. ", "These loops should be distinguished from multi-modal sensory-motor loops, which include sensory-motor arcs that link different modalities (e.g., eye -- hand or eye -- whisker; [Figure 4B](#fig4){ref-type=\"fig\"}) -- these inter-modal loops and arcs are not addressed here.", "\n\nThe closed-loop architecture of the perceptual systems challenges the OLP doctrine. ", "How would an open-loop mechanism emerge, and how would it function, in such a closed-loop system? ", "In natural conditions every sensory activity will affect the movement of the sensory organ and evoke new sensory activations, assuming that the external object does not disappear after its first interaction with the brain. ", "As loop cycle times are typically shorter than the typical perceptual epoch (e.g., [@bib44]), a sequence of such sensory activations is typically expected within each perceptual epoch (i.e., a period of continuous engagement with the object). ", "How would this sequence of activations be ignored? ", "And, more importantly perhaps, why would it be ignored? ", "Moreover, it is known that increased stimulus exposure durations increase perceptual accuracy and confidence ([@bib138]; [@bib159]); if this is achieved in an open-loop manner, then it would mean that the brain does use those additional sensory signals, and \"corrects for\" the motion that evoked them using efference copy signals. ", "Unfortunately, as mentioned above (in *Sensory signals convey ambiguous information*), efference copy signals are not accurate enough to account for fine perception.", "\n\n### Perception can be masked \"backwardly\" {#s1-2-4}\n\nAlthough the loops are anatomically closed, they can be opened functionally. ", "For example, projecting a flash of an image on the retina or skin, for a duration that is shorter than the duration of the minimal MSM-loop cycle, does not allow closure of the loop. ", "When such a 'virtual knife' is used, the system is forced to function in an open-loop mode, regardless of its architecture. ", "According to the OLP doctrine, this reductionist step does not interfere with the fundamental process underlying perception and thus the natural perceptual process can be reconstructed from such individual open-loop processes. ", "However, backward masking, a robust perceptual phenomenon, challenges this assumption. ", "The presentation of a second object within tens of milliseconds after the presentation of a target object prevents or impairs the perception of this target object ([@bib53]). ", "Such \"backward in time\" effect can occur in some open loop scenarios, for example if perception would depend on the integration of two processes, one fast and one slow, such that the fast process activated by the mask would interfere with the slow process activated by the target ([@bib25]). ", "Experimental data, however, were found to be inconsistent with such open loop schemes, while supporting a dependency of perception on closed loop (\"re-entrant\") mechanisms, in which the stimulus is repetitively sampled ([@bib53]). ", "The dependency on repetitive sampling strongly challenges the assumption that the 'virtual knife' does not interfere with the natural process of perception. ", "Backward masking indicates that flashed stimuli allow, at best, an examination of the first step of a perceptual process, as explained below (see *CLP propositions*).", "\n\n### Perception involves motor-sensory convergence {#s1-2-5}\n\nPerception takes time -- typical perceptual epochs last hundreds of milliseconds. ", "The first wave of sensory-driven neuronal activity typically reaches most of the relevant cortical areas within \\~100 milliseconds, and quick saccadic reports on the crude category of the perceived item can be generated as fast as 150 milliseconds after stimulus onset ([@bib184]). ", "Yet, the identification of more delicate categories and the perception of item details take typically hundreds of milliseconds from first sensor-object encounter, a period during which perceptual acuity continuously improves ([@bib123]; [@bib138]; [@bib159]). ", "Consistently, scalp EEG recordings reveal that perceptual thresholds are correlated with neuronal activities that are recorded after the first transient neuronal response ([@bib30]).", "\n\nCareful analyses of rodent and human behavior during tactile perception reveal signatures of a converging process. ", "Object features, such as location and texture, are perceived via a sequence of sensor-object interactions whose motor and sensory variables show a pattern of convergence towards asymptotic values ([@bib32]; [@bib83]; [@bib101]; [@bib120]; [@bib159]; [@bib160]; [@bib178]). ", "This behavior is consistent with previous descriptions of perception as a dynamic process ([@bib10]; [@bib13]; [@bib96]; [@bib136]; [@bib145]; [@bib147]; [@bib182]), but not with an open-loop one. ", "Converging dynamics, i.e., dynamics during which the state of the entire system gradually approaches a steady state, are hallmarks of closed-loops -- an open-loop system does not converge as a whole. ", "Thus, while the OLP doctrine could accept neuronal convergence in local circuits, it cannot account for perceptually-relevant MSM converging dynamics.", "\n\nHypothesis and Results {#s2}\n======================\n\nThe closed-loop perception (CLP) hypothesis {#s2-1}\n-------------------------------------------\n\nHere we propose a closed-loop scheme of perceptual acquisition, and suggest to refer to it as a possible alternative to the OLP doctrine. ", "Within the scope of this paper we describe the acquisition of information about the organism's immediate environment and do not address the interactions between perceptual acquisition and perceptual report. ", "The CLP scheme is consistent with the same data challenging OLP, primarily because it considers sensor motion as an integral part of perception rather than as a factor that needs to be corrected for. ", "We propose to continue comparing the two alternative schemes on equal grounds against accumulating data, and for aiding such a comparison we list potentially discriminative experiments towards the end of this article.", "\n\n### The CLP hypothesis is based on the following assumptions {#s2-1-1}\n\ni. Sensation is normally active. ", "Sensory organs obtain information about external objects via active interactions with the physical attributes of the object.", "\n\nii. ", "MSM-loops are fundamental units of mammalian perception. ", "These loops, as every closed loop, can approach lag-less, steady states. ", "During steady-states all changes in the loop are fully predictable and the loop functions as one unit, with no beginning or end and with no causal order; changes in one component of the loop cannot be considered as lagging or leading changes in any other component of the loop.", "\n\niii. ", "There are two basic types of MSM-loops ([Figure 4C](#fig4){ref-type=\"fig\"}, left). ", "The first uses proprioceptive (re-afferent; [Figure 4C](#fig4){ref-type=\"fig\"}, green) signals to monitor sensor state. ", "Such loops are always closed; that is, information about the sensor state is always conveyed back to the rest of the loop. ", "Importantly, these loops can also sense external features in a rough way ([@bib18]), probably via sensing significant deviations between intended and actual sensor kinematics. ", "The other type uses sensory signals to directly monitor features of external objects (ex-afferent; [Figure 4C](#fig4){ref-type=\"fig\"}, magenta). ", "The receptors of \"ex-afferent loops\", i.e., loops that contain ex-afferents, do not respond to sensor movement per-se, but to sensor interactions with external objects. ", "These loops remain open if no object exists in the external field scanned by the sensor. ", "They will be closed (i.e., meaningful neuronal activity will flow along the loop) only through interactions of the sensory organ with specific external features to which their receptors are responsive. ", "For example, whisker contacts with external objects activate a family of vibrissal mechanoreceptors that otherwise would remain silent (\\\"Touch cells\\\") ([@bib100]; [@bib169]) - the loops containing these neurons will be closed only through the interaction of whiskers with an external object present in the field of whisking ([Figure 4C](#fig4){ref-type=\"fig\"}). ", "Similarly, most photoreceptors are activated by luminance changes and thus would remain silent when the eye rotates against a uniform background. ", "Visual ex-afferent MSM-loops are thus likely to be closed only via the existence of specific optical features in the visual field.", "\n\n### CLP propositions {#s2-1-2}\n\nThe following set of propositions is consistent with our assumptions and defines a hypothesis for perception.", "\n\nI. *Perception (of external feature(s)) ≡ a process of inclusion in MSM-loop(s)*. ", "During this process the entire MSM-loop, including its muscles, receptors and neurons, and with the external feature being included, converges towards a steady-state. ", "Had the loop, with the external feature included, reached steady-state, that feature could be considered as been \"directly perceived\" by the loop, with no mediation and no delay. ", "However, as such a steady-state is an idealized state in which nothing new is perceived, MSM-loops never reach the absolute steady-states. ", "Rather, they rove dynamically between being perturbed (by external or internal processes) and approaching steady-states.", "\n\nOur hypothesis thus asserts that a given percept is associated with a given steady-state of the motor-sensory-neuronal variables space. ", "This steady-state can be referred to as the IvR of the relevant feature or object. ", "The steady-states can be of various types: a fixed point in the motor-sensory-neuronal space, a closed trajectory within this space (limit-cycle) or a chaotic attractor. ", "We name these attractors *perceptual attractors* ([@bib58]; [@bib96]; [@bib145]) since perceiving according to our hypothesis is equivalent to converging towards one such specific attractor in the relevant motor-sensory-neuronal space. ", "A crucial aspect of such an attractor is that the dynamics leading to it encompass the entire relevant MSM-loop and thus depend on the function transferring sensor motion into receptors activation; this transfer function describes the perceived object or feature via its physical interactions with sensor motion. ", "Thus, 'memories' stored in such perceptual attractors are stored in brain-world interactions, rather than in brain internal representations (see also [@bib49]; [@bib122]; [@bib135]).", "\n\nDuring the dynamic convergence process the state of the entire MSM-loop (with the external feature included) gradually approaches a steady-state. ", "This can be illustrated by the dynamics of an internal variable, termed here \"perceptual confidence\" (*C~j~*, where *j* indicates the perceived feature), whose maximal value is obtained at steady-state ([Figure 5A](#fig5){ref-type=\"fig\"}). *", "C~j~* starts to build up upon the first interaction with the object and gradually increases towards the steady-state asymptote as additional interactions occur (see thalamo-cortical correlates of such a process in [Figure 6](#fig6){ref-type=\"fig\"} of [@bib186]). ", "This convergence process allows for partial perception (e.g., binary classification) to occur even with very brief presentations of external stimuli ([@bib176]) ([Figure 5A](#fig5){ref-type=\"fig\"}, red mark).", "\n\nAccording to CLP, thus, artificially flashed stimuli initiate a perceptual process, and provide some perceptual information, but do not allow further accumulation of perceptual information as would normally occur with natural stationary objects ([Figure 5A](#fig5){ref-type=\"fig\"}). ", "CLP thus predicts that, although the percepts evoked by flashed stimuli can be robust, they would typically include significantly less information than the information actively acquired from continuously-present objects during typical perceptual epochs. ", "Within the CLP scheme, psychophysical data obtained with flashed stimuli are valuable for assessing the degree of convergence that can be reached upon a single interaction with the object, and its reportable resolution.", "\n\nWe leave the details of the generation of the confidence signal, *C~j~*, outside the scope of this article. ", "Yet, for the sake of clarity, we outline here one possible mechanism, which is based on internal models ([@bib11]; [@bib3]; [@bib94]; [@bib108]; [@bib130]; [@bib183]). ", "Internal models implement simulations of the interactions of the brain with the external world, simulations that are tightly coupled to the actual interactions. ", "A continuous comparison of the predictions of internal models with the signals resulting from the actual interactions can provide a measure of the deviation of the actual convergence process from an expected one - the closer the actual and simulated processes the higher the confidence. ", "If internal models are also continuously updated along with the developing history of the organism, as usually assumed, they can provide a close estimation of *C~j~*. ", "Internal models are often hypothesized to be implemented via cerebro-cerebellar, basal-ganglia, or thalamo-cortical loops; in principle, internal models affiliated with different MSM-loops can be implemented via different brain areas or circuits. ", "Furthermore, the internal models are likely active players in the operation of the MSM-loop and its convergence dynamics, which is consistent with reports of neuronal signals that are involved in both perceptual processing and perceptual confidence ([@bib55]).", "\n\nThe converging process is expected to end by another external perturbation, by reaching a certain level of *C~j~* (as in bounded evidence accumulation, [@bib162]), by the passage of a certain time interval or by an overriding or coordinated operation of another MSM-loop. ", "The guiding principle of brain-object disengagement, when controlled by the brain, is likely to be based on information gain -- when subsequent interactions are expected to provide relatively little relevant information, the brain would typically detach from the perceived feature or object and orient its MSM-loops towards other features or objects ([@bib39]; [@bib83]; [@bib113]; [@bib142]; [@bib159]). ", "In principle, modeling of loop disengagement can follow the modeling of decision making dynamics ([@bib67]; [@bib162]) and dynamic perception ([@bib96]), targeted to entire MSM-loops rather than to local circuits and assuming active, self-induced sampling of evidence.", "\n\nI. *Perception of an external object ≡ a coordinated process of inclusion in a collection of MSM-loops.* ", "An individual MSM-loop is assumed here to typically perceive an individual feature. ", "An 'object' is a certain set of such features, proposed here to be a set that is delineated by a coordinated convergence process. ", "As the dynamics of such multiple-loop convergence are beyond the scope of this article, we would only mention that they should depend on two major processes. ", "One is a binding process in which the loops share information - one candidate vehicle for inter-loop binding is a link established by fast frequency oscillations ([@bib59]; [@bib171]), as they allow several inter-loop iterations per each motor-sensory-motor iteration. ", "The second is a selection process ([@bib86]; [@bib149]) that determines the control over the sensory organ. ", "This selection process is not unique to 'within object' loops -- it should operate constantly, as naturally more than one MSM-loop is expected to be functional at any given time. ", "We consider two, not mutually exclusive, major schemes of control selection. ", "In one, every loop controls a sub-set of the muscle units attached to the sensory organ (e.g., [@bib170]). ", "In the other, there is a dynamic selection of the MSM-loop(s) that control sensor-object interactions at any given moment. ", "This process can be implemented by a variety of architectures, including subsumption-like ([@bib26]), hierarchical curiosity ([@bib3]; [@bib69]; [@bib70]) and others ([@bib12]). ", "The binding between the loops is expected to break at the end of the perceptual epoch, upon the disengagement of one or more of the loops from their external features.", "\n\nHierarchical dynamics of MSM-loops can be illustrated by considering a visual scanning of an object or a scene or a tactile scanning of a surface ([Figure 2](#fig2){ref-type=\"fig\"}). ", "For example, when looking at an object or a scene the eyes saccade through a sequence of fixation areas, following a trajectory that is often termed \"scanpath\" ([@bib102]; [@bib133]; [@bib179]; [@bib185]), and drift around within each fixation area for several hundreds of milliseconds ([@bib4]; [@bib157]; [@bib167]). ", "The scanpath trajectory, which moves the visual gaze from one region of interest to another, is considered in our scheme to be part of converging dynamics in one level of MSM-loops, and the local drift scanning trajectories, which acquire local visual details ([@bib52]), are considered to be parts of converging dynamics of MSM-loops at lower levels ([@bib4]). ", "Moving on from a given fixation area depends on the *C~j~s *obtained at that area by the lower loops, on the perceptual dynamics of the scanpath loop, on variables of still higher loops depending on the context, task and brain state and on changes in the external object or scene.", "\n\nI. *Perceptual time is determined by the MSM-loop's cycle time*. ", "Physical time is unlikely to have a neuronal metric, or 'yardstick,' enabling its direct measurement. ", "In contrast, a yardstick that is available for each MSM-loop is its own cycle time, which can be sensed by each of its components. ", "Durations of external events can be measured by the counts of such 'ticks' ([@bib1]). ", "In this case, the resolution of perceptual time is the loop cycle time; events occurring within one cycle are considered simultaneous ([@bib144]). ", "A possible relationship between physical and perceptual times can be described using a helix metaphor ([Figure 5B](#fig5){ref-type=\"fig\"}). ", "The helix should be considered flexible in its 'perceptual axis', being affected by the state of the perceiving loop. ", "As changes in the loop's cycle time can also be sensed by neurons ([@bib1]; [@bib10]; [@bib27]), online calibration between perceptual and physical time is possible to some extent. ", "The assessment of physical time by an MSM-loop is predicted here to depend on the loop cycle time, which of course can change according to the perceptual scenario.", "\n\n### Corollaries of the CLP hypothesis {#s2-1-3}\n\nMajor corollaries of the CLP propositions are:\n\ni. An individual MSM-loop is the elemental unit of perception, namely is both necessary and sufficient for perception (of at least one external feature) to emerge in natural conditions. ", "Thus, any reductionist study of perception must include at least one MSM-loop.", "\n\nii. ", "Nested MSM-loops can present different dynamics simultaneously. ", "A higher-order loop can perceive (i.e., include) a scene at (close to) a steady-state, while lower-order loops dynamically rove along their perturbed -- steady-state axis. ", "Thus, an environment (e.g., a room) can be perceived in (close to) a \"direct\" manner by higher loops for the entire period in which its details are sequentially scanned by lower-order loops.", "\n\niii. ", "Perception is a continuous dynamic and interactive process and not a momentary event ([@bib33]; [@bib50]); during the perceptual process, a percept gradually emerges.", "\n\niv. ", "Perception is associated with changes in brain dynamics rather than with the construction of invariant internal representations. ", "Given that sensor movements are never identical, and in fact vary significantly between perceptual epochs even when objects and contexts are constant (e.g., [@bib101]; [@bib160]), what remain invariant are the relationships between the variables of the entire MSM-loop(s)(see also [@bib122]; [@bib136]). ", "Individual neuronal variables anywhere in the brain are unlikely to remain invariant ([@bib156]).", "\n\nv. Perceptual time is determined by the dynamics of the relevant MSM-loops and thus depends on the perceived environment. ", "Also, within one loop cycle period, changes in external features and internal processes occur at different physical times but at the same perceptual time.", "\n\nvi. ", "Perception is not necessarily conscious. ", "The brain can perceive external features by loops that are not accessible, at that moment, to conscious report. ", "Thus, conscious perception is defined here as one category of perception.", "\n\n](elife-12830-fig5){#fig5}\n\nCLP mathematical framework and models {#s2-2}\n-------------------------------------\n\nOne natural choice of a mathematical framework for CLP is the framework of dynamical systems ([@bib96]; [@bib145]). ", "Within this framework each MSM-loop is modeled as a dynamical system that includes motor, sensory and neuronal variables, as well as the differential equations which describe their relations. ", "The following is a general mathematical description of such a model ([Figure 6A](#fig6){ref-type=\"fig\"}):$$\\begin{matrix}\n\\overline{s} & {= f(\\overline{m},u)} \\\\\n\\overline{\\overset{˙}{n}} & {= g(\\overline{n},\\overline{s})} \\\\\n\\overline{\\overset{˙}{m}} & {= h(\\overline{m},\\overline{n})} \\\\\n\\end{matrix}$$\n\nThe bars above the letters indicate that they represent a vector (of one variable or more). *", "g* and *h* are functions describing the intrinsic dynamics of the variables ($\\overline{n}$ and $\\overline{m}$ respectively) and their dependency on the variables in the preceding stations of the loop ($\\overline{s}$ and $\\overline{n}$ respectively). ", "The sensory variables ($\\overline{s}$) do not depend on their intrinsic dynamics in this formalization, which assumes short sensory time constants; they are determined by the motor variables ($\\overline{m}$) and the state of the environment (*u*), according to the function *f*. ", "The function *f* encapsulates the physical laws governing the sensory organ-environment interactions and the transduction of physical signals to neuronal ones.", "\n\nThe state of the system is defined as the vector containing all the variables ($\\overline{m},\\overline{s},$ $\\overline{n}~$). ", "Perception is achieved through the convergence of the system to a steady-state within this state-space. ", "The information of the perceived feature is contained in the values of the dynamic variables (the system's state) at this steady-state. ", "High-level functions such as integration of the general context or a report mechanism are not included in this model of single-feature acquisition.10.7554/eLife.12830.008Figure 6.Synthesis of closed-loop perception in a robotic setup.(**A**) A sketch of the MSM-loop model template.m, motor variable; SO, sensory organ; s, sensory variable; n, neuronal variable; h, f, g, transfer functions; u the environment dynamics. ", "The arrows depict the direction of information flow within the loop.", " (**B**) The SYCLOP robotic platform. ", "A sketch of the robot with its different components: Pan-Tilt control unit (PTCU, only the pan axis was used here) (1), DVS camera (2), and desktop computer (3). ", "The computer sends commands to the PTCU which controls the camera's rotations in the azimuth (θ) and elevation (ε) axes. ", "The DVS camera sends visual 'on' and 'off' events to the computer.", " (**C-F**) Implementation of a specific contrast perceiving CLP model (see text). (**", "C**,**D**) n~1~, the integrated difference between 'ON' and 'OFF' events, and ω, sensor angular velocity along the pan axis, (C and D, respectively) as a function of time in two different runs of the CLP algorithm, one facing a contrast of 0.9 (red) and one facing a contrast of 0.5 (green). ", "n~1~ is scaled in units of 1000 events.", " (**E**) System's trajectories in the 2D n~1~-ω state space. ", "Same data as in C and D. (**F**) Example of emergent smooth-pursuit like behavior when using a moving edge as a stimulus. ", "The trajectory of the system in the n~1~-ω plane (gray line) overlaid on a heat map where the color of each segment corresponds to the amount of time in seconds the system spent within this segment. ", "The smooth pursuit periods are represented by the white and light red squares. ", "While in a smooth pursuit, the camera was moving with a constant angular velocity -- smoothly tracking the edge.**DOI:** [http://dx.doi.org/10.7554/eLife.12830.008](10.7554/eLife.12830.008)\n\nSynthesis of CLP in a robotic setup {#s2-3}\n-----------------------------------\n\nOne way to test such CLP models and demonstrate their basic behavior is to implement them using a synthetic agent. ", "We built a simple robot for this purpose; the robot (SYCLOP: SYnthetic Closed-LOop Perceiver) includes two motors, one sensor and their bilateral connections ([Figure 6B](#fig6){ref-type=\"fig\"}). ", "This platform allows the implementation of minimal MSM-loops based models (one motor DOF and one sensor). ", "The SYCLOP uses a biomimetic camera (DVS128, iniLabs Ltd Zurich, Switzerland, [@bib112]) as its sensor; this camera, like a retina, sends signals only upon luminance intensity changes. ", "The camera is mounted on a pan-tilt control unit (PTU-46-17, DirectedPerception, CA, USA). ", "The motor-to-sensory connection is implemented by moving the camera along the pan-tilt axes while the sensory-to-motor connection is implemented by a computer that implements the model\\'s equations.", "\n\nThe SYCLOP platform was used, for example, to implement and test the behavior of a single MSM-loop model which was designed to perceive a visual contrast. ", "The stimulus, in this case, was presented on a computer screen: half of the screen was kept dark and on the other half a uniform grayscale surface was displayed. ", "The grayscale values ranged from dark to white. ", "We defined two sensory variables r~on~ and r~off~ - the rate of 'ON' events (single-pixel events in which the luminance intensity increased) and the rate of 'OFF' events (single-pixel events in which the luminance intensity decreased) - integrated over the entire camera's field. ", "The characterization of the dependency of these two sensory variables on the chosen motor variable (sensor angular velocity along the pan axis, ω) and the external feature (contrast, γ) resulted in the following equation:$$r_{on} - r_{off} = C_{1}\\gamma\\omega$$\n\nWhere C~1~ represents a constant and noise is ignored. ", "The MSM-loop model is completed by the addition of two transfer functions that define two differential equations, sensory-to-neuronal (g) and neuronal-to-motor (h):$$\\left\\{ \\begin{matrix}\n{{\\overset{˙}{n}}_{1} = g(n_{1},r_{on},r_{off}) = C_{2}(r_{on} - r_{off}) = C_{2}C_{1}\\gamma\\omega} \\\\\n \\\\\n{\\overset{˙}{w} = h(\\omega,n_{1}) = \\frac{1}{C_{3}}(\\mu(1 - C_{4}{n_{1}}^{2})C_{3}\\omega - n_{1})} \\\\\n\\end{matrix} \\right.$$\n\nWhere $n_{1}$ is defined as the (single) neuronal variable, which integrates the difference between r~on~ and r~off~ ([@bib43]), ω is the (single) motor variable defined as the sensor's angular velocity and C~2~, C~3~ and C~4~ represent constants. ", "The functions *g* and *h* were chosen such that the resulting dynamical system would be equivalent (up to constants multiplications, assuming all constants and parameters are positive) to a Van der Pol oscillator ([@bib92]). ", "This specific system was chosen due to its known dynamics: the system converges to a single closed trajectory within its 2D phase plane (i.e. a limit cycle) independently of the initial values of the variables. ", "After convergence each of the dynamic variables is a periodic function of time (e.g., [Figure 6C and D](#fig6){ref-type=\"fig\"}). ", "Clearly, other dynamical systems could fit as well.", "\n\nThis model was implemented on the SYCLOP platform with the aid of a c program running on the computer incorporated in the platform ([Figure 6B](#fig6){ref-type=\"fig\"}, item 3). ", "The program received the ON and OFF events from the DVS camera, computed the r~on~ and r~off~ sensory variables and used them to compute the values of $n_{1}$ and ω by integrating the two differential equations described above. ", "The value of ω was then sent by the program to the pan-tilt controller and modified the camera's pan velocity. ", "This implementation illustrates a simple CLP convergence process ([Figure 5](#fig5){ref-type=\"fig\"}) and shows how different precepts can be differentiated in CLP. ", "The convergence dynamics involves different dynamics of the sensory (r~on~ and r~off~), neuronal ($n_{1}$, [Figure 6C](#fig6){ref-type=\"fig\"}) and motor ($\\omega$, [Figure 6D](#fig6){ref-type=\"fig\"}) variables. ", "Yet, the variables are strongly linked, as demonstrated by the phase diagram of the neuronal and motor variables ([Figure 6E](#fig6){ref-type=\"fig\"}); these two variables quickly converge to a limit cycle (i.e., a constant closed trajectory in the phase plane). ", "Similar behavior is observed in the other phase planes (sensory-motor and sensory-neuronal, not shown). ", "Importantly, in all these phase planes the limit cycle depends on the external contrast (γ); while maintaining all loop parameters constant, a monotonic change in γ results in a corresponding monotonic change of the limit cycle (green and red trajectories in [Figure 6E](#fig6){ref-type=\"fig\"} for contrasts of 0.5 and 0.9, respectively). ", "Hence, the image's contrast can be inferred from the asymptotic behavior of the system or, in other words, the motor-sensory-neuronal trajectory that is uniquely associated with (or, equivalently, the CLP's IvR of) a given contrast can be \"retrieved\" by the presentation of that contrast to the perceiver.", "\n\nThe behavior of the SYCLOP is described here in order to demonstrate how a possible implementation of our CLP model would look like. ", "Interestingly, however, it is worth mentioning that the SYCLOP also exhibits behaviors that it was not intentionally designed to exhibit -- for example, a smooth pursuit behavior. ", "When presented with a moving image (back and forth horizontal movement of the contrast image at a constant speed) SYCLOP tended to track the image smoothly in each direction (as indicated by the \"dwelling spots\" at $\\omega \\approx 5$; and $- 5\\ deg/s$ [Figure 6F](#fig6){ref-type=\"fig\"}).", "\n\nDiscussion {#s3}\n==========\n\nSummary of the CLP hypothesis {#s3-1}\n-----------------------------\n\nCLP suggests that perception of the external environment is a process in which the brain temporarily '*grasps*' external objects and incorporates them in its MSM-loops. ", "Such objects become virtual components of the relevant loops, hardly distinguishable, as long as they are perceived, from other components of the loop such as muscles, receptors and neurons. ", "What primarily distinguishes external objects from body parts are inclusion duration and state; short and transient inclusions mark external objects while long and steady inclusions mark body parts (see also [@bib173]). ", "Interestingly, the perceptual dynamics suggested by this hypothesis reconciles a conflict between objective scientific observations and the subjective everyday experience of perceiving objects with no mediation (see also *A philosophical angle* below). ", "Everyday perception of a given external object, CLP suggests, is the dynamic process of inclusion of its features in MSM-loops. ", "This process starts with a perturbation, internal or external, and gradually converges towards a complete inclusion - approaching, although never reaching, a state of \"direct\" perception. ", "A laboratory-induced flashed stimulus, according to this model, probes the initiation of a perceptual process, whereas dreaming and imagining evoke internal components of the process.", "\n\nContrasting OLP and CLP -- discriminatory testable predictions {#s3-2}\n--------------------------------------------------------------\n\nWe consider here all versions of OLP, i.e., all versions of hypotheses in which perception does not depend on the integrity of the MSM-loop and its closed-loop dynamics within individual perceptual epochs. ", "We consider here two major OLP classes: in one, sensory OLP (sOLP), the movement of the sensory organ is not an essential component of perception, and in the other, motor-sensory OLP (msOLP), it is ([Figure 7](#fig7){ref-type=\"fig\"}). ", "sOLP thus assumes that IvRs are confined to the brain (i.e., they are specific NRs) and can be fully retrieved by sensory activations alone when the sensor is passive. ", "msOLP, in contrast, postulates that IvRs are not confined to the brain, and can form the basis for perception only if they include the relevant MS-contingencies ([Figure 7](#fig7){ref-type=\"fig\"}). ", "According to msOLP, IvRs cannot be retrieved with passive sensory organs. ", "Importantly, however, msOLP does not assume a motor-sensory-motor loop; that is, its scheme includes a motor-to-sensory arc but not a sensory-to-motor arc ([Figure 7](#fig7){ref-type=\"fig\"}). ", "Hence, with msOLP, movements of the sensory organ are predetermined for each perceptual epoch and are not affected by the ongoing sensory input during that epoch. ", "In contrast to the OLP hypotheses, using the same representational terminology, CLP postulates that IvRs can form the basis for perception only if they contain the dynamics and state of the entire MSM-loop including the relevant features of the object ([Figure 7](#fig7){ref-type=\"fig\"}). ", "Thus, the minimal set of variables that must be included in the IvR of each object, or feature, is different for each hypothesis ([Figure 7](#fig7){ref-type=\"fig\"}, bluish ellipses): internal-only sensory variables in sOLP, internal sensory variables and MS-contingencies in msOLP and the entire perceiving loop in CLP.10.7554/eLife.12830.009Figure 7.Functional connectivity and essential elements of perceptual schemes.", "The essential elements in each scheme are indicated by solid curves and blue titles.", "MSM, motor-sensory-motor; MS, motor-sensory; S, sensory; NR, neuronal representation; green curves, re-afferent related pathways; magenta curves, ex-afferent related pathways. ", "Note that re-afferent related pathways can form closed-loops with their sensory organs also in OLP schemes (dashed curves). ", "Arrows indicate optional whisker (black) or object (magenta) movement; solid arrows indicate movements that are essential for perception; in the sOLP scheme none of the movements is essential in itself, but it is essential that at least one of them will occur in order to activate the receptors. ", "Appropriate experimental paradigms are indicated by green titles; CLP and msOLP schemes can be studied only via active sensing paradigms.", "The minimal sets for invariant representations (IvRs) of external features, i.e., the components that must be included in any IvR according to each perceptual scheme, are marked by the bluish ellipses. ", "sOLP: internal, sensory only NRs. ", "msOLP: sensory NRs + motor-object-sensory contingencies. ", "CLP: entire motor-object-sensory-motor loops.**DOI:** [http://dx.doi.org/10.7554/eLife.12830.009](10.7554/eLife.12830.009)\n\nPerhaps the first question that comes to mind when considering msOLP and CLP is whether paralyzed subjects perceive stationary (i.e., not flashing or moving) objects similarly to non-paralyzed subjects. ", "If they do - here go the msOLP and CLP hypotheses. ", "Unfortunately, however, this is not a trivial test. ", "Note that the paralysis must include the relevant sensory organ and the object must be entirely stationary. ", "In the case of touch it should be evident that while contacts may be detectable, no object perception is possible with paralyzed hands -- we are not aware of any study contradicting this conjecture. ", "In contrast, our intuition regarding hearing is that action is not a fundamental requirement for hearing. ", "Yet, two important points are relevant here. ", "First, our intuition may be misled by the fact that we cannot be aware of motor activation of the outer hair cells and the muscles of the middle ear -- we are not aware of perceptual experiments in which these activations were blocked, or measured. ", "Second, no stationary object exists in audition. ", "Acoustic waves are always dynamic and always activate the inner hair cells. ", "This makes auditory sensation less dependent on self-motion, a fact that indeed may put audition in a motor-sensory regime that is distinct from those of touch and vision.", "\n\nRegarding vision, we are aware of only one study analysing visual perception in a congenital ophthalmoplegic patient, a patient who had no eye movements since birth; in this case, the patient developed a pattern of head movements that resembled that of natural eye movements, only on a slower rhythm ([@bib66]). ", "This adaptation clearly indicates the need in active sensation for visual perception, at least in that patient. ", "Natural employment of active vision is indicated by the \\\"weird, confusing and indescribable\\\" forms of perceptions reported during acute partial paralysis of the ocular muscles ([@bib168]). ", "These data are certainly not consistent with sOLP. ", "Yet, these data, as well as part of the OLP-challenging data presented above, may still be consistent with msOLP. ", "The distinction between msOLP and CLP hypotheses is thus more demanding, and requires specifically designed experiments.", "\n\nWe describe here examples of potentially discriminative experiments in three categories.", "\n\n1. ", " *The motor-to-sensory arc.* ", "The following manipulations are predicted to impair perception according to msOLP or CLP but not according to sOLP: (i) Paralysis of the sensory organ while keeping the sensory flow unimpaired. (", "ii) Replacing continuous presentation of an object with a series of one or more brief presentations (flashes) while keeping the total stimulus time and/or energy equal.", "\n\n2. ", " *The sensory-to-motor arc.* ", "The following manipulations are predicted to impair perception according to CLP but not according to sOLP or msOLP: (i) Limiting or forcing sensor movement trajectory via instructions in humans or interventions in rodents. ", "For example, asking humans to scan a scene according to verbal instructions or by pursuing a target, or moving the sensory organ according to a trajectory that was recorded in a previous active session. (", "ii) Allowing active touch but with the motion of one hand determining the sensory flow to the other hand. (", "iii) Perturbing neuronal specific sensory-to-motor pathways, such as those connecting the sensory cortex to the motor cortex ([@bib35]), those connecting sensory cortex to motor nuclei (typically via layer 5B neurons), or those connecting the thalamus to motor (cortical and sub-cortical) stations ([@bib165]) ([Figure 4A](#fig4){ref-type=\"fig\"}). ", "The exact design should depend on available genetic markers and the testing of these predictions should be conducted in a balanced way, using appropriate sham perturbations. ", "The following observations are predicted by CLP but not by sOLP or msOLP during natural perception: (iv) The motion trajectories of the sensory organ will differ for different object features (expected from affective sensory-to-motor connections). (", "v) The motion of the sensory organ will depend on the concurrent sensory input; for example, when a rat perceives an object's shape or texture, the movement trajectory of its whiskers will depend on the sequence of curvatures and stick-slip events preceding it within the same perceptual epoch. ", "Similarly, the motion trajectory of the eye will depend on the retinal activations preceding it within the same perceptual epoch.", "\n\n3. ", " *Motor-sensory-motor convergence.* ", "The following observations are predicted by CLP but not by sOLP or msOLP: (i) The movement trajectory of the sensory organ will show convergence dynamics, i.e., gradual approach to a steady-state pattern, during natural perception. (", "ii) Convergence will be to different steady-state patterns while perceiving different features or values. (", "iii) Specific steady-state patterns will be associated with specific perceptual reports. (", "iv) Convergence dynamics can predict perceptual report timing and/or error. (", "v) A virtual object can be perceived when sensory neuronal activity is manipulated to mimic the activity expected by the movement of the sensory organ and the presence of a real object ([@bib134]); with reliable mimicry a convergence process should follow. (", "vi) CLP predicts that the lag between the actual and perceived times of an external transition (\"perceptual lag\") should decrease along the process of perceptual convergence, when in steady-state no lag is expected. ", "It has been previously shown that perceptual lags of the onset of transient stimuli are longer than those of continuously-present ones ([@bib131]). ", "CLP thus predicts that with similar experimental protocols (e.g., a rotating arm is shown continuously and a dot is transiently displayed (flashed) for various durations at various positions traversed by the rotating arm), when looking at the offset of the transient stimulus rather than its onset, the temporal perceptual lag of the offset will decrease with increasing transient durations. (", "vii) With a motion-induced-blindness (MIB) protocol, in which stationary targets are surrounded by moving background dots, the targets 'disappear' occasionally ([@bib22]). ", "In one possible implementation of CLP the visual system would control the velocity of retinal image slip, and maintain it within a certain working range, instead of directly controlling drift velocity. ", "This would be achieved by modifying drift speed in a manner that is inversely proportional to the speed of the retinal slip. ", "When the retinal slip is dominated by external motion, such as in MIB, eye drift speed would be reduced significantly. ", "When the drift speed will be reduced below a certain level, retinal receptors at corresponding eccentricities may not receive sufficient luminance changes to be activated by the stationary parts of the image. ", "Thus, in MIB conditions in which the drift speed is inversely correlated with the dots' speed, target disappearance is expected to be preceded by a reduction of the drift speed below a certain threshold; threshold level should depend on the eccentricity of the disappearing target.", "\n\nIdeally, the comparison of the behaviors predicted by CLP and OLP, related to the inter-dependencies of motor, object, sensory and report variables, should be done in natural conditions. ", "Practically, as the scientific method enforces reductionist steps, it is important to notice what reductions are allowed, as behavioral predictions of CLP or msOLP, regarding natural perception, cannot be tested in paradigms in which their basic assumptions are \"reduced out.\" ", "Clearly, if eye or whisker motion is prevented, critical predictions of CLP or msOLP cannot be tested. ", "Experiments in which eye or whisker motion is allowed but head motion is restrained have a limited discriminative power - conclusions in these cases should take into account the possibility that head-restrained animals develop unique compensatory active strategies which may not be indicative for the head-free condition. ", "When MSM-loops are not given enough time to converge, as is the case with passive sensing (e.g., visual flashes) for example, discrimination between CLP and OLP is usually not possible (as both predict partial perception, [Figure 5](#fig5){ref-type=\"fig\"}).", "\n\nA philosophical angle {#s3-3}\n---------------------\n\nFor at least four centuries the philosophical community, and during the last century also the neuroscience community, have been puzzled by the contrast between objective scientific observations that relate to perception and the everyday subjective experience of perception. ", "What feels direct and immediate to every human perceiver appears indirect and mediated when physical constrains are taken into account ([@bib37]; [@bib96]; [@bib145]; [@bib174]). ", "Our CLP hypothesis proposes a reconciliation of objective scientific observations and subjective everyday experience via closed-loop dynamics between the perceiver and the perceived. ", "Such closed-loops converge gradually to a state in which the perceiver and the perceived are inseparable. ", "The idea is that, although the loops never actually reach an ideal steady-state, they get closer and closer to these states during a perceptual epoch and typically quit the convergence process when the distance from a steady state is barely sensible. ", "Being close enough to the steady state can give rise to the feeling of direct and immediate perception.", "\n\nIn practical terms, this article proposes to open the discussion about the phenomenology and mechanisms of perception, and in particular to confront open- and closed-loop schemes. ", "We hope that the set of predictions listed here will serve as a starting point for informative experimental confrontation.", "\n\nFunding Information\n===================\n\nThis paper was supported by the following grants:\n\n- http://dx.doi.org/10.13039/501100003977Israel Science Foundation 1127/14 to Ehud Ahissar.", "\n\n- http://dx.doi.org/10.13039/501100001742United States-Israel Binational Science Foundation 2011432 to Ehud Ahissar.", "\n\n- The NSF-BSF Brain Research EAGER program 2014906 to Ehud Ahissar.", "\n\n- The Minerva Foundation funded by the Federal German Ministry for Education and Rsearch to Ehud Ahissar.", "\n\n- The Israel Ministry of Defense to Ehud Ahissar.", "\n\nWe thank Merav Ahissar, Amos Arieli, Asher Cohen, Coralie Ebert, Ram Frost, Andrei Gorea, Liron Gruber, Ealan Henis, Rafi Malach, Guy Nelinger, Tess Oram, Kevin O'Regan, Dov Sagi and Avi Saig for helpful comments and discussions and Michal Ahissar for linguistic editing. ", "This work was supported by the Israel Science Foundation (grant \\#1127/14), the United States-Israel Bi-national Science Foundation (grant \\#2011432), the NSF-BSF Brain Research EAGER program, (grant \\#2014906), Israel Ministry of Defense and the Minerva Foundation funded by the Federal German Ministry for Education and Research. ", "EA holds the Helen Diller Family Chair in Neurobiology.", "\n\nAdditional information {#s4}\n======================\n\nThe authors declare that no competing interests exist.", "\n\nEAh, Contributed to all aspects of this work.", "\n\nEAs, Contributed to all aspects of this work.", "\n\n10.7554/eLife.12830.010\n\nDecision letter\n\nKleinfeld\n\nDavid\n\nReviewing editor\n\nUniversity of California, San Diego\n\n,\n\nUnited States\n\nIn the interests of transparency, eLife includes the editorial decision letter and accompanying author responses. ", "A lightly edited version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included.", "\n\nThank you for submitting your work entitled \\\"Perception as a closed-loop convergence process\\\" for consideration by *eLife*. ", "Your article has been reviewed by 3 peer reviewers -- including the Reviewing editor, David Kleinfeld --, and the evaluation has been overseen by Eve Marder as the Senior Editor. ", "The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission. ", "While there was considerable interest and enthusiasm for this work, the reviewers also had some substantive critiques that will require attention.", "\n\nSummary:\n\nThe basic premise of this manuscript is that \\\"...passive paradigms cannot reveal how sensory information is actually processed during active perception \\[...\\] For that, a unified analysis of the motor and sensory components engaging brains with their environments is required.\\\" Toward addressing this premise, \\\"The current paper describes an attempt to bring the motor variables back to theoretical modeling of perception, by proposing a motor-sensory closed-loop scheme for the perception of the external environment.\\\" The crux proposal is that internal representation may be a time-varying signal that reaches a steady state behavior perhaps, if only because \\\"Mammalian sensory organs usually acquire information via movements...\\\".", "\n\nThis is a \\\"Viewpoint\\\" with some original material as opposed to an \\\"Original Article\\\" per se. ", "Yet it is timely and important. ", "One would think that most rational neuroscientists would agree. ", "Yet much of mammalian systems neuroscience went through a dark period of working with primarily anesthetized animals or highly constrained animals. ", "This was particularly egregious in vision, where one could argue that a generation of neuroscientists attended to second-order effects to Hubel and Wiesel receptive fields while a basic role of visual areas for motion control went undiscovered until a few years back; see, e.g., Carandini (Nat Neurosci 2013), Bonhoeffer (Neuron 2012), and Stryker (Neuron 2010). ", "The current work reviews this dark period, although the authors should note that some areas, including the study of the VOR and the OKR, the study of hippocampal function during learning and memory (2015 Nobel prize), and clearly the study of motor control for locomotion and manipulation, did not fall into this trap. ", "The pioneering gating experiments of Chapin and Woodward (Exp Neurol 1982), which show how motor output gates sensation, deserve special mention as counterpoint to the authors\\' sarcasm, i.e., \\\"The (re) discovery that mammalian sensation is active...\\\".", "\n\nThe authors propose that the internal representation of a stimulus depends on motor output. ", "Thus, unless the animal acts on the information, one does not know if the representation, presumably the pattern of neurons spiking in different brain areas, is a complete or only a partial representation. ", "Further, the partial representation could be too incomplete for action to occur. ", "I think we all would agree. ", "Many highly cited studies on internal representation view a change in motor output in response to a change in internal representation -- which could be the act of pushing a lever to declare a sensorimotor process is terminating- as a gold standard. ", "There is a fair literature on this -- including the pioneering ICMS experiments of Newsome and colleagues (Nature 1990, J Neurophysiol 1992, Neuron 2014). ", "In the vibrissa literature, which appears prominently in this manuscript, there are the reafferent coding studies of Kleinfeld and colleagues (J Neurophysiol 1997; Neuron 2011). ", "The authors go through many arguments to describe why the notion of a motor-free, or open loop representation, will fail. ", "A key argument involves the time it takes -- presumably cycles of recurrence -- to form an internal representation. ", "This is reminiscent of the argument by Martin (TiNS 1988) on the formation of visual representation as a recurrent of feedback, which was written as a challenge to the feed forward processing implicit in the wiring maps of Feldman and Van Essen.", "\n\nEssential revisions:\n\nThe full reports of all reviewers are appended. ", "All reviewers found merit with the timeliness and importance of the work but all reviewers also found faults that require attention. ", "It is essential to address these issues:\n\n1\\) Draw a clear distinction about dynamics that spread beyond sensory areas to involve decision making and motor output, each of which may contain local feedback loops, as opposed to brain-wide feedback dynamics per se.", "\n\n2\\) Provide clearer and more thoughtful experiments to distinguish between the manifestation of open loop and closed loop representation of the sensory world -- at least an object!", "\n\n3\\) Properly define and clarify the output from the model / robot ([Figure 7](#fig7){ref-type=\"fig\"}).", "\n\nSpecific points:\n\nReviewer \\# 1 (annotated by BRE David Kleinfeld):\n\n1\\) In their paper, \"Perception as a closed-loop convergence process\", Ahissar and Assa conceptualize perception as an interactive dynamical process. ", "Specifically the authors propose that perception is a convergence process that involves about 4 repeated sensory-interactions through which an object percept is dynamically generated. ", "Further the authors emphasize the constitutive active nature of sensing and stress the presence of loops rather than of a feed-forward architecture in the brain.", "\n\nDK: This summary is telling. ", "The reviewer focuses solely on dynamics per se rather than on motor output and control as an integral part of sensation. ", "This implies that the larger message from Ahissar and Assa may have failed to get through.", "\n\n2\\) The paper is a strange mix out high-level assumptions and details of rodent active touch. ", "To me these two different levels never fully merged, i.e. it did not become clear to me, where in the rodent brain the dynamical process happens that forms the perceptual object.", "\n\nDK: In fact, there is published evidence that all of vibrissa L5b cells (in both sensory and motor cortices) have a role in motor control; this goes back to work by Glickman. ", "So this is a clear place to note the origin of a perception and one that is, in terms of hypothesis testing, (just barely) accessible with Ca^2+^-imaging.", "\n\n3\\) The predictions that differentiate the OpenLoop and the ClosedLoop model of perception are neither very strong nor very clear. ", "More work is required here.", "\n\nDK: All reviewers agree on this point. ", "The section on predictions is a crux aspect of the paper that requires significant improvement, as the key is to entice experimentalists to try to falsify or verify the ideas inherent in representation through motor control. ", "This will take thought and time and still may not work out!", "\n\n4\\) I have major doubts that the authors are right. ", "It is obvious from the literature that passive, or briefly flashed stimulus presentations, which do not allow active sensing, still evoke robust percepts. ", "I would predict that we will find also a lot more single touch percepts in the active touch system, once we look harder in situations, where animals sensing under time pressure.", "\n\nDK: I think the confusion results from a mixing of loops for perception, which are hypothesized to include sensory and motor function, and local sensory loops solely for reverberation. ", "The latter are well known to occur with sensory processes, and the most dramatic case is the \\> 20 s of reverberatory signal in AIT cortex during the delay period of a match to sample task (Fuster & Alexander 1971 Science). ", "Please clarify your text.", "\n\nReviewer \\# 2 (annotated by BRE David Kleinfeld):\n\n1\\) The distinction between \\\"neural representation\\\" and \\\"internal representation\\\" seems unnecessary -- and ill-defined.", "\n\nDK: This should be fixed.", "\n\n2\\) Although I think I understand the intuition behind referring to a sensory-motor loop as \\\"motor-sensory-motor loop\\\", this seems unnecessary; \\\"loop\\\" already implies circularity.", "\n\nDK: I suspect that this was done to separate loops that are local and lie just in solely sensory or solely regions from brain-wide loops that span the nervous system. ", "As noted above, this needs to be clarified.", "\n\n3\\) It is unclear to me what the distinction between msOLP and CLP is?", "\n\nDK: Please either drop or clarify this issue. ", "It should be a straight forward fix.", "\n\n4\\) At times the argument is speculative and unnecessarily strong -- to the point of likely already being wrong? ", "E.g., in the subsection \"Contrasting OLP and CLP -- discriminatory testable predictions\" \\\"the question is \\[...\\] whether paralyzed subjects perceive. ", "If they do -- here goes the closed-loop hypothesis\\\". ", "We clearly perceive by hearing without moving. ", "I will grant the authors that it is still unclear what the function of outer hair cells is -- but as far as we know, this is a counter example to their hypothesis?", "\n\nDK: please provide a more graded presentation. ", "The manuscript started out this way, in that open loop representations were a primarily seen as a subset of the larger internal representation.", "\n\n5\\) The \\\"mathematical model\\\" and the robotic setup seem to add little to the manuscript. ", "The robotic system example only proves that an oscillatory system can be driven to different attractors with different inputs?", "\n\nDK: All reviewers commented on the opaque nature of this presentation. ", "It needs to be rewritten. ", "I do not see a fundamental flaw.", "\n\n6\\) The testable predictions part is a great idea -- but as formulated they are not very helpful. ", "A specific motor output can be thought of as the correlate of a dynamic neural attractor instead of an \\\"instantaneous state\\\".", "\n\nDK: All reviewers agree. ", "The section on predictions is a crux aspect of the paper that requires significant improvement, as the key is to entice experimentalists to try to falsify or verify the ideas inherent in representation through motor control. ", "This will take thought and time and still may not work out!", "\n\nReviewer \\# 3 (RE Kleinfeld):\n\n1\\) The statement that \\\"\\[motor-sensory-motor\\]-loops are fundamental units of mammalian perception\\\" cannot be right. ", "These loops can support activity and thus a motor-sensory-motor representation, but anatomical loops per se is not a representation.", "\n\n2\\) The discussion of two types of loops notes that the \\\"first uses proprioceptive signals \\[...\\] The other type uses sensory signals to monitor features of external objects...\\\". ", "In fact, this extends confusion in the literature. ", "Signals from muscle spindles, usually regarded as proprioceptive in the sense that are used only for motor feedback, are also sensory. ", "See the pioneering work by Hsiao (2006 J Neurophysiol) on discriminating the size of objects based on muscle stretch.", "\n\n3\\) The discussion of reading out the convergence, say, to a limit cycle is muddled. ", "Are convergence cycles related to the accumulation of evidence? ", "If so, it is an interesting idea. ", "But the authors need to describe a mechanism to link dynamics with estimated of confidence. ", "They end with \\\"although the loops never reach the ultimate steady-states, they typically quit the convergence process when the distance from that state is no more sensible\\\". ", "This seems too soft a statement for a serious article.", "\n\n4\\) The authors discuss the need to share information between limit cycles (perceptual loops). ", "They are a bit glib in listing possibilities as the locking and unlocking of activity in different loops is essential to their scheme of hierarchical loops. ", "Coherence between different loops is tricky -- if the interactions cause a pair of loops to phase-lock, then it is not clear how they separate and dephase. ", "The authors have neglected issues of noise, which is a mechanism to break locking and to dephase.", "\n\n5\\) The equations for the SYCLOP model need to be explained. ", "As it stands, this section will lose almost all readers. ", "None of the symbols are explained. ", "I would also start by saying that the simplest model of a loop uses Van der Pol relaxation dynamics. ", "On the one hand it is a bit of a let-down to have the work condensed to a single oscillator that came out of the days of vacuum triodes. ", "On the other hand, the presentation of the realization with the Van der Pol oscillator ([Figure 7](#fig7){ref-type=\"fig\"}) is very condensed. ", "I think [Figure 7](#fig7){ref-type=\"fig\"} needs to be considerably unpacked. ", "Panels A, B, and example dynamics like panel H can be one figure, while panels D-G and I could be a second figure. ", "Also, define \\\"k-events\\\", label the ordinates of panels H and I.\n\n6\\) The authors end with a number of proposed experiments to address the claims of closed versus open loop object representation. ", "One involves the detection of the phase of contact in the whisking cycle, yet is followed by the claim that \\\"...predictions of CLP and OLP can be distinguished only in natural perceiving conditions.\\\" This appears to obviate the use of head-fixed animals, an excellent preparation for combined behavior and electrophysiology. ", "Why is head fixing bad for whisking? ", "It seems that perception must often work under partial constraints.", "\n\n\\[Editors\\' note: further revisions were requested prior to acceptance, as described below.\\]\n\nThank you for resubmitting your work entitled \\\"Perception as a closed-loop convergence process\\\" for further consideration at *eLife*. ", "Your revised article has been favorably evaluated by Eve Marder (Senior editor), Reviewing editor David Kleinfeld, and one reviewer.", "\n\nThe manuscript has been improved but there are a few remaining issues raised by the reviewer and verified by Reviewing editor Kleinfeld. ", "In order to complete this odyssey, please address these queries.", "\n\n1\\) In the subsection \"Synthesis of CLP in a robotic setup\". ", "Please expand on the solution of the model, a van der Pol oscillator, to make it transparent to the \\\"typical\\\" biologically trained reader. ", "The statement \\\"The implementation of these equations using the SYCLOP platform\\\" needs to be detailed -- even in the appendix -- so a reader can duplicate your calculation.", "\n\n2\\) In the subsection \"Perception can be masked \"backwardly\"\" -- \\\"If perception could be reduced to a sequence of pure open loop processes backward masking should not occur.\\\" One might think that any slow integration step in a feed-forward processing system would explain backward masking through injection of a signal within the integration time. ", "Perhaps your statement could be better explained as dependent on a system with only \\\"fast\\\" integration.", "\n\n3\\) In the subsection \"Perception can be masked \"backwardly\"\" -- \\\"Perceptual masking thus challenges the validity of the \\'virtual knife\\' reduction and the ability to reconstruct perception based on experiments with flashed stimuli only.\\\" The argument leading up to this is not clear.", "\n\nFinally, please reread the manuscript in a \\\"copy-edit\\\" manner to improve the grammar and correct any number of typos in punctuation.", "\n\n10.7554/eLife.12830.011\n\nAuthor response\n\nThe basic premise of this manuscript is that \\\"...passive paradigms cannot reveal how sensory information is actually processed during active perception \\[...\\] For that, a unified analysis of the motor and sensory components engaging brains with their environments is required.\\\" Toward addressing this premise, \\\"The current paper describes an attempt to bring the motor variables back to theoretical modeling of perception, by proposing a motor-sensory closed-loop scheme for the perception of the external environment.\\\" The crux proposal is that internal representation may be a time-varying signal that reaches a steady state behavior perhaps, if only because \\\"Mammalian sensory organs usually acquire information via movements...\\\".", "\n\nThis is a \\\"Viewpoint\\\" with some original material as opposed to an \\\"Original Article\\\" per se. ", "Yet it is timely and important. ", "One would think that most rational neuroscientists would agree. ", "Yet much of mammalian systems neuroscience went through a dark period of working with primarily anesthetized animals or highly constrained animals. ", "This was particularly egregious in vision, where one could argue that a generation of neuroscientists attended to second-order effects to Hubel and Wiesel receptive fields while a basic role of visual areas for motion control went undiscovered until a few years back; see, e.g., Carandini (Nat Neurosci 2013), Bonhoeffer (Neuron 2012), and Stryker (Neuron 2010). ", "The current work reviews this dark period, although the authors should note that some areas, including the study of the VOR and the OKR, the study of hippocampal function during learning and memory (2015 Nobel prize), and clearly the study of motor control for locomotion and manipulation, did not fall into this trap. ", "The pioneering gating experiments of Chapin and Woodward (Exp Neurol 1982), which show how motor output gates sensation, deserve special mention as counterpoint to the authors\\' sarcasm, i.e., \\\"The (re) discovery that mammalian sensation is active...\\\".", "\n\nThank you for this concise summary. ", "We would only comment here that our crux proposal is that the perception of external objects is a dynamical process encompassing loops that integrate the organism and its environment and converging towards organism-environment steady-states. ", "We now emphasize this in the Abstract.", "\n\nThe Introduction was revised to cover (and cite) the studies mentioned above and the sarcastic term was removed (subsection \"Sensation is normally active\", third paragraph).", "\n\nThe authors propose that the internal representation of a stimulus depends on motor output. ", "Thus, unless the animal acts on the information, one does not know if the representation, presumably the pattern of neurons spiking in different brain areas, is a complete or only a partial representation. ", "Further, the partial representation could be too incomplete for action to occur. ", "I think we all would agree. ", "Many highly cited studies on internal representation view a change in motor output in response to a change in internal representation -- which could be the act of pushing a lever to declare a sensorimotor process is terminating- as a gold standard. ", "There is a fair literature on this -- including the pioneering ICMS experiments of Newsome and colleagues (Nature 1990, J Neurophysiol 1992, Neuron 2014). ", "In the vibrissa literature, which appears prominently in this manuscript, there are the reafferent coding studies of Kleinfeld and colleagues (J Neurophysiol 1997; Neuron 2011). ", "The authors go through many arguments to describe why the notion of a motor-free, or open loop representation, will fail. ", "A key argument involves the time it takes -- presumably cycles of recurrence -- to form an internal representation. ", "This is reminiscent of the argument by Martin (TiNS 1988) on the formation of visual representation as a recurrent of feedback, which was written as a challenge to the feed forward processing implicit in the wiring maps of Feldman and Van Essen.", "\n\nThank you for these valuable points. ", "We have modified the text to refer to these points and cite the relevant papers -- ICMS and confidence (subsection \"CLP propositions\"), reafference and efference-copy signals (subsection \"Perceptual systems are organized as motor-sensory-motor (MSM) loops\") and feedforward versus recurrent processing (subsection \"The open loop perception (OLP) doctrine\").", "\n\nEssential revisions:\n\nThe full reports of all reviewers are appended. ", "All reviewers found merit with the timeliness and importance of the work but all reviewers also found faults that require attention. ", "It is essential to address these issues:\n\n1\\) Draw a clear distinction about dynamics that spread beyond sensory areas to involve decision making and motor output, each of which may contain local feedback loops, as opposed to brain-wide feedback dynamics per se.", "\n\nThis distinction is now clearer. ", "The common dynamics of all components of the relevant MSM-loop(s) is now clearly stated in the Abstract, subsection \"CLP propositions\", I, the legend of [Figure 5](#fig5){ref-type=\"fig\"} and the predictions section. ", "The distinction from dynamics of local circuits, as in typical models of decision making, was also added (subsections \"The open loop perception (OLP) doctrine\" and \"CLP propositions\", I).", "\n\n2\\) Provide clearer and more thoughtful experiments to distinguish between the manifestation of open loop and closed loop representation of the sensory world -- at least an object!", "\n\nThe predictions section was substantially revised. ", "We have categorized the predictions in three groups, focusing on motor-to-sensory, sensory-to-motor, and convergence effects. ", "We have also clarified all predictions, made them more explicit, added examples, and added points raised by the reviewers. ", "In order to emphasize the differences between the predictions of the different schemes we are referring now to the invariant representation (IvR), instead of internal representation (IR), as the representational comparative variable throughout the article. ", "We thank the reviewers for these comments, which significantly helped clarifying our thoughts.", "\n\n3\\) Properly define and clarify the output from the model / robot ([Figure 7](#fig7){ref-type=\"fig\"}).", "\n\nThe output of the model, as demonstrated by the robot, is now clarified and explained. ", "We modified the description substantially by simplifying the figure ([Figure 7](#fig7){ref-type=\"fig\"}, now [Figure 6](#fig6){ref-type=\"fig\"}) and extending the text (see below).", "\n\nSpecific points:\n\nReviewer \\# 1 (annotated by BRE David Kleinfeld):\n\n1\\) In their paper, \"Perception as a closed-loop convergence process\", Ahissar and Assa conceptualize perception as an interactive dynamical process. ", "Specifically the authors propose that perception is a convergence process that involves about 4 repeated sensory-interactions through which an object percept is dynamically generated. ", "Further the authors emphasize the constitutive active nature of sensing and stress the presence of loops rather than of a feed-forward architecture in the brain.", "\n\nDK: This summary is telling. ", "The reviewer focuses solely on dynamics per se rather than on motor output and control as an integral part of sensation. ", "This implies that the larger message from Ahissar and Assa may have failed to get through.", "\n\nWe have modified the Abstract to sharpen the crucial suggestions of our hypothesis and make them more explicit, and in particular the crucial role of organism-environment loops. ", "Also, our modifications throughout the paper were done with this issue in mind.", "\n\n2\\) The paper is a strange mix out high-level assumptions and details of rodent active touch. ", "To me these two different levels never fully merged, i.e. it did not become clear to me, where in the rodent brain the dynamical process happens that forms the perceptual object.", "\n\nDK: In fact, there is published evidence that all of vibrissa L5b cells (in both sensory and motor cortices) have a role in motor control; this goes back to work by Glickman. ", "So this is a clear place to note the origin of a perception and one that is, in terms of hypothesis testing, (just barely) accessible with Ca^2+^-imaging.", "\n\nWe probably failed to state it clearly. ", "The dynamical process that forms the perceived object is occurring along the entire MSM-loop(s). ", "Thus, in principle there is no single brain site that preferably represents the object. ", "Still, the comment about L5b makes sense -- we now added it to the list of potential tests for the dependency of perception on S-M coupling (subsection \"II. ", "The sensory-to-motor arc\"). ", "We also make clearer statements about the whole-loop representation in the Abstract and along the paper.", "\n\n3\\) The predictions that differentiate the OpenLoop and the ClosedLoop model of perception are neither very strong nor very clear. ", "More work is required here.", "\n\nDK: All reviewers agree on this point. ", "The section on predictions is a crux aspect of the paper that requires significant improvement, as the key is to entice experimentalists to try to falsify or verify the ideas inherent in representation through motor control. ", "This will take thought and time and still may not work out!", "\n\nThe predictions section was substantially revised. ", "Please see our detailed description in reply to Essential revisions ([@bib136]) above.", "\n\n4\\) I have major doubts that the authors are right. ", "It is obvious from the literature that passive, or briefly flashed stimulus presentations, which do not allow active sensing, still evoke robust percepts. ", "I would predict that we will find also a lot more single touch percepts in the active touch system, once we look harder in situations, where animals sensing under time pressure.", "\n\nDK: I think the confusion results from a mixing of loops for perception, which are hypothesized to include sensory and motor function, and local sensory loops solely for reverberation. ", "The latter are well known to occur with sensory processes, and the most dramatic case is the \\> 20 s of reverberatory signal in AIT cortex during the delay period of a match to sample task (Fuster & Alexander 1971 Science). ", "Please clarify your text.", "\n\nWe agree with the reviewer that briefly flashed stimuli evoke robust percepts. ", "However, we argue that this observation is consistent with both OLP and CLP schemes. ", "According to CLP such artificial stimuli initiate the perceptual process, which indeed normally would continue longer and include motor-sensory dynamics but which also can gain information from this initial step ([Figure 5](#fig5){ref-type=\"fig\"} and associated text). ", "What precludes discrimination between OLP and CLP based on flashed stimuli is that although the percepts evoked by flashed stimuli can be robust, they most likely include significantly less information than the information actively acquired from stationary objects. ", "Subjects indeed can differentiate between flashed cars and houses, or animals and humans, but probably cannot perceive the details of the images. ", "We have added a paragraph explaining this in subsection \"I. Perception (of external feature(s)) ≡ a process of inclusion in MSM-loop(s)\", fourth paragraph.", "\n\nWe use the terms \"most likely\" and \"probably\" because we are not aware of a systematic quantitative comparison of perceptual accuracies of complex images when they are flashed versus being stationary. ", "The first set of predictions in our list includes such a comparison (prediction I-ii; we now added the word \"flashes\" to make it more explicit) -- there we suggest to equalize the total time or energy of the stimuli and thus to use a series of flashes rather than a single one.", "\n\nReviewer \\# 2 (annotated by BRE David Kleinfeld):\n\n1\\) The distinction between \\\"neural representation\\\" and \\\"internal representation\\\" seems unnecessary -- and ill-defined.", "\n\nDK: This should be fixed.", "\n\nWe have fixed it. ", "We now distinguish between a \"Neuronal Representation\" (NR), which can be any pattern that shows some correlation with the external feature, and the \"Invariant Representations (IvR), which is *the* representation that represents the feature consistently and uniquely -- i.e., it occurs *always* and *only* when that feature occurs. ", "This is now explained better in the subsection \"The open loop perception (OLP) doctrine\". ", "The minimal sets for IvR according to each perceptual scheme are now described better in [Figure 7](#fig7){ref-type=\"fig\"} (previously Figure 8), its legend and associated text (subsection \"Contrasting OLP and CLP -- discriminatory testable predictions\").", "\n\n2\\) Although I think I understand the intuition behind referring to a sensory-motor loop as \\\"motor-sensory-motor loop\\\", this seems unnecessary; \\\"loop\\\" already implies circularity.", "\n\nDK: I suspect that this was done to separate loops that are local and lie just in solely sensory or solely regions from brain-wide loops that span the nervous system. ", "As noted above, this needs to be clarified.", "\n\nBoth the criticism and comment are well taken. ", "The major reason for using the term MSM-loop instead of MS-loop is that our repeated experience with presenting the ideas discussed in this paper to colleagues indicated that people often automatically refer to sensory-motor arcs, or to inter-modal sensory-motor loops, when sensory-motor loops are mentioned (see our [Figure 4](#fig4){ref-type=\"fig\"}). ", "Thus, many people imagine a kind of a loop that combines visual sensation with arm movement, for example, closing the loop via visual sensation of the arm. ", "This is of course not what we refer to in this paper -- we refer to loops that include only one sensory organ, control its movement and sense its signals. ", "We try to emphasize the flow of the loop signals from and to the same sensory organ by using the term motor-sensory-motor loop. ", "We have now expanded the explanation of this term (subsection \"subsection \"Perceptual systems are organized as motor-sensory-motor (MSM) loops\", third paragraph), which we believe will also help clarifying the scheme we are talking about.", "\n\n3\\) It is unclear to me what the distinction between msOLP and CLP is?", "\n\nDK: Please either drop or clarify this issue. ", "It should be a straight forward fix.", "\n\nThis distinction is important, and we hope that we are now doing a better job in explaining it. ", "The difference is that in msOLP there is no loop -- the sensory-to-motor arc is open. ", "We now explain it better in the subsection \"Contrasting OLP and CLP -- discriminatory testable predictions\", and emphasize it via the classification of our predictions.", "\n\n4\\) At times the argument is speculative and unnecessarily strong -- to the point of likely already being wrong? ", "E.g., in the subsection \"Contrasting OLP and CLP -- discriminatory testable predictions\" \\\"the question is \\[...\\] whether paralyzed subjects perceive. ", "If they do -- here goes the closed-loop hypothesis\\\". ", "We clearly perceive by hearing without moving. ", "I will grant the authors that it is still unclear what the function of outer hair cells is -- but as far as we know, this is a counter example to their hypothesis?", "\n\nDK: please provide a more graded presentation. ", "The manuscript started out this way, in that open loop representations were a primarily seen as a subset of the larger internal representation.", "\n\nThe auditory case is indeed interesting. ", "We agree with the reviewer that, based on currently available knowledge, it could very well be the case that hearing does not crucially depend on motor outputs. ", "Yet, the experiment had not been yet done -- one needs to paralyze or block the outputs to the outer hair cells and the muscles of the middle ear in order to test it. ", "We now state it in the second paragraph of the subsection \"Contrasting OLP and CLP -- discriminatory testable predictions\".", "\n\nThere is an additional point here. ", "The auditory stimulus is fundamentally different than the visual and tactile ones -- it can never be stationary. ", "There is no stationary acoustic wave. ", "Thus, the inner hair cells are always activated by a sound. ", "This makes the dependence on sensor motion less crucial. ", "Thus, we have modified the question to \"whether paralyzed subjects perceive stationary (i.e., not flashing or moving) objects similarly to non-paralyzed subjects\" (see aforementioned paragraph). ", "Given the reviewer's comment we also found it important to elaborate further on the special case of auditory sensation.", "\n\n5\\) The \\\"mathematical model\\\" and the robotic setup seem to add little to the manuscript. ", "The robotic system example only proves that an oscillatory system can be driven to different attractors with different inputs?", "\n\nDK: All reviewers commented on the opaque nature of this presentation. ", "It needs to be rewritten. ", "I do not see a fundamental flaw.", "\n\nWe agree with the criticism -- the description was too laconic and encrypted. ", "We modified this section substantially by simplifying the figure ([Figure 7](#fig7){ref-type=\"fig\"}, now [Figure 6](#fig6){ref-type=\"fig\"} -- removing the open-loop responses) and explaining the outcome of the robotic model and its significance (subsection \"Synthesis of CLP in a robotic setup\"). ", "We think that the demonstrations of how a convergence process may look like, and how a steady-state may look like, are of value in this paper as they can help the reader capturing the type of processes we refer to -- we thus prefer to leave this section in.", "\n\n6\\) The testable predictions part is a great idea -- but as formulated they are not very helpful. ", "A specific motor output can be thought of as the correlate of a dynamic neural attractor instead of an \\\"instantaneous state\\\".", "\n\nDK: All reviewers agree. ", "The section on predictions is a crux aspect of the paper that requires significant improvement, as the key is to entice experimentalists to try to falsify or verify the ideas inherent in representation through motor control. ", "This will take thought and time and still may not work out!", "\n\nThe predictions section was substantially revised. ", "Please see our detailed description in reply to Essential revisions (2) above.", "\n\nReviewer \\# 3 (BRE David Kleinfeld):\n\n1\\) The statement that \\\"\\[motor-sensory-motor\\]-loops are fundamental units of mammalian perception\\\" cannot be right. ", "These loops can support activity and thus a motor-sensory-motor representation, but anatomical loops per se is not a representation.", "\n\nGood point. ", "Indeed, whenever we refer to MSM loops we refer to both their anatomical and functional levels. ", "We are now stating this explicitly in the subsection \"Perception can be masked \"backwardly\".", "\n\n2\\) The discussion of two types of loops notes that the \\\"first uses proprioceptive signals \\[...\\] The other type uses sensory signals to monitor features of external objects...\\\". ", "In fact, this extends confusion in the literature. ", "Signals from muscle spindles, usually regarded as proprioceptive in the sense that are used only for motor feedback, are also sensory. ", "See the pioneering work by Hsiao (2006 J Neurophysiol) on discriminating the size of objects based on muscle stretch.", "\n\nAnother good point -- thank you! ", "Indeed, proprioceptive loops can provide (limited) information about external objects. ", "For example, when a large error between the planned and executed movement occurs, an external object that blocks the movement is a natural interpretation of the brain. ", "We now added this point and a citation of Hsiao's paper in the subsection \"The closed-loop perception (CLP) hypothesis\", last paragraph.", "\n\n3\\) The discussion of reading out the convergence, say, to a limit cycle is muddled. ", "Are convergence cycles related to the accumulation of evidence? ", "If so, it is an interesting idea. ", "But the authors need to describe a mechanism to link dynamics with estimated of confidence. ", "They end with \\\"although the loops never reach the ultimate steady-states, they typically quit the convergence process when the distance from that state is no more sensible\\\". ", "This seems too soft a statement for a serious article.", "\n\nIn general we consider the formalization of the link between dynamics and confidence to lie outside the scope of the current paper. ", "Yet, we agree that the description of possible mechanisms is in place here. ", "We have thus added a paragraph describing the potential mechanism we prefer, which is based on internal models (subsection \"I Perception (of external feature(s)) ≡ a process of inclusion in MSM-loop(s)\", fifth paragraph).", "\n\n4\\) The authors discuss the need to share information between limit cycles (perceptual loops). ", "They are a bit glib in listing possibilities as the locking and unlocking of activity in different loops is essential to their scheme of hierarchical loops. ", "Coherence between different loops is tricky -- if the interactions cause a pair of loops to phase-lock, then it is not clear how they separate and dephase. ", "The authors have neglected issues of noise, which is a mechanism to break locking and to dephase.", "\n\nWe assume here that the loops composing an object perception remain engaged until the perceptual epoch ends. ", "In this case dephasing will automatically follow. ", "We have added a sentence mentioning that in the first paragraph of the subsection \"II. ", "Perception of an external object ≡ a coordinated process of inclusion in a collection of MSM-loops\".", "\n\n5\\) The equations for the SYCLOP model need to be explained. ", "As it stands, this section will lose almost all readers. ", "None of the symbols are explained. ", "I would also start by saying that the simplest model of a loop uses Van der Pol relaxation dynamics. ", "On the one hand it is a bit of a let-down to have the work condensed to a single oscillator that came out of the days of vacuum triodes. ", "On the other hand, the presentation of the realization with the Van der Pol oscillator ([Figure 7](#fig7){ref-type=\"fig\"}) is very condensed. ", "I think [Figure 7](#fig7){ref-type=\"fig\"} needs to be considerably unpacked. ", "Panels A, B, and example dynamics like panel H can be one figure, while panels D-G and I could be a second figure. ", "Also, define \\\"k-events\\\", label the ordinates of panels H and I.\n\nThe equations of the SYCLOP model are now better explained (subsection \"Synthesis of CLP in a robotic setup\"). ", "The outcome of SYCLOP model is now described in detail and the motivation for using Van der Pol dynamics is now explained as well (in the aforementioned subsection).", "\n\n[Figure 7](#fig7){ref-type=\"fig\"} (now [Figure 6](#fig6){ref-type=\"fig\"}) was substantially simplified -- the open-loop response panels were removed and the figure now conveys the main messages in a clearer manner.", "\n\n6\\) The authors end with a number of proposed experiments to address the claims of closed versus open loop object representation. ", "One involves the detection of the phase of contact in the whisking cycle, yet is followed by the claim that \\\"...predictions of CLP and OLP can be distinguished only in natural perceiving conditions.\\\" This appears to obviate the use of head-fixed animals, an excellent preparation for combined behavior and electrophysiology. ", "Why is head fixing bad for whisking? ", "It seems that perception must often work under partial constraints.", "\n\nWe agree. ", "The scope of the term \"natural conditions\" is too wide. ", "We have modified this paragraph substantially and now explain better which reductionist paradigms would not allow a meaningful testing of the hypotheses. ", "We also now explain better in that paragraph how different conditions, including head fixation, should be taken into account (subsection \"III. ", "Motor-sensory-motor convergence\", last paragraph).", "\n\n\\[Editors\\' note: further revisions were requested prior to acceptance, as described below.\\]\n\nThe manuscript has been improved but there are a few remaining issues raised by the reviewer and verified by Reviewing editor Kleinfeld. ", "In order to complete this odyssey, please address these queries.", "\n\n1\\) In the subsection \"Synthesis of CLP in a robotic setup\". ", "Please expand on the solution of the model, a van der Pol oscillator, to make it transparent to the \\\"typical\\\" biologically trained reader. ", "The statement \\\"The implementation of these equations using the SYCLOP platform\\\" needs to be detailed -- even in the appendix -- so a reader can duplicate your calculation.", "\n\nWe have expanded on the solution of the model, and explained the choice of the van der Pol oscillator (subsection \"Synthesis of CLP in a robotic setup\"). ", "We also provide more details on the SYCLOP implementation, and explain how the model equations were implemented (in the aforementioned subsection).", "\n\n2\\) In the subsection \"Perception can be masked \"backwardly\"\" -- \\\"If perception could be reduced to a sequence of pure open loop processes backward masking should not occur.\\\" One might think that any slow integration step in a feed-forward processing system would explain backward masking through injection of a signal within the integration time. ", "Perhaps your statement could be better explained as dependent on a system with only \\\"fast\\\" integration.", "\n\nThe section on backward masking is now clearer. ", "We explain the 'standard model' for open loop schemes, which is based on dual channel (fast and slow) integration and interaction (Breitmeyer & Ogmen's 2000, reference added), its inconsistency with experimental data, and the challenge it forms for OLP (subsection \"Perception can be masked \"backwardly\").", "\n\n3\\) In the subsection \"Perception can be masked \"backwardly\"\" -- \\\"Perceptual masking thus challenges the validity of the \\'virtual knife\\' reduction and the ability to reconstruct perception based on experiments with flashed stimuli only.\\\" The argument leading up to this is not clear.", "\n\nWe hope that the improved explanation of the backward masking challenge (point 2) provides a better background for understanding the statement about the virtual knife. ", "In addition, we have modified this sentence to be more explicit and clear (subsection \"Perception can be masked \"backwardly\"). ", "A related change was introduced in the fourth paragraph of the subsection \"I Perception (of external feature(s)) ≡ a process of inclusion in MSM-loop(s)\".", "\n\nFinally, please reread the manuscript in a \\\"copy-edit\\\" manner to improve the grammar and correct any number of typos in punctuation.", "\n\nWe have reread the entire paper, fixed typos and grammatical mistakes (with the aid of a linguistic editor) and improved the clarity of the text where needed -- thanks for noting that. [", "Figures 1](#fig1){ref-type=\"fig\"} and [7](#fig7){ref-type=\"fig\"} were slightly modified ([Figure 1](#fig1){ref-type=\"fig\"}: eye -- object arrows added; [Figure 7](#fig7){ref-type=\"fig\"}: graphics).", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "FOCUS On: Honor Killings in Jordan\n\nDespite an initial rejection by the Board of Immigration Appeals, Olga Jad Kamar, under threat of murder by her own family, will be allowed to stay in the United States. ", "The 6th Circuit U.S. Court of Appeals officially ruled in favor of Kamar’s petition against deportation after finding “substantial evidence” that, if she were forcibly returned to Jordan, she would be killed by cousins.", "\n\nThe threat of “intending to perform an honor killing,” in accordance with the Jordanian cultural custom against pre-marital pregnancy, was the basis for the court’s ruling.", "\n\nDespite being considered the most progressive Arab nation in the Middle East, Jordan maintains one of the highest rates of honor crimes in the world, reports Human Rights Watch. ", "In 2013, researchers at Cambridge University’s Institute of Criminology found that of the 850 students surveyed, almost half of boys and one in five girls interviewed believe that killing a daughter, sister, or wife who has “dishonoured” or shamed the family, is justified, reports Al Jazeera.", "\n\nJordan averages out at about 20 deaths per year, according to Human Rights Watch, but this number is rising. ", "Over 36 “justified” honor killings were reported by the Jordanian government in 2017; the rate of change comes out at an 89% increase from the 19 deaths reported in 2002.", "\n\nHowever, there is a distinct discrepancy between the numbers that the government reports and the findings of NGOs. ", "The Sisterhood is Global Institute in Amman found that honor crimes rose by 60% since 2016, and there are no signs of that rate slowing down.", "\n\nProtections for at-risk women remain limited. ", "The Fair Observer reports that “the state puts women who are at risk of honor crimes into ‘protective custody,’ which often means prison without charge.” ", "65% of all 1,700 incarcerated women in Jordan are detained “indefinitely” for this reason, with limited options.", "\n\nReuters interviewed one woman with the alias “Fatima,” whose father attempted to kill her and her sister after he found out her sister was pregnant out of wedlock. ", "She was rescued by neighbors and placed in the custody of the local police; her sister died.", "\n\nFatima was subsequently imprisoned for her own protection, and was not released for over 22 years. ", "While there, she experience frequent and heavy abuse by her fellow inmates. “", "When I went inside and they put me in cells with murderers, narcotics, thieves and prostitutes, I no longer knew who I was and what I am,” she said.", "\n\nAdam Coogle, a Middle East researcher at Human Rights Watch, confirms that “A woman who is held for her own protection is in the same cell with a convicted murder or someone who has actually committed an act of violence. ", "This can lead to a lot of psychological problems and real fear,” reports Reuters.", "\n\nAccording to Reuters, alternatives to imprisonment include voluntary release and arranged marriage, but neither option is ideal. ", "Women who are granted release must have a male family member act as a guardian, but these relatives are more often than not the same ones that threatened the women’s lives to begin with.", "\n\nArranged marriage is almost impossible, and there is no guarantee of safety. ", "Twenty-six-year-old Swason, also an alias, spent two years in a Jwaideh detention facility before a man arrived to determine if she was suitable for marriage\n\n“The very next day I was transferred to the governor’s office and the governor signed my marriage certificate,” she reported. ", "Now four years later, she is looking to escape this very arrangement, as her husband is an abusive alcoholic." ]

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[ "Q:\n\niOS: Custom permission alert view text\n\nAnyway to custom permission alert view like: Contacts, Photo Album, Push Notifications... before they get access, they will pop up an alert view like this:\n\nHow to custom Contacts, photo album, push notifications alert view text?", "\nUPdate:\n\nSee the update image above, translate into english:\n\n\"To seek for your family and friends, Path needs to transfer your\n contacts to our server\"\n\nAnd click OK to get contacts access without any other access permission alert view pops up.", "\n\nA:\n\nUnder iOS 6 and above, these can be setup to show specific messages. ", "Edit your Info.plist by adding a few new entries. ", "The keys all begin with \"Privacy - \" (the raw keys are NSxxxUsageDescription where xxx is Contacts, Locations, Reminders, PhotoLibrary, or Calendards). ", "The value is the text you wish to display to the user.", "\n\n" ]

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[ "Doppler tissue imaging.", "\nThis paper try to give a general overview of the main areas of DTI clinical application, its main technical limitations, new directions still under investigation and some potential future developments of this emerging imaging technique. ", "In this review article we pretend to discuss the main aspects of the new DTI method, its present \"state of the art\" and future perspectives of scientific and technical development." ]

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[ "The Lighthouse is a 2018 period piece thriller directed by Chris Crow, written by Paul Bryant, Chris Crow and Michael Jibson. ", "The film stars Mark Lewis Jones as Thomas Griffiths and Michael Jibson as Thomas Howell. ", "This tale of two Thomas’ lights up a dark film.", "\n\nThe plot revolves around two men. ", "Thomas Howell(Jibson), a recently religious man after his mistake cost the lives of six men, and Thomas Griffiths(Jones), a man who lost his family and spends his time bare knuckle boxing. ", "It is their shift at Smalls Lighthouse, a small lighthouse on a tiny island. ", "Their time is spent between operating the lighthouse and trying to pass the time. ", "A storm rolls in cause both men to reexamine their lives, what is left of them while running out of food.", "\n\nThe Movie (3.5/5)\n\nOverall the film feels very authentic. ", "The scenery, the costumes, the acting all feels like it is right out of the 1800s, when the film takes place. ", "Only one scene towards the end looks out of place or faked. ", "Besides the one scene, the rest of the film feels like an accurate representation of the time. ", "The location of the small island feels like a character all its own. ", "A tiny rock island with a small lighthouse that feels isolated beyond the norm. ", "Jibson and Jones do an good job at interacting and playing their parts as men on the verge of mental breakdown.", "\n\nThe film walks the line between supernatural thriller and just thriller. ", "Some supernatural elements turnout to be dreams or the mind playing tricks on the characters. ", "The storm and the fog that precedes the storm bring the sense of foreboding to an all time high. ", "These effects also look real, which makes the world feel more real. ", "Other elements are introduced to add a little mystery to the thriller. ", "A mysterious box is pulled out of a wall by Griffiths that leads to a turning point in the film.", "\n\nA major downside of the film, that also hampers many period pieces, is the pacing. ", "The characters are often just sitting trying to pass the time or having a conversation. ", "While this helps show the feeling of isolation from the rest of the world, it does feel grating when they have a repeat conversation. ", "The middle of the film is the real dragging point. ", "The storm has set in and the two Toms end up arguing about religion, a one sided argument that they had already had. ", "With only two characters to be the focus of the film it is hard not to have dead time with a run time of an hour and a half.", "\n\nSome Extra Thoughts: Very bleak. ", "Last 30 minutes are watching a man go insane. ", "Goes from beating one another to drinking together. ", "Hard to tell at the end what is real and what is a dream. ", "A lot of time spent just hanging out, which builds atmosphere but drags. ", "Lots of shouting about God and why he sucks. ", "Can’t tell it actually based on a true story or pretending to be based on a true story. ", "Solid ending, protects the idea might not just be isolation on that island, might be hell.", "\n\nAudio(4/5)\n\nThe sound design of the movie is very good. ", "The sounds of the storm and the wind are really well done. ", "It feels like the filming took place during an actual storm. ", "It is especially impressive when both characters are outside in the wind and the rain. ", "Their shouts are understandable, while still hearing the loud roar of the wind. ", "There isn’t much music, but the two main characters do sing at one point and do a fantastic job together. ", "They did a fine job singing a drinking song and actually looked liked they enjoyed themselves while doing it. ", "Sound effects with the wood of the lighthouse, like the creaking in the floor or the slamming of wooden doors was good and felt consistent with a storm raging outside.", "\n\nOverall(3.5/5)\n\nThe Lighthouse is a solid period piece that sets the mood and atmosphere up extremely well. ", "While the film may drag for many contemporary movie goers, fans of historical dramas and thrillers will certainly enjoy this one." ]

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[ "Q:\n\nCannot find my IPv6\n\nI have been having networking issues, now out of the blue my IPv6 does not appear, my router is set up for IPv6 and I have looked through the logs. ", " I am running Ubuntu Server 20.04\nip address\nroot@sturtz001:/etc# ip address\n1: lo: <LOOPBACK,UP,LOWER_UP> mtu 65536 qdisc noqueue state UNKNOWN group default qlen 1000\n link/loopback 00:00:00:00:00:00 brd 00:00:00:00:00:00\n inet 127.0.0.1/8 scope host lo\n valid_lft forever preferred_lft forever\n inet6 ::1/128 scope host \n valid_lft forever preferred_lft forever\n2: enp0s25: <BROADCAST,MULTICAST,UP,LOWER_UP> mtu 1500 qdisc fq_codel state UP group default qlen 1000\n link/ether 00:23:24:08:58:1f brd ff:ff:ff:ff:ff:ff\n inet 192.168.1.8/24 brd 192.168.1.255 scope global dynamic enp0s25\n valid_lft 86091sec preferred_lft 86091sec\n inet6 fe80::223:24ff:fe08:581f/64 scope link \n valid_lft forever preferred_lft forever\n3: ens2: <NO-CARRIER,BROADCAST,MULTICAST,UP> mtu 1500 qdisc fq_codel state DOWN group default qlen 1000\n link/ether 00:1b:21:bf:e7:28 brd ff:ff:ff:ff:ff:ff\n\n cat /etc/netplan/*.yaml\n# This is the network config written by 'subiquity'\nnetwork:\n version: 2\n renderer: NetworkManager\n ethernets:\n enp0s25:\n dhcp4: yes\n dhcp6: no\n accept-ra: true\n ens2:\n dhcp4: no\n dhcp6: yes\n accept-ra: true\n\nA:\n\nAre you sure your ISP provides you with IPv6? ", "My router is also set up for IPv6 (and IPv4) but my ISP only gives IPv4. ", "I would have to ask them to change it if I wanted IPv6.", "\nIn my router interface I can see in the status that IPv6 is dissconnected. ", "Maybe you could look there.", "\nEdit:\nYou could use Wireshark. ", "I don't know how you should run it from CLI but it is possible and it should also show your IPv6 if you have any connections to or from it.", "\nWireshark Docs on CLI\nAlso note the Ubuntu Docs on Wireshark. ", "You need to grant at least some privileges to your user.", "\n\nA:\n\nI contacted my ISP and they turned on the Ipv6 DNS\nIPv6 was already on but they told me to reboot my router so I did.", "\n\n" ]

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[ ".. _contributing:\n\nContributing\n============\n\nThere are many ways to contribute to the GeoServer documentation. ", " The following are listed roughly in order of \"least involved\" to \"most involved\".", "\n\nPost Snark on Twitter\n---------------------\n\nBecause there is nothing we developers like more than a pointless argument about\nhow bad our documentation is. ", "It's even better if it is in public so our bosses\ncan see how we are productively using our time. ", "\n\n**Hint**: don't do this, if you have a problem with the documentation then at\nleast make a note of the issue so that someone might fix it for you.", "\n\nFile an issue\n-------------\n\nIf you don't want to write the documentation, and/or would like to suggest a page that isn't included, you can request it. ", " Use JIRA to file an issue. ", " Please include the name of the page, content, and the place where this new information should be included. ", " As with all issues, it is not guaranteed that someone will fulfill your request.", "\n\n.. _file_an_issue_with_patch:\n\nFile an issue and include a documentation patch\n-----------------------------------------------\n\nGeoServer uses `JIRA <https://osgeo-org.atlassian.net/projects/GEOS>`_ for issue tracking. ", " New documentation is treated like part of the code, so those who want to submit content (patches etc) can use a pull request or file an issue with JIRA and attach the content to the issue. ", " If the content is deemed satisfactory, a contributor with commit rights will add the content to the documentation.", "\n\nFor more information see `CONTRIBUTING.md <https://github.com/geoserver/geoserver/blob/master/CONTRIBUTING.md>`_ in GitHub.", "\n\nGitHub supports direct reviewing and editing of documentation pages, any edit you make will be automatically forked and submitted to the project team as a pull request.", "\n\n.. _commit_rights:\n\nGet commit rights\n-----------------\n\nThe documentation is now under version control, just like the source code. ", " Also, like the source code, one must be granted \"commit rights\" before being able to make changes. ", " This helps keep the quality of the documentation as high as possible.", "\n\nTo gain documentation commit rights, the process is similar to gaining commit rights for code. ", " One should submit some documentation (see the section on how to :ref:`file_an_issue_with_patch` below). ", " If one demonstrates quality work, then a `contributor <https://github.com/orgs/geoserver/teams/team-geoserver>`_ can nominate this person for commit rights.", "\n\nTo request commit rights, please send an email to the `GeoServer developers list <https://lists.sourceforge.net/lists/listinfo/geoserver-devel>`_. ", " Please note that this access may only be to the documentation, and not the source code.", "\n\nOnce you have commit rights, please see the section on :ref:`workflow` for creating and editing the documentation.", "\n\n" ]

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[ "<?", "php\n/**\n * @package Joomla.", "Site\n * @subpackage Layout\n *\n * @copyright Copyright (C) 2005 - 2017 Open Source Matters, Inc. All rights reserved.", "\n * @license GNU General Public License version 2 or later; see LICENSE.txt\n */\n\ndefined('JPATH_BASE') or die;\n\nJHtml::_('behavior.core');\n\n$doTask = $displayData['doTask'];\n$class = $displayData['class'];\n$text = $displayData['text'];\n$btnClass = $displayData['btnClass'];\n\n?", ">\n<button onclick=\"<?php echo $doTask; ?", ">\" class=\"<?php echo $btnClass; ?", ">\">\n\t<span class=\"<?php echo trim($class); ?", ">\" aria-hidden=\"true\"></span>\n\t<?", "php echo $text; ?", ">\n</button>\n" ]

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[ "Tem (queen)\n\nTem was an ancient Egyptian queen consort of the 11th dynasty, a wife of Pharaoh Mentuhotep II and the mother of Mentuhotep III. ", "She was buried in Tomb DBXI.15 in Deir el-Bahari, in her husband's mortuary complex.", "\n\nShe outlived her husband and was buried during her son's reign. ", "It is likely that she was of commoner origin, as there is no evidence in her grave that points to a royal origin. ", "She is only named on her sarcophagus and on an offering table. ", "Her titles are \"King's beloved wife\" (ḥmt-nỉswt mrỉỉ.t=f), King's Mother\" (mwt-nỉswt), Mother of the King of Upper and Lower Egypt (mwt-nỉswt-bỉt), Great of Sceptre (wr.t-ḥt=s).", "\n\nHer tomb was discovered in 1859.", "\n\nSources\n\nCategory:Queens consort of the Eleventh Dynasty of Egypt\nCategory:Mentuhotep II" ]

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[ "Changing patterns of medical practice: protein restriction for chronic renal failure.", "\nThe use of dietary protein restriction for renal failure has fluctuated during the past 125 years. ", "These fluctuations reflect not only the state of medical knowledge but also social, economic, and cultural factors. ", "Factors inhibiting use of dietary treatment have been its status as an aspect of hygiene rather than as active therapy; the opinions of dominant practitioners and scientists around midcentury, including a presumption that renal adaptation to a high-protein diet must be appropriate; fear of malnutrition and a cultural belief in the virtue of dietary protein; unwillingness by physicians and patients to restrict consumption or lifestyle; and professional identification with the technologies of dialysis and renal transplantation. ", "Factors promoting dietary treatment have been rediscovery of previous work on protein-induced renal injury; a sense that homeostatic compensations could have adverse consequences; federal incentives to curb consumption of scarce resources such as renal dialysis; and the integration of research on, and therapeutic use of diet into scientific medicine. ", "A large ongoing study of dietary protein restriction to limit renal injury will add to our knowledge of this treatment; its application will surely be informed by social and cultural considerations." ]

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[ "Q:\n\nWhy encryption in codeigniter working in local server but not on the server?", "\n\nI used the below code in my local wamp server and everything is perfect.", "\n$this->encryption->encode($result['wo_id']);\n\nBut the same code is showing error when uploading to the web server online. ", "Why?", "\n\nA:\n\nSince PHP version of my server was old. ", "I enabled PHP extension php_mcrypt from\n\nWAMP icon -> PHP ->PHP extensions -> php_mcrypt\n\nNow it works fine.", "\n\n" ]

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[ "Q:\n\nMySQL changes to Kafka Using Debezium - Capturing only DDL stmts\n\nConfigured MySQL-Debezium for CDC. ", "It was capturing DDL changes like create/Drop table, but not capturing DML events.", "\nUsing MySQL 8.0.11 and Embedded debezium version 0.8.3.Final. ", "\nNo additional configurations were done in MySQL server while creating table.", "\nConfiguration bean is created with below code\n@Bean\npublic io.debezium.config.", "Configuration customerConnector() {\n return io.debezium.config.Configuration.create()\n .with(EmbeddedEngine.", "CONNECTOR_CLASS, \"io.debezium.connector.mysql.", "MySqlConnector\")\n .with(EmbeddedEngine.", "OFFSET_STORAGE, \"org.apache.kafka.connect.storage.", "FileOffsetBackingStore\")\n .with(EmbeddedEngine.", "OFFSET_STORAGE_FILE_FILENAME, \"path-to-file\")\n .with(\"offset.flush.interval.ms\", 60000)\n .with(EmbeddedEngine.", "ENGINE_NAME, \"customer-mysql-connector\")\n .with(MySqlConnectorConfig.", "SERVER_NAME, databaseServer)\n .with(MySqlConnectorConfig.", "HOSTNAME, databaseServer)\n .with(MySqlConnectorConfig.", "PORT, databasePort)\n .with(MySqlConnectorConfig.", "USER, databaseUser)\n .with(MySqlConnectorConfig.", "PASSWORD, databasePassword)\n .with(MySqlConnectorConfig.", "DATABASE_WHITELIST, databaseSchemaName)\n .with(MySqlConnectorConfig.", "TABLE_WHITELIST, databaseTable)\n .with(MySqlConnectorConfig.", "DATABASE_HISTORY,\n MemoryDatabaseHistory.class.getName()).build();\n}\n\nBelow is the log when starting it as Springboot application\n2020-05-29 21:24:28.028 INFO 5576 --- [pool-1-thread-1] i.d.connector.mysql.", "MySqlConnectorTask : MySQL has the binlog file 'binlog.000009' required by the connector\n2020-05-29 21:24:28.072 INFO 5576 --- [pool-1-thread-1] io.debezium.util.", "Threads : Requested thread factory for connector MySqlConnector, id = localhost named = binlog-client\n2020-05-29 21:24:28.074 INFO 5576 --- [ main] o.s.s.concurrent.", "ThreadPoolTaskExecutor : Initializing ExecutorService 'applicationTaskExecutor'\n2020-05-29 21:24:28.074 INFO 5576 --- [pool-1-thread-1] io.debezium.util.", "Threads : Creating thread debezium-mysqlconnector-localhost-binlog-client\n2020-05-29 21:24:28.090 INFO 5576 --- [-localhost:3306] io.debezium.util.", "Threads : Creating thread debezium-mysqlconnector-localhost-binlog-client\n2020-05-29 21:24:28.121 INFO 5576 --- [-localhost:3306] c.g.shyiko.mysql.binlog.", "BinaryLogClient : Connected to localhost:3306 at binlog.000009/3786 (sid:6293, cid:36)\n2020-05-29 21:24:28.121 INFO 5576 --- [-localhost:3306] i.debezium.connector.mysql.", "BinlogReader : Connected to MySQL binlog at localhost:3306, starting at binlog file 'binlog.000009', pos=3786, skipping 8 events plus 0 rows\n2020-05-29 21:24:28.121 INFO 5576 --- [-localhost:3306] io.debezium.util.", "Threads : Creating thread debezium-mysqlconnector-localhost-binlog-client\n2020-05-29 21:24:28.183 INFO 5576 --- [ main] d.s.w.p.", "DocumentationPluginsBootstrapper : Context refreshed\n2020-05-29 21:24:28.199 INFO 5576 --- [ main] d.s.w.p.", "DocumentationPluginsBootstrapper : Found 1 custom documentation plugin(s)\n2020-05-29 21:24:28.199 INFO 5576 --- [ main] s.d.s.w.s.", "ApiListingReferenceScanner : Scanning for api listing references\n\nAny Clue?", "\nThanks!", "\n\nA:\n\ntable.whitelist should be set to to <schema>.<table> so in your case source.customer\n\n" ]

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[ "[Study on unrelated donor allogeneic bone marrow transplantation with Bu-CY2 conditioning regimen for myelodysplastic syndrome].", "\nTo evaluate the efficacy and safety of Bu-CY(2) conditioning regimen on allogeneic bone marrow transplantation (BMT) with unrelated donor for myelodysplastic syndrome. ", "Six patients received chemotherapy regimen of busulfan (Bu) and cyclophosphamide (CY) before allogeneic BMT (Bu 4 mg . ", "kg(-1) . ", "d(-1), -7 d - -4 d, CY 60 mg . ", "kg(-1) . ", "d(-1), -3 d - -2 d). ", "Mycophenolate mofetil combined with cyclosporin A and methotrexate was used for prevention of acute graft-versus-host disease after transplantation. ", "Lipo prostaglandin E(1)was used in prophylactic regimen for hepatic veno-occlusive disease. ", "Neutrophil count began to be higher than 0.5 x 10(9)/Lat the 18th day after BMT. ", "Platelet count began to be higher than 20 x 10(9)/Lat the 21st day after BMT. ", "Disease-free survival in the six patients was 27 months. ", "Bu-CY(2) conditioning regimen on allogeneic bone marrow transplantation with unrelated donor is an effective therapy for patients with myelodysplastic syndrome." ]

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[ "Halifax regional council voted against development plans for the Blue Mountain Birch Cove wilderness area on Tuesday.", "\n\nCouncillors voted 15-1 in support of a staff recommendation to not let people build in the area, which has long been proposed as a regional park. ", "An earlier facilitator's report backed development.", "\n\n\"You have sent us an amazing love story,\" Coun. ", "Jennifer Watts said of the 1,400 letters council received on the proposed park.", "\n\nWatts said people could access the proposed park by bus.", "\n\nMayor wants biggest park possible\n\n\"I think it's a great step,\" said Mayor Mike Savage. \"", "We've just given staff authority to go ahead and start negotiating both the boundary and the acquisition of land.\"", "\n\nHe said when staff have that worked out they will come before council. \"", "Developers should not make an undue profit; on the other hand they should be fairly compensated for the land they own,\" the mayor said.", "\n\nHe wants it to be \"as large as it can possibly be.\"", "\n\nThe province owns much of the land as a wilderness reserve. ", "Two developers, Susie Lake Developments and The Annapolis Group, own 346 hectares of the more than 1,619 hectares in the conceptual park's area. ", "The Stevens Group runs a quarry in the area. ", "In total, 518 hectares of the area are owned privately.", "\n\nMcCluskey backs development\n\nRaymond Plourde, wilderness co-ordinator for the Ecology Action Centre, said he's \"breathing a big sigh of relief.", "\n\n\"Council quite firmly has set things off — finally — in the right direction. ", "After ten years, I think we're going to start seeing some movement,\" he said.", "\n\nHe said when the park is finally realized, it will be \"the envy of any city in the country, if not North America.\"", "\n\nCoun. ", "Gloria McCluskey was the lone councillor supporting development, arguing residents in her Dartmouth district would not use the park much. ", "She also felt development would be better for taxpayers.", "\n\nStaff to start talks with land owners\n\nBob Bjerke, the city's planning director, said staff will now meet with land owners, conservation groups and other government agencies interested in the proposed park. ", "The next report will come within six months.", "\n\n\"It will be a much more defined program for how to get from where we are now, to really looking at how to really achieve the objectives of the park that have been expressed in the regional plan,\" he said.", "\n\n​The city first flagged the area as a possible regional park in 2006. ", "It included that idea in the current regional plan." ]

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[ "In the first instance of an abducted police officer being executed by Maoists,Jharkhand Special Branch Inspector Francis Induwar was beheaded and his body thrown on a forest stretch of National Highway 33 near Raisa,23 km from Ranchi,this morning. ", "He was killed three days after the Maoists reportedly demanded the release of their arrested leaders,including Kobad Ghandy,in exchange for the officer.", "\n\nAdvertising\n\nIn Delhi,Union Home Minister P Chidambaram called the act unacceptable. ", "“The cold-blooded murder is simply not acceptable. ", "I condemn it.” The Jharkhand DGP,he said,had informed him that no demand for a swap had been made. ", "Chidambaram said the government was governed by rule of law and prisoners under custody of courts could not be swapped with those outside the law.", "\n\nInduwar’s body and severed head were found this morning by a police team led by SP (Rural) Hemant Toppo. ", "“It appears he was beheaded with a sharp-edged weapon,” Toppo told The Indian Express. ", "Police found three hand-written posters stating that the Inspector had been killed by CPI (Maoist) cadres.", "\n\nInduwar,an Adivasi Christian,was abducted from Hembrom Bazaar in Arki,45 km from Raisa,by four armed Maoists on September 30 when he was out shopping.", "\n\nAdvertising\n\nOn October 3,CPI(Maoist) South Chotanagpur Division spokesperson Samarji issued a press release claiming Induwar was safe in their custody. ", "He said the officer would be freed if police released three Maoist leaders — Kobad Ghandy,Chhatradhar Mahato and Bhushan Yadav. ", "While Ghandy was arrested in New Delhi,Mahato and Yadav were held in West Bengal.", "\n\nBut police assumed that this was only Samarji’s demand and not that of the CPI (Maoist). ", "“We learnt about his stand from newspapers reports. ", "Since we had not received any message from the outfit,we did not attach any significance to it,” said IG S N Pradhan,the police spokesperson.", "\n\nLatest Videos\n\nInduwar is survived by his wife Sunita and three sons,Animesh (13),Anitesh (12) and Abhishek (10). ", "On October 1,the children met the police top brass to seek the safe return of their father. ", "IG (Special Branch) B B Pradhan said “we told them we are doing our best to trace him,get him released from the clutches of extremists.” Sunita had appealed to the Maoists to release her husband,saying “we will be finished if anything happens to him,we are common people who have no access to authorities to get these arrested leaders freed”.\n\nAnd this morning,after word spread that his body had been found,Argora village on the outskirts of Ranchi,where the Induwars lived in a rented house,plunged into grief. ", "Nephew Anup said: “My uncle was a very honest man. ", "He is a martyr now but we have lost him forever. ", "Who will take care of us?”\n\nBorn and brought up in neighbouring Gumla district,Induwar became a Sub-Inspector in 1989,was officer-in-charge of more than a dozen police stations including Bermo,Lohardaga and Bokaro. ", "Promoted to the rank of Inspector last year,he was assigned to the Special Branch. ", "He was posted to Khunti in February this year.", "\n\nThe killing of Induwar outraged policemen and a section even accused seniors of not doing enough to free him. ", "Some 3,500 personnel of the Special Branch are deployed across the state,gathering intelligence.", "\n\nA section of policemen led by Jharkhand Policemen’s Association Special Branch unit president Lal Manohar Singh refused to let the police get Induwar’s post-mortem done at the state-run RIMS hospital. ", "“The police are shedding crocodile tears. ", "After he was kidnapped,they did nothing to trace him. ", "Now they want to do a post-mortem on his beheaded body. ", "We will not let them do it,” said Singh while his colleagues picked up the body from the RIMS and carried it to the police headquarters.", "\n\nAdvertising\n\nThe policemen calmed down only after Additional DGP G S Rath and IG B B Pradhan intervened and the body was returned to the RIMS. ", "Later,it was taken to the Jharkhand Armed Police premises. ", "Singh said “each one of us who has worked in these remote areas is easily identifiable. ", "We demand security of life and property.” IG S N Pradhan said: “We have told them that all are men in uniform. ", "The challenge has to be overcome.”" ]

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[ "Autocrats and the Environment or It's Easy Being Green\n\nIt is generally assumed that autocrats set low environmental standards. ", "The rationale for this is straightforward. ", "High environmental standards raise the cost of production in society, lowering national income. ", "Because the autocrat expropriates a large fraction of national income, he faces a disincentive to protect the environment. ", "However, this argument misses an important consideration of the autocrat. ", "He may be willing to sacrifice some income in order to extend his rule. ", "High environmental standards represent one tool the autocrat could use to placate his people without providing them with any revolutionary resources. ", "This paper presents a model in which the autocrat explicitly recognizes the endogeneity of his tenure length when he chooses an environmental standard, leading to high environmental standards relative to more democratic regimes. ", "The paper presents empirical evidence in support of this implication." ]

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[ " UNPUBLISHED\n\n UNITED STATES COURT OF APPEALS\n FOR THE FOURTH CIRCUIT\n\n\n No. ", "13-7158\n\n\nGUSTAVO L. JUAREZ,\n\n Petitioner – Appellant,\n\n v.\n\nROBERT LEWIS, Director of Prisons,\n\n Respondent - Appellee.", "\n\n\n\nAppeal from the United States District Court for the Eastern\nDistrict of North Carolina, at Raleigh. ", "James C. Dever, III,\nChief District Judge. (", "5:12-hc-02285-D)\n\n\nSubmitted: October 22, 2013 Decided: October 25, 2013\n\n\nBefore WILKINSON, NIEMEYER, and THACKER, Circuit Judges.", "\n\n\nDismissed by unpublished per curiam opinion.", "\n\n\nGustavo L. Juarez, Appellant Pro Se.", "\n\n\nUnpublished opinions are not binding precedent in this circuit.", "\n\fPER CURIAM:\n\n Gustavo L. Juarez seeks to appeal the district court’s\n\norder dismissing as untimely his 28 U.S.C. § 2254 (2006)\n\npetition. ", " The order is not appealable unless a circuit justice\n\nor judge issues a certificate of appealability. ", " 28 U.S.C.\n\n§ 2253(c)(1)(A) (2006). ", " A certificate of appealability will not\n\nissue absent “a substantial showing of the denial of a\n\nconstitutional right.” ", " 28 U.S.C. § 2253(c)(2) (2006). ", " When the\n\ndistrict court denies relief on the merits, a prisoner satisfies\n\nthis standard by demonstrating that reasonable jurists would\n\nfind that the district court’s assessment of the constitutional\n\nclaims is debatable or wrong. ", " Slack v. McDaniel, 529 U.S. 473,\n\n484 (2000); see Miller-El v. Cockrell, 537 U.S. 322, 336-38\n\n(2003). ", " When the district court denies relief on procedural\n\ngrounds, the prisoner must demonstrate both that the dispositive\n\nprocedural ruling is debatable, and that the petition states a\n\ndebatable claim of the denial of a constitutional right. ", " Slack,\n\n529 U.S. at 484-85.", "\n\n We have independently reviewed the record and conclude\n\nthat Juarez has not made the requisite showing. ", " Accordingly, we\n\ndeny a certificate of appealability, deny leave to proceed in\n\nforma pauperis, and dismiss the appeal. ", " We dispense with oral\n\nargument because the facts and legal contentions are adequately\n\n\n\n 2\n\fpresented in the materials before this court and argument would\n\nnot aid the decisional process.", "\n\n\n\n DISMISSED\n\n\n\n\n 3\n\f" ]

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[ "How to get reimbursed for payments you made\n\nIn most cases when you visit the doctor your Medicare and supplemental insurance will be billed by your physician. ", "The first step is to make sure that you see a doctor who takes and the supplemental insurance that you have. ", "If you ever have to file a claim online, this will make that process a lot easier. ", "When you have chosen the correct Doctor and you need to file a claim there will be very little for you to do. ", "In a few specific instances, you might have to file the claim yourself, and in these situations you will need to make sure that you are reimbursed from your supplemental insurance or from Medicare.", "\n\nIf you do not yet have a Medicare supplemental insurance plan, this might be the best time to take a look at some of the policies here on our website. ", "If you already have Medicare, you probably have already noticed that it will not pay for all your medical bills in full. ", "If this is your situation, you will want to find a helping hand anywhere that you can. ", "Medicare supplemental insurance can be that helping hand, you will finally be able to pay for many of those costs that Medicare does not cover. ", "If you are seeing the doctor more regularly as you grow older, this will not only be a helpful advantage, but it will become a necessity.", "\n\nThe time it takes to get reimbursed\n\nIf your doctor does not accept Medicare then chances are he or she will not accept your Medicare supplemental insurance either. ", "When this is the case you have to pay for your visits to the doctor out-of-pocket. ", "Even if this does happen it doesn’t mean that you are completely responsible for the payment. ", "You can still file a claim post-visit with your Medicare provider after you have obtained your supplemental insurance. ", "Of course this option will be a little bit more complicated than having supplemental insurance before your visit, but if you are just coming to this website and you need to pay for a past medical visit that Medicare did not cover, then you have options.", "\n\nIn the future, should you not have supplemental medical insurance; you will actually have to pay for the visit before you have any work done. ", "You will pay the high rates that doctor’s charge within their office rather than paying the rate that Medicare would pay. ", "When it comes time for you to get reimbursed you only get reimbursed for the amount that Medicare pays that specific doctor’s office. ", "This means that if you see a doctor who actually charges more than what Medicare is willing to pay all that money will have to come right out of your pocket. ", "It is with supplemental insurance that you can get that extra fee covered.", "\n\nOnce you have already seen your doctor it will be time to contact your Medicare representatives as well as the representative from your supplemental insurance company and speak with them about how you need to file your claim. ", "Each Medicare supplemental insurance provider is different in the way they approach claims.", "\n\nSome will require you to file the claim while others will do it for you. ", "Once the claim has finally been filed, you will receive a check from Medicare as well as your supplemental insurance provider. ", "Obviously this takes time to process, so it is best to avoid the whole hassle by initially finding a doctor that takes Medicare and supplemental insurance.", "\n\nAs you can see from this article, getting reimbursed for payments can be a stressful endeavor. ", "Like most things in life you want to make the process as smooth as possible and the best way to do that is by not going to doctors who will not accept your coverage. ", "If you have no choice but to see a doctor who does not accept the specific type of insurance that you carry, just bear in mind that after the visit you will have options. ", "When the time comes to file your claim the best place to look for instructions would be on your insurance company’s website. ", "For the most part there will be specific instructions that will help guide you step-by-step through the process of filing a claim through their interface.", "\n\nIn the end the most pragmatic step is to be prepared and do your research early. ", "This website is specifically designed to help you do just that. ", "Feel free to use our easy to use interface and search side-by-side comparisons of the best supplemental insurance for your specific needs." ]

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[ "Basketball at the 2014 South American Games\n\nThere were 2 basketball events at the 2014 South American Games.", "\n\nMedal summary\n\nMedal table\n\nMen's basketball\n\nGroup stage\n|}\n\nBronze Medal Match\n\nGold Medal Match\n\nWomen's basketball\n\nGroup stage\n|}\n\nBronze Medal Match\n\nGold Medal Match\n\nReferences\n\nCategory:2013–14 in South American basketball\nbasketball\nCategory:Basketball at the South American Games\nCategory:International basketball competitions hosted by Chile" ]

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[ "Free Standard Shipping above $30\n\nSandra Boynton saves the day—every day! ", "The Mom's Family Calendar is the brilliantly designed, 17-month calendar-meets-planner that busy parents just can't live without. ", "It's the ultimate marriage of the practical—a large vertical grid that allows Mom (and Dad) to see each family member's daimore" ]

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[ "Top\n\n30\n\nDoctor insights on:\nCafe Au Lait Spots\n\nCafe Au Lait Spots (Overview)\n\nLiterally french for \"coffee with milk\" these spots look like irregularly shaped large flat light tan moles. ", "Their significance increases if you have more than 6 before puberty as it can be a sign of a condition called \"neurofibromatosis\".", "\n\n1\n\nCoffee spot:\nThese are flat, well defined pigment patches that may not be evident at birth. ", "A few <6 and < 1cm size at puberty are likely unimportant.", "They are common in the general population as benign but permanent findings. ", "In greater numbers and larger size they may indicate a form of neurofibromatosis (there are several). ", "Your dr can sort out your specific issue with after an exam & family history.", "\n...Read more\n\nCafe Au Lait Spots (Overview)\n\nLiterally french for \"coffee with milk\" these spots look like irregularly shaped large flat light tan moles. ", "Their significance increases if you have more than 6 before puberty as it can be a sign of a condition called \"neurofibromatosis\".", "\n\n2\n\nCafe au lait:\nCafé au lait macules are observed in 95% of patients with neurofibromatosis type 1 (nf1), which is the most frequently occurring neurocutaneous syndrome. ", "These spots may also be observed in patients without nf1. ", "Other conditions in which they may be observed include mccune-albright syndrome, tuberous sclerosis, and fanconi anemia.", "\n...Read more\n\n4\n\nNumber of spots:\nMany people who do not have nf have a few café-au-lait spots . ", "If a young child has five or more, at least ½ inch or 15 mm in size post puberty lookfor other signs such as neurofibromas — tumors along skin and lisch nodules, tiny, noncancerous tumors on the iris (the colored part of the eye). ", "Consult physician to better assess individual signs for diagnosis.", "\n...Read more\n\n6\n\nYes, it is possible:\nWhenever a child has more than one thing going on, or one thing (e.g. Seizures) and additional physical findings (e.g. Cafe au lait spots) the possibility of a genetic condition behind findings increases. ", "Both seizures and cafe au lait spots separately are relatively common. ", "Combination increases, but does not diagnose, a genetic cause. ", "I would recommend formal evaluation by a clinical geneticist.", "\n...Read more\n\n8\n\nPossibly:\nThat many cafe au lait spots measuring at least 1.5cm in size suggests neurofibromatosis.", "This condition can have lifelong implications.", "I would bring the issue up with your doc at the next regular visit.", "\n...Read more\n\n9\n\nUnlikely:\nAccording to diagnostic criteria for nf1 at least 2 of the following clinical features must be present in order to make diagnosis (for your age group): >5 cals (>15mm in diameter), >1 neurofibroma, freckling in axillary or groin area, optic glioma, >1 lisch nodule, a distinctive bony lesion, a 1st degree relative with nf1 according to the above criteria. ", "Diagnosis may be confirmed by genetic test.", "\n...Read more\n\n12\n\nCoffee spot:\nThese are flat, well defined pigment patches that may not be evident at birth. ", "A few <6 and < 1cm size at puberty are likely unimportant.", "They are common in the general population as benign but permanent findings. ", "In greater numbers and larger size they may indicate a form of neurofibromatosis (there are several). ", "Your dr can sort out your specific issue with after an exam & family history.", "\n...Read more\n\n13\n\nCafe au lait:\nCafé au lait macules are observed in 95% of patients with neurofibromatosis type 1 (nf1), which is the most frequently occurring neurocutaneous syndrome. ", "These spots may also be observed in patients without nf1. ", "Other conditions in which they may be observed include mccune-albright syndrome, tuberous sclerosis, and fanconi anemia.", "\n...Read more\n\n14\n\nCafe au lait spots:\nCafé au lait spots are benign and do not cause any ailment themselves. ", "They can be treated by laser. ", "Having more than six spots or large spots is associated with other potentially important illnesses so check with your doctor if you have many of them.", "\n...Read more\n\n15\n\nTan skin lesions:\nLiterally french for \"coffee with milk\" these spots look like irregularly shaped large flat light tan moles. ", "Their significance increases if you have more than 6 before puberty as it can be a sign of a condition called \"neurofibromatosis\".", "\n...Read more\n\n16\n\nPossibly:\nIt depends. ", "If you are going to get some ornamental tattoo then it could possibly hide your spots. ", "However, if you are considering tattooing your spots individually to \"fill them in\" then, technically yes, it might work. ", "The trouble will be in getting the tattoo ink to match your skin color. ", "And when your skin tans (if you tend to tan) the tattoos will not darken. ", "Hope this helps.", "\n...Read more\n\n17\n\nNumber and size:\nSymptoms of nf1 may be seen at birth and may include light brown sports, six or more measuring 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals.", "Two or more growths on the iris of the eye, a tumor of optic nerve, , development of two or more subcut. ", "Nodules, neurofibromas and bone abnormalities of tibia, skull, and spine.", "\n...Read more\n\n18\n\nNumber of spots:\nMany people who do not have nf have a few café-au-lait spots . ", "If a young child has five or more, at least ½ inch or 15 mm in size post puberty lookfor other signs such as neurofibromas — tumors along skin and lisch nodules, tiny, noncancerous tumors on the iris (the colored part of the eye). ", "Consult physician to better assess individual signs for diagnosis.", "\n...Read more\n\n19\n\nPossible:\nNIH diagnostic criteria for NF1 with two or more of following features:1)6 or more café-au-lait macules over 5 mm in diameter prepubertal individuals over 15 mm in greatest diameter in postpubertal..2) 2or more neurofibromas or one plexiform neurofibroma.3)Freckling in armpit or groin areas4)Optic glioma (optic nerve tumor)5) > 2 Lisch nodules(iris of eye)6)typical bone lesions 7)1deg relative nf1\n...Read more\n\n20\n\nNot necessarily:\nMany people who do not have nf have a few café-au-lait spots . ", "Usually start appearing in infancy.", "If a young child has five or more, at least ½ inch or 15 mm in size post puberty look for other signs such as neurofibromas — tumors along skin and lisch nodules, tiny, noncancerous tumors on the iris (the colored part of the eye). ", "Consult physician to better assess individual signs for diagnosis.", "\n...Read more\n\n21\n\nSee derm:\nWith any change is shape/size/irregular borders, new lesions showing up, it is best to see the Dermatologist and get a good skin evaluation so your worries are alleviated by knowing you are being taken care of by the best doctor to do so. ", "good luck.", "\n...Read more\n\n23\n\nVariable:\nNf is very variable in expression and progression.", "Nf1 can affect the skin(neurofibromas, cafe au lait spots) , eyes( gliomas), bones( scoliosis and pseudarthrosis)nerves with neurofibromas, and a person's general constitution (adhd and mental retardation).More severe cases are usually detected earlier in life.", "Brain areas of dysplasia or tumor can occur.", "Neurologist and possible mr of brain suggested.", "\n...Read more\n\n24\n\nMaybe,maybe not:\nNF patients are at risk of seizures, as are any other kid. ", "I would discuss the matter with your doc, with more data about the time, length, type ,frequency and other features.", "With enough data, your doc may help you8 sort that out.", "\n...Read more\n\n26\n\nMutation:\nYou can acquire many genetically inherited illnesses by spontaneous mutation in utero, or when the baby is developing inside mom during the pregnancy. ", "This is a force of nature that is recignized by many Geneticists\n...Read more\n\n27\n\n?", "Von Recklinghausen':\nProbably, some hereditary component here, and sounds like incomplete penetrance. ", "This, however, can be blood tested and confirmed or disconfirmed, so not a bad idea to get a clear fix on risk factors. ", "However, possibility of future acoustic neuromas in other family members is low statistically.", "\n...Read more\n\nUnclear, but...:\nWhat you have noted would not indicate the diagnosis, since there are specific criteria for the neurofibromatosis diagnosis. ", "You should consult your local doctor who can do a complete physical examination and history for further assessment..\n...Read more\n\n30\n\nYes, it is possible:\nWhenever a child has more than one thing going on, or one thing (e.g. Seizures) and additional physical findings (e.g. Cafe au lait spots) the possibility of a genetic condition behind findings increases. ", "Both seizures and cafe au lait spots separately are relatively common. ", "Combination increases, but does not diagnose, a genetic cause. ", "I would recommend formal evaluation by a clinical geneticist.", "\n...Read more" ]

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[ "D-cycloserine for the treatment of ataxia in spinocerebellar degeneration.", "\nWe studied the effects of D-cycloserine, a partial NMDA receptor allosteric agonist, on ataxia in patients with spinocerebellar degeneration. ", "Fifteen Japanese ataxic patients enrolled in a 14-day single-blind trial of D-cycloserine (daily oral dose of 50 mg) following a 14-day single-blind placebo phase. ", "At the end of the D-cycloserine administration, there was a significant reduction in the posture, gait and total score of the international cooperative ataxia rating scale and in the time for walking and speech tasks. ", "D-Cycloserine was well-tolerated and no adverse effect was observed. ", "D-Cycloserine may have therapeutic efficacy for spinocerebellar ataxia." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "\n642 A.2d 125 (1994)\nCITIZENS ASSOCIATION OF GEORGETOWN, et al., ", "Petitioners,\nv.\nDISTRICT OF COLUMBIA BOARD OF ZONING ADJUSTMENT, Respondent, and\nDistrict of Columbia, Intervenor.", "\nNo. ", "92-AA-1165.", "\nDistrict of Columbia Court of Appeals.", "\nArgued April 13, 1994.", "\nDecided May 26, 1994.", "\nSteven M. Schneebaum, with whom Martha M. Kendrick, Washington, DC, was on the brief, for petitioners.", "\nLutz Alexander Prager, Asst. ", "Deputy Corp. Counsel, with whom John Payton, Corp. Counsel at the time the brief was filed, and Charles L. Reischel, Deputy Corp. Counsel, Washington, DC, were on the brief, for intervenor.", "\nBefore FERREN, Acting Chief Judge, TERRY, Associate Judge, and PRYOR, Senior Judge.", "\nFERREN, Acting Chief Judge:\nThe District of Columbia filed an application with the Board of Zoning Adjustment (BZA) for a special exception, pursuant to 11 DCMR § 218.7 (1991),[1] to establish the Hurt Home as a youth residential care home for twenty-four persons. ", "The BZA granted the special exception. ", "Petitioners, the Citizens Association of Georgetown and other individuals, challenge the BZA's authority to grant *126 the special exception, arguing (among other things) that the zoning regulations do not permit special exceptions for youth residential care homes for more than fifteen persons. ", "We agree with petitioners and reverse the BZA's order.", "\n\nI.\nIn 1987, the District of Columbia purchased the Hurt Home for the Blind, an institution located in Georgetown at 3050 R Street, N.W., and zoned R-1-B. Before the District bought the Hurt Home, the Department of Human Services announced its intention to establish a residential treatment center for twenty-four emotionally disturbed young people. ", "Certain neighbors of the Hurt Home opposed the District's plan.", "\nAfter the District acquired the Hurt Home, it began the necessary renovations to prepare the building for its intended use. ", "Relying on a June 23, 1988 Superior Court opinion by Judge Weisberg, which held that the District's zoning laws did not apply to the District as property owner, the District did not initially seek zoning review of its proposed facility. ", "After this court's opinion in Speyer v. Barry, 588 A.2d 1147 (D.C.1991), however, which reversed in part Judge Weisberg's opinion, the District applied for a Certificate of Need from the State Health Planning and Development Agency. ", "That agency eventually granted the Certificate of Need, which is now under review by the Board of Appeals and Review and is not before us in this appeal.", "\nAlso in response to our Speyer opinion, the District applied to the BZA on July 9, 1991 for a special exception to the zoning regulations to allow the District to establish the Hurt Home as a youth residential care home for more than fifteen persons.[2] The application, filed pursuant to 11 DCMR § 218.7,[3] see supra note 1, described the proposed facility as a \"Residential Treatment Facility for 24 Youths\" \"designed to serve 24 emotionally disturbed boys and girls, ages 6 to 12 years upon admission, who have demonstrated a need for 24 hour intensive therapeutic services in a residential setting.\" ", "The BZA held a hearing on October 9, 1991, where the Citizens Association of Georgetown and a number of individuals appeared and offered testimony.", "\nThe Citizens Association opposed the District's special exception application on four grounds: (1) Chapter 11 DCMR § 218.7, supra note 3, does not authorize the BZA to grant a special exception of any kind, and thus a variance would be required for the District's proposal;[4] (2) even if § 218.7 grants the BZA special exception authority, the proposed facility is not a \"youth residential care home,\" as defined by applicable regulations;[5] (3) even if the proposed facility *127 would meet the criteria for such a home, the BZA cannot grant the District a special exception because § 218.7 authorizes a special exception only for a \"community residence facility,\"[6] not for a \"youth residential care home;\" and (4) even if the BZA had authority to grant a special exception for a youth residential care home for more than fifteen persons, reversal is required because the BZA ignored, and the District presented no evidence to satisfy, the § 218.7 requirement permitting special exceptions only when \"there is no other reasonable alternative to meet the program needs of that area of the District.\" ", "Supra note 3.", "\nIn an order dated August 27, 1992, the BZA granted the District's application for a special exception. ", "The BZA concluded, contrary to the Citizens Association's contentions, that \"the children to be served [by the proposed facility] meet the characteristics of persons described in the definition of youth residential care home,\" and that \"special exception relief for a youth residential care home under [11 DCMR § 218.7] is consistent with the intent of the Zoning Regulations.\" ", "Petitioners now challenge the BZA's order in this court.", "\n\nII.", "\nWe can dispose of the petition by considering petitioners' third argument, and thus we do not address the others.", "\n\nA.\nPetitioners contend that the plain language of 11 DCMR § 218.7 clearly states that the BZA has authority to approve a facility for more than fifteen persons only \"[i]n the case of a community residence facility,\" 11 DCMR § 218.7, supra note 3, and, therefore, that the BZA implicitly lacks the additional authority to approve a \"youth residential care home,\" which § 218.7 fails to mention. ", "Petitioners stress that there is a fundamental difference between these two types of facilities that would justify different zoning treatment because of the different populations involved and thus the different potential impacts on neighborhoods; community residence facilities are for adults age eighteen and over; youth residential care homes are for youths under age eighteen. ", "See supra notes 5 and 6. ", "The District does not dispute the clarity of the language of § 218.7 but argues that the legislative history of § 218.7 reflects that \"§ 218.7's failure to refer to residential youth care homes was an inadvertent omission.\"", "\nThe BZA agreed with the District, concluding that\nspecial exception relief for a youth residential care home under Subsection [218.7], is consistent with the intent of the Zoning Regulations as set forth in Zoning Commission Order No. ", "347. ", "In that order, both terms — \"youth residential care home\" and \"community residence facility\" — are defined and listed as sub-categories of the general term \"community-based residential facility.\" ", "It is the Board's view that the Zoning Commission intended to allow both youth care homes and community residence facilities for more than 15 persons if certain conditions were met.[7]\n\n\n*128 B.\n\"This court's review of the decision of the Board of Zoning Adjustment is limited to a determination of whether the decision is arbitrary, capricious, or otherwise not in accordance with the law.\" ", "Davidson v. Board of Zoning Adjustment, 617 A.2d 977, 981 (D.C.1992). \"", "The Board's interpretation of the [zoning] regulations must be accorded great weight, and must be upheld unless it is plainly erroneous or inconsistent with the regulations.\" ", "Glenbrook Rd. ", "Ass'n. ", "v. Board of Zoning Adjustment, 605 A.2d 22, 30 (D.C.1992).", "\nOn the other hand, in construing the regulation, while giving due deference to the BZA, we cannot abandon our traditional rules for interpreting statutes. ", "More specifically, when interpreting a statute or regulation, we first look to the language of the act, see McDonald v. United States, 496 A.2d 274, 276 (D.C.1985), and when the language is unambiguous and does not produce an absurd result, we will not look beyond its plain meaning. ", "See J. Frog, Ltd. v. Fleming, 598 A.2d 735, 738 (D.C.1991); see also Peoples Drug Stores, Inc. v. District of Columbia, 470 A.2d 751, 755 (D.C.1983) (en banc). ", "We have stated on numerous occasions that \"when the language of a statute is clear and admits of no more than one meaning, we are not empowered to look beyond the literal words of the statute.\" ", "Nova Univ. ", "v. Educ. ", "Inst. ", "Licensure Comm'n, 483 A.2d 1172, 1179 (D.C.1984), cert. ", "denied, 470 U.S. 1054, 105 S.Ct. ", "1759, 84 L.Ed.2d 822 (1985); see also Auger v. District of Columbia Bd. ", "of Appeals & Review, 477 A.2d 196, 211 (D.C.1984). ", "Thus, if the meaning of the plain language of a statute is clear, we must enforce it according to its terms, see United States v. Edelen, 529 A.2d 774, 778 (D.C.1987), and \"there is no need to engage in an analysis of legislative intent.\" ", "Butler v. Butler, 496 A.2d 621, 622 (D.C.1985).", "\nIn this case, despite the deference we owe to the BZA interpretation of the zoning regulations, we must conclude that the BZA's interpretation of § 218.7 is \"plainly erroneous\" and \"inconsistent with the regulations,\" id., because that interpretation violates the rules of construction traditionally applicable to statutes and regulations. ", "We do agree, as the BZA noted, that one sentence in Zoning Commission Order No. ", "347 appears to suggest an intention to treat youth residential care homes and community residence facilities the same way for all purposes. ", "See supra note 7. ", "But, as elaborated below, whatever that sentence in the legislative history may indicate — and, given its generality, it is hardly conclusive — it cannot dictate the result when the plan language of the regulation is to the contrary.", "\nWe agree with petitioner's position for three reasons. ", "First, the language of the regulation at issue here, 11 DCMR § 218.7, is unambiguous, does not produce an absurd result, and plainly does not provide the BZA with the authority it purported to exercise in this case: \"In the case of a community residence facility, the Board may approve a facility for more than fifteen (15) persons....\" 11 DCMR § 218.7 (emphasis added), supra note 3. ", "Section 218.7, therefore, gives the BZA authority to grant special exceptions for more than fifteen persons only for a category of residential facilities that differs from the category at issue here. ", "Compare supra notes 5 and 6. ", "We are guided by a traditional rule of statutory construction: \"[w]hen a legislature makes express mention of one thing, the exclusion of others is implied, because `there is an inference that all omissions should be understood as exclusions.'\" ", "McCray v. McGee, 504 A.2d 1128, 1130 (D.C.1986) (quoting 2A SUTHERLAND, STATUTES AND STATUTORY CONSTRUCTION § 47.23 (4th ed. ", "1984)). ", "Section 218.7 specifically mentions a community residential facility; it does not mention a youth residential care home. ", "We therefore must conclude that, by referring only to community residence facilities in § 218.7, the Zoning Commission implicitly denied the BZA authority to grant special exceptions for youth residential care homes.", "\nSecond, it is clear from looking at 11 DCMR § 218 as a whole that the Zoning Commission, in drafting § 218.7, intended to treat community residence facilities and youth residential care homes differently. ", "Section 218 of the Zoning Regulations, entitled \"Youth Care Homes and Community Residence Facilities,\" regulates the zoning *129 for both types of places. ", "All the subsections of § 218, with the exception of subsection 218.7, treat community residence facilities and youth residential care homes identically. ", "Subsection 218.7, on the other hand, distinguishes between those two types of facilities, expressly granting the BZA special exception authority for the one while not mentioning the other. ", "Accordingly, it seems clear that the Zoning Commission was aware of the distinction it made between community residence facilities and youth residential care homes when it drafted § 218.7. ", "See In re Bicksler, 501 A.2d 1, 6 (D.C.1985) (\"statutory provisions must be construed together with related provisions and not in isolation\").", "\nFinally, we have said that \"[w]hen interpreting any portion of an act, the statutory meaning of a term or phrase must `be derived not from the reading of a single sentence or section, but from consideration of [the] entire enactment against the backdrop of its policies and objectives.\" ", "Carey v. Crane Serv. ", "Co., 457 A.2d 1102, 1105 (D.C.1983) (quoting Don't Tear It Down v. Pennsylvania Ave. ", "Dev. ", "Corp., 206 U.S.App.", "D.C. 122, 128, 642 F.2d 527, 533 (1980)). ", "We therefore may interpret § 218 by taking into account the regulations that govern all community-based residential facilities,[8] which include youth residential care homes.", "\nSections 218 through 221 of Chapter 11 DCMR regulate seven categories of community-based residential facilities. ", "See supra note 8. ", "Section 218, the regulation at issue here, regulates zoning of youth residential care homes and community residence facilities; section 219 regulates zoning of health care facilities; section 220 regulates zoning of emergency shelters; and section 221 regulates zoning of youth rehabilitation homes, adult rehabilitation homes, and substance abusers' homes. ", "See supra note 8. ", "It is interesting to note that every subsection of § 221, which regulates three types of facilities, treats them identically in every respect. ", "See, e.g., 11 DCMR § 221.7 (limiting approval of a youth rehabilitation home, adult rehabilitation home, or substance abusers' home to not more than one in a square of within 1,000 feet of each other). ", "In contrast with § 221, § 218 distinguishes in at least one respect between the two types of facilities it regulates, expressly giving the BZA authority to grant a special exception for more than fifteen persons for a \"community residence facility\" but not for a \"youth residential care home.\" ", "This analysis, therefore, buttresses our conclusion that the Zoning Commission knew how to draft regulations that treated separate categories of facilities the same while treating others differently, and that the Commission accordingly intended in § 218.7 to treat community residence facilities and youth residential care homes differently by withholding special exception authority from the BZA as to the latter.[9]\n\n* * *\n*130 In sum, we conclude that § 218.7 does not grant the BZA authority to approve a youth residential care home for more than fifteen persons in an R-1 zone. ", "We reverse the BZA's order granting the District a special exception to establish the Hurt Home as a youth residential care home for 24 persons.", "\nReversed and remanded.", "\nNOTES\n[1] The BZA's decision refers to this provision of the zoning regulations as 11 DCMR § 219. ", "The regulations were renumbered in the 1991 edition of 11 DCMR, and § 218 now governs youth care homes and community residence facilities. ", "The text of the regulations was not changed when they were renumbered. ", "We use the more current numbering, which presumably will be applicable to similar cases in the future.", "\n[2] We do not address the question whether special exceptions are required for all youth residential care homes, irrespective of the number of persons occupying them. ", "We note that 11 DCMR § 218.1 provides:\n\nYouth residential care home or community residence facility for nine (9) to fifteen (15) persons, not including resident supervisors and their family, shall be permitted in an R-1 district if approved by the Board of Zoning Adjustment in accordance with the conditions specified in § 3108 [\"special exceptions\"] of chapter 31 of this title, subject to the provisions of this section.", "\n[3] Chapter 11 DCMR § 218.7 provides:\n\nIn the case of a community residence facility, the Board may approve a facility for more than fifteen (15) persons, not including resident supervisors and their families, only if the Board finds that the program goals and objectives of the District cannot be achieved by a facility of a smaller size at the subject location, and if there is no other reasonable alternative to meet the program needs of that area of the District.", "\n[4] Petitioners base their argument on the fact that, in companion regulations governing community-based residential facilities, in par-particular 11 DCMR §§ 218.1, 219.1, 220.1, and 221.1 (1991), there are express cross-references to the BZA's special exception authority specified in 11 DCMR § 3108, whereas § 218.7 contains no reference to § 3108. ", "See supra note 2 (quoting 11 DCMR § 218.1).", "\n[5] The regulations define a \"youth residential care home\" as\n\na facility providing safe, hygienic, sheltered living arrangements for one (1) or more individuals less than eighteen (18) years of age, not related by blood, adoption, or marriage to the operator of the facility, who are ambulatory and able to perform the activities of daily living with minimal assistance.", "\n11 DCMR § 199.1. ", "Petitioners contend that the Hurt Home residents would not satisfy the last clause: \"able to perform the activities of daily living with minimal assistance.\"", "\n[6] The regulations define \"community residence facility\" as\n\na facility providing safe, hygienic sheltered living arrangements for one (1) or more individuals aged eighteen (18) years or older (except that, in the case of group homes for mentally retarded persons, no minimum age limitation shall apply), not related by blood or marriage to the residence director, who are ambulatory and able to perform the activities of daily living with minimal assistance.", "\n22 DCMR 3099.1 (1986); see also 11 DCMR 199.1.", "\n[7] Zoning Commission Order No. ", "347, 28 D.C.Reg. ", "3547-55 (1981), is the \"legislative history\" for the 1981 amendments to the relevant zoning regulations, which revised the definitions and locations of community-based residential facilities. ", "In concluding that \"special exception relief for a youth residential care home under Subsection 218.7 is consistent with the intent of the Zoning Regulations,\" the BZA relied primarily on a single sentence in Order No. ", "347. ", "In a discussion of the seven subcategories of community-based residential facilities, Order No. ", "347 states:\n\nCommunity residence facilities ... are permitted in the same zones and in the same manner as youth residential care homes.", "\n28 D.C.Reg. ", "at 3551.", "\n[8] \"Community-based residential facility\" is defined as\n\na residential facility for persons who have a common need for treatment, rehabilitation, assistance, or supervision in their daily living.... If an establishment is a community-based residential facility as defined in this section, it shall not be deemed to constitute any other use permitted under the authority of these regulations ... All community-based residential facilities shall be included in one (1) or more of the following subcategories:\n(a) Adult rehabilitation home\n(b) Community residence facility\n(c) Emergency shelter\n(d) Health care facility\n(e) Substance abusers home\n(f) Youth rehabilitation home\n(g) Youth residential care home\n11 DCMR § 199.1 (1991).", "\n[9] Petitioners have supplemented the record with a very recent Zoning Commission Order, No. ", "754, Case No. ", "93-4, 41 D.C.Reg. ", "1616-20 (March 25, 1994), which denied a petition submitted by the Mayor on February 1, 1993, \"request[ing] the [Zoning] Commission to permit the Board of Zoning Adjustment (BZA) to consider for approval more than 15 residents as a special exception for a youth residential care home in the R-1 zone district.\" ", "41 D.C.Reg. ", "at 1616. ", "The Mayor proposed the following language to amend the text of zoning regulation § 218.7:\n\nThe Board may approve a youth residential care home or a community residence facility for more than fifteen (15) persons, not including resident supervisors and their families, only if the Board finds that the program goals and objectives of the District cannot be achieved by a facility of a smaller size at the subject location, and if there is no other reasonable alternative to meet the program needs of the District.", "\nId. (emphasis added). ", "The Commission denied the Mayor's petition, stating:\nThe Commission concurred with the position of all the ANC's and determined that the proposed amendments will not be in the interest of the District of Columbia. ", "The Commission believes that a [youth residential care home] with more than 15 residents is not an appropriately sized facility of this type to be given special exception relief in the R-1 zone district. ", "In considering and balancing all the testimony relative to the proposal, the Commission believes that the proposed amendments are not in the best interest of the District of Columbia, and are inconsistent with the intent and purpose of the Zoning Regulations and Zoning Act. ", "In consideration of the reasons set forth herein, the Zoning Commission for the District of Columbia orders DENIAL of Z.C. Case No. ", "93-4.", "\n41 D.C.Reg. ", "at 1620. ", "Our decision in this case does not rely on Order No. ", "754 because that order is not relevant legislative history. ", "See McIntosh v. Washington, 395 A.2d 744, 750 n. 12 (D.C.1978) (\"[T]he views of a subsequent Congress form a hazardous basis for inferring the intent of an earlier one.\") (", "quoting United States v. Price, 361 U.S. 304, 313, 80 S.Ct. ", "326, 332, 4 L.Ed.2d 334 (1960)). ", "We cite Order No. ", "754 simply to show that the present Zoning Commission apparently reads the language of § 218.7 as we do.", "\n" ]

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[ "Altered hepatic foci in rat liver as weight of evidence of carcinogenicity: the Canadian perspective.", "\nThe use of AHF in the rat as a predictive lesion for carcinogenesis has been frequently suggested. ", "Regulatory agencies require that the data used to determine carcinogenic potential and for estimating risk cannot be open to different interpretations. ", "The degree of uncertainty in establishing relationships between the different foci phenotypes, their fate, and the difference in results with different protocols precludes the use of these data is establishing carcinogenic hazard or in quantitative risk estimation." ]

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[ "Townhomes of dreams\n\nEight families get a second chance because of the efforts of Covington, Habitat\n\nThe Covington chapter of Habitat for Humanity selected eight families to move into newly renovated townhomes in Walker's Bend. ", "Six of are show here posing in front of their homes, which were purchased by Covington through the Neighborhood Stabiliz...\n\nLakisha Johnson was moving backwards and grasping for something, anything to hold onto. ", "Several years ago life had seemed so bright — she’d been in a relationship and had just bought her own house.", "\n\nThe relationship turned sour along with the economy, so she moved into a more manageable apartment. ", "Though the mortgage changed to a rent payment, her other bills remained high — eventually too high. ", "And just like that, Johnson found herself and her three children living in her grandmother’s house, without a place of their own.", "\n\n\"I was trying to find out where I was going next. ", "Me and my kids were all in the same room, I was trying to figure … I didn’t know which direction we were going in, she said. \"", "I was just lost.\"", "\n\nHer compass came in the form of a friend, who told Johnson that Habitat for Humanity was accepting applications at the Covington library. ", "Even then, Johnson thought the application was just a shot in the dark.", "\n\nBut then the phone rang and Johnson was called in for an interview. ", "Another step, but help still seemed like a distant dream.", "\n\nJohnson is still expecting to wake up, to be pinched, to be told it isn’t real. ", "Because not even in her dreams did she see such a turnaround in store for herself; not even there did she expect the phone call to come. ", "Not even there did she herself in a house again.", "\n\n\"When I got the call it was like God calling, like a savoir had come for me. ", "It’s really a blessing. ", "I never thought I’d be able to own a house again,\" Johnson said. \"", "In the process of me trying to catch up on my bills that phone call came. ", "They told me to go pick out my house. ", "I said ‘Go pick out my house?’ ", "Until I got the keys I was in shock. ", "I’m still in shock now.\"", "\n\nJohnson was one of eight families that were sold townhomes in Walker’s Bend. ", "The foreclosed homes had been purchased by the City of Covington using Neighborhood Stabilization Program money, courtesy of the stimulus package.", "\n\nWhile the program has been ineffective and maligned in other communities, Covington managed to spend its money quickly and all in one place. ", "The city partnered with the Covington chapter of Habitat for Humanity; the non-profit group renovated the homes, chose the families and took care of the complicated monetary agreements with the state.", "\n\nHabitat President Jeremy Shearer had hoped to move the families in before Christmas, but it was that complicated stimulus reporting process that held everything up. ", "The families eventually moved in on Feb. 25.", "\n\nThe properties cost nearly $400,000, while repairs cost around $23,000. ", "Covington was the first governmental entity to spend all of its money and received an additional $75,000 from the Georgia Department of Community Affairs earlier this year. ", "City Planning Director Randy Vinson said the city would continue to pursue properties in Walker’s Bend if possible.", "\n\nMayor Kim Carter said the NSP is a big-part of the city’s overall housing plans, and she hopes it sets the stage for even greater improvement.", "\n\n\"The big winners are eight families that now have an affordable new home to live in. ", "At the end of the day, we hope we have positively impacted the quality of life for those eight families and all of the families living in the Walker's Bend subdivision,\" Carter said in an e-mail. \"", "Long term, we hope to have a safe, stable, mixed use neighborhood that everyone can be proud to call home.\"", "\n\nHeather and James Sorrows are another one of the eight families that are proud to call the subdivision their new home. ", "Like Johnson, the Sorrows had lost their home and had been forced to move in with one of Heather’s relatives.", "\n\n\"It seemed like everything fell apart at one time,\" said Heather. ", "Though they were struggling, the Sorrows used that time to pay their bills and get out of debt. \"", "We put everything in perspective and gave it our best shot.\"", "\n\nShe said her family had thought about owning a home again, but it’s always a risky proposition. ", "But by working with Habitat, she managed to have peace of mind, because the group understands hardships and works with its’ mortgage owners to solve problems. ", "In addition, Habitat repaired everything and gave the families appliances that had been donated.", "\n\nOne of her greatest joys is the pride that her young daughter and older son show in having their own rooms.", "\n\nHabitat’s humanitarian spirit hasn’t been lost on Johnson either; she’s knows how truly blessed she is.", "\n\n\"The mortgage, and everything, is reasonable, more than reasonable. ", "It’s like a survival (rate). ", "Who moves into a house and pays a $300 mortgage a month? ", "It hasn’t event set in, even though I paid my first month,\" she said. \"", "I paid $300; that’s it. ", "It’s like the light of God — a true blessing.\"" ]

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[ "Diane Follingstad\n\nDiane R. Follingstad is an American psychologist and author, currently the Women's Circle Endowment Professor of Psychology and Director of the Center for Research on Violence Against Women at the University of Kentucky She was previously a Distinguished Professor Emerita at the University of South Carolina.", "\n\nReferences\n\nExternal links\nWorldCat\n\nCategory:University of Kentucky faculty\nCategory:University of South Carolina faculty\nCategory:American psychologists\nCategory:American psychology writers\nCategory:University of Colorado alumni\nCategory:Augsburg University alumni\nCategory:Living people\nCategory:Year of birth missing (living people)\nCategory:Place of birth missing (living people)\nCategory:Kentucky women writers\nCategory:Kentucky women psychologists\nCategory:American women non-fiction writers" ]

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[ "Q:\n\nWhat is this hidden directory doing on my Desktop?", "\n\nOn my Mac I just encountered a hidden directory on my desktop. ", "I don't recall putting it there.", "\nWhen I type ls -la in Terminal on the desktop I get the following:\n\nThe last folder is what triggered my attention. ", "It is also highlighted.", "\nWhen I cd into that directory and type ls -la I see:\ntotal 16\ndrwxrwxrwx@ 4 user staff 136 Oct 18 2012 .", "\ndrwx---rwx 17 user staff 578 Dec 17 15:03 ..\n-rw-rw-rw-@ 1 user staff 231 Jan 16 2013 6VR16NQEUJ456542VDR66LS7\n-rw-rw-rw-@ 1 user staff 226 May 8 2013 K7wuT15oKsg=\n\nThe 6VR... file can be opened in Sublime Text as a Hex file, the other shows up empty.", "\nWhat is this folder doing on my desktop? ", "Googling the exact name does not give any results.", "\n\nA:\n\nWhen a file or folder is highlighted, it means that file has the read, write, and execute permissions set for Owner, Group, and Other (chmod 777). ", "The folder is not a \"sticky\" folder. ", "\nFor Mac OSX a sticky bit is designated in the \"EXECUTE\" (x) bit within the file or directory properties.", "\nFor example:\ndrwtrwxrwx \nBreaking down the above line:\nd = directory\nrwt = The OWNER of the file has read, write, and is the only one who has permissions to delete this file (oh and execute)\nrwx = Any user part of the GROUP \"staff\" which you kindly displayed above in your example has the power to read, write, and execute.", "\nthe last rwx = anyone not part of the group staff and not an owner has the right to read, write, and execute.", "\nThat directory could've been created possibly by a program, someone hijacking your machine, etc. ", "There could be any number of reasons that was placed there.", "\nI'd advise deleting it and if you'd like perform a scan on your machine.", "\nCheck to see if your machine has any ports open for listening using netstat -antp in terminal.", "\n\n" ]

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[ "Introduction {#Sec1}\n============\n\nPlants and plant materials have always been components of the indigenous cultures throughout the world since ancient times. ", "Fibers from plants have been of primary importance in almost all human cultures and history of processing plant fibers is more than 10,000 years old \\[[@CR1]\\]. ", "Uses of fibers in handicrafts, utensils, and other goods have a significant contribution in the evolution of cultures and ultimately people's comforts and quality of daily life \\[[@CR2]\\]. ", "Significant numbers of these fiber goods are linked to domestic activities such as the production and use of furniture, the preparation of food, and the production of cloths \\[[@CR3]\\]. ", "Despite these facts, ethnobotanical and/or ethnographic studies focusing specifically on handcrafted products are still scarce and even more rare those studies that try to investigate cultural variations of Traditional Knowledge linked to handicrafts.", " Human societies, on the other hand, have used palm species since more than 10,000 years \\[[@CR4]\\]. ", "Palm leaves exhibit a large flexibility for being used in different ways and hence they have been often harvested by many local communities around the globe \\[[@CR5]\\]. ", "Moreover, palms are culturally valuble sources of foods, medicines, and especially handcrafted products \\[[@CR6]\\].", "\n\nSpecies belonging to the Arecaceae (Palmae) family are of primary importance for many traditional societies in general and in Pakistan in particular. ", "Sixteen genera and eighteen palm species do occur in Pakistan, out of which 14 genera and 15 species are cultivated and 2 genera and 3 species are wild \\[[@CR7]\\]. *", "Nannorrhops ritchiana* (Griff) Aitch is one of these species native to Pakistan (and Afghanistan and Iran too). ", "It is a gregarious and versatile shrub that can survive in intense winds, severe cold, blazing heat and scarce water and can grow in extreme environments \\[[@CR8]\\].", "\n\nMazri palm grows wild in different areas of Pakistan: in Sindh and West Punjab \\[[@CR9]\\], Peshawar Valley, Kohat, Indus gorge \\[[@CR10]\\], Kohe safid \\[[@CR11]\\], Kurram valley \\[[@CR12]\\], South Waziristan \\[[@CR13]\\], North Waziristan \\[[@CR14]\\], Frontier Region Bannu \\[[@CR15]\\], Malakand \\[[@CR16]\\], Hangu \\[[@CR17]\\], Dera Ismail Khan \\[[@CR18]\\], Mohmand \\[[@CR19], [@CR20]\\], and Sheikh Baddin National Park \\[[@CR21]\\]. ", "It is extensively distributed in a number of regions in Baluchistan \\[[@CR22]\\], Mekran, Loralai \\[[@CR23]\\], Khirthar National Park \\[[@CR24]\\], Gawadar \\[[@CR25]\\], and Shahi Tump Baluchistan \\[[@CR2]\\]. ", "It is found in depressions of sandy soil within an elevation range of 600--1100 meters a.s.l. ", "in the Suleiman Range \\[[@CR26]\\] and it forms a very patchy vegetation called *Tal* in Pashto language.", "\n\nMazri palm plays a significant role in the livelihood of the local communities and indigenous peoples of Pakistan and a considerable portion of the population of ex-FATA (Federally Administrated Tribal Areas) and Baluchistan are involved in its cultivation and in the processing of its leaves \\[[@CR27]\\]. ", "The harvesting period of this plant usually ranges from October to February. ", "A single compound leaf yields about 30 to 40 leaflets and five kilograms of dry leaves generally give about four kilograms of products, with a usual waste of about 20% of materials \\[[@CR28]\\]. ", "Mazri palm is one of the hardest palms used as a source of fibers for weaving various utensils and rope making \\[[@CR2], [@CR29]\\]. ", "Historically, the leaves and stems were utilized in mats, fences, and house roofing \\[[@CR30]\\]. ", "Leaves alone are were to manufacture hand fans, baskets, brooms, trays, small prayer mats, large prayer mats, grain bins, hot pots, hats, and sandals \\[[@CR18]\\]. ", "The reddish moss-like wool of the petioles of Mazri palm was sometimes utilized as tinder, while the fruits are edible and the hard-coated seeds were utilized for producing rosaries \\[[@CR24]\\]. ", "Dried leaves, stems, and peduncles of Mazri Palm were used as domestic fuel as well. ", "In southern Europe and southern and subtropical America, the Mazri plam is grown as an ornamental plant \\[[@CR31]\\]. ", "In summary, the most interesting economical botanical use of this species is linked to the preparation of traditional handcrafted products. ", "These products are on the verge of extinction in Pakistan due to (1) the reduction in the natural population of this palm, (2) the loss of specific ethnobotanical knowledge, and (3) the wide diffusion of synthetic fibers in the market under triggered trends of globalization, industrialization, and communication processes. ", "Keeping in mind the importance of Mazri plant's multifold ecosystem services, ancient hadicrafts-based ethnobotanical knowledge of rural communities, and anthropogenic and envionmental threats, the current study was aimed to: document the importance of Mazri palm in terms of both ecosystemic and cultural services;identify the local specific utilizations of Mazri palm based on availability of plant material and the Traditional and Indigenous Knowledge that the communities still retain;understand regional and cultural variations in the uses of this palm in Pakistan;possibly promote the local cultural, economic, and environmental significance of this palm and its future small-scale, sustainable manufacturing activities based on the recorded Traditional Knowledge.", "\n\nMaterials and methodology {#Sec2}\n=========================\n\nStudy area {#Sec3}\n----------\n\nPakistan overall has an area of 796,095 Km^2^ and lies between the following coordinates: 60° 55′ to 75° 30′ E (longitude) and 23° 45′ to 36° 50′ N (latitude). ", "It hosts more than 6000 species of higher plants \\[[@CR32]\\] of which 70% are uni-regional and about 30% are bi-or pluri-regional distributed across four Floristic regions i.e., Irano-Turanian (45% of species), Sino-Himalayan (10%), Saharo-Sindian (9.5%), and Indian region (6%) \\[[@CR33]\\]. ", "Pakistan is custodian of four seasons, i.e., winter (December to March), spring (April to June), summer (July to September), and autumn (October to November) \\[[@CR34]\\]. ", "Most parts of the country are arid and semi-arid with the exceptions of the the southern slopes of the Himalayas and Hindu Kush, i.e., the whole of Sindh province, a major part of Baluchistan, southern parts of Punjab, and central parts of the Gilgit-Baltistan \\[[@CR35]\\]. ", "Pakistan has a rich cultural/ethnic diversity, with major ethnic groups of Pashtuns (also named Pathans or Pakhtuns), Punjabis, Baluchis, Sindhis, Gujjars, Kashmiris, Hindkowans, Chitralis, Gilgitis, Baltis, etc. ", "who have their own languages, unique traditions, and customs. ", "Fig. ", "1Map of the study area in Pakistan showing (in green) the localities where the surveys were conducted\n\nWe focused on diverse Mazri palm growing and Mazri manufacturing and marketing regions (Districts) of the country (Fig. [", "1](#Fig1){ref-type=\"fig\"}). ", "The Mazri growing and manufacturing areas are: Jhandai Mardan (inhabited by the following ethnic/tribal groups: Utmankhel, Mohmand, Yusafzai, and Mashwani), Lundkhwar Mardan (Utmankhel, Mohmand, Yusafzai, Gujjar), Bajaur (Tarkani, Utmankhel, Mughal, Khalji), Kohat (Bangash, Khattak, Turi, Afridi, Orakzai), Dera Ismail Khan (Kundi, Gandapur, Hasan Khel, Wazir, Mehsood, Dawar), Bannu (Banusi, Wazir, Mehsood), and Quetta (mainly populated by Pashtuns). ", "The marketing regions include Timergara, Dir Lower (Diruji, Utmankhel, Mashwani, Tajak), Qissa Khwani Bazar Peshawar (Afghani, Yousafzai, Mohmand, Afridi, etc.), ", "Charsadda (Umarzai, Turangzai, Sherpao, Barazai, Mohmand), Mingora Swat (Yusafzai, Kohistani), Pir Baba Buner (Bachagan, Gujjar, Sikhs, Hindus), Karachi (Muhajir, Pashtun, Sindhi, Baloch, Punjabi), Bharakahu Islamabad (Kyani, Raja, Awan, Abbasi), Raja Bazar Rawalpindi (Ghazni, Janjua, Sheikh, Gujjar, Gakhar), Hasan Abdal (Awan, Rajput, Syeds), Mansehra (Abbasi, Tanoli, Gujjar, Syeds, Awan), Abbottabad (Abbasi, Jadoon, Syeds, Gujjar, Tanoli), Haripur (Awan, Syeds, Dalazak, Rajput), and Bahawalpur (Jat, Arain, Rajput, Awan, Gujjar).", "\n\nMazri palm grows from the coastal region of Baluchistan up to the North of ex-Federally Administrated Tribal Areas (ex-FATA) and to western mountainous belt of the Khyber-Pakhtunkhwa (KP). ", "Owing a geographically varied landscape and climatic diversification, western parts of Pakistan are gifted with rich natural resources and diverse cultures \\[[@CR36]\\]. ", "Mazri handicrafts represent a common source of livelihood for the people of those and adjacent areas; in these regions, the leaves are processed to various handcrafted products and the they are also sold in the nearby regions in fresh forms.", "\n\nField study {#Sec4}\n-----------\n\nThe research work was carried out from the spring of 2017 until the autumn of 2018. ", "Palm growers, Mazri farmers, handicrafts experts, manufacturers, middlemen, shopkeepers, and people related to palms marketing were selected as focus groups. ", "These focus groups were classified in two main clusters based on their location. ", "Focus Group 1 includes palm growers, local farmers, manufacturers, middlemen, and marketing people who live predominantly in the Pakistani-Afghan and Pakistani-Iran borders' regions, while Focus Group 2 include business communities or shopkeepers who are localized in very specific markets in various urban areas of the country. ", "These two different focus groups were visited and interviewed via 86 structured and semi-structured interviews, conducted with the help of an ad-hoc designed questionnaire (Additional file [1](#MOESM1){ref-type=\"media\"}).", "\n\nBorder regions of Pakistan and Afghanistan (ex-FATA-Federally Administered Tribal Areas) were visited, and interviews were conducted with 17 palm growers (of which 12 were men and 5 women), 27 Mazri farmers (all men), 23 handicrafts experts/manufacturers (21 men and 2 women), and 19 sellers/middlemen. ", "We used mainly Pashto and Urdu languages during the interviews. ", "We started our field study from the Mazri palms farmers.", " They were briefed about the purpose of the collection of the data and photographs of the utensils, goods, and handicrafts made up of the Mazri palm (already stored on a tablet) were shown to them for helping us to locate manufacturers, middlemen, and further actors involved in the Mazri-business. ", "We then approached the middlemen whom informed us about the manufacturers and markets where these handicrafted goods and utensils were produced and sold. ", "Name, educational level, location, and profession of each interviewee were recorded. ", "Questions related to the season of leaves collection, people involved in the collection, factors causing a threat to the plants, types of handicrafts, goods, utensils, prices and ways of transportation, etc. ", "were asked and noted. ", "Market values, cultural importance, and its manufacturing techniques were also asked. ", "Interviews of Focus Group 1 were mainly related to the cultivation, culture, and economics of the Mazri palm. ", "We then approached to Focus Group 2 that includes the local shopkeepers of the handicrafts and business communities related to Mazri handicrafts in the urban regions. ", "Different markets were visited where 19 shopkeepers (all men) and Mazri handicrafts traders were interviewed. ", "Questions related to prices, priorities, highly sold products, better season for sale, types of customers, supply, demand, and future resilience of the Mazri palm markets were asked during the interviews (Additional file [1](#MOESM1){ref-type=\"media\"}). ", "All the regions (districts) of Pakistan, which have been included in this study, host specific ethnic and tribal groups.", "\n\nData analyses {#Sec5}\n-------------\n\nData were analyzed both qualitatively and quantitatively for having a pattern of use of Mazri palms among the various ethnic groups considered in both focus groups. ", "Uses of different items prepared from Mazri palm in the areas from where it was collected and the regions from where its use was documented during the market survey were arranged in a table \\[[@CR37], [@CR38]\\]. ", "Table 1Age groups and literacy level of the considered sampleAge groupsNumber of interviewed study participantsNumber of male participantsNumber of female participantsPercentageLiteracy levelNumber of interviewed study participantsPercentage14--255505.8Illiterate3743.026--351111012.8Primary2933.736--451717019.8Middle1112.846--552219325.6Secondary78.156--651917222.1University22.466--75+1210213.9\n\nMultivariate statistical analyses on the obtained data were undertaken with the starting hypothesis that uses and preferences for each handcrafted products could change among the diverse considered ethnic and tribal groups as well as between rural and urban communities. ", "Data sets of 39 different items recorded from the regions of both the focus groups at 20 stations (hosting identical ethnic groups) were analyzed in PCORD software for analysing the indigenous knowledge among these ethnicities via cluster analysis. ", "Availability and non-availability of a specific use (1, 0) data were used for cluster and two-way cluster analyses.", "\n\nThe ethnoecological data documented during questionnaire surveys was quantitatively analyzed via relative frequency citation (RFC) index to show the local importance of each palm use and especially handcrafted product, following \\[[@CR39]\\]:\n\n$$\\documentclass[12pt]{minimal}\n \\usepackage{amsmath}\n \\usepackage{wasysym} \n \\usepackage{amsfonts} \n \\usepackage{amssymb} \n \\usepackage{amsbsy}\n \\usepackage{mathrsfs}\n \\usepackage{upgreek}\n \\setlength{\\oddsidemargin}{-69pt}\n \\begin{document}$$ \\mathrm{RFC}=\\frac{\\mathrm{FC}}{N}\\ \\left(0<\\mathrm{RFC}<1\\right) $$\\end{document}$$\n\nwhere FC represents the number of informants mentioning a particular handcrafted product, while *N* represents the total number of the informants participated in the survey.", "\n\nResults {#Sec6}\n=======\n\nProfile of the study participants {#Sec7}\n---------------------------------\n\nThe largest proportion of informants was represented by elders, above 45 years old (61.6) (Table [1](#Tab1){ref-type=\"table\"}). ", "Among the 86 informants, 43% were illiterate and 33% have had a primary education; that shows the scarce availability of formal education facilities among Traditional Knowledge holders in the study regions. ", "Local knowledge about the items prepared from Mazri palm was common and very popular among the Focus Group 1 (tribal peoples living in close vicinity with these palms) but was decreasing rapidly among the youngsters, as well as among the Focus Group 2 members (people living far from the Mazri growing areas). ", "There is a strong decline in marketing as well (based on interviews of Focus Group 2) due to the availability of the synthetic alternatives to Mazri handicrafts, though of very low quality and durability.", "\n\nMazri palm processing {#Sec8}\n---------------------\n\nPreparation of fibers from Mazri leaves is a tough and laborious task. ", "Leaves are soaked in water for 20 to 30 days until they are softened and then hammered with a wooden hammer to remove the peel. ", "The remaining bulks of the leaves are then washed with water and rinsed into fibers and dried again. ", "The dried fibers are then utilized for shoes, ropes, and various other handcrafted products (Table [2](#Tab2){ref-type=\"table\"}). ", "Table 2Various local uses of Mazri palm in PakistanS. noEnglish name of the use or handcrafted productsPashto name of the use or handcrafted productsCodes for two-way cluster and cluster analysisParts usedRelative frequency of citationUse details1Hot pot (Fig. [", "4](#Fig4){ref-type=\"fig\"}a)Petwar (3 sizes)Hot PotLeaves0.76It is used to keep breads, toasts, etc. ", "warmer for a while after baking them2Salt pot (Fig. [", "4](#Fig4){ref-type=\"fig\"}b)Malge wala LokhaySalt-PotLeaves0.65It is used as a pot to store salt in the kitchen / kitchen table3Mat for bedsKat pozakay (1 × 2 m)Mat-BedsLeaves0.60It is used as a mattress mostly during the summer season due to its insulating nature and cooling effects4Mat for poultry cagePanjre da para pozakay (1 × 1 m)Mat-P-CgLeaves0.57It is used in poultry cages to avoid grains from falling on the earth or becoming dirty5Mat for vehicles (Fig. [", "4](#Fig4){ref-type=\"fig\"}d)Garo wala chetai (1.5 × 1 m)Mat-VehiLeaves0.57Conductors and drivers of heavy vehicles or trucks covering long distances use to rest on the ground or truck floor on these mats6Mat for grainsDano wala Chetai (4 × 4 m)Mat-GraiLeaves0.49It is used to dry cereal grains after thrashing the crops7Mat for guestsChetai melmano da para (2 × 3 m)Mat-GuesLeaves0.44It is used for setting the guest especially in large cultural gatherings and also while serving a meal8Prayer mat for one individualMusala/Jai Namaz/PuzakayP-M-O-InLeaves0.41It is used for praying by a single person at home or mosque9Prayer mat for group of individual (Fig. [", "4](#Fig4){ref-type=\"fig\"}f)Saf/Purr (1 × 8 m)P-M-G-InLeaves0.41It is used for prayer of many people at homes as well as mosques10Small broomWara Jaro/JarogaiS-BroomLeaves0.38It is used to clean shops, rooms, vehicles, water mills, etc.11Large broom (Fig. [", "4](#Fig4){ref-type=\"fig\"}h)Ghata Jaro/JaroL-BroomLeaves0.38It is used to clean large houses, mosques, office buildings, roads, and lawns13Hand fan (Fig. [", "4](#Fig4){ref-type=\"fig\"}i)BabozayHand-FanLeaves0.36They are used as hand fans during journeys and when in hot days there are breakdowns of electricity14Shoes for common uses (Fig. [", "4](#Fig4){ref-type=\"fig\"}j)SaflaiSh-C-UseLeaves0.33They are used in social gatherings and recreational activities15Shoes for ice skiingWawro safelyShoe-IceLeaves0.19They were used in past to walk on ice16Large basketTokraL-BasketLeaves0.21It is used for trasporting different items from one place to another, especially food and cloths17Middle-size basket (Fig. [", "4](#Fig4){ref-type=\"fig\"}l)ShkaraiM-S-BaskLeaves0.30It is used to keep bread warmer for longer period especially during social gatherings18Large-size flat basket (Fig. [", "4](#Fig4){ref-type=\"fig\"}m)Shkor/chajL-S-F-BasLeaves0.31It is used to remove husks from the grains by thining and shaking methods19Basket used in hotelsShkor hotel walaB-U-HotLeaves0.27It is used in hotels to keep bread warm and soft for a longer period20Cover for animal mouth (Fig. [", "4](#Fig4){ref-type=\"fig\"}o)Koaray da janwaro da khole da para/BhokaC-A-MoutLeaves0.22It is used to cover the mouth of a newborn or unhealthy cattle to avoid the animal eating harmful substances. ", "It is also used while ploughing to avoid grazing21Bags for packing grasses (Fig. [", "4](#Fig4){ref-type=\"fig\"}p)KwarayB-P-GrasLeaves0.24It is used to pack fodder for cattle. ", "It is also used by street sellers for packing steel, silver, plastic, pots, shoes, cloths, food items etc22Packing bags for sweets (Fig. [", "4](#Fig4){ref-type=\"fig\"}q)PachaiP-B-SweeLeaves0.23It is used for packing various kinds of baked items, rice, and unrefined sugar cane (*Gurrh*)23Hat (Fig. [", "4](#Fig4){ref-type=\"fig\"}r)TopayHatLeaves0.21It is used to protect human head from heat, torrential rain, snowfall etc., ", "during different seasons24Grains bin (Fig. [", "4](#Fig4){ref-type=\"fig\"}s)Tatra or KandoGrai-BinLeaves0.13It is used to store different kinds of grains and cereals25BoxPetaiBoxLeaves0.15It is used to store varoius grains, flours and dry food items at home in farming communities26Ropes (Fig. [", "4](#Fig4){ref-type=\"fig\"}t)BonrRopesLeaves0.19It is used to produce bed steads (Fig. [", "4](#Fig4){ref-type=\"fig\"}v), tying up different goods, animals, livestock, etc.27One seater small bed (Fig. [", "4](#Fig4){ref-type=\"fig\"}u)KatkayO-S-S-BeLeaves0.28It is used for setting a single person28RopeLange wala rasaiRopeLeaves0.05It is used to form one half of the bed from where it\\'s titghened when gets loose; that end of the bed is known as *Langa* or *Piarrma* in Pashto language29Rope for wellKohi wala rasaiR-F-WelLeaves0.08Use to take water out from the wells via wheel or deeper springs30Ornamental plant (Fig. [", "4](#Fig4){ref-type=\"fig\"}w)Gamle wala plantOrnament0.02Mazri palm is cultivated for esthetic purposes31\\--(Fig. [", "4](#Fig4){ref-type=\"fig\"}x)LadLaudLeaves0.06It is used to transport goods on donkeys from one place to another32Fuel (Fig. [", "4](#Fig4){ref-type=\"fig\"}y)Khashak/LargayFuelLeaves, stem sheaths0.09Dry leaves, stem sheaths, and roots are used as fuel33Toothbrush (Fig. [", "4](#Fig4){ref-type=\"fig\"}z)MiswakT-BrushPetiole0.13Petiole of the leaf is used as a toothbrush34Fruit, shoot (Fig. [", "4](#Fig4){ref-type=\"fig\"}aa)PatawaFr-Ne-ShFruits, fresh shoots0.06Fruits and young shoots are used as food ingredients35Marbles (Fig. [", "4](#Fig4){ref-type=\"fig\"}ab)BeloureeMarblesSeeds0.14In some areas, kids play marble game using its hard-round seeds, and the game is locally known as *Belouree*36Roofs or ceilingSapar/ChapparConstrucLeaves0.03In some areas, the leaves are used for roofing or thatching37Medicinal usesTibi istimal/DawaiMed-UseLeaves0.76Fresh leaves' extract is used for treating stomach problems38FodderGayah/WakhaAnimal-FLeaves0.65Young leaves are grazed by animals or they are also used in powedered form39CagesPanjraB-CagesLeaves0.60These are used to keep appreciated and/or birds like Chukar, Parrot, and Mayana.", " People also keep such bird cages in the wild in order to attract and hunt other birds (esp.", " in the tribal belt of Pakistan).", "\n\nDifferent dyes such as green, blue, red, black, pink, and yellow are used to color the leaves and fibers of the Mazri palm for ornamentation purposes. ", "Dyes are mixed with fresh boiled water, they are then continuously stirred with the help of a wooden stick till the colors are deeply absorbed into the fibers. ", "The fibers are washed with tap water and then hanged on ropes or scattered in sand to get dry. ", "The dried coloured leaves are then used in combination with normal leaves in various handicrafts.", "\n\nDiversity of Mazri handicrafts {#Sec9}\n------------------------------\n\nEach item processed from the leaves of Mazri is valueable even though a few items only achieve more attention and maximum cash income, hence contributing to the socioeconomic uplift of the locals due to their high demand. ", "Our findings showed that the highest preferences were recorded for hotpots followed by salt pots and mats, brooms, hand fans, shoes, and baskets. ", "Hotpots are used in dayly life (Fig. [", "4](#Fig4){ref-type=\"fig\"}a) and every house keeps hotpots for breads in order to keep them fresh and warm for a longer time after they are baked. ", "Salt pot is used for salt packing and keeping in kitchens (Fig. [", "4](#Fig4){ref-type=\"fig\"}b). ", "Mats of different sizes are of wide use and importance for a number of purposes, e.g., prayer gatherings, drying grains, seating guests, sleep, and poultry cages and truck (Fig. [", "4](#Fig4){ref-type=\"fig\"}c--f). ", "The demand of sleeping mats increases in the summer season as these retain a cooling effect due to its insulating and hydrophilic nature. ", "These mats do not absorb heat and water if compared to the mats made up of cotton and other synthetic materials. ", "Brooms of different sizes are used to clean houses, shops, and other places (Fig. [", "4](#Fig4){ref-type=\"fig\"}g, h) while hand fans locally known as *Babozey* are unique sort of fans used for aeration by the indigenous people where they cannot use electric fans or in the breakdowns of electricity (Fig. [", "4](#Fig4){ref-type=\"fig\"}i). ", "Traditional shoes made up of Mazri leaves are used mostly in spiritual and cultural ceremonies and gatherings (Fig. [", "4](#Fig4){ref-type=\"fig\"}j). ", "Baskets of four different types and sizes, i.e., larger, large flat, medium, and small (Fig. [", "4](#Fig4){ref-type=\"fig\"}k--n), are used in the restaurants and hotels for keeping various food items warmer and safe from fermentation. ", "Mouth cages locally known as *Bhoka* cover the mouths of livestock and are used to prevent cattle from eating harmful things or fodder during illness or while ploughing in crop fields (Fig. [", "4](#Fig4){ref-type=\"fig\"}o). ", "Bags for collecting fodder locally known as *Kwaray* used by shepherds and farmers to collect grasses and fodders, either in their fields, from the wild, or both (Fig. [", "4](#Fig4){ref-type=\"fig\"}p). ", "Bags locally known as *Pachai* are used to pick the fruits and vegetables from orchard trees and vegetable gardens (Fig. [", "4](#Fig4){ref-type=\"fig\"}q). ", "Similarly, special *Pachai* are used for packing bakery sweets and especially a sweet locally known as *Amrassae;*. ", "Lund Khuar city in Mardan, Warrai in Dir Upper, and Batkhela in Malakand are popular cities for *Amrassae*. ", "Hats prepared from leaves of Mazri palms are worn during prayers in the mosques as well as by labor workers to protect their heads from the sun's heat (Fig. [", "4](#Fig4){ref-type=\"fig\"}r). ", "Grain box are used to store and keep various seed grains and flour safe from moisture, heat, and insects (Fig. [", "4](#Fig4){ref-type=\"fig\"}s). ", "Ropes for *Kats* (beds), *Khatkey* (small chairs), *Kursae* (chairs), and other purposes are prepared from the fresh and dried leaves of *Nannorrhops* locally termed as *Bonr* or *Rasai* (Fig. [", "4](#Fig4){ref-type=\"fig\"}t--v). ", "These ropes are also used to pull out water from the wells; people bind their cattles with some support via these ropes as well.", "\n\nDiversity of cultural heritage concerning Mazri palm uses {#Sec13}\n---------------------------------------------------------\n\nPeople of Pakistan in general and tribal areas in particular are well-known for their hospitality, which is strongly linked to traditional cultural norms and beliefs. *", "Hujra* and *Betak* (types of guests houses) are important and significant entities in this respect Local people of Baluchistan, Khyber-Pakhtunkhwa, and former Federally Administrated Tribal Areas (ex-FATA) keep different items made up of this palm in their guesthouses which are used in one way or the other as cultural obligations. ", "They prepare certain items made up of this palm for example, *Kats*, *Khatkey*, (sofa) stools, mats for setting, mat to cover beds, mats for prayers, and hand fans which are essential part of the hospitality culture. ", "Many people from urban regions use to visit rural areas to see experience these cultural services that promote the ecotourism sector.", "\n\nTourists visit colder areas of the country such as Swat, Muree, Abbottabad, Ayubia, Quetta, Ziarat, and others, to enjoy such hospitality cultures during the summer season. ", "On the way to these regions, a number of markets trade such items, whose charming beauty attracts several tourists (Figs. [", "2](#Fig2){ref-type=\"fig\"} and [3](#Fig3){ref-type=\"fig\"}). ", "Fig. ", "2Cluster dendrogram showing the various ethnic and tribal groups who use Mazri palm in PakistanFig. ", "3Two-way cluster dendrogram showing the distribution of the various Mazri plant uses among the different cultural zones/stations considered\n\nMultivariate statistical analyses summarizing the places that have similarity and dissimilarity in uses shows that ethnoecological practices and knowledge among various ethnic groups and local communities vary from place to place, hence can be clustered into five different associations or groups (Fig. [", "2](#Fig2){ref-type=\"fig\"}). ", "A two-way cluster diagram highlights the distribution of various handicrafts among the considered ethnic groups living in different areas and with similarity in Mazri palm uses in a more comprehensive way (Fig. [", "3](#Fig3){ref-type=\"fig\"}).", "\n\nZone 01: Lower Khyber-Pakhtunkhwa and Baluchistan {#Sec14}\n-------------------------------------------------\n\nThe zone shown in cluster 01 comprises 7 sites, i.e., Jhandai Mardan, Lund Khwar Mardan, Khar Bajaur, Kohat, Dera Ismaiel Khan, Bannu, and Quetta, which are the areas of Lower Khyber-Pakhtunkhwa and Baluchistan where Yousafzai Pakhtuns communities live. ", "Quetta in the province of Baluchistan is situated in the same cluster as Pakhtuns/Pathans live there as well. ", "It shows that Pakhtuns have same cultural values and hence similar preferences for the considered kinds of goods and handicrafts irrespective of living in different provinces. ", "Moreover, these are the areas where Mazri palms grow or have been grown in the recent past.", "\n\nZone 02: Upper Khyber-Pakhtunkhwa {#Sec15}\n---------------------------------\n\nThis association comprises a few localities, namely Timergara Dir Lower, Qissa Khwani Bazar Peshawar, Charsadda, Mingora Swat, and Pir Baba Buner. ", "The people of these areas use *Nannorrhops ritchiana* for various purposes such as baskets, hand fans, brooms, and ropes. ", "These are the colder areas of the country also known as provincially administrated tribal areas (PATA). ", "The palm does not grow in the regions grouped in this cluster, and hence, people import it from the adjacent areas where it abundantly grows.", "\n\nZone 03: Karachi, the only cosmopolitan city of Pakistan {#Sec16}\n--------------------------------------------------------\n\nThe third zone is represented by Karachi the largest and the only metropolitan city of Pakistan situated on the coast of the Arabian Sea. ", "Many peoples coming from all parts of the country use to migrate here for jobs and businesses and hence generate a multicultural environment. ", "Peoples of Karachi use or carry different goods and utensils of Mazri and other palms from different parts of the country. ", "That is why Karachi retains a unique position in the cluster and in the dendrograms.", "\n\nZone 04: Hindko and Pothwari belt {#Sec17}\n---------------------------------\n\nCultural zone 04 consists of Bharakahu Islamabad, Raja Bazar Rawalpindi, Hasanabdal, Haripur, Abbottabad, and Mansehra which lie in the Lesser Himalayan and Potohar plateau around the capital territory and Hazara Division. ", "People of these areas have different culture from Pakhtuns. ", "It is somehow a transitional between Punjabi and Pakhtun traditions. ", "Hindku and Pahari-Pothwari are the local languages of these areas. ", "The cluster and two-way cluster analyses separate this zone from other areas based on different kinds of uses and preference for Mazri handicrafts. ", "This cluster also suggests a similarity in the cultures of this zone, as Hindko and Pahari-Pothwari cultures are considered as sister cultures for being custodians of closely related micro-climatic conditions/geographies, languages, and history.", "\n\nZone 05: Bahawalpur {#Sec18}\n-------------------\n\nBahawalpur stood out in a unique position - like Karachi - in the cluster analyses based on the recorded ethnobotanical data. ", "This area retains a unique culture and has a peculiar history, since Bahawalpur has been the main center of the Saraiki belt, which had a long diversity of *Nawabs* (Kings) who ruled the region for hundreds of years. ", "Bahawalpur is also special for its unique cultural heritage and palaces which were built by the its kings. ", "The use of Mazri palm in this station includes hats, hand fans, mats, and baskets of special kind.", "\n\nDiscussion {#Sec19}\n==========\n\nIn the current study, we have tried to emphasize the role of Mazri palm for the local communities living in the dry climatic zones of ex-FATA and Baluchistan on the one hand and its role in the economic chain from Mazri growers to the urban business communities on the other. ", "Local communities in the country retains different kind of Traditional Knowledge linked to this palm. ", "The findings show that there is a considerable variation from area to area and tribe to tribe in terms of handcrafted items produced from the Mazri palm. ", "Moreover, the data provide an important documentation of a large variety of folk uses, as fodder, food, fuel, medicine, and especially in handicrafts retained by the traditional communities. ", "The data show that the Mazri palm has been and still is a source of fibers for weaving various utensils and ropes and for producing mats, fences, houses, roofs, hand fans, baskets, brooms, trays, prayer mats of various sizes, grain bins, hot pots, hats, and traditional sandals \\[[@CR2]\\] (Fig. [", "4](#Fig4){ref-type=\"fig\"}). ", "Our findings confirm the data arising from \\[[@CR30]\\] a study conducted on Baluchistain ethnobotany; these similarities may be due to the deep mutual relationship that the various ethnic communities living in Baluchistan and Khyber-Pakhtunkhwa have had across centuries, by also sharing similar cultural values and norms. ", "According to \\[[@CR24]\\], reddish moss-like wool of the petioles of *Nannorrhops* is used as tinder and the seeds are utilized for producing rosaries. ", "In the current study, we could not record such kinds of use by locals. ", "Findings of this article also suggest close ties between the cultural services provided by Mazri palm and human wellbeing in Pakistan and adjacent areas. ", "High rate of exploitation of Mazri palm in the 20th Century have decreased the cultural services of this palm. ", "Fig. ", "4Handicrafts made up of Mazri palm. (**", "a**) Hot pot. (**", "b**) Salt pot. (**", "c**) Mat for beds. (**", "d**) Mat for vehicles. (**", "e**) Prayer mat for one individual. (**", "f**) Prayer mat for group of individuals. (**", "g**) Small broom. (**", "h**) Large broom. (**", "i**) Hand fan. (**", "j**) Shoes for common use. (**", "k**) Large basket. (**", "l**) Middle-size basket. (**", "m**) Large-size flat basket. (**", "n**) Basket used in hotels. (**", "o**) Cover for animal mouth. (**", "p**) Bags for packing grasses. (**", "q**) Packing bags for sweets. (**", "r**) Hat. (**", "s**) Grain bin. (**", "t**) Ropes. (**", "u**) One-seater small bed. (**", "v**) Cot or bed stead. (**", "w**) Ornamental plant. (**", "x**) Lad. (**", "y**) Fuel. (**", "z**) Toothbrushes. (**", "aa**) Fruit of Mazri palm. (**", "ab**) Seeds of Mazri palm used as marbles. (**", "ac** and **ad**) Artisans weaving ropes from Mazri leaves in Dera Ismail Khan\n\nResults of cluster and two-way cluster dendrograms indicate that the people of the northwestern part of the country had more knowledge about the uses of Mazri palm if compared to those inhabiting the urban areas. ", "Authors in other ethnobotanical studies have assessed cultural variations in a similar manner \\[[@CR40]--[@CR42]\\]. ", "Another significant finding of the current study is the link between the inhabitants' perception of various services and their resident municipalities. ", "The maximum uses of handicrafts were found in rural areas and this can be explained by the fact that rural peoples directly collect the plant species from the wild in order to process it to handcrafted products. ", "People from urban areas can easily reach and afford various types of artificial handicrafts and do less effort to get more durable and natural  materials from rural territories. ", "Previously available literature on *Nannorrhops ritchiana* confirmed that this species was used for various purposes and was known by different vernacular names in various regions of cultures in Pakistan as well as in other parts of the world. ", "These Mazri palm names vary from area to area and tribe to tribe. ", "In Arabic language, it is called *Ghadaf* or *Sa'f* \\[[@CR22]\\]; Mazri palm in English \\[[@CR27]\\]; *Merez* in Afghani Pashto \\[[@CR43]\\]; *Patha* in Balochistani Pashto \\[[@CR23]\\]; *Mazri* in Saraiki \\[[@CR18]\\]; *Purk* in Persian \\[[@CR44]\\]; *Daz* in Balochi \\[[@CR24]\\]; *Mezaray* in Malakand, Swat, Dir, Bajaur, and Mardan ares were Pashto is spoken \\[[@CR16]\\]; *Mazara* in the Bannu Pashto \\[[@CR15]\\]; and *Mazarai* in South Waziristan Pashto \\[[@CR13]\\]. ", "The palm family is one of the richest families in terms of fiber-producing plants and several researchers reported a broad variety of uses of different palm taxa in different wolrdwide regions; for example, \\[[@CR37]\\] reported that the natives of Tucurui Lake in the Eastern Amazon use *Attalea speciosa* (Babassu) palm for utensils, tools, human food, animal fodder, construction, fuel, and medicines. ", "Uses of *Attalea speciosa* reflects similarities to our findings linked to *Nannorrhops ritchiana* in the current study. ", "Ethnoecological studies of *Braheae dulcis* showed its traditional use for two dozens of different purposes: leaves are harvested for eight decades providing several handcrafted products, mainly utilized during religious practices \\[[@CR45]\\]. *", "Afzelia africana* is also an important palm species used for various cultural purposes in Africa. ", "Local communities of Burkina Faso use this species as fodder, medicinal plant, food, and as raw material in carpentry. ", "Rakotoarivelo et al. ", "\\[[@CR46]\\] studied the ethnobotanical and economic value of *Ravenala madagascariensis* in East Madagascar; according to them, the species is of immense importance for the indigenous communities and its trunk, palm heart, leaves, and petioles are the main exploited parts. ", "Locals use them as utensils and tools, as food, and as construction material. ", "Zambrana et al. ", "\\[[@CR47]\\] documented the context of use of *Euterpe precatoria* and *Euterpe oleracea* in Bolivia and Peru; the inhabitants of Peru use fruits and hearts of *Euterpe precatoria* palm more than the inhabitants of Bolivia for commercial and human food purposes. ", "This findings show similarities to our data, since we recorded an important variability of Mazri palm uses among diverse cultural areas \\[[@CR48], [@CR49]\\].", "\n\n*Nannorrhops ritchiana* has a great esthetic value too, can be grown in arid conditions, and hence can be recommended for being planted along main highways and motorways in Pakistan for both its beauty and for counterfighting pollution along roadsides. ", "This opportunity could increase the production of raw material for a variety of potential handicrafts, provide some esthetic beauty to the roads, and contribute to a better environment as well. ", "Moreover, the products prepared from the leaves of Mazri palm have major advantages if compared with artificial fibers since the palm materials are environmentally friendly, nontoxic, biodegradable, easily available, compostable, and heat resistant. ", "These products have great capacity of absorbing sound weaves, heat, and water, while artificial fibers have instead much less virtues and cannot be easily recycled. ", "Moreover, fibers of Mazri palm have a better elasticity and a higher toughness. ", "Keeping the immense importance of this palm in providing crucial ecosystemic and cultural services to local populations, it is advisable that governmental and non-governmental organizations continue fostering the sustainable management of Mazri palm forests for a better future of Pakistani local communities and we sincerely hope that this paper could assist them in such endeavors.", "\n\nConclusions {#Sec20}\n===========\n\nMazri palm still play a significant role in the livelihoods of the local communities, especially in the ex-FATA belt and adjacent areas. ", "It contributes to the livelihood of rural as well as urban populations. ", "Handcrafted products and their utilization vary from place to place based upon diverse cultural customs and Traditional Knowledge variation is significant among the various ethnic and tribal groups. ", "We believe that this study will offer a robust baseline of data to foster this heritage concerning the handcrafted products prepared from this palm. ", "These findings could be also of interest for the scholars and experts working on/with plant handicrafts, especially from palm species, around the globe. ", "We also recommend researchers and managers to bring more innovation in the further development of small-scale cottage industries by introducing new kinds of handicrafts based on Traditional Knowledge, as well as in re-envisioning community-centred and sustainable ways to organize Mazri breeding (or gathering), trade, and uses.", "\n\nSupplementary information\n=========================\n\n {#Sec21}\n\n**Additional file 1: Appendix 1.**", "\n\n**Publisher's Note**\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.", "\n\nSupplementary information\n=========================\n\n**Supplementary information** accompanies this paper at 10.1186/s13002-020-00394-0.", "\n\nAuthors are very thankful to the local farmers, shopkeepers, and traders who generously shared their knowledge related to Mazri palm and its products. ", "We also thank the Divisional Forest and Range Officers of D.I. Khan, Paniala, Orakzai, Lakki Marwat, Sheikh Baddin, Karak, Kohat, Banda Dawood Shah, Hangu, Kurram, and Mohmand areas for their hospitality, guidance, and facilitation during the field surveys. ", "We are also thankful to the Department of Wild Life & National Parks Khyber-Pakhtunkhwa for their support, especially in the Sheikh Baddin National Park. ", "We are grateful to Mr. Abid Sarwar, GIS Analyst, Directorate of Soil and Water conservation Khyber-Pakhtunkhwa, for designing the map of the study area for us.", "\n\nThe authors are also very thankful to all members of the visited local communities for the documentation of the ethnobotanical information related to Mazri palm.", "\n\nAbdullah carried out the field and experimental work. ", "SMK contributed in the study design and overall supervision of the study. ", "AP contributed in the methodological design and in revising the manuscript. ", "ZUH assissted in the fieldwork and in administering the questionnaires. ", "ZA contributed in the data analyses and in drafting the manuscript. ", "All the authors read and approved the final version of the manuscript.", "\n\nN/A.\n\nN/A.\n\nN/A.\n\nN/A.\n\nAll the authors declared that they have no competing interest.", "\n" ]

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[ "[Heart arrest in cemented hip arthroplasty].", "\nHip arthroplasty is a common surgical intervention in our hospital practice, involving high perioperative risk related to patients age and multiple concomitant diseases. ", "Hemodynamic complications described vary from slight hypotension during surgery to heart failure and sudden death, particularly if the operation involves a cemented femoral component. ", "Because of the type of patients undergoing such operations (elderly patients, with osteoporosis and scarce cardiopulmonary reserve), the unclear origin of complications and the lack of consensus on what constitutes adequate monitoring during surgery, hip arthroplasty is problematic for the specialists involved. ", "We report on five deaths during cemented hip arthroplasty; after reviewing the case history and autopsy report of one, we believe the events leading to death were triggered by massive pulmonary embolism." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "When I'm too drunk and can't aim I'll just pee in the bath tub\n\n340 shares" ]

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[ "\"Brought to you by WITH S2 Written In The Heavens Subbing Squad\" \"Also, don't ever stagger in front of me again.\" \"", "You're not allowed within 2 meters of me.\" \"", "Why can't I come near you?\" \"", "Why are you playing with me?\" \"", "Didn't you say you liked me?\" \"", "Didn't you say that we should become sworn brothers?\" \"!\" \"", "At the most, one month.\" \"", "It'll be over in a month.\" \"", "I'll endure it until that day so you should too.\" \"", "Everything will be okay if you leave this place, don't concern yourself over whether I stay or go...\" \"Is Go Eun Chan a woman?\" \"", "That's a real secret.\" \"", "Do you know how tired Han Kyul hyung is?\" \"", "How could you keep this from him?\" \"", "I like you, it doesn't matter if you are a man or an alien.\" \"", "I don't care anymore.\" \"", "If we sort it out, I might feel even more tired and even more unbearable...\" \"Let's go wherever it takes us, let's go forward together.\" \"", "I can't just answer it, I just can't.\" \"", "I should endure it.\" \"", "One, two, yes?\" \"", "It's me.\" \"", "Episode 11\" \"Are you safely home?\" \"", "Yeah.\" \"", "Why do you keep sighing and not talking?\" \"", "That...\" \"Are you safely home?\" \"", "Hello?\" \"", "Hello?\" \"", "Hello?\" \"", "I miss you.\" \"", "We've only just separated so why...\" \"Me too.\" \"", "You said... will we have smiles on our faces when we see each other tomorrow?\" \"", "We won't argue anymore, we'll just talk and smile...\" \"Is that right?\" \"", "That's right.\" \"", "That's good then.\" \"", "I'm hanging up now.\" \"", "Let's talk a little more.\" \"", "Like this.\" \"", "What?\" \"", "All right then.\" \"", "We'll talk for a little more.\" \"", "Are you sleeping?\" \"", "I can't.\" \"", "I have to hang up now, my mom is calling me.\" \"", "See you tomorrow.\" \"", "We...\" \"Alright, sleep well.\" \"", "I thought my heart was going to explode.\" \"", "I should say it now.\" \"", "Isn't that right?\" \"", "It's time to say it now.\" \"", "Answer me.\" \"", "Yes!\" \"", "That's right, that's right, answer me, hurry up!\" \"", "I have someone I like.\" \"", "Who?\" \"", "My manager.\" \"", "Does he know you're a woman?\" \"", "I'm going to tell him tomorrow.\" \"", "It must be hard on you.\" \"", "Mom.\" \"", "Yeah?\" \"", "I'm so nervous.\" \"", "Yes, this is Choi Han Kyul.\" \"", "Hello?\" \"", "Hello?\" \"", "I...\" \"I am Lee Myung Jae.\" \"", "Mr. Lee Myung Jae?\" \"", "She's gone crazy, crazy.\" \"", "Hey, are you really going to wear that to work?\" \"", "You're going to cause such a huge problem with what you're going to do today.\" \"", "I'm going.\" \"", "Go Eun Chan.\" \"", "It'll be fine, it'll be fine.\" \"", "Fighting!\" \"", "I think I'm going crazy.\" \"", "I like the Manager as well.\" \"", "The Manager likes me too, then what's the problem?\" \"", "What's the problem?\" \"", "It'll be fine!\" \"", "It'll be fine!\" \"", "Go Eun Chan, it'll be fine!\" \"", "Right now, Han Kyul should be meeting Lee Myung Jae.\" \"", "Yeah.\" \"", "What will they say to each other?\" \"", "Why are you eating an ice-cream in the morning?\" \"", "My father told me that when I was little,\" \"I really liked my uncle and I was always following you around...\" \"Actually I don't really remember much.\" \"", "Of course, it was a very long time ago.\" \"", "No matter what, thank you for coming out to see me on behalf of your father.\" \"", "It's all right.\" \"", "Your father told me that, aside from work, you're even more interested in other things.\" \"", "He's very worried about me over my obsession with toy making.\" \"", "I used to design robots.\" \"", "The elders all wished that I wouldn't carry on in that field of work.\" \"", "But after doing all kinds of different work, that's the only thing that interests me...\" \"That's why I'm still quite involved in it.\" \"", "You get your stubbornness from your mother.\" \"", "My mother is not stubborn.\" \"", "She's been through a lot and has had to make many compromises because of my father and my stubbornness.\" \"", "Do you know... my birth mother?\" \"", "What kind of country is this irritating?\" \"", "Why can't I find any good news to make my mood better?\" \"", "What war, what kind of politics...\" \"My head hurts.\" \"", "Stop annoying me.\" \"", "You've been whispering a song that doesn't sound like a song since this morning.\" \"", "That's not called whispering, it's called singing a song.\" \"", "Old people can't sing it.\" \"", "Old people?\" \"", "Did you just call me old?\" \"", "Sorry, sorry, sorry.\" \"", "Hyungnim.\" \"", "Your clothes...\" \"You're early today, Ahjussi.\" \"", "Yes.\" \"", "This...\" \"Hyungnim...\" \"Today...\" \"I think you're wearing the wrong clothes.\" \"", "Where's the Manager?\" \"", "What?\" \"", "He's not here yet.\" \"", "But your clothes...\" \"The way I see it, she's never had any breasts.\" \"", "Hyung, you're here?\" \"", "What is this?\" \"", "You're not trying to hide it anymore now that I've found out right?\" \"", "Are you making the first move?\" \"", "Hey, Hwang Min Yeop, Manager Hong,\" \"No Sun Ki, your movements are quick\" \"Did they teach you to do this already?\" \"", "They are so clever.\" \"", "I'm really sorry, Hyung.\" \"", "I didn't want to lie to you guys from the beginning...\" \"Is that so?\" \"", "Then why did you have to plan it all out and make a fool out of a person?\" \"", "I'm sorry.\" \"", "Other than saying sorry right now, I have nothing else to say.\" \"", "Sorry?\" \"", "Do you just say sorry after you've killed someone?\" \"", "Hey, then just take me as a person with no consideration at all.\" \"", "What about Han Kyul hyung?\" \"", "Do you know why he didn't come to work for the past few days?\" \"", "So you do know.\" \"", "Hey, do you know how tough it was for him?\" \"", "Do you know that was the first time I've seen him fall apart like that?\" \"", "Who are you?\" \"!\" \"", "How dare you play around like this?\" \"!\" \"", "Even if you want to lie to someone, there should at least be a limit.\" \"", "Did you really think you could play us around like that?\" \"", "Do you know you've already turned a few people into cripples?\" \"", "I can't even hit you, this is crazy...\" \"Wait a minute, Hyung.\" \"", "Let go.\" \"", "Does the Manager know too?\" \"", "Did you tell him?\" \"", "Is that why he hasn't come?\" \"", "Don't hold back the tears.\" \"", "You're a woman now, aren't you?\" \"", "So you want to use your tears to gain pity right?\" \"", "Wow, you're so scary.\" \"", "How could there be a person like you in this world?\" \"", "All the feelings I've accumulated are gone.\" \"", "You should go back.\" \"", "About my mother....\" \"No one has ever talked to me about it with so much detail.\" \"", "Thank you so much for today uncle.\" \"", "What are you thanking me for?\" \"", "Thanks to you, I've thought of the past and that has brightened up my mood.\" \"", "I'll see you next time.\" \"", "This is your mother's picture.\" \"", "That's all I can give you.\" \"", "What are you doing?\" \"", "I've put all your things in the wardrobe.\" \"", "I'm taking the almond colored shirt.\" \"", "Mine got ruined in the wash.\" \"", "I asked what are you doing?\" \"", "Because DK's schedule has been pushed forward a day,\" \"I'll be leaving next Sunday.\" \"", "Didn't I say not to leave?\" \"", "Let's end this.\" \"", "I know what's in your heart and you know what's in mine.\" \"", "If we carry on like this, nothing's going to change.\" \"", "Tell me what my heart is like.\" \"", "Do you really know what's in my heart?\" \"", "You know and you're still doing this?\" \"", "I told you to give me some time.\" \"", "I admit that I did waver about.\" \"", "And I said that I would sort it out.\" \"", "I told you to wait for me.\" \"", "Wait for you?\" \"", "What?\" \"", "Wait for you to come around?\" \"", "What should I do during that period?\" \"", "Pray for you?\" \"", "Pray that you won't waver about?\" \"", "Don't let that \"man\"....\" \"Keep you in a loop.\" \"", "Because she likes another man, she likes Choi Han Sung's cousin.\" \"", "So Choi Han Sung can only come back.\" \"", "Do you want me to be that impatient and endure everything during that period?\" \"", "Should I pray and wait for you at the same time?\" \"", "Yes, even if you have to do that.\" \"", "You should be clear about what you've done.\" \"", "Should I not understand what you've done?\" \"", "Is this what you mean?\" \"", "I've already lived with another man so I should accept you too, right?\" \"", "I just wavered for a little while, why can't you understand that, right?\" \"", "I know.\" \"", "I know I don't have the right to say those things.\" \"", "So that's why I have to leave.\" \"", "I don't want to become your burden.\" \"", "Don't sort out your own feelings because of me.\" \"", "Just go ahead with your own feelings.\" \"", "Because I've done that before as well.\" \"", "Don't go.\" \"", "If you tell me to stay, then I'll stay.\" \"", "If you tell me to go then I'll go.\" \"", "I'm not that kind of person.\" \"", "Don't go.\" \"", "Don't you know me at all?\" \"", "I'm leaving.\" \"", "Han Yoo Ju.\" \"", "Can't you just keep one eye closed and one eye open and just follow me?\" \"", "I'll come again to pick up my things.\" \"", "Why don't you just tell me the truth... it's because of work isn't it?\" \"", "Don't try to find an excuse.\" \"", "It doesn't matter if I wavered or not, that means absolutely nothing to you.\" \"", "Is there really another reason?\" \"", "I really believe that you like this job.\" \"", "Or have you been kept in the loop by that jerk?\" \"", "What's wrong?\" \"", "Is your conscience acting up because you're abandoning me again?\" \"", "The excuses you've found... they're just tiny, meaningless reasons, they're nothing.\" \"", "Han Yoo Ju.\" \"", "Han Yoo Ju!\" \"", "I'm here.\" \"", "Sorry, I'm late.\" \"", "It's fine, you're the Manager so that's possible.\" \"", "I'm late.\" \"", "Where's Eun Chan?\" \"", "On the first floor.\" \"", "Why are you the only one cleaning up the first floor?\" \"", "You should've asked them all to help.\" \"", "Really...\" \"Why did you come late?\" \"", "That's hard to say.\" \"", "Did you sleep well yesterday?\" \"", "Yes.\" \"", "Why are you answering like that?\" \"", "Did you not sleep well?\" \"", "No.\" \"", "I didn't sleep well.\" \"", "I've been very shocked.\" \"", "Let me see your face.\" \"", "Why have you been staring at the floor since I've arrived?\" \"", "Is cleaning more important than me?\" \"", "What are you saying?\" \"", "Are you not well?\" \"", "No.\" \"", "I'm fine.\" \"", "I thought...\" \"My head hurts.\" \"", "I said my head hurts.\" \"", "Should I get some medicine for you?\" \"", "Wait a sec.\" \"", "Sit down.\" \"", "This morning, I went to see someone my father knows.\" \"", "He told me he knew the woman who gave birth to me.\" \"", "I'll show you my mother.\" \"", "She's pretty, right?\" \"", "I heard she was a tomboy when she was young.\" \"", "She was really outstanding at university.\" \"", "She was really popular with the boys as well.\" \"", "Now you know why I'm so good looking.\" \"", "I'm so tired.\" \"", "A day like today, I really don't feel like working.\" \"", "Console me.\" \"", "How?\" \"", "Like this.\" \"", "It's warm.\" \"", "The birthmark....\" \"What could that be?\" \"", "It's like a piece of ice in my heart.\" \"", "Why is it so heavy, so cold?\" \"", "What is this?\" \"", "Go Eun Chan.\" \"", "Why are both of us men?\" \"", "How about we jump across to America?\" \"", "I...\" \"You don't know.\" \"", "This is good.\" \"", "It's good to have a lover.\" \"", "I'm going to be 30 the day after tomorrow.\" \"", "For my mother, I haven't made a good showing.\" \"", "Are you all right?\" \"", "I originally wanted to come and give her a good beating today.\" \"", "But with one look, she's a woman.\" \"", "A girl is a girl.\" \"", "By her pretty little face, she doesn't know how many people she's already played.\" \"", "Hyung, don't ponder over it.\" \"", "As they say, even if you hate the crime committed, don't hate the criminal.\" \"", "I think that kid is pretty upset over it as well.\" \"", "So just forget it, just forget it.\" \"", "What are you talking about?\" \"", "You don't know?\" \"", "What?\" \"", "Go Eun Chan.\" \"", "Really...\" \"No matter how much I like that kid, you shouldn't call him a girl.\" \"", "Don't let him hear it.\" \"", "His fist is really powerful.\" \"", "Go Eun Chan didn't tell you?\" \"", "Tell me what?\" \"", "That girl, she wore women's clothing today.\" \"", "So I personally asked her if she was a woman.\" \"", "She had tears in her eyes and kept saying sorry to me.\" \"", "We were too stupid.\" \"", "Since she's a woman, how come we didn't find out sooner?\" \"", "I really wanted to scratch my eyes out.\" \"", "Really, what are you talking about?\" \"", "Go Eun Chan is a woman.\" \"", "Manager Hong, Hwang Min Yeop, No Sun Ki, they all knew except for you and me, Hyung.\" \"", "Thinking about it, I couldn't find anything confirming the fact that she is a man.\" \"", "I've never seen her identity card.\" \"", "Hyung, have you seen her identity card?\" \"", "Going to the apple farm, playing basketball, she never wanted to wash with us, she wanted to wash on her own.\" \"", "We should've realized it then.\" \"", "If we think about it seriously, those are not just two strange things.\" \"", "She hasn't got a beard, her body is so weak and she has no muscle.\" \"", "She's totally a woman, why didn't we figure it out earlier?\" \"", "I'm a fool, I'm a fool!\" \"", "Really...\" \"Go Eun Chan.\" \"", "Hyung.\" \"", "Hyung, don't say anything right now.\" \"", "Lift your head.\" \"", "Ha Rim says that you're a woman.\" \"", "Are you really a woman?\" \"", "What?\" \"", "Are you really a woman?\" \"", "Answer me you jerk, are you a woman?\" \"", "I asked if you are a woman?\" \"!\" \"", "Hyung!\" \"", "Manager!\" \"", "Manager!\" \"", "Manager!\" \"", "Manager...\" \"Manager!\" \"", "Are you a man or a woman?\" \"", "You look like a girl.\" \"", "Have you been in the army?\" \"", "Identity card number.\" \"", "850805-2371291...\" \"Isn't it 13 right?\" \"", "13?\" \"", "Can't you even tell if you're a man or a woman?\" \"", "Why don't you have a beard?\" \"", "That's because I don't eat well.\" \"", "Prince?\" \"", "A man?\" \"", "What about me then?\" \"", "Say hi, this is Hang Sung's girlfriend.\" \"", "What would happen if I was a woman?\" \"", "If I was a woman then could we date?\" \"", "Would you like me even if I was your younger brother?\" \"", "Where am I the prettiest?\" \"", "From now on, we're sworn brothers.\" \"", "Would you like me even more?\" \"", "Is that your first kiss with me?\" \"", "Didn't you say that if I was a woman you wouldn't like it?\" \"", "You said that you only liked me because I was a man.\" \"", "Being in that kind of mood, it'll be a relief he doesn't get in trouble.\" \"", "It's so pitiful.\" \"", "Two special waffles please.\" \"", "Eun Chan Noonim doesn't look too good as well.\" \"", "She looks like she's going to fall over.\" \"", "How dare you call her Noonim?\" \"", "Now you're up to date with us.\" \"", "What?\" \"", "Why are you so angry?\" \"!\" \"", "How amusing...\" \"You big gorilla!\" \"", "If he's a big gorilla, then you're a sparrow.\" \"", "Hello?\" \"", "Who else knows?\" \"", "Does everyone else know besides me?\" \"", "Manager Hong, Sun Ki, Ha Rim, Min Yeop, who else knows?\" \"", "Does Han Sung hyung know too?\" \"", "Does Han Yoo Ju know too?\" \"", "Where are you now?\" \"", "Let's meet.\" \"", "Let's talk when we meet.\" \"", "Answer me, you jerk.\" \"", "Does Choi Han Sung know?\" \"", "Answer me, does Choi Han Sung know?\" \"!\" \"", "He knows.\" \"", "What are you doing here at this hour?\" \"", "What's wrong?\" \"", "Why didn't you tell me that Go Eun Chan is a woman?\" \"", "Do you want a glass of red wine?\" \"", "Do you think I'm kidding with you now?\" \"", "When did you find out?\" \"", "What's the reason for not telling me when you knew?\" \"", "Don't you know I've been so frustrated because of that kid?\" \"", "You dare say you don't know?\" \"!\" \"", "You never asked me.\" \"", "You didn't ask me.\" \"", "What other reason do I have to tell you?\" \"", "Hyung, you knew from the beginning that she is a woman.\" \"", "You knew that she is a girl and yet you still let her come to your art shop?\" \"", "On the day of the performance, I asked Han Yoo Ju to come out and you were out with that kid.\" \"", "What was the reason?\" \"", "Do you like that kid?\" \"", "Were you laughing at me behind my back?\" \"!\" \"", "Why are you angry about this?\" \"", "It's good for you that Go Eun Chan is a woman.\" \"", "Eun Chan says she likes you too so what's the problem?\" \"", "So you knew everything.\" \"", "Whatever happened between us, you knew everything.\" \"", "But you never told me anything.\" \"", "Han Yoo Ju told me that you have another woman, she means Go Eun Chan right?\" \"", "The woman you took to the exhibition that day....\" \"It was Go Eun Chan right?\" \"", "Is that the reason why you kept this from me?\" \"", "That's because Eun Chan was in a difficult position...\" \"What difficult position?\" \"!\" \"", "If I knew that she is a woman would the sky fall down?\" \"!\" \"", "That's right.\" \"", "I'm sorry.\" \"", "Maybe I thought things were too simple.\" \"", "But I didn't want to make things harder for a kid who wanted to work at the coffee shop.\" \"", "Also, since you two like each other...\" \"I thought that was enough.\" \"", "Answer me.\" \"", "If you don't answer me, then I don't know what I'll do.\" \"", "When Han Yoo Ju said that Choi Han Sung has another woman, who was that woman?\" \"", "Should I go and ask Han Yoo Ju?\" \"", "That's my business.\" \"", "It has nothing to do with you.\" \"", "It does, answer me!\" \"", "That's enough.\" \"", "I don't want to talk.\" \"", "Fine, then don't talk.\" \"", "Han Yoo Ju, since Hyung is not talking, then you tell me.\" \"", "The woman that Hyung brought to the exhibition, was that Go Eun Chan?\" \"", "You said that Choi Han Sung has another woman.\" \"", "Is that woman Go Eun Chan?\" \"!\" \"", "What are you doing?\" \"", "That's right, I did like Go Eun Chan.\" \"", "But Eun Chan says she doesn't.\" \"", "I've already sorted it, all right?\" \"", "This is Choi Han Kyul.\" \"", "I'm not here right now so please leave a message.\" \"", "It's me.\" \"", "You're not answering your cell so I thought...\" \"Are you at home?\" \"", "If you're at home then...\" \"please pick up the phone.\" \"", "I'm really sorry.\" \"", "You haven't had an accident have you?\" \"", "Right?\" \"", "I have something to tell you.\" \"", "Move.\" \"", "Let's talk.\" \"", "I never thought about lying to you in the first place.\" \"", "But I...\" \"At first....\" \"At first, it was because of the money.\" \"", "The rite was closed down.\" \"", "And I had no job.\" \"", "It was really good working at the Coffee Prince.\" \"", "I really wanted to continue working there, but if I told you I was a woman then...\" \"I was afraid you'd kick me out.\" \"", "That's why...\" \"I didn't tell you, I'm really sorry.\" \"", "I wanted to tell you...\" \"I wanted to tell you but before you go to America.\" \"", "I wanted to get along well with you.\" \"", "I was afraid you wouldn't want to see me again if I told you I was a woman.\" \"", "I was worried about that, that's why I didn't tell you.\" \"", "I'm sorry.\" \"", "Tell me you're not.\" \"", "I beg you, tell me you're not.\" \"", "Eun Chan.\" \"", "I won't be angry, so just tell me the truth.\" \"", "You didn't lie to me did you?\" \"", "No matter the reason, you wouldn't lie to me would you?\" \"", "It's not for a day or two days...\" \"It's been a few months now.\" \"", "You can't be like this right?\" \"", "You're not a woman.\" \"", "You haven't once lied to me.\" \"", "A person who loves you doesn't lie.\" \"", "Hurry up and tell me that everything is just a misunderstanding!\" \"", "I'm sorry.\" \"", "I'm really sorry.\" \"", "You lied to me?\" \"", "Is that it?\" \"", "You...\" \"You lied to me?\" \"", "Now I've traveled across the ocean\" \"With the same shoes\" \"Just longer hair\" \"Still carry that picture in my wallet\" \"From the photo booth, yeah, it's still there\" \"Just give me some kind of sign\" \"Is this the right place\" \"Or the right time\" \"Is this the right time\" \"So you couldn't say anything?\" \"", "You dummy!\" \"", "Still, he got that angry?\" \"", "Isn't he going overboard?\" \"", "I didn't like him from the start.\" \"", "He looked difficult to please.\" \"", "Just get rid of him!\" \"", "I'll introduce you to someone else!\" \"", "Even if I can't see him anymore... even if he refuses to see me...\" \"I want to tell him.\" \"", "That I really, really love him.\" \"", "You idiot.\" \"", "Then tell him!\" \"", "My daughter's grown up, crying over a man.\" \"", "What's so great about crying over a man that you'd cut these so nicely for her?\" \"", "Go in.\" \"", "Two ice mochas.\" \"", "Welcome.\" \"", "Why aren't you coming?\" \"", "Is the cafe a joke to you?\" \"", "Waffles to table 8.\" \"", "I'm completely busy.\" \"", "I can't stand to watch this, so you come and fire her yourself.\" \"", "If the employee did something wrong, fire them.\" \"", "Why should the manager be absent?\" \"", "Come out!\" \"", "Go Eun Chan.\" \"", "If the manager tells you to quit, quit.\" \"", "Dr. Kim is coming today.\" \"", "Please come home early.\" \"", "Okay.\" \"", "You're taking that well, without any complaint.\" \"", "I've got to eat and live.\" \"", "But mother, no matter how I think about it,\" \"I don't think it's right to just send him away.\" \"", "Lee Myung Jae, I mean.\" \"", "Leaving him in front of his biological father without telling him makes me feel guilty.\" \"", "And I feel scared that he'll ask to meet.\" \"", "It doesn't look like he's going to just leave.\" \"", "He's supposed to leave this week, but I haven't heard from him.\" \"", "He's his bloodline, of course he'd feel possessive.\" \"", "Even if he doesn't reveal he's his father, he'll want to drop by at least once a year.\" \"", "In his position, that's natural.\" \"", "Let's think of what's easiest for Han Kyul.\" \"", "What's best for him?\" \"", "Seems like just yesterday we took him in as a baby.\" \"", "Thank you.\" \"", "What are you thinking, coming to work?\" \"", "What would you like?\" \"", "Ice coffee?\" \"", "Don't you know only guy princes work here?\" \"", "I'll quit when he tells me to, but till then,\" \"I thought I should show my sincerity.\" \"", "You're really shameless.\" \"", "Do you have to get your way?\" \"", "I can't understand at all.\" \"", "Then don't.\" \"", "If you can't understand, don't understand.\" \"", "What's the problem?\" \"", "Clear that table over there.\" \"", "I'll handle things here.\" \"", "Okay.\" \"", "What the hell are you so mad about?\" \"", "They like each other.\" \"", "Isn't it a good thing if she's a girl?\" \"", "Is liking each other everything?\" \"", "She lied, and destroyed his trust.\" \"", "Does a guy who values trust so much just date this girl, that girl, left and right?\" \"", "Hey, when do you have time?\" \"", "Let's fight this out.\" \"", "Manager, I...\" \"It was because of Eun Sae...\" \"I'm really sorry.\" \"", "You sure are good at acting innocent, then lying and stabbing someone in the back.\" \"", "I got Go Eun Chan's pay ready.\" \"", "But we've still got five or six days left this month.\" \"", "Should I deduct that or not?\" \"", "Do whatever you want.\" \"", "Have you ever deferred to me?\" \"", "That girl's done anything and everything to keep her family fed.\" \"", "Since her father died when she was sixteen, she was the head of the household, it was easier to act as a guy.\" \"", "So that's why she turned out like that.\" \"", "Do you think she enjoyed it?\" \"", "Forget it.\" \"", "It's your problem, not mine.\" \"", "Get her pay ready and send her out.\" \"", "You hired her, so you fire her.\" \"", "Do you really want to live with me?\" \"", "This job isn't that exciting.\" \"", "So isn't agreeing to go to New York suggesting that you want to start over with me?\" \"", "Hello.\" \"", "I'm running away.\" \"", "What'll you do if he comes to catch you?\" \"", "The person running away is the criminal, and the one chasing is the cop.\" \"", "Is that right?\" \"", "Then there are criminals who wait to be caught by cops.\" \"", "You know each other, don't you?\" \"", "Is this the second time?\" \"", "We met once in New York.\" \"", "This is the third time.\" \"", "We met twice in New York.\" \"", "Did you have dinner?\" \"", "We just ate.\" \"", "Do you want anything?\" \"", "Just coffee.\" \"", "Okay.\" \"", "I saw a film you worked on in Japan.\" \"", "Are you interested in working together?\" \"", "It might be fun to mix music and art in a performance.\" \"", "Ah.\" \"", "I'm all out of coffee.\" \"", "Have tea instead.\" \"", "DK, do you remember this tea?\" \"", "It's lemon chestnut.\" \"", "I bought it from that place before.\" \"", "You know, that tea place behind your villa.\" \"", "Don't you remember?\" \"", "You know, it had a small herb garden out in the back.\" \"", "I know, Joy Coffee Shop.\" \"", "That's right, Joy.\" \" ", "Do you still like their walnut pies?\" \" ", "Excuse me.\" \"", "I'm sorry, but could you leave us?\" \"", "I was on my way out anyway.\" \"", "Just a minute.\" \"", "I'm sorry.\" \"", "I'm doing that because I'm mad at him, so please understand.\" \"", "You like him, and he likes you.\" \"", "What's the problem?\" \"", "Do I have to answer?\" \"", "You know I still like you....\" \"Don't you?\" \"", "It's a bit uncool to know that and be working a different guy in front of me.\" \"", "I'm sorry.\" \"", "I don't know why I'm like this, either.\" \"", "Tell me honestly.\" \"", "What's the reason?\" \"", "Why?\" \"", "I don't like him looking at other women.\" \"", "Should I praise you for being honest?\" \"", "Or do I curse you for not considering my feelings?\" \"", "I'm always sorry to you.\" \"", "I don't like walnut pies now.\" \"", "Bye.\" \"", "Do you want to call a taxi?\" \"", "I'm going to take a walk.\" \"", "Go in.\" \"", "I feel jealous, seeing him again.\" \"", "Isn't that funny of me?\" \"", "Is work what you want?\" \"", "Even without me, can you be happy just working?\" \"", "Or do you want to go back to New York with DK...\" \"What do you really want?\" \"", "We can't have everything we want.\" \"", "Just like you can't have Eun Chan.\" \"", "What are you talking about?\" \"", "I've never thought that.\" \"", "Yoo Ju.\" \"", "Let's stop doing this.\" \"", "I needed time to get my chaotic thoughts in order, but I'm over her now.\" \"", "Are you really over her?\" \"", "When I said I was leaving, you asked for time.\" \"", "I thought you'd tell me not to leave because you'd already settled your feelings.\" \"", "But you asked for time to get over her.\" \"", "I know you're not one for saying empty words, but in that moment, you should have said,\" \"\"I'm over her, she's nothing to me.\" \"", "Han Yoo Ju, I only want you. \"\" \"", "That's what I hoped you'd say.\" \"", "What does that mean?\" \"", "That means you're not really over her.\" \"", "You know I can't say empty words.\" \"", "Why don't you trust me?\" \"", "Look me in the eyes and answer me.\" \"", "Is Eun Chan really nothing to you?\" \"", "It's been too short of a time for you to be completely over her.\" \"", "Maybe not for me, but it is for you.\" \"", "I can change quickly and end things quickly, but you can't.\" \"", "Your feelings can't change direction quickly, and once they have, it's difficult for you to change them back.\" \"", "You're different from me.\" \"", "That's why it makes me more frightened and more angry.\" \"", "Yoo Ju.\" \"", "From the time I met you, until you met Eun Chan, there was nobody but me in your eyes.\" \"", "There were plenty of suitable women around you, but they were nothing to you.\" \"", "You wouldn't even have a cup of coffee with another woman!\" \"", "When I needed you, you were always by my side, and whatever I did, you'd forgive me and accept me.\" \"", "I was always number one.\" \"", "But now, I expect too much from you.\" \"", "Nothing's changed.\" \"", "No, so much has changed,\" \"Because I can't trust you anymore.\" \"", "So... you're leaving no matter what?\" \"", "If you leave like this, it's really over for us.\" \"", "I hate this place.\" \"", "I don't want to see you!\" \"", "What are you telling me to do, when my man keeps another girl tucked away in his heart?\" \"", "So you want to break up again?\" \"", "You don't give me any chances, and decide everything by yourself.\" \"", "What did I do that was so wrong?\" \"", "Both then and now... you sure do break up easily.\" \"", "I'm going home.\" \"", "Goodbye.\" \" ", "Are you leaving?\" \" ", "Yeah.\" \"", "Drinking beer makes going to the bathroom such a pain.\" \"", "What are you saying?\" \"", "What's wrong?\" \"", "This thing called your heart.\" \"", "If it were a piece of paper, you could fold it.\" \"", "If it were kimbap, you could roll it up.\" \"", "If it were flowing water, you could block it.\" \"", "Even if it's scary, a plane can be put in reverse...\" \"\"Put a plane in reverse?\"\" \"", "Haven't you seen it on Armed Forces Day?\" \"", "Anyway, things can be blocked, or reversed, but why not this heart?\" \"", "It's really difficult for me.\" \"", "Is there something in the water in this neighborhood?\" \"", "Why is it so full of pure, simple-hearted fools?\" \"", "I might be better off waiting for\" \"Donghaemul* and Baekdusan* to wear down.\" \"(*", "mountains in South Korea)\" \"I'm tired, waiting for her heart.\" \"", "Did you not like the woman you met on the blind date?\" \"", "I didn't even look at her.\" \"", "She'd made up her face, tucked things here and there and did herself up.\" \"", "But my heart... this heart...\" \"Why are you here so late at night and making things annoying for me?\" \"", "Buy some liquor.\" \"", "Who's got liquor?\" \"", "Come on, you're my only friend around here, go buy some beer.\" \"", "Hey, I hear you're making lots of money these days.\" \"", "I keep hearing about how people come from far away just to taste your coffee.\" \"", "Ah, money sure is nice.\" \"", "Why is that because of money?\" \"", "It's because of my coffee.\" \"", "They're coming because of all the money that was used to renovate everything.\" \"", "Think of how it used to be.\" \"", "Who'd go to a dump like that?\" \"", "There's no reason to.\" \"", "True, it's not just because of my coffee.\" \"", "The kids work hard.\" \"", "I didn't think I'd get attached to them, but they can act cute.\" \"", "You're old, seeing kids as cute.\" \"", "Ku Young Dal wants to date you.\" \"", "He's pretty decent.\" \"", "Mr. Ku's a nice man.\" \"", "I know that.\" \"", "Since I know that, I hope he can meet a nice lady and live happily.\" \"", "I hear the woman he met on the date is still an unmarried lady.\" \"", "I'm sure they'll be good together.\" \"", "Think it over carefully.\" \"", "Don't kick him aside and regret it later.\" \"", "Oh, right.\" \"", "That cafe manager and my Eun Chan...\" \" How are they at the cafe?\" \" ", "Huh?\" \"", "She's completely depressed, and doesn't eat.\" \"", "Don't worry too much.\" \"", "Sure, she might feel like she'll die now, but time takes care of that.\" \"", "That's what's great about youth.\" \"", "Is the manager really angry?\" \"", "Why wouldn't he be?\" \"", "Of course he is.\" \"", "Man, I want a drink.\" \"", "You don't even buy me any beer.\" \"", "Good night.\" \"", "Don't drink!\" \"", "Just like a wife.\" \"", "When did you get here?\" \"", "In the afternoon.\" \"", "You should have called.\" \"", "I'd have come home earlier.\" \"", "It's been a long time since I have had these noodles.\" \"", "Looks great.\" \"", "Mom, you have some too.\" \"", "You're not just acting like you want to eat to make me feel better, are you?\" \"", "Do you think I'm stupid?\" \"", "Why would I eat all this if I wasn't hungry?\" \"", "Mom, have some.\" \"", "If I eat at this hour, it'll go straight to my stomach.\" \"", "No.\" \"", "But it's okay for your twenty-something son to develop a belly?\" \"", "Yes.\" \"", "Eat slowly.\" \"", "I met Dad's friend.\" \"", "I heard from your father.\" \"", "You miss your birth mother, don't you?\" \"", "I saw her picture.\" \"", "He gave it to me.\" \"", "He did?\" \"", "Seems they were close.\" \"", "Are you sad?\" \"", "Not really.\" \"", "She gave me such a handsome son... and passed away first without being able to see you grow up.\" \"", "I feel worse for her.\" \"", "I feel very sorry, and grateful.\" \"", "Mom.\" \"", "Yes?\" \"", "I just want to say this.\" \"", "I think you're the only person in the whole world who has faith in me.\" \"", "Who could that be at this hour?\" \"", "Madam, it's you.\" \"", "It's Manager Hong.\" \"", "Wow, the view's great here.\" \"", "When I've made tons of money, sell this place to me.\" \"", "Okay.\" \"", "You're a lot softer than you look.\" \"", "Is that not true?\" \"", "You look like you wouldn't bleed a drop if you were pricked with a needle.\" \"", "But you totally fell for such a little girl.\" \"", "It's a little weird to call her a girl.\" \"", "Should I just call her a guy?\" \"", "Or jerk?\" \"", "That jerk!\" \"", "Or should I just say girl?\" \"", "You sure had fun watching.\" \"", "In the past... there was this girl I loved a ton.\" \"", "Who?\" \"", "Someone you ran the cafe with?\" \"", "She was a really, really good liar.\" \"", "Everything she said was a lie.\" \"", "She'd say she was going to meet friends, but ending up drinking with guy classmates.\" \"", "She'd say she was stopping by at home, and then go out dancing with friends.\" \"", "If I gave her money to go to the hospital because she said she was sick, she'd go and buy rings and bags.\" \"", "I don't know how she was such a good liar.\" \"", "Do you know what she said when she left me?\" \"", "That she was going to study abroad.\" \"", "There was something she'd wanted to study since she was young, and she said she wanted to go really badly.\" \"", "So even though it hurt me to let her go, I even gave her money and sent her off, and said I'd wait.\" \"", "Then a year later, she wound up marrying some other guy.\" \"", "You really loved someone like that?\" \"", "Because of her, I added to my debts, I lost long time friends...\" \"What's so funny?\" \"", "It should make you angry.\" \"", "Whenever I think of that woman, I just laugh.\" \"", "She must've really liked me though.\" \"", "Going out with friends, drinking, playing, and I still liked her.\" \"", "She must've thought I'd dislike her if I knew all that about her.\" \"", "How much must she have liked me to keep lying like that?\" \"", "I'd never even fought with her once.\" \"", "That's a lie.\" \"", "No, it's true.\" \"", "If I got angry, there was one decisive way to melt that anger at once.\" \"\"", "Hong Gae Sik, so you're angry.\" \"", "Can you really live without that woman?\"\" \"", "I'd ask myself that.\" \"", "Then, my anger would just die away.\" \"", "Is that what you came to tell me?\" \"", "That if I'm not going to break up with Eun Chan,\" \"I should let this go, that a good thing is a good thing.\" \"", "You're always like that.\" \"", "Don't, if you don't want to.\" \"", "Gotta have another drink.\" \"", "Go Eun Chan, taking care of your family.\" \"", "Here's a present for you.\" \"", "Whether you're a man, or an alien...\" \"I hate you.\" \"", "I said I hate you.\" \"", "I miss you.\" \"", "I miss you.\" \"", "I miss you.\" \"", "Honestly, it was fun watching.\" \"", "It was funny watching you act as brothers.\" \"", "If the Manager was serious about you, I'd be angry too.\" \"", "I understand him.\" \"", "What do you call each other now?\" \"", "Is he your oppa now?\" \"", "I don't really care if I'm called hyung or oppa.\" \"", "What?\" \"", "You don't care?\" \"", "You don't think about how others feel around you, and you don't care?\" \"", "Must be nice to be as carefree as you, No Sun Ki.\" \"", "Everyone's on your side here.\" \"", "How great to have so much support.\" \"", "I'm sorry.\" \"", "I was short-sighted.\" \"", "I should have said so from the start.\" \"", "I didn't know things would come to this.\" \"", "I don't want to hear it, so pack up and leave.\" \"", "Wait, listen to me.\" \"", "It must've been fun for you.\" \"", "A guy out of his mind asked you to act as his boyfriend, and paid you for going along, and found you a job, and said he liked you even as a man.\" \"", "That's how it must've been.\" \"", "I must've looked like such a pushover.\" \"", "Miss Go Eun Chan, when were you planning on telling me?\" \"", "You must've had plenty of opportunities.\" \"", "When I said we should be sworn brothers, didn't you understand what feelings drove me to say that?\" \"", "Couldn't you figure out how I felt toward you?\" \"", "Do you know how hard it was for me when we were at the beach, and why I didn't come to work for days?\" \"", "Did you really not know, you bastard?\" \"!\" \"", "Tell me.\" \"", "Did you really not know?\" \"", "I couldn't say the words.\" \"", "I didn't know how I'd act if you got this angry, and I thought I might not be able to see you ever again.\" \"", "I was wrong, truly wrong.\" \"", "You were only thinking of yourself.\" \"", "You didn't care about how much you were putting me through.\" \"", "When I said I liked you as a man, when I said let's go as far as we can go,\" \"you knew and still didn't say anything?\" \"", "Was it fun?\" \"", "It wasn't fun at all!\" \"", "I liked you too much, so I couldn't say it.\" \"", "You said you were going to America in a month...\" \"We'd have to separate in the end anyway...\" \"So I tried to pretend not to know.\" \"", "Here I was, even thinking of taking you with me to America, but you were already thinking about sending me away.\" \"", "What was I to you?\" \"", "You... said you wouldn't like me as a girl.\" \"", "You said you were glad I was a guy.\" \"", "What could I do, when I wanted to see you...\" \"The kiss was better when you were a guy.\" \"", "What's left between us?\" \"", "Was there ever any trust there?\" \"", "I'd abandoned so much in my life just to have you.\" \"", "It feels so unfair.\" \"", "You calculated everything to make sure you wouldn't get hurt.\" \"", "Without a care for me.\" \"", "Brought to you by WITH S2 Written In The Heavens Subbing Squad\" \"Main Translators: javabeans, s@nbi, wingyee\" \"Spot Translator: javabeans\" \"Timer:\" \"ltrang\" \"Editor/QC: maggie\" \"Coordinators: mily2, ay_link\" \"Ask yourself this carefully.\" \"", "Ask if you can live separated from Go Eun Chan.\" \"", "The fact that Eun Chan told you, even now when it's so late is probably because she has faith in you.\" \"", "I feel angry at Choi Han Sung for wavering, and hateful toward Eun Chan.\" \"", "Don't go, Han Yoo Ju.\" \"", "If you hurt Han Sung hyung again, I think I'd hate you.\" \"", "If I knew this is how things would end up, I should've said the truth from the start.\" \"", "It would've been better if I'd never liked him.\" \"", "Go Eun Chan.\" \"", "I'm glad you're a girl.\"" ]

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[ "The city Health Department last week began sending brochures to businesses that would be affected by the latest ban, including restaurants, bars and any “food service” establishment subject to letter grades.", "\n\nAnd merchants were shocked to see the broad sweep of the new rules.", "\n\n“It’s not fair. ", "If you’re gonna tell me what to do, it’s no good,” said Steve DiMaggio of Caruso’s in Cobble Hill, Brooklyn. “", "It’s gonna cost a lot more.”", "\n\nAnd consumers, especially families, will soon see how the rules will affect their wallets — forcing them to pay higher unit prices for smaller bottles." ]

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[ "1. ", "Field of the Invention\nThe present invention relates to a method and apparatus for cooling molded plastic articles after the molding operation is finished. ", "In particular, the present invention relates to method and apparatus for an injection molding machine equipped with a post mold cooling (“PMC”) device mounted on a moving platen that cooperates with a multi-position robot take out plate to both cool the interior of the parts and to (preferably) selectively unload some of the molded part carriers on the multi-position take out plate. ", "The method and apparatus are particularly well suited for cooling injection molded thermoplastic polyester polymer materials, such as polyethylene terephthalate (“PET”) preforms.", "\n2. ", "Related Art\nA variety of post mold cooling methods are currently employed on injection molding machines to optimize the cooling of freshly molded plastic parts. ", "Such methods include conductively cooling the parts while they are still inside the mold cavities, blowing air on the exteriors of the molded parts after they are extracted from the mold, and blowing air into the interiors of the molded parts. ", "Some parts (for example plastic preforms) are typically injection-molded using PET resin, and can have wall thicknesses varying from about 2.00 mm to greater than 4.00 mm, and require extended cooling periods to solidify into substantially defect-free parts. ", "Heavy walled parts (such as those made from a material that has a high resistance to thermal heat transfer, like plastic resin) can exhibit “reheating” phenomena that can produce defective parts after they have been ejected from the mold.", "\nIn the case of PET preforms, some manufacturing defects are: Crystallinity: The resin recrystallizes due to the elevated temperature of the core resin not cooling quickly enough. ", "The white appearance of the crystals impairs the clarity of the final product and provides an area of potential weakness in a resultant blown product. ", " Surface blemishes: The ejected performs, initially having solidified surfaces are reheated by the core material which causes the surface to soften and be easily marred. ", "Sometimes this surface reheating can be severe enough to cause touching parts to weld together. ", " Geometric inaccuracies: Handling partly-cooled performs or attempting to further cool them in devices that do not maintain their geometric shape while their surfaces are reheated can cause the preform's round diameter to become oval shaped or the smooth surface to become wrinkled or non-linear.", "\nThe above-noted problems could be alleviated somewhat by extending the cooling time of the injection molded performs in their mold. ", "However, this will cause the injection molding cycle to be lengthened, typically 25 seconds or longer, wherein the majority of this time would be used solely for cooling purposes. ", "In an effort to improve the production efficiency of this process, several techniques are employed to perform a post mold cooling function, wherein partially cooled preforms are ejected from the injection mold after an initially cooled surface skin has formed to allow the part to be ejected without deformation. ", "The partially cooled preforms are then handed off to a downstream device that continues to hold the preform while removing the remaining heat so that the preform can subsequently be handled without damage. ", "Typically, the preform surface temperature needs to be lowered to about 70° C. to ensure safe handling.", "\nThe early ejection of partially cooled preforms releases the injection molding equipment earlier in the molding cycle, thereby significantly improving the production efficiency of the equipment. ", "Injection molding cycle times typically were halved from 25 seconds to about 12 seconds or less (in some instances) depending on the preform design being molded.", "\nSome examples of post mold cooling technology are shown in U.S. Pat. ", "Nos. ", "3,804,568; 4,729,732; 4,836,767; Re. ", "33,237; U.S. Pat. ", "Nos. ", "5,447,426; and 6,171,541.", "\nU.S. Pat. ", "No. ", "Re. ", "33,237 discloses a robotically-controlled multi-position take out plate for removing partially cooled injection molded parts from the core side of an injection mold. ", "The parts are ejected from the mold directly into cooled carriers, as disclosed in U.S. Pat. ", "No. ", "4,729,732, and transported by the robot to an outboard position where some of the parts are ejected onto a conveyor. ", "The plate has multiple sets of carriers, each set being sufficient in number to hold one part from each of the cores of the multi-cavity mold. ", "There are multiple sets of carriers on the plate so that multiple sets of molded parts can be held and cooled, the set that is ejected being the set that has been cooling the longest in the tubes of the plate. ", "However, these patent documents do not disclose cooling the interior of the parts. ", "Moreover, the disclosed method of ejecting the parts relies on the termination of a vacuum that is holding the parts in the carriers, thereby allowing gravity to cause the parts to fall out when the take out plate has been rotated 90 degrees to a discharge position.", "\nU.S. Pat. ", "No. ", "6,171,541 discloses inserting a cooling pin (CoolJet™) into the interior of partially cooled part to discharge a cooling fluid therein to assist cooling. ", "Also disclosed therein is a procedure to apply a vacuum through the same cooling pin to cause the part to remain attached to the pin when it is moved away from the carrier holding the part, thereby removing the part from the carrier. ", "The pins, mounted to a frame, are then rotated 90 degrees to a discharge position and the vacuum terminated to allow the parts to fall off the pins. ", "However, there is no disclosure of mounting the frame and pins onto a moving platen to utilize the motion of the moving platen to insert and retract the pins with respect to the parts.", "\nU.S. Pat. ", "No. ", "4,836,767 discloses a rotatable table mounted on the moving platen on which are mounted two core sets for the mold. ", "While one core set is in the closed mold position for injection molding parts, the other is positioned outboard for ejecting the parts into cooled carriers that are mounted on an indexable, four-sided carousel that is mounted to the stationary platen of the machine. ", "Four sets of molded parts can be carried on the carousel allowing an extended cooling time to be performed. ", "The parts remain on the cores for one additional cycle time sequence that provides a small extension of cooling time of the interior of the parts before they are transferred to the carousel. ", "However, there is no disclosure of repeated or multiple cooling of the parts' interiors.", "\nU.S. Pat. ", "No. ", "3,804,568 discloses a robot mounted to the moving platen of an injection molding machine, wherein the robot drives a take out plate into and out of the open mold area to remove ejected parts. ", "A second transfer plate then unloads the take out plate while it is in the outboard position. ", "The motion of the moving platen is used, via cams and linkages, to actuate the take out plate vertical motion and to synchronize it mechanically so that there is no risk of collision with the mold during its operation. ", "However, there is no disclosure of part cooling, either exterior or interior, while the parts are being transported by either plate.", "\nU.S. Pat. ", "No. ", "5,354,194 discloses a molded part removal unit mounted to the side of the fixed platen. ", "However, there is no disclosure of any cooling treatment.", "\nAn earlier Husky preform molding system used a robot with a single position take out plate with carriers to unload PET preforms. ", "The robot was mounted on the stationary platen and moved the take out plate vertically. ", "In the outboard position, above the mold, a vacuum tube carrier of a transfer plate was aligned with the carriers and removed the molded parts therefrom by application of vacuum to their interiors. ", "The transfer plate moved to a second outboard position at the non-operator side of the machine and rotated to allow the parts to drop from the tubes when the vacuum was terminated. ", "However, there was no blowing or cooling of the interior of the parts during their handling.", "\nWith reference to FIGS. ", "1-4, top plan views of an injection molding machine 10 are shown comprising, an injection unit 11, a clamp unit 12, a robot unit 13, and a CoolJet™ unit 14. ", "Also included is an injection mold comprising two halves: (i) the cavity half 15, containing mold cavities 19, attached to the stationary platen 16 of the machine 10; and (ii) the core half 17 which is attached to the moving platen 18 of the machine 10.", "\nThe robot unit 13 is mounted atop the stationary platen 16 and includes a horizontal “Z” beam 20 that projects to the non-operator side of the machine and upon which rides a carriage 21, moved along the beam by (typically) a servo-electric driven belt drive (not shown). ", "Vertical “Y” beam 22 is attached to the carriage 21 and this supports the multi-position take out plate 23 upon which are mounted multiple sets of carriers 24 that may be cooled for transporting multiple molded shots of parts ejected from the mold from an inboard (loading) position, as shown in FIG. ", "1, to an outboard position as shown in FIGS. ", "2-4 inclusive.", "\nThe transfer device 14 includes a plate 25 upon which are mounted multiple transfer pins 26, one for each carrier 24 on the multi-position take out plate 23. ", "The plate 25 is supported on slides 27 and can be moved toward and away from the carriers 24, when in their outboard position, by cylinder 28.", "\nIn operation, one shot of molded parts is transferred into the carriers 24 when the mold is open and the multi-position take off plate 23 is positioned such that empty carriers are aligned with parts on the mold cores 29. ", "In the example shown in FIG. ", "1, a 48-cavity mold is transferring 48 parts into 48 carriers on a 3 position take off plate 23. ", "The multi-position take off plate 23 is then moved to its outboard position by the robot 13, as shown in FIG. ", "2. ", "The mold is then closed and clamped for the next molding cycle. ", "Meanwhile, the transfer device 14 activates a cylinder 28 to move the plate 25 and its transfer pins 26 so as to enter the parts held in the carriers 24. ", "This engaged position is shown in FIG. ", "3.", "\nJust before the molding cycle ends, the transfer pins 26 are extracted from the parts, and the robot 13 causes the multi-position take off plate 23 to rotate 90 degrees (as shown in FIG. ", "4) by means of a servo motor on the end of an arm 22, or alternatively a crank and cylinder arrangement (not shown). ", "The respective vacuums holding the parts in the carriers 24 are selectively shut off in the order of the parts that have been held in the carriers the longest, in this example for three molding cycles. ", "These parts fall out of the carriers onto a conveyor beneath (not shown). ", "The remaining parts continue to be held in their carriers by vacuum. ", "The multi-position take off plate 23 is then returned to the vertical orientation ready for entry into the open mold area to pick up the next shot of molded parts in the recently vacated carriers 24.", "\nThe injection molding machine described above therefore unloads the molded parts into the multi-position take off plate 23 by positioning the plate at various inboard locations to fill the most recently vacated carriers, and then moves them to one outboard position aligned with the transfer device. ", "This outboard position is the same in all cases, where all the parts are dealt with by the transfer device. ", "Thus, each part receives the same treatment the same number of times as there are sets of carriers 24 on the multi-position take off plate 23, in this example three times.", "\nA number of disadvantages are present in the injection molding machine configuration described with respect to FIGS. ", "1-4. ", "First, the multi-position take off plate 23 is heavy. ", "In larger systems such as those with 432 carriers (to operate with a mold having 144 cavities), the plate can weigh in excess of several hundred kilograms (Kg), as the weight includes not only the structure of the plate and carriers themselves but also the weight of multiple shots of parts plus the weight of any cooling fluid in the plates and carriers, typically water. ", "The effect of this heavy weight when mounted on the end of a cantilevered Y beam 22 (which itself is movably mounted on a cantilevered Z beam 20) is to cause difficulty in maintaining alignment of the carriers 24 with the mold cores and the carriers 26 after the take of plate 23 has moved quickly from the inboard position to the outboard position, and vise versa. ", "The inertia of the plate can cause it to vibrate when quickly being brought to rest in one of its stationary positions, and cycle time can be lost in waiting for motion oscillations to damp out sufficiently before attempting a part transfer or cooling tube insertion.", "\nA second disadvantage in the injection molding machine configuration described above is that when unloading the carriers 24, the entire multi-position take off plate 23 must be rotated 90 degrees and back again quickly. ", "Again, because of the weight and inertia involved, a high-performance, high-cost actuation device must be used if the rotation is not to take too long, since the time taken for this motion is time unavailable for CoolJet™ treatment.", "\nFurthermore, since the transfer device 14 engages each part in each carrier on every cycle, all the parts receive multiple applications of the same treatment. ", "The ability to provide different treatments to the parts in these multiple events is not possible.", "\nA third disadvantage is that the time available for treatment to be applied by the CoolJet™ device is reduced by the time it takes for the multi-position take off plate 23 to rotate to the horizontal position, eject selected parts and rotate back to the vertical position." ]

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[ "Mortgage Brokers in Hamhaugh Island\n\nWhat is a mortgage broker\n\nMortgage loans are brokered on behalf of companies and individuals by mortgage brokers, who effectively act as intermediaries. ", "Mortgage brokers strive to find a bank or direct lender that will agree to meet the particular loan an individual requires. ", "If you work with a mortgage broker in Hamhaugh-Island, it won’t be so difficult to get a great deal on the mortgage loan you require. ", "Even if you have a poor credit score or any other issues that could affect your mortgage application, working with a reputable mortgage broker will still boost your chances considerably.", "\n\nThere are regulations in place to guide professional mortgage brokers and make sure they adhere to banking and finance laws in the jurisdiction of customers, so you can be sure you’re in good hands.", "\n\nWhat Is A Mortgage?", "\n\nSimply put, a mortgage is a loan. ", "Unlike personal loans, a mortgage is specifically tied to a piece of property, so that it acts as security against the loan. ", "If you default on your payments, your mortgage provider has the right to take back (repossess) the property.", "\n\nWhile shorter or longer terms are available, mortgages are usually set for a 25-year period. ", "As soon as you borrow the money, a plan for repayment is implemented. ", "Even though the available mortgage plans vary, those that involve repayment plans on a monthly capital basis are very popular.", "\n\nAside from repaying the money you borrowed initially, you will be charged interest on the amount you’ve been loaned (the ‘capital’). ", "A mortgage is a debt instrument that is acquired using the collateral of a particular property that the loanee must repay in predetermined amounts. ", "Individuals and businesses use mortgages to buy property, without having to pay the total value up front. ", "The property can be owned by the borrower without a mortgage after the loan plus interest are repaid by them over a period of time. ", "If the borrower defaults in making mortgage payments, the property on which the mortgage is secured can be repossessed by the lender.", "\n\nThe property can be repossessed by the lender if the home buyer fails to make mortgage payments, since the bank has a charge on the house. ", "If there is a repossession, the tenants can be evicted by the bank and the property sold to repay the mortgage debt.", "\n\nMortgages come in many forms. ", "With a fixed rate mortgage, even though there is provision for longer fixed rate terms, borrowers are expected to pay the same interest rate for the initial terms (being two, three or five years). ", "Monthly payments remain constant during the fixed rate term. ", "An increase in interest rates in the market won’t change the payments of the borrower if they have a fixed rate. ", "Changes in market interest rates have no effect on the borrower’s mortgage repayment if they have a fixed rate.", "\n\nReach out to the Mortgage Saving Experts in Hamhaugh-Island. ", "You can do this by dialling 01273 738 072 for a friendly chat.", "\n\nYour mortgage will usually revert to a ‘standard variable rate’ laid down by the bank, building society or lender that lends you the money, once the fixed rate ends. ", "Lenders may change the rates as they see fit; to avoid paying higher monthly rates, you must remember to re-mortgage if you have a good broker or diary system in place. ", "Otherwise, call your current lender and adjust the rate around three months before it’s increased to the variable rate.", "\n\nA mortgage may appear cheaper than it really is, because the initial interest rate is mostly a low rate. ", "If interest rates increase at a later date, the borrower may not be able to afford the higher monthly payments. ", "With the possibility of the variable rates being changed at any time after the initial term, monthly payments subsequently become unpredictable.", "\n\nOther less common types of mortgages – such as interest-only mortgages, tracker rates, offset mortgages, buy to lets, bridging loans and secured loans – could also be available to you, so speak with an independent broker to determine your options. ", "In Hamhaugh-Island, our mortgage brokers can assist you in finding the ideal mortgage deal to match your unique circumstances and specifications.", "\n\nHandy Tools and Calculators\n\nYou can easily plan your future once you have an idea of the maximum you can borrow and how much the loan will cost. ", "Find out just how much your mortgage repayments are going to be, dependent on your interest rate and full loan amount, using this handy calculator. ", "Just enter those values together with your term and press ‘Click to calculate’ to instantly see how much you’ll need to repay each month.", "\n\nMortgage Calculator\n\n£\n\nMortgage Amount\n\nInterest Rate (%)\n\nDown Payment (%)\n\nYears\n\nMonths\n\nTerm\n\nWhy Use A Mortgage Broker?", "\n\nThere are a wide range of benefits to be enjoyed from working with a mortgage broker in Hamhaugh-Island with regards your mortgage application. ", "Some of the more obvious benefits include:\n\nSave Money\n\nOf all the benefits working with a mortgage broker provides, the possibility of cutting costs would be the most obvious. ", "You only need to provide a few details, before an experienced professional committed to protecting your interests handles the hard work.", "\n\nSome people are not fully convinced about this, what with the concept of a mortgage broker still vaguely understood universally. ", "So, there has to be a catch somewhere, surely? ", "A mortgage broker wouldn’t stand to gain anything by not working in your favour. ", "You’ll need to bear this in mind, even though any concerns you might have are understandable.", "\n\nIn short, a broker is required to give proof of their reasons for recommending the mortgage they have (to you, their regulators, the Prudent Regulation Authority or Financial Conduct Authority) or they could be penalised. ", "Many mortgage brokers can obtain exclusive mortgage deals not found on the high street, potentially making the total loan cost lower for the client. ", "Reputable mortgage brokers will usually inform you how they get paid for their services, as well as disclose the details of the entire cost of the loan. ", "Filing the pockets of a broker is of little value to a mortgage advisor company when compared to making sure customers have a positive experience.", "\n\nFinds The Most Advantageous Deal\n\nA mortgage broker will work towards protecting your interests, rather than those of the lending institution. ", "Acting as your agent isn’t all they should do, but also problem solvers and knowledgeable consultants too. ", "With access to a wide range of mortgage products, a broker can offer you the greatest value in terms of interest rates, repayment amounts, and loan products. ", "You’ll be required to meet with the mortgage broker to document your needs, as well as your short and long term goals. ", "Sophisticated solutions and innovative mortgages are distinct advantages of working with experienced broker, because simple 15 or 30-year mortgages aren’t enough in some situations. ", "These include mortgages to raise capital for debt repayment, money for your children, important home renovations or even the purchase of other properties like buy to lets.", "\n\nHas Flexibility Expertise to Meet Your Needs\n\nA mortgage broker navigates the client through any situation, handling the process and smoothing any bumps in the road along the way. ", "For example, borrowers with bad credit issues can find great products that will suit their needs through brokers who know lenders that offer such products. ", "If a borrower requires a loan too large for the bank to approve, a broker can be of benefit by providing the knowledge and ability to successfully source financing.", "\n\nSave Time & Hassle\n\nIt’s not all about money. ", "While it’s a good thing to save some extra money, your sanity and time matter just as much. ", "Imagine how much time it would take to find out about the numerous types of loans available from multiple lenders. ", "Unlike working with different lenders – which would require you to complete different forms every time – you’d only need one form with a mortgage broker. ", "A formal comparison of the loans recommended can be provided by your mortgage broker to act as a guide for the information that accurately illustrates the differences in cost, showing present rates and points, as well as closing costs for each loan. ", "Major lenders and those not so popular will be compared by your broker to seek out the most suitable deal for you, in terms of lower rates and total cost.", "\n\nTake some of the work off your shoulders and outsource it to someone who can offer expert advice. ", "A mortgage broker can provide an array of support throughout the application and approval process. ", "This can include assisting with paperwork, responding to questions and helping with government scheme applications, as well as explaining all the available options and loan features you may not have considered or been aware of. ", "A few of the features may include options to make extra repayments, as well as drawdown facilities and offset accounts. ", "These features can make a massive difference to your mortgage experience and overall costs. ", "If you don’t know much about these concepts and how they can work for you, reach out to your broker over the phone for clarification and answers.", "\n\nAccess to exclusive non-advertised deals\n\nThere are exclusive deals that aren’t advertised by banks to which brokers have access. ", "These deals are passed by the banks to the brokers, who then have the responsibility of selling the products. ", "Speaking to a broker unlocks these extra perks you would otherwise miss out on by going directly to a bank.", "\n\nA bank can only sell their own deals – not those of the other banks as well – whereas a broker can search the whole market for the best deal.", "\n\nBetter chance of pre-approval success\n\nIf your request for an Agreement in principle/Decision in principle of a loan is turned down, a mark is left on your credit rating. ", "You’ll need the necessary knowledge and experience a broker has to secure approval on your first attempt.", "\n\nAccess to expert knowledge\n\nHelping people secure loans is what mortgage brokers do for a living. ", "They have access to information and select deals you wouldn’t discover by yourself. ", "If you’re not on the lookout for them, you might not notice the subtleties that accompany loans. ", "The difference to your mortgage could ultimately be made by these subtleties. ", "Having the services of an experienced professional who can point these out for you is a huge benefit.", "\n\nRather than sacrifice a chunk of your day researching thousands of loans and lenders (and still potentially missing out on key subtleties), why not let someone with industry experience handle the work? ", "Just like you’d acquire the services of a hairdresser to replenish damaged hair or a plumber for leaking pipes, a mortgage broker is an excellent option for any of your home loan needs.", "\n\nGet in touch with the Mortgage Saving Experts in Hamhaugh-Island. ", "You can do this by dialling 01273 738 072 for a friendly chat.", "\n\nAbout Mortgage Saving Experts\n\nMortgages and insurance are not as complex as they seem at first. ", "That’s why finding honest advisers with invaluable experience and knowledge is so important. ", "Our mortgage savings experts will ease the process for you and make it as simple as possible. ", "After all, why make everything more stressful than it ought to be? ", "Let us make everything easy for you and ensure you get the best possible deal.", "\n\nMortgage Saving Experts provide an honest and transparent service that will leave our customers thinking that mortgages and insurance aren’t as daunting as they may seem. ", "At Mortgage Saving Experts, we handle every single mortgage and insurance application like they belong to us. ", "This is what we do. ", "No matter the circumstances – whether this is your first time buying, you’re a landlord, moving onto a new chapter or even re-mortgaging, Mortgage Saving Experts are here to help. ", "We are here to assist! ", "Approximately “Find out about 1000s of mortgage deals by putting 15 minutes aside to talk to 1 adviser.”", "\n\nOur Team of Brighton Mortgage Experts\n\nAs we are bound by regulations of the Financial Conduct Authority (FCA), we must ensure we get you the best available deal on the market. ", "We must justify to our customers and regulators why we make the mortgage recommendations we do, so you know just why you have that mortgage.", "\n\nDown to Earth Mortgage\n\nWe are an honest, passionate, enthusiastic and very experienced team of mortgage and insurance experts.", "\n\nOur mortgage insurance experts take pride in listening to the current and future objectives our customers have. ", "We will make these goals happen by working meticulously alongside you.", "\n\nWhy chose Mortgage Saving Experts?", "\n\nYou’ll get an initial rate for the first few years after taking out a mortgage. ", "After the initial rate period, the rate is then raised to the lender’s variable rate. ", "Three months before this rate is up for renewal, our team will contact you again to put a new deal in place before your rate and monthly payments increase. ", "Here are some of the other advantages you’ll enjoy if you work with us:\n\nWith a deal better than the bank variable rate, you’ll subsequently save money.", "\n\nYou won’t have to remember when the deal is due to end, as we will do this for you.", "\n\nYou can take a breather, while we do the bulk of the work.", "\n\nWe know our onions, so you’ll only ever be advised by a qualified mortgage expert.", "\n\nComparing, advising and setting up the best possible mortgage deal from amongst the many available is what we do.", "\n\nYou’ll be provided expert advice and support right through the mortgage process.", "\n\nFor a first-hand experience of how amazing our services are, give us a call today\n\nMortgage Types We Provide Expert Advice On\n\nWe dispense expert advice on a wide range of mortgage products. ", "In collaboration with our team, you won’t have any trouble finding the best mortgage products to match your specific requirements. ", "Some of the most commonly requested mortgage types we help with include:\n\nFirst time buyers\n\nFirst Time Buyers are classified by the majority of mortgage lenders as those who have either:\n\nNever owned a property or\n\nPeople who have owned a property in the past, but not owned one for six months or more.", "\n\nThe rules and ideas on this are different across various lenders. ", "Being a First Time Buyer is usually not an issue. ", "In order to qualify for stamp duty relief, it’s necessary for First time Buyers to have never been property owners before; this applies anywhere in the world.", "\n\nMortgages can seem a daunting process, but they do not have to be. ", "Buying your first home can be exciting, so if you come across a suitable broker who can handle the process for you at a fair price, do take advantage of their expertise. ", "The purpose of using one is straightforward enough. ", "Besides, if your car breaks down and you have no knowledge of cars, you wouldn’t attempt to fix it yourself; you would use the services of a mechanic. ", "The same applies to mortgages. ", "Mortgage brokers can save you time, effort and money, so why not use one? ", "The initial consultation is free of charge.", "\n\nBuying a home\n\nIf you’re considering a home purchase in the near future (or even within a few years, you should certainly brush up on your mortgage knowledge. ", "Study what you should do before the application, during the process of application, and how to utilise the mortgage after buying your property. ", "If you’d prefer a different approach, then speak to an adviser who can guide you through it.", "\n\nYour credit is vital.", "\n\nA mortgage is not to be taken lightly. ", "Banks risk a large amount of money and have been steadily more careful since the subprime mortgage crisis in 2008. ", "Good credit helps to qualify for a mortgage, but it isn’t a necessity. ", "We can also offer guidance regarding how much you can afford to pay for your new home and how to set your limit, depending on your ongoing situation. ", "We will help you with funding, the lowest cost and most suitable deal on offer, in addition to helping you buy your dream home.", "\n\nRe-mortgage your home\n\nIn short, this means you’ll switch from one lender to another to get a more affordable rate or cheaper deal. ", "The two do not necessarily go hand in hand. ", "Let me explain. ", "If you’ve got a small mortgage, paying the arrangement fee to a new lender to go on a lower rate might not seem practical to you. ", "You might find it cheaper by going on a slightly higher rate and paying no arrangement fee to the lender at all. ", "Even with a lower rate, you could end up having a costlier deal in total, which is why it’s always prudent to talk to someone before you make any decisions. ", "Pay close attention.", "\n\nThe potential absence of valuation or solicitors fees is one of the plus points of re-mortgaging, even though not everyone qualifies for this. ", "This is due to the fact that it is based solely on your disposition at the time of re-mortgaging. ", "So please check or ask your adviser.", "\n\nPerforming a re-mortgage in time is a practical way to reduce your mortgage costs significantly. ", "Depending on your specific needs, a re-mortgage deal might not be the best option, even though it does have its advantages.", "\n\nReasons for remortgaging your property\n\nBased on your individual circumstances, like…\n\nMortgage debt is fairly minor.", "\n\nFinancial circumstances have changed.", "\n\nEarly repayment charge is on the high side.", "\n\nA drop in the value of your home.", "\n\nYou’re dealing with credit problems.", "\n\nPresent rate is very agreeable.", "\n\nWe will provide guidance to help you choose whether to re-mortgage.", "\n\nBuy to Let\n\nA ‘buy to let’ property is one bought with a view to renting to others. ", "You are not allowed to legally live in the property. ", "If you’re a First Time Buyer, the number of available lenders will be restricted if you’re purchasing a buy to let, while extra checks would be carried out by the lender in such cases.", "\n\nYou may need to know certain things when purchasing a buy to let property.", "\n\nThe loan amount you can borrow is mostly based on the total rental income you receive.", "\n\nYou will have to pay 3% stamp in addition to your normal stamp duty.", "\n\nEven if the value of the property isn’t enough to be liable for stamp duty, you are still required to pay an extra 3% of the purchase price.", "\n\nTIP: You should ask your solicitor/conveyancer to figure out how much you must pay when considering buying a second property.", "\n\nA reputable adviser will know just what questions to ask in order to figure out the best mortgage for your specific needs.", "\n\nContact our advisers to find out whether you’re eligible.", "\n\nHow Much Do Mortgage Brokers Charge?", "\n\nThe majority of mortgage brokers receive commission from lenders, which is a percentage of the mortgage loan you secure. ", "This is usually around 0.33%, although this does vary massively, depending on what mortgage you require. ", "For example, this would take into account buy to let or residential mortgages and whether you’ve had any credit problems in the recent past. ", "A flat fee of roughly £500 is usually charged by the majority of independent brokers. ", "Don’t forget to find out how brokers collect payment. ", "They must be completely clear, letting you know the exact figure and fee structure in place.", "\n\nWe have a fee structure based on charging our clients £695. ", "From that figure, we then deduct any commission received from the mortgage lender If we receive a commission below the value of £695, we ask the client to pay the difference between the received commission and £695. ", "For instance, if the commission we receive is £495, then we would require you to pay £200 to make up the difference. ", "This can be paid when your mortgage offer has been produced, meaning we only get paid on results.", "\n\nHow Much Can I Borrow?", "\n\nA lot of factors influence this, like the number of children you have, the deposit amount, your income and any debts you might have in the background. ", "How much a lender is willing to lend is based upon a full affordability assessment, whereby they will look to understand your income, as well as any loan or credit card commitments and regular essential household expenditure. ", "Other than this, they will also carry out a credit check to ensure you have an agreeable credit rating for mortgage purposes.", "\n\nGet a decision in principle before you finish your mortgage application; this way, you can form a clearer idea with regards the amount you can borrow. ", "Make plans today for an appointment with one of our capable mortgage experts. ", "Without the need for credit checks, we can at least provide an initial estimate.", "\n\nThe Latest Best Mortgage Rates\n\nWhether you want a re-mortgage, move home, find a mortgage for a first-time buyer or purchase a buy to let, we can help. ", "We make comparisons on thousands of recent mortgage deals to help you find just what you’re looking for.", "\n\nWhat Our clients say About us\n\nWe have a list of clients in Hamhaugh-Island that is both lengthy and diverse. ", "If you doubt that we are the professionals most capable of finding you the best mortgage deal in Hamhaugh-Island at the lowest price, check out what some of our customers have to say about their experience with us. ", "Reach out to us today for a personal experience of how effective our services are.", "\n\nStuart from Mortgage Savings Experts has been extremely supportive and helpful when securing a mortgage for us under complex circumstances. ", "Stuart was very patient and knowledgable and explained the process every step of the way. ", "He stayed in touch regularly and was always there to help us, if we had a problem or question, no matter how small. ", "I would have no hesitation in using Stuart and the team again or recommending to anyone.", "\n\nWe could not of asked for a better mortgage experience. ", "My boyfriend is self employed and came with some challenges, but not for Mortgage Saving Experts, they were highly experienced and found nothing but solutions and nothing was too much trouble. ", "I would highly recommended them to anyone, they made the process as smooth sailing as it could be and truly felt cared about. ", "Thankyou Barry so much for getting us into our home 🙂\n\nAfter searching the market for a new mortgage, I was referred to Barry and his team. ", "Nothing was too much trouble finding me a fantastic rate saving me thousands over the course of my mortgage.", "Barry was always on hand no matter what time of day it was. ", "Communication was second to none!Thanks for everything! ", "I'll be back in 2 years for the remortgage!All the best for the future!", "\n\nI was referred to Barry Webb for a first time buyer mortgage. ", "Barry was really easy to speak to and explained everything well. ", "The AIP was in place really quickly ready for putting an offer in. ", "I wanted to make some changes to the mortgage further down the line and was all sorted quickly. ", "Took the hassle and stress out of the part of the house buying process. ", "Would definitely recommend!", "\n\nBarry and his team at Mortgage Savings Experts applied their experience and knowledge to find us exactly the deal we needed. ", "Barry was able to provided us with all of the necessary details, walked us through the process and provided an excellent level of service. ", "He was proactive in contacting us with the latest mortgage developments and keeping us right up-to-date, worthy of a five star rating. ", "Many thanks.", "\n\nWe have been utilising Barry Webb as our mortgage advisor for over 10 years now and have found his services to be very professional and knowledgeable. ", "Barry has always made timely contact with us, particularly when our existing lender agreement is about to expire and presenting us with new favourable rates and terms keeping us on track as we move forward. ", "Easy and fun to deal with and happy to explain everything in layman's terms; we would highly recommend his services and will continue to avail upon his assistance in the future.", "Paul & Jo\n\nI have used Barry several times over the years. ", "He is very supportive in giving the lastedt information about the market and the best way remortgage. ", "There have been times when remortgaging seemed impossible, with out Barry I wouldn't of been where I am today. ", "I recommend using Barry as the mortgage is tailored to you rather than a bank or estate agent having a few options to offer.", "\n\nFriendly, fast and thorough. ", "Barry made the process of buying our house so much less stressful. ", "Always happy to go the extra mile, he worked with us every step of the way to ensure things went as smoothly as possible. ", "Highly recommended.", "\n\nBarry was a great help to us when arranging our life assurance. ", "He was knowledgeable and extremely helpful. ", "My working hours often Meant he had to contact us in the evening which he was happy to do. ", "Highly recommended!", "\n\nI have been using Barry’s mortgage services for quite a few years, he has probably arranged around 5 + Mortgage’s for me.", "I don’t know how he does it but he always manages to find the best deal on the market which suits my needs.", "He is professional, very quick and just gets the job done with no messing around or trying to upsell other products.", "I have recommended him to many friends and colleagues and they are extremely happy with his services.", "I would highly recommend Barry to help you finding your perfect mortgage.", "CharlieBrighton\n\nExcellent service from initial consultation to completion. ", "Barry was able to find mortgage products that suited our needs and always took the time to provide clear explanations to our queries. ", "I wouldn't hesitate to recommend his services.", "\n\nProfessional and friendly service. ", "I got an exhaustive answer to all the questions and everything was explained to me in a simple and clearly way. ", "The whole procedure of all matters related to the mortgage was carried out in a quick and easy way, which I am very pleased with. ", "Barry is a professional in his profession with a good sense of humor. ", "Highly recommend 👍🏻\n\nI have used Barry twice and both times the service has been first class. ", "He explained things clearly and simply and did not use complicated jargon. ", "Always did what’s best for me and a genuine nice bloke. ", "Would 100 percent recommend and use again.", "\n\nBarry is a brilliant mortgage advisor. ", "Very concercious of the needs of his clients. ", "We have had the pleasure of using Barry's services for our mortgage, and have never been disappointed with the service he has provided. ", "Always works hard to ensure we have a positive outcome and thoroughly investigates options to suit our financial requirements.", "Very professional and knowledgeable in his field, with a good sense of humour and down to earth nature. ", "Barry is trustworthy and gives advice clearly, without the 'jargon'! ", "Flexible in dealing with your questions and will contact you regularly to keep you informed and updated with important information.", "We have been very happy with the mortgage service we have received, and will hopefully continue to use Barry in the future. ", "Jacqui and Danny\n\nI've used Barry's services twice now and will not forget how brilliant and amazing he is. ", "I really thought I’d struggle to get a mortgage after my previous debt problems but he gave me peace of mind and ensured I got the best deal ever. ", "He took all the stress and worry away from me. ", "He is a mortgage God!! ", "Not only is he factual, professional and efficient, he gives the best advice and I have complete trust in the information given. ", "We've built a wonderful rapport over the last few years and I would not hesitate to recommend him to any of my friends or family. ", "I wouldn't go anywhere else in the future. ", "Barry is the answer to your best mortgage deal! ", "Well worth the minimal fee he charges. ", "He's utterly brilliant!", "\n\nI've been using Barry at Mortgage Saving Experts to find me the best deal for my past two mortgages. ", "His services have also helped me to save money on related insurances. ", "Barry is very personable and professional in his manner and I would highly recommend.", "\n\nI very rarely write reviews, actually this is the first one ever I’ve done. ", "However I can not recommend Mortgage Saving Experts highly enough... straight forward, easy to understand advice. ", "Keep up the good work!!", "\n\nBarry provides an amazing service, goes really above and beyond to help you get the right mortgage. ", "He understands the pressures of family life, it really feels like he cares about your future. ", "He worked with us to get our first mortgage and has helped us renew and move house since. ", "Have recommended him to many friends and will continue to do so.", "\n\nFor many years and even more mortgages, MSE have provided a very prompt and efficient service of completing mortgages for me. ", "As a property invester, I am always in the market for competitive mortgage products of various type with a quick turnaround, MSE's knowledge of the mortgage market place is second to none.", "\n\nLatest Mortgage News\n\nThe more information you have available when looking for the most suitable mortgage deal, the more beneficial this is for you. ", "To provide insight and help you get started, find recent news on mortgages below.", "\n\nMortgage Regulatory Information\n\nIn the UK, most mortgages are provided by building societies, specialised mortgage lenders and banks. ", "In total, there are roughly 200 financial institutions that provide mortgages in Britain, even though the biggest share of the market is owned by Lloyds Banking Group and Nationwide Building Society.", "\n\nAlthough banks and building societies have always been closely regulated in the UK, the former Financial Services Authority (now the FCA) implemented a regulatory scheme specifically for mortgages as a result of the Financial Services Act of 2000.", "\n\nThe professional services of mortgage providers are monitored by the FCA. ", "Tough rules are in place concerning checks that ensure customers are fairly treated in terms of contracts for financial services, as well as misleading and unfair adverts and promotions. ", "Regulations were originally set out in the rules for Mortgage Conduct of Business (MCOB), but these were overhauled as a result of the FCA Mortgage Market Review (MMR) in 2014.", "\n\nWith regards their financial conduct, deposit-taking firms in the UK come under the jurisdiction of FCA’s sister organisation, the Prudential Regulation Authority. ", "They make sure firms have a substantial level of capital to offset their lending risks.", "\n\nIf there is something bothering you about your mortgage provider, talking to them about it is the first step to take. ", "You utilise a complaint procedure via the FCA if you don’t think it has been suitably dealt with. ", "In turn, this can be referred to the Financial Ombudsman Service if deemed necessary. ", "Some mortgages are not regulated by the Financial Conduct Authority such as moist Buy to Let mortgages and if you make a complaint about these you are unable to take these to the Financial Ombudsman Service\n\nWhat To Ask Your Brighton Mortgage Broker?", "\n\nHow quickly will you respond to my messages?", "\n\nIf a problem arises during the loan application process, you’ll want your broker to respond quickly – hence this question.", "\n\nAgain, demand a specific answer – “Within three hours”, say, rather than “Quickly”.", "\n\nHow much hand-holding will you do during the buying process?", "\n\nThe reason for this question is so you can discover whether the broker will closely guide you through what is a complicated and stressful process – or expect you to figure it out for yourself.", "\n\nWhy should I choose you rather than another broker?", "\n\nOrganising finance and purchasing property can be complicated and stressful, so you want to know you’re in safe hands. ", "That’s why, before you settle on a particular broker, you should challenge the broker with this question.", "\n\nDon’t let the broker get away with vague statements like “Because I’m the best” or “Because I provide great service”. ", "Use follow-up questions to demand detail. “", "What specific things make you better than other brokers? ", "What, specifically, do you do to deliver great service?”", "\n\nWhat happens if you don’t respond to my messages within that timeframe?", "\n\nThis is a logical follow-up question. ", "Again, insist on a specific reply.", "\n\nAnd once you’ve received answers to these questions, ask if the broker would be willing to put both claims in writing. ", "That will indicate how seriously those claims should be taken.", "\n\nWhat sort of clients do you specialise in?", "\n\nAnother important question to ask. ", "That’s because while most brokers focus on ‘plain vanilla’ clients, others might focus on, say, sophisticated investors or borrowers with credit problems.", "\n\nHypothetically; Broker A might have done 450 vanilla loans and 50 bad-credit loans, while Broker B might have done 50 vanilla loans and 250 bad-credit loans. ", "So if you were a borrower with credit problems, you might be better off with Broker B.\n\nNext, probe them about their customer service standards\n\nWhat will the true cost of my home loan be?", "\n\nA great way to utilise the knowledge and experience of a broker is to get them to work out the true cost of your home loan. ", "Based on whether you’re paying Repayment or interest only, how much of a deposit you have, the length of your loan term and the rates payable your broker will be able to obtain a mortgage illustration which will have the true cost on it. ", "This is normally depicted by the Annual Percentage Rate (APR)\n\nBy maximising your deposit amount and minimising your loan term, you stand to significantly reduce the overall cost of your loan. ", "However, there is much more to answering what the true cost of your home loan will be. ", "Upfront fees such as valuation fees, conveyancing and legal fees need to be added to the total cost. ", "Ongoing fees such as those you can incur for using a drawdown facility.", "\n\nWhile it’s impossible to forecast the entire cost of your mortgage to the penny – and let’s not forget how life circumstances and changes can affect your ability to pay your loan too – a broker can can help clarify the big picture details. ", "Mortgage Saving Experts can recommend any protection or insurances to protect you and your family to cover life unfortunate eventualities and our team of advisers can use this information to help you decide which loan is best for your circumstances.", "\n\nHow much can I borrow?", "\n\nThe big question plaguing home buyers tends to be, ‘how much can I borrow?’ ", "Each lender is massively different in this area so as a maximum depending on many factors. ", "In the majority of cases, you can borrow up to around 5 times your gross annual salary but in some instances, you may borrow up to 5.5 times your gross annual income\n\nOnce you speak to us, however, we’ll be able to give you a much more accurate indication of your borrowing capacity. ", "Brokers act as the go-between for you and the lender. ", "Lenders will need to know your living expenses, debts, credit score and whether you have dependents. ", "A broker can factor all these things into the right loan.", "\n\nA broker can also explain home loan terms you’ll need to know, such as LTV, which is the initialism for Loan-to-Value and refers to the percentage of the total loan amount you seek to borrow as a percentage of the property purchase price or value. ", "They can also explain things like the differences in interest rates and repayment types such as Interest Only and Repayment (Capital & Interest)\n\nHow many loans have you written during that time?", "\n\nThis is a good follow-up question to ask, as it will give you a better understanding of the mortgage broker’s experience.", "\n\nFor example, imagine two brokers joined the industry in 2013, but that Broker A had written 500 loans during that time and Broker B had written 300. ", "In that case, even though both parties would be able to claim five years of industry experience, there would be a clear difference in hands-on experience.", "\n\nHow much experience do you have?", "\n\nThis is a good place to start, because a more experienced broker will generally be more knowledgeable than a less experienced broker.", "\n\nPress the broker to give you a specific answer, such as “Eighteen years” or “I’ve been a broker since 2007 and in the mortgage industry since 2001”, rather than something vague like “I’ve got a lot of experience”.", "\n\nGet in contact with the Mortgage Saving Experts in Hamhaugh-Island. ", "You can do so by calling us on 01273 738 072 for a friendly conversation.", "\n\nAfter nearly 20 years in the financial services industry, I started Mortgage Saving Experts. ", "I thrive on helping people save money and come up with simple and clever little ideas which make massive savings to my clients. ", "I want the company’s core focus to be great customer service. ", "You don’t get good customer service anymore and this is about time that changed, It’s about taking responsibility and always going the extra mile.", "\n\nGet In Touch\n\nFind Us\n\nFollow Us\n\nYOUR HOME MAY BE REPOSSESSED IF YOU DO NOT KEEP UP REPAYMENTS ON ANY LOAN OR MORTGAGE SECURED ON IT.Mortgage Saving Experts Ltd is authorised and regulated by the Financial Conduct Authority FCA number 779662. ", "We charge a fee of £695, however, any commission we receive from the mortgage lender is deducted from this fee, therefore, if the amount of commission we receive from the lender is more than £695 then no fee will be charged. ", "If the commission received from the lender is less than £695 then you will be charged the difference." ]

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[ "J/APG-1\n\nThe J/APG-1 is an active electronically scanned array (AESA) radar system designed and manufactured by Mitsubishi Electric for use on the Mitsubishi F-2 fighter aircraft. ", "It was the first series production AESA to be introduced on a military aircraft in service. ", "It is currently being upgraded to the J/APG-2 standard for compatibility with the new AAM-4B air-to-air missile.", "\n\nSee also\n Phased array\n Active electronically scanned array\n\nReferences\n\nCategory:Aircraft radars\nCategory:Military radars of Japan" ]

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[ "“I hope. ", "I don’t think you should be in a relationship pag hindi ‘yun ang iniisip mo. ", "You shouldn’t think that it’s just a pastime,” he added.", "\n\nAs he celebrates his 12th anniversary in showbiz, Milby released his new CD called “Sam:12.”", "\n\n“This album was supposed to be released last year. ", "Halos lahat ng songs na-record na. ", "And it was gonna be released April of last year. ", "Pero ako ‘yung nag-request na wag munang i-release kasi sabay sa ‘Doble Kara’ so wala akong time para mag-promote ng tama,” said the Filipino-American actor.", "\n\nCritics have described his latest musical offing as solid and strong, said Abunda.", "\n\n“Thank you sa mga nagsasabi n’yan. ", "Even me I feel this is my strongest album. ", "It’s called ‘Sam:12’ because this year marks my 12th year in show business. ", "There’s nine tracks on it, all original except one cover song which is ‘Chasing Cars,’” Milby said.", "\n\nMilby will also be seen in the new movie with Kapamilya star Yassi Pressman entitled “Ang Pambansang Third Wheel.” ", "It also stars Alonzo Muhlach and Sam Pinto." ]

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[ "Well there you go, I couldn’t hold it in anymore – I’m going to the Bahamas !", "\n\nThanks to all my fans and their suggestions, and although no one specifically recommended Bahamas, it was with your help that I decided on this place. ", "Although, it wasn’t without some very critical thinking..\n\nMany people recommended Hollywood, which would of course make sense for a celebrity such as myself. ", "But here’s my reasoning; Hollywood is where the stars work.. not where they vacation (generally speaking). ", "So where do they vacation?", "\n\nWell, there is a popular island of the Bahamas that is known as a celebrity getaway because it’s quiet, secluded, pristine, and not as busy as the main island. ", "It’s called Eleuthera & Harbour Island. ", "In fact, the Wall Street Journal once did an article on Eleuthera, describing it as the next trendy island destination that has already become the vacation home of many celebrities such as Mick Jagger, Lenny Kravitz, the Royal Family, Cameron Diaz, Mariah Carey, Jennifer Aniston, and more.", "\n\nSo that’s where I’m headed! ", "I’m sure I’ll fit in just great.", "\n\nAnd of course, being a celebrity I need to travel in style. ", "So I’ve asked Mum to book me a first class ticket to the island. ", "She said we probably couldn’t afford to all go in first class, so I told her I wouldn’t mind if she just got me a first class ticket and her and Dad go in economy.", "\n\nLast time I was stuck in a cramped up economy seat.", "\n\nAnd after we landed I even had to get my own bags! ", "That’s hardly a celebrity service. ", "I can tell you I will have much higher standards for this trip. ", "After all, it is my birthday present.", "\n\nI also rented a nice private villa for myself (and family). ", "Since the whole point of this vacation is to ‘getaway’ from all the paparazzi and hubbub of the city, I won’t tell you where on the island it is. ", "But here’s some photos!", "\n\nThis will be a great place to use my snorkel gear and meet some babes! ", "Maybe even meet some fellow celebrity babes.. (that’s right, I’m a babe ; )\n\nNow this is all great news, but of course there is still the matter at hand – which is that Mum is leaving for St. Lucia without me on Sunday for a whole two weeks. ", "So until then, I will be giving her my best guilt trip performance to extract as many sympathy gifts as possible.", "\n\nI was successful in scoring this big teddy (doggy), which with the help of my fans I have named, Big T, where the letter T is up for your interpretation. ", "I also told Mum and Dad that Big T would be accompanying us to Bahamas, and so to book him a seat.", "\n\nI don’t think I can contain myself until the end of November. ", "It’s going to feel like so long, but will be so worthwhile. ", "I can’t wait to find me some ‘Bahama Mamas’ , and I’m not taking about the drink ; )\n\nI also have a lot of preparations to do with getting my passport and documents all together. ", "I’ll let you know how it goes. ", "I also have some other exciting things coming up before then !", "\n\nKeep ballin’,\n\n~ Crusoe\n\nZ79BQZANCF6C\n\nMy New Book! ", "Featuring my worldly travels far and wide, from Europe to Mexico and more, and the whole story of my surgery and recovery! ", "Rated 5 stars on Amazon! ", "Get Yours!", "\n\nComments\n\ncomments" ]

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[ "Hijack, what hijack?", "\n\nShare\n\nTHEY say ignorance is bliss. ", "I cannot help thinking that - had I been on the hijacked jetfoil 'Guia' on Tuesday - I would have been in a state of total ignorance, but certainly not bliss. ", "That is not a state you achieve on a jetfoil. ", "My rather limited expectations of jetfoil travel explain my attitude.", "\n\nNot understanding Cantonese very well, I would have missed out on crucial little words like 'bomb' and 'kill'. ", "As a result, I would have sat through the hijack quite unable to differentiate it from an ordinary run.", "\n\nI would have followed my normal custom of browsing through the newspaper, dozing off and waking up in irritation at the fact that we still weren't there yet.", "\n\nI think my only intimation that all had not gone as normal would have been when we arrived back at Macau - where we started.", "\n\nEven then I could have recalled the time last week when I turned a taxi round and went back to where I had come from because of total traffic constipation on Gloucester Road. ", "Perhaps the jetfoil captain could have come to the same decision over the marine congestion in what is left of Hong Kong's harbour.", "\n\nI would have been amazingly unhelpful to the Organised Crime and Triad Bureau officers waiting keenly to interview me.", "\n\nAfter all, what would there have been about the hijack goings-on to alert a dumb foreigner? ", "You have to understand that once a six foot, 250 lb gweilo has squeezed himself into a jetfoil seat and inserted his knees neatly up his nostrils, there is already a strong sense of captivity. ", "It would never occur to him that this would need to be further enforced from the aisle.", "\n\nI am told two slimmer men suddenly jumped from their seats and started shouting at people. ", "So what? ", "On jetfoils people are always jumping up and shouting at people. ", "It is a local form of on-board socialising.", "\n\nThe last time I was on a jetfoil a man jumped up and hollered at the row behind him. ", "A Chinese companion told me he was telling his mates he had just lost $175,000 at the casino. ", "A good enough reason to shout, I'd have thought.", "\n\nI am told one robber walked down the aisle with a gun. ", "Had I noticed it, it would have sparked no curiosity in my mind. ", "This could have been an interesting refinement to the 'threat school' of hard-sell which the cabin staff use when pushing the refreshment trolley. ", "Invariably one of them looks not-so-much like a jolly Jack Tar, but a retired bouncer.", "\n\n'You eat sawdust cookie or sugary thing in plastic bag. ", "Drink eh? ", "No gasi bak. ", "Only San lik.' ", "What is a man with a gun compared to the promise of that? ", "At one point everybody did put their hands on their heads. ", "I might have thought that was an indication that someone had got lucky scraping one of those lottery tickets you can buy before you enter the moral purity of Hong Kong waters. ", "Mind you, given the cautiousness of gambling operators, it would have been unlikely that everybody had won. ", "Perhaps this was a communal class in sedentary tai-chi being led in Portuguese over the tannoy.", "\n\nI would have joined in for a little while for fear of looking snooty and aloof and, purely by accident, would have avoided having my brains blown out.", "\n\nIt is unlikely I would have understood the gunshots. ", "I would have put them down to an irate passenger banging a Lucozade bottle with a tight cap against the bulkhead.", "\n\nOr it could have been a desperate passenger banging on the lavatory door. ", "That old woman who spends the entire journey inside the lavatory would have been the only one, apart from me, to miss the drama.", "\n\nThe bridge crew surrendered after three rounds were pumped into the locked bridge door. ", "They could have emptied a Kalashnikov clip into the lavatory door and that old crone would still not have moved.", "\n\nThey say there was not actually a bomb on board as threatened. ", "If one of the three robbers had been lured into the loo, he would have found clear evidence of prolonged detonations.", "\n\nHad I noticed the bridge crew laid flat out in the bow section of the cabin, I would have nodded my head in quiet sympathy. ", "Much the same happened to me while the vessel was still tied up alongside at the Hong Kong pier.", "\n\nEvery seventh wave coming through the dock was near tidal. ", "One caught me getting to my seat. ", "I fell, rolling over and over across the legs of two understandably excited women and lodged myself between two rows. ", "This was, be assured, before lunch.", "\n\nThe disappearance of the entire cabin crew would have caused me no alarm. ", "After the distribution of the lottery tickets, disappear is exactly what they normally do.", "\n\nThat must be why we never get landing cards for Hong Kong anymore.", "\n\nI would have been in snooze mode during much of the hijack journey to China's Qi'ao Island and no amount of stopping, starting and bottoming would have stirred me. ", "Had I woken, not recognising where I was, this would have been unremarkable. ", "I can rarely tell Cheung Chau from Hei Ling Chau - and when the driver decides to go to Macau via Castle Peak round the north of Lantau, I regularly resign myself to having got on the Tuen Mun ferry by mistake.", "\n\nThere was only one reported moment during the hijack which might have caused me some alarm. ", "After the gunshots on the bridge all the passengers are said to have fallen into silence. ", "Only breathing could be heard. ", "Total silence on Hong Kong public transport is an ominous portent that should certainly put the wind up anybody.", "\n\nThe jetfoil hijack was inventive. ", "Opportunities to extend this kind of thinking over the wider sphere of public transport are few. ", "There are short, green cash-collecting trains which run along the MTR from time to time. ", "But MTR trains are difficult to divert to China. ", "The alternative of abandoning one and carting $10 million in small change through the tunnel - with trains coming at intervals of three minutes - has limited appeal.", "\n\nEven on rip-off grave sweeping and race days, the amount of money public light buses carry make them hardly worth the effort and the passengers are unlikely to be bursting with jewellery, either. ", "There is an added disadvantage. ", "As well as the police, the PLB's triad operator will be after you too.", "\n\nOf all buses, I would suggest the Aberdeen tunnel route to Stanley as long as you are prepared to pillage the passengers. ", "Potential hijackers may suffer some confusion when they first get on board. ", "The bus will be being driven as though it has already been hijacked.", "\n\nIt looks as though Mr Stanley Ho's jetfoils will be the hot favourite for some time to come. ", "But he can take some comfort.", "\n\nLike traditional Hong Kong workers who toil fifty one weeks of the year and blow their savings on gambling at Chinese New Year, as soon as gangsters have pulled off a heist they blow the proceeds at the casino at his Macau hotel, the Lisboa.", "\n\nWhatever strange routes the money will follow, most of it, eventually, will end its journey with Mr Ho." ]

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[ "Q:\n\nWhat is the difference between a question and an invitation?", "\n\nWhat is the difference between a question and an invitation?", "\nIs there any difference?", "\nDo they accomplish different things? ", "\nAre they structurally different?", "\n\nA:\n\nI realize that Stephen's answer is pretty thorough, but can't help but think that side-by-side comparison of their definitions may help a bit, so...\n\nQuestion: Noun: A sentence worded or expressed so as to elicit information.", "\n\nand\n\nInvitation: A written or verbal request inviting someone to go somewhere or to do something.", "\n\nSo the answer to your question \"Do they accomplish different things?\" ", "is \"Yes\".", "\nThey do. ", "question is for obtaining information, and invitation is more for giving information. ", " \n\nA:\n\nAn invitation is a statement or question that says are welcome to a party or an event. ", "A question is something which you want answered.", "\nExample of a question:\n\nWhere is your party?", "\n\nIn this example you expect an answer. \"", "The party is at my house.\"", "\nExamples of an invitation as a statement:\n\nYou may come to my party.", "\n You are invited to my party.", "\n\nHere you just make it clear that the other person may attend.", "\nExample of an invitation as a question:\n\nWill you come to my party?", "\n\nBoth are considered invitations but one expects a response on whether or not you are coming.", "\n\n" ]

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[ "Lanka de Silva\n\nSanjeewa Kumara Lanka De Silva (born July 29, 1975, Kurunegala), or Lanka De Silva, is a former Sri Lankan cricketer who played in 3 Tests and 11 ODIs in 1997.", "\n\nInternational career \n\nHe was right-hand wicket-keeper batsman. ", "de Silva is only the tenth player in Sri Lankan cricket history to pass 10,000 runs in first-class cricket after starting his career in 1991/92 season for Kurunegala Youth Cricket Club.", "\n\nHe played three Test for Sri Lanka all against Indian national cricket team when Sri Lanka toured to India in 1997 without any success and lost his place to Romesh Kaluwitharana.", "\n\nCoaching career \n\nIn 2015, de Silva was named as head coach of Sri Lanka national cricket team replacing Jeevantha Kulatunga along with physio Neha Karnik.", "\n\nReferences\n\nExternal links \n\n Cricinfo\n\nCategory:1975 births\nCategory:Living people\nCategory:Sri Lanka Test cricketers\nCategory:Sri Lanka One Day International cricketers\nCategory:Sri Lankan cricketers\nCategory:Cricketers at the 1998 Commonwealth Games\nCategory:Colombo Cricket Club cricketers\nCategory:Wayamba cricketers\nCategory:Sri Lankan cricket coaches\nCategory:Sportspeople from Kurunegala" ]

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[ "Molly Yeh is well-known for her popular blog my name is yeh and best-selling cookbook, and this summer she is bringing her charm, unique background and spin on comfort food to Food Network with the brand-new series Girl Meets Farm. ", "A transplant from\ncity to farm life who has embraced her new home, Molly welcomes viewers to her cozy farmhouse on the Minnesota/North Dakota border and shares her love for the country life. ", "The series celebrates the very best of Molly's food, with recipes inspired by her\nJewish and Chinese heritage and a taste of the Midwest. ", "With fresh, tasty ideas and food that's both delicious and beautiful, the seven-episode series brings inspiration and fun into kitchens across the country.", "\n\nGirl Meets Farm premieres June 24 at 11 a.m. ET/PT.", "\n\n\"Molly is full of life and her unlikely journey from the big city to a food-centered life on a Midwest farm is fascinating,\" said Courtney White, Executive Vice President, Programming, Food Network and HGTV. \"", "Her passion for food, her family and farm life are\nfront and center in all of her recipes, which are truly written from the heart.\"", "\n\nIn the premiere episode, Molly makes a delicious buffet for her sister-in-law Anna's baby shower. ", "n the menu, there's Fish Tacos with Crunchy Cabbage Slaw and Cilantro Dressing, Pigs in a Blanket with Harissa Ketchup and Honey Mustard and Molly's\nsignature Meatball Sliders with a Twist. ", "Then Molly's Baked Donuts with Rhubarb, Blood Orange and Blueberry Glaze take center stage on the dessert table. ", "Upcoming episode themes include family visits, girl's brunch, farm supper and a special anniversary\ncelebration, along with Molly's recipes for Garlic and Onion Challah, Dark Chocolate Scone Loaf with Marzipan and Scallion Pancakes with Maple Carrot Slaw.", "\n\nYeh is the author of the International Association of Culinary Professionals award-winning cookbook \"Molly on the Range.\" ", "She is the creator of the critically-acclaimed and highly popular food and lifestyle brand my name is yeh, which has been recognized by\nthe likes of the New York Times, Food & Wine, New York Magazine, Saveur (\"Blog of the Year\") and Yahoo (\"Food Blog of the Year\"). ", "She was also on Forbes' \"30 Under 30\" list for 2017. ", "Molly grew up in the Chicago suburbs with a Chinese father and\nJewish mother, followed by a post-high school life in New York City studying percussion at Juilliard. ", "She then got married and started her food blog, relocating with her husband to a sugar beet farm in the upper Midwest where she currently resides." ]

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[ "Estrogenic activity of tropical fish food can alter baseline vitellogenin concentrations in male fathead minnow (Pimephales promelas).", "\nVitellogenin (VTG) is a precursor of egg-yolk protein and is therefore present at high concentrations in the plasma of female fish. ", "In male fish, VTG concentrations are usually undetectable or low but can be induced upon exposure to estrogenic substances either via the water or the diet. ", "This work was performed to determine the reason for the apparently elevated VTG concentrations in unexposed stock male fathead minnow maintained in our laboratory. ", "The results showed clearly that some of the food given to the fish was estrogenic and that replacement of this with nonestrogenic food led to a significant reduction in the basal VTG levels measured in male fish after a six-month period. ", "This reduction in male VTG concentrations drastically increased the sensitivity of the VTG test in further studies carried out with these fish. ", "Moreover, a review of published concentrations of VTG in unexposed male fathead minnow suggests that this problem may exist in other laboratories. ", "The fathead minnow is a standard ecotoxicological fish test species, so these findings will be of interest to any laboratory carrying out fish tests on endocrine-disrupting chemicals." ]

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[ "Q:\n\nEqual cost multipath Dijkstra's Algorithm in python\n\nUsing python recipes proposed here: \nhttp://code.activestate.com/recipes/119466-dijkstras-algorithm-for-shortest-paths/\nand\nhttp://code.activestate.com/recipes/117228-priority-dictionary/\nand using as input the following graph:\n graph_2 = {\n 'R1':{'R2':5,'R3':5},\n 'R2':{'R1':5,'R4':5},\n 'R3':{'R1':5,'R4':5},\n 'R4':{'R2':5,'R3':5},\n}\n\nI'm trying to get ALL shortest paths between R1 and R4. ", " However, I'm only getting one shortest path (R1-R2-R4), and not (R1-R3-R4). ", " I need to simulate ECMP (such as OSPF does). ", " What I need is that function shortestPath returns all shortest path (i.e [[R1-R2-R4],[R1-R3-R4]]) in case of Equal Cost Multipath (like graph_2 on top) and only the shortest path in case of Single Path like for example:\n graph_3 = {\n 'R1':{'R2':5,'R3':5},\n 'R2':{'R1':5,'R4':5},\n 'R3':{'R1':5,'R4':10},\n 'R4':{'R2':5,'R3':5},\n}\n\nI've modified the code in the Dijkstra function like that:\nfrom priodict import priorityDictionary\n\ngraph_2 = {\n\n'R1':{'R2':5,'R3':5},\n'R2':{'R1':5,'R4':5},\n'R3':{'R1':5,'R4':5},\n'R4':{'R2':5,'R3':5},\n}\n\ndef Dijkstra(G,start,end=None):\n\n D = {} # dictionary of final distances\n P = {} # dictionary of predecessors\n Q = priorityDictionary() # est.dist. ", "of non-final vert.", "\n Q[start] = 0\n for v in Q:\n D[v] = Q[v]\n if v == end: break\n\n for w in G[v]:\n vwLength = D[v] + G[v][w]\n\n if w in D:\n if vwLength < D[w]:\n raise ValueError, \\\n elif w not in Q or vwLength < Q[w]:\n Q[w] = vwLength\n P[w] = [v]\n elif w not in Q or vwLength == Q[w]: <---adding this part\n Q[w] = vwLength\n P[w] += [v]\n\n return (D,P)\n\ndef shortestPath(G,start,end):\n D,P = Dijkstra(G,start,end)\n print D,P\n Path = []\n while 1:\n Path.append(end)\n print end\n if end == start: break\n end = P[end]\n Path.reverse()\n return Path\n\nprint shortestPath(graph_2,'R1','R4')\n\nand I'm getting the following output and error:\n{'R4': 10, 'R1': 0, 'R2': 5, 'R3': 5} {'R4': ['R2', 'R3'], 'R2': ['R1'], 'R3': ['R1']}\n\nTraceback (most recent call last):\nFile \"next-hop-resolver.py\", line 194, in <module>\nprint shortestPath(graph_2,'R1','R4')\nFile \"next-hop-resolver.py\", line 172, in shortestPath\nend = P[end]\nTypeError: unhashable type: 'list'\n\nWhat I would like to get using graph_2 is :\n[['R1', 'R2', 'R4'], ['R1', 'R3', 'R4']]\nand using graph_3:\n[['R1', 'R2', 'R4']]\nIf I execute the code as is, i.e without any kind of code modification I get the following result, no matter if I use graph_2 or graph_3:\n[['R1', 'R2', 'R4']]\ni.e always the shortest path, even if there is more than one path.", "\nI know that a list can't be a key in a dictionary, but to be honest I'm stuck with that, so any help is more than welcome\n\nA:\n\nFinally, I think I got what I was looking for :) \nHere's the final code\nfrom priodict import priorityDictionary\nfrom collections import defaultdict\nfrom collections import OrderedDict\nimport sys\ngraph_2 = {\n\n'R1':{'R2':5,'R3':5},\n'R2':{'R1':5,'R4':5},\n'R3':{'R1':5,'R4':5},\n'R4':{'R2':5,'R3':5,'R5':5},\n'R5':{'R4':5}\n\n}\n\ngraph_3 = {\n\n'192.168.255.1':{'192.168.255.2':10,'192.168.255.3':10},\n'192.168.255.2':{'192.168.255.1':10,'192.168.255.3':50},\n'192.168.255.3':{'192.168.255.1':20,'192.168.255.2':50},\n'192.168.255.4':{'192.168.255.3':20},\n'192.168.255.3':{'192.168.255.4':20}\n}\n\ngraph_4 = {\n'R1':{'R2':5},\n'R2':{'R1':5},\n'R2':{'R3':5},\n'R3':{'R2':5},\n'R3':{'R4':5},\n'R4':{'R3':5}\n}\n\ngraph_5 = {\n\n'A':{'B':5,'C':10,'E':2},\n'B':{'A':5,'C':5},\n'C':{'B':5,'A':10,'E':8,'D':4},\n'D':{'C':4,'E':5},\n'E':{'A':2,'D':5,'C':8}\n\n}\n\ndef Dijkstra(g,start,end=None):\n\n d = {} # dictionary of final distances\n p = {} # dictionary of predecessors\n q = priorityDictionary() # est.dist. ", "of non-final vert.", "\n q[start] = 0\n for v in q:\n d[v] = q[v]\n if v == end: break \n for w in g[v]:\n vwLength = d[v] + g[v][w]\n if w in d:\n if vwLength < d[w]:\n raise ValueError\n elif w not in q or vwLength < q[w]:\n q[w] = vwLength\n p[w] = [v]\n elif w not in q or vwLength == q[w]:\n q[w] = vwLength\n p[w] += [v] \n return (d,p) \n\ndef shortestPath(g,start,end):\n\n d,p = Dijkstra(g,start,end)\n path = [[end]]\n while True:\n if len(p[end]) > 1:\n path.append(p[end])\n for node in p[end]:\n if node !", "= start:\n if ''.join(p[end]) == start: break\n end = node\n path.append(p[end])\n if ''.join(p[end]) == start: break\n for node in p[end]:\n if node == start: break\n end = node \n return path[::-1]\n\nprint shortestPath(graph_2,'R1','R5')\nprint shortestPath(graph_3,'192.168.255.1','192.168.255.2')\nprint shortestPath(graph_4,'R1','R4')\nprint shortestPath(graph_5,'A','C')\n\nand the output for each graph :\n[['R1'], ['R2', 'R3'], ['R4'], ['R5']]\n[['192.168.255.1'], ['192.168.255.2']]\n[['R1'], ['R2'], ['R3'], ['R4']]\n[['A'], ['A', 'E', 'B'], ['C']]\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "NCAA GPA Eligibility\n\nDear Parent/Guardian,\n\nWe are pleased to inform you that Camdenton High School is making the Core Course GPA Calculator, a web-based interactive tool, available to all Camdenton High School student-athletes and their parents/guardians free of charge.", "\n\nIf your child has aspirations of competing athletically as a freshman at an NCAA Division I or Division II school, they must meet NCAA Initial-Eligibility minimum standards, including core course GPA and SAT/ACT test score requirements. ", "The Core Course GPA Calculator is an innovative tool that allows you to easily track your son or daughter’s progress towards meeting these requirements, beginning as soon as the first semester of their freshman year.", "\n\n2. ", "Enter your Member Name and Password in the Existing Member Login box.", "\n\n**Use the Member Name and Password you created during the account activation process**\n\n3. ", "Click “Login.”", "\n\nBegin using your Core Course GPA Calculator!", "\n\nThe Core Course GPA Calculator incorporates NCAA recognized core courses for Camdenton High School into the online course entry forms, calculates BOTH Division I and Division II core course GPA, automatically factors weighted grades into calculations and tracks course requirements for BOTH Division I and Division II. ", "Your son or daughter’s core course information is saved for the duration of their high school career.", "\n\nCamdenton High School is proud to make this innovative software available to you free of charge. ", "We believe the Core Course GPA Calculator will be a very useful academic tool for you and your student-athlete." ]

{ "pile_set_name": "Pile-CC" }

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[ "Strategies for the empirical management of infection in cancer patients with emphasis on the emergence of resistant gram-negative bacteria.", "\nCombinations of antibiotics (namely penicillins and aminoglycosides) have been advocated in the 1970s for the empirical therapy of FN in cancer patients in order to take advantage of the possible synergism between these agents and to extend the potential antimicrobial spectrum of empirical therapy. ", "Later, with the development of potent broad spectrum antibiotics, the need for combinations became less obvious as monotherapy with these new agents appeared as effective and less toxic than previously used combinations. ", "However, today we are facing a major challenge through the emergence of multi-resistant microrganisms. ", "With such bacteria, we might be coming back to the pre-antibiotic era when no active agents were available. ", "This situation is due, in part, by the excessive use of antibiotics, namely as a prophylaxis for infection, and is complicated by the fact that very few new effective antibiotics are being developed by the pharmaceutical industry. ", "Under these circumstances, it is likely that we will have to resort to \"old timers\" such as the polymyxins. ", "It is also possible that combination therapy will come back in favor to take advantage of the synergism and extend the spectrum of coverage, just as it has been the case for the management of resistant tuberculosis. ", "At the same time, the development of multidisciplinary antimicrobial stewardship is mandatory for efficient infection control and minimizing emergence of antimicrobial resistance." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "INTRODUCTION\n============\n\nTo be eligible for renal transplantation (RT), patients treated by dialysis must first be registered on an official RT waiting list. ", "Access to such a registration has been described in several epidemiological studies as the end-result of a complex selection process depending on medical and non-medical determinants.^[@r01]--[@r09]^ Significant disparities have also been observed between countries, as availability of kidney donors and access to RT depend on the degree of economic development of the country, national health policies on RT, and cultural factors associated with organ donation and transplantation.^[@r09],[@r10]^\n\nSurprisingly, studies that analyze mortality of patients on dialysis do not currently take into account registration on the waiting list. ", "However, patients registered on the RT waiting list are very different from patients who are not wait-listed for two main reasons. ", "First, wait-listed patients are invariably younger and healthier than other dialysis patients.^[@r01]--[@r09]^ Second, wait-listed patients may benefit from an RT and stop dialysis, while patients who are not wait-listed remain on dialysis until death. ", "In a study based on simulations, the probabilities of death during dialysis were systematically overestimated because wait-listed patients were given better survival probabilities but stopped dialysis early for RT.^[@r11]^ It therefore remains unclear whether wait-listed patients have longer survival than other dialysis patients in real life, irrespective of characteristics associated with placement on the waiting list.", "\n\nSeveral important methodological issues affect the analysis of the relationship between registration on the waiting list and mortality on dialysis. ", "First, registration on the RT waiting list is an event that usually occurs after the initiation of dialysis. ", "Second, wait-listed patients may undergo an RT, which is a second event that may occur during the follow-up while on dialysis. ", "Third, after RT, wait-listed patients are, by definition, no longer on dialysis and exposed to new specific risk factors for death, such as use of immunosuppressive drugs.^[@r12]--[@r14]^\n\nA multi-state model is a stochastic process that at any time occupies one of a set of discrete states, which can be health conditions or disease stages. ", "Use of a multi-state model has been shown to be a pertinent and accurate method of analyzing complex clinical issues with multiple outcomes.^[@r15],[@r16]^ Such a model may be appropriate for describing and analyzing the complex relationships between covariates and the following states: 'Hemodialysis (HD), wait-listed', 'HD, not wait-listed', 'death', and 'RT'.", "\n\nThe aim of the present study was to determine if registration on the RT waiting list is associated with mortality on dialysis, independently of the comorbidities associated with such registration. ", "We identified HD patients from the French national Renal Epidemiology and Information Network (REIN) registry and used a multi-state model to analyze outcomes of placement on RT waiting list, death, or RT over a 4-year period.", "\n\nMETHODS\n=======\n\nREIN registry\n-------------\n\nThe REIN registry includes all incident patients treated for end-stage renal disease either by dialysis or RT in France. ", "It was set up in 2002 to provide a tool for public health decision-making, evaluation, and research related to renal replacement therapies for end-stage renal disease. ", "It relies on a patient database which is regionally and nationally maintained by a network of nephrologists, epidemiologists, and public health representatives. ", "An ongoing registration process ensures that all dialysis and transplant patients are listed. ", "Details about this registry have been published elsewhere.^[@r17]^\n\nStudy population\n----------------\n\nAdult patients aged 18 years or older at initiation of dialysis who started HD between January 1, 2002, and December 31, 2006, were identified through the French REIN registry exclusively in the 12 regions equipped with software connected to the software currently used for the national RT waiting list. ", "In the present study, HD patients were exclusively included, as they accounted for 93% of dialysis patients in France.", "\n\nStudy design\n------------\n\nPatients were followed up until the occurrence of death while on dialysis, RT, loss to follow-up, or the end of the study. ", "Patients were identified at registration on the RT waiting list; removal from the waiting list was not taken into account in the analysis. ", "When patients were registered, they were wait-listed patients until the end of the study, death, or RT. ", "All patients were followed up for at least 2 years, as the cut-off date was December 31, 2008.", "\n\nData collection\n---------------\n\nThe following baseline characteristics were retrieved from the REIN registry: age, sex, height, weight, albumin levels at initiation of dialysis, modality of first dialysis, smoking habits, and presence or absence of selected co-morbidities (diabetes, chronic obstructive pulmonary disease, congestive heart failure, myocardial infarction, peripheral arterial disease, cerebrovascular disease, cirrhosis, amputation, inability to ambulate, or severe behavioral disorder). ", "Data regarding registration on the waiting list were also collected. ", "The etiology of renal disease was classified according to the REIN classification.^[@r17]^\n\nEthics statement\n----------------\n\nApprovals from the National Commission on Informatics and Liberty and from the Advisory Committee on Information Processing in Material Research in the Field of Health were obtained through the national REIN registry. ", "Each patient was petitioned for written informed consent at the time of inclusion in the REIN registry.", "\n\nStatistical methods\n-------------------\n\nBaseline characteristics were presented in terms of mean and standard deviation (SD) for continuous variables and expressed as frequency and percentage for categorical variables. ", "All statistical calculations were carried out using R Statistical Software (The R Project for Statistical Computing, Vienna, Austria), including the Survival, Mstate, and MICE packages.^[@r21],[@r22],[@r27]^\n\n### Multi-state model\n\nA multi-state model including the four following states was applied: 1) 'HD, not wait-listed', ie, HD patients who were not registered on the RT waiting list; 2) 'HD, wait-listed', ie, HD patients who were registered on the RT waiting list; 3) 'death'; and 4) 'kidney transplantation'. ", "Usually, a multi-state process is assumed to be a time-inhomogeneous Markov process^[@r18]^; this means that the future state of the process only depends on the current state and the elapsed time since the time of origin. ", "As this model required the presence of a unique initial state, all patients were considered as 'HD, not wait-listed' at the onset; for patients who were already wait-listed at the initiation of HD, registration was set at day one. ", "Death and RT were absorbent states, while being wait-listed was a transient state. ", "Consequently, four transitions were possible, which are detailed in Figure [1](#fig01){ref-type=\"fig\"}.", "\n\n{#fig01}\n\nThe probabilities of being in each state at each time point of follow-up were estimated by the Aalen-Johansen estimator^[@r19]^ and were stacked for graphic presentation. ", "As recommended, the duration shown on curves was 4 years, because only 10% of the patients were still under follow-up at the time \"4 years\".^[@r20]^\n\nThe Cox proportional hazards regression model was used to investigate the influence of demographic, biological, and clinical factors on the transition from one given state to another. ", "In each transition, this model provided a hazard ratio (HR) for each covariate, which was assessed by bi- and multi-variable analyses.^[@r19]^ The main objective of the present study was to estimate the influence of being wait-listed on the risk of death during HD. ", "This corresponded to estimating the HR for transition 'HD, not wait-listed' → 'death' versus that for 'HD, wait-listed' → 'death'. ", "To do this, a transition-specific model was used, which was similar to considering the 'HD, wait-listed' state as a time-dependent covariate.^[@r19],[@r21]^\n\n### Management of missing data\n\nIn the extracted data, 17 covariates had missing values, as shown in Table [1](#tbl01){ref-type=\"table\"}. ", "Values for covariates with missing values were obtained by multiple imputations using the MICE package, as recommended for Cox proportional hazards model analysis.^[@r22]^ Regression switching imputation was performed using linear or logistic regression models, depending on the nature of the incomplete covariate fitted.^[@r22],[@r23]^ This procedure was repeated five times to obtain five draws for each missing value in five distinct datasets.", "\n\n###### Baseline characteristics of the study population (*n* = 7138)\n\n Characteristics Patients (*n* = 7138) Missing data (%)\n ------------------------------------------- ----------------------- ------------------\n Age^a^, years \\[mean (SD)\\] 67.5 (14.9) 0\n Women, *n* (%) 2659 (37.3%) 0\n Body mass index^a^, kg/m^2^ \\[mean (SD)\\] 25.2 (5.3) 26.2\n Albumin^a^, g/l \\[mean (SD)\\] 33.7 (5.9) 54.3\n Unplanned first dialysis, *n* (%) 2205 (31.0%) 0.6\n Dialysis on catheter, *n* (%) 3119 (43.9%) 1.8\n Smoking habits, *n* (%)    \n  Non smoker 4005 (63.8%) 11.7\n  Former smoker 1604 (25.6%) 11.7\n  Current smoker 666 (10.6%) 11.7\n Selected co-morbidities^b^, *n* (%)    \n  Diabetes 2313 (35.6%) 8.6\n  Chronic obstructive pulmonary disease 726 (11.2%) 8.6\n  Congestive heart failure 1760 (27.1%) 8.6\n  Myocardial infarction 747 (11.5%) 8.7\n  Peripheral arterial disease 1494 (23.1%) 9\n  Cerebrovascular disease 639 (9.8%) 8.6\n  Cirrhosis 142 (2.2%) 8.9\n  Amputation 155 (2.2%) 1.5\n  Inability to ambulate 1325 (21.3%) 12.3\n  Severe behavioral disorder 249 (3.5%) 1.3\n Primary renal disease, *n* (%)    \n  High blood pressure 1645 (23.0%) 0\n  Diabetes 1508 (21.1%) 0\n  Glomerulonephritis 810 (11.3%) 0\n  Pyelonephritis 311 (4.4%) 0\n  Polycystic kidney disease 491 (6.9%) 0\n  Vascular 129 (1.8%) 0\n  Other 1161 (16.3%) 0\n  Unknown 1083 (15.2%) 0\n\nSD, standard deviation.", "\n\n^a^Expressed as mean (SD).", "\n\n^b^Co-morbidities examined in this study and listed for data collection.", "\n\nIn the multivariable analysis, covariates were selected using a stepwise procedure adapted to multiple imputation methodology.^[@r24]^ The covariates selected could vary for each transition. ", "For an easier interpretation of the results, when a covariate was selected for a transition from a given initial state, this covariate was included in the two transitions relating to this initial state. ", "Rubin's approach was adopted, whereby the coefficients and variances obtained with the final model on each imputed dataset were averaged by taking into account the intra-variance of the model and the inter-variance between the imputed datasets.^[@r25]^\n\n### Sensitivity analysis\n\nA sensitivity analysis was conducted to investigate the possible interaction between age and waiting list registration for the risk of death. ", "The whole analysis strategy (ie, multi-state model analysis and management of missing data) was performed among five age groups: 18 to 39 years, 40 to 49 years, 50 to 59 years, 60 to 69 years, and 70 years and older.", "\n\n### Log-linearity assumption\n\nThe log-linear assumption of the Cox model was assessed using Martingale residuals.^[@r26]^ Since the log-linearity assumption was violated for age and body mass index (BMI), these variables were transformed into categorical variables. ", "The scatter plots of Martingale residuals are presented as supplementary data in [eFigure 1](#sm03){ref-type=\"supplementary-material\"}. ", "The cut-off values were identified first by graphic investigations using Martingale residual plots, then by maximization of the Gray test, and finally on the basis of medical expertise and consensus.", "\n\nRESULTS\n=======\n\nPatients\n--------\n\nWe identified 7138 patients starting HD as first renal replacement therapy between January 1, 2002, and December 31, 2006. ", "Their baseline characteristics are detailed in Table [1](#tbl01){ref-type=\"table\"}. ", "A total of 176 (2.5%) patients were already wait-listed at the time of HD initiation, and 1392 patients (19.5%) were wait-listed at the cut-off date. ", "This corresponded to 13 210 person-years observed in the not wait-listed group, and 2907 person-years observed in the wait-listed group, 1552 of which was on the waiting-list. ", "The baseline characteristics of the patients according to the registration on the RT waiting list, as observed at the end of the study, are detailed as supplementary data in [eTable 1](#sm01){ref-type=\"supplementary-material\"}.", "\n\nLikelihood of events\n--------------------\n\nIn the multi-state model, the initial state of all the patients corresponded to the 'HD, not wait-listed' state. ", "The probabilities of being in a given state at each follow-up time point, as estimated by the Aalen-Johansen estimator, are shown in Figure [2](#fig02){ref-type=\"fig\"}. ", "The probability of remaining not wait-listed and alive on HD was only 33.2% four years after the initiation of HD; the probability of remaining not wait-listed and dying was estimated at 46.0% (Figure [2](#fig02){ref-type=\"fig\"}). ", "Thus, patients who remained not wait-listed had a very high probability of death on HD.", "\n\n{#fig02}\n\nThe probability of being wait-listed progressed in two stages, with an increase in the first year followed by a constant and regular decline, as illustrated in Figure [2](#fig02){ref-type=\"fig\"}. ", "The registration rate was therefore higher at the onset, then subsequently lower, than the rate of RT. ", "Most of the wait-listed patients were registered on the RT waiting list in the first year after HD initiation, with a median time before registration of 0.8 years (inter-quartile range, 0.4 to 1.4 years). ", "The probability of undergoing RT increased rapidly after the first year and was estimated at 16.4% at 4 years, as shown in Figure [2](#fig02){ref-type=\"fig\"}. ", "Conversely, the probability of death while being wait-listed was very low (estimated at 0.6% at 4 years).", "\n\nThese results show that patients who remained not wait-listed had a much higher probability of death than wait-listed patients. ", "Of the 2954 deaths observed in the entire cohort during follow-up, 2921 (98.9%) were observed in the not wait-listed group compared with only 33 (1.1%) in the wait-listed group.", "\n\nFactors associated with registration on the RT waiting list\n-----------------------------------------------------------\n\nUsing bivariate analysis, all co-morbidities were found to be significantly associated with registration on the waiting list and death while on HD (data not shown). ", "The results of the multivariable analysis are presented in Table [2](#tbl02){ref-type=\"table\"}. ", "All selected covariates except for gender were significant contraindications for registration on the waiting list (transition 'HD, not wait-listed' → 'HD, wait-listed'). ", "Notably, patients older than 70 years had an 80-fold (1/0.0126) lower probability of being wait-listed than patients under 50 years of age. ", "Conversely, all selected co-morbidities except for diabetes, myocardial infarction, and stroke were significant risk factors for death on dialysis (transition 'HD, not wait-listed' → 'death'), as shown in Table [2](#tbl02){ref-type=\"table\"}.", "\n\n###### Hazard ratio for transition 1 → 2 (Not wait-listed → Wait-listed) and transition 1 → 4 (Not wait-listed → Death during dialysis) in the multi-state model\n\n ------------------------------------------------------------------------------------------------------------------------\n   Transition 1 → 2\\ Transition 1 → 4\\ \n Not wait-listed → Wait-listed Not wait-listed → Death \n ---------------------------------------- ------------------------------- ------------------------- ------ --------------\n Age (years)        \n\n  \\<50 1.00   1.00  \n\n  50--55 0.64 (0.55, 0.75) 1.41 (1.02, 1.95)\n\n  55--60 0.54 (0.46, 0.63) 1.92 (1.45, 2.53)\n\n  60--65 0.31 (0.26, 0.37) 2.04 (1.58, 2.65)\n\n  65--70 0.14 (0.11, 0.18) 2.26 (1.77, 2.88)\n\n  \\>70 0.01^a^ (0.01, 0.02) 3.77 (3.03, 4.70)\n\n Gender: female 0.92 (0.82, 1.03) 0.82 (0.76, 0.89)\n\n BMI (kg/m^2^)        \n\n  22--30 1.00   1.00  \n\n  \\<22 0.84 (0.74, 0.95) 1.25 (1.14, 1.37)\n\n  \\>30 0.68 (0.57, 0.81) 0.91 (0.80, 1.02)\n\n Albumin (increase of 1 g/l) 1.02 (1,01, 1.04) 0.99 (0.98, 0,99)\n\n Dialysis on catheter 0.71 (0.63, 0.81) 1.37 (1.27, 1.49)\n\n Selected co-morbidities^b^        \n\n  Diabetes 0.69 (0.54, 0.88) 1.10 (0.99, 1.23)\n\n  Chronic obstructive pulmonary disease 0.58 (0.43, 0.78) 1.20 (1.08, 1.33)\n\n  Congestive heart failure 0.61 (0.49, 0.75) 1.27 (1.17, 1.39)\n\n  Myocardial infarction 0.66 (0.48, 0.91) 1.10 (0.98, 1.22)\n\n  Peripheral arterial disease 0.60 (0.47, 0.77) 1.14 (1.04, 1.25)\n\n  Cerebrovascular disease 0.65 (0.48, 0.87) 1.12 (1.00, 1.26)\n\n  Cirrhosis 0.25 (0.11, 0.61) 1.78 (1.43, 2.22)\n\n  Inability to ambulate 0.35 (0.23, 0.54) 1.77 (1.62, 1.95)\n\n  Severe behavioral disorder 0.27 (0.16, 0.47) 1.52 (1.28, 1.81)\n\n Primary renal disease        \n\n  Polycystic kidney disease 1.00   1.00  \n\n  High blood pressure 0.57 (0.46, 0.71) 1.35 (1.06, 1.71)\n\n  Diabetes 0.55 (0.41, 0.75) 1.49 (1.15, 1.94)\n\n  Glomerulonephritis 1.08 (0.92, 1.27) 1.19 (0.91, 1.56)\n\n  Pyelonephritis 0.65 (0.50, 0.84) 1.49 (1.11, 2.00)\n\n  Vascular 0.57 (0.32, 0.99) 1.62 (1.17, 2.24)\n\n  Other 0.56 (0.46, 0.68) 1.98 (1.55, 2.52)\n\n  Unknown 0.61 (0.50, 0.75) 1.62 (1.26, 2.07)\n ------------------------------------------------------------------------------------------------------------------------\n\nBMI, body mass index; CI, confidence interval; HR, hazard ratio.", "\n\n^a^Estimated HR amounted to 0.012 600 21.", "\n\n^b^Co-morbidities listed for data collection.", "\n\nPatients who remained not wait-listed tended to be significantly older and to have more co-morbidities; these characteristics significantly increased their probability of death.", "\n\nHazard ratio for death associated with registration on the RT waiting list\n--------------------------------------------------------------------------\n\nThe comparison between the risk of death for wait-listed patients and patients who were not wait-listed was carried out by means of the transition-specific model. ", "The results are presented in Table [3](#tbl03){ref-type=\"table\"}. ", "In bivariate analysis, patients who were not wait-listed displayed a greater risk of death than wait-listed patients (HR 8.83; 95% CI, 6.26--12.44). ", "The adjusted HR for death associated with not being wait-listed was 3.52 (95% CI, 1.70--7.30). ", "Remaining not wait-listed significantly increased the risk of death while on HD, regardless of the impact of co-morbidities on the probability of being wait-listed. ", "Sensitivity analysis showed that the results were similar for death associated with being not wait-listed between the different age groups. ", "Results are displayed as supplementary data in [eTable 2](#sm02){ref-type=\"supplementary-material\"}.", "\n\n###### Hazard ratio for death associated with being not wait-listed, estimated using the transition-specific model\n\n   HR^a^ 95% CI\n --------------------------------------- ------- ---------------\n Unadjusted 8.83 (6.26, 12.44)\n Adjusted on age and co-morbidities^b^ 3.52 (1.70, 7.30)\n\nCI, confidence interval; HR, hazard ratio.", "\n\n^a^The HR describes the ratio for the transition hazard 1 → 4 (Not wait-listed → Death during dialysis) and the transition hazard 2 → 4 (Wait-listed → Death during dialysis).", "\n\n^b^Adjusted for age, sex, BMI, albumin level, dialysis on catheter, diabetes, chronic obstructive pulmonary disease, congestive heart failure, myocardial infarction, peripheral arterial disease, cerebrovascular disease, cirrhosis, amputation, inability to ambulate, severe behavioral disorder, and primary renal disease.", "\n\nFactors associated with death and RT after registration\n-------------------------------------------------------\n\nIn the multi-state model analysis, the factors associated with RT (transition 'HD, wait-listed' → 'RT') and death of the wait-listed patients (transition 'HD, wait-listed' → 'death') were investigated. ", "The results of the multivariate analysis are presented in Table [4](#tbl04){ref-type=\"table\"}. ", "It was found that only age over 60 years and inability to ambulate significantly increased the probability of receiving a transplant, and only age over 60 years and a history of myocardial infarction were significant risk factors for death. ", "These results show that very few comorbidities influenced the outcome of patients following registration on the waiting list.", "\n\n###### Hazard ratio for transition 2 → 4 (Wait-listed → Death during dialysis) and 2 → 3 (Wait-listed → Renal transplantation \\[RT\\]) in the multi-state model\n\n ------------------------------------------------------------------------------------------\n   Transition 2 → 4\\ Transition 2 → 3\\ \n (Wait-listed → Death) (Wait-listed → RT) \n ----------------------- ----------------------- -------------------- ------ --------------\n Age (years)        \n\n  \\<60 1.00   1.00  \n\n  \\>60 2.49 (1.20, 5.15) 1.26 (1.08, 1.46)\n\n Female sex 1.97 (0.98, 3.98) 0.99 (0.87, 1.13)\n\n Myocardial infarction 6.46 (2.24, 18.65) 1.05 (0.65, 1.70)\n\n Inability to ambulate ---^a^ --- 1.64 (1.06, 2.54)\n ------------------------------------------------------------------------------------------\n\nCI, confidence interval; HR, hazard ratio.", "\n\n^a^HR could not be estimated because no death events were observed for waiting-list patients with an inability to ambulate.", "\n\nDISCUSSION\n==========\n\nIn the present study, we identified an independent relationship between registration on the RT waiting list and the probability of death while on dialysis. ", "Patients who remained not wait-listed were 8.83 times more likely to die while on dialysis than wait-listed patients during follow-up. ", "This HR for death was explained in part by the fact that age and co-morbidities were both significant factors that constituted contraindications for registration on the waiting list. ", "However, even after adjustment for age and co-morbidities, patients who were not wait-listed were still 3.52 times more likely to die while on dialysis than wait-listed patients.", "\n\nOur large cohort of incident HD patients identified through the national REIN registry in regions connected to the national information system of the French Transplantation Agency makes our findings especially noteworthy. ", "We showed that adjustment for baseline characteristics in a classic multivariate model is not enough to account for the association with mortality and registration on the RT waiting list. ", "Registration on the RT waiting list is the result of a complex decision-making process based on medical expertise in accordance with medical guidelines.^[@r01],[@r28],[@r29]^ The adjusted HR for death associated with being not wait-listed highlights that this medical expertise provides additional and detailed information on the probability of death while on dialysis, regardless of co-morbidities.", "\n\nRegistration on the waiting list is an administrative event. ", "Neither the health status of patients nor the dialysis treatment status change at the date of registration. ", "Therefore, registration cannot in itself modify the probability of death of a patient, like a myocardial infarction or chemotherapy would do. ", "The high hazard of death associated with being not wait-listed may reflect the effect of numerous other risk factors for death in wait-listed patients, like socio-economic and psychological characteristics, treatment adherence, and miscellaneous diseases. ", "Such risk factors are usually not reported in registries or studies on mortality in dialysis. ", "Consequently, registration on the waiting list appears as an essential adjustment factor in the survival analysis of dialysis patients.", "\n\nIt is well-recognized that co-morbid conditions strongly and independently limit access to the RT waiting list, especially diabetes in elderly patients.^[@r08]^ Thus, dialysis patients have been shown to have worse co-morbid conditions than transplant recipient.^[@r05]^ In the present study, we have clarified such findings; the multi-state model analysis allowed us to show simultaneously that all co-morbidities examined in this study, except history of diabetes, myocardial infarction, and stroke, were contraindications to placement on the RT waiting list and risk factors for death while on dialysis. ", "In particular, elderly patients over 70 years were 80 times less likely to be wait-listed than patients under 50 years, whereas their risk of death was only 3.7 times greater than patients under 50 years. ", "Our results are consistent with previous reports that elderly patients are less likely to be wait-listed than their younger counterparts, but we found a greater risk of not being wait-listed among elderly patients than previously published studies.^[@r05],[@r07],[@r08],[@r10]^ Consequently, elderly patients over 70 years had a lower chance of being evaluated for RT in France, regardless of their health status.", "\n\nUsing a multi-state model, we have shown that most of the risk factors for death identified in patients who were not wait-listed (Table [2](#tbl02){ref-type=\"table\"}) were different from those identified in wait-listed patients (Table [4](#tbl04){ref-type=\"table\"}). ", "This finding suggests that failure to consider registration on the RT waiting list in outcome analysis could lead to incomplete or erroneous interpretation of data. ", "Let us suppose that *A* is a risk factor for death in patients who were not wait-listed, but not in wait-listed patients; a study not taking into account placement on the waiting list when analyzing data could wrongly conclude that *A* is a risk factor for death in all HD patients, including wait-listed patients. ", "Given such a hypothesis, wait-listed patients may receive unnecessary medical treatment to correct *A*, which could be a source of potential error, adverse effects, and unnecessary expense.", "\n\nRegistration on the waiting list, a time-dependent event, was examined using a multi-state model. ", "Considering registration as a baseline covariate, regardless of the time spent on HD before registration, would cause a bias known as immortality bias.^[@r30],[@r31]^ A classical survival analysis with a time-dependent covariate would not take into account the competing risk of RT. ", "The multi-state model corresponds to the general framework of competing risks.^[@r18]^ The use of this model in the present study showed that it is well suited to assessing the effect of registration on the waiting list, an intermediate and time-dependent state, on the outcome of patients on HD.", "\n\nOur results were obtained on the basis of data extracted from a national registry, which allowed adjustments to be made for a number of covariates on a large number of patients. ", "The information regarding registration on the waiting list was accurate. ", "Therefore, given the size of the study cohort analyzed and the statistical model used, the present results appear reliable.", "\n\nSeveral limitations, however, must be considered in interpreting our findings. ", "First, the structure for allocating organs, the decision-making process, and the waiting time before registration and RT vary between countries,^[@r03],[@r09],[@r10],[@r32]^ so the present results may be specific to France. ", "However, low death rates for patients on RT waiting lists have also been reported in other western countries.^[@r33]--[@r35]^ Although the low death rates reported among other studies of RT waiting lists suggest a similar effect of registration on the waiting list on the probability of death, this apparent trend should be confirmed by further studies in other countries. ", "Second, all factors associated with registration on the waiting list, as reported in the literature, may not have been fully adjusted for. ", "However, as registration is a dynamic process that does not depend only on co-morbidities at baseline, it would be extremely difficult to take into account all factors that could influence waiting list registration. ", "Finally, statistical analysis is underpowered for the analysis of risk factors for death among wait-listed patients due to the low number of events (only 33 deaths were observed in this patient group). ", "However, the majority of wait-listed patients underwent RT, and death while on dialysis was not observed in these patients. ", "When conducting a multivariate survival analysis, it is recommended to have at least 10 events observed for each covariate.^[@r36]^ According to the incidence of death events and registration on the waiting list among wait-listed patients in our study, it would be necessary to include at least 20 000 HD patients to study 10 covariates in the wait-listed group, which is impractical.", "\n\nConclusion\n----------\n\nIn conclusion, this study demonstrated that registration on the RT waiting list should be considered in the survival analysis of patients on dialysis. ", "Indeed, registration on the waiting list appeared to be a selection process leading patients with a worse prognosis to remain on dialysis and those with a better prognosis to undergo RT. ", "Further, wait-listed patients and patients who were not wait-listed did not share the same risk factors for death, but the interpretation of our result was limited by a lack of power. ", "Further studies of larger cohorts are needed to confirm these preliminary data. ", "Finally, our findings suggest that using a multi-state model and considering registration on the RT waiting list as an intermediate state may avoid misinterpretation of the risk factors for death.", "\n\nONLINE ONLY MATERIALS\n=====================\n\n###### Baseline characteristics of patients according to registration on the renal transplantation waiting list. ", "Comparisons between the two groups of patients were not performed because the groups were constituted during the study, not at baseline.", "\n\n###### Hazard ratio for death associated with not being wait-listed by age groups, estimated by the transition-specific model.", "\n\n###### Scatter plots of Martingale residuals for age and body mass index for each transition of the multi-state model used in the study.", "\n\nWe would like to thank the Scientific Committee and the people in charge of the REIN Registry for their invaluable assistance, in particular Dr. Cécile Couchoud, Mathilde Delasalle, and Dr. Christian Jacquelinet. ", "We are also extremely grateful to all of the nephrologists and centers involved in this study for their kind cooperation and for providing high-quality data.", "\n\nConflicts of interest: None declared.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Preclinical animal models are used extensively in cancer research to evaluate drug efficacy and toxicity and to better understand the disease's complex fundamental underlying processes. ", "In vivo imaging studies enable researchers to longitudinally assess tumor presence, functional status, and response the therapy without the need to sacrifice animals for each read point. ", "Anatomical imaging modalities (MRI, CT, and Ultrasound) enable the visualization and assessment of tissue structures, which are necessary to localize the signals acquired via the molecular imaging modalities (PET, SPECT, and Optical), which assess the functional status of tissues (tumor metabolic demand, molecular signal expression, drug biodistribution, etc.). ", "Ultrasound is the least expensive of the anatomical modalities with the fastest acquisition time, but there is no ultrasound product on the market for whole body imaging, thus researchers often resort to MR or CT based anatomical imaging for their dual modality studies. ", "MR and CT imaging studies are slow, expensive, and reduce study throughput. ", "We propose to build a high throughput and low cost ultrasound-optical hybrid modality system which could speed up preclinical drug research, as well as drive down costs. ", "Our company, SonoVol, is the result of several years of strong collaborative academic-industry research between Dr. Paul Dayton's ultrasound imaging lab at UNC and Dr. Stephen Aylward's image analysis lab at Kitware. ", "Unlike MR or CT, our SonoVol device is an inexpensive and benchtop imaging system which can capture a whole body mouse image in less than 5 minutes. ", "We are proposing to build the after- market hardware and software components necessary to transfer a mouse between existing commercially available imaging systems to create a fusion between a whole-body anatomical ultrasound image, and a bioluminescence image. ", "We will test this system in both a controlled in vitro environment, as well as a pilot small animal study implementing SonoVol's proprietary hardware. ", "This SonoVol device allows any ultrasound probe to be manipulated around an animal to build up a cohesive whole-body 3D volume, as well as leverage several powerful image processing and analysis tools to align the two modalities, allowing one-to-one mapping between the anatomical and functional images. ", "Furthermore, it will be possible to target ultrasound images, on-the-fly, to regions in the mouse's body which have strong bioluminescence signal expression. ", "The next phase of commercialization of this product will be to build a dedicated system which does not require a physical transfer of the animal between systems, thereby further increasing throughput." ]

{ "pile_set_name": "NIH ExPorter" }

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[ "Q:\n\nSearch for commands (for the present user) starting with some particular letter\n\nWhich command could I use list all commands that start with the letter g?", "\nI have read the question here but I seek for an answer without arbitrary limits. ", "If shell completion gives an answer, it should be included.", "\nHowever, if there is an answer which runs in many/most shells that would be preferable.", "\nWould:\n( set -f; find ${PATH//:/ } -type f -maxdepth 1 -executable )\n\nbe a suitable answer? ", "Not all finds have all those options, correct?", "\n\nA:\n\nThe find command that you show,\n( set -f; find ${PATH//:/ } -type f -maxdepth 1 -executable )\n\nwould be suitable for most circumstances, given that it was run on a machine with GNU find installed, which implements both -maxdepth and -executable (and I really don't want to try to craft an equivalent test for -executable using standard find predicates). ", "It also requires bash for doing the parameter substitution on the value of PATH, changing each : into a space (this could also be done through setting IFS=: and using the variable unquoted as is, removing the requirement for bash).", "\nIn another answer to a similar question, I also I protected the find command from interpreting the search paths as potential options with --. ", "The command shown here is using the approach with IFS, and is also slightly tweaked after doing some proper testing of it:\n(\n set -f; IFS=:\n find -L -- $PATH -maxdepth 1 ! ", "-type d -executable\n) \n\nThe ! ", "-type d ensures that executable symbolic links, but not directories, are also found. ", " The -L option makes sure that meta data relating to found symbolic links are taken from the thing that the link is pointing to (this prevents finding symbolic links to accessible, i.e. executable, subdirectories).", "\nTesting this against compgen -c in bash shows that compgen -c will produce a list of commands overlapping with the result from the above find command, and that any additional commands that compgen -c finds is limited to built-in commands that have no external implementation.", "\nObviously, to limit this to commands starting with the character g, you would also want to use -name 'g*' (compgen -c g in bash).", "\nA shell that provides tab completion of commands, like bash, may expose commands for interacting with this mechanism. ", "These commands will unlikely be portable between shells, and possibly not even between versions of the same shell. ", " The find command above, seems to provide a fairly good approximation to what a tab completion of external commands would give you though, and only relies on the presence af GNU find.", "\nFor a rewrite of the -executable predicate using standard find predicates, see Stéphane Chazelas' answer to another question (which deals with -readable, but the solution is analogous to -executable).", "\nThe -maxdepth predicate is also non-standard, but are more commonly implemented across various variations of the find command.", "\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "JrubyRails4::Application.configure do\n # Settings specified here will take precedence over those in config/application.rb.", "\n\n # The test environment is used exclusively to run your application's\n # test suite. ", "You never need to work with it otherwise. ", "Remember that\n # your test database is \"scratch space\" for the test suite and is wiped\n # and recreated between test runs. ", "Don't rely on the data there!", "\n config.cache_classes = true\n\n # Do not eager load code on boot. ", "This avoids loading your whole application\n # just for the purpose of running a single test. ", "If you are using a tool that\n # preloads Rails for running tests, you may have to set it to true.", "\n config.eager_load = false\n\n # Configure static asset server for tests with Cache-Control for performance.", "\n config.serve_static_assets = true\n config.static_cache_control = \"public, max-age=3600\"\n\n # Show full error reports and disable caching.", "\n config.consider_all_requests_local = true\n config.action_controller.perform_caching = false\n\n # Raise exceptions instead of rendering exception templates.", "\n config.action_dispatch.show_exceptions = false\n\n # Disable request forgery protection in test environment.", "\n config.action_controller.allow_forgery_protection = false\n\n # Tell Action Mailer not to deliver emails to the real world.", "\n # The :test delivery method accumulates sent emails in the\n # ActionMailer::Base.deliveries array.", "\n config.action_mailer.delivery_method = :test\n\n # Print deprecation notices to the stderr.", "\n config.active_support.deprecation = :stderr\nend\n" ]

{ "pile_set_name": "Github" }

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[ "---\nabstract: 'We have analyzed Chandra ACIS observations of 32 nearby spiral and elliptical galaxies and present the results of 1441 X-ray point sources that were detected in these galaxies. ", "The total [*point-source*]{} X-ray (0.3$-$8.0 keV) luminosity L$_{XP}$ is well correlated with the B-band, K-band, and FIR+UV luminosities of spiral host galaxies, and is well correlated with the B-band and K-band luminosities for elliptical galaxies. ", "This suggests an intimate connection between L$_{XP}$ and both the old and young stellar populations, for which K and FIR+UV luminosities are reasonable proxies for the galaxy mass $M$ and star-formation rate $SFR$. We derive proportionality constants $\\alpha =$ 1.3 $\\times$ 10$^{29}$ erg s$^{-1}$ M$_\\odot^{-1}$ and $\\beta =$ 0.7 $\\times$ 10$^{39}$ erg s$^{-1}$ (M$_\\odot$ yr$^{-1}$)$^{-1}$, which can be used to estimate the old and young components from $M$ and $SFR$, respectively. ", "The cumulative X-ray luminosity functions for the point sources have significantly different slopes. ", "For the spiral and starburst galaxies, $\\gamma \\approx$0.6$-$0.8, and for the elliptical galaxies, $\\gamma \\approx$1.4. ", "This implies that [*the most luminous point sources – those with L$_X \\gapprox$ 10$^{38}$ erg s$^{-1}$ — dominate L$_{XP}$ for the spiral and starburst galaxies.*]{} ", "Most of the point sources have X-ray colors that are consistent with soft-spectrum (photon index $\\Gamma \\sim$ 1$-$2) low-mass X-ray binaries, accretion-powered black-hole high-mass (BH HMXBs), or Ultra-Luminous X-ray sources (ULXs a.k.a. ", "IXOs). ", "We rule out hard-spectrum neutron-star HMXBs (e.g. accretion-powered X-ray pulsars) as contributing much to L$_{XP}$. Thus, for spirals, L$_{XP}$ is dominated by ULXs and BH HMXBs. ", "We find no discernible difference between the X-ray colors of ULXs (L$_X \\ge$ 10$^{39}$ erg s$^{-1}$) in spiral galaxies and point sources with L$_X \\approx$ 10$^{38}$$-$10$^{39}$ erg s$^{-1}$. We estimate that $\\gapprox$20% of all ULXs found in spirals originate from the older (pop II) stellar populations, indicating that many of the ULXs that have been found in spiral galaxies are in fact pop II ULXs, like those in elliptical galaxies. ", "We find that L$_{XP}$ depends [*linearly*]{} (within uncertainties) on both $M$ and $SFR$, for our sample galaxies ($M \\lapprox$ 10$^{11}$ M$_\\odot$ and $SFR \\lapprox$ 10 M$_\\odot$ yr$^{-1}$).'", "\nauthor:\n- 'Edward J. M. Colbert, Timothy M. Heckman, Andrew F. Ptak, and David K. Strickland'\n- 'Kimberly A. Weaver'\ntitle: 'Old and Young X-ray Point Source Populations in Nearby Galaxies'\n---\n\nIntroduction\n============\n\nAs the resolution and sensitivity of X-ray imaging detectors continues to improve, it becomes more and more feasible to study individual X-ray point sources in external galaxies. ", "The point-spread function (PSF) of the Einstein IPC imaging spectrometer ($\\sim$ 1$^\\prime$) was typically too poor to distinguish emission from individual point sources in galaxies with distances $\\gapprox$ 2 Mpc, and, for more nearby galaxies, it was usually only sensitive to very luminous sources with L$_X \\gapprox$ 10$^{38}$ erg s$^{-1}$. The ROSAT PSPC (PSF $\\sim$ 20$^{\\prime\\prime}$) offered some improvement, and some nearby galaxies could be studied in the soft (0.2$-$2.4 keV) band. ", "Fabbiano (1989) gives a comprehensive review of X-ray sources in nearby galaxies in the pre-Chandra era. ", "The Chandra ACIS instrument has a tremendous improvement in both spatial resolution (PSF $\\sim$ 1$^{\\prime\\prime}$) and sensitivity, and covers the bandpass 0.2$-$8.0 keV. We are now able to study the properties of individual point sources in galaxies out to $\\sim$20 Mpc, for which L$_X \\approx$ 10$^{38}$ erg s$^{-1}$ sources are detected in a reasonable (50 ks) exposure time. ", "Although the bright X-ray sources in the Milky Way (MW) are easily studied, many of the MW point sources are viewed through the obscuring galaxy disk, so one must correct for completeness when doing statistical work. ", "Furthermore, in order to study how properties of classes of point sources correlate with host galaxy properties, it is imperative to study large samples of different types of galaxies. ", "We are now able to study properties of low-mass X-ray binaries (LMXBs), high-mass X-ray binaries (HMXBs), and Ultra-Luminous X-ray sources (L$_X \\ge$ 10$^{39}$ erg s$^{-1}$; ULXs, a.k.a. ", "Intermediate-luminosity X-ray Objects \\[IXOs\\]) in large samples of external galaxies with Chandra.", "\n\nHard (kT $\\sim$ 2$-$10 keV) X-ray emission is often present in the halos of elliptical galaxies, and sometimes also in starburst galaxy nuclei (e.g. Moran & Lehnert 1997 and Ptak et al. ", "1997). ", "ASCA was not able to resolve or diagnose the origin of the hard emission because of its poor spatial resolution (PSF $\\sim$ 1$^\\prime$). ", "However, Chandra has shown that X-ray [*point sources*]{} in spiral and elliptical galaxies often emit a large fraction of the total hard X-ray luminosity. ", "We can now address some important questions with large surveys of galaxies with Chandra. ", "How do the X-ray point source populations of all of the different types of X-ray binaries (XRBs) and ULXs depend on the properties of the host galaxy? ", "What is the exact connection between starbursts (or young star formation) and XRB creation and evolution? ", "How does the host galaxy environment affect the evolution of the sources? ", "Is there a connection between the XRB population and the ULX population? ", "Results from the many Chandra observations of spiral and elliptical galaxies already show important progress in many of these areas of study (e.g., see review articles by Irwin et al. ", "2002a, Roberts et al. ", "2001, and Miller & Colbert 2003, and references therein).", "\n\nHere we present results from a study of the properties of the X-ray point source population in a sample of 5 Merger and Irregular galaxies and 18 spiral galaxies, many of which have high star formation rates (SFRs), and 9 elliptical galaxies, which typically have negligible SFRs. ", "We have analyzed the ACIS data for these 32 galaxies in exactly the same way. ", "Thus, results from our processed data will not be affected by different analysis techniques, as might have been the case if results from already published work on individual objects were used for the present study, such as tabulations listed in the many papers on Chandra observations of galaxies (e.g, Eracleous et al. ", "2002, Swartz et al. ", "2003, Sarazin, Irwin & Bregman 2001, and Irwin, Sarazin & Bregman 2002b). ", "Since our calibration data, analyses software, or filtering criteria may be different (see section 3.1), our results (e.g. number of sources, count rates, fluxes, and luminosities) may differ slightly from those already reported in the literature.", "\n\nIn section 2, we describe the galaxy sample. ", "Data reduction techniques are discussed in section 3 and results are given in section 4. ", "We discuss the implications of the results in section 5, and summarize in section 6.", "\n\nDescription of Data and Galaxy Sample\n=====================================\n\nData for twenty-seven of the galaxies in the sample were selected randomly from the nearby (D $<$ 30 Mpc) NGC and Messier galaxies that were were in the public Chandra archives on September 3, 2001. ", "Proprietary data for galaxies NGC 3079, NGC 3628, NGC 5253 and NGC 4449 were also added. ", "When the Chandra observation of the very nearby elliptical galaxy NGC 3379 became public in February 2002, we added it as well.", "\n\nSince most of the data were taken from the Chandra archives and therefore the sample is already biased toward galaxies that are historically interesting in the X-ray band, there is no obvious way to select a ‘complete,’ unbiased sample. ", "Therefore, our goal was to select $\\sim$30 galaxies of all morphological types, and with a wide range in “starburst power,” since we are interested in studying how the X-ray point source population varies with host galaxy properties. ", "Since the XASSIST software (see section 3.1) typically requires $\\sim$1 day of computer processing (or re-processing) per dataset, a sample size of $\\sim$30 galaxies was both feasible, and large enough for useful statistical work. ", "We imposed the restriction that all of the sample galaxies must have X-ray luminosity sensitivity t/D$^2 >$ 0.044 ks Mpc$^{-2}$, where $t$ is the exposure time after filtering (see Table 1), and $D$ is the distance to the galaxy (Table 2). ", "This corresponds to a luminosity sensitivity of $\\approx$10$^{38}$ erg s$^{-1}$ for a back-illuminated (BI) CCD, such as CCD 7.", "\n\nSince our intent is to study the relationship between the X-ray point source populations and the properties of the stellar component of the host galaxies (and not the active super-massive black holes \\[SMBHs\\] and their possible connection with intermediate-mass black holes \\[IMBHs\\], for example), we intentionally omitted the three powerful active galaxies NGC 1068, NGC 4151, and M87. ", "Although the peculiar elliptical galaxy Cen A has an AGN with a radio jet, like M87, it is the only “elliptical” galaxy with significant star formation, so we decided to keep it in our sample. ", "LINERs and weak Seyferts were not omitted intentionally (see column 4 of Table 2). ", "The composite starburst/AGN galaxy NGC 4945 was also kept.", "\n\nOur final sample of 32 galaxies (see Table 1) includes 28 galaxies from the archive, and proprietary data for four galaxies (NGC 3079, NGC 3628, NGC 4449, and NGC 5253).", "\n\nIn Table 2, we list some host galaxy properties that are related to the stellar content of the galaxy, in particular properties that are related to the star-formation rate (SFR) and the stellar mass (M). ", "The far-infrared (FIR) and far-ultraviolet luminosities are proxies for the SFR, while the B-band and K$_s$-band luminosities are proxies for the mass (e.g. Kennicutt 1998, Bell & de Jong 2001). ", "Note that the galaxies in our sample span a wide range in both morphological type, and in SFR/M (see L$_{FIR}$/L$_{B}$ or L$_{FIR+UV}$/L$_{K}$; Table 2).", "\n\nFor galaxies with recessional velocities $<$ 1000 km s$^{-1}$, as listed in the Third Reference Catalog of Bright Galaxies (RC3; de Vaucouleurs et al. ", "1991), distances were taken directly from Tully (1988). ", "We used 21-cm recessional velocities when available, otherwise optical recessional velocities. ", "For galaxies with recessional velocities $\\ge$ 1000 km s$^{-1}$, we calculated the distance using H$_0 =$ 75 km s$^{-1}$ Mpc$^{-1}$. The distances to NGC 4038 and NGC 5094 were used for X-ray sources in NGC 4038/9 and NGC 5194/5, respectively.", "\n\nData Reduction\n==============\n\nX-ray Data\n----------\n\nAll of the public ACIS data were retrieved from the SAO Chandra archives. ", "All of the data were reprocessed and reduced using a modified version of the XASSIST v0.757 (Ptak & Griffiths 2003) scripts, LHEASOFT v5.2, and CIAO v2.2.", "\n\nLevel-1 event files were reprocessed to level-2 event files with CIAO, using XASSIST. ", "XASSIST uses the basic data reduction steps recommended by the CXC “threads.” ", "The optional 0.5 pixel position randomization was not performed. ", "After this reprocessing step, each CCD is treated as a different detector, and individual CCD data are processed separately. ", "For data processing, PI values were constrained to be in the range 14$-$548, corresponding to the energy range 0.2$-$8.0 keV, although fluxes and counts for X-ray colors were computed from the data in the 0.3$-$8.0 keV range.", "\n\nThe CIAO [wavdetect]{} source detection routine was then used on the reprocessed level-2 event data to produce a preliminary list of point sources. ", "For all sources with more than 10 net counts, we further tested the robustness of the detection using a CPU-intensive 2D Gaussian image-fitting algorithm. ", "If a reasonable fit to the image was obtained with a Gaussian (source) plus sloping plane (background) model, we were able to estimate a more accurate count rate, and better estimates of the major and minor axes of the source. ", "If the ratio of the major to minor axis was larger than 2.0, the source was initially flagged as ‘extended.’ ", "Likewise, if the size of the major or minor axes was larger than the PSF (at that off-axis angle), the source was also flagged as ‘extended.’ ", "Sources detected at S/N $<$ 2.0 were rejected, as were sources with fitted Gaussian sizes too small to be consistent with the ACIS PSF.", "\n\nWe then filtered only those sources inside the galaxy major and minor R$_{25}$ ellipse, as listed in RC3. ", "Each source was then individually inspected on-screen, and re-classified as ‘point-like’ or ‘extended.’ ", "Any X-ray sources that were within 5$^{\\prime\\prime}$ of the galaxy nucleus (as listed in NED) were considered potential active nuclei and were flagged for further examination. ", "After checking each case by hand, a single nuclear X-ray source was omitted in each of the following seven galaxies: NGC 3079, NGC 4258, NGC 4374, NGC 4579, NGC 4945, NGC 5128, and NGC 5194. ", "The ‘jet’ sources in NGC 4258 and Cen A were also rejected. ", "We also rejected all of the artificial X-ray sources that were produced along the readout column of high count-rate sources (NGC 4579 and NGC 5128). ", "After screening, we found a total of 1441 point sources in 32 galaxies (see Table 1 and Appendix). ", "As mentioned in section 1, our data reduction techniques and filtering methods may be different from those of other workers, so our point source lists may also differ.", "\n\nThe major and minor axes for elliptical source regions were determined directly from the Gaussian fitting, or from [wavdetect]{} if the Gaussian fitting was not performed, or failed. ", "Local annular regions surrounding the source, and centered on the source position, were used for background. ", "In crowded regions, when other source regions overlapped with the background region, the contaminating part(s) of the background region were omitted.", "\n\nThese source and background regions were used directly to compute counts in three energy ranges, for hardness ratios (see Table A1). ", "X-ray fluxes in the 0.3$-$8.0 keV band were determined for each source using the net count rates from the Gaussian fitting algorithm when available. ", "Otherwise, the count rates from [wavdetect]{} were used. ", "We converted the count rates to fluxes and luminosities using a simple power-law model with $\\Gamma =$ 1.8, and the Galactic Hydrogen columns and distances listed in Table 2. ", "Auxiliary Response Files (ARFs) generated using CIAO [psextract]{} were used to compute fluxes, when they were available. ", "Otherwise, on-axis ARF files were used.", "\n\nWe can estimate the uncertainties in our X-ray point-source luminosities using a simple absorbed power-law model in XSPEC. ", "For a typical Galactic column of N$_H =$ 3 $\\times$ 10$^{20}$ cm$^{-2}$, the flux/count-rate ratio varies by 5$-$10% when $\\Gamma$ varies by $\\pm$0.2 ($\\Gamma =$ 1.6$-$2.0). ", "If $\\Gamma$ varies by $\\pm$0.7 ($\\Gamma =$ 1.1$-$2.5), the ratio varies by 30$-$40%. ", "Uncertainties in the absorption column are also important. ", "Compared with a model with N$_H =$ 3 $\\times$ 10$^{20}$ cm$^{-2}$, a more higly absorbed model with N$_H =$ 3 $\\times$ 10$^{21}$ cm$^{-2}$ has flux/count-rate ratios 5$-$25% higher. ", "This would cause our quoted luminosities to underestimate the true luminosities. ", "For an highly-absorbed source with N$_H =$ 3 $\\times$ 10$^{22}$ cm$^{-2}$, the correction is severe ($\\approx$100$-$190%). ", "Thus, unless the source is highly absorbed, our estimates of the observed X-ray luminosities are within $\\approx$30$-$40% of their actual value.", "\n\nThe total galaxy point-source X-ray luminosity L$_{XP}$ was then computed by summing all of the individual X-ray luminosities for each of the point sources (see Tables A1 and 3). ", "We list in Table 3 the fraction of L$_{XP}$ at L$_X \\ge$10$^{38}$ erg s$^{-1}$, and the fraction at L$_X \\ge$10$^{39}$ erg s$^{-1}$ (i.e., the ULXs). ", "We also list the fraction of the total [*number*]{} of sources, and the total number of sources in these two high-luminosity ranges. ", "The relatively small scatter in the ratio of L$_{XP}$ to L$_K$ in the last column of Table 3 shows the strong correlation between the stellar light and the X-ray light. ", "As discussed in section 3.2, we believe our values of L$_{XP}$ approximate the actual total point source luminosity within $\\sim$20% for most of our galaxies. ", "The exceptions are M82, NGC 253, and the elliptical galaxies, for which we estimate an uncertainty of 40%.", "\n\nHardness ratios were computed for all sources (Table A1), but we used only the sources with $\\ge$ 20 net counts for our analyses. ", "A total of 1017 sources met this criterion. ", "Most (810) of these sources were detected on BI CCD 7. ", "One additional source was detected on BI CCD5, and the rest of the sources were detected on front-illuminated (FI) CCDs (0, 1, 2, 3 and 6).", "\n\nWe selected three energy bands for computing hardness ratios: S (soft, 0.3$-$1.0 keV), M (medium, 1.0$-$2.0 keV), and H (hard, 2.0$-$8.0 keV). ", "Counts were extracted directly from the source and background event files described above. ", "Hardness ratios of the form HR $=$ (C2$-$C1)/(C2$+$C1) were computed, where C1 and C2 are the net counts in the lower and higher energy bands, respectively. ", "Hardness ratios from sources detected on the FI CCDs were transformed to the corresponding ratio for BI CCDs using effective area (EA) curves from the CXC website[^1]. ", "Corrections to the hardness ratio were obtained by estimating the correction to the counts in each energy band. ", "For each of the sources on the FI CCDs, we first fit a power-law model to spectra in each energy band. ", "We then computed the correction factor $f$ to the FI counts using the best-fit photon index for that band $\\Gamma_{band}$ and the equation $$f_{band} = {{\\int_{band} E^{-\\Gamma_{band}}EA(BI) dE}\\over{\\int_{band} E^{-\\Gamma_{band}}EA(FI) dE}}. ", " \\eqno(1)$$ The corrected counts are then C1$^\\prime = f_1$C1 and C2$^\\prime = f_2$C2, where $f_1$ and $f_2$ are the correction factors for the lower and high energy bands, respectively. ", "Corrected hardness ratios HR$^\\prime$ were then computed from HR$^\\prime$ = ($\\phi +$ HR) / (1 $+ \\phi$ HR), where $\\phi =$ (1 $- f_1/f_2$)/(1 $+ f_1/f_2$). ", "Corrected hardness ratios for the sources are listed in Table A1.", "\n\nUnresolved X-ray Point Sources and Diffuse Hard X-ray Emission\n--------------------------------------------------------------\n\nIn order to test the accuracy of L$_{XP}$ due to the omission of blended point sources, the erroneous addition of spurious point sources, and “compact” clumps of diffuse emission, we computed the total hard (2.0$-$8.0 keV) counts from the individual point sources and compared with the total hard counts from the images within the R$_{25}$ ellipse. ", "Hard counts are expected only for point sources (e.g., XRBs) and diffuse hard X-ray emission, since the AGN and jet sources were omitted. ", "In general, the hard counts for each method were consistent within $\\sim$20%, which is typical of the uncertainty in the total hard counts due to the large number of background counts in the ellipse. ", "For M82 and NGC 253, there were excess hard counts, either in diffuse hard emission, or blended “unresolved” point sources (both are edge-on spiral galaxies). ", "We also found evidence for excess hard counts in the elliptical galaxies. ", "This is expected, since they are well known to have diffuse hard X-ray emission. ", "The diffuse hard emission in elliptical galaxies could be from multiple unresolved XRBs, or could be emission from diffuse, hot gas (e.g., Irwin et al. ", "2002b and references therein).", "\n\nHost Galaxy Luminosities\n------------------------\n\nAs mentioned above, we calculated total luminosities from the galaxies in four separate energy bands: FIR, NIR K$_s$-band, optical B-band, and the far-ultraviolet (FUV). ", "All fluxes were converted to luminosities using the distances listed in Table 2. ", "Far-infrared fluxes over the 40$-$120 $\\mu$m band were derived from the 60$\\mu$m and 100$\\mu$m IRAS fluxes using the method of Fullmer & Lonsdale (1989). ", "Near-infrared K$_s$-band spectral fluxes F$_\\lambda$ were calculated from 20 mag arcsec$^{-2}$ isophotal magnitudes listed in the 2MASS Large Galaxy Atlas (Jarrett et al. ", "2003). ", "Optical B-band spectral fluxes F$_\\lambda$ were calculated from B$_T^0$ magnitudes (or m$_B^0$ magnitudes for NGC 4038/9) listed in RC3. ", "For NGC 4038/9 and NGC 5194/5, the total spectral flux was calculated using the sum of F$_\\lambda$ for each galaxy. ", "In order to quote all luminosities in roughly the same size band, we have calculated L$_{K}$ and L$_B$ as $\\lambda$L$_\\lambda$.\n\nFar-ultraviolet fluxes were estimated using SED-fitting to broad-band total optical magnitudes (usually UBVRI, but in some cases UBVR or UBV), from Prugniel & Heraudeau (1998). ", "We experimented with a wide range of different SED databases, and obtained the best results using the observationally-based SEDs of Kinney & Calzetti (Kinney et al. ", "1996, Calzetti et al. ", "1994) and the simulated HYPERZ SEDs (cf. ", "Bolzonella et al. ", "2000). ", "There was generally good agreement between our estimated FUV fluxes and published measurements (e.g., Rifatto et al. ", "1995, Marcum et al. ", "2001). ", "The best-fit SEDs were then integrated from 1500$-$3500Å to obtain the FUV flux. ", "We list the B, K, FIR and FUV luminosities for each galaxy in Table 2.", "\n\nResults\n=======\n\nSimple Correlations of Total X-ray Point Source Luminosity with Host Galaxy Properties\n--------------------------------------------------------------------------------------\n\nIn Figure 1, we plot the total [*point-source*]{} X-ray luminosity L$_{XP}$ against the optical B-band, NIR K-band, FIR and FIR$+$FUV luminosities of the host galaxy. ", "As noted by Fabbiano et al. (", "1988), both spiral and elliptical galaxies show a good correlation between the X-ray and B-band luminosity, suggesting that the X-ray luminosity is directly related to the number (or mass) of stars in the galaxy. ", "The NIR K-band luminosity is a more accurate measure of the galaxy stellar mass and we prefer to use it for a proxy for the stellar mass instead of the B-band luminosity.", "\n\nFor all 32 galaxies in our sample, we find that L$_{K}$ is slightly better correlated with L$_{XP}$ (Pearson correlation coefficient r$=$0.93) than is L$_B$ (r$=$0.90). ", "The best fit yields L$_K \\propto$ L$_{XP}^{0.97}$. When elliptical or spiral galaxies are considered separately, for both $B$ and $K$, the correlation is quite strong, with $r \\approx$ 0.9 (although $r \\approx$ 0.8 for $B$ and the spirals).", "\n\nThe FIR luminosity, which is an approximate measure of [*current*]{} star formation in late-type spirals and starburst galaxies, is only correlated ($r >$ 0.50) with L$_{XP}$ for the Merger/Irr and Spiral galaxies. ", "When all of the galaxies are considered, there is no correlation between L$_{FIR}$ and L$_{XP}$ ($r \\approx$ 0.3). ", "For ellipticals only, we find $r \\approx$ 0.1. ", "The correlation is better ($r =$ 0.68) for the spiral galaxies. ", "We find the best correlation ($r =$ 0.93) for the Merger/Irr galaxies, which, in general, have large SFR/M ratios (Table 2, columns 9 and 10). ", "This suggests that a significant fraction of L$_{XP}$ in high SFR/M galaxies is due to current star formation, whereas in low-to-moderate SFR/M galaxies, much of L$_{XP}$ could be due to the older population of X-ray sources. ", "The correlation between SFR indicators and the [*total*]{} X-ray luminosity has been well noted in the literature (e.g. Helfand & Moran 2001, Ranalli et al. ", "2003, Grimm et al. ", "2003). ", "Here, we show specifically that the [*point-source*]{} X-ray luminosity L$_{XP}$ is also well correlated with $SFR$ (and $M$).", "\n\nSince some of the light from young, massive stars escapes directly from the galaxy as UV radiation, we use L$_{FIR+UV}$ (L$_{FIR} +$ L$_{FUV}$) as a more accurate proxy for the current SFR. ", "As with L$_{FIR}$, when all galaxies are considered, there is only a weak correlation ($r \\approx$ 0.5) between L$_{FIR+UV}$ and L$_{XP}$. We see a stronger correlation for the Merger/Irr and Spiral galaxies (r$=$0.94 and 0.69, respectively). ", "For ellipticals only, there is absolutely no correlation ($r \\approx$ 0.01).", "\n\nA careful inspection of the L$_{XP}$$-$L$_{K}$ scatter plot in Figure 1 (upper right) reveals that the Merger/Irr and Spiral galaxies are systematically offset toward larger L$_{XP}$, when compared to the Elliptical galaxies. ", "This merely illustrates that there is a significant component of the point-source X-ray luminosity that is due to current star formation and is not directly related to the galaxy stellar mass. ", "We discuss this effect further in section 5.", "\n\nX-ray Point Source Luminosity Functions\n---------------------------------------\n\nIn Figures 2 and 3, we show the cumulative point source X-ray Luminosity Functions (XLFs) N($>$L) for all of the points sources from each of the 32 datasets. ", "We list the slope[^2] $\\gamma =$ $-$dlogN($>$L)/dlogL for each of the galaxies in Table 4. ", "For the Merger/Irr group, the mean and standard deviation for $\\gamma =$ 0.65$\\pm$0.16, with the most prominent outlier being the dwarf galaxy NGC 5253 with $\\gamma \\approx$ 0.9 (see Table 4). ", "The spirals have very similar slopes: $\\gamma =$ 0.79$\\pm$0.24. ", "The luminosity functions of the elliptical galaxies, however, have steeper slopes: $\\gamma =$ 1.41$\\pm$0.38. ", "These differences in XLF slopes has been known for some time (e.g., Primini et al. ", "1993, Kilgard et al. ", "2002, Eracleous et al. ", "2002). ", "The steeper slope for the ellipticals could be indicative of a different mode of X-ray binary formation, or, perhaps more likely, an older XRB population that is in a later stage of X-ray evolution (e.g., see Grimm et al. ", "2002 and Wu 2001).", "\n\nThe total point source luminosity L$_{XP}$ can be theoretically defined as $$L_{XP}^{theor.} ", "= \\int_{L_{min}}^{L_{max}} L n(L) dL \\propto L_{max}^{1-\\gamma} - L_{min}^{1-\\gamma}, \\eqno(2)$$ where, for simplicity, we have assumed $\\gamma \\ne$ 1. ", "Here $n(L)$ is the differential luminosity function \\[$n(L) = N_0 \\gamma L^{-(\\gamma+1)}$ when N($>$L) $=$ N$_0$ L$^{-\\gamma}$\\], and L$_{min}$ and L$_{max}$ are the X-ray luminosities of the least and most luminous X-ray point sources in the galaxy, respectively. ", "Since the slope of the cumulative XLF $\\gamma < 1$ for the Merger/Irr and spiral galaxies, L$_{XP}$ is most sensitive to the upper limit L$_{max}$. Although L$_{min}$ and L$_{max}$ are different for each galaxy, in general, the ratio L$_{max}$/L$_{min}$ $\\gapprox$10$^2$ (see Figures 2 and 3), so that the L$_{max}$ term of the integral dominates over the L$_{min}$ term by factors $\\gapprox$5.0 and $\\gapprox$2.6, for the Merger/Irr and spiral galaxies, respectively. ", "This is quite interesting, since it implies that for galaxies with shallow XLFs, such as spiral galaxies, the most luminous point sources, such as the ULXs, dominated L$_{XP}$. Furthermore, for galaxies with several sources above 10$^{38}$ erg s$^{-1}$, observational measurements of L$_{XP}$ using very deep imaging data sensitive to very faint (e.g., $\\gapprox$10$^{36}$ erg s$^{-1}$) sources should give approximately the same value for L$_{XP}$ as a shorter observation sensitive to sources above $\\sim$10$^{37}$ erg s$^{-1}$. Therefore, we argue that the values we quote for L$_{XP}$ in Table 3 are reliable for the spiral and Merger/Irr galaxies.", "\n\nX-ray Color-color diagrams \\[ccdiagrams\\]\n-----------------------------------------\n\nX-ray color-color (CC) diagrams were constructed using net counts in three X-ray bands, soft (S – 0.3$-$1.0 keV), medium (M – 1.0$-$2.0 keV), and hard (H – 2.0$-$8.0 keV). ", "In our CC diagrams (Figure 4), we plot soft hardness $MS = (M - S)/(M + S)$ against hard hardness $HM = (H - M)/(H + M)$. The Poisson uncertainty in $HM$ and $MS$ is $\\lapprox$0.30 and $\\lapprox$0.35, respectively.[^3] Tabulated values of the net counts in each of the three bands, and hardness ratios, are listed in Table A1. ", "In Figure 5, we show a grid of the expected locations of X-ray sources, for a simple power-law model with foreground absorption. ", "X-ray colors were simulated using the response of BI CCD 7. ", "No foreground absorption corresponds to the lowest values of MS in the diagram, while increasing absorption pushes the source up, and eventually to the right, when the medium band (1.0$-$2.0 keV) begins to be affected by absorption. ", "In Figure 5, we show the areas of the CC diagram that would be occupied by three sample types of point sources found in galaxies: typical MW LMXBs, typical SMC HMXBs, which are much harder, and (spiral galaxy) ULXs, based on survey results from Church & Balucinska-Church (2001), Yokogawa (2002), Foschini et al. (", "2002), and Roberts et al. (", "2002).", "\n\nWe first examine the CC diagrams of the elliptical galaxies in Figure 4, since they seem to be the least complex. ", "Most of the point sources in the elliptical galaxies are consistent with the MW LMXBs (HM $\\sim$ $-$0.5), with little or no (N$_H <$ 3 $\\times$ 10$^{21}$ cm$^{-2}$) absorption. ", "Some of the sources have harder X-ray colors (HM $\\sim$0.25). ", "One would not expect HMXBs in elliptical galaxies, and we offer two explanations. ", "The harder sources are predominantly the faintest sources with a small number of total counts, so the uncertainties in their X-ray colors is larger than the other sources. ", "Since the scatter of the points in the CC diagram appears nearly symmetric, this seems like the most likely explanation. ", "A second consideration is that the MW LMXBs have lower X-ray luminosities (L$_X \\sim$ 10$^{36}$$-$10$^{38}$ erg s$^{-1}$) than the elliptical galaxy sources (L$_X \\gapprox$ 10$^{38}$ erg s$^{-1}$), so there could be an additional smaller population of very-luminous harder-spectrum LMXBs in elliptical galaxies.", "\n\nWe next turn to the spiral galaxies (see Figure 4). ", "There is noticeably more scatter in the CC diagram for the spiral galaxy sources than for the elliptical galaxy sources. ", "The scatter is from the lower left to the upper right of the diagram, as one would expect for point sources with absorption columns ranging from negligible to $\\sim$10$^{23}$ cm$^{-2}$. Most of the sources in the spiral galaxies are not consistent with the hard-spectrum SMC HMXBs, which generally have HM $\\sim$ 0.25. ", "Their colors are more consistent with an absorbed power-law spectrum with $\\Gamma \\approx$ 1$-$2. ", "Even the most luminous sources (the ULXs, which are filled circles in Figure 4) in the spiral and Merger/Irr galaxies have soft ($\\Gamma \\sim$ 1$-$2) spectra. ", "As mentioned in section 4.2, the most luminous X-ray point sources dominate L$_{XP}$ in the spiral and Merger/Irr galaxies, and, for most galaxies, this corresponds to point sources with L$_X >$ 10$^{38}$ erg s$^{-1}$ (see XLFs in Figure 4). ", "For convenience, in Figure 6, we show a CC diagram for only the sources with L$_X >$ 10$^{38}$ erg s$^{-1}$ in the spiral and Merger/Irr galaxies. ", "From this plot, it is quite obvious that hard-spectrum ($\\Gamma \\approx$ 0.5$-$1) HMXBs are not dominating L$_{XP}$ in these galaxies. ", "The point-source luminosity L$_{XP}$ in these two galaxy groups are ostensibly dominated by young (pop I) X-ray sources, so exactly what type of soft-spectrum sources are those that are plotted in Figure 6? ", "Obviously, the ULXs (filled circles) will dominate L$_{XP}$ when they are present; however, ULXs are generally present in only one of every $\\sim$5 disk galaxies (e.g. Sipior 2003). ", "The sources with L$_X \\approx$ 10$^{38}$$-$10$^{39}$ erg s$^{-1}$ occupy essentially the same regions of the CC diagram as the ULXs, i.e., [ *spectrally, there is no distinction between these two types of objects.*]{}", "\n\nWe can examine the spectral properties of well-studied (i.e. the nearest) luminous HMXBs to see if they are consistent with the hardness ratios of the spiral galaxy sources. ", "In Table 5, we list all of the HMXBs with L$_X \\ge$ 10$^{38}$ erg s$^{-1}$, as listed in the XRB catalog of Guseinov et al. (", "2000; v0.1, URL: [www.xrbc.org]{}). ", "These nine objects are the most luminous HMXBs in the MW and Magellanic Clouds. ", "There are three Be/transient sources, three accretion-powered X-ray pulsars, two black hole candidates, and Cyg X-3, which is not well categorized. ", "We also list the photon power law index $\\Gamma$ from a simple absorbed power-law fit, even for those XRBs with complex X-ray spectral models (see Table 5 footnote).", "\n\nTwo of the three HMXB transients have hard spectra ($\\Gamma \\lapprox$ 1), similar to the SMC HMXBs plotted in Figure 5. ", "The transient EXO 2030$+$375 is soft ($\\Gamma \\sim$ 1.8) during outburst, but hardens to $\\Gamma \\sim$ 1 as it fades to $\\sim$10$^{37}$ erg s$^{-1}$ (e.g., Reig & Coe 1999). ", "The accretion-powered NS HMXBs (SMC X-1, LMC X-4, and Cen X-3) have high and low states that are similar to those of the BH HMXB Cyg X-1 (high/soft and low/hard), but they have much harder spectra in their high states ($\\Gamma_{high} \\sim$ 1, compared to $\\Gamma_{high} \\sim$ 2.5 for Cyg X-1). ", "The two black-hole candidate (BHC) HMXBs LMC X-3 and LMC X-1 have high states with $\\Gamma \\sim$ 2$-$3, similar to Cyg X-1. ", "Cyg X-3 has a relatively soft spectrum ($\\Gamma \\sim$ 2) in its high state, which hardens to $\\Gamma \\sim$ 1 in its low state, when the X-ray flux is reduced by a factor of $\\sim$2 (White & Holt 1982).", "\n\nAlthough a sample of nine luminous HMXBs is not a large sample, it is clear that the different types of very-luminous HMXBs have fairly unique spectral properties. ", "Based on the CC diagram in Figure 6, the dominant X-ray sources in the spiral and Merger/Irr groups are generally inconsistent with accretion-powered NS HMXBs, which have $\\Gamma \\lapprox$ 1. ", "They are more consistent with BHC HMXBs, such as LMC X-3 and LMC X-1 in their soft state, with $\\Gamma \\sim$ 2$-$3. ", "It is not clear what fraction of L$_{XP}$ from spiral and starbursting galaxies is from HMXB transients. ", "If we could extrapolate from the MW and Magellanic Cloud HMXBs listed in Table 5, the accretion-powered (non-transient) HMXBs should dominate the soft-spectrum X-ray luminosity, since the X-ray luminosity of EXO 2030$+$375 is only $\\sim$1/6 that of the combined X-ray luminosity of the “soft” accretion-powered HMXBs LMC X-3, LMC X-1, and Cyg X-3.", "\n\nAs we note in section 4.2, the pop II X-ray sources have a steeper XLF, and thus “normal” pop I BH HMXBs and pop I ULXs should dominate L$_{XP}$ in the spiral and Merger/Irr galaxies. ", "It is important to note that many of the ULXs may, in fact, be pop I BH HMXBs (e.g. King 2002), and, until ULXs are better understood, one should allow that there may be a substantial overlap between these two classes. ", "In other words, ULXs are not necessarily distinct from the many known types of XRBs.", "\n\nWe conclude that the total point-source luminosity in spiral and starburst galaxies is [*not*]{} simply dominated by accretion powered, hard-spectrum NS HMXBs from the young stellar population. ", "It is dominated by the very-luminous, soft-spectrum accretion-powered BH HMXBs, and soft-spectrum ULXs. ", "These sources seem to have knowledge of (and are correlated with) both the current SFR, as measured by L$_{FIR}$ and L$_{FIR+UV}$, and the mass of the galaxy, as measured by L$_B$ and L$_{K}$. Since [*the exact nature of ULXs are not well known*]{} and they will dominate L$_{XP}$, if present, it is premature to say that the X-ray emission from the young stellar population is dominated by “high-mass X-ray binaries” (e.g. Grimm et al. ", "2003).", "\n\nBy inspecting the locations of the ULXs in the CC diagrams in Figure 4, one notices that, whereas the ULXs in the elliptical galaxies are clustered near HM $\\sim$ $-$0.4, the ULXs in the Merg/Irr and Spiral groups are slightly harder in HM. ", "For example, there are no ULXs with HM $<$ $-$0.4 in the spiral group. ", "This could possibly be a result of obscuration by the gas in spirals, but this would require the ULXs to be highly obscured. ", "As our simulations in Figure 5 (top left plot) show, absorption columns $\\gapprox$10$^{22}$ cm$^{-2}$ are required to increase HM by a factor $\\gapprox$0.4. ", "Alternatively, this could be a manifestation of two physically different types of ULXs (e.g., King 2002).", "\n\nDiscussion\n==========\n\nSummary of Results\n------------------\n\nIn the previous section, we showed that the total [*point source*]{} X-ray luminosity L$_{XP}$ is indeed correlated with properties of the host galaxy that are associated with the mass and SFR in the galaxy. ", "Based on the XRB populations in our Galaxy, one might therefore suppose that the correlations merely represent an extrapolation of the total X-ray luminosity from the LMXB and HMXB populations, scaled to the galaxy mass and SFR (e.g., Grimm et al. ", "2002). ", "Using X-ray color-color diagrams, we showed that the SFR component of L$_{XP}$ is dominated by soft-spectrum BH HMXBs and ULXs, not hard-spectrum NS HMXBs. ", "Since ULXs are not present in our Galaxy, X-ray studies of external galaxies are necessary to understand their effect on X-ray point source populations. ", "Since we can actually measure the correlation between L$_{XP}$ and either L$_K$ or L$_{FIR+UV}$, both the mass and SFR components of L$_{XP}$ are significantly strong. ", "Since the slope $\\gamma$ of the XLFs is shallow for the spiral galaxies, the most luminous point sources (i.e., BH HMXBs and ULXs with L$_X \\gapprox$ 10$^{38}$ erg s$^{-1}$) dominate L$_{XP}$. We emphasize that the ULX distinction is purely based on X-ray luminosity and does not necessarily represent a unique, or homogeneous class of objects. ", "For the spiral and Merger/Irr galaxies, we find no particular distinction between the X-ray colors of the ULXs and the less luminous point sources with L$_X \\approx$ 10$^{38}$$-$10$^{39}$ erg s$^{-1}$. As our CC diagrams show, the X-ray colors of the point sources are generally consistent with LMXBs or ULXs, not hard-spectrum NS HMXBs, such as accretion-powered X-ray pulsars. ", "This is also true of the most luminous point sources (e.g., the ULXs).", "\n\nMulti-variate Correlations Between L$_{XP}$ and Host Galaxy Luminosities\n------------------------------------------------------------------------\n\nWe would like to deconvolve L$_{XP}$ into two components, one from the older stellar population (including LMXBs), and another from the younger stellar population (including HMXBs). ", "We assume the old and young components are directly related to the mass and SFR of the galaxy, respectively, and initially explore a simple relationship between L$_{XP}$ and the host galaxy K and FIR+UV luminosities, which are reasonable proxies for the mass and SFR.", "\n\nWe use the simple linear relationship $$L_{XP} = A L_{K} + B L_{FIR+UV}, \\eqno(3)$$ where $A$ and $B$ are dimensionless constants. ", "We have used $\\chi^2$ fitting to estimate A and B and their uncertainties.[^4] The best fit values of $A$ and $B$ are listed in Table 6. ", "Since star formation is negligible in the elliptical galaxies, we can also estimate $A$ directly from L$_{XP}$ by ignoring the SFR term. ", "If we omit the peculiar elliptical galaxy NGC 5128 (Cen A), which has ongoing star-formation, $\\chi^2-$fitting yields $A =$ 1.26$^{+0.30}_{-0.31}$ $\\times$ 10$^{-4}$. This value for ellipticals is $\\sim$20% larger than that found from multi-variate $\\chi^2$ fitting for samples involving Merger/Irr and Spiral galaxies (see Table 6), although the two values are consistent within the uncertainties. ", "Since AGN emission in the K, FIR and FUV bands has not been subtracted from any of the host galaxy luminosities, we computed $A$ and $B$ for two subsamples of galaxies without AGNs, and arrive at a slightly smaller (larger) value for $A$ ($B$) than if AGNs are included. ", "If the elliptical galaxies are also omitted from the sample, the best fit value of $A$ is also lower. ", "We then suggest that the value of $A$ for early-type and elliptical galaxies is inherently different from that in late-type galaxies.", "\n\nThe fact that $A$ and $B$ are the same order of magnitude, and that L$_K$ and L$_{FIR+UV}$ are also the same order of magnitude, supports our earlier statement that both the old (mass) and young (SFR) component can contribute significantly to L$_{XP}$.\n\nWe conclude, based on our best fit to the Merger/Irr plus spiral sample without AGNs, that the the point-source X-ray luminosity L$_{XP}$ in Merger/Irr and spiral galaxies can be reliably estimated from: $$L_{XP} = (0.9\\pm0.1) \\times 10^{-4} L_K + \n (0.5\\pm0.1) \\times 10^{-4} L_{FIR+UV}, \\eqno(4)$$ and that L$_{XP}$ for elliptical galaxies can be estimated from $$L_{XP} = (1.3\\pm0.3) \\times 10^{-4} L_K. \\eqno(5)$$\n\nThe robustness of this formula for the Merger/Irr and spiral galaxies can be seen in Figure 7 (top), where we plot L$_{XP}$ against the estimated value using equation 4. ", "The Merger/Irr galaxies and Spiral galaxies are both in good agreement, although L$_{XP}$ for the elliptical galaxies is under-estimated. ", "As we argue in the next section, the larger (M/L)$_K$ ratio for ellipticals (see Table 7) should likely cause the $A$ value for ellipticals and spirals to be inherently different.", "\n\nWe note that the reduced-$\\chi^2$, $\\chi^2_\\nu$, for all of the fits (see Table 6) is highly sensitive to the estimated errors in the luminosity uncertainties, which are not well defined. ", "Therefore, we do not use $\\chi^2_\\nu$ as an absolute measure of the goodness of fit. ", "We also note that the ranges of $A$ for spirals and ellipticals overlap, and we cannot rigorously show that the values of $A$ are different for ellipticals and spirals, although, as we show in the next section, the effect from including an M/L correction is very noticeable.", "\n\nMulti-variate Correlations between L$_{XP}$ and M and SFR\n---------------------------------------------------------\n\nWe next write L$_{XP}$ in terms of the mass M and SFR of the galaxy $$L_{XP} = \\alpha M + \\beta SFR, \\eqno(6)$$ where L$_{XP}$, M, and SFR have units erg s$^{-1}$, M$_\\odot$, and M$\\odot$ yr$^{-1}$, respectively, and $\\alpha$ and $\\beta$ are constants with the appropriate units.", "\n\nWe use the optical/NIR B$-$K color and the K-band luminosity (Table 2) to estimate the mass of the sample galaxies, and L$_{FIR+UV}$ to estimate the SFR. ", "Bell & de Jong (2001) list correlation coefficients for M/L ratios as a function of optical and NIR colors. ", "We use the coefficients for their formation model with bursts. ", "The SFR can be estimated from L$_{FIR+UV}$ if we assume L$_{FIR+UV}$ is a “corrected” IRAS FIR luminosity. ", "We use a proportionality constant of 5.7 $\\times$ 10$^{-44}$ M$_\\odot$ yr$^{-1}$ (erg s$^{-1}$)$^{-1}$, which includes a bolometric correction of 1.4 from the IRAS FIR band (Meurer et al. ", "1999). ", "The resulting values for SFR, (M/L)$_K$ and $M$ are listed in Table 7.", "\n\nAgain, we find $\\alpha$ and $\\beta$ and their uncertainties using minimum-$\\chi^2$ techniques. ", "The uncertainties in M and SFR were computed from the uncertainties in all of the luminosities (or magnitudes) used in computing M and SFR. ", "In Table 6, we list the resulting values for the Merger/Irr plus spirals sample (omitting AGNs). ", "We find that the mass-component constant $\\alpha$ is slightly different for the elliptical and spiral samples, but this time $\\alpha$ is smaller for the ellipticals, although both $\\alpha$ values are consistent within their uncertainties. ", "As can be seen in Figure 7 (bottom), with the M/L correction applied, the simulated value of L$_{XP}$ now agrees better with the observed value. ", "The simulated value of L$_{XP}$ for the elliptical galaxies is now much closer to the observed value (compare top and bottom plots in Figure 7). ", "This indicates that $\\alpha =$ 1.25 $\\times$ 10$^{29}$ erg s$^{-1}$ M$_\\odot^{-1}$ is a [*universal constant*]{} for estimating the point-source X-ray luminosity from the older stellar population.", "\n\nThus, we find the following empirical relationship to hold for high-SFR/M Merger/Irr galaxies, spiral galaxies, and low-SFR/M elliptical galaxies: $$L_{XP}(erg~s^{-1}) = (1.3\\pm0.2) \\times 10^{29} M(M_\\odot) + \n (0.7\\pm0.2) \\times 10^{39} SFR(M_\\odot~yr^{-1}) \\eqno(7).$$\n\nAs noted in the caption to Figure 7, the observed values for L$_{XP}$ for the two starburst galaxies NGC 4449 and NGC 4038/9 are in excess of the values predicted by Equations (4) and (7), by factors of $\\approx$4 and $\\approx$5, respectively. ", "Since L$_{XP}$ is dominated by the $SFR$ component for starburst galaxies, an error in the $SFR$ by $\\sim$4$-$5 would be needed to “correct” the problem. ", "This is unlikely. ", "Poisson uncertainty in the number of high-luminosity sources (which dominate L$_{XP}$) could possible explain the excess, but it is also possible that these two starburst galaxies have significantly high efficiency for forming luminous BH HMXBs and ULXs. ", "It is interesting that NGC 4038/9 is a merging system and NGC 4449 has evidence for two physical counter-rotating systems within the galaxy (Sabbadin et al. ", "1984). ", "More extensive tests would be needed to determine if merger activity is really responsible for the abnormally high values of L$_{XP}$ in these two galaxies.", "\n\nThe Linearity of L$_{XP}$, $M$, and $SFR$\n-----------------------------------------\n\nIn order to test the linear form we have assumed in Equation (7), we performed a number of tests. ", "A least-squares fit between $logL_{XP}$ and $logM$ for the eight elliptical galaxies in our sample with no star formation (NGC 5128 omitted) implies a best fit for $L_{XP} \\propto M^{0.99}$ (r $=$ 0.89). ", "A more rigorous test from a multi-variate fit to the sample of 18 Merg/Irr and spiral galaxies without AGN gives the best fit for the mass component of L$_{XP} \\propto M^{1.01}$ (See Figure 9). ", "Therefore, we can argue with good confidence that the pop II component of L$_{XP}$ is essentially linear in $M$. Similarly, a multi-variate fit to $L_{XP} = \\alpha M + \\beta SFR^{p_{SFR}}$ gives a best fit for p$_{SFR} =$ 1.06, with a 90% confidence range of 0.85$-$1.25 (for three free parameters: $\\Delta\\chi^2 <$ 6.25; see Figure 9). ", "We arrive at the a very similar result ($p_{SFR} =$ 1.09) if we use only the five Merger/Irr galaxies, which have a very weak mass component, and fit $log($L$_{XP})$ against $log(SFR)$ ($r =$ 0.94). ", "Thus, within the uncertainties, [*we find L$_{XP}$ to be linear in both the mass and the star-formation rate.*]{}", "\n\nNature of the ULXs\n------------------\n\nAs mentioned previously, we assume the mass component of L$_{XP}$ is from point sources from an older stellar population (including LMXBs), and the SFR component is from point sources from a younger stellar population (including HMXBs). ", "It is not known if ULXs, which can dominate L$_{XP}$ (section 4.2), are predominantly associated with older or younger stellar population, or are a largely heterogeneous group (e.g., King 2002). ", "Thus, they could contribute significantly in either component. ", "We know that ULXs exist in elliptical galaxies (e.g. Colbert & Ptak 2002). ", "If LMXBs are formed in globular clusters (e.g. Kundu et al. ", "2003), pop II ULXs might also be formed in the same environment. ", "On the other hand, in the high-SFR galaxy pair NGC 4038/9 (The “Antennae”), L$_{FIR}$ is very high and an extraordinarily large number of ULXs are found (Fabbiano, Zezas & Murray 2001), suggesting that the ULXs in the Antennae are associated with the young stellar population. ", "So what about ULXs in the normal spirals, in which old and young stellar populations (ie the K and FIR+UV luminosities) can be comparable?", "\n\nIn Figure 8, we plot the fraction of L$_{XP}$ from the younger stellar population against galaxy morphological type. ", "As expected, in late-type galaxies with high SFR/M ratios, the SFR term dominates, and in early-type galaxies, the mass term dominates. ", "This plot also shows that the older population contributes $\\approx$20$-$90% of L$_{XP}$ in Merger/Irr and spiral galaxies. ", "As described in section 4.2, since the slope of the XLF for these groups is shallow ($\\gamma \\lapprox$ 1), the most luminous X-ray point sources dominate L$_{XP}$. This would imply that, if the old and young components of the XLF have exactly the same shape, $\\sim$20$-$90 percent of the ULXs are from the older population. ", "However, this is not likely to be the case since the XLFs for older point sources in the elliptical galaxies is much steeper than the XLFs for old+young point sources in the spirals, and many of the ULXs are from the younger population. ", "However, it does suggest that type II (pop II) ULXs could have significant numbers in spiral galaxies. ", "Since we now know that L$_{XP}$ from the older stellar population is proportional to the galaxy mass $M$, we can estimate the fraction of type II ULXs in spirals by scaling the number found in ellipticals by the galaxy mass $M$. If we exclude NGC 5128 since it has ongoing star formation, the total mass of the remaining eight ellipticals is 1.06 $\\times$ 10$^{12}$ M$_\\odot$, and eleven ULXs are found. ", "This implies an expected 1.0 $\\times$ 10$^{-11}$ ULXs M$_\\odot^{-1}$, with a Poisson error of 30%. ", "The total mass of all of the Merg/Irr and spiral galaxies is 6.6 $\\times$ 10$^{11}$ M$_\\odot$, so we expect $\\approx$5$-$9 pop II ULXs to be found. ", "A total of 32 ULXs were detected, implying that, on average, [*$\\sim$15$-$25% of the ULXs in Merger/Irr and spiral galaxies are pop II ULXs.*]{} ", "The same calculation for the Merger/Irr and spiral galaxy samples alone yield rates of $\\sim$5$-$10% and $\\sim$25$-$50% of pop II ULXs for the “high-SFR/M” Merger/Irr galaxies, and normal spirals, respectively.", "\n\nSummary and Conclusions\n=======================\n\nWe have used archival and proprietary Chandra ACIS data for 32 spiral, elliptical, and Merger/Irr (starburst) galaxies to study X-ray point source populations, and how they depend on properties of the host galaxy. ", "A total of 1441 X-ray point sources are analyzed here, using the CPU-intensive XASSIST data reduction scripts (Ptak & Griffiths 2003) to rigorously verify the validity of the point sources.", "\n\nThe total [*point-source*]{} X-ray (0.3$-$8.0 keV) luminosity L$_{XP}$ is well correlated with the B-band, K-band, and FIR+UV luminosities of spiral host galaxies, and is well correlated with the B-band and K-band luminosities for elliptical galaxies. ", "This has been known for some time, and it suggests an intimate connection between L$_{XP}$ and both the old and young stellar populations, for which K and FIR+UV luminosities are reasonable proxies for the galaxy mass $M$ and star-formation rate $SFR$.\n\nWe derive proportionality constants $\\alpha =$ 1.3 $\\times$ 10$^{29}$ erg s$^{-1}$ M$_\\odot^{-1}$ and $\\beta =$ 0.7 $\\times$ 10$^{39}$ erg s$^{-1}$ (M$_\\odot$ yr$^{-1}$)$^{-1}$, which can be used to estimate the old and young components from $M$ and $SFR$, respectively.", "\n\nThe cumulative X-ray luminosity functions for the point sources have significantly different slopes. ", "For the spiral and starburst galaxies, $\\gamma \\approx$0.6$-$0.8, and for the elliptical galaxies, $\\gamma \\approx$1.4. ", "This implies that [*the most luminous point sources – those with L$_X \\gapprox$ 10$^{38}$ erg s$^{-1}$ — dominate L$_{XP}$ for the spiral and starburst galaxies.*]{} ", "We find that L$_{XP}$ depends [*linearly*]{} (within uncertainties) on both $M$ and $SFR$, for our sample galaxies ($M \\lapprox$ 10$^{11}$ M$_\\odot$ and $SFR \\lapprox$ 10 M$_\\odot$ yr$^{-1}$).", "\n\nMost of the point sources have X-ray colors that are consistent with soft-spectrum ($\\Gamma \\sim$ 1$-$2) low-mass X-ray binaries (XRBs), accretion-powered black-hole high-mass (BH HMXBs), or Ultra-Luminous X-ray sources (ULXs a.k.a. ", "IXOs). ", "We rule out hard-spectrum neutron-star HMXBs (e.g. accretion-powered X-ray pulsars) as contributing much to L$_{XP}$. Thus, for spirals, L$_{XP}$ is dominated by ULXs and BH HMXBs. ", "We find no discernible difference between the X-ray colors of ULXs (L$_X \\ge$ 10$^{39}$ erg s$^{-1}$) in spiral galaxies and point sources with L$_X \\approx$ 10$^{38}$$-$10$^{39}$ erg s$^{-1}$, suggesting ULXs in spiral galaxies could be predominantly BH HMXBs. ", "This would not be surprising, since ULXs are defined purely by their X-ray luminosity, and not by their accretion mode, or type of companion star. ", "More work on ULXs is needed to test whether most are simply a special mode of a “normal” stellar-mass BH XRB (e.g. King 2002), or exotic accreting intermediate-mass BH systems (e.g. Colbert & Mushotzky 1999).", "\n\nWe estimate that $\\gapprox$20% of all ULXs found in spirals originate from the older (pop II) stellar populations, indicating that many of the ULXs that have been found in spiral galaxies are in fact pop II ULXs, like those in elliptical galaxies.", "\n\nWe thank the anonymous referee for many helpful suggestions that helped to improve the quality of the paper. ", "We are grateful to T. Jarrett for providing 2MASS K$_s$ magnitudes from the Large Galaxy Atlas before publication. ", "We thank A. Zezas, T. Roberts, T. Yaqoob and A. Prestwich for helpful discussions, and T. Budavari for expert help with SED fitting. 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J. 1999, MNRAS, 302, 700 Rice, W., et al. ", "1988, ApJS, 68, 91 Rifatto, A., Longo, G., & Capaccioli, M. 1995, A&AS, 114, 527 Roberts, T. P., Goad, M. R., Ward, M. J., Warwick, R. S., & Lira, P. 2002, in “New Visions of the X-ray Universe in the XMM-Newton and Chandra Era,” (ESTEC: The Netherlands) (astro-ph/0202017) Sabbadin, F., Ortolani, S., & Bianchini, A., 1984, A&A, 131, 1 Sandage, A., & Tammann, G. A. 1981, Revised Shapley-Ames Catalog of Bright Galaxies (Carnegie Institute of Washington Publication 635) Sarazin, C. L., Irwin, J. A., & Bregman, J. N. 2001, ApJ, 556, 533 Sipior, M. 2003, Ph. ", "D. Thesis, The Pennsylvania State University Soifer, B. T., Boehmer, L., Neugebauer, G., & Sanders, D. B. 1989, AJ, 98, 766 Swartz, D. A., Ghosh, K. K., McCollough, M. L., Pannuti, T. G., Tennant, A. F., & Wu, K. 2003, ApJS, 144, 213 Thronson, H. A., Jr., Hunter, D. A., Telesco, C. M., Decher, R., & Harper, D. A. 1987, ApJ, 317, 180 Tully, R. B. 1988, Nearby Galaxies Catalog (Cambridge: Cambridge Univ. ", "Press) White, N. E., & Holt, S. S. 1982, ApJ, 257, 318 Wu, K. 2001, PASA, 18, 443 Yokogawa, J., 2002, Ph. ", "D. Thesis, Kyoto University Yokogawa, J., Torii, K., Kohmura, T., & Koyama, K. 2001, PASJ, 53, 227\n\n**Figures are not included here. ", "Please download full manuscript from the following website for version with figures. ", "Sorry. ", "This URL is also listed in the notes to the astro-ph abstract, so you may be able to just click on it there.**", "\n\nhttp://www.pha.jhu.edu/$\\sim$colbert/chps\\_accepted.ps\n\n[llrccr]{} NGC 1569 & & 782 & 7 & 85.1 & 12\\\nNGC 3034 & M82 & 361 & 0/1/2/3 & 33.2/32.8/33.1/33.0 & 27\\\nNGC 4038/9 & Antennae & 315 & 6/7 & 72.1/70.2 & 65\\\nNGC 4449 & & 2031 & 7 & 26.2 & 22\\\nNGC 5253 & & 2032 & 7 & 46.7 & 10\\\nNGC 253 & & 969 & 2/3/6/7 & 13.9/13.9/13.9/11.8 & 49\\\nNGC 628 & M74 & 2057 & 6/7 & 46.2/44.7 & 60\\\nNGC 1291 & & 2059 & 6/7 & 11.2/12.0 & 56\\\nNGC 2681 & & 2061 & 7 & 78.3 & 17\\\nNGC 3079 & & 2038 & 7 & 26.3 & 17\\\nNGC 3184 & & 804 & 7 & 37.1 & 45\\\nNGC 3628 & & 2039 & 7 & 54.8 & 32\\\nNGC 4244 & & 942 & 7 & 48.1 & 3\\\nNGC 4258 & M106 & 350 & 6/7 & 14.0/13.9 & 26\\\nNGC 4314 & & 2062 & 7 & 8.3 & 12\\\nNGC 4579 & M58 & 807 & 7 & 32.8 & 8\\\nNGC 4631 & & 797 & 6/7 & 59.1/57.6 & 25\\\nNGC 4736 & M94 & 808 & 7 & 47.3 & 28\\\nNGC 4945 & & 864 & 6/7 & 35.2/5.1 & 36\\\nNGC 5194/5 & M51a/b & 354 & 6/7 & 14.8 & 52\\\nNGC 5236 & M83 & 793 & 6/7 & 50.9/48.2 & 84\\\nNGC 5457 & M101 & 934 & 2/3/5/6/7 & 98.1/98.1/96.3/98.2/95.6 & 140\\\nNGC 6503 & & 872 & 7 & 9.1 & 7\\\nNGC 1395 & & 799 & 3 & 22.2 & 30\\\nNGC 1399 & & 319 & 7 & 55.5 & 100\\\nNGC 3379 & M105 & 1587 & 7 & 31.0 & 35\\\nNGC 4374 & M84 & 803 & 7 & 28.3 & 28\\\nNGC 4472 & M49 & 321 & 6/7 & 39.2/33.8 & 78\\\nNGC 4636 & & 323 & 7 & 45.2 & 37\\\nNGC 4649 & M60 & 785 & 6/7 & 36.7/22.3 & 98\\\nNGC 4697 & & 784 & 7 & 39.0 & 69\\\nNGC 5128 & Cen A & 316 & 0/1/2/3 & 35.5/35.3/35.4/35.5 & 133\\\n\n[lccccccccc]{} NGC 1569 & 1.6 & Sm & & 42.2 & 41.3 & 41.8 & 40.3 & 0.4 & 3.6\\\nNGC 3034 & 5.2 & I0 & & 43.4 & 43.6 & 44.2 & 41.7 & 6.0 & 4.0\\\nNGC 4038/9 & 21.7 & Sc/Sc (tides) & & 44.3 & 43.8 & 44.1 & 43.4 & 0.7 & 2.2\\\nNGC 4449 & 3.0 & Sm & & 42.5 & 42.0 & 42.4 & 42.1 & 0.7 & 3.6\\\nNGC 5253 & 3.2 & I0 & & 42.4 & 41.7 & 42.2 & 41.9 & 0.7 & 5.5\\\nNGC 253 & 3.0 & Sc & & 43.7 & 43.5 & 43.6 & 41.8 & 0.9 & 1.4\\\nNGC 628 & 9.7 & Sc & & 43.6 & 43.1 & 43.2 & 42.8 & 0.4 & 1.7\\\nNGC 1291 & 8.6 & SBa & & 43.7 & 43.6 & 42.1 & 42.1 & 0.02 & 0.06\\\nNGC 2681 & 13.3 & Sa & & 43.4 & 43.3 & 42.9 & 41.9 & 0.3 & 0.5\\\nNGC 3079 & 15.0 & Sc pec: & S2 & 43.7 & 43.5 & 43.8 & 42.2 & 1.3 & 2.4\\\nNGC 3184 & 8.7 & Sc & & 43.3 & 42.9 & 42.8 & 42.6 & 0.3 & 1.3\\\nNGC 3628 & 7.7 & Sbc & & 43.6 & 43.3 & 43.3 & 42.4 & 0.5 & 1.1\\\nNGC 4244 & 3.1 & Scd & & 42.8 & 41.8 & 41.6 & 41.6 & 0.06 & 1.3\\\nNGC 4258 & 6.8 & Sb & S1.9 & 43.8 & 43.5 & 43.0 & 42.4 & 0.2 & 0.4\\\nNGC 4314 & 9.7 & SBa & & 43.0 & 43.0 & 42.4 & 41.6 & 0.2 & 0.3\\\nNGC 4579 & 20.3 & Sab & S1.9/L1.9 & 44.0 & 44.0 & 43.3 & 42.7 & 0.2 & 0.2\\\nNGC 4631 & 6.9 & Sc & & 43.8 & 43.1 & 43.3 & 42.9 & 0.3 & 2.3\\\nNGC 4736 & 4.3 & RSab & & 43.3 & 43.2 & 42.9 & 42.3 & 0.4 & 0.6\\\nNGC 4945 & 5.2 & Sc & AGN & 44.0 & 43.7 & 43.8 & 41.7 & 0.6 & 1.4\\\nNGC 5194/5 & 7.7 & Sbc/SB & S2 & 43.9 & 43.8 & 43.3 & 43.1 & 0.2 & 0.5\\\nNGC 5236 & 4.7 & SBc & & 43.7 & 43.5 & 43.2 & 42.5 & 0.4 & 0.7\\\nNGC 5457 & 5.4 & Sc & & 43.7 & 43.1 & 43.3 & 43.4 & 0.4 & 3.2\\\nNGC 6503 & 6.1 & Sc & & 43.1 & 42.7 & 42.4 & 42.0 & 0.2 & 0.8\\\nNGC 1395 & 22.7 & E2 & & 44.0 & 43.9 & 41.6 & 42.3 & 0.003 & 0.03\\\nNGC 1399 & 19.3 & E1 & & 43.9 & 44.0 & 41.3 & 42.5 & 0.002 & 0.03\\\nNGC 3379 & 8.1 & E0 & & 43.3 & 43.3 & $<$40.3 & 41.7 & $<$0.001 & $<$0.02\\\nNGC 4374 & 16.8 & E1 & & 44.0 & 44.0 & 42.0 & 42.4 & 0.01 & 0.04\\\nNGC 4472 & 16.8 & E1/S0 & S2:: & 44.3 & 44.3 & $<$41.1 & 42.8 & $<$0.0006 & $<$0.03\\\nNGC 4636 & 14.6 & E0/S0 & & 43.7 & 43.7 & 41.2 & 42.4 & 0.003 & 0.05\\\nNGC 4649 & 14.9 & S0 & & 44.0 & 44.1 & 42.0 & 42.5 & 0.01 & 0.03\\\nNGC 4697 & 16.5 & E6 & & 43.9 & 43.9 & 42.0 & 42.3 & 0.01 & 0.04\\\nNGC 5128 & 4.9 & S0+S pec & AGN & 44.0 & 43.8 & 43.4 & 42.5 & 0.3 & 0.4\\\n\n[lcccclclc]{} NGC 1569 & 21.4 & 35.4 & 37.9 & 0.00 & 0.00(0) & 0.00 & 0.00(0) & $-$3.4\\\nNGC 3034 & 20.6 & 36.9 & 40.0 & 0.97 & 0.56(15) & 0.61 & 0.11(3) & $-$3.6\\\nNGC 4038/9 & 20.6 & 37.7 & 40.8 & 0.99 & 0.82(53) & 0.77 & 0.22(14) & $-$3.0\\\nNGC 4449 & 20.1 & 36.3 & 39.0 & 0.66 & 0.14(3) & 0.00 & 0.00(0) & $-$3.0\\\nNGC 5253 & 20.6 & 36.2 & 38.0 & 0.00 & 0.00(0) & 0.00 & 0.00(0) & $-$3.6\\\nNGC 253 & 20.2 & 36.7 & 39.4 & 0.65 & 0.12(6) & 0.00 & 0.00(0) & $-$4.1\\\nNGC 628 & 20.7 & 37.2 & 39.6 & 0.54 & 0.15(9) & 0.00 & 0.00(0) & $-$3.6\\\nNGC 1291 & 20.3 & 37.6 & 39.7 & 0.65 & 0.23(13) & 0.00 & 0.00(0) & $-$3.8\\\nNGC 2681 & 20.4 & 37.2 & 39.7 & 0.93 & 0.53(9) & 0.59 & 0.12(2) & $-$3.6\\\nNGC 3079 & 19.9 & 37.7 & 39.6 & 0.84 & 0.41(7) & 0.43 & 0.06(1) & $-$3.8\\\nNGC 3184 & 20.0 & 37.1 & 39.4 & 0.44 & 0.07(3) & 0.00 & 0.00(0) & $-$3.5\\\nNGC 3628 & 20.3 & 36.8 & 39.5 & 0.71 & 0.09(3) & 0.63 & 0.03(1) & $-$3.9\\\nNGC 4244 & 20.2 & 36.1 & 37.6 & 0.00 & 0.00(0) & 0.00 & 0.00(0) & $-$4.2\\\nNGC 4258 & 20.1 & 37.3 & 39.6 & 0.83 & 0.42(11) & 0.00 & 0.00(0) & $-$3.8\\\nNGC 4314 & 20.3 & 37.9 & 39.0 & 0.66 & 0.33(4) & 0.00 & 0.00(0) & $-$3.9\\\nNGC 4579 & 20.4 & 37.9 & 40.2 & 1.00 & 1.00(8) & 0.87 & 0.25(2) & $-$3.8\\\nNGC 4631 & 20.1 & 36.7 & 39.5 & 0.86 & 0.20(5) & 0.53 & 0.04(1) & $-$3.6\\\nNGC 4736 & 20.2 & 36.4 & 39.6 & 0.90 & 0.29(8) & 0.55 & 0.07(2) & $-$3.6\\\nNGC 4945 & 21.2 & 37.6 & 39.8 & 0.88 & 0.39(14) & 0.39 & 0.06(2) & $-$3.8\\\nNGC 5194/5 & 20.2 & 37.4 & 40.0 & 0.84 & 0.33(17) & 0.33 & 0.04(2) & $-$3.8\\\nNGC 5236 & 20.6 & 36.5 & 39.8 & 0.69 & 0.17(14) & 0.18 & 0.01(1) & $-$3.7\\\nNGC 5457 & 20.1 & 36.3 & 39.8 & 0.66 & 0.06(8) & 0.25 & 0.01(1) & $-$3.4\\\nNGC 6503 & 20.6 & 37.4 & 39.1 & 0.85 & 0.43(3) & 0.00 & 0.00(0) & $-$3.6\\\nNGC 1395 & 20.3 & 38.4 & 40.2 & 1.00 & 1.00(30) & 0.49 & 0.10(3) & $-$3.7\\\nNGC 1399 & 20.1 & 37.6 & 40.4 & 0.91 & 0.74(74) & 0.23 & 0.03(3) & $-$3.6\\\nNGC 3379 & 20.4 & 37.1 & 39.5 & 0.73 & 0.23(8) & 0.00 & 0.00(0) & $-$3.8\\\nNGC 4374 & 20.4 & 37.8 & 40.2 & 0.98 & 0.86(24) & 0.63 & 0.04(1) & $-$3.8\\\nNGC 4472 & 20.2 & 37.7 & 40.3 & 0.96 & 0.87(68) & 0.14 & 0.03(2) & $-$4.0\\\nNGC 4636 & 20.3 & 37.5 & 39.6 & 0.69 & 0.49(18) & 0.00 & 0.00(0) & $-$4.1\\\nNGC 4649 & 20.3 & 37.8 & 40.2 & 0.80 & 0.56(55) & 0.07 & 0.01(1) & $-$3.9\\\nNGC 4697 & 20.3 & 37.6 & 40.1 & 0.86 & 0.58(40) & 0.11 & 0.01(1) & $-$3.8\\\nNGC 5128 & 20.9 & 36.9 & 40.1 & 0.66 & 0.19(25) & 0.15 & 0.01(1) & $-$3.8\\\n\n[lcccc]{} NGC 1569 & 36.0 & 37.5 & 5 & 0.44\\\nNGC 3034 & 37.5 & 39.5 & 20 & 0.57\\\nNGC 4038/9 & 38.0 & 40.0 & 53 & 0.63\\\nNGC 4449 & 37.0 & 38.4 & 12 & 0.70\\\nNGC 5253 & 36.5 & 37.7 & 8 & 0.92\\\nNGC 253 & 37.0 & 38.6 & 36 & 0.75\\\nNGC 628 & 37.5 & 38.6 & 38 & 1.11\\\nNGC 1291 & 37.7 & 38.9 & 31 & 1.16\\\nNGC 2681 & 37.8 & 39.2 & 10 & 0.65\\\nNGC 3079 & 37.5 & 39.2 & 17 & 0.80\\\nNGC 3184 & 37.5 & 38.7 & 20 & 1.15\\\nNGC 3628 & 37.0 & 39.3 & 28 & 0.82\\\nNGC 4244 & 36.6 & 37.5 & 3 & 0.46\\\nNGC 4258 & 37.5 & 38.8 & 23 & 0.79\\\nNGC 4314 & 37.7 & 38.2 & 7 & 1.20\\\nNGC 4579 & 38.5 & 40.1 & 5 & 0.47\\\nNGC 4631 & 37.0 & 39.2 & 23 & 0.69\\\nNGC 4736 & 37.2 & 39.1 & 19 & 0.55\\\nNGC 4945 & 37.6 & 39.1 & 22 & 0.70\\\nNGC 5194/5 & 37.7 & 39.1 & 29 & 0.78\\\nNGC 5236 & 37.5 & 39.0 & 34 & 0.91\\\nNGC 5457 & 37.0 & 39.2 & 68 & 0.85\\\nNGC 6503 & 37.5 & 38.7 & 4 & 0.37\\\nNGC 1395 & 38.3 & 39.7 & 22 & 1.05\\\nNGC 1399 & 38.0 & 39.4 & 79 & 1.26\\\nNGC 3379 & 37.8 & 39.0 & 12 & 1.07\\\nNGC 4374 & 38.0 & 38.6 & 26 & 1.16\\\nNGC 4472 & 38.5 & 39.2 & 19 & 1.63\\\nNGC 4636 & 38.0 & 38.6 & 22 & 2.36\\\nNGC 4649 & 38.0 & 39.0 & 62 & 1.58\\\nNGC 4697 & 38.0 & 39.1 & 39 & 1.34\\\nNGC 5128 & 38.0 & 39.2 & 28 & 1.28\\\n\n[lccccll]{} SMC X-2 & Be/T & 1 & ASCA & 0.7 & 1 & outburst\\\nA 0538$-$66 & Be/T & 6 & ASCA & 1.16 & 2 & outburst\\\nEXO 2030$+$375 & Be/T & 1 & EXOSAT & 1.83 & 3 & outburst\\\nSMC X-1 & AcPXP & 6 & ASCA & 1.05 & 4 & high state\\\nLMC X-4 & AcPXP & 6 & ASCA & 0.70 & 4 & high state\\\nLMC X-3 & BHC & 3 & RXTE & 1.8 & 5 & high state\\\nLMC X-1 & BHC & 2 & RXTE & 2.9 & 5 & high state\\\nCen X-3 & AcPXP & 1 & BBXRT & 1.1 & 6 & high state\\\nCyg X-3 & ? & ", "1 & & $\\sim$2 & 7 & high state\\\n& & 0.4 & & $\\sim$1 & 7 & low state\\\n\n[llrllrl]{} 1.26$^{+0.30}_{-0.31}$ & [...]{} & 0.81 & 0.88$^{+0.22}_{-0.21}$ & [...]{} & 0.90 & Elliptical galaxies only (8)\\\n1.11$^{+0.11}_{-0.11}$ & 0.31$^{+0.10}_{-0.10}$ & 4.61 & 1.05$^{+0.11}_{-0.11}$ & 0.74$^{+0.15}_{-0.15}$ & 3.79 & All galaxies with FIR flux measurements (30)\\\n1.01$^{+0.14}_{-0.14}$ & 0.44$^{+0.14}_{-0.13}$ & 5.53 & 1.09$^{+0.14}_{-0.14}$ & 0.86$^{+0.19}_{-0.19}$ & 4.40 & All galaxies with FIR flux measurements, excepting AGN (24)\\\n0.93$^{+0.15}_{-0.15}$ & 0.49$^{+0.14}_{-0.13}$ & 7.21 & 1.25$^{+0.17}_{-0.17}$ & 0.74$^{+0.20}_{-0.18}$ & 5.56 & Only M/I and Spiral galaxies, no AGN (18)\\\n\n[lccc]{} NGC 1569 & 0.037 & $-$0.6 & 7.9\\\nNGC 3034 & 9.3 & $-$0.1 & 10.8\\\nNGC 4038/9 & 8.3 & $-$0.4 & 10.7\\\nNGC 4449 & 0.21 & $-$0.4 & 8.9\\\nNGC 5253 & 0.14 & $-$0.5 & 8.4\\\nNGC 253 & 2.4 & $-$0.3 & 10.5\\\nNGC 628 & 1.3 & $-$0.4 & 10.0\\\nNGC 1291 & 0.13 & $-$0.2 & 10.7\\\nNGC 2681 & 0.47 & $-$0.3 & 10.3\\\nNGC 3079 & 4.0 & $-$0.3 & 10.5\\\nNGC 3184 & 0.56 & $-$0.4 & 9.8\\\nNGC 3628 & 1.3 & $-$0.3 & 10.3\\\nNGC 4244 & 0.047 & $-$0.7 & 8.4\\\nNGC 4258 & 0.69 & $-$0.3 & 10.4\\\nNGC 4314 & 0.16 & $-$0.2 & 10.1\\\nNGC 4579 & 1.4 & $-$0.2 & 11.1\\\nNGC 4631 & 1.6 & $-$0.5 & 9.8\\\nNGC 4736 & 0.58 & $-$0.2 & 10.4\\\nNGC 4945 & 3.6 & $-$0.3 & 10.6\\\nNGC 5194/5 & 1.8 & $-$0.2 & 10.8\\\nNGC 5236 & 1.2 & $-$0.3 & 10.5\\\nNGC 5457 & 2.5 & $-$0.5 & 10.0\\\nNGC 6503 & 0.20 & $-$0.4 & 9.6\\\nNGC 1395 & ... & $-$0.2 & 11.0\\\nNGC 1399 & ... & $-$0.1 & 11.2\\\nNGC 3379 & ... & $-$0.1 & 10.5\\\nNGC 4374 & ... & $-$0.2 & 11.1\\\nNGC 4472 & ... & $-$0.1 & 11.5\\\nNGC 4636 & ... & $-$0.1 & 10.9\\\nNGC 4649 & ... & $-$0.1 & 11.2\\\nNGC 4697 & ... & $-$0.2 & 11.0\\\nNGC 5128 & 1.7 & $-$0.2 & 10.9\\\n\n[rrlcrrrrrrrrrrr]{} 253 & 00:47:01.4&$-$25:23:23 & 2 & 37.15 & 4.3 & 3.8 & 11.1 & 4.6 & 3.0 & 3.2 & $-$0.4 & 0.40 & $+$0.6 & 0.38\\\n& 00:47:06.7&$-$25:21:26 & 3 & 37.41 & 12.8 & 4.7 & 11.9 & 4.6 & 8.8 & 4.1 & $-$0.0 & 0.27 & $-$0.3 & 0.30\\\n& 00:47:10.2&$-$25:22:33 & 2 & 37.30 & 20.5 & 5.7 & 6.0 & 3.6 & 0.0 & [...]{} & $+$0.5 & 0.23 & $+$1 & [...]{}\\\n& 00:47:11.1&$-$25:23:31 & 2 & 38.02 & 40.6 & 7.5 & 83.9 & 10.2 & 15.7 & 5.1 & $-$0.4 & 0.10 & $+$0.5 & 0.09\\\n& 00:47:17.6&$-$25:18:11 & 7 & 38.48 & 188.2 & 14.8 & 323.8 & 19.0 & 176.3 & 14.3 & $-$0.3 & 0.05 & $+$0.3 & 0.05\\\n& 00:47:17.6&$-$25:18:27 & 7 & 37.77 & 25.9 & 6.3 & 74.8 & 9.7 & 31.3 & 6.7 & $-$0.5 & 0.11 & $+$0.4 & 0.10\\\n& 00:47:18.5&$-$25:19:14 & 7 & 37.81 & 43.6 & 7.7 & 58.6 & 8.7 & 49.0 & 8.1 & $-$0.1 & 0.11 & $+$0.1 & 0.11\\\n& 00:47:19.6&$-$25:17:21 & 7 & 37.34 & 0.7 & 2.3 & 18.0 & 5.3 & 29.8 & 6.5 & $-$0.9 & 0.24 & $-$0.2 & 0.17\\\n& 00:47:21.0&$-$25:17:47 & 7 & 36.97 & 3.7 & 3.2 & 12.8 & 4.7 & 4.7 & 3.4 & $-$0.6 & 0.33 & $+$0.5 & 0.32\\\n& 00:47:22.6&$-$25:20:51 & 7 & 38.54 & 119.9 & 12.0 & 330.5 & 19.2 & 301.0 & 18.4 & $-$0.5 & 0.05 & $+$0.1 & 0.04\\\n& 00:47:25.2&$-$25:19:45 & 7 & 37.78 & 34.7 & 7.0 & 55.6 & 8.5 & 47.4 & 8.0 & $-$0.2 & 0.12 & $+$0.1 & 0.11\\\n& 00:47:25.4&$-$25:16:43 & 7 & 37.21 & 17.8 & 5.3 & 15.9 & 5.1 & 2.8 & 2.9 & $+$0.1 & 0.22 & $+$0.7 & 0.28\\\n& 00:47:25.5&$-$25:18:04 & 7 & 36.70 & 0.0 & [...]{} & 3.5 & 3.2 & 8.6 & 4.4 & $-$1 & [...]{} & $-$0.4 & 0.43\\\n& 00:47:26.5&$-$25:19:14 & 7 & 37.29 & 8.9 & 4.1 & 22.8 & 5.9 & 13.3 & 4.8 & $-$0.4 & 0.21 & $+$0.3 & 0.21\\\n& 00:47:28.0&$-$25:18:20 & 7 & 37.52 & 27.9 & 6.4 & 31.9 & 6.7 & 13.5 & 4.8 & $-$0.1 & 0.15 & $+$0.4 & 0.17\\\n& 00:47:28.4&$-$25:17:09 & 7 & 36.90 & 1.9 & 2.7 & 10.7 & 4.4 & 5.6 & 3.6 & $-$0.7 & 0.38 & $+$0.3 & 0.35\\\n& 00:47:28.6&$-$25:19:23 & 7 & 37.08 & 11.7 & 4.6 & 14.7 & 5.0 & 1.2 & 2.7 & $-$0.1 & 0.26 & $+$0.9 & 0.32\\\n& 00:47:29.9&$-$25:17:38 & 7 & 37.01 & 1.9 & 2.7 & 18.6 & 5.5 & 3.4 & 3.2 & $-$0.8 & 0.24 & $+$0.7 & 0.26\\\n& 00:47:30.9&$-$25:14:50 & 7 & 36.88 & 15.8 & 5.1 & 2.0 & 2.7 & 0.0 & [...]{} & $+$0.8 & 0.27 & $+$1 & [...]{}\\\n\\\n& 14:04:25.1&$+$54:25:51 & 3 & 37.39 & 18.8 & 6.1 & 36.4 & 7.2 & 7.9 & 4.3 & $-$0.4 & 0.17 & $+$0.5 & 0.17\\\n6503 & 17:49:12.5&$+$70:09:31 & 7 & 38.40 & 15.7 & 5.1 & 44.9 & 7.8 & 35.7 & 7.1 & $-$0.5 & 0.14 & $+$0.1 & 0.13\\\n& 17:49:26.4&$+$70:08:40 & 7 & 37.44 & 1.8 & 2.7 & 7.8 & 4.0 & 0.8 & 2.3 & $-$0.6 & 0.47 & $+$0.8 & 0.50\\\n& 17:49:27.9&$+$70:08:37 & 7 & 37.76 & 4.7 & 3.4 & 7.0 & 3.8 & 10.0 & 4.3 & $-$0.2 & 0.43 & $-$0.2 & 0.33\\\n& 17:49:28.8&$+$70:08:33 & 7 & 37.85 & 7.9 & 4.0 & 11.8 & 4.6 & 6.8 & 3.8 & $-$0.2 & 0.30 & $+$0.3 & 0.31\\\n& 17:49:29.1&$+$70:08:44 & 7 & 38.42 & 29.7 & 6.5 & 39.7 & 7.4 & 31.7 & 6.7 & $-$0.1 & 0.14 & $+$0.1 & 0.14\\\n& 17:49:31.7&$+$70:08:20 & 7 & 38.68 & 72.9 & 9.6 & 83.6 & 10.2 & 23.9 & 6.0 & $-$0.1 & 0.09 & $+$0.6 & 0.10\\\n& 17:49:38.1&$+$70:08:32 & 7 & 37.25 & 0.0 & [...]{} & 0.9 & 2.3 & 5.8 & 3.6 & $-$1 & [...]{} & $-$0.7 & 0.61\\\n\n[^1]: URL http://asc.harvard.edu/cal/Acis/Cal\\_prods/effarea/4\\_99/, EA $*$ QE $*$ filt.trans. ", "curve files files orbit\\_i.dat \\[FI\\] and orbit\\_s.dat \\[BI\\]\n\n[^2]: We have taken special care to omit luminosity ranges on the lower end that could be incomplete due to poor luminosity sensitivity within the luminosity bin. ", "The exact ranges used are listed in the notes to Table 4. ", "We have also used a weighted least-squares technique to compute $\\gamma$, which gives much less weight to the highest luminosity bins, compared to a simple least-squares technique. ", "Our measurement of $\\gamma$ may differ from other measurements reported in the literature (e.g. Kilgard et al. ", "2002), especially if different luminosity ranges were used, or the galaxy point-source lists are different.", "\n\n[^3]: This estimate was determined empirically using the approximate Poisson error formula $\\delta N \\approx 1 + \\sqrt{N + 0.75}$ (e.g., Gehrels 1986) for the raw counts. ", "For all of the sources with 20$-$100 net counts, the mean and standard deviation for $\\Delta HM$ and $\\Delta MS$ are 0.30$\\pm$0.21 and 0.34$\\pm$0.57, respectively. ", "For sources with $>$100 net counts $\\Delta HM =$ 0.10$\\pm$0.14 and $\\Delta MS =$ 0.11$\\pm$0.14.", "\n\n[^4]: Errors for L$_K$ and L$_{FIR}$ were estimated from the errors in the flux measurements (see references in notes to Table 2). ", "We estimated a 30% error for the FUV fluxes, due to uncertainties in fitting SEDs to the data (see section 3.3). ", "We also experimented with other fitting methods (principal component analysis, simple least-squares, and robust weighted least-squares) and arrive at the same $A$ and $B$ values, within the $\\chi^2$ uncertainties.", "\n" ]

{ "pile_set_name": "ArXiv" }

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[ "// @flow\nimport Checkbox from '@material-ui/core/Checkbox';\nimport IconButton from '@material-ui/core/IconButton';\nimport TextField from '@material-ui/core/TextField';\nimport Chip from '@material-ui/core/Chip';\nimport Menu from '@material-ui/core/Menu';\nimport MenuItem from '@material-ui/core/MenuItem';\nimport { makeStyles } from '@material-ui/core/styles';\nimport AddBoxOutlined from '@material-ui/icons/Add';\nimport Folder from '@material-ui/icons/Folder';\nimport RadioButtonUnchecked from '@material-ui/icons/RadioButtonUnchecked';\nimport KeyboardArrowRight from '@material-ui/icons/KeyboardArrowRight';\nimport KeyboardArrowDown from '@material-ui/icons/KeyboardArrowDown';\nimport CheckCircle from '@material-ui/icons/CheckCircle';\nimport Check from '@material-ui/icons/Check';\nimport Info from '@material-ui/icons/Info';\nimport Cancel from '@material-ui/icons/Cancel';\nimport MoreVertIcon from '@material-ui/icons/MoreVert';\nimport * as React from 'react';\nimport type { Client, Collection, SyncStatus } from '../../../../../packages/client-bundle';\nimport { useItem, useItems } from '../../../../../packages/client-react';\nimport { type ItemT, newItem, newDay } from '../types';\nimport { useLocalStorageSharedToggle } from '../useLocalStorage';\nimport { cx, showDate, today, isToday, tomorrow } from '../utils';\nimport { fade } from '@material-ui/core/styles';\n\nimport { ItemChildren } from './ItemChildren';\nimport Description from './Description';\n\nimport { type DragInit, type OnDragRef } from './dragging';\n\nconst INDENT = 24;\n\ntype Props = {\n path: Array<string>,\n level: number,\n item: ItemT,\n idx: number,\n client: Client<SyncStatus>,\n // showAll: boolean,\n show: (ItemT) => boolean,\n onDragRef: OnDragRef,\n onDragStart: (DragInit) => void,\n setRootPath: (Array<string>) => void,\n\n selection?: ?{ ", "map: { [key: string]: boolean }, set: (string, boolean) => void },\n};\n\nexport type DragRefs = {\n [key: string]: {\n id: string,\n path: Array<string>,\n parent: boolean,\n node: any,\n idx: number,\n },\n};\n\nconst scheduleItem = async (client, id, dayId) => {\n const dayCol = client.getCollection('days');\n let day = await dayCol.load(dayId);\n if (day == null) {\n day = newDay(dayId);\n await dayCol.save(dayId, day);\n }\n dayCol.insertId(dayId, ['toDoList', 'others'], day.toDoList.others.length, id);\n};\n\nconst getMenuItems = ({\n client,\n item,\n col,\n path,\n setEditing,\n showDescription,\n setShowDescription,\n setOpen,\n open,\n setCommenting,\n}) => {\n const menuItems = [\n {\n title: 'Edit text',\n onClick: () => {\n setTimeout(() => {\n setEditing(item.title);\n }, 5);\n },\n },\n [\n {\n title: 'now',\n selected: item.horizon === 0,\n onClick: () => {\n col.setAttribute(item.id, ['horizon'], item.horizon === 0 ? ", "null : 0);\n },\n },\n {\n title: 'near',\n selected: item.horizon === 1,\n onClick: () => {\n col.setAttribute(item.id, ['horizon'], item.horizon === 1 ? ", "null : 1);\n },\n },\n {\n title: 'far',\n selected: item.horizon === 2,\n onClick: () => {\n col.setAttribute(item.id, ['horizon'], item.horizon === 2 ? ", "null : 2);\n },\n },\n ],\n ];\n if (item.style !", "== 'group') {\n menuItems.push({\n title: 'Add attempt',\n onClick: () => {\n col.setAttribute(item.id, ['checkDates', Date.now().toString(36)], true);\n },\n });\n } else {\n if (item.completedDate == null) {\n menuItems.push({\n title: 'Mark completed',\n onClick: () => {\n col.setAttribute(item.id, ['completedDate'], Date.now());\n },\n });\n } else {\n menuItems.push({\n title: 'Mark incomplete',\n onClick: () => {\n col.setAttribute(item.id, ['completedDate'], null);\n },\n });\n }\n }\n if (item.children.length === 0 && !", "open) {\n menuItems.push({ title: 'Add child', onClick: () => setOpen(true) });\n }\n if (!", "showDescription) {\n menuItems.push({\n title: item.description ? '", "Show description' : 'Add description',\n onClick: () => {\n setShowDescription(true);\n },\n });\n }\n if (item.completedDate == null && item.style !", "== 'group') {\n menuItems.push({\n title: 'Schedule today',\n onClick: () => {\n scheduleItem(client, item.id, showDate(today()));\n },\n });\n menuItems.push({\n title: 'Schedule tomorrow',\n onClick: () => {\n scheduleItem(client, item.id, showDate(tomorrow()));\n },\n });\n }\n if (showDescription) {\n menuItems.push({\n title: 'Hide description',\n onClick: () => {\n setShowDescription(false);\n },\n });\n }\n if (item.style === 'group') {\n menuItems.push({\n title: 'Convert to checkbox',\n onClick: () => {\n col.setAttribute(item.id, ['style'], null);\n },\n });\n } else {\n menuItems.push({\n title: 'Convert to group',\n onClick: () => {\n col.setAttribute(item.id, ['style'], 'group');\n },\n });\n }\n menuItems.push({\n title: 'Add comment',\n onClick: () => setCommenting(true),\n });\n menuItems.push({\n title: 'Delete',\n onClick: async () => {\n const pid = path[path.length - 1];\n await Promise.all([\n col.clearAttribute(pid, ['children', item.id]),\n col.delete(item.id),\n ]);\n },\n });\n return menuItems;\n};\n\nconst SelectionButton = ({ selection, id }) => {\n return (\n <IconButton onClick={() => selection.set(id, !", "selection.map[id])}>\n {selection.map[id] ? ", "<CheckCircle /> : <RadioButtonUnchecked />}\n </IconButton>\n );\n};\n\nexport const Item = React.memo<Props>(\n ({\n item,\n idx,\n onDragStart,\n client,\n level,\n show,\n path,\n onDragRef,\n setRootPath,\n selection,\n }: Props) => {\n const [col, items] = useItems(React, client, 'items', item.children);\n\n const [open, setOpen] = selection\n ? ", "React.useState(item.style === 'group' ? ", "level < 3 : false)\n : useLocalStorageSharedToggle('planner-ui-state', item.id + '%open');\n const [showDescription, setShowDescription] = selection\n ? ", "React.useState(false)\n : useLocalStorageSharedToggle('planner-ui-state', item.id + '%desc');\n const [editing, setEditing] = React.useState(null);\n const styles = useStyles();\n const [commenting, setCommenting] = React.useState(false);\n\n const [menu, setMenu] = React.useState(false);\n const [anchorEl, setAnchorEl] = React.useState(null);\n const [dragging, setDragging] = React.useState(false);\n const [newFocus, setNewFocus] = React.useState(false);\n\n const childPath = React.useMemo(() => path.concat([item.id]), [path]);\n\n const menuItems = getMenuItems({\n client,\n item,\n col,\n path,\n setCommenting,\n setEditing,\n showDescription,\n setShowDescription,\n setOpen,\n open,\n });\n\n if (!", "items) {\n // I think this is what we want?", "\n return null;\n }\n\n const visibleChildren = Object.keys(items)\n .map((k) => items[k])\n .filter(Boolean)\n .filter((item) =>\n // showAll ? ", "true : item.style === 'group' || item.completedDate == null,\n show(item),\n ).length;\n\n return (\n <div className={cx([styles.itemWrapper, dragging ? ", "styles.dragItem : null])}>\n <div className={styles.item} style={{ paddingLeft: level * INDENT }}>\n {item.style === 'group' || item.children.length > 0 || open ? (", "\n <div\n style={{\n marginTop: 4,\n padding: 4,\n display: 'flex',\n alignItems: 'center',\n justifyContent: 'center',\n }}\n onClick={() => setOpen(!open)}\n >\n {open ? ", "<KeyboardArrowDown /> : <KeyboardArrowRight />}\n </div>\n ) : !!", "item.description ||\n (item.comments && Object.keys(item.comments).length) ? (", "\n <div\n style={{\n padding: 6,\n paddingTop: 11,\n display: 'flex',\n alignItems: 'center',\n justifyContent: 'center',\n }}\n onClick={() => setShowDescription(!showDescription)}\n >\n <Info\n fontSize=\"small\"\n className={showDescription ? ", "styles.infoIcon : styles.infoIconOff}\n />\n </div>\n ) : (\n <div style={{ width: 32 }} />\n )}\n <div\n style={{ display: 'flex', flex: 1, alignItems: 'flex-start' }}\n ref={(node) => {\n if (node) {\n onDragRef(item.id, {\n path,\n node,\n idx,\n parent:\n item.children.length > 0 || item.style === 'group' || open,\n });\n // dragRefs[item.id] = {\n // id: item.id,\n // path,\n // node,\n // idx,\n // parent:\n // item.children.length > 0 || item.style === 'group' || open,\n // };\n } else {\n // delete dragRefs[item.id];\n onDragRef(item.id, null);\n }\n }}\n >\n <div\n className={newFocus ? ", "styles.itemNewFocus : undefined}\n style={{\n position: 'relative',\n display: 'flex',\n flexDirection: 'row',\n flex: 1,\n alignItems: 'flex-start',\n }}\n >\n <div\n className={cx([\n styles.horizon,\n item.horizon !", "= null\n ? [", "\n styles.horizonNow,\n styles.horizonNear,\n styles.horizonFar,\n ][item.horizon]\n : null,\n ])}\n ></div>\n {item.style === 'group' ? (", "\n <div\n style={{ padding: 9 }}\n onClick={() => setRootPath(path.concat([item.id]))}\n >\n <Folder />\n </div>\n ) : selection ? (", "\n <SelectionButton selection={selection} id={item.id} />\n ) : (\n <Checkbox\n // type=\"checkbox\"\n checked={!!item.completedDate}\n onChange={() => {\n col.setAttribute(\n item.id,\n ['completedDate'],\n item.completedDate !", "= null ? ", "null : Date.now(),\n );\n }}\n onClick={(evt) => evt.stopPropagation()}\n />\n )}\n <div\n className={`${\n item.style === 'group' ? ", "styles.groupTitle : styles.itemTitle\n } ${item.completedDate !", "= null ? ", "styles.completed : ''}`}\n >\n {editing !", "= null ? (", "\n <TextField\n autoFocus\n multiline\n className={styles.input}\n // inputProps={{\n // style: { fontSize: 'inherit' },\n // }}\n // size=\"medium\"\n onClick={(evt) => evt.stopPropagation()}\n value={editing}\n onChange={(evt) => setEditing(evt.target.value)}\n onKeyDown={(evt) => {\n if (evt.key === 'Enter' && editing.trim().length > 0) {\n col.setAttribute(item.id, ['title'], editing);\n setEditing(null);\n }\n }}\n onBlur={() => setEditing(null)}\n />\n ) : (\n item.title\n )}\n </div>\n {Object.keys(item.checkDates).length ? (", "\n <div\n style={{\n position: 'absolute',\n bottom: 0,\n right: 0,\n display: 'flex',\n flexDirection: 'row',\n }}\n >\n {Object.keys(item.checkDates).map((date) => {\n const today = isToday(new Date(parseInt(date, 36)));\n return (\n <div\n key={date}\n className={styles.check}\n title={new Date(\n parseInt(date, 36),\n ).toLocaleString()}\n >\n <Check\n color={today ? '", "primary' : 'disabled'}\n fontSize=\"inherit\"\n />\n </div>\n );\n })}\n </div>\n ) : null}\n </div>\n\n {!", "open && visibleChildren > 0 ? ", "<Chip label={visibleChildren} /> : null}\n\n <IconButton\n aria-label=\"more\"\n // aria-controls=\"long-menu\"\n aria-haspopup=\"true\"\n style={{ touchAction: 'none' }}\n onTouchStart={(evt) => {\n console.log('touch');\n // evt.preventDefault();\n onDragStart({\n id: item.id,\n path,\n onStart: () => setDragging(true),\n onFinish: () => setDragging(false),\n pos: { x: evt.clientX, y: evt.clientY },\n });\n }}\n onMouseDown={(evt) => {\n onDragStart({\n id: item.id,\n path,\n onStart: () => setDragging(true),\n onFinish: () => setDragging(false),\n pos: { x: evt.clientX, y: evt.clientY },\n });\n }}\n onClick={(evt) => {\n evt.stopPropagation();\n setMenu(true);\n }}\n ref={setAnchorEl}\n >\n <MoreVertIcon />\n </IconButton>\n </div>\n {menu ? (", "\n <Menu\n id=\"long-menu\"\n anchorEl={anchorEl}\n keepMounted\n open={menu}\n onClick={(evt) => evt.stopPropagation()}\n onClose={() => setMenu(false)}\n >\n {menuItems.map((item, i) =>\n Array.isArray(item) ? (", "\n <div style={{ display: 'flex' }} key={i}>\n {item.map((item, i) => (\n <MenuItem\n selected={item.selected}\n key={item.title}\n onClick={() => {\n item.onClick();\n setMenu(false);\n }}\n >\n {item.title}\n </MenuItem>\n ))}\n </div>\n ) : (\n <MenuItem\n key={item.title}\n onClick={() => {\n item.onClick();\n setMenu(false);\n }}\n >\n {item.title}\n </MenuItem>\n ),\n )}\n </Menu>\n ) : null}\n </div>\n {showDescription ? (", "\n <div style={{ paddingLeft: level * INDENT, marginLeft: 42, marginBottom: 8 }}>\n <Description\n text={item.description}\n onChange={(text) => {\n col.setAttribute(item.id, ['description'], text);\n }}\n />\n {item.comments ? ", "<ShowComments comments={item.comments} /> : null}\n </div>\n ) : null}\n {open ? (", "\n <ItemChildren\n selection={selection}\n onNewFocus={setNewFocus}\n setRootPath={setRootPath}\n path={childPath}\n onDragStart={onDragStart}\n onDragRef={onDragRef}\n show={show}\n item={item}\n items={items}\n level={level}\n client={client}\n col={col}\n />\n ) : null}\n {commenting ? (", "\n <AddCommentDialog\n onClose={() => setCommenting(false)}\n onAdd={(text) => {\n const id = client.getStamp();\n if (!", "item.comments) {\n // TODO we want this \"comments\" object to have the MIN stamp\n // ideally\n col.setAttribute(item.id, ['comments'], {\n [id]: { date: Date.now(), text },\n });\n } else {\n col.setAttribute(item.id, ['comments', id], {\n date: Date.now(),\n text,\n });\n }\n setCommenting(false);\n }}\n />\n ) : null}\n </div>\n );\n },\n);\n\nconst ShowComments = ({ comments }) => {\n return (\n <React.", "Fragment>\n {Object.keys(comments).map((id) => (\n <div style={{ padding: 8 }}>\n {comments[id].text}\n <div style={{ fontStyle: 'italic', textAlign: 'right' }}>\n {new Date(comments[id].date).toDateString()}\n </div>\n </div>\n ))}\n </React.", "Fragment>\n );\n};\n\nimport Dialog from '@material-ui/core/Dialog';\nimport DialogTitle from '@material-ui/core/DialogTitle';\nimport Button from '@material-ui/core/Button';\nconst genId = () => Math.random().toString(36).slice(2);\nconst AddCommentDialog = ({ onClose, onAdd }) => {\n const id = React.useMemo(() => 'id-' + genId(), []);\n const [text, setText] = React.useState('');\n return (\n <Dialog open={true}>\n <DialogTitle id={id}>Data Export</DialogTitle>\n <div style={{ padding: 16 }}>\n <TextField\n label=\"Comment text\"\n value={text}\n fullWidth\n multiline\n onChange={(evt) => setText(evt.target.value)}\n />\n <Button\n onClick={() => {\n if (text.trim().length > 0) {\n onAdd(text);\n }\n }}\n disabled={text.trim().length === 0}\n >\n Add comment\n </Button>\n <Button onClick={() => onClose()}>Cancel</Button>\n </div>\n </Dialog>\n );\n};\n\nconst useStyles = makeStyles((theme) => ({\n container: {},\n infoIconOff: {\n color: theme.palette.text.disabled,\n },\n infoIcon: {\n color: theme.palette.info.light,\n },\n input: {\n color: 'inherit',\n width: '100%',\n // fontSize: 32,\n padding: '4px 8px',\n backgroundColor: 'inherit',\n border: 'none',\n // borderBottom: `2px solid ${theme.palette.primary.dark}`,\n ...theme.typography.body1,\n fontWeight: 300,\n },\n inputWrapper: {\n display: 'flex',\n flexDirection: 'row',\n alignItems: 'center',\n },\n itemWrapper: {\n transition: `background-color ease .5s`,\n },\n dragItem: {\n backgroundColor: theme.palette.primary.dark,\n },\n item: {\n display: 'flex',\n flexDirection: 'row',\n // alignItems: 'center',\n alignItems: 'flex-start',\n // cursor: 'pointer',\n },\n groupTitle: {\n flex: 1,\n // padding: theme.spacing(2),\n ...theme.typography.h5,\n fontWeight: 500,\n // color: theme.palette.primary.dark,\n margin: 5,\n },\n itemTitle: {\n flex: 1,\n // padding: theme.spacing(2),\n ...theme.typography.body1,\n fontWeight: 300,\n margin: 5,\n wordBreak: 'break-word',\n display: 'flex',\n alignItems: 'center',\n minHeight: 34,\n },\n itemChildren: {\n // paddingLeft: theme.spacing(2),\n },\n completed: {\n // textDecoration: 'line-through',\n // textDecorationColor: theme.palette.text.disabled,\n fontStyle: 'italic',\n // textDecorationColor: theme.palette.primary.light,\n // color: theme.palette.primary.light,\n color: theme.palette.text.disabled,\n },\n itemNewFocus: {\n color: theme.palette.primary.light,\n },\n numHidden: {\n color: theme.palette.text.disabled,\n paddingLeft: theme.spacing(2),\n marginBottom: theme.spacing(1),\n },\n check: {\n fontSize: 20,\n },\n horizon: {\n // borderRadius: '50%', // theme.spacing(2),\n // borderWidth: 5,\n // borderColor: 'transparent',\n // borderLeftStyle: 'solid',\n height: 18,\n width: 5,\n marginTop: theme.spacing(2) - 4,\n },\n horizonNow: {\n backgroundColor: fade(theme.palette.error.main, 0.5), // 'red',\n },\n horizonNear: {\n backgroundColor: fade(theme.palette.info.main, 0.5),\n },\n horizonFar: {\n backgroundColor: theme.palette.text.disabled,\n },\n}));\n" ]

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[ "Q:\n\ncreate a formula for excel to find a value using row and col\n\nI have 1st table with the information:\n\nand this is my second table (pivot kind of...)\n\n i want to have the information from the 1st table into the 2nd table (2nd image).", "\nIe. ", "formula return me the values as checking the row as eg. ", "Arabic and col heading as AEG and return the corresponding ar_AR ...\n\nA:\n\nUse this formula: \n=IF(VLOOKUP($A3,Sheet2!$A$2:$B$6,2,FALSE)=Sheet3!B$2,VLOOKUP(Sheet3!$A3,Sheet2!$A$2:$C$6,3,FALSE),\"Value Not Found\")\n\nAssuming your data is on Sheet2 and you want the result on Sheet3. ", "Copy paste the formula in cell B3 and drag it across all the rows and columns. ", " \n \n*Note: I've added column AEG in E just to show the sample result.", "\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "Q:\n\nJSON - how to convert plain format into json format?", "\n\nI got the response after invoke from worklight adapter. ", "\n\n{\"text\": \"{\\n \\\"responseCode\\\" : \\\"00\\\",\\n \\\"responseMsg\\\" : null,\\n \n \\\"buildFromAccountsMap\\\" : {\\n \\\"1000071000005844 D\\\" :\n \\\"1000071000005844\\\",\\n \\\"1000791000030636 D\\\" :\n \\\"1000791000030636\\\",\\n \\\"1001911000036935 D\\\" :\n \\\"1001911000036935\\\",\\n \\\"1002021000029411 D\\\" :\n \\\"1002021000029411\\\",\\n \\\"1005071000029666 D\\\" :\n \\\"1005071000029666\\\",\\n \\\"1005071000033139 D\\\" :\n \\\"1005071000033139\\\",\\n \\\"1005071000037533 D\\\" :\n \\\"1005071000037533\\\",\\n \\\"1005071000038605 D\\\" :\n \\\"1005071000038605\\\",\\n \\\"1005071000045298 D\\\" :\n \\\"1005071000045298\\\",\\n \\\"1005071000045517 D\\\" :\n \\\"1005071000045517\\\",\\n \\\"1005071000046989 D\\\" :\n \\\"1005071000046989\\\",\\n \\\"1005071000056183 D\\\" :\n \\\"1005071000056183\\\",\\n \\\"1005491000019560 D\\\" :\n \\\"1005491000019560\\\",\\n \\\"2000071000163308 S\\\" :\n \\\"2000071000163308\\\",\\n \\\"2000071000163361 S\\\" :\n \\\"2000071000163361\\\"\\n }}\n\nMy worklight adapter\nfunction buildFromAccounts(userId) {\n path = \"xxxxxxxxxxxxxxxxx\";\n\n var input = {\n method : 'post',\n returnedContentType : 'plain',\n path : path,\n body:{\n contentType:'application/json; charset=UTF-8',\n content:\n JSON.stringify({\n \"userId\": userId.toString()\n\n })\n }\n };\n\n return WL.Server.invokeHttp(input);\n}\n\nThe problem is, how I can convert this plain format into json format in worklight?", "\n\nA:\n\nWhat did you set for returnedContentType? ", "JSON or plain?", "\nEdit: since you are returning plain...\nTry something akin to the following: var obj = JSON.parse(response.text)\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "using System.", "Collections.", "Concurrent;\r\nusing CoreBoy.cpu;\r\n\r\nnamespace CoreBoy.controller\r\n{\r\n public class JoyPadButtonListener : IButtonListener\r\n {\r\n private readonly InterruptManager _interruptManager;\r\n private readonly ConcurrentDictionary<Button, Button> _buttons;\r\n\r\n public JoyPadButtonListener(InterruptManager interruptManager, ConcurrentDictionary<Button, Button> buttons)\r\n {\r\n _interruptManager = interruptManager;\r\n _buttons = buttons;\r\n }\r\n\r\n public void OnButtonPress(Button button)\r\n {\r\n if (button !", "= null)\r\n {\r\n _interruptManager.", "RequestInterrupt(InterruptManager.", "InterruptType.", "P1013);\r\n _buttons.", "TryAdd(button, button);\r\n }\r\n }\r\n\r\n public void OnButtonRelease(Button button)\r\n {\r\n if (button !", "= null)\r\n {\r\n _buttons.", "TryRemove(button, out _);\r\n }\r\n }\r\n }\r\n}" ]

{ "pile_set_name": "Github" }

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[ "[Demonstration, content and distribution of glycogen in rat ova during segmentation].", "\nA large amount of glycogen can be detected in the cytoplasm of rat eggs; it is evenly distributed in all the cytoplasm of blastomeres and polar globules. ", "During cleavage, eggs show non significative change in glycogen content. ", "This polysaccharide was observed and identified in ultrathin sections. ", "It exists in the form of beta particles." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Q:\n\nHow to configure Nginx upstream for a stopped backend host\n\nI am using nginx as a load balancer (reverse proxy) and everything looks fine till now.", "\nThe problem I am trying to solve is to somehow make nginx to understand an upstream backend server is down and do not send requests to it. ", "By means of down, I realy mean that there is no server like that or shutdown.", "\nCase 1 : 2 backend server defined on upstream, both running instances and 1 backend application is stopped. ", "Than nginx understands that it is down and doesn't try to send requests again during fail_timeout (by default 10secs) -- This is ok and already acceptable.", "\nCase 2 : 2 backend server defined on upstream but 1 real running instance. ", "Nginx still tries to balance the requests like both of them are up and doesn't mark stopped (not existing) backend as unhealty. ", "In this case I receive 504 gateway timeout. ", "\nWhat I would like to achieve is to make nginx work like case 1 and mark the backend as unhealthy w/o receiving 504 gateway timeout.", "\nAny ideas? ", "Configuration option?", "\n\nA:\n\nA little more investigation on nginx configuration directed me to this configuration line. ", "Incase anyone needs;\nproxy_next_upstream error timeout http_504;\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU.", "\nPhenylketonuria (PKU; OMIM 261600) is an autosomal recessive inborn error of phenylanaline metabolism. ", "PKU is characterized by deficient or defective phenylalanine hydroxylase activity and persistantly increased levels of the essential amino acid phenylalanine in the circulation. ", "The present article examines current understanding of the etiology of PKU, along with a meta-analysis examining neuropsychological and intellectual presentations in continuously treated adolescents and adults. ", "Patients with PKU differed significantly from controls on Full-Scale IQ, processing speed, attention, inhibition, and motor control. ", "Future research utilizing an integrative approach and detailed analysis of specific cognitive domains will assist both the scientist and clinician, and ultimately the patient." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Pathology and correction of the stenosed nasal vestibule.", "\nStenosis of the nasal vestibule is a frequent cause of nasal obstruction. ", "An anatomical study of the region will enable one to understand the physiopathology of the stenosis of the floor of the vestibule which frequently accompanies septal deformities in the premaxilla region, or which occurs after septal surgery. ", "The correction of this circumferential stenosis has been handled satisfactorily by the use of a \"Z\" plasty of the floor of the vestibule. ", "Pertinent anatomical material, schematic drawings, and clinical cases are presented." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Introduction {#sec1}\n============\n\nComputational theories of valuation provide a quantitative framework linking emotions to choices. ", "They have carved out distinguishable but interacting decision-making systems (Daw & Dayan, [@ref9]) including a reflective goal-directed system where choices are flexibly based on a prospective consideration of likely outcomes, and an 'automatic' Pavlovian system that inflexibly mandates evolutionarily ingrained reflex responses to emotional stimuli (Dayan *et al.* [", "@ref12]; Guitart-Masip *et al.* [", "@ref21]). ", "In the context of depression, the interaction between these systems is particularly worth investigating as it might provide a quantitative handle on how reflexive emotional responses shape reflective cognitions, and vice versa (Huys *et al.* [", "@ref24]).", "\n\nDepression appears to alter reflexive emotional responses. ", "In the appetitive domain, depression reduces reflexively evoked approach responses to a variety of appetitive stimuli such as films, images or monetary incentives (Rottenberg, [@ref37]; Steele *et al.* [", "@ref39]; Bylsma *et al.* [", "@ref7]; Eshel & Roiser, [@ref15]). ", "If approach to positive situations or stimuli no longer occurs reflexively, but only after effortful reflection, then this might reduce the perceived ease of earning rewards and their experienced prevalence, both aspects of anhedonia. ", "On the aversive side, an impairment in Pavlovian forms of behavioural inhibition (possibly mediated by serotonin: Dayan & Huys, [@ref11]; Crockett *et al.* [", "@ref8]; Geurts *et al.* [", "@ref19]*a*) could suppress an automatic avoidance of potentially stressful situations and help explain why depression seems to both cause and be caused by stressful life events (Kendler *et al.* [", "@ref28], [@ref29]).", "\n\nImportantly, failures in reflexive Pavlovian approach or avoidance might have consequences for the internal working of other aspects of emotion (Huys *et al.* [", "@ref25]): Because internal choices about what to think about are in many ways similar to external actions about what to do (Anderson & Oates, [@ref2]; Huys *et al.* [", "@ref24]), failures in internally directed Pavlovian approach might reduce positive emotion regulation strategies, such as the tendency to imagine positive events to up-regulate one\\'s mood (Joormann & Vanderlind, [@ref27]). ", "A failure to consider positive explanations of events reflexively might contribute to negative cognitive distortions. ", "Conversely, a reflexive sense of overwhelming failure might prevent reflective problem-solving (Elliott *et al.* [", "@ref14]).", "\n\nHow reflexive Pavlovian responses interact with, and influence, other decision-making processes has yet to be studied explicitly in the setting of depression. ", "To address this lacuna, we employed a Pavlovian-instrumental transfer (PIT) task and studied the influence of reflexive responses to incidental valued stimuli on ongoing deliberations about whether to approach and withdraw.", "\n\nThe task consisted of two blocks, each in three parts ([Fig. ", "1](#fig01){ref-type=\"fig\"} and online Supplement S1). ", "One block was an instrumental approach block where subjects first learned whether or not to collect mushrooms. ", "Specifically, in this instrumental training, they were presented with six mushrooms and rewarded or punished for either collecting three mushrooms or not collecting the other three by approaching or not approaching them ([Fig. ", "1*a*](#fig01){ref-type=\"fig\"}). ", "Next, Pavlovian compound conditioned stimuli (CSs) were trained ([Fig. ", "1*b*](#fig01){ref-type=\"fig\"}). ", "In the PIT component itself, subjects were told to continue to choose either to collect or leave the mushrooms, but now the background was tiled with task-irrelevant Pavlovian CSs and outcomes were no longer explicitly presented ([Fig. ", "1*c*](#fig01){ref-type=\"fig\"}). ", "The PIT effect in the approach block is a bias in instrumental performance due to the presence of the Pavlovian CS. ", "Even though the Pavlovian CS was actually uninformative about whether the mushroom should be collected or not, control subjects approached (collected) more mushrooms when the Pavlovian CS was positively valued and fewer when the Pavlovian CS was negatively valued (Huys *et al.* [", "@ref23]). ", "Fig. ", "1.Task description. ", "The task consisted of counterbalanced approach and withdrawal blocks, each subdivided into three parts: instrumental training, Pavlovian conditioning and Pavlovian-instrumental transfer (PIT). (*", "a*) Instrumental approach training. ", "Subjects started each trial by clicking inside a central square. ", "Subjects were told they were collecting mushrooms in the woods and had to choose whether to move the cursor towards the mushroom (instrumental stimulus) and click inside the blue frame (approach go) to collect it, or not emit a response to not collect (approach no-go). ", "Probabilistic outcomes (±20 cents) were presented immediately after go actions, or after a timeout period of 1.5 s had elapsed to define a no-go action. (*", "b*) Pavlovian conditioning. ", "Subjects passively viewed fractal stimuli and heard auditory tones, deterministically followed after 1 s by wins and losses of 100, 10, 0, −10 or −100 cents for the best (henceforth labelled as ++), good (+), neutral (0), bad (--) and worst (-- --) audiovisual Pavlovian conditioned stimuli (CSs), respectively. ", "Tone frequency increased or decreased with CS value (counterbalanced). (*", "c*) Approach PIT stage. ", "Subjects responded to mushrooms (instrumental stimuli) as before but now with fractals (Pavlovian CSs) tiling the background of the display and a tone corresponding to the fractal playing. ", "No outcome was presented, but subjects were instructed to continue performing the instrumental task and that their choices counted towards the final total. ", "No explicit instruction about the contribution of Pavlovian stimuli towards the final total was given. (*", "d*) To measure the acquisition of Pavlovian associations, passive Pavlovian conditioning trials (*c*) were interspersed with free choice trials administered on every fifth trial throughout Pavlovian conditioning (*d*). ", "Here, subjects chose between two fractals presented concurrently. ", "No outcome was presented, but subjects were told that the choices on these trials counted, with wins or losses added to the total provided at the end of the experiment. (*", "e*) Instrumental withdrawal training. ", "As in approach training, except now subjects were told they were at home and had to throw away or not throw away mushrooms from their basket. ", "They moved the cursor away from the mushroom and clicked in the empty blue frame to throw it away (withdrawal go) or did nothing to keep it (withdrawal no-go). (*", "f*) Withdrawal PIT. ", "As in the approach PIT stage, the fractal stimuli tiled the background and subjects continued to perform the instrumental withdrawal task in extinction. ", "For further details, see online Supplement S1. ", "See online for the colour version of the figure.", "\n\nExactly the opposite was observed in the withdrawal block (Huys *et al.* [", "@ref23]), which had the same sequence of three parts, except that subjects were asked to decide whether or not to throw away a mushroom by withdrawing from it, or keeping it by doing nothing ([Fig. ", "1*e*](#fig01){ref-type=\"fig\"} and [*f*](#fig01){ref-type=\"fig\"}). ", "While in the approach block the active response involved movement towards the mushroom, in the withdrawal block it involved movement away from the mushroom. ", "It was otherwise exactly the same. ", "We previously found that, during the PIT part of the withdrawal block, appetitive CSs reduced the tendency to throw away mushrooms, while aversive CSs increased it (Huys *et al.* [", "@ref23]). ", "Hence the PIT effect was action-specific: when the active behaviour being modulated was approach, appetitive CSs promoted and aversive CSs inhibited it, while the opposite was true when withdrawal was being modulated.", "\n\nWe hypothesized that depression would reduce both appetitive and aversive PIT during approach. ", "In addition, we examined whether reflexive Pavlovian processes might afford a less specific and more general guidance of instrumental choices by incidental valued stimuli by also testing whether action specificity is reduced. ", "Finally, because we expected behaviourally observable PIT to parallel the internal biases of cognition by emotion, we predicted that these variables would be related to the longitudinal course of the disorder.", "\n\nWe recruited healthy controls and subjects with major depressive disorder (MDD) or dysthymia (DTH) in a naturalistic longitudinal follow-up study. ", "In an attempt to examine the specificity of the findings with respect to depression, we also attempted to recruit patients with co-morbid anxiety (generalized anxiety disorder; GAD) and depression (MDD/DTH), and with anxiety (GAD) alone. ", "All patients were re-contacted after 4 months to assess the state dependence of any effects that distinguished patients and controls at initial contact, as well as to examine whether these effects were related to future symptom course. ", "As insufficient anxiety patients could be recruited, this report focuses on the depression dataset.", "\n\nMethod {#sec2}\n======\n\nSubjects and procedure {#sec2-1}\n----------------------\n\nPatients were recruited from the Berlin area while in-patients at the Charité Hospital, via their community psychiatrists, or via self-referral through advertisements. ", "Controls were recruited via advertisements and email alerts.", "\n\nPrior to the experimental session, subjects completed the Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P; First *et al.* [", "@ref17]*b*) screening questionnaire, and the sections on mood disorder and GAD. ", "Inclusion criteria were age 18--65 years and satisfying criteria for a current MDD or DTH or GAD. ", "After the experimental session, all subjects underwent a full structured diagnostic interview performed by trained raters (First *et al.* [", "@ref16]*a*, [@ref17]). ", "Self- and observer-rated scales (Hamilton, [@ref22]; Beck *et al.* [", "@ref3]*a*, [@ref4]) and intelligence quotient (IQ) (German vocabulary test *Wortschatztest*; Schmidt & Metzler, [@ref38]) were obtained at this point. ", "For patients, exclusion criteria included Axis I disorders other than GAD, MDD or DTH, and for controls any current or past Axis I diagnosis. ", "Additional exclusion criteria for all subjects were neurological, endocrine and cardiac disorder or use of drugs of abuse in the past 6 months. ", "Patients were re-contacted after 4 months, and retested at T2 between 4 and 6 months after initial testing at T1. ", "All testing sessions including follow-up were performed by E.F. and M.G. between February 2009 and November 2010 (inter-rater reliability on 10 patients assessed by both: *κ* = 0.92). ", "All participants gave written informed consent and ethical approval was obtained from the ethics committee of Charité -- Universitätsmedizin Berlin.", "\n\nA total of 45 patients were tested on the task ([Fig. ", "2](#fig02){ref-type=\"fig\"}). ", "Analyses focused on the 28 patients without anxiety (MDD *n* = 26 or DTH *n* = 2) because insufficient patients with pure GAD (*n* = 1) or co-morbid GAD + depression (GAD + MDD *n* = 10 and GAD + DTH *n* = 1) could be recruited. ", "Two MDD subjects were excluded due to performance-related issues (online Supplement S3) and one DTH subject *post-hoc* due to low symptom scores \\[Beck Depression Inventory (BDI) score \\<11 at T1\\]. ", "Two of the patients were unavailable for follow-up, resulting in a final sample of 25 depressed patients at T1, 23 depressed patients at T2, and 40 healthy controls. ", "Results including patients with co-morbid anxiety are included in the online Supplementary material. ", "A total of 61 healthy controls were tested. ", "Data for six controls were lost (three technical errors, three incomplete). ", "Of the controls, 46 were part of our previously published PIT study (Huys *et al.* [", "@ref23]). ", "To allow for matching, nine healthy males over 35 years had to be added. ", "From the total pool of 55 controls we extracted the 40 that matched the 40 patients best for age, sex and education (online Supplement S2). ", "Fig. ", "2.CONSORT (Consolidated Standards of Reporting Trials) diagram for patients in the study. ", "A total of 45 patients with major depressive disorder, dysthymia and/or generalized anxiety disorder were recruited. ", "Data were lost due to technical errors (*n* = 2), incomplete psychometric measures (*n* = 1) and due to co-morbidities identified in the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) after task completion (*n* = 2), resulting in 40 valid datasets. ", "Analyses focused on patients with depression only.", "\n\nAnalysis {#sec2-2}\n--------\n\n### Pavlovian and instrumental training {#sec2-2-1}\n\nThe number of correct choices on the Pavlovian free choice trials ([Fig. ", "1*c*](#fig01){ref-type=\"fig\"}) was compared with chance level (0.5) for each subject individually using a binomial test.", "\n\nAcquisition of instrumental training was assessed by examining the overall number of correct responses and comparing this with chance (50%). ", "To examine the rate of learning, we computed a learning curve for each stimulus separately, averaged these within each subject and fitted a linear function of time to this learning curve. ", "Tests were performed as in the Statistical tests section.", "\n\n### PIT behaviour {#sec2-2-2}\n\nWe computed the proportion of go responses in the presence of each of the five valenced Pavlovian CSs in the approach and withdrawal blocks separately. ", "This analysis averaged over all instrumental stimuli within a block and was orthogonal to the relative value of go and no-go instrumental stimuli. ", "Appetitive approach PIT was measured as the linear regression coefficient of the go probability across all instrumental stimuli for neutral and positive (0, +, ++) CSs. ", "For aversive approach PIT, we regressed the go probability across all instrumental stimuli on neutral and negative (0, --,-- --) CS values. ", "For each action frame (approach and withdrawal), we then performed a single linear regression over all five CS values. ", "Action specificity was calculated as the difference between the linear regression coefficients in approach and withdrawal blocks.", "\n\nPlanned analyses involved comparisons between controls and patients at T1, and between patients at T1 and T2 on action specificity, and on approach appetitive and approach aversive PIT.", "\n\n### Longitudinal course {#sec2-2-3}\n\nThe relationship of behavioural measures to longitudinal course was assessed by relating T1 behavioural measures to T2 depression scores. ", "To control for baseline scores, we also regressed T2 scores onto T1 scores and asked whether behavioural measures were related to the residuals.", "\n\nFor categorical analyses, improvers were patients with a MDD or DTH diagnosis at T1 who achieved either a reduction in BDI scores greater than the median (a reduction of nine BDI points or more), or whose T2 BDI score was \\<50% of their T1 BDI score.", "\n\n### Statistical tests {#sec2-2-4}\n\nAnalyses were performed in Matlab. ", "Outlier data points, i.e. data points \\>3 standard deviations from the relevant mean, were removed prior to performing any test. ", "If there was a significant departure from Gaussianity (*p* \\< 0.05, Kolmogorov--Smirnoff test), we performed non-parametric tests (Wilcoxon signed-rank tests to test against null effects and Mann--Whitney *U* tests to compare populations) and otherwise *t* tests. ", "For the effects of time we computed the statistics in a paired manner. ", "Residual BDI scores at time T2 were computed by retaining the residuals after linearly regressing BDI T2 onto BDI T1 scores.", "\n\nResults {#sec3}\n=======\n\n[Table 1](#tab01){ref-type=\"table\"} shows subject characteristics. ", "Controls and patients were matched for age, sex, IQ and education (online Supplement S2). ", "Roughly half the patients were medication-free. ", "Patients were, on average, moderately depressed at T1 and only mildly depressed at T2 (Beck *et al.* [", "@ref6]*b*). ", "Patients and controls acquired instrumental and Pavlovian contingencies equally and well at T1 and patients learned the instrumental task on retesting at T2 faster than at T1 (online Supplement S3). ", "Table 1.Subject characteristicsControlsPatients T1Patients T2*n*402523Male, %383230Age, years27.3 (7)28.3 (8)Education, years12.8 (1.7)13.3 (1.6)IQ114.2 (10.1)117.3 (10.6)117.8 (10.6)BDI-II2.8 (3.7)23.4 (8.6)[\\*](#tfn1_3){ref-type=\"table-fn\"}14.5 (10.7)[†](#tfn1_4){ref-type=\"table-fn\"}HAM-D0.8 (1.4)17.3 (5.6)[\\*](#tfn1_3){ref-type=\"table-fn\"}9.1 (7.0)[†](#tfn1_4){ref-type=\"table-fn\"}BAI4.3 (3.8)13.5 (7.8)[\\*](#tfn1_3){ref-type=\"table-fn\"}9.7 (7.4)[‡](#tfn1_5){ref-type=\"table-fn\"}HAM-A0.6 (1.2)14.8 (5.1)[\\*](#tfn1_3){ref-type=\"table-fn\"}7.6 (6.8)[†](#tfn1_4){ref-type=\"table-fn\"}Medication status, *n*None401313SSRI0325-HT033Other065[^2][^3][^4][^5][^6]\n\nAppetitive and aversive PIT during approach {#sec3-1}\n-------------------------------------------\n\nWe first examined valence-specific PIT effects during approach only. ", "We regressed each subject\\'s response probability, averaged across all instrumental stimuli, onto neutral and positive (0, +, ++) CSs to measure appetitive PIT, or onto neutral and negative (0, --, -- --) CSs to measure aversive PIT. ", "Comparison of the resulting linear regression coefficients yielded no group differences in appetitive or aversive approach PIT at T1, nor was there an effect of time in patients (all *p* \\> 0.1).", "\n\nAction-specificity at T1 {#sec3-2}\n------------------------\n\nA central finding in one of our previous studies (Huys *et al.* [", "@ref23]) was that the effects of Pavlovian CSs depended on the nature of the instrumental action, with positive *v.* negative CS valence promoting active approach *v.* active withdrawal, respectively. ", "We computed approach and withdrawal PIT effects by regressing each subject\\'s response probability during each of the two blocks on all five CS values (again averaging across instrumental stimuli). ", "PIT action-specificity was the difference between the linear regression coefficients during approach and withdrawal.", "\n\nAt T1, PIT was action-specific in controls (*p* = 0.002, signed rank, [Fig. ", "3*a*](#fig03){ref-type=\"fig\"}), but not in patients (*p* = 0.72, signed rank, [Fig. ", "3*b*](#fig03){ref-type=\"fig\"}) and there was a trend-wise difference between patients and controls (*p* = 0.07, *U* test, [Fig. ", "3*c*](#fig03){ref-type=\"fig\"}). ", "Exploring approach and withdrawal blocks separately, there was a trend-wise difference between patients and controls during approach (*p* = 0.07, *U* test), but none during withdrawal (*p* = 0.8, *U* test), suggesting that any group difference in action specificity was driven more by approach than withdrawal effects at T1. ", "Fig. ", "3.Pavlovian-instrumental transfer (PIT) data. (*", "a*) Choice data for control subjects show an action specificity, i.e. the valence of Pavlovian conditioned stimuli (CSs) is positively related to an active response during approach, but negatively during withdrawal (*p* = 0.002). (*", "b*) In major depressive disorder patients, PIT effects during approach and withdrawal did not differ, i.e. PIT effects are not action-specific (*p* = 0.7). (*", "c*) Action specificity (difference in linear CS valence effects between approach and withdrawal conditions) is trend-wise greater in controls than patients at T1 (*p* = 0.07). (*", "d*) The strength of action specificity correlates negatively with residual Beck Depression Inventory (BDI) score at follow-up T2, i.e. after correcting for BDI score at T1 (ϱ = −0.53, *p* = 0.009). (*", "e*) Action specificity is greater in those patients who go on to improve at follow-up compared with those who do not (*p* = 0.04). (*", "f*) and (*g*) PIT effects at T1 for improvers (*f*) and non-improvers (*g*). ", "In panels (*a*), (*b*), (*f*) and (*g*), red dots show means, red error bars 1 standard error, green error bars 95% confidence intervals, and black lines are linear regressions (see online for the colour version of the figure).", "\n\nAction-specificity at T1 predicts the course of depression {#sec3-3}\n----------------------------------------------------------\n\nSome patients improved more than others over the follow-up period. ", "The size of the improvement was proportional to action-specificity at T1: action-specific PIT scores correlated with the BDI scores at T2 (ϱ = −0.47, *p* = 0.02, Spearman rank correlation) and with the residual BDI scores after correcting for (regressing out) the BDI scores at T1 (ϱ = −0.53, *p* = 0.009, Spearman rank correlation, [Fig. ", "3*d*](#fig03){ref-type=\"fig\"}).", "\n\nImprovers (*n* = 14) and non-improvers (*n* = 9) had similar numbers of previous episodes of depression and hospitalizations and did not differ in depression severity at T1, but did so at time T2 ([Table 2](#tab02){ref-type=\"table\"}). ", "While improvers showed PIT action-specificity at T1, non-improvers did not (group difference: *p* = 0.04, *U* test, [Fig. ", "3*e*](#fig03){ref-type=\"fig\"}--[*g*](#fig03){ref-type=\"fig\"}). ", "Hence, patients who had intact action-specificity had a better outcome over the course of follow-up. ", "Table 2.Characteristics of improvers and non-improversImproversNon-improversStatisticsPrevious episodes2.5 (3.1)1.3 (1.3)*p* = 0.7, *U* testHospitalizations1.1 (0.7)0.3 (0.5)*p* = 0.6, *U* testBDI T123.3 (9.8)22.7 (5.8)*p* = 0.9, *t*~21~ = 0.17BDI T28.3 (6.2)24.2 (8.8)*p* = 4.6 × 10^−5^, *t*~21~ = −5.1[^7][^8]\n\nExploring these effects further, we found that the difference in PIT action-specificity between improvers and non-improvers was driven by withdrawal effects. ", "At T1, withdrawal was modulated by Pavlovian stimuli in improvers but not so in non-improvers (*p* = 0.02 and *p* = 0.2, respectively, both signed rank tests), and the groups differed in the withdrawal but not the approach condition (*p* = 0.02 and *p* = 0.5, respectively, *U* tests). ", "Furthermore, withdrawal PIT correlated with residual BDI scores at T2 (ϱ = 0.55, *p* = 0.01, rank correlation), while approach PIT did not (*p* = 0.2). ", "Finally, action-specificity correlated with improvement across symptom subdomains, but most strongly with changes in anhedonic symptoms (online Supplement S4).", "\n\nEffects of medication, time and anxiety {#sec3-4}\n---------------------------------------\n\nThere were no effects of medication, and the findings persisted when controlling for medication (online Supplement S5). ", "In the depressed group, a trend for action specificity was present at T2 (*p* = 0.08, signed rank) but it did not interact with time and did not differentiate improvers from non-improvers (online Supplement S6).", "\n\nAll results held when including patients with co-morbid anxiety (online Supplement S7). ", "At T1, there was no action specificity in patients *p* = 0.7. ", "At T1, there was a significant difference between patients and controls (*p* = 0.04) and between improvers and non-improvers (*p* = 0.009). ", "Action specificity at T1 also correlated negatively with residual BDI scores at T2 after correcting for scores at T1 (ϱ = −0.48, *p* = 0.005). ", "Notably, there was a significant effect of time on withdrawal PIT when including GAD subjects (*p* = 0.04; online Supplementary Table S3).", "\n\nDiscussion {#sec4}\n==========\n\nAdvances in understanding decision-making have identified multiple separate and parallel, but interacting decision-making systems (Killcross & Coutureau, [@ref30]; Daw *et al.* [", "@ref10]; Huys *et al.* [", "@ref25]; Dolan & Dayan, [@ref13]; Lee *et al.* [", "@ref31]). ", "PIT is one paradigmatic examination of how incidental valued stimuli interact with and influence ongoing decisions about how to act. ", "In the context of depression, this may tap into how unrelated but affectively salient events are coupled to current thought and behavioural selection processes.", "\n\nPavlovian stimuli exerted action-specific effects in healthy subjects. ", "During depressive episodes, this was absent, but the relative preservation of action specificity predicted a better recovery. ", "Thus, this first in-depth PIT examination suggests that in the depressed state the guidance of choices afforded by Pavlovian stimuli is reduced and lacks specificity. ", "The finer differentiation between different types of behaviours seen in controls is lost during a clinical episode of depression.", "\n\nTwo facets of depression appeared to be differentially associated with the Pavlovian modulation of approach and withdrawal, which jointly make up action specificity. ", "The distinction between improvers and non-improvers was driven by differences during withdrawal. ", "Thus a more advantageous disease trajectory characterized those patients with relatively more intact Pavlovian guidance of withdrawal behaviours. ", "Conversely, a distinction between patients and controls was more prominent during approach. ", "A tempting, though emphatically tentative, interpretation is that the blunted modulation of approach might contribute more to a trait distinction between patients and controls. ", "This contrasts with an alteration in the modulation of avoidance relating more to the trajectory and repair of depression itself.", "\n\nThe (marginally) blunted influence of both appetitive and aversive CSs on approach was broadly in keeping with reports of a symmetric blunting in responses to affective material (Bylsma *et al.* [", "@ref7]) in depression. ", "However, a straightforward insensitivity to rewards and losses should also have expressed itself in impairments in the acquisition of the instrumental or Pavlovian tasks, which was not the case. ", "Hence, to the extent that a reduced PIT effect captures a similar underlying process as blunting, this might relate more to aspects of the expression than to the acquisition of value.", "\n\nThe fate of negative emotional reactions, i.e. the modulation of aversive behaviours in depression, is subject to much debate. ", "Some emphasize a likely increase (Beck *et al.* [", "@ref5]; Roiser *et al.* [", "@ref36]) such that patients suffering from mood and anxiety disorders show more reactive aggression against themselves and others (Monahan *et al.* [", "@ref34]). ", "Experience sampling studies have shown that aversive events have greater affective consequences in never-depressed monozygotic twins with a depressed co-twin (Wichers *et al.* [", "@ref40]). ", "However, a meta-analysis showed that emotional reactions to negative stimuli are, overall, blunted in MDD (Bylsma *et al.* [", "@ref7]). ", "Akin to the finding that appetitive rather than aversive stimuli potentiate startle reflexes in MDD (Allen *et al.* [", "@ref1]), our data suggest more subtle effects than a simple increase or decrease of PIT, specifically an alteration in the balance between approach and withdrawal. ", "Our data also suggest that the affective control of aversive behaviours (by both appetitive and aversive expectations) is of particular importance to recovery. ", "This hints that aversive influences, such as inappropriate inhibition of withdrawal, may have an unduly large effect on the maintenance of depression, for instance, by inhibiting rather than promoting withdrawal in dangerous situations. ", "Maladaptive avoidance may in turn facilitate individuals' self-selection into high-risk environments (Kendler *et al.* [", "@ref28]) and thereby set up vicious depression--stress cycles.", "\n\nAt a neural level, we have shown that behavioural suppression due to aversive CSs is related to both serotonin (Geurts *et al.* [", "@ref20]*b*) and to how aversive CSs modulate connectivity between the ventromedial prefrontal cortex (extending into the subgenual cortex, itself also predictive of the course of depressive episodes: Mayberg, [@ref33]; Fu *et al.* [", "@ref18]) and the caudate nucleus (Geurts *et al.* [", "@ref19]*a*), raising the possibility that a lack of action specificity during depression might be related to neurobiological deficits previously described in MDD (Mayberg *et al.* [", "@ref32]).", "\n\nThe generalization to severely depressed clinical samples requires verification as the present study contained a large fraction of moderately depressed students with relatively high average IQ. ", "Second, we did not find significant medication effects, though the study was neither designed nor powered to detect these, and due to the small number of non-improvers we were unable to differentiate between subjects whose condition deteriorated *v.* remained stable. ", "Third, we did not assess depressive episode length. ", "Modulation of withdrawal responses at T1 was predictive of better recovery over the observation period. ", "Hence it was surprising to see significant modulation of withdrawal even in non-improvers at T2. ", "One possibility is that the recovery of withdrawal modulation is an early sign of improvement appearing before symptomatic improvement, and might predict recovery over a longer follow-up period even in the non-improvers. ", "Conversely, improvers may have been at this advanced stage already when they were tested at T1. ", "Finally, it should be noted that the number of subjects is relatively small for a longitudinal study, limiting both robustness and power, and hence the ability to detect reliable predictive relationships.", "\n\nIn conclusion, the current results provide a strong motivation to pursue computationally inspired decision-making tasks to examine the structure of emotional processes in depression. ", "Aspects of decision-making that have predictive value may become useful for the guidance of treatment or for alternative (and complementary) classifications of psychiatric disorders and individual patients.", "\n\nThis work was funded by a Wellcome Trust Grant (Senior Investigator Award 098362/Z/12/Z) and a Max Planck Award to R.J.D. R.C. has received funding from the Human Frontiers Science Programme, the James McDonnel Foundation and the Netherlands Organization for Scientific Research; and has been a consultant to AbbVie and Pfizer but is neither employee nor stockholder. ", "P.D. is funded by the Gatsby Charitable Foundation and has received an unrestricted research gift from Google, Inc.; R.J.D. by the Wellcome Trust, the Mary Kinross Trust and the Max Planck Society. ", "A.H. has received research funding from the German Research Foundation (Deutsche Forschungsgemeinschaft; Excellence Cluster) and the German Federal Ministry of Education and Research as well as unrestricted grants from Eli Lilly & Company, Janssen-Cilag, and Bristol-Myers Squibb. ", "Q.J.M.H. and E.F. have received funding from the German Federal Ministry of Education and Research (DFG FOR 1617), and Q.J.M.H. additionally from the Swiss National Science Foundation (320030L_153449/1). ", "The funders had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; or preparation, review or approval of the manuscript; and decision to submit the manuscript for publication. ", "We thank Jonathan P. Roiser for helpful comments on the manuscript. ", "Q.J.M.H. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.", "\n\nQ.J.M.H., A.H., R.C., P.D. and R.J.D. conceived the study. ", "Q.J.M.H., M.G., E.F., R.C. and P.D. designed the task; M.G. and E.F. collected the data; Q.J.M.H. analysed the data; Q.J.M.H., M.G., E.F., A.H., R.C., P.D. and R.J.D. interpreted the data and wrote the manuscript. ", "All authors viewed the final version of the manuscript prior to submission and are accountable for all aspects of the work.", "\n\nSupplementary material {#sec5}\n======================\n\nFor supplementary material accompanying this paper visit http://dx.doi.org/10.1017/S0033291715002597.", "\n\n###### \n\nclick here to view supplementary material\n\nNone.", "\n\n[^1]: Equal contribution.", "\n\n[^2]: Data are given as mean (standard deviation) unless otherwise indicated.", "\n\n[^3]: IQ, Intelligence quotient; BDI, Beck Depression Inventory-II; HAM-D, Hamilton Depression Rating Scale; BAI, Beck Anxiety Index; HAM-A, Hamilton Anxiety Rating Scale; SSRI, only selective serotonin inhibitor; 5-HT, on one mainly serotonergic medication; other, lithium, antipsychotic medication, benzodiazepines or combination of multiple treatments.", "\n\n[^4]: Significantly (*p* \\< 0.05) different from controls.", "\n\n[^5]: Significantly (*p* \\< 0.05) different from T1.", "\n\n[^6]: Trend difference from T1 (*p* \\< 0.1). ", "All other comparisons are non-significant (*p* \\> 0.2).", "\n\n[^7]: Data are given as mean (standard deviation).", "\n\n[^8]: BDI, Beck Depression Inventory.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Immunogenic epitopes of the p55 chain of the IL-2 receptor. ", "Relationships to high-affinity IL-2 binding and modulation of the p55 chain.", "\nMonoclonal antibodies were used to determine the relationships between epitopes on the p55 chain of the IL-2 receptor and high-affinity IL-2 binding. ", "Five monoclonal antibodies to the human P55 chain of the IL-2 receptor were induced by immunizing mice with murine L cells that were transfected with human p55 cDNA. ", "Since the p55 chain is the only human antigen expressed on these cells, all antihuman MABs thus generated were directed against this molecule. ", "These antibodies were used to map epitopes on the p55 chain and determine their relationship to high-affinity IL-2 binding. ", "Extensive flow cytometric studies with these MABs and a large panel of other anti-p55 MABs revealed three major patterns of competition. ", "Type I MABs compete with anti-Tac extensively but not with antibodies of other groups. ", "Type II MABs do not block anti-Tac but do block 7E11. ", "Type III MABs do not block either type I or type II antibodies. ", "125I-IL2 competition studies under high-affinity conditions revealed that types I and II MABs inhibit IL-2 binding. ", "Type III MABs can be resolved into two subgroups, one that inhibits IL-2 binding and one that does not. ", "Together these data suggest that there are at least four distinct immunogenic epitopes on the human p55 chain, with three epitopes related to IL-2 binding. ", "The competitive component evident by a change in Kd on the Scatchard plots suggests that all three epitopes are close to or part of the IL-2-binding site of the p55 chain. ", "The noncompetitive component, as evidenced by the lower number of high-affinity IL-2 receptors induced by these antibodies, suggests that the same epitopes are also close to the site(s) of interaction between the p55 and p70 chains to form the high-affinity receptor. ", "These studies indicated that the IL-2-binding site and site of interaction between the p55 and p70 chains are close together or identical. ", "Modulation studies revealed that one type II antibody (7E11) modulates the p55 chain in the absence of IL2 and the p70 chain, thus revealing that modulation of the p55 chain can occur by an active process, and not merely passively comodulate by the p70 chain upon IL-2 binding. ", "Modulation of the p55 chain alone has no proliferative effect on IL-2-responsive T lymphoblasts. ", "Potentially this antibody-dependent modulation may be used to deliver toxin to activated lymphocytes." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "What is home? ", "While the word “home” denotes a structure in which people live, it carries a heavy connotation. ", "A home is more than just a building or place; it is an emotional attachment. “", "Home” can connote ideas of safety, place, and, ultimately, identity. ", "An empty house is a coffer, waiting for life to exist within its confines so that it can, at last, become a home.", "\n\nThe House by Spanish cartoonist Paco Roca was originally published in 2015 but was re-released with Andrea Rosenberg’s translation last year by Fantagraphics. ", "The book examines this intersection between the ideas of a house and the ideas of a home in a beautifully paced, inventively laid out, rectangle of a book saturated in rich yet muted browns and greens full of tight lines and deep shadows. ", "It is a story about the power of place to transcend time, create bonds, and form families.", "\n\nThe House follows three siblings, Vicente, José, and Carla, who return to their family vacation home a year after their father’s death. ", "As they prepare the structure to be sold, each character relives episodic memories of their childhood in that place. ", "In doing so, they also confront their role and function in its existence, and, most importantly, their understanding of their father. ", "They have come to see the house as an extension of their father, his identity, and his dreams for himself and his family.", "\n\nThe father built the house as a reflection of who he wanted to be. ", "Part of the underclass due to poverty, the father had put his aspirations of place and status into the structure, pulling the entire family into the exercise. ", "His children at the time had little to no appreciation for this, viewing the family vacations there as akin to a work camp rather than any sort of legacy building. ", "It is only in the absence of the father that they begin to understand what the house meant to him. ", "And as they begin to understand the house, so too do they begin to understand the father.", "\n\nLocations also evoke a certain type of personality memory. ", "As the three siblings join together to fix up their father’s house, old arguments and personality tics come to the forefront. ", "In a way, the three of them revert to the family dynamics that existed when they lived together, tensions that have really never been fully explored or resolved. ", "Coming back to the house allows for a type of healing and understanding that could never be obtained in any other location. ", "The house itself provides the space necessary to confront that which had previously been pushed aside. ", "Paco Roca does an amazing job, specifically in his use of color and layout, of both linking the space with memory, as well as documenting the healing of what is broken in their relationship as the siblings repair what is broken in the house.", "\n\nIn the end, the act of confronting this house leads them to understand its role as their home. ", "In this act, they draw together as a family. ", "In this act, they finally understand their father.", "\n\nIn one of the most poignant sequences in The House, Paco Roca juxtaposes a running hose slowly being turned off with a conversation between the oldest brother, Vicente, and his young sister, Carla, about the day their father died. ", "Vicente, in his role as the one tasked with his father’s care at the end of his life, was alone when the decision came down to either try to resuscitate his truly sick father who had lapsed into a coma, or “sedate him and let him go.” ", "Alone, he had to make that choice and the question of whether it was the right one. ", "The question haunts him as much as the father’s spirit haunts the house they are repairing. ", "If they sell their father’s house, how much more of him do they lose? ", "Again, what is the right choice? ", "What are the ramifications of no longer having a place that they could collectively call home?", "\n\nFor the most part, we live in a highly mobile society. ", "Many families have the luxury of having several different houses to call home in the course of their lifetimes. ", "Likewise, generations leave home to find economic opportunity or to establish their own identity in new places, sometimes a continent away. ", "Those left behind either downsize or are forced to relocate due to health concerns. ", "All those abandoned homes become houses once more.", "\n\nIf identity is in some way tied into place, what does it mean for the self when place is only a temporary stop along a continuous journey? ", "What happens to ideas of memory and legacy if, in fact, you CAN never go home again? ", "If we are ultimately just tourists in the places we live, how can we ever be FROM anywhere, really?", "\n\nPaco Roca’s The House is a bittersweet reminder of what we lose in our restlessness. ", "This sweet and complex comic serves as a pause, an opportunity to reflect, and access to an understanding of the importance of family and, more to the point, the value of home.", "\n\nIf you like the work we’re doing here at SOLRAD, please consider making a tax-deductible donation to our parent company, Fieldmouse Press, to help keep the lights on. ", "Thanks!" ]

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[ "In a variety of applications in which a gas is present, it may be necessary to know the identity of the gas. ", "For example, a hydrogen-cooled generator typically uses a high purity of hydrogen gas which flows within sealed chambers of the generator for maintaining power generation efficiency. ", "However, a small amount of air may penetrate the sealed chamber of the generator. ", "Thus, a gas analyzer may be needed, to determine the hydrogen gas purity within the generator, to ensure that the purity of hydrogen gas is within a concentration range, such as 95-98%, for example. ", "In the event that the generator encounters an operating problem, it may be necessary to open a generator case, in order to troubleshoot the problem. ", "However, the generator case initially contains pure hydrogen gas, and may cause a safety hazard if the case was prematurely opened. ", "Thus, a secondary gas such as carbon dioxide (CO2) or nitrogen gas (N2) may be used to purge the generator case until the relative concentration of hydrogen gas is less than a threshold concentration, such as 4%, for example, before the case can be safely opened. ", "Thus, a gas analyzer may be needed, to determine the relative concentration of the secondary gas and the hydrogen gas within the generator case, in order to determine that the generator case can be safely opened during a shutdown time.", "\nVarious gas analytical techniques have been developed to analyze gas and gas compositions, such as infrared absorption and thermal conductivity detection. ", "However, these conventional techniques have several drawbacks, such as not providing a single gas sensor which is capable of sensing a wide range of gases, thereby necessitating a separate sensor/system for different gases. ", "Additionally, for example, infrared absorption is used to sense a limited amount of gases, such as hydrocarbon-based gases, but is incapable of sensing various common gases, such as hydrogen. ", "Additionally, for example, a conventional thermal conductivity detection technique is used to sense certain gases, but is less accurate at sensing a wide range of gases, based on a lack of required thermal sensitivity and baseline drift.", "\nThus, it would be advantageous to provide a gas detection system which overcomes the noted drawbacks of conventional gas sensing technologies, and is conveniently capable of sensing a wide variety of gases, with the required sensitivity." ]

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[ "class Solution:\n \"\"\"\n @param r: a Integer represent radius\n @return: the circle's circumference nums[0] and area nums[1]\n \"\"\"\n def calculate(self, r):\n # write your code here\n pi = 3.14\n c = int(pi * 2.0 * r * 100.0)\n s = int(pi * r * r * 100.0)\n return [c / 100.0, s / 100.0]\n\neasy: https://www.lintcode.com/problem/calculate-circumference-and-area\n" ]

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[ "<?", "xml-stylesheet href=\"chrome://global/skin\" type=\"text/css\"?", ">\n<window xmlns=\"http://www.mozilla.org/keymaster/gatekeeper/there.is.only.xul\"\n screenX=\"200\" screenY=\"200\" width=\"300\" height=\"300\"\n\tonload=\"setTimeout(doTest, 0)\">\n<script type=\"application/javascript\" src=\"chrome://mochikit/content/tests/SimpleTest/EventUtils.js\"></script>\n<script><![CDATA[\nvar is = window.opener.SimpleTest.is;\n\nfunction doTest() {\n // from test_resizer.xul\n var expectX = 200;\n var expectY = 200;\n var expectXMost = 500;\n var expectYMost = 500;\n var screenScale = expectX/window.screenX;\n var root = document.documentElement;\n\n var oldScreenX = window.screenX;\n var oldScreenY = window.screenY;\n var oldWidth = window.outerWidth;\n var oldHeight = window.outerHeight;\n\n function testResizer(dx, dy) {\n var offset = 20;\n var scale = 5;\n // target the centre of the resizer\n var offsetX = window.innerWidth/2 + (window.innerWidth/3)*dx;\n var offsetY = window.innerHeight/2 + (window.innerHeight/3)*dy;\n\n for (var mouseX = -1; mouseX <= 1; ++mouseX) {\n for (var mouseY = -1; mouseY <= 1; ++mouseY) {\n var newExpectX = expectX;\n var newExpectXMost = expectXMost;\n var newExpectY = expectY;\n var newExpectYMost = expectYMost;\n if (dx < 0) {\n newExpectX += mouseX*scale;\n } else if (dx > 0) {\n newExpectXMost += mouseX*scale;\n }\n if (dy < 0) {\n newExpectY += mouseY*scale;\n } else if (dy > 0) {\n newExpectYMost += mouseY*scale;\n }\n\n synthesizeMouse(root, offsetX, offsetY, { type:\"mousedown\" });\n synthesizeMouse(root, offsetX + mouseX*scale, offsetY + mouseY*scale, { type:\"mousemove\" });\n is(window.screenX*screenScale, newExpectX,\n \"Bad x for \" + dx + \",\" + dy + \" moving \" + mouseX + \",\" + mouseY);\n is(window.screenY*screenScale, newExpectY,\n \"Bad y for \" + dx + \",\" + dy + \" moving \" + mouseX + \",\" + mouseY);\n is(window.outerWidth, newExpectXMost - newExpectX,\n \"Bad width for \" + dx + \",\" + dy + \" moving \" + mouseX + \",\" + mouseY);\n is(window.outerHeight, newExpectYMost - newExpectY,\n \"Bad height for \" + dx + \",\" + dy + \" moving \" + mouseX + \",\" + mouseY);\n\n // move it back before we release! ", "Adjust for any window movement\n synthesizeMouse(root, offsetX - (newExpectX - expectX),\n offsetY - (newExpectY - expectY), { type:\"mousemove\" });\n synthesizeMouse(root, offsetX, offsetY, { type:\"mouseup\" });\n }\n }\n }\n\n testResizer(-1, -1);\n testResizer(-1, 0);\n testResizer(-1, 1);\n testResizer(0, -1);\n testResizer(0, 1);\n testResizer(1, -1);\n testResizer(1, 0);\n testResizer(1, 1);\n\n var resizers = document.getElementsByTagName(\"resizer\");\n Array.forEach(resizers, function (element) {\n is(getComputedStyle(element, \"\").cursor,\n element.getAttribute(\"expectedcursor\"),\n \"cursor for \" + element.dir);\n });\n\n // now check the cursors in rtl. ", "The bottomend resizer\n // should be reversed\n document.getElementById(\"bottomend\").setAttribute(\"rtl\", \"true\");\n Array.forEach(resizers, function (element) {\n is(getComputedStyle(element, \"\").cursor,\n element.dir == \"bottomend\" ? \"", "sw-resize\" :\n element.getAttribute(\"expectedcursor\"),\n \"cursor for \" + element.dir);\n });\n\n window.close();\n window.opener.lastResizerTest();\n}\n]]></script>\n\t<hbox id=\"container\" flex=\"1\">\n\t\t<vbox flex=\"1\">\n\t\t\t<resizer dir=\"topleft\" expectedcursor=\"nw-resize\" flex=\"1\"/>\n\t\t\t<resizer dir=\"left\" expectedcursor=\"ew-resize\" flex=\"1\"/>\n\t\t\t<resizer dir=\"bottomleft\" expectedcursor=\"sw-resize\" flex=\"1\"/>\n\t\t</vbox>\n\t\t<vbox flex=\"1\">\n\t\t\t<resizer dir=\"top\" expectedcursor=\"ns-resize\" flex=\"1\"/>\n\t\t\t<resizer id=\"bottomend\" dir=\"bottomend\" expectedcursor=\"se-resize\" flex=\"1\"/>\n\t\t\t<resizer dir=\"bottom\" expectedcursor=\"ns-resize\" flex=\"1\"/>\n\t\t</vbox>\n\t\t<vbox flex=\"1\">\n\t\t\t<resizer dir=\"topright\" expectedcursor=\"ne-resize\" flex=\"1\"/>\n\t\t\t<resizer dir=\"right\" expectedcursor=\"ew-resize\" flex=\"1\"/>\n\t\t\t<resizer dir=\"bottomright\" expectedcursor=\"se-resize\" flex=\"1\"/>\n\t\t</vbox>\n\t</hbox>\n</window>\n" ]

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[ "Introduction {#s1}\n============\n\nOral cancer is the sixth most common cancer worldwide (Parkin et al., [", "@B36]); more than 90% of oral cancers are squamous cell carcinoma (SCC; Pai and Westra, [@B35]). ", "While the global incidence of oral cancer has been decreasing due to a reduction in smoking, the incidence of oral cancer in the USA is increasing, especially in young people and women (Hussein et al., [", "@B23]; Tota et al., [", "@B58]). ", "Orofacial pain is the most common initial symptom that leads to the diagnosis of oral cancer in patients (Marshall and Mahanna, [@B30]; Lam and Schmidt, [@B28]) and impairs speech, eating, drinking, and interpersonal relations (Bjordal et al., [", "@B2]). ", "Preoperative oral cancer pain also predicts poor patient outcomes (Reyes-Gibby et al., [", "@B40]). ", "The opioid requirement for oral cancer pain is high. ", "While there is some pain relief, opioids generate debilitating side effects including respiratory depression, nausea, constipation and sedation. ", "The reports on the prevalence and intensity of oral cancer pain in women and men are contradictory; previous studies have reported greater pain in men (Connelly and Schmidt, [@B7]; Cuffari et al., [", "@B10]), equal pain between the sexes (Sato et al., [", "@B46]) and greater pain in women (Reyes-Gibby et al., [", "@B40]). ", "The discrepancies between these reports are most likely due to small sample size and/or an incomplete phenotypic characterization of cancer pain. ", "Thus, there is a clinical need to understand the sex difference in the experience of oral cancer pain in women and men.", "\n\nAcross all orofacial pain conditions, prevalence is higher in women (Dao and LeResche, [@B12]; Fillingim et al., [", "@B17]). ", "This sex difference is attributed in part to gonadal hormones, which have effects throughout the peripheral and central nervous systems (CNSs), including pain and analgesic signaling (Craft et al., [", "@B9]; Craft, [@B8]; Fillingim et al., [", "@B17]). ", "Hormones also influence inflammation which is involved in pain pathophysiology (Grace et al., [", "@B19]). ", "Women show a heightened inflammatory response compared with men in response to sepsis and the proinflammatory effects of chronic autoimmune diseases (Straub, [@B56]). ", "Sex differences in the role of immune cell signaling in mechanical pain hypersensitivity have been reported in the CNS (Sorge et al., [", "@B49]). ", "Microglia, fundamental to neuropathic pain signaling in males, are not involved in female pain processing; female mice achieve similar levels of pain hypersensitivity using adaptive immune cells, likely T lymphocytes (Sorge et al., [", "@B49]). ", "We described a role for peripheral infiltrating T cells in oral cancer pain in female mice (Scheff et al., [", "@B47]). ", "The role of infiltrating immune cells in oral cancer pain in males, however, has not been investigated.", "\n\nWhile the immune system is known to contribute to inflammatory pain, it can also be responsible for an endogenous opioid-based mechanism of pain control (Hua, [@B21]). ", "Clinical and animal studies demonstrate that under environmental stressful stimuli immune cells can secrete opioids, which activate opioid receptors localized on peripheral sensory nerves to produce analgesia (Stein et al., [", "@B52], [@B55]; Mousa et al., [", "@B33]; Hua and Cabot, [@B22]). ", "Endogenous mediators that trigger opioid release within inflamed tissue are corticotropin-releasing factor (CRF) and cytokines (Stein, [@B50]; Stein and Yassouridis, [@B51]). ", "Opioid peptides, β-endorphin and met-enkephalin are found in human synovial cells as well as in lymphocytes, macrophages and mast cells; only minor amounts of dynorphin are detectable (Stein et al., [", "@B54]). ", "In the early stage of inflammation, neutrophils are the major opioid-containing leukocyte, whereas monocytes/macrophages and lymphocytes predominate at later stages (Rittner et al., [", "@B41]; Brack et al., [", "@B4]).", "\n\nTo investigate sex differences in oral cancer pain in patients with oral SCC, we utilize the University of California San Francisco Oral Cancer Pain Questionnaire (UCSFOCPQ) to quantify pain and to identify functions that generate oral cancer pain (Connelly and Schmidt, [@B7]). ", "The UCSFOCPQ measures oral cancer pain and is the only validated instrument (Kolokythas et al., [", "@B26]). ", "There is a lack of information regarding sex differences in nociceptive behavior in oral cancer pain animal models. ", "We use preclinical immune competent models to study oral cancer pain in female and male rodents. ", "We find that women experience greater oral cancer pain and that neutrophil-mediated endogenous analgesia contributes to suppression of pain in male mice.", "\n\nMaterials and Methods {#s2}\n=====================\n\nUCSF Oral Cancer Pain Questionnaire {#s2-1}\n-----------------------------------\n\nThe UCSFOCPQ was administered to 72 oral cancer patients (35 women, 37 men; mean age = 64.5 ± 14.4 (SD) years) referred to the New York University Oral Cancer Center from 2010 to 2017. ", "The UCSFOCPQ was administered to patients at a preoperative clinic visit before being prescribed analgesics for their oral cancer pain and before any treatment, as described previously (Kolokythas et al., [", "@B26]). ", "Inclusion criteria for patients in the study were diagnosis of oral cancer and comprehension of the UCSFOCPQ. ", "Exclusion criteria included a diagnosed psychiatric condition, addiction to pain medications or recreational drugs, and analgesic usage in the previous 6 months. ", "Detailed demographic information, which included age, sex, anatomic location of the oral cancer, stage and evidence of metastasis is presented in Supplementary Table [S1](#SM2){ref-type=\"supplementary-material\"}. ", "The study was carried out in accordance with the recommendations of the Institutional Review Board at New York University. ", "All subjects gave written informed consent in accordance with the Declaration of Helsinki. ", "The validated questionnaire (Supplementary Figure [S1](#SM1){ref-type=\"supplementary-material\"}) comprises eight questions that are answered by the patient on a visual analog scale of 0--100 mm (Kolokythas et al., [", "@B26]; Lam and Schmidt, [@B28]). ", "The questions differentiate spontaneous vs. function-related pain and characterize pain quality. ", "Questions one through six elicit patient response related to pain intensity, sharpness, and ache in the orofacial region. ", "Question seven concerns sensitivity to touch. ", "Question eight queries functional restriction secondary to orofacial pain. ", "Patients were instructed to place a vertical line along the 100 mm horizontal scale to approximate their orofacial pain level (if any) for each question.", "\n\nCell Culture and Supernatant Collection {#s2-2}\n---------------------------------------\n\nHuman oral cancer cell line, HSC-3, and non-tumorigenic keratinocyte cell line, HaCaT, were utilized to produce the acute supernatant cancer pain and control models, respectively. ", "Cells were maintained and culture supernatant was collected as previously described (Scheff et al., [", "@B47]). ", "All cell lines were cultured in 10 cm^2^ cell culture dishes at 37°C with 5% CO~2~ in Dulbecco's modified Eagle's medium (DMEM, Gibco, Waltham, MA, USA) supplemented with 10% fetal bovine serum and penicillin/streptomycin (50 U/mL). ", "For collection of supernatant for the acute pain model, the culture medium was changed to serum-free DMEM without phenol red (3 mL total volume) when cells reached 70%--80% confluency (1.5 × 10^6^ cells) and cells were incubated for a further 48 h. Cell culture supernatant was collected, centrifuged at 300× *g* to remove cell debris, and frozen at −20°C until needed. ", "HSC-3 and HaCaT cell culture supernatant was collected from passage 8 and 11, respectively.", "\n\nAnimals {#s2-3}\n-------\n\nAdult (10--12 weeks, 20--30 g) female and male C57BL/6 mice (stock \\#000664, Jackson Labs, Bar Harbor, ME, USA) were used for all experiments. ", "All mice were housed in a temperature-controlled room on a 12:12 h light:dark cycle (07:00--19:00 h light), with unrestricted access to food and water. ", "All animal experiments were carried out in accordance with the recommendations of the National Institute of Health guidelines and the PHS Policy on the Humane Care and Use of Laboratory Animals. ", "The protocol was approved by the New York University Institutional Animal Care and Use Committee.", "\n\nOrofacial Behavior {#s2-4}\n------------------\n\nThe dolognawmeter, a device and assay, was designed to quantify gnawing activity. ", "The outcome variable (gnaw-time for the second dowel) is a validated index of orofacial nociception in mice with oral cancer (Dolan et al., [", "@B14]). ", "Each mouse was placed into a confinement tube; forward movement in the dowel is obstructed by two dowels in series in front of the mouse. ", "The mouse voluntarily gnaws through both dowels to escape the device. ", "Each obstructing dowel is connected to a digital timer. ", "The timer automatically records the duration required for the mouse to sever the dowel. ", "To acclimatize the mice and improve consistency in gnawing behavior, all mice were trained for 5--7 sessions in the dolognawmeter. ", "Training is accomplished by placing the mice in the device and allowing them to gnaw through the obstructing dowels in the same manner as the subsequent experimental gnawing trials. ", "For both oral cancer pain models, a baseline gnaw-time (mean of the final three training sessions) was established for each mouse. ", "The investigator was blinded to the treatment groups. ", "After baseline gnaw-times were determined, treatment or drug injections were initiated and the mice underwent behavioral testing one time per week for 28 weeks. ", "Each mouse was compared to its own baseline gnaw-time and data are presented as a percent change ± standard error of the mean.", "\n\nOral Cancer Pain Models {#s2-5}\n-----------------------\n\n### Acute Oral Cancer Pain Model {#s2-5-1}\n\nWe developed an acute oral cancer pain model by injecting cell culture supernatant into the tongue (Scheff et al., [", "@B47]). ", "Mice received 50 μl injections (under isoflurane general anesthesia) of either HSC-3 or HaCaT cell culture supernatant over a 5 s period, into the left lateral tongue for three consecutive days. ", "Nociceptive orofacial behavior measurements using the dolognawmeter assay and device were recorded in awake mice 1 h after the third supernatant injection. ", "Inflammatory infiltrate was measured using flow cytometry 12 h after the third injection. ", "Naloxone (500 μg/kg; Sigma Aldrich, St. Louis, MO, USA) was co-injected with HSC-3 cell culture supernatant for three consecutive days in between behavioral assay trials for experiments designed to inhibit endogenous opioid-mediated analgesic signaling in response to oral cancer supernatant in female and male mice. ", "Data is displayed as three stable baseline gnaw-time measurements followed by one gnaw-time measurement following the three injections. ", "Data is analyzed as a percent change from an average across the three baseline gnaw-times.", "\n\n### 4-Nitroquinoline-1-Oxide (4NQO)-Induced Oral Cancer Pain Model {#s2-5-2}\n\nTo study the development of oral nociception with carcinogenesis, female and male mice were first trained in the dolognawmeter over 5--7 sessions (Dolan et al., [", "@B14]). ", "Subsequently these mice were offered carcinogen 4-nitroquinoline-1-oxide (4NQO; 100 μg/mL; Sigma Aldrich, St. Louis, MO, USA) in their drinking water or the equivalent dilution of the vehicle, propylene glycol for 16 weeks (Scheff et al., [", "@B47]). ", "The mice were then monitored weekly under light anesthesia for tumor incidence, location and size for an additional 12 weeks. ", "Functional allodynia, resulting from 4NQO-induced carcinogenesis, was assessed using the dolognawmeter assay and device once per week for the entire duration of the model (28 weeks); gnaw-time in seconds was used as a behavioral index of functional mechanical allodynia (Figure [](#F1){ref-type=\"fig\"}[2A](#F2){ref-type=\"fig\"}). ", "Tongue tissue was then harvested and a 1--2 mm coronal section was dissected from the most clinically suspicious region, fixed in 10% formalin, and processed for paraffin embedding and slide preparation. ", "Three 5 μm hematoxylin & eosin stained tongue sections separated by 100 μm were evaluated for the presence of papillary and invasive SCC and the remaining tissue was used for flow cytometry or protein quantification. ", "Histopathologic analysis was performed by an oral and maxillofacial pathologist (AB) blinded to group identity. ", "Only mice with histologically confirmed papillary and/or invasive lesions were included in the analysis of nociceptive behavior. ", "Out of 55 mice, we identified six invasive lesions (female *n* = 2, male *n* = 3) and 21 papillary lesions (female *n* = 12, male *n* = 19). ", "All invasive lesions were accompanied by a papillary component. ", "Three male mice and two female mice had ≥2 distinct papillary lesions identified in the biopsy. ", "We recognize that papillary and invasive cancers are histologically distinct subtypes, which may have dissimilar interactions with the tongue microenvironment impacting nociceptive behavior. ", "However, for this initial analysis we have chosen to combine both lesion subtypes to a single group for comparison to vehicle-treated mice.", "\n\n{ref-type=\"supplementary-material\"}). ", "Mean visual analog scale pain scores for each question were compared between women and men. ", "Women (red bars) experienced significantly more spontaneous and function-related pain, as well as increased functional restriction compared to men (blue bars). ", "\\**P* \\< 0.05 by Mann-Whitney *U*.](fnint-12-00052-g0001){#F1}\n\n{#F2}\n\nTongue Immune Cell Quantification and Sorting {#s2-6}\n---------------------------------------------\n\n### Tongue Tissue Dissociation {#s2-6-1}\n\nTongue tissue was dissected into cold DMEM containing antibiotics (penicillin/streptomycin, 10 U/mL) and 20 mM HEPES and was dissociated as previously described (Scheff et al., [", "@B47]). ", "Tongue tissue was dissected and minced in DMEM with antibiotics, collagenase-H (0.5 mg/mL; Sigma Aldrich, 34 Units/mg), DNase (0.5 mg/mL) and 20 mM HEPES, and then incubated at 37°C for 1 h. The tissue was then mechanically dissociated using a fire-polished pipette, washed twice with fresh DMEM containing antibiotics and HEPES, and resuspended in Ca^2+^/Mg^2+^ free phosphate buffered saline (Sigma Aldrich) containing 3% fetal bovine serum, 1 mM EDTA, and 0.02% sodium azide and filtered through a 40 μm cell strainer (Falcon brand, Fisher Scientific, Waltham, MA, USA).", "\n\n### Flow Cytometry {#s2-6-2}\n\nFlow cytometry was used to characterize immune cell types in the tongue tissue from female and male mice with 4NQO-induced oral SCC compared to tongue tissue in vehicle-treated female and male mice using the antibody panel and flow cytometry gating strategy as previously defined (Scheff et al., [", "@B47]). ", "Within CD45^+^ hematopoietic cells, six subpopulations were detected and quantified using antibodies specific to receptors expressed on each cell type. ", "Single-cell suspensions were prepared as described above and samples were incubated in rat anti-mouse purified CD16/CD32 to block unspecific FC receptor binding. ", "CD45 monoclonal antibody (mAb) conjugated with V450 dye (1:400; BD Biosciences Franklin Lakes, NJ, USA) was used to label all hematopoietic cells. ", "To differentiate leukocyte subpopulations, we stained cell suspensions with fluorescently conjugated rat anti-mouse mAbs recognizing neutrophils (Ly6G, Cat\\# 561105, 1:500), monocytes/macrophages (CD11b, Cat\\# 561690, 1:1,000), dendritic cells (CD11c, Cat\\# 561044, 1:250), T lymphocytes (CD3, Cat\\# 561824, 1:250), natural killer cells (NK1.1, Cat\\# 561111, 1:300), or B cells (CD45R/B220, Cat\\# 561877, 1:500; all BD Biosciences). ", "The specificity of the staining was verified by incubation of cell suspensions with appropriate isotype-matched control antibodies. ", "The gating strategy for isolation of these populations was to first exclude dead cells in the population using propidium iodide (PI; Molecular Probes, Eugene, OR, USA). ", "Of the recovered live cells, CD45^+^ immune cells were selected and then sorted into CD3^+^ T cells and CD3^−^ leukocytes; the latter were further sorted into CD45R^+^ B-cells or NK1.1^+^ natural killer cells. ", "The remaining CD3^−^CD45R^−^NK1.1^−^ cells were then sorted into CD11b^+^ monocyte/macrophages/neutrophils and CD11c^+^ dendritic cells. ", "CD11b^+^/c^−^ immune cells were further sorted into CD11b^+^/Ly6G^+^ and Ly6G^−^ to isolate monocyte/macrophages and neutrophils respectively. ", "Viability was uniformly 70%--85%, as determined by PI staining. ", "An average of 8.11 × 10^5^ ± 4.1 × 10^4^ live cells were recovered from each naïve tongue. ", "Spleen cells were used for compensation controls. ", "Data were acquired using a Fluorescence-activated cell sorting (FACS) Calibur (BD Biosciences) and analyzed using FlowJo software (Tree Star, San Carlos, CA, USA).", "\n\n### Fluorescence-Activated Cell Sorting (FACS) {#s2-6-3}\n\nFACS was used to collect myeloid and lymphoid populations of immune cells from dissociated tongue tissue treated with HSC-3 cell culture supernatant. ", "Tongue tissue was dissected and dissociated in a manner similar to that used for flow cytometry. ", "To isolate subpopulations, cells were stained with fluorescently conjugated rat anti-mouse mAbs: CD450 (1:400), CD11b (1:1,000), and Ly6G (1:500). ", "PI was used to exclude dead cells. ", "Neutrophils were defined as CD45^+^CD11b^+^Ly6G^+^. Post-sort purity was \\>97%. ", "FACS was performed on a 3 laser, 10 detector FACSAria cell sorter (BD Biosciences). ", "Samples were sorted into phosphate buffered saline containing RNAse inhibitor, pelleted (300× g), and snap frozen in liquid nitrogen for further processing.", "\n\n### Antibody-Mediated Neutrophil Depletion {#s2-6-4}\n\nIn the acute oral cancer pain model, anti-mouse Ly6G mAb (αLy6G, clone 1A8; BioXCell, West Lebanon, NH, USA) was used to specifically deplete neutrophils (Daley et al., [", "@B11]) *in vivo*. ", "Female and male mice were trained in the dolognawmeter and then administered a single i.p. ", "injection of αLy6G (1 mg/mouse) or isotype control IgG2A (clone 2A3) 12 h prior to three consecutive injections of HSC-3 or HaCaT cell culture supernatant into the lateral tongue. ", "Dolognawmeter behavior measurements were recorded in awake mice 1 h after the third supernatant injection. ", "Inflammatory infiltrate was measured using flow cytometry 12 h after the third injection.", "\n\nTo deplete neutrophils during 4NQO-induced carcinogenesis, male mice were trained in the dolognawmeter and then administered 4NQO treatment (100 μg/mL) or the equivalent dilution of propylene glycol in drinking water for 16 weeks. ", "The mice were then monitored for an additional 9 weeks. ", "Starting at week 22, mice received an i.p. ", "injection of αLy6G (1 mg/mouse) or isotype control IgG2A every 72 h for 2.5 weeks. ", "Orofacial behavior was measured 24 h after each injection. ", "At week 25, the tongues were harvested for flow cytometry analysis to verify the loss of neutrophils and measure the impact of neutrophil depletion on other infiltrating immune cell subtypes.", "\n\nElectrophysiology {#s2-7}\n-----------------\n\n### Retrograde Tracer Labeling {#s2-7-1}\n\nAt least 10 days prior to tissue harvest, the retrograde tracer 1,1′-dioctadecyl-3,3,3′,3′-tetramethy lindocarbocyanine perchlorate (DiI, Invitrogen, Carlsbad, CA, USA) was injected peripherally into the anterior lateral tongue to retrograde label tongue afferents. ", "For the 4NQO carcinogenesis model, mice were injected with DiI 10 days prior to carcinogen treatment. ", "The tracer was dissolved at 170 mg/mL in dimethylsufoxide (DMSO), diluted 1:10 in 0.9% sterile saline, and injected bilaterally using a 30 g needle for a total volume of 5--7 μL per tongue under isoflurane (Abbott Laboratories, North Chicago, IL, USA) anesthesia.", "\n\n### Tongue Primary Afferent Primary Culture {#s2-7-2}\n\nAdult mice were anesthetized with isoflurane and transcardially perfused with cold Ca^2+^/Mg^2+^-free Hank's balanced salt solution (Invitrogen). ", "Bilateral trigeminal ganglia (TG) were dissected into cold Hank's balanced salt solution and dissociated as previously described (Scheff et al., [", "@B47]). ", "Cells were plated in Dulbecco's Modified Eagle Medium: nutrient Mixture F12 (DMEM/F12, Gibco) containing 5% fetal bovine serum and antibiotics (penicillin/streptomycin, 50 U/mL). ", "Coverslips were flooded 2 h later with Leibovitz's L-15 media (Gibco) containing 10% FBS, 5 mM HEPES and 5 mM glucose, and used at room temperature. ", "Experiments were performed within 8 h of tissue harvest.", "\n\n### Current Clamp Physiology {#s2-7-3}\n\nWhole cell patch clamp recording was used to assess changes in the excitability of cultured retrograde labeled TG neurons from naïve, vehicle-treated mice and mice with 4NQO-induced oral SCC. ", "Borosilicate glass electrodes were filled with 110 mM K-methanesulfonate, 30 mM KCl, 5 mM NaCl, 1 mM CaCl~2~, 2 mM MgCl~2~, 10 mM HEPES, 11 mM EGTA, 2 mM Mg-ATP, 1 mM Li-GTP, pH 7.2 (adjusted with Tris-base), 310 mOsm (adjusted with sucrose). ", "Neurons were continuously superfused with a bath solution that contained 3 mM KCl, 130 mM NaCl, 2.5 mM CaCl~2~, 0.6 mM MgCl~2~, 10 mM HEPES, 10 mM glucose, pH 7.4 (adjusted with Tris-base), 325 mOsm (adjusted with sucrose). ", "Cell culture supernatants were applied with a computer-controlled perfusion fast-step system (switching time \\<20 ms; Warner Instrument Co, Hamden, CT, USA, Model SF-77B). ", "Oral cancer-induced changes in excitability were assessed in current-clamp mode with four measures: spontaneous activity, action potential (AP) threshold, rheobase, and accommodation. ", "Spontaneous activity was assessed at resting membrane potential (Vm) for 30 s at baseline and up to 90 s after the application of culture supernatant. ", "The second two measures were determined with a 750 ms depolarizing square-pulse current injection. ", "AP threshold was defined as the greatest depolarization reached before spike generation in response to depolarizing current injections. ", "Rheobase was defined as the smallest amount of current needed to evoke a single AP. ", "Because rheobase is positively correlated with cell size, values were normalized with respect to membrane capacitance to facilitate comparisons between neurons. ", "Passive properties assessed included Vm, capacitance and input resistance (R~in~). ", "R~in~ was measured with five 750 ms hyperpolarizing current injections (2--5 pA) from Vm. ", "Active electrophysiological properties were assessed with an AP evoked by a 4 ms depolarizing current pulse. ", "These properties included: AP duration at 0 mV, magnitude of AP overshoot, magnitude of the after-hyperpolarization (AHP), and AHP decay (τ AHP). ", "The magnitude of the overshoot was measured from 0 mV. The magnitude of the AHP was measured from the Vm. ", "Decay of the AHP was estimated by fitting the decay phase of the AHP with a single exponential function. ", "Neurons with a cell body diameter greater than 10 μm and an inflection in the falling phase of the AP were included in the study. ", "For each afferent neuron isolated for study, a continuous recording was obtained for 60 s without the delivery of external stimulus. ", "If spontaneous discharge persisted during this period, the neuron was classified as spontaneously active and disregarded.", "\n\nEnzyme-Linked Immunosorbent Assay {#s2-8}\n---------------------------------\n\nThe granulocyte-macrophage-colony stimulating factor (GM-CSF) protein concentration in tongue tissue from female and male mice with 4NQO-induced oral SCC compared to vehicle-treated female and male mice by ELISA (MyBioSource, Inc; San Diego, CA, USA). ", "Frozen tissue (20--40 mg) was homogenized in the T-PER Reagent (Pierce Biotechnology, Inc., Rockford, IL, USA) and agitated for an additional 2 h at 4°C. ", "Lysates were centrifuged at 13,000 rpm for 5 min. ", "Cell culture supernatants were removed, aliquoted and protein concentrations were determined using a Bradford Assay (Bio-Rad Laboratories, Inc., Hercules, CA, USA). ", "ELISA was run per the manufacturer's instructions. ", "The optical density of the standards and samples was read at 450 nm using a Model 680 Microplate Reader (Bio-Rad Laboratories, Inc., Hercules, CA, USA).", "\n\nPolymerase Chain Reaction (PCR) {#s2-9}\n-------------------------------\n\nFAC sorted immune cell populations were resuspended in RNA lysis buffer and total RNA isolation of each sample was conducted with a Zymo Research Quick-RNA MicroPrep Kit (Zymo Research, Irvine, CA, USA). ", "The RNA (concentration ≥5 ng/μL as determined by fluorometry) was reverse transcribed into cDNA with a High Capacity cDNA Reverse Transcription Kit (Applied Biosystems Inc. Carlsbad, CA, USA) according to the manufacturer's instructions. ", "SYBR green-based real-time quantitative polymerase chain reaction (PCR) was used to assess relative expression of opioid precursors in FAC sorted neutrophils on a real-time thermal cycler (Agilent Technologies, Santa Clara, CA, USA) using a 40-cycle protocol with a denaturation step at 95°C for 15 s and annealing step at 60°C for 60 s. All samples were run in triplicate in a final volume of 20 μL that includes 2 μL of cDNA (2.5 ng/μL) and 10 μM of each gene specific primer. ", "The melting curve of all PCR products produced a single peak and the gene primer efficiencies were calculated according to the equation *E* = 10^\\[−1/slope\\]^. The primer pairs for gene expression assays were purchased from Integrated DNA Technologies (IDT, Coralville, IA, USA): *Pomc* (Forward-TAGACGTCCAAACCCTCGTT; Reverse-AGCGAGAGGTCGAGTTTGC), *Penk* (Forward-CAGCCAGGACTGCGCTAAAT; Reverse-GAAGCCTCCGTACCGTTTCAT), *Pdyn* (Forward-GCCCTCTAATGTTATGGCGGA; Reverse-TCCTTCAGGACGGGTTCCAA). ", "The housekeeping gene *Actb* (Forward-AGTGTGACGTTGACATCCGT; Reverse-GTAACAGTCCGCCTAGAAGCA) was used as the internal control gene. ", "Relative quantification analysis of gene expression data from male mice was calculated using the pfaffl method (Pfaffl, [@B37]) and normalized relative to the average expression ratio in female mice.", "\n\nStatistical Analysis {#s2-10}\n--------------------\n\nThe Mann-Whitney *U* test was used to evaluate sex differences in responses to the UCSFOCPQ. ", "Unpaired *t*-test and analysis of variance (ANOVA) were employed to evaluate the difference between groups regarding sex and treatment in animal studies. ", "Three-way ANOVA repeated measure was used to determine the difference between groups when considering sex and treatment over time in animal studies. ", "To adjust for multiple comparisons, the *post hoc* Holm-Sidak test statistic was employed. ", "Statistical significance was set at *p* \\< 0.05. ", "Pearson correlation was used to measure the linear relationship between two variables (i.e., gnaw-time and neutrophil count). ", "All statistical analyses was performed using Prism (version 7) statistical software (Graphpad Software Inc., La Jolla, CA, USA) with the exception of the three-way ANOVA, which was performed using SPSS Statistics (IBM Corporation). ", "Results were presented as mean ± standard error of the mean.", "\n\nResults {#s3}\n=======\n\nSex Differences in Oral Cancer Pain in Patients With Oral Cancer {#s3-1}\n----------------------------------------------------------------\n\nUsing the UCSFOCPQ, 35 women diagnosed with oral cancer reported significantly greater cumulative pain score (median = 287) compared to 37 men with oral cancer (median = 226; *U* = 447.5, *P* = 0.024, Mann-Whitney *U*). ", "Specifically, women with oral cancer reported significantly greater spontaneous and functional pain intensity (Q1: *U* = 453, *P* = 0.028; Q2: *U* = 458, *P* = 0.032), greater sharp/stabbing pain during function (Q4: *U* = 441, *P* = 0.019), and greater functional restriction (Q8: *U* = 433.5, *P* = 0.015) compared to men with oral cancer (Figure [1](#F1){ref-type=\"fig\"}).", "\n\nSex Differences in Nociceptive Behavior During 4NQO-Induced Carcinogenesis {#s3-2}\n--------------------------------------------------------------------------\n\nTo establish an oral SCC model that enabled assessment of nociceptive behavior induced by cancer in an intact mouse, C57BL/6 mice ingested the carcinogen, 4NQO, in the drinking water on an unrestricted basis for 16 weeks followed by a 12-week monitoring period (Figure [2A](#F2){ref-type=\"fig\"}). ", "Control mice received water containing the diluent, propylene glycol (vehicle). ", "Nociceptive behavior was measured using the dolognawmeter assay in which gnaw-time is a validated index of orofacial nociception (Dolan et al., [", "@B14]). ", "All 40 female and 40 male mice treated with 4NQO in the drinking water exhibited clinical and pathologic changes in the tongue by 8 weeks after the termination of 4NQO (week 28, Figure [2A](#F2){ref-type=\"fig\"}). ", "Ten female and 10 male mice treated with propylene glycol (vehicle) showed no clinical or pathologic changes in the oral cavity (Figure [2Ba](#F2){ref-type=\"fig\"}). ", "Moderate or severe dysplastic changes were detected in 62.3% of female mice and 60.0% of male mice. ", "Oral SCC, both papillary (Figure [2Bb](#F2){ref-type=\"fig\"}) and invasive (Figure [2Bc](#F2){ref-type=\"fig\"}), were identified in 37.5% of female mice and 40.0% of male mice. ", "There was no difference in tumor location identified between male and female mice with 4NQO-induced oral SCC (Figure [2C](#F2){ref-type=\"fig\"}). ", "By contrast, a sex difference in orofacial nociceptive behavior was observed during 4NQO-induced carcinogenesis (Treatment × Sex × Time, *P* = 0.040 Three-way ANOVA; Figure [2D](#F2){ref-type=\"fig\"}). ", "When comparing males to females, 15 female mice with 4NQO-induced oral SCC exhibited significantly longer gnaw-time compared to 16 males with 4NQO-induced oral SCC at 25--28 weeks (Figure [2D](#F2){ref-type=\"fig\"}). ", "Additionally, females with 4NQO-induced oral SCC had significantly longer gnaw-time compared to 10 vehicle-treated females at 22--23 weeks (*P* \\< 0.05) and 24--28 weeks (*P* \\< 0.01, Figure [2D](#F2){ref-type=\"fig\"}), whereas males with 4NQO-induced oral SCC had significantly longer gnaw-time compared to 10 vehicle-treated males at 28 weeks only (*P* = 0.002, Figure [2D](#F2){ref-type=\"fig\"}).", "\n\nNo Sex Difference in Tongue Primary Afferent Excitability {#s3-3}\n---------------------------------------------------------\n\nBaseline neuronal excitability was not significantly different in retrograde labeled (DiI+) tongue primary afferent neurons from six male mice and four female mice with 4NQO-induced oral SCC (Sex × Treatment, *P* = 0.595 for membrane potential, *P* = 0.571 for Rheobase, *P* = 0.172 for AP threshold, Two-way ANOVA). ", "No difference in the size distribution of acutely dissociated, DiI+ neurons from vehicle-treated mice or mice with 4NQO-induced oral SCC was observed (Table [1](#T1){ref-type=\"table\"}). ", "However, when pooled, 23 DiI+ neurons from female and male mice with 4NQO-induced oral SCC exhibited a significantly more depolarized resting membrane potential (−16.3 ± 3.1%, *P* = 0.0002 Unpaired Student's *t*-test; Figure [3A](#F3){ref-type=\"fig\"}) and a significantly lower rheobase (−25.6 ± 1.1%, *P* = 0.041; Figure [3B](#F3){ref-type=\"fig\"}) compared to 31 neurons from vehicle-treated female and male mice. ", "We found no significant difference in AP threshold (11.5 ± 1.7%, *P* = 0.401 Unpaired Student's *t*-test; Figure [3C](#F3){ref-type=\"fig\"}). ", "There was also no sex difference in the active electrophysiological parameters, as defined in Figure [3D](#F3){ref-type=\"fig\"}, in neurons from female and male mice with 4NQO-induced oral SCC (Table [1](#T1){ref-type=\"table\"}). ", "When neurons from female and male mice were pooled, the peak amplitude of the AP (overshoot) was significantly smaller (*P* = 0.0001, Unpaired Student's *t-test*) in 23 neurons from mice with 4NQO-induced oral SCC (45.3 ± 3.4 mV) compared to 31 neurons from vehicle-treated mice (61.7 ± 1.7 mV). ", "While there was no change in the AHP magnitude between groups (*P* = 0.304), the AHP time constant (τ) of decay was significantly increased (*P* = 0.0035, Unpaired Student's *t*-test) in neurons from mice with 4NQO-induced oral SCC (164.5 ± 15 ms) compared to neurons from vehicle-treated mice (64.5 ± 10 ms).", "\n\n###### \n\nPassive and active electrophysiological parameters of the evoked action potential (AP) in tongue afferents from female and male cancer free (vehicle) and 4-nitroquinoline-1-oxide (4NQO)-induced cancer bearing (oral squamous cell carcinoma, oSCC) mice.", "\n\n Capacitance (pf) Input resistance (mΩ) Overshoot (mV) Duration (ms) Mag of AHP (mV) τ of decay (ms)\n ---------------------------- ------------------ ----------------------- ---------------- --------------- ----------------- -----------------\n **Female** \n Vehicle (*n* = 10) 12.2 ± 1.1 1541.1 ± 224.8 60.7 ± 2.5 3.2 ± 0.3 −15.5 ± 1.5 65.1 ± 12.1\n oSCC (*n* = 11) 14.2 ± 1.5 1389.3 ± 453.6 38.3 ± 4.2 2.6 ± 0.2 −16.7 ± 2.1 160.3 ± 33.5\n **Male** \n Vehicle (*n* = 13) 13.0 ± 0.7 1763.4 ± 353.6 57.2 ± 1.3 3.4 ± 0.1 −15.9 ± 1.0 63.9 ± 15.6\n oSCC (*n* = 12) 15.5 ± 1.1 1611.7 ± 240.5 32.3 ± 4.1 4.2 ± 0.6 −18.2 ± 2.0 168.6 ± 52.1\n **Pooled male and female** \n Vehicle (*n* = 23) 14.9 ± 1.0 1686 ± 238.9 61.7 ± 1.7 3.3 ± 0.3 −15.7 ± 0.8 64.5 ± 10\n oSCC (*n* = 23) 14.9 ± 0.9 1512 ± 237.5 45.3 ± 3.4\\*\\* 3.4 ± 0.4 −17.5 ± 1.4 164.5 ± 15\\*\\*\n\n*AHP is afterhyperpolarization, τ is the time constant of AHP decay, Two-way ANOVA, Treatment × Sex interaction P \\> 0.05; Pooled Male and Female, Unpaired Student's t-test \\*\\*P \\< 0.01*.", "\n\n{ref-type=\"table\"}. ", "AHP is afterhyperpolarization; τ is time constant of AHP decay.](fnint-12-00052-g0003){#F3}\n\nOpioid-Mediated Analgesic Mechanism in Male Mice Only {#s3-4}\n-----------------------------------------------------\n\nTo measure oral cancer pain behavior in the absence of tumor burden and illness that accompany carcinogenesis, we used the acute oral cancer pain mouse model (Scheff et al., [", "@B47]). ", "Using the dolognawmeter assay, baseline gnaw-time was established and mice received three consecutive injections of cell culture supernatant. ", "Nociceptive behavior was measured 1 h after the third injection. ", "Peripheral opioid receptor antagonist, naloxone methiodide, revealed an endogenous analgesic mechanism in male mice. ", "We found a significant interaction between sex and treatment with HSC-3 cell culture supernatant, naloxone in cell culture media (DMEM/naloxone), or naloxone co-injected with HSC-3 supernatant (*P* = 0.006, Two-way ANOVA). ", "Five female mice had significantly longer gnaw-time in response to HSC-3 supernatant (*P* = 0.012) when compared to 5 female mice injected with DMEM/naloxone (Figure [4A](#F4){ref-type=\"fig\"}). ", "However, when naloxone was co-injected with HSC-3 supernatant, 10 male mice showed significantly longer gnaw-time compared to five males injected with DMEM/naloxone (461.4 ± 70.9%, *P* = 0.001) or five male mice that received HSC-3 alone (7370.5.4 ± 70.7%, *P* = 0.033; Figure [4B](#F4){ref-type=\"fig\"}). ", "Co-injection with naloxone and HSC-3 supernatant was not significantly different from DMEM/naloxone in eight female mice (*P* = 0.717).", "\n\n{#F4}\n\nSex Difference in Neutrophil Recruitment Associated With 4NQO-Induced Oral SCC {#s3-5}\n------------------------------------------------------------------------------\n\nSex differences in myeloid and lymphocytic immune cell subpopulations were found in immune infiltrate (CD45^+^ tongue cells) from mice with 4NQO-induced oral SCC compared to vehicle-treated mice. ", "There was a significant interaction between sex and 4NQO treatment for Ly6G^+^ neutrophils (*P* = 0.048) and CD3^+^ T cells (*P* = 0.048, Two-way ANOVA). ", "Significantly more Ly6G^+^ neutrophils were quantified in tongues from 10 male mice with 4NQO-induced oral SCC compared to tongues from nine vehicle-treated male mice (2605.8 ± 97.7%, *P* = 0.002) and eight female mice with 4NQO-induced oral SCC (121.1 ± 10.3%, *P* = 0.026). ", "Alternatively, significantly more CD3^+^ T cells were quantified in eight female mice with 4NQO-induced oral SCC compared to nine vehicle-treated female mice (980.5 ± 33.6%, *P* \\< 0.0001) and 10 male mice with 4NQO-induced oral SCC (65.6 ± 3.5%, *P* = 0.046; Figure [5A](#F5){ref-type=\"fig\"}). ", "There was no significant interaction between sex and 4NQO treatment in the number of monocytes/macrophages (*P* = 0.632), B cells (*P* = 0.800), or NK cells (*P* = 0.768) quantified (Two-way ANOVA, Figure [5A](#F5){ref-type=\"fig\"}). ", "Data expressed as a percent of live cells quantified from both 4NQO and vehicle treatment are available in Table [2](#T2){ref-type=\"table\"}.", "\n\n###### \n\nImmune cell subpopulations from female and male cancer free (vehicle) and 4NQO-induced cancer bearing (oSCC) mice.", "\n\n CD45^+^ cells Female Male \n --------------- ------------- -------------------- ------------- --------------------\n CD11b^+^ 1.48 ± 0.14 2.58 ± 0.17 1.1 ± 0.14 2.41 ± 0.30\n Ly6G^+^ 0.24 ± 0.05 1.39 ± 0.33\\* 0.11 ± 0.02 3.07 ± 0.97\\*,^\\#^\n CD3^+^ 0.13 ± 0.03 1.42 ± 0.33\\*,^\\#^ 0.23 ± 0.01 0.86 ± 0.12\\*\n B220^+^ 0.31 ± 0.08 0.65 ± 0.15 0.43 ± 0.09 0.90 ± 0.37\n NK1.1^+^ 0.12 ± 0.03 0.19 ± 0.03 0.13 ± 0.04 0.22 ± 0.06\n\n*Data is presented as percent of total live cells counted, Two-way ANOVA, Treatment × Sex interaction P \\< 0.05, Holm-Sidak post hoc analysis for Treatment, \\*P \\< 0.05, for Sex ^\\#^P \\< 0.05*.", "\n\nA sex difference in the tongue tissue of mice with 4NQO-induced oral SCC compared to vehicle-treated mice was also found in the protein concentration of granulocyte macrophage-colony stimulating factor (GM-CSF), a prominent cytokine secreted at high concentration by oral cancer (Scheff et al., [", "@B47]) and responsible for circulating neutrophil recruitment (Shi et al., [", "@B48]). ", "Significantly more GM-CSF protein was present in five tongues from male mice with 4NQO-induced oral SCC compared to four tongues from female mice with 4NQO-induced oral SCC (243.2 ± 9.3%, *P* = 0.015 Unpaired Student's *t*-test; Figure [5B](#F5){ref-type=\"fig\"}).", "\n\n{ref-type=\"table\"}. *", "P* \\< 0.05 for Sex vs. Treatment by Two-way ANOVA; \\**P* \\< 0.05, \\*\\**P* \\< 0.01 for Holm-Sidak *post hoc* comparisons for treatment; ^\\#^*P* \\< 0.05 for Holm-Sidak *post hoc* comparisons for sex. **(", "B)** Granulocyte macrophage-colony stimulating factor (GM-CSF) protein was measured in homogenized tongue tissue from male (*N* = 5) and female (*N* = 4) mice with 4NQO-induced oSCC compared to vehicle-treated male (*N* = 4) and female (*N* = 4) mice. ", "GM-CSF protein concentration was significantly higher in male mice (blue bar) with 4NQO-induced oSCC compared to female mice (red bar). ", "Data are represented as percent change from vehicle-treated mice. ", "\\*\\**P* \\< 0.01 by Unpaired Student's *t*-test.](fnint-12-00052-g0005){#F5}\n\nLeukocytes in the Oral Cancer Microenvironment Express Opioids {#s3-6}\n--------------------------------------------------------------\n\nNeutrophil infiltration negatively correlated with nociceptive behavior in 15 male mice (*r* = −0.538, *P* = 0.038) but not in 10 female mice (*r* = −0.254, *P* = 0.478, Pearson correlation; Figures [6A,B](#F6){ref-type=\"fig\"}). ", "To determine if cancer-recruited neutrophils express opioid precursor mRNA, CD45^+^CD11b^+^Ly6G^+^ cells were isolated after HSC-3 supernatant treatment from mouse tongues using FACS (Figure [6C](#F6){ref-type=\"fig\"}). ", "Presence of *Pomc* and *Penk* transcripts was detected in cancer supernatant-recruited neutrophils isolated from four male and Four female mice, but prodynorphin (*Pdyn*) was below the level of detection. ", "Furthermore, *Pomc* and *Penk* mRNA expression in neutrophils isolated from male mice was significantly greater than in neutrophils isolated from female mice (*P* = 0.031 for *Pomc* and *P* = 0.006 for *Penk*, Unpaired Student's *t*-test; Figure [6D](#F6){ref-type=\"fig\"}).", "\n\n{#F6}\n\nMonoclonal Antibodies Against Ly6G^+^ Can Deplete Neutrophils in the Tongue Microenvironment {#s3-7}\n--------------------------------------------------------------------------------------------\n\nHSC-3 supernatant injection into the tongue resulted in an increase in Ly6G^+^ neutrophils into the cancer microenvironment in 12 male and 10 female mice compared to supernatant from non-tumorigenic keratinocyte cell line, HaCaT (Figure [7A](#F7){ref-type=\"fig\"}). ", "However, there was no significant interaction between sex and treatment (*P* = 0.218, Two-way ANOVA). ", "Systemic treatment of the anti-mouse Ly6G mAb (αLy6G) in a healthy mouse resulted in full depletion of Ly6G^+^ cells in the tongue by 12 h and lasted at least 72 h (Figures [7Ba--c](#F7){ref-type=\"fig\"}). ", "Similarly, αLy6G treatment prevented neutrophil recruitment in response to three consecutive HSC-3 supernatant injections (Figures [7Bd--f](#F7){ref-type=\"fig\"}). ", "To determine the effect of neutrophil infiltration on acute oral cancer pain, we depleted neutrophils in the acute oral cancer pain model. ", "Female and male mice were administered a single i.p. ", "injection of either αLy6G or IgG2A isotype control. ", "After 12 h, HSC-3 or HaCaT cell culture supernatant was injected into the tongue for three consecutive days. ", "There was no significant interaction between sex and treatment (*P* = 0.262, Two-way ANOVA). ", "However, analysis of each sex independently found that HSC-3 cell culture supernatant in the presence of either IgG2A isotype control or αLy6G resulted in significantly longer gnaw-time compared to HaCaT supernatant in both female (*P* = 0.0001 for IgG2A, *P* \\< 0.0001 for αLy6G, One-way ANOVA, Figure [7C](#F7){ref-type=\"fig\"}) and male mice (*P* = 0.039 for IgG2A and *P* = 0.0002 for αLy6G, One-way ANOVA; Figure [7D](#F7){ref-type=\"fig\"}). ", "However, in male mice, HSC-3 supernatant injection in the presence of αLy6G resulted in significantly longer gnaw-time compared to HSC-3 supernatant in the presence of IgG2A isotype control (*P* = 0.020, One-way ANOVA; Figure [7D](#F7){ref-type=\"fig\"}).", "\n\n{#F7}\n\nLoss of Neutrophils During Carcinogenesis Results in Nociceptive Behavior in Males {#s3-8}\n----------------------------------------------------------------------------------\n\nIn the presence of 4NQO-induced oral SCC, an abundance of neutrophils were evident in the oral cancer microenvironment in male mice (Figure [5A](#F5){ref-type=\"fig\"}). ", "We subsequently identified an analgesic role for neutrophils in male mice during 4NQO-induced carcinogenesis using chronic antibody-mediated neutrophil depletion by repeated αLy6G injection (Treatment by time interaction *P* = 0.003, Two-way ANOVA). ", "There was a significant increase in gnaw-time in αLy6G-treated mice compared to IgG2A isotype control at week 23 (*P* = 0.004) and week 23.5 (*P* = 0.021) in the 4NQO oral cancer model (Figure [8A](#F8){ref-type=\"fig\"}). ", "However, the increased nociceptive behavior was not sustained for the duration of αLy6G treatment; nociceptive behavior returned to baseline at week 24 of chronic neutrophil depletion (*P* = 0.710, Figure [8A](#F8){ref-type=\"fig\"}). ", "At week 25, quantification of immune cells in the tongue revealed significantly less neutrophil recruitment in αLy6G-treated mice compared to IgG2A-treated mice during 4NQO carcinogenesis (−65.16 ± 2.5%, *P* = 0.033, One-way ANOVA; Figure [8B](#F8){ref-type=\"fig\"}). ", "However, neutrophil recruitment in 4NQO-treated mice receiving αLy6G was still significantly greater than vehicle-treated mice receiving αLy6G (695.7 ± 5.1%, *P* = 0.009, One-way ANOVA; Figure [8B](#F8){ref-type=\"fig\"}). ", "Furthermore, tongues from 4NQO-treated mice receiving αLy6G also had a significant increase in CD11b^+^Ly6G^−^ monocyte/macrophage infiltration into the cancer microenvironment compared to IgG2A-treated mice (154.9 ± 36.7%, *P* = 0.028, One-way ANOVA; Figure [8C](#F8){ref-type=\"fig\"}) suggesting a compensatory response to the αLy6G-induced decrease in neutrophil infiltration.", "\n\n{#F8}\n\nDiscussion {#s4}\n==========\n\nWe report a mechanism to explain the sex difference in oral cancer pain. ", "Our clinical and preclinical findings of increased cancer pain in females are consistent with results by Reyes-Gibby et al. ([", "@B40]) who show that women with oral cancer report more pain than men across 2,340 subjects. ", "Here, we report that tongue afferent neuronal excitability in female and male mice with oral cancer is similar; therefore, primary neuronal plasticity is unlikely the explanation for the sex difference. ", "Although inflammation is a hallmark of cancer (Hanahan and Weinberg, [@B20]), little is known about the contribution of the cancer-associated immune infiltrate to oral cancer pain. ", "Wang et al. ([", "@B60]) show that neutrophil infiltration is more abundant in human tongue SCC tissues and that the neutrophil density is higher in men compared to women. ", "Our investigation of inflammation reveals differential neutrophil infiltration in the 4NQO oral cancer microenvironment of female and male mice. ", "However, neutrophil-mediated analgesia inhibits nociceptive behavior only during the early stage of 4NQO-induced oral cancer development. ", "The antinociceptive effect following αLy6G-mediated neutrophil depletion is lost by 24 weeks. ", "Possibly, a reduction in neutrophil recruitment during 4NQO-induced carcinogenesis results in a delayed compensatory increase in CD45^+^CD11b^+^ monocyte/macrophages, or other leukocyte subpopulations, that contribute to nociception (Przewłocki et al., [", "@B39]; Plein and Rittner, [@B38]). ", "The underlying cause of the sex difference in neutrophil infiltration remains unidentified; however, sex hormones are a potential candidate. ", "Estrogen affects the number of circulating neutrophils and neutrophil lifespan (Bouman et al., [", "@B3]). ", "Studies using injury and burn rodent models find that testosterone potentiates, whereas estrogen limits Ca^2+^ mobilization in neutrophils (Deitch et al., [", "@B13]), suggesting that gonadal hormones can regulate neutrophil activity.", "\n\nOral cancer patients consistently report significantly higher function-related pain rather than spontaneous pain (Connelly and Schmidt, [@B7]). ", "We found a significant sex difference in functional intensity, functional sharpness and functional restriction in our clinical patient cohort. ", "In an attempt to recapitulate these clinical findings in rodents, we measured a behavioral index of gnawing-induced nociception with the dolognawmeter assay. ", "Gnawing is a routine orofacial function that is coordinated by the trigeminal somatosensory and motor systems and activates the temporomandibular joint, muscles of mastication, jaws, incisors, lips, tongue, buccal mucosa, palate and gingiva in a fashion that is similar to the chewing associated with mastication in humans. ", "In addition to function-related pain, we also found a significant sex difference in reported intensity of spontaneous pain. ", "Conditioned place preference could be used to test the hypothesis that there is a sex difference in spontaneous pain secondary to oral cancer in mice (King et al., [", "@B25]).", "\n\nWe find that cancer-recruited neutrophils express β-endorphin and met-enkephalin, which are antinociceptive in male mice; neutrophil depletion produces nociception. ", "Immune cells drive endogenous antinociception in non-cancer pain. ", "Opioid-containing leukocytes contribute to endogenous pain inhibition during early complete Freund's adjuvant (CFA)-induced inflammatory pain (Mousa et al., [", "@B32]) and in models of chronic neuropathic pain (Labuz et al., [", "@B27]; Chao et al., [", "@B5]). ", "Labuz et al. ([", "@B27]) report that immune infiltration during nerve injury produces suppression of mechanical allodynia by the secretion of opioids. ", "Similar to our results with naloxone, immune-mediated anti-allodynia is blocked by naloxone methiodide. ", "Exogenous granulocyte-colony stimulating factor alleviates thermal hyperalgesia and mechanical allodynia in rats with chronic constriction injury through leukocyte-derived endogenous opioids (Chao et al., [", "@B5]). ", "In humans, opioid peptides released locally by leukocytes decrease pain intensity following surgery (Stein et al., [", "@B55]). ", "Awad et al. ([", "@B1]) report that neutrophils in a wound, collected from sternotomy patients, contain high levels of endogenous opioids and possibly contribute to peripheral analgesia.", "\n\nAnimal and human data support the role of peripheral opioids for analgesia (Stein et al., [", "@B53]; Kapitzke et al., [", "@B24]). ", "Administration of the peripherally restricted opioid morphine-6-glucoronide reduces hyperalgesia induced by freezing skin to −30°C and delayed onset muscle soreness (Tegeder et al., [", "@B57]). ", "Opioid peptides from keratinocytes contribute to endogenous analgesia following administration of endothelin-1 (Viet et al., [", "@B59]). ", "Oral carcinoma is comprised of malignant oral keratinocytes, which might serve as a potential source of opioids within the cancer microenvironment. ", "Viral- and nonviral-mediated delivery of genes for the μ-opioid receptor and the endothelin B receptor (*OPRM1* and *EDNRB*, respectively) produce endogenous analgesia through the secretion of opioids by the carcinoma in preclinical oral cancer pain models (Viet et al., [", "@B59]; Yamano et al., [", "@B62]). ", "Adenoviral transduction produces immune effects that prohibit clinical use (Nayak and Herzog, [@B34]). ", "Furthermore, concerns for adenoviral-mediated transduction of cancer include limited transduction efficiency and replication specificity (Yamamoto and Curiel, [@B61]). ", "However, there are no studies in cancer pain for immune-mediated endogenous analgesia. ", "Analgesia targeted to the cancer microenvironment obviates off-target effects of opioids in the CNS and gastrointestinal tract. ", "Immune-mediated endogenous analgesia could be enhanced through immune cell number (Chao et al., [", "@B5]) or opioid peptide production (Chuang et al., [", "@B6]). ", "Neutrophils, T cells and macrophages contain opioid peptide mRNA (Przewłocki et al., [", "@B39]; Plein and Rittner, [@B38]). ", "Recently developed immunotherapy for cancer (Ferris et al., [", "@B16]) may increase infiltration of opioid-containing immune cells that could inhibit pain as well as reduce tumor burden.", "\n\nThere are three limitations of our experimental design. ", "The first is the lack of comprehensive neutrophil characterization within the cancer microenvironment. ", "Neutrophils in mice are recognized as CD11b^+^Ly6G^+^ (Daley et al., [", "@B11]; Fridlender and Albelda, [@B18]), markers which do not differentiate between neutrophil subtypes. ", "The cancer microenvironment can be infiltrated by anti- (N1) or pro-tumoral (N2) neutrophils (Fridlender and Albelda, [@B18]; Sagiv et al., [", "@B45]). ", "N1 and N2 neutrophil phenotypes are morphologically similar; however, transcriptional profiling can distinguish them (Elpek et al., [", "@B15]). ", "Single-cell analysis might allow for classification of N1 and N2 infiltrating neutrophils during 4NQO-induced carcinogenesis in the mouse model. ", "The second limitation is the inconsistent outcomes in the two cancer models with sex differences and neutrophil recruitment. ", "While we find a sex difference in neutrophil infiltration with the 4NQO model there is not a difference in the HSC-3 supernatant-induced model. ", "The administration of oral cancer cell culture supernatant allows for us to isolate the nociceptive effect of inflammatory cell infiltration in the absence of the cancer. ", "However, the supernatant model lacks cancer microenvironment constituents (e.g., tumor cells, cancer-associated fibroblasts) that play a role in immune cell recruitment (Le Bitoux and Stamenkovic, [@B29]). ", "A final limitation is that we did not monitor gonadal hormones. ", "Sex differences in endogenous analgesia depend on hormonal regulation. ", "Female rats exhibit less swim stress-induced analgesia (SIA); furthermore, swim SIA is reversed by opioid blockade in males, but not in females (Romero et al., [", "@B44], [@B43]). ", "Mogil et al. ([", "@B31]) find that estrogen contributes to sex-dependent efficacy of naloxone during swim SIA. ", "We inferred that a component(s) of the oral cancer microenvironment is the source of opioid-mediated analgesia in male mice based on our result that peripherally restricted naloxone methiodide (Rohde et al., [", "@B42]) increased HSC-3 supernatant-induced nociceptive behavior in male mice only. ", "Naloxone had the opposite effect in female mice. ", "The underlying mechanism for the antinociceptive effect of naloxone in female mice is unknown. ", "Additional experiments to address this limitation are to repeat the study using gonadectomized mice or administer gonadal hormones.", "\n\nOur data highlight sex differences in oral cancer pain, which we attribute to endogenous opioids secreted by neutrophils. ", "Our findings suggests that sex is an important variable when considering treatment for oral cancer patients. ", "Female patients may benefit more from peripherally restricted opioids due to a decreased opioidergic neutrophil presence in the tumor microenvironment. ", "Furthermore, therapeutic approaches to activate the immune response in the cancer microenvironment in both sexes are potentially a strategy for the treatment of oral cancer associated pain. ", "Such an approach would avoid the systemic side effects of opioid-based treatments.", "\n\nAuthor Contributions {#s5}\n====================\n\nAll authors listed contributed substantially to the work. ", "NS designed the research, conducted the experiments, performed data analyses and wrote the manuscript. ", "AB provided oral histopathological data analyses and guidance. ", "ED and RD provided technical support and data collection for all behavior experiments. ", "JD provided animal behavior expertise and technical support. ", "SW and HK provided technical support and data analysis for oral cancer patient pain questionnaires. ", "BS and DA assisted in research design and writing of the manuscript.", "\n\nConflict of Interest Statement {#s6}\n==============================\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.", "\n\nWe thank Mr. Yogin Patel as well as Dr. David Levy and the New York University College of Dentistry Flow Cytometry Facility for their technical contributions. ", "We acknowledge the cell sorting technologies provided by NYU Langone's Cytometry and Cell Sorting Laboratory that is supported in part by NIH/NCI P30CA016087.", "\n\n**Funding.** ", "This work was supported by the National Institute of Dental and Craniofacial Research through individual investigator grant F32 DE027269 (NS) and grant R01 DE025393 (BS). ", "Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. ", "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.", "\n\nSupplementary Material {#s7}\n======================\n\nThe Supplementary Material for this article can be found online at: <https://www.frontiersin.org/articles/10.3389/fnint.2018.00052/full#supplementary-material>\n\n###### \n\nClick here for additional data file.", "\n\n###### \n\nClick here for additional data file.", "\n\n[^1]: Edited by: Phillip R. Kramer, College of Dentistry, Texas A&M University, United States\n\n[^2]: Reviewed by: Dayna Loyd Averitt, Texas Woman's University, United States; Marcos Fabio DosSantos, Universidade Federal do Rio de Janeiro, Brazil\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "\n\n\n\nIdiopathic diseases remain a thorn in both physicians' and patient’s sides from a diagnostic and therapeutic perspective. ", "For instance, diagnosis of chronic fatigue syndrome (CFS)—an idiopathic disorder marked by lengthy spells of weakness, fatigue, and depression—is predominantly based on symptoms and on ruling out any underlying medical condition, rather than on laboratory tests and physical examination. ", "Yet now, new research from investigators at the University Medical Centre Groningen, The Netherlands, demonstrates a link between CFS symptoms and lower thyroid hormone levels. ", "Findings from the new study were published today in Frontiers in Endocrinology, in an article entitled “Higher Prevalence of “Low T3 Syndrome” in Patients With Chronic Fatigue Syndrome: A Case–Control Study.”", "\n\nThe new study indicates that CFS, a condition with unknown causes, can be explained by lower thyroid hormones—but may be distinct from thyroidal disease. ", "This finding can be seen as a first step to finding treatment for a debilitating illness for which there is no recognized treatment. ", "Interestingly, the researchers found that several symptoms resemble those of hypothyroidism—a condition where the thyroid gland does not produce enough thyroid hormone. ", "In hypothyroidism, the body tries to encourage thyroid hormone activity by releasing more thyroid-stimulating hormone—however, this does not happen in patients with CFS.", "\n\nThis contrast in thyroid-stimulating activity led investigators to hypothesize that CFS is caused by low activity of thyroid hormones in the absence of thyroidal disease. ", "The researchers compared thyroid function and markers of inflammation between 98 CFS patients and 99 healthy controls. ", "Remarkably, the CFS patients had lower serum levels of certain key thyroid hormones such as triiodothyronine (T3) and thyroxine (T4), but normal levels of thyroid-stimulating hormone.", "\n\n“We measured parameters of thyroid function, (metabolic) inflammation, gut wall integrity and nutrients influencing thyroid function and/or inflammation,” the authors wrote. “", "Most remarkably, CFS patients exhibited similar thyrotropin, but lower free triiodothyronine (FT3) (difference of medians 0.1%), total thyroxine (TT4) (11.9%), total triiodothyronine (TT3) (12.5%), %TT3 (4.7%), sum activity of deiodinases (14.4%), secretory capacity of the thyroid gland (14.9%), 24-h urinary iodine (27.6%), and higher % reverse T3 (rT3) (13.3%). ", "FT3 below the reference range, consistent with the “low T3 syndrome,” was found in 16/98 CFS patients vs. 7/99 controls (OR 2.56; 95% confidence interval = 1.00–6.54). ", "Most observations persisted in two sensitivity analyses with more stringent cutoff values for body mass index, high-sensitive C-reactive protein (hsCRP), and white blood cells (WBC).”", "\n\nThrough additional analyses, the research team found that CFS patients had a lower urinary iodine status and low-grade inflammation, which possibly mirrored the symptoms of patients with hypothyroidism. ", "These CFS patients, however, had relatively higher levels of another thyroid hormone called “reverse T3” or rT3. ", "This appeared to be due to a shift in hormone production, where the body preferred to convert T4 to rT3 instead of producing T3. ", "The low T3 levels found in CFS patients coupled with this switchover to rT3 could mean that T3 levels are severely reduced in tissue.", "\n\n“We found possible evidence of (chronic) low-grade metabolic inflammation (ferritin and HDL-C [high-denisty lipoprotein cholesterol]). ", "FT3, TT3, TT4, and rT3 correlated positively with hsCRP in CFS patients and all subjects,” the authors penned. “", "TT3 and TT4 were positively related to hsCRP in controls. ", "Low circulating T3 and the apparent shift from T3 to rT3 may reflect more severely depressed tissue T3 levels. ", "The present findings might be in line with recent metabolomic studies pointing at a hypometabolic state. ", "They resemble a mild form of “non-thyroidal illness syndrome” and “low T3 syndrome” experienced by a subgroup of hypothyroid patients receiving T4 monotherapy.”", "\n\nThe researchers believe the inclusion of patient information, such as duration of illness, would enable a correlation with their biochemical profiles. ", "Furthermore, even though the study demonstrates a link between CFS symptoms and low levels of key thyroid hormones, a definitive cause for CFS remains unknown.", "\n\n“One of the key elements of our study is that our observations persisted in the face of two sensitivity analyses to check the strength of the association between CFS and thyroid parameters and low-grade inflammation,” concluded lead study investigator Begoña Ruiz-Núñez, a doctoral candidate at the University Medical Center Groningen. “", "This strengthens our test results considerably.”", "\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n" ]

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[ "Discipline (Throbbing Gristle song)\n\nDiscipline is a song by the English electronic group Throbbing Gristle.", "\n\nSingle\nThe \"Discipline\" single features two versions of the title track, recorded in Berlin and Manchester, respectively. ", "The center labels are cream with black printing, and a Glossy picture sleeve depicts the band standing outside the ex-Nazi Ministry of Propaganda in Berlin, with another picture on the other side featuring Val Denham holding a Hitler Youth dagger centre back. ", "The words \"Techno Primitive\" were scratched on side A and \"Psykick Youth Squad\" on side B. Both tracks were later released on the CD version of 20 Jazz Funk Greats. ", "\n\nThe word \"Techno Primitive\" was later used by electronic duo Chris & Cosey for their 1985 album of the same name, while the name \"Psykick Youth Squad\" can be seen as a reference to the later band Psychic TV, both groups made up of ex-Throbbing Gristle members.", "\n\nTrack listing\nSide A:\n\"Discipline (Manchester)\" - 8:06\nSide B:\n\"Discipline (Berlin)\" - 10:45\n\nSong\n\"Discipline\" may be Throbbing Gristle's most infamous song. ", "First played at the S036 Club in Berlin (as documented on the single), it was at first entirely improvised, based upon a topic suggestion given by Cosey Fanni Tutti before the show. ", "The song is driven by a minimal, pulsing synthesizer drumbeat, over which Genesis P-Orridge would declaim lyrics surrounding the concept of discipline, slowly introducing other musical elements, such as electric bass and walls of guitar or synth noise. ", "After Berlin, it was played at nearly every TG show up to the group's demise. ", "Often it would range in length from eight to twelve minutes, although it could be stretched out much longer: A version from one of their last shows at the Lyceum in London was over half an hour, as documented on the bootleg Once Upon a Time and the VHS release Destiny.", "\n\nThe song was covered by Marc Almond and Friends on a flexi disc that was issued free with an issue of Flexi-Pop Magazine. ", "He performed it solo on Siouxsie and the Banshees' Join Hands tour at the Hammersmith Odeon, an extended version of the song forming the entirety of his set, which preceded The Cure, the main support band. ", "Discipline was also covered by Boyd Rice and by German synthpop group Propaganda as \"Disziplin\".", "\n\nCharts\n\nReferences\n\nExtended links\nDiscogs entry\n\nCategory:1981 singles\nCategory:Throbbing Gristle songs\nCategory:1981 songs" ]

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[ "Alex Jones explains the significance of President Trump’s epic joint press conference with the President of Finland. ", "Share this link!", "\n\nAlso:\n\nPresident Trump Attacks Corrupt Fake News in Joint Press Conference With Finnish President\n\n\n\nFull breakdown of Trump’s meeting with the Finnish president!", "\n\nDon’t miss:\n\nPresident Trump Unloads On Hoax Impeachment\n\n\n\nTrump goes on the offensive in a meeting with the President of Finland.", "\n\nBy the way, we are in the final days of the Black Friday Comes Early sale! ", "Get 50% off products with double Patriot Points and free shipping right now!", "\n\nThe Emergency Election Sale is now live! ", "Get 30% to 60% off our most popular products today!" ]

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[ "FREE now and never miss the top politics stories again. ", "SUBSCRIBE Invalid email Sign up fornow and never miss the top politics stories again. ", "We will use your email address only for sending you newsletters. ", "Please see our Privacy Notice for details of your data protection rights.", "\n\nThe Thomas G Thompson research vessel stopped in the port of Kaohsiung on the southern side of the disputed island on Monday, in a move which has angered officials in Beijing. ", "Taiwan’s Defence Minister, Yen De-fa, defended the 274ft ship’s activities and said the docking was “unrelated to military activity” while the country’s state-owned Central News Agency said the ship was only there to refuel and change crew. ", "But China’s foreign ministry spokesman Lu Kang hit back and issued a stark warning to the Pentagon. ", "He said they saw the scientific research vessel’s movements in the South China Sea as threatening. ", "He said that China wanted to “express our solemn concerns to the US” about the ship’s visit which has been viewed by officials in Beijing as a military action which has escalated tensions between the two countries.", "\n\nMr Kang added his country “opposes all kinds of military contacts between the US and Taiwan” and said the United States should “stop all forms of official exchanges and military interactions with Taiwan and handle the Taiwan-related issues with caution”. ", "The 27-year-old boat, which is owned by the US Navy’s Office of Naval Research, operates under an agreement with the University of Washington and has capacity for 21 officers, two marine technicians and 36 scientists. ", "Since the end of the Second World War, the Chinese Government has maintained that the island, which is 180km east of the mainland, is still part of their territory but Taipei disputes the claim. ", "Most western countries, including the UK and the US, maintain unofficial relations with Taiwan but the Trump administration’s decision to sell more than £200milion worth of military equipment, including fighter jet parts, last month enraged Beijing.", "\n\nTensions between China's Xi Jinping and Donald Trump could rise over the US Navy move\n\nThe Pentagon announced in September that a deal had been struck with the Taiwanese administration who agreed to buy $330million (£229million) worth of spare parts for F-16, C-130 and F-5 aircraft. ", "At the time, the Pentagon’s Defence Security Cooperation Agency said the deal also included “systems and related elements of logistics and programme support”. ", "A Pentagon statement said: “This proposed sale will contribute to the foreign policy and national security of the United States by helping to improve the security and defensive capability of the recipient, which has been and continues to be an important force for political stability, military balance and economic progress in the region.” ", "But the move infuriated Beijing who saw the sale as a clear sign the US was helping to strengthen Taiwan’s aerial fleet at a time when military might was swinging in favour of China.", "\n\nChina has become embroiled in a trade war with America\n\nDonald Trump and Melania Trump returning to White House earlier this week after a visit to Florida" ]

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[ "A Pro-nociceptive State in Sensory Modulation Disorder (SMD) {#s1}\n============================================================\n\nTactile over-responsiveness was characterized some decades ago as consisting of defensive-protective behaviors which are accompanied by stress responses to nociceptive qualities of sensory stimuli (Ayres, [@B6]; Fisher and Dunn, [@B45]). ", "Specifically, non-painful sensory stimuli are often experienced by individuals with this disorder as aversive, bothersome (Kinnealey et al., [", "@B66]) and lingering (Miller et al., [", "@B84]). ", "Despite these reports, the pain sensory system has been neglected in both the Sensory modulation disorder (SMD) clinical and research domains. ", "Interestingly, *allodynia*, a clinical term not implying a mechanism, refers to pain due to a stimulus that does not normally provoke pain \\[[@B640]\\]. ", "Consequently, allodynia represents a condition where the response mode differs from the stimulus mode \\[[@B640]\\], the latter of which may be induced by various non-painful stimuli such as light touch, cool or warm stimuli (Price, [@B99]; Zeilhofer, [@B128]). ", "Therefore, we suggest allodynia to mirror sensory over-responsivity (SOR), a subtype of SMD, by perceiving non-painful sensations as irritating, unpleasant or painful (Miller et al., [", "@B84]). ", "According to the International Association for the Study of Pain \\[[@B640]\\], pain is \"an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.\" ", "This definition of pain has led our research efforts for the past decade, where we have endeavored to further our understanding of the SOR phenomenon, by studying its phenotype as well as its underlying mechanisms.", "\n\nPain and other sensory systems are measured in the laboratory setting by performing quantitative sensory testing (QST), a standardized method to test for and characterize sensory sensitivity. ", "QST measures the perceived intensity of a given stimulus (i.e., the subjective experience) while controlling the intensity of the stimulus (Dyck et al., [", "@B43]; McGrath and Brown, [@B82]; Hansson et al., [", "@B59]; Arendt-Nielsen and Yarnitsky, [@B5]). ", "Moreover, it is used to indirectly evaluate the underlying sensory functioning by testing a spectrum of peripheral nerve system functions, as well as revealing abnormalities related to disorders of the central nervous system (CNS; Bartlett et al., [", "@B14]; Hagander et al., [", "@B58]; Arendt-Nielsen and Yarnitsky, [@B5]). ", "Previous studies in our lab have used QST to evaluate somatosensory *detection thresholds* \\[i.e., ", "the minimum intensity levels at which 50% of stimuli are recognized; [@B640]\\], including those of light touch, vibration, warm and cool sensations. ", "We found no differences between individuals with SOR and those without, neither in children nor in adults. ", "Furthermore, when measuring heat and cold *pain thresholds* \\[i.e., ", "the minimum intensity levels of a stimulus that are perceived as painful; [@B640]\\], again, no such group differences were found (Bar-Shalita et al., [", "@B12], [@B11]). ", "In light of these findings, we showed that somatosensory detection and pain thresholds are not impacted in SOR. ", "Intact sensory detection thresholds denote the absence of peripheral nerve system lesions. ", "However, when we investigated laboratory-induced suprathreshold stimuli to measure the perceived pain intensity, we found group differences in both children and adults; individuals with SOR rated heat and mechanical painful stimuli as more painful than those without SMD, demonstrating hyperalgesia in the former group (Bar-Shalita et al., [", "@B12], [@B11]; Weissman-Fogel et al., [", "@B119]). *", "Hyperalgesia* denotes abnormally increased pain from a stimulus that normally provokes pain, and like allodynia, it is a clinical term rather than a mechanism \\[[@B640]\\]. ", "Furthermore, we revealed that in individuals with SOR the evoked pain sensation is higher in intensity and lingers for a longer duration after stimulus termination vs. non-SMD subjects who showed an expected gradual reduction in pain intensity that reached a level of no-pain within a 5--6 min time period (Bar-Shalita et al., [", "@B12], [@B11], [@B13]; Weissman-Fogel et al., [", "@B119]). ", "This lingering sensation, termed *after-sensation*, validates the clinical symptoms reported by clients and could explain the accumulation of aversive sensations experienced by individuals with SMD throughout the day (Kinnealey et al., [", "@B67]).", "\n\nAfter-sensation and hyperalgesia are both excitatory signs indicating central-sensitization that impacts pain perception (Andersen et al., [", "@B2]; Woolf and Salter, [@B123]; Woolf and Max, [@B122]; Gottrup et al., [", "@B53]; D'Mello and Dickenson, [@B36]). ", "In SOR, we were the first to report the existence of a pro-nociceptive state resulting in pain amplification (Weissman-Fogel et al., [", "@B119]). ", "Searching for this pro-nociceptive state underlying mechanism, we found inhibitory mechanisms which did not differ from non-SMD controls, though clearly presented a delayed process of inhibition. ", "This emerged when testing the conditioned pain modulation (CPM) neurophysiological phenomenon, where one painful stimulus, the \"conditioning stimulus,\" inhibits a concomitant or subsequent painful \"test stimulus\" (Weissman-Fogel et al., [", "@B119]). ", "Thus, individuals with SOR have central sensitization which is expressed as a pro-nociceptive state due to over excitation rather than reduced inhibition. ", "Incoming sensory stimuli from the peripersonal space (\"the spatial region surrounding the body that a person regards as theirs psychologically\"; Senkowski et al., [", "@B103]) are experienced by an individual with SOR as painful (allodynia) and therefore require greater recruitment of top-down inhibitory mechanisms to support survival. ", "In children and adults with SOR, their survival efforts are expressed by defensive-protecting behaviors when confronted with sensory stimuli intruding their peripersonal space. ", "Indeed, quality of life is reduced in individuals with SOR, specifically due to bodily pain.", "\n\nAbnormal Central Sensory Processing in SMD {#s2}\n==========================================\n\nCurrent neurophysiological methods such as electroencephalography (EEG) have been used to define the neural origins of SMD. ", "It has been found that the behavioral phenotype of SMD is due to atypical neural processing of both single *non-painful* sensory stimulus (i.e., somatosensory or auditory) and integration of simultaneous multi-sensory stimulation (i.e., somatosensory and auditory), This has been manifested by greater (Parush et al., [", "@B92], [@B93]) and prolonged (Zlotnik et al., [", "@B130]) early event-related potentials (ERPs; a brain response to a specific external event) in response to tactile and auditory stimuli, respectively, along with smaller (Gavin et al., [", "@B48]) or greater (Davies et al., [", "@B30]) amplitudes of late auditory ERPs. ", "This abnormally intense processing and lingering of sensory stimuli may result in individuals with SMD feeling overwhelmed when facing everyday sensory experiences. ", "On top of this, adaptation deficiency to repetitive stimuli has been evident in ERPs (Kisley et al., [", "@B68]; Davies and Gavin, [@B29]; Brett-Green et al., [", "@B22]; i.e., ERP amplitude inhibition in response to repetitive paired-click stimulation), indicating a deficiency in pain inhibition probably due to an inefficient gating process. ", "Moreover, atypical (neural integration of simultaneous multisensory stimulation (i.e., multisensory integration) has been indicated by spatio-temporal distribution of ERP responses to dual auditory and somatosensory stimuli (Brett-Green et al., [", "@B22]). ", "Specifically, while in typically developing children multisensory integration occurs in central and post-central scalp regions during both early and later stages of sensory information processing (Brett-Green et al., [", "@B21]), those with SMD demonstrate a fronto-central distribution (Brett-Green et al., [", "@B22]). ", "Accordingly, we have recently found (Granovsky et al., [", "@B57]) that subjects with SOR have different topographical dispersions of resting state EEG activity within the alpha band; while non-SMD individuals demonstrated increased activity toward parietal sites, those with SOR did not show this topographical distribution. ", "Finally, novel findings from our lab point at an abnormal basic neurophysiological activity under a task-free condition in SOR individuals whereby there was a global reduction of cortical activity in theta, alpha and beta bands, most prominently in the alpha band, compared to non-SMD individuals. ", "Thus, individuals with SOR demonstrate a neurophysiological state of a \"non-resting\" brain, which may partly explain their reported ongoing daily alertness to peripersonal stimuli. ", "Furthermore, based on the \"Gating by Inhibition\" theory (Jensen and Mazaheri, [@B65]), alpha activity in higher-order cortical areas is mandatory for inhibiting task-irrelevant input. ", "Thus, reduced alpha activity may consequently result in excessive sensory input processing which may contribute or result in SOR.", "\n\nStudies have found associations between neurophysiological measures and behavioral manifestations of SMD, based on self- and caregiver reports of daily experience of sensory stimuli and functional performance on sensory tasks (Kisley et al., [", "@B68]; Gavin et al., [", "@B48]; Zlotnik et al., [", "@B130]). ", "Namely, more sensory responsive or more avoiding behavior was correlated with higher amplitudes and more prolonged latencies of sensory response ERPs. ", "This may reflect the major resources needed to process daily sensory stimuli among people with SMD. ", "Moreover, such brain responses to sensory stimuli have correctly distinguished children with SMD from typically developing children and adults with 77%--96% accuracy (Davies and Gavin, [@B29]; Davies et al., [", "@B30]; Gavin et al., [", "@B48]). ", "We, therefore, suggest that these neurophysiological differences may serve as characteristic markers of SMD that are underpinned by the anatomical abnormalities in sensory pathways (Owen et al., [", "@B91]) and which may contribute to the sensitive and/or avoidance behavior. ", "This experience-induced neural plasticity may further mark its footprint in a sensory signature and thereby contribute to the sensory symptoms and daily life challenges experienced by individuals with SMD. ", "Whether such a neurophysiological anomaly in individuals with SMD is nature or nurture, there is no doubt it reduces their successful social and functional participation in their home, school and community environments.", "\n\nAn Excitatory/Inhibitory (E/I) Imbalance as a Shared Mechanism for SMD and Pain {#s3}\n===============================================================================\n\nThe neurophysiological studies described above which investigated the central processes in response to external non-painful stimuli suggest an imbalance between excitatory and inhibitory processes in the brain. ", "A balanced excitatory (glutamatergic) and inhibitory \\[γ-aminobutyric acid (GABA)ergic and glycinergic\\] ratio is essential for the brain to work appropriately in response to different sensory inputs. ", "In adults, the tightly regulated E/I balance is achieved by homeostatic control of the strength and weight of transmissions in response to external stimuli. ", "An increased E/I ratio can lead to a prolonged neocortical activity which may be associated with abnormal sensory processing such as hypersensitivity to different sensory stimuli (Zhang and Sun, [@B129]).", "\n\nThe E/I balance is one of the fundamental elements required for a normal sensory threshold and for regulating supra-threshold stimuli that originate from different sensory organs. ", "In her early work, Ayres (Ayres, [@B6]) described the interrelationship of excitatory and inhibitory processes as modulation. ", "Sufficient modulation occurs when the two processes work in harmony. ", "Dunn ([@B38], [@B40]) developed a model of sensory modulation to explain the relationship between behavior and neurophysiological responses. ", "Based on Dunn's model of sensory processing, the nervous system's functionality is represented by neurological thresholds whereby a \"high threshold\" requires a greater sensory input for activation while a \"low threshold\" requires lower stimulation for activation of sensory processing (Dunn, [@B39]). ", "Behaviorally, individuals with low thresholds notice and respond to sensory stimuli more readily than the typical individuals, and thus represent a sensory profile that is sensory sensitive and sensory avoiding, defined as SOR (Miller et al., [", "@B84]). ", "It is suggested by both Dunn ([@B40]) and Miller et al. ([", "@B84]) that individual sensory profiles are grouped based on psychophysiological measures, such as sensory thresholds and responses to supra-threshold stimuli, rather than by responses to specific sensory modalities. ", "This, therefore, suggests that there are neurophysiological mechanisms common to more than one sensory system including the pain, auditory, tactile, and visual systems.", "\n\nThe hypersensitivity and lingering in response to experimental pain observed in individuals with SOR (Bar-Shalita et al., [", "@B12], [@B11], [@B13]; Weissman-Fogel et al., [", "@B119]) despite efficient habituation and inhibition capabilities (Weissman-Fogel et al., [", "@B119]) indicates increased neuronal excitation in the pain-transmitting pathways with no inhibition deficiency. ", "We, therefore, suggest that the enhanced activity of pain-facilitatory pathways with preserved pain-inhibitory mechanisms in SMD may be related to an E/I imbalance (Weissman-Fogel et al., [", "@B119]). ", "Glutamate, the main excitatory neurotransmitter, and GABA, the main inhibitory transmitter within the CNS play key roles in central pain processing. ", "Specifically, glutamate plays an important role in pain transmission and modulation (see review: Goudet et al., [", "@B54]). ", "The glutamate receptors are widely distributed throughout the CNS where they regulate cell excitability and synaptic transmission at different levels of the pain matrix. ", "Expression of glutamate receptors have been reported in the thalamus (Lourenço Neto et al., [", "@B87]), amygdala (Neugebauer, [@B88]), and the midbrain periaqueductal gray region (PAG; Marabese et al., [", "@B78]) and generally serve a pro-nociceptive role (Goudet et al., [", "@B54]). ", "The ascending dorsal horn nociceptive neurons project toward all these brain areas with the PAG being an important center for the processing of nociceptive information and descending modulatory circuitry. ", "Glutamate receptors that have also been detected in glial cells which are active regulators and protectors of nervous system and therefore play a role in pain. ", "On the other hand, GABA receptors have an important anti-nociceptive role in acute and chronic pain. ", "At the supra-spinal level, they depress ascending adrenergic and dopaminergic input to the brainstem, and facilitate the descending noradrenergic input to the spinal cord dorsal horn (Goudet et al., [", "@B54]). ", "Importantly, elevated brain glutamate levels (Harris et al., [", "@B63]; Prescot et al., [", "@B98]; Petrou et al., [", "@B94]) and lower levels of GABA (Foerster et al., [", "@B46]; Petrou et al., [", "@B94]) have been reported in chronic pain conditions. ", "This neurotransmitter imbalance is manifested by neuronal hyperexcitability, which can be alleviated by anticonvulsants. ", "Anticonvulsants inhibit neuronal hyperexcitability by multiple mechanisms including direct or indirect enhancement of inhibitory GABAergic neurotransmission, or inhibition of glutamatergic neurotransmission (Sullivan and Robinson, [@B108]).", "\n\nThe coupling between SOR to daily non-painful stimuli and enhanced pain facilitation suggests a common brain mechanism that is due to an E/I imbalance. ", "This shared mechanism in SMD individuals who are pain-free may further serve as a predisposing factor for the development of pain disorders. ", "Indeed, we recently found SMD to be a contributing factor for having complex regional pain syndrome (CRPS). ", "CRPS is a chronic pain syndrome of unknown pathophysiology that develops after limb surgery or injury in 4%--7% of patients (Harden et al., [", "@B60]; Bruehl, [@B23]). ", "Though the origin and progress of CRPS varies, it usually evokes a severe state of disablement in the affected limb, which robustly reduces function and quality of life (Lohnberg and Altmaier, [@B75]; van Velzen et al., [", "@B114]; Bean et al., [", "@B15]). ", "No specific clinical sign or symptom has been found as a risk factor for CRPS onset (Pons et al., [", "@B97]). ", "Yet, early identification of those at risk for CRPS is linked to enhanced outcomes (Li et al., [", "@B74]; Wertli et al., [", "@B120]). ", "Our findings revealed that for a person with SMD the risk of CRPS is 2.68--8.21 times higher than for a person without SMD. ", "Consequently, including the SMD domain as a risk factor in the CRPS clinical discussion prior to intervention may allow for an early diagnosis and a significant prognostic improvement.", "\n\nMulti-Sensory Processing Shaping the Pain Experience in SMD {#s4}\n===========================================================\n\nApplying a nociceptive stimulus to the skin evokes activity imaged in a large network of brain regions which is referred to as the \"pain matrix.\" ", "The pain matrix comprises the primary (S1) and secondary (S2) somatosensory cortices, the insula, and the anterior cingulate cortex (ACC; Treede et al., [", "@B109]; Peyron et al., [", "@B95]; Apkarian et al., [", "@B3]). ", "However, Mouraux et al.", "'s ([@B86]) findings challenge this model and suggest that the pain matrix regions are equally involved in processing non-nociceptive and nociceptive stimuli. ", "Moreover, they postulate that most parts of the pain matrix are likely involved in cognitive brain processes that detect and process salient multisensory stimuli. ", "Based on the hypothesis that most of the neocortex is multisensory (Ghazanfar and Schroeder, [@B51]), Senkowski et al. ([", "@B103]) argue that pain-related neural responses at all processing stages can be shaped by non-painful stimuli. ", "Different factors, such as stimulus intensity and valence, affect the way other sensory stimuli shape the pain perception. ", "Specifically, painful stimuli accompanied by environmental input from other sensory modalities can impact not only the pain perception but also the processing of these stimuli. ", "Other sensory modality stimuli may draw attention away and subsequently reduce the perceived pain intensity, or conversely, these stimuli can amplify the saliency of the painful stimuli and evoke an augmented pain experience. ", "This suggests that non-painful stimuli in the peripersonal space have an important role in shaping the pain experience. ", "Exploring this association, we found that the correlation between daily pain sensitivity and hyper-responsiveness tripled in individuals with SOR compared to non-SMD individuals (Bar-Shalita et al., [", "@B9]). ", "Moreover, an unpleasant sensation intruding the peripersonal space usually evokes a defense response (Senkowski et al., [", "@B103]). ", "Indeed, children and adults with SOR demonstrate and report protective responses to non-painful stimuli (Miller et al., [", "@B84]), which may be explained similarly to the main function of pain, warning of danger and preventing future tissue damage (Crombez et al., [", "@B28]; Dowman, [@B37]; Senkowski et al., [", "@B103]). ", "Taken together, research on the multisensory shaping of pain has definite clinical implications (e.g., Senkowski and Heinz, [@B102]), but also offers an important novel understanding of the mechanisms as well as the relevance of multisensory processing to pain processing.", "\n\nClinical Manifestation of SOR in Chronic Pain Conditions {#s5}\n========================================================\n\nIncreased sensitivity to non-painful sensory stimuli is widely described for many chronic pain states. ", "For example, in migraine, lower sensory thresholds, enhanced psychophysical and neurophysiological responses, and reduced adaptation and habituation to a specific sensory modality (usually visual or auditory) have all been reported including during the inter-ictal state (Harriott and Schwedt, [@B62]; Demarquay and Mauguière, [@B35]). ", "Furthermore, many migraineurs report inter-ictal discomfort to everyday stimuli such as odors, light and sound, which may even trigger or worsen headache intensity (Vanagaite et al., [", "@B115]; Martin et al., [", "@B79]; Borini et al., [", "@B19]; Friedman and De Ver Dye, [@B47]; Noseda and Burstein, [@B89]; Schwedt, [@B101]). ", "Thus, this multi-sensory hypersensitivity may point to an abnormal central multisensory integration in migraine (Schwedt, [@B101]).", "\n\nSimilar to the suggested SMD pathophysiology, the underlying neurophysiological mechanisms of increased sensitivity in inter-ictal migraine suggest alterations in the cortical circuits and neurotransmitters which maintain the E/I balance (Pietrobon and Moskowitz, [@B96]; Demarquay and Mauguière, [@B35]). ", "Moreover, the results of our recent study have revealed that 45% of migraine patients are diagnosed with SMD (Granovsky et al., [", "@B56]), an incidence far above the \\~10% SMD incidence (range 5%--16%) among pain-free healthy pediatric and adult populations (Ahn et al., [", "@B1]; Ben-Sasson et al., [", "@B16]; Bar-Shalita et al., [", "@B9]). ", "The association of SOR with migraine pain symptoms such as having sensory aura, a higher frequency of monthly attacks, and an enhanced activity of pain facilitatory pathways (Granovsky et al., [", "@B56]) further support the inter-relation between non-painful sensory and pain transmitting pathways (Schwedt, [@B101]). ", "An example of this is a study reporting that experimentally-evoked trigeminal pain further enhances the cortical hyperexcitability and the lack of habituation to light in migraine patients (Boulloche et al., [", "@B20]). ", "This phenomenon can be related to the anatomical integration of pain and visual processing in thalamic nuclei (Noseda and Burstein, [@B89]) that project to cortical areas involved in the processing of pain and visual perception. ", "We can only hypothesize about a similarity of the central neuroanatomical integration alterations in sensory and pain-transmitting pathways to that described in migraine.", "\n\nAnother chronic pain state characterized by a global disturbance in sensory responsiveness is fibromyalgia (FM). ", "Many studies have reported on greater sensitivity to various non-painful sensory experimental stimuli (tactile, thermal, electrical, auditory) in FM (Lautenbacher et al., [", "@B70]; Montoya et al., [", "@B85]; Geisser et al., [", "@B50]; Hollins et al., [", "@B64]). ", "Similar to migraine, FM patients have also enhanced sensory responses to everyday real-life stimuli such as auditory stimuli (Geisser et al., [", "@B50]) and cutaneous sensations (Borg et al., [", "@B18]). ", "This greater sensitivity is known as a \"generalized hypervigilance\" and is considered as one of the pathophysiological mechanisms of FM (McDermid et al., [", "@B81]; Rollman, [@B100]). ", "Some authors also refer to heightened affective, sensory and pain responses as an abnormality of the interoceptive system in FM (Lovero et al., [", "@B77]; Seth and Friston, [@B105]; Duschek et al., [", "@B42]; Valenzuela-Moguillansky et al., [", "@B112]; Martínez et al., [", "@B80]). ", "Along with the widely reported pro-nociceptive pattern of psychophysical and neurophysiological responses (Staud and Spaeth, [@B107]; Staud, [@B106]; O'Brien et al., [", "@B90]), sensory over-responsiveness in FM can point to a decrease in inhibitory and/or an increase in facilitatory activity in the CNS.", "\n\nSince pain is a multidimensional and complex experience composed of sensory, affective-motivational, cognitive-evaluative components (Melzack and Casey, [@B83]), we propose the SMD as another factor that may shape the pain experience.", "\n\nAbnormal EEG Responses as a Shared Mechanism for SMD and Pain {#s6}\n=============================================================\n\nIn migraine and FM, along with enhanced pain psychophysical responses, cortical activity has been repeatedly shown to be abnormal. ", "More specifically, reports from many studies have pointed to higher amplitudes of early (A-delta mediated) pain-evoked ERPs (Gibson et al., [", "@B52]; Lorenz et al., [", "@B76]; Lev et al., [", "@B72]; de Tommaso et al., [", "@B31]; Truini et al., [", "@B110]), along with deficient habituation of these and other neurophysiological responses (Valeriani et al., [", "@B113]; Lev et al., [", "@B72]; de Tommaso et al., [", "@B32], [@B34]; Harriott and Schwedt, [@B62]). ", "Similarly, research in SMD has also indicated higher (Parush et al., [", "@B92], [@B93]) and prolonged (Zlotnik et al., [", "@B130]) early ERPs in response to non-painful sensory stimuli along with an adaptation deficiency (Kisley et al., [", "@B68]; Davies and Gavin, [@B29]; Brett-Green et al., [", "@B22]). ", "These neurophysiological markers again suggest a shared mechanism in SMD and chronic pain, namely, enhanced cortical activity and deficient inhibition.", "\n\nThough brain imaging studies in SMD are yet to come, we can deduce from a standardized low resolution brain electromagnetic tomography (sLORETA) study in migraine that these neurophysiological markers may be linked with enhanced activity of S1 and reduced activity of the orbitofrontal cortex (the part of the prefrontal cortex associated with initiation of pain inhibition; Lev et al., [", "@B72]). ", "In migraine, these neurophysiological activity patterns are observed in painful as well as non-painful stimuli (de Tommaso et al., [", "@B33]) and moreover are correlated with the clinical characteristics (Lev et al., [", "@B73]).", "\n\nAn abnormal pattern of EEG responses in chronic pain patients is also reported in resting-state conditions. ", "The most consistent reported findings refer to the abnormal alpha, theta or beta activity in migraine and FM. ", "More specifically in migraine, increased alpha power has been recorded in posterior brain regions, while activity in the frontal lobe has revealed decreased activity in alpha generators (Clemens et al., [", "@B27]; Cao et al., [", "@B24]). ", "Other studies have also reported on a global inter-ictal decrease of EEG activity (Tsounis and Varfis, [@B111]; Cao et al., [", "@B25]) and on an association between slower alpha activity and greater disease and attack durations (Bjørk et al., [", "@B17]). ", "Whereas in FM, decreased alpha, increased beta (Vanneste et al., [", "@B116]) and augmented theta activity (Fallon et al., [", "@B44]) have been found in different cortical areas and have also been reported to positively correlate with clinical symptoms. ", "Interestingly, abnormal alpha activity and a global reduction of cortical activity in theta, alpha and beta bands has also been observed in SMD (Granovsky et al., [", "@B57]).", "\n\nFurther validation for the suggested link between chronic pain and SMD is evident in our recent unpublished data on migraineurs (article in preparation). ", "Our research has indicated that lower connectivity values in the theta band at centro-parietal region are correlated with higher scores in SOR.", "\n\nSensory Modulation Alterations as a Shared Mechanism for Chronic Pain and SMD {#s7}\n=============================================================================\n\nThe assessment of pain modulation is performed by using various stimulation protocols which include a combination of different stimulus modalities and psychophysical tests. ", "The latter selectively engage the pain facilitatory bottom-up or pain inhibitory top-down pathways and are believed to reflect the \"real-life\" modulation process exerted by patients when exposed to clinical pain. ", "One of the most studied mechanisms of the supraspinally-mediated descending pain inhibitory system is the diffuse noxious inhibitory control (DNIC). ", "DNIC engages the activation of the endogenous analgesia system, where upon arrival of data to the brainstem the ascending pain activates descending pain inhibitory pathways, exerting effects on incoming nociceptive inputs (Le Bars, [@B71]). ", "The pain alleviating efficiency of DNIC relates on the balance between the anti-nociceptive effect of noradrenergic neurotransmission, and pro- or anti-nociceptive effect of serotonergic neurotransmission, that depends on the type of serotonin receptor (Bannister and Dickenson, [@B7]). ", "The neurophysiological mechanism for the activation of bottom-up facilitatory pathways is associated with the glutamate-mediated windup of second-order neurons and reflects the state of central neuronal sensitization (Woolf and Thompson, [@B124]). ", "Moreover, imbalance between the excited pain facilitatory systems, and the reduced activity in pain inhibitory pathways, including reduced functional connectivity with the brain regions associated with pain inhibition and/or enhanced connectivity with the brain regions associated with pain facilitation (Wang et al., [", "@B117]; Harper et al., [", "@B61]) point on a pro-nociceptive pain modulation profile as reported in many chronic pain states (Granovsky and Yarnitsky, [@B55]; Yarnitsky et al., [", "@B127]; Yarnitsky, [@B125]), including migraine and FM. ", "Despite the still open chicken-and-egg question on the causality of the interrelations between the modulation state and the presence of the various pain syndromes, it is believed that a pre-existing facilitatory state of the CNS leads to the establishment of a pro-nociceptive profile and the acquisition of chronic pain syndromes. ", "This causative relation was found in a longitudinal study on pain-free pre-thoracotomy patients, demonstrating that those with less-efficient endogenous pain inhibition had a higher incidence and intensity of chronic post-operative pain (Yarnitsky et al., [", "@B126]). ", "These results were later reproduced for cesarean section and major abdominal surgery patients, respectively (Landau et al., [", "@B69]; Wilder-Smith et al., [", "@B121]). ", "All the above findings taken together demonstrate that SMD is a pro-nociceptive condition (Weissman-Fogel et al., [", "@B119]). ", "We propose that SOR is a predisposing factor or risk factor for chronic pain.", "\n\nSummary {#s8}\n=======\n\nWe propose a neurophysiological mechanism-based model for the interrelation between pain and SMD, namely the SMDolor Model ([Figure 1](#F1){ref-type=\"fig\"}; the numbers guide the following explanation). ", "Shared central neural mechanisms between SOR and pain, E/I imbalance; cortical hyper-excitation and sensory modulation alterations, are the cornerstone of this proposed model. ", "These shared mechanisms are behaviorally expressed (1) as SOR in sensory systems processing non-painful stimuli, and as a pro-nociceptive state when processing painful stimuli. ", "Daily life events require a multi-sensory integration for adaptive responding. ", "This warrants a convergence of sensory stimuli from different modalities including pain which in turn causes pain to be influenced by these other sensory stimuli and vice versa (3), consequently, daily life events are experienced as aversive, irritating, and painful by individuals with SOR. ", "These experiences induce neuronal plasticity (2) that may further result in a sensory signature which strengthens the abnormal shared mechanisms, contributing to the sensory symptoms that shape the daily life challenges experienced by individuals with SOR. ", "These loop reactions may in some cases accumulate up to the point of developing a chronic pain condition (4). ", "Chronic pain may then further nurture the shared central neural mechanisms (5).", "\n\n{#F1}\n\nAuthor Contributions {#s9}\n====================\n\nAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.", "\n\nConflict of Interest Statement {#s10}\n==============================\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.", "\n\n[^1]: Edited by: Elizabeth B. Torres, Rutgers University, The State University of New Jersey, United States\n\n[^2]: Reviewed by: Anthony H. Dickenson, Independent Researcher, London, United Kingdom; Guilherme Lucas, University of São Paulo, Brazil\n\n[^3]: ^†^These authors have contributed equally to this work\n" ]

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[ "Bob Mueller is famously nonchalant amid life’s toughest moments. ", "Much of that public calm stems from the fact that he’s a Magnificent Bastard and, specifically, the lessons of December 11, 1968. ", "That day, then Second Lieutenant Mueller’s squad—part of the Second Platoon, Hotel Company, Second Battalion, Fourth Marine Regiment, the so-called “Magnificent Bastards”—was on patrol in Quang Tri Province when they came under heavy fire from as many as 200 North Vietnamese troops. ", "They almost immediately began to take casualties.", "\n\nMueller organized a defensive perimeter and moved among his Marines, encouraging them to return fire; they fought for hours. ", "At one point, Mueller led a fire team into enemy territory to retrieve a mortally wounded comrade. ", "The rest of his unit survived, and he received a Bronze Star, with Valor, for his actions and leadership that day.", "\n\nThat day wasn’t Bob Mueller’s first time in combat, and it wouldn’t be his last. ", "It wouldn’t even necessarily be his most consequential: Four months later, he was shot through the leg by an AK-47.", "\n\nThe time in Vietnam, though, gave him a hard-won perspective on the bureaucratic fights where he’d spend most of the rest of his career. ", "He considers himself lucky to have survived Vietnam—and his life of public service ever since stems, in part, from that gratitude. ", "His college classmate David Hackett never got the chance to come home, and he speaks regularly of Hackett’s sacrifice.", "\n\nEven in Mueller’s toughest moments stateside—the months after 9/11, when he was FBI director, and the 2004 hospital showdown that brought him and Jim Comey eyeball to eyeball with the Bush administration—he’s evinced a certain calm amid Washington’s slings and arrows. ", "As FBI director, even facing the daily fears of terrorism, spy plots, and cyberattacks, he used to joke, “I’m getting a lot more sleep now than I ever did in Vietnam.”", "\n\nStill, you have to wonder how well Mueller is sleeping these days. ", "It’s hard to imagine that he has faced a more challenging—or more potentially consequential—week than this past one, which has seen a steady series of attacks from the Trump administration and congressional Republicans on both his own investigation and the two institutions that he devoted almost his entire life to serving, the FBI and the Justice Department.", "\n\nSo let’s do a quick review of recent developments in Washington and then consider a question that has yet to get a thorough airing in the coverage of the Russia investigation and its attendant sideshows: What would happen to the investigation if Mueller were to be fired?", "\n\nFirst, the recent barrage of developments. ", "It’s hard to keep the hits straight; they’ve come so quickly and we’ve grown so desensitized to major, Earth-moving news stories coming and going ephemerally in the Trump Age. ", "Just in the past 10 days, we’ve seen news that Mueller’s team has interviewed the sitting attorney general, Jeff Sessions, as well as the former FBI director Jim Comey, and begun to talk to the White House about interviewing the president himself—all signs that Mueller’s efforts are reaching a critical moment.", "\n\nThen there was the news that last summer, in June, President Trump ordered White House counsel Don McGahn to fire Mueller as special counsel—a power that doesn’t technically belong to McGahn—and that McGahn resisted, saying that he’d resign rather than begin to implement the order, a powerful sign that the president’s own lawyer saw a corrupt intent behind the president’s direction.", "\n\nOn Capitol Hill, we’ve borne witness to a fantastical pas de deux between congressmembers Devin Nunes and Adam Schiff, the top Republican and top Democrat respectively on the House Intelligence Committee, as Nunes—who last year breathlessly reported that he uncovered evidence of “deep state” malfeasance against President Trump and rushed to the White House to brief the president, only to later admit that his evidence itself came from the White House, an incident that so compromised his own integrity that he was forced to the sidelines of the Russia investigation—now claims to have singlehandedly uncovered a vast government conspiracy underway at the FBI and the Justice Department." ]

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[ "Popular Posts\n\nRiding to snow\n\n\"22 degrees!\" ", "Bill called out, as though a temperature rise of 1 degree was the best news of the night. ", "His headlight beam cast a streaming glow on the whitewashed forest, starkly framed against the black sky. ", "Trees wore new snow like children in oversized dresses, bewildered by the heavy formality of winter. ", "I clenched my numb fingers inside my mittens and pressed my palms against the handlebars. ", "A fountain of fine powder streamed from Bill's rear wheel. ", "I shifted my shoulders in an attempt to follow his line. ", "Once powder is six inches deep or more, you don't so much ride a bike as surf with it, feathering the handlebars and gently shifting your weight as the wheels slice through the swift current. ", "The rear wheel was swept sideways and my mountain bike fishtailed wildly through the snow. ", "I pressed the brakes and righted it, then veered away from Bill, who was fishtailing himself. ", "I blinked against the weight of ice frozen to my eyelashes. ", "City lights sparkled in a distance far below.", "\n\n\"What are you doing tonight?\" ", "Bill wrote to me eight hours earlier.", "\n\n\"I brought my mountain bike to work, so probably a bike ride,\" I wrote back.", "\n\n\"Where to?\" ", "he asked.", "\n\n\"I don't know. ", "I kind of want to ride to the snow.\"", "\n\nSnow had fallen in the mountains just outside Missoula over the weekend. ", "It was the first significant snow cover of the year, and snow line looked like it was up around 5,500 feet. ", "I was trying to think of how I could access it the fastest when Bill sent me a list of possibilities. ", "And for some strange reason, I read through them and picked the destination that was both the longest and highest of all.", "\n\nBill met me at my office at 5:20. ", "Our pace was too fast right off the bat. ", "Whenever I feel cruddy while riding with others, I'm never sure if they're pushing it more than we usually do together, or if I'm just having a bad day. ", "Either way, my heart rate was severely elevated and I was breathing hard enough I had to deliberately enunciate each word in response to Bill's questions. ", "We veered up Grant Creek canyon and my responses nearly trickled out altogether.", "\n\nThe larch trees were in the peak of fall splendor - golden towers tinted with scarlet light at sunset. ", "My throat started to burn from breathing excessive quantities of cool air. ", "Bill let up on his pace a bit when I stopped chasing him. ", "More than an hour and 15 miles had passed and we still hadn't reached the base of Snowbowl. ", "My mind still hadn't registered that this was likely going to turn into a long ride.", "\n\nBut it was one of those evenings where time didn't really matter. ", "The crisp air, the color, the sunlight - it was all so idyllic that nothing else really mattered. ", "The pressures of our day-to-day lives and our routines and our obligations didn't matter. ", "Even the fact that my body was feeling cruddy and I was perhaps riding too hard didn't matter.", "\n\nBill and I rode toward the alpenglow and the one thing that did matter in that moment - the mountains with their inaugural snowfall, and the white silent world we were seeking.", "\n\nWe climbed and climbed. ", "The dirt road turned to mud, and then frozen mud, and then ice. ", "The first dusting of snow came into the beam of our headlamps. ", "Then the snow grew deeper, the forest more saturated, until we found ourselves in a frozen world entirely different from the city's bright autumn hues. ", "Bill watched his thermometer and announced the status of the rapidly plummeting temperature. \"", "28 degrees ... 27 ... 26.\" ", "Because I had come straight from work, and didn't anticipate riding in temperatures lower than the mid- to high-30s when I left in the morning, I didn't have all the gear I normally would for temperatures in the 20s. ", "I was a bit underdressed, especially on my feet, so I occasionally jumped off the bike to run beside it. ", "I ran until my throat burned, then jumped back on until my toes tingled. ", "When I became too exhausted to run, I just walked, but by then the snow was so thick that I could easily keep up with Bill, even as he pedaled and I pushed.", "\n\nThe snow started to become too deep to ride at all. ", "Our wildly ambitious destination, Point 6, still loomed 1,000 feet above us. ", "It was late. ", "We were both cold, shedding heat and dreading the descent as it was. ", "We pulled off at the top of Snowbowl - the ski resort we had been riding the perimeter of - and pushed toward an A-frame on the tenuous hope that the door would be unlocked. ", "It was. ", "We ducked inside and put on our remaining layers. ", "It was time to stop seeking the snow, and start facing it.", "\n\nBefore we left, Bill pulled out his special surprise - curry lentil soup in a thermos. ", "It was halfway cold - a result of a ride that ended up being much colder and longer than planned. ", "Bill's thermometer read 21 degrees. ", "There was more frost than snow on the windblown building. ", "I sucked at my Camelbak hose, but it had long since frozen solid. \"", "Let's do this thing,\" I said.", "\n\nWe surfed the steep downhill powder and picked up speed in a single truck track pressed into the road. ", "The wind hit my face like sharp ice so I pulled up my face mask, which quickly started to fill with ice. ", "21 degrees with a 20 mph windchill equals a stinging slap of reality this early in the season. ", "Eventually bodies acclimate and winter gear is figured out all over again and the biting edge of winter finally dulls. ", "But right at the beginning, the cold is as sharp and forceful as a razor blade, and Bill and I cried out with equal amounts of exhilaration and pain, right at that center point where bodies feel the entire scope of what it is to be alive.", "\n\nMore strategic running got us back to town with hands, torsos and feet that had reached a workable equilibrium. ", "I felt more tired than I had after a post-work ride in a long time, so I asked Bill what the numbers were. ", "45 miles. ", "4,524 feet of climbing. ", "Max elevation 6,933 feet. ", "Time 5:35. ", "Moving time 4:51. ", "But GPS knew nothing of the high-friction snow, of the battles with the cold, of the silence and beauty and peace. ", "That's because GPS isn't alive, and we are, which is why we seek these high places, steeped in the wonder of life.", "\n\nI read you post with a twinge of envy. ", "I skipped out of my bootcamp class this am b/c my body was just too tired and sore. ", "8 weeks of pushing this 45 yrs old's body is taking its toll. ", "My measly 1 hr boot camp..then I see, what in my eyes, is an *epic* ride, and for you is merely an after work ride. ", "Bless you Jill for inspiring me\n\nJill, you can't begin to imagine the enjoyment this blog has brought to me in both pictures and words - I live where the seasons are only summer and winter and the one high point locally is a 'massive' 2000ft.", "\n\nI totally agree with everyones comments above!Thanks again for bringing your world into my home." ]

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[ "Facebook is facing new questions over its handling of the Cambridge Analytica debacle even after a record settlement with the FTC ended a year-long investigation by regulators into the matter.", "\n\nFacebook has maintained that it first became aware of Cambridge Analytica's illegal harvesting of user data in December of 2015, when The Guardian first reported it.", "\n\nBut internal emails from Facebook employees, first described in a lawsuit from the attorney general for Washington, D.C. in March, show that Cambridge Analytica had been flagged within the company as early as September 2015 over suspicions that it had been “scraping” Facebook data in violation of the platform’s policies.", "\n\nADVERTISEMENT\n\nThose warnings were further detailed last week, in a filing from the Securities and Exchange Commission (SEC) as part of that agency’s $100 million settlement with Facebook over charges that it misled investors about the material risk of the scandal.", "\n\nMonths before the Guardian first revealed that Cambridge Analytica had obtained data on tens of millions of Facebook users without their knowledge, Facebook employees had requested an investigation of the right-wing political consulting firm over suspicions it had misused data.", "\n\nBefore declaring bankruptcy last year as a result of the debacle, Cambridge Analytica had deep ties with the Republican party and in 2016 worked for the Trump campaign, assembling voter profiles based on data from a range of sources, including social media sites.", "\n\nAfter the Guardian story ran, the employees again raised concerns about Cambridge Analytica, describing it as a “sketchy (to say the least) data modeling company that has penetrated our market deeply,” according to the SEC complaint.", "\n\nThe SEC’s filing has raised further questions from the UK Parliament, where MP Damian Collins, who chairs the Digital, Culture, Media and Sport Committee (DCMS), has been investigating the data scandal. ", "Collins sent a letter to Facebook on Thursday saying that the complaint “seemingly directly contradicts” testimony that the company has offered to the committee.", "\n\n“We have serious and justifiable concerns that, despite the significant and continuous red flags raised by Facebook employees about Cambridge Analytica since potentially as early as September 2015, these incidents did not reach senior management, deliberately or otherwise,” Collins wrote.", "\n\n“We therefore request that you respond to our concerns as to why senior management, including [CEO] Mark Zuckerberg Mark Elliot ZuckerbergKey Democrat opposes GOP Section 230 subpoena for Facebook, Twitter, Google Many Google staff may never return to office full time Hillicon Valley: FBI, DHS warn that foreign hackers will likely spread disinformation around election results | Social media platforms put muscle into National Voter Registration Day | Trump to meet with Republican state officials on tech liability shield MORE, were not informed about these incidents until they were reported in the press,” he added. “", "We believe this to be particularly egregious given that we have been told that these issues should have been reported through senior management and that the buck ultimately stops with Mr. Zuckerberg himself.”", "\n\nFacebook declined to comment on the letter, but the company has said that the activity deemed suspicious by employees prior to the Guardian story was different from the partnership between Cambridge Analytica and the creator of a personality quiz app that collected the user data.", "\n\nDavid Carroll, a professor at the Parsons School of Design, whose battles with Cambridge Analytica were the focus of the recently-released Netflix documentary “The Great Hack,” said there are still plenty of open questions about Facebook’s handling of the incident.", "\n\n“I share the questions about the timeline of who knew what when,” Carroll told The Hill. “", "Even if you believe Zuckerberg, that he learned about it in The Guardian in December 2015 — even if that's true, it means that he has a sort of catastrophical management problem that it didn't get escalated to the C-suites.\"", "\n\nFacebook is currently fighting to keep the September 2015 emails sealed as it tries to fend off a lawsuit from Washington, D.C. Attorney General Karl Racine (D).", "\n\nThe emails were first detailed in a filing in the case earlier this year. ", "And on Friday, the two sides squared off in court over whether the records should be unsealed. ", "Racine’s office argued that the substance of the emails has already been alluded to by the SEC and should be included in the court record and released to the public.", "\n\n“This document has now been referred to, has been directly quoted, by the Securities and Exchange Commission,” Jimmy Rock, an attorney in Racine’s office, said in court Friday. “", "So here there cannot be legitimate prejudice at this point to Facebook with the document of direct quotations and the substance of it being part of the public record.\"", "\n\nFacebook argued the emails should remain under seal because they contain sensitive information about the company's practices and are \"irrelevant and unnecessary to these proceedings.\"", "\n\nThose emails aren’t the only part of the timeline drawing extra scrutiny from Facebook’s critics. ", "In June of 2016, Facebook and Cambridge Analytica reached a settlement that required the consulting group to delete all of the data it had obtained through researcher Aleksandr Kogan’s app.", "\n\nIn his letter on Thursday, Collins noted red flags that arose in the months after that should have tipped off Facebook’s management that the group was still abusing user data to create voter profiles for clients like President Trump Donald John TrumpSteele Dossier sub-source was subject of FBI counterintelligence probe Pelosi slams Trump executive order on pre-existing conditions: It 'isn't worth the paper it's signed on' Trump 'no longer angry' at Romney because of Supreme Court stance MORE's 2016 campaign.", "\n\nA Washington Post article that ran days before the presidential election, for example, noted that Cambridge Analytica was using “psychological tests” combined with data from “social-media sites.”", "\n\nAnd as the SEC wrote in its complaint, “As an additional indication to Facebook that Cambridge might have been misusing Facebook user data, some employees on Facebook’s political advertising team knew from August 2016 through November 2016 that Cambridge named Facebook and Instagram advertising audiences by personality trait for certain clients that included advocacy groups, a commercial enterprise, and a political action committee.”", "\n\nThe renewed scrutiny comes as the FTC is under fire for its own settlement with Facebook despite imposing a headline-dominating $5 billion fine for the company. ", "Critics, including officials at the agency, have criticized the agreement for not doing more to curtail Facebook’s business practices or putting more of a check on the decision-making powers of Mark Zuckerberg, who serves as both CEO and chairman of the board of directors.", "\n\nThe FTC did not interview Zuckerberg as part of its year-long investigation into the scandal, likely because Facebook would have fiercely opposed the move, escalating the possibility that it would lead to a lengthy, high-profile court battle.", "\n\n“The last thing Zuckerberg’s handlers would do is subject him to deposition by an FTC attorney. ", "Depositions are serious and more of a crucible than a congressional hearing,” Chris Hoofnagle, a law professor at University of California, Berkeley, said in an email to The Hill. “", "If I were Zuckerberg’s lawyer, I’d do anything to keep him away from a direct interaction with the FTC lawyers.”", "\n\nWith Facebook still struggling to turn the page from the Cambridge Analytica fallout, there will also be lingering questions over how regulators handled the investigation.", "\n\n“People wonder why the FTC always settles,” Hoofnagle added. “", "It’s actually the defendants that want to settle. ", "The FTC investigates and invariably uncovers other wrongdoing and knowledge of the action by executives.”" ]

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[ "1. ", "Field\nThe present invention generally relates to techniques for charging a battery. ", "More specifically, the present invention relates to a method and apparatus for charging a lithium-ion battery which adaptively controls the lithium surface concentration to remain within set limits.", "\n2. ", "Related Art\nRechargeable lithium-ion batteries are presently used to provide power in a wide variety of systems, including laptop computers, cordless power tools and electric vehicles. ", "FIG. ", "1 illustrates a typical lithium-ion battery cell, which includes a porous graphite electrode, a polymer separator impregnated with electrolyte, and a porous cobalt dioxide electrode. ", "The details of the transport of lithium and lithium ions in and out of the electrode granules and through the material between them are complex, but the net effect is dominated by slow diffusion processes for filling one electrode with lithium while removing it from the other.", "\nNote that FIG. ", "1 provides a physical model for the layout of a typical lithium-ion cell, wherein the oxidation and reduction processes that occur during charging are also illustrated. ", "The physical model shows the current collectors, which are in turn connected to the battery terminals; the polymer separator; and the positive and negative porous electrodes. ", "Note that an electrolyte permeates the porous electrodes and the separator.", "\nThe negative electrode includes granules of graphite held together with a conductive binder (in practice, there may also be a nonconductive binder). ", "Surrounding each graphite particle is a thin passivating layer called the solid-electrolyte interphase (SEI) that forms when a fresh cell is charged for the first time from the lithium atoms in the graphite reacting directly with the electrolyte. ", "This occurs because the tendency for the lithium atoms to remain in the graphite is relatively weak when the cell is fully charged, but after the SEI is formed, the SEI acts as a barrier against further reactions with the electrolyte. ", "Nevertheless, the SEI still allows transport of lithium ions, albeit with some degree of extra resistance.", "\nThe positive electrode includes granules of lithiated cobalt dioxide held together with binders similar to the negative electrode. ", "Any SEI-like layer surrounding these particles is likely to be of much less significance than in the negative electrode because lithium atoms strongly favor remaining in these particles rather than leaving and reacting directly with the electrolyte.", "\nLithium transport in the negative graphite electrode (also referred to as the “transport-limiting electrode”) is slower than in the positive cobalt dioxide electrode (also referred to as the “non-transport-limiting electrode”), and therefore limits the maximal speed of charging. ", "During charging, the slow diffusion causes a transient build-up of lithium on the surfaces of the graphite that varies in direct proportion to the charging current and a characteristic diffusion time.", "\nThe diffusion time is typically on the order of hours and has a strong dependence on temperature and other variables. ", "For instance, a cell at 15° C. can have a diffusion time which is ten times slower than a cell at 35° C. The diffusion time can also vary significantly between cells, even under the same environmental conditions, due to manufacturing variability.", "\nIf the concentration of lithium at the surface reaches the saturation concentration for lithium in graphite, more lithium is prevented from entering the graphite electrode until the concentration decreases. ", "A primary goal of conventional battery-charging techniques is to avoid lithium surface saturation, while keeping the charging time to a minimum. ", "For example, one conventional technique charges at a constant current until a fixed upper voltage limit (e.g., 4.2 V) is reached, and then charges by holding the voltage constant at this upper limit until the current tapers to some lower limit. ", "Note that it is common practice to express all currents in terms of the cell capacity. ", "For example, for a cell with a capacity of Qmax=2500 mA·hr, a “1 C” current would be 2500 mA. In these units, the constant current charging is usually done at less than 1 C (e.g., 0.3 C), and the constant voltage phase is terminated when the current tapers to some value less than 0.05 C.\nFIG. ", "2 illustrates a representative conventional charging profile. ", "The problem with a conventional charging scheme is that it largely operates blindly; the only information used is the cell voltage, which does not directly correlate to the lithium surface concentration. ", "Consequently, conventional charging both misses the opportunity to use more current when it is possible to do so, and enters the saturation region if lithium transport is slower than expected.", "\nHence, what is needed is a method and an apparatus for charging a lithium-ion battery that does not suffer from the drawbacks of these existing techniques." ]

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[ "Chinese Students to Celebrate Lunar New Year at Baylor\n\nThe Chinese Student Association at Baylor University will host an Eastern Festival in celebration of the Chinese Lunar New Year from 1- 5 p.m. Saturday, Feb. 10, at the Marrs McLean Gymnaisum.", "\n\nAsian student organizations will provide a taste of Asian culture with authentic dishes and desserts. ", "Martial arts demonstrations will be given as well as a variety of other activities, including games, a fashion show with ancient Chinese costumes, ribbon dancers and booths featuring different Asian artifacts. ", "The festival will end with a traditional lion and dragon dance performed by the J. K. Wong Chin Woo Academy of Dallas.", "\n\nThe Chinese Lunar New Year began Jan. 24.", "\n\nAdmission is $3. ", "Tickets may be purchased at the door. ", "For more information, contact Pearl Beverly at 710-2371." ]

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[ "Overview\n\nDevelopment of new market positioning following change of career. ", "The course was very well focused on brand development, objectives appropriately paced and very well delivered in an effective but relaxed friendly style.", "\n- Course delegate, Develop your personal brand\n\nEveryone has a personal brand, a uniqueness that helps them stand out from the crowd - whether or not they're aware of it. ", "After all, we have qualities that shape and influence how people see us and how we see ourselves.", "\n\nWhat's this course about?", "\n\nThis course uses the latest tools and techniques to explore what makes a successful personal brand. ", "It also outlines how personal branding can help you manage how other people see you - both instantly and in the long term - as well as improve your confidence.", "\n\nBy completing this course you'll understand how personal branding is an essential aspect of career adaptability that can help you communicate more effectively and create good relationships in and out of work. ", "It explains how you can use your strengths, skills, passions and values to send a clear, consistent message about who you are and what you offer.", "\n\nWhat will you get out of it?", "\n\nBy completing this course you'll learn how to undertake an open and honest review of yourself. ", "It will help you understand how others see you and to practise the skills you need to develop your personal brand and create a powerful first impression.", "\n\nAfter completing this course you will be able to\n\nUnderstand the importance of personal branding\n\nIdentify what sets you apart from others\n\nUse strategies to build your personal brand\n\nUse effective non-verbal communication\n\nUnderstand how to build a social media presence\n\nReduce anxiety under pressure\n\nImprove your social awareness and effectiveness\n\nDesign a plan to build your personal brand\n\nIs this course for you?", "\n\nOur develop your personal brand course takes place in several UK locations and is suitable for past and present ICAEW members and their families working at any level within the public, voluntary, corporate and private sector. ", "It's ideal for anyone who wants to improve their confidence and communication skills in order to stand out and achieve their goals. ", "Delegates will learn the skills to create a positive and lasting impression, showcasing their skills and strengths.", "\n\nRequirements\n\nDelegates need to be open to some self-analysis within a safe and supportive environment." ]

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[ "Introduction\n============\n\nUpper and lower airways are considered a unified morphological and functional unit, and the connection existing between them has been observed for many years, both in health and in disease.[@b1-jaa-9-093],[@b2-jaa-9-093] More than 2,000 years ago, Claudius Galenus studied the upper airway and paranasal sinuses as integral parts of the respiratory tract, and he assumed that rhinitis and asthma were caused by secretions dripping from the brain into the nose and lung.[@b3-jaa-9-093] More recently, the concept of united airway disease (UAD) was suggested.[@b4-jaa-9-093]--[@b6-jaa-9-093]\n\nThe nose is situated at the entrance of the airway and protects the lower airway from the harmful effects of the inspired air by acting as efficient air-conditioning. ", "The nose warms, filters, and humidifies the inspired air so that clean air that is fully saturated with water vapor at a temperature of 37°C is delivered to the lungs. ", "During nose breathing, the majority of particles with an aerodynamic equivalent diameter (AED) \\>15 μm are deposited in the upper respiratory tract. ", "Particles with AEDs \\>2.5 μm are primarily deposited in the trachea and bronchi, whereas those with lower AEDs penetrate into the gas-exchange region of the lungs.[@b7-jaa-9-093] The nasal and bronchial mucosa present similarities, and one of the most important concepts regarding nose--lung interactions is the functional complementarity, which assigns the protector role of the nose to the lungs.[@b4-jaa-9-093] However, the functions of the upper airway and their interactions with the lower airway are much broader than merely air-conditioning.", "\n\nThe Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines published in 2001[@b1-jaa-9-093] achieved some goals: 1) development of a guideline proposing a standardized management plan for allergic rhinitis (AR), 2) establishment of the ARIA concept, 3) spreading of the guideline to general and specialist physicians, and 4) establishment of a multiprofessional forum to study rhinitis and asthma. ", "There is strong epidemiologic, pathophysiologic, and clinical evidence supporting an integrated view of rhinitis and asthma: UAD in the present review. ", "We can also consider UAD an airway-hypersensitivity syndrome, because rhinitis and asthma are chronic inflammatory diseases of the upper and lower airways, which are induced and reproduced by allergic or nonallergic hypersensitivity reactions, and present several phenotypes ([Table 1](#t1-jaa-9-093){ref-type=\"table\"}).", "\n\nUnited airway disease: epidemiologic evidence\n=============================================\n\nAR is the most common of all atopic diseases, and although it can develop at any age, most patients report the onset of symptoms before 30 years of age, making it the most common chronic disorder in children.[@b6-jaa-9-093] AR can be considered a major public health problem, due to its prevalence and impact on patients' quality of life, work/school performance, and productivity economic burden.[@b4-jaa-9-093],[@b6-jaa-9-093] It is characterized by the classic symptoms of nasal itching, sneezing, rhinorrhea, and nasal obstruction. ", "In addition, AR is associated with a variety of comorbidities, such as atopic dermatitis, sleep-disordered breathing, conjunctivitis, rhinosinusitis, otitis media, asthma, and emotional problems.[@b6-jaa-9-093],[@b8-jaa-9-093] At the same time, AR is a disease that is underdiagnosed and overlooked by patients and physicians.[@b9-jaa-9-093],[@b10-jaa-9-093]\n\nAR is considered a risk factor for developing asthma.[@b4-jaa-9-093],[@b6-jaa-9-093] Asthma is a heterogeneous disease characterized by chronic airway inflammation and hyperresponsiveness (AHR) to direct or indirect stimuli, which can persist even when symptoms are absent or lung function is normal but may normalize with treatment.[@b11-jaa-9-093] Asthma is defined by the history of episodic respiratory symptoms, such as wheeze, shortness of breath, chest tightness, and cough, and is associated with variable expiratory airflow limitation.[@b11-jaa-9-093]\n\nAllergic asthma is the most prevalent disease phenotype, which often begins in childhood and is associated with a personal and/or family history of allergic diseases, such as eczema and AR.[@b11-jaa-9-093] In the same way of the allergic phenotype, patients with non-AR (NAR) are at increased risk of developing nonallergic asthma. ", "NAR presents later in life than AR and is not a single disorder but is composed of a heterogeneous group of diseases.[@b12-jaa-9-093]\n\nAccording to the International Study on Asthma and Allergy in Childhood, the prevalence of AR in Europe was found to be ∼25% and in Brazil ∼15%--20%. ", "The prevalence of asthma worldwide was observed to be ∼20% (Global Initiative for Asthma) and 10%--20% in Brazil (Global Initiative for Asthma, ARIA). ", "Countries with a very high prevalence of rhinitis had asthma prevalence ranging from 10% to 25%.[@b4-jaa-9-093],[@b11-jaa-9-093],[@b13-jaa-9-093]\n\nThe management of asthma should include assessment of asthma control, future risks, and any comorbidity that could contribute to symptom burden and poor quality of life. ", "The main associated comorbidities are rhinitis, rhinosinusitis, gastroesophageal reflux, obesity, obstructive sleep apnea, depression, and anxiety.[@b11-jaa-9-093] We evaluated the prevalence of comorbidities in patients with severe asthma and observed that rhinitis and gastroesophageal reflux disease were the most common, rhinitis being observed in 91% and gastroesophageal reflux disease in 71% of the asthmatic patients.[@b14-jaa-9-093]\n\nInteractions between the lower and the upper airways are well known and have been extensively studied since 1990. ", "Over 80% of asthmatics have rhinitis, and 10%--40% of patients with rhinitis have asthma, suggesting the concept of \"one airway, one disease\".[@b4-jaa-9-093] Rhinitis symptoms have been reported in 98.9% of allergic asthmatics and in 78.4% of nonallergic asthmatics. ", "Furthermore, ∼30% of patients with only AR who do not have asthma present hyperresponsiveness to methacholine or histamine.[@b2-jaa-9-093],[@b4-jaa-9-093],[@b15-jaa-9-093] However, there are large differences in the magnitude of airway reactivity between patients with rhinitis and asthma. ", "Patients with perennial rhinitis have greater bronchial reactivity than those with seasonal rhinitis, in whom the presence of hyperresponsiveness was observed especially during the pollen season.[@b4-jaa-9-093],[@b15-jaa-9-093],[@b16-jaa-9-093] AHR, which is a paramount feature of asthma, is a strong risk factor for the onset of asthma in patients presenting with AR.[@b6-jaa-9-093]\n\nSeveral studies suggest that AR and NAR are risk factors for new onset of asthma and persistence of asthma.[@b17-jaa-9-093],[@b18-jaa-9-093] In a cohort of 690 individuals with a follow-up of 23 years, it was observed that the incidence of asthma was 10.5% in subjects with rhinitis and 3.6% in those without rhinitis. ", "Therefore, the development of asthma was tripled in rhinitis patients compared to those without rhinitis.[@b19-jaa-9-093] In the Tucson Epidemiologic Study of Obstructive Lung Diseases, the odds ratio for developing asthma was 2.59 (95% confidence interval 1.54--4.34) if rhinitis was present and 6.28 (95% confidence interval 4.01--9.82) in the presence of rhinitis plus sinusitis.[@b20-jaa-9-093] A European Survey confirmed the presence of perennial rhinitis as a major risk factor for asthma, with odds ratios of 11 for the atopic and 17 for the nonatopic phenotype.[@b21-jaa-9-093]\n\nAsthma and rhinitis share common risk factors and present common susceptibility to different agents, such as allergens (atopy) and infections.[@b4-jaa-9-093],[@b6-jaa-9-093] The presence of AHR and concomitant atopic manifestations in childhood increases the risk of developing asthma and should be recognized as a marker of prognostic significance, whereas the absence of these manifestations predicts a very low risk of future asthma.[@b22-jaa-9-093]\n\nUnited airway disease: pathophysiological evidence\n==================================================\n\nThe upper and lower respiratory tracts form a continuum, allowing the passage of air into and out of the lungs and sharing many anatomical and histological properties.[@b2-jaa-9-093] They share common structures, including the ciliary epithelium, basement membrane, lamina propria, glands, and goblet cells, forming the so-called united airway.[@b23-jaa-9-093] On the other hand, differences between the upper and lower airways do exist. ", "Nasal mucosa, which is attached to bone, is enriched with vessels, whereas bronchial mucosa, which is attached to cartilage, is enriched with smooth-muscle cells.[@b24-jaa-9-093] Therefore, the major cause of airway obstruction, especially in the early phase of the allergic response, is different: upper airway obstruction is caused by vasodilation and edema, whereas lower airway obstruction arises from smooth-muscle constriction.[@b24-jaa-9-093]\n\nIt is reasonable to think that because of anatomic reasons, the upper airway constitutes the first target for allergens and for physical and chemical environmental stimuli; therefore, they tend to be the first to be affected by the allergic airway disease, and if the intensity of this disease is low, the upper airway may be the only part of the respiratory tract that is affected. ", "However, when the entire respiratory tract is involved, rhinosinusitis and asthma follow a parallel course.[@b25-jaa-9-093] Unfortunately, systematic research in this field has not been performed, and the evidence supporting these postulates is scarce.[@b25-jaa-9-093]\n\nUAD presents two main phenotypes: allergic (atopic or extrinsic) and nonallergic (nonatopic or intrinsic). ", "With regard to asthma, most children and at least 50% of adults have the allergic phenotype, in which the disease is associated with allergic sensitization defined by the presence of serum-specific immunoglobulin (Ig)E antibodies and/or positive skin tests to the proteins of common inhaled allergens, such as house dust mites, animal dander, fungal spores, pollens, and cochroaches.[@b26-jaa-9-093] On the other hand, in nonallergic asthma, we do not observe IgE reactivity to allergens.[@b26-jaa-9-093] In the same way, there are two important phenotypes or rhinitis, allergic and nonallergic, both of them associated with increased prevalence of asthma.[@b27-jaa-9-093] We focus on the allergic pathophysiology of UAD.", "\n\nAR and atopic asthma result from an IgE-mediated allergic reaction associated with airway inflammation of variable intensity.[@b4-jaa-9-093] Since the first class of Ig presented on the surface of B-cells is IgM, it is necessary that IgM is switched to IgE so that allergic inflammation can develop. ", "Isotype switching to IgE requires antigen presentation and two other signals.[@b28-jaa-9-093] Signal one is provided by interleukin (IL)-4 and/or IL-13, acting through IL-4R and IL-13R via STAT6, which activate transcription to the IgE isotype. ", "Signal two is provided mainly by ligation of CD40 on B-cells to CD40L on T-cells, which activates DNA-switch recombination.[@b28-jaa-9-093] The IgE-mediated immune response is initiated when the allergens are taken up by antigen-presenting cells via the cell-surface Ig receptor. ", "Processed fragments are then presented in the context of major histocompatibility complex class II to T-helper (T~H~) cells, which recognize the allergen--major histocompatibility complex II composite and are activated. ", "The allergen-specific T~H~2 cells produce IL-4 and IL-13, and express CD154, leading to IgE class switching.[@b26-jaa-9-093],[@b28-jaa-9-093] Although class switching is generally thought to occur in the germinal center of lymphoid tissues, it has also been reported to occur in the respiratory mucosa of patients with AR and atopic asthma and in the gastrointestinal tract in patients with food allergy.[@b28-jaa-9-093]\n\nOnce IgE is produced by B-cells, the Ig will bind to the high-affinity receptor Fc~ε~R1 on mast cells and basophils.[@b28-jaa-9-093] In future, contacts with the polyvalent sensitizing allergen, these cells will be activated through Fc~ε~R1, initiating an immediate hypersensitivity reaction that is central in the pathogenesis of AR and allergic asthma.[@b28-jaa-9-093] The reaction has an immediate phase that is induced by the release of preformed and rapidly synthesized mediators from mast cells and basophils, resulting in erythema, edema, and itching in the skin, sneezing and rhinorrhea in the upper respiratory tract, and cough, bronchospasm, edema, and mucous secretion in the lower respiratory tract.[@b28-jaa-9-093] A late phase mediated by cytokines and chemokines and characterized by edema and leukocytic influx can occur 6--24 hours after the immediate phase. ", "Eosinophils recruited mainly by IL-5 produced by T~H~2 cells stand out and are essential to maintain the chronic inflammatory process and tissue damage.[@b28-jaa-9-093]\n\nEosinophil activation directly contributes to vasodilation, edema, mucous production, bronchoconstriction, and dysfunctional remodeling of the airway.[@b29-jaa-9-093] These processes are mainly induced by eosinophil-derived products, such as eosinophil peroxidase, which causes AHR and activates dendritic cells.[@b26-jaa-9-093] Murine studies have shown that eosinophils also contribute to airway-wall remodeling and subepithelial membrane thickening via the release of TGFβ.[@b26-jaa-9-093] Finally, similarly to neutrophils, upon activation, eosinophils undergo cytolysis and release mediators from the eosinophilic granules, such as eosinophil-derived neurotoxin, cationic proteins (eosinophil peroxidase), and major basic protein, which can damage structural cells of the airway.[@b26-jaa-9-093] It has been demonstrated that humans who died from asthma presented eosinophilic inflammation all over the respiratory tract, from nasal mucosa to lung tissue, showing that the airways really are unique, even in pathologic conditions.[@b30-jaa-9-093] Therefore, AR and asthma share immunopathological features, including a T~H~2-type immune response, thickness of the basement membrane, and goblet-cell hyperplasia.[@b24-jaa-9-093]\n\nIn contrast to allergic UAD, the pathophysiology of which is well characterized, the etiology of and mechanisms involved in nonallergic UAD remain unclear. ", "Some of the possibilities include allergy triggered by unknown antigens (fungi), persistent infection (caused by *Chlamydia trachomatis*, *Mycoplasma* spp., ", "or viruses), and autoimmunity.", "\n\nA central concept of UAD is the influence of the upper airway in the function of the lower airway, which is particularly evident and relevant in the allergic phenotype.[@b25-jaa-9-093] The pathological interactions between the upper and lower airways are summarized in [Figure 1](#f1-jaa-9-093){ref-type=\"fig\"} and can be divided into: air-conditioninginflammationneural reflexes.", "\n\nAir-conditioning\n----------------\n\nGalen was the first to offer insights on the function of the nose as protector of the lower airway through its ability to clean, warm, and humidify inhaled air.[@b5-jaa-9-093] In addition, the nasal mucosa, with its abundant submucosal glands, takes part of the innate and adaptive immune defense by releasing antibacterial proteins, such as lysozyme and lactoferrin, chemical defenses, antioxidants, and secretory IgA, that can protect the lower airway from pathogens and allergens.[@b25-jaa-9-093] Patients with AR present partial or complete loss of function of the nose due to mucosal congestion, since nasal airways are bypassed during oral breathing.[@b25-jaa-9-093] In this situation, inhalation of cold and dry air may directly induce bronchoconstriction. ", "Therefore, the lower airway would be quite \"opened\" to the entrance of allergens and pathogens, increasing the risk of asthma exacerbation.", "\n\nInflammation\n------------\n\nPropagation of inflammation from the upper airway to lower airway may occur via postnasal drip and systemic circulation. ", "The concept that inflammatory secretions from the upper airway of patients with rhinosinusitis or even with rhinitis are aspirated into the lower airway with adverse consequences has been viewed as one of the principal mechanisms for lower airway symptoms, especially after an upper respiratory infection.[@b25-jaa-9-093] It is quite possible that early morning coughing in individuals with rhinitis is associated with accumulation of secretions in the lower pharyngeal area stimulating irritant receptors.[@b25-jaa-9-093] It is questionable, however, whether these secretions can reach the intrathoracic lower airway in adequate quantities to alter their physiology and to generate exacerbations or chronically worsen lower airway function in patients with asthma.[@b25-jaa-9-093] The development of sinusitis in rabbits is associated with lower AHR, even after eliminating upper--lower airway communication with the use of an inflated endotracheal tube cuff.[@b31-jaa-9-093]\n\nOn the other hand, there is good evidence that allergic inflammation developing in the respiratory mucosa may result in systemic inflammatory events.[@b25-jaa-9-093] Blood eosinophilia may be observed in patients with allergic asthma, and can be considered a biomarker of inflammation of the lower airway. ", "There is less evidence that upper airway inflammation can lead to an increase in eosinophil blood count.[@b25-jaa-9-093],[@b32-jaa-9-093] Moreover, there is no experimental information indicating that nasal inflammation leads to systemic inflammatory signals that induce changes in lower airway physiology,[@b25-jaa-9-093] even though it seems reasonable to speculate that cytokines released in nasal mucosa could activate bone marrow with chemotaxis of white blood cells to both upper and lower airways.[@b25-jaa-9-093]\n\nThe opposite direction for propagation of the inflammatory process, beginning in the lower airway and getting to the upper airway, has been postulated. ", "A study showed that segmental bronchial allergen provocation in patients with nonasthmatic AR can induce nasal inflammation, nasal and bronchial symptoms, and reduction in pulmonary and nasal function.[@b33-jaa-9-093] However, there are recent data suggesting that this lung--nasal propagation of inflammation might not be relevant. ", "In a very elegant murine model of allergic respiratory inflammation induced by ovalbumin, Balb/c mice were submitted to intratracheal challenge after sensitization by an intraperitoneal route. ", "This provocation induced lung inflammation and AHR, but no signs of inflammation were found in the nose.[@b34-jaa-9-093]\n\nNeural reflexes\n---------------\n\nThe existence of a nasobronchial reflex that originates from the sensory nerve endings in the nose, travels to the central nervous system through the trigeminal nerve, and follows an efferent pathway through the vagus nerve to produce airway smooth-muscle contraction has been under debate for years.[@b25-jaa-9-093] Despite being well documented in animal models, its existence and relevance in humans are still controversial.", "\n\nSome studies performed in healthy individuals and asthmatics have demonstrated that lower airway resistance increased after nasal inhalation of cold and dry air.[@b35-jaa-9-093],[@b36-jaa-9-093] Another important study showed an increase in AHR after a nasal allergen provocation in asthmatics who had reported worsening of asthma symptoms following seasonal exacerbations of rhinitis.[@b37-jaa-9-093] The authors observed that none of the solutions delivered to the nose during allergen provocation could be detected in the lower airway, showing that the increase in AHR was not due to inadvertent inhalation of the allergen.[@b37-jaa-9-093] It is important to point out that the classic nasobronchial reflex is a component of the diving reflex.[@b38-jaa-9-093] Immersion of the head into cold water leads to immediate suppression of respiration (apnea), laryngospasm, and bronchoconstriction, in order to protect the lower airway from diving.[@b38-jaa-9-093] Nasal inhalation of dust, pollutants, and irritants can induce immediate bronchoconstriction with cessation of respiration in the expiratory phase, due to relaxation of inspiratory muscles.[@b38-jaa-9-093] Therefore, in individuals with allergic respiratory disease, this reflex could lead to an increase in asthma symptoms after nasal injury.", "\n\nThere is less evidence showing the occurrence of a bronchonasal reflex. ", "It has been demonstrated that inhalation of ultrasonically nebulized distilled water increased nasal airway resistance in patients with AR, without the involvement of parasympathetic efferent reflexes, since patients did not present sneezing or rhinorrhea.[@b39-jaa-9-093] The clinical relevance of this bronchonasal reflex has yet to be demonstrated.", "\n\nIn conclusion, upper and lower airways seem to constitute a unique system, named \"united airway\", that share similarities in terms of histology, physiology, and pathology. ", "UAD is triggered by a T~H~2 immune response of the airway, leading to an extended inflammatory process that begins in nasal mucosa and ends in bronchioles and alveoli, particularly in symptomatic asthmatics.", "\n\nUnited airway disease: clinical evidence\n========================================\n\nThere is also clinical evidence supporting the concept of UAD. ", "Studies have demonstrated that the presence of severe rhinitis is associated with an increased risk of asthma[@b20-jaa-9-093] and in patients with asthma a less favorable evolution.[@b40-jaa-9-093]--[@b42-jaa-9-093] It has also been shown that the treatment of rhinitis can be beneficial to the lower airway, reducing symptoms, emergency room visits, and hospitalizations, as well as the severity of bronchial hyperresponsiveness.[@b43-jaa-9-093]--[@b47-jaa-9-093] In protocols of difficult-to-control asthma, rhinitis was included as one of the main comorbidities to be assessed and treated.[@b48-jaa-9-093]\n\nTherapy for UAD includes avoidance of relevant allergens and irritants, pharmacotherapy, and allergen-specific immunotherapy (SIT). ", "Allergen avoidance has been suggested not only to prevent UAD onset and progression but also to reduce its burden, improving symptoms and quality of life. ", "However, there is a lack of evidence supporting the effectiveness of environmental control.[@b4-jaa-9-093]\n\nThe pharmacologic approach of AR includes antihistamines, oral leukotriene antagonists, and intranasal corticosteroids, the last being considered the most efficacious drug.[@b4-jaa-9-093] Agondi et al reported a decrease in asthma symptoms and AHR after intranasal corticosteroid treatment of rhinitis.[@b43-jaa-9-093] A recent meta-analysis confirmed the beneficial effect of intranasal steroids in AHR.[@b44-jaa-9-093] Oral and intranasal antihistamines, as well as leukotriene antagonists, are less effective than intranasal corticosteroids in improving the symptoms of AR.[@b49-jaa-9-093]--[@b52-jaa-9-093] A protective effect of cetirizine against AHR measured 6 hours after nasal allergen challenge in patients with AR was shown.[@b53-jaa-9-093]\n\nAllergen-SIT is defined as a procedure to administer increasing amounts of specific allergens in patients diagnosed with IgE-mediated disease, in order to induce immune tolerance.[@b8-jaa-9-093],[@b54-jaa-9-093] Subcutaneous and sublingual IT can reduce symptoms of AR and need of reliever medication, as well as improve the control of comorbid conditions, such as asthma and conjunctivitis.[@b8-jaa-9-093],[@b55-jaa-9-093]\n\nAllergen-SIT is indicated in moderate/severe AR for which response to pharmacotherapy is inadequate. ", "Other potential indications are adverse effects of medications, coexisting allergic asthma, bad adherence to therapy, and patient preference for IT instead of pharmacotherapy.[@b8-jaa-9-093],[@b56-jaa-9-093] Furthermore, SIT has been positioned as the only treatment that can modify the natural course of allergic diseases that includes prevention of new sensitizations and reduction of risk of developing asthma in subjects with AR, even after termination of treatment.[@b57-jaa-9-093]--[@b61-jaa-9-093] The Preventive Allergy Treatment study was a randomized controlled trial that showed clinical benefits and a preventive effect on asthma development in children suffering from seasonal rhinoconjuctivitis undergoing subcutaneous IT with grass- and/or birch-allergen extracts for 3 years. ", "This positive effect of SIT in preventing the progression from rhinitis to asthma was observed to persist in the same patients for 7 years after the termination of the treatment.[@b57-jaa-9-093]--[@b59-jaa-9-093] Another study found that after 3 years of sublingual grass-pollen IT in children with AR, eight of 45 actively treated subjects and 18 of 44 controls developed asthma, with 3.8-fold more frequent development of asthma in the untreated patients.[@b62-jaa-9-093]\n\nSome studies have shown that IT was able to prevent new sensitizations in monosensitized individuals.[@b63-jaa-9-093] A research assessing the effects of subcutaneous IT in 147 house dust mite-monosensitized children over 5 years found similar results: 75.3% in the treated group and 46.7% in the control group had no new sensitizations.[@b64-jaa-9-093] A randomized controlled study involved 216 children with AR (with or without intermittent asthma) receiving drugs alone or drugs plus sublingual IT for 3 years showed new sensitizations in 34.8% of controls and in 3.1% of the IT group. ", "Moreover, they demonstrated that this protective effect extended to AHR, which significantly decreased in the IT group.[@b65-jaa-9-093]\n\nNovel targeted therapeutic approaches using biological agents have been studied in the treatment of AR and allergic asthma, especially for the management of severe uncontrolled phenotypes. ", "Among these, omalizumab, a humanized monoclonal antibody that binds circulating IgE and prevents its attachment to high-affinity IgE receptors, is available worldwide. ", "Omalizumab improves both upper and lower airway diseases, reducing nasal and asthma symptoms, decreasing exacerbations, and improving quality of life.[@b66-jaa-9-093] Mepolizumab, a monoclonal antibody that blocks the binding of IL-5 to eosinophils, has also shown a beneficial effect on severe eosinophilic airway diseases, such as asthma and nasal polyposis in adults.[@b67-jaa-9-093]--[@b69-jaa-9-093] Because these treatments have systemic effects, it is not possible to design a study to assess how much the improvement in asthma is, due to direct effects or indirect effects associated with rhinitis improvement.", "\n\nThe management of rhinitis may promote better adherence to therapy. ", "It should consider severity and duration of the disease and patient preference, as well as the efficacy, availability, and cost of medications. ", "Therefore, management of rhinitis and asthma must be jointly carried out, including environmental control, pharmacotherapy, and SIT.", "\n\nConclusion\n==========\n\nThe treatment of rhinitis is indispensable in patients with asthma, since it leads to better control of both diseases, and the lessons of the ARIA initiative cannot be forgotten. ", "Further studies regarding UAD are needed to better understand the interactions between the upper and lower airways, but there is no doubt that rhinitis and asthma have to be studied and managed in an integrated manner.", "\n\n**Disclosure**\n\nThe authors report no conflicts of interest in this work.", "\n\n{#f1-jaa-9-093}\n\n###### \n\nAirway hypersensitivity syndrome phenotypes\n\n ---------------------------------------------------------------------------------------\n 1\\. Rhinitis[a](#tfn1-jaa-9-093){ref-type=\"table-fn\"}\n 2\\. Rhinitis[a](#tfn1-jaa-9-093){ref-type=\"table-fn\"} with airway hyperresponsiveness\n 3\\. Eosinophilic bronchitis\n 4\\. Asthma\n 5\\. Rhinitis[a](#tfn1-jaa-9-093){ref-type=\"table-fn\"} and asthma\n ---------------------------------------------------------------------------------------\n\n**Note:**\n\nRhinitis can be associated with conjunctivitis.", "\n\n[^1]: These authors contributed equally to this work.", "\n" ]

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[ "Destroying the left-wing narrative\n\nMaxine Waters attacks Trump, accidentally admits that Americans are subjected to painful levels of taxation\n\nFor whatever reason, the voters of California have decided that Maxine Waters is the kind of crazy person they want to keep in Congress. ", "I’m not sure why that is, but left-coasters also keep Pelosi employed so, clearly, there’s something in the water out there. ", "Anyway, Ms. Waters hates Trump. ", "She wants him impeached. ", "She’s vowed to impeach him herself. ", "On what grounds she intends to do this, no one seems to be sure.", "\n\nIt appears to have something to do with his tax returns, since she’s still leading a doomed effort to see them released. ", "Never mind that “auditing the President” isn’t her job. ", "Ignore the fact that we now know he did pay taxes during the time she likes to claim he didn’t. ", "Reality is not Ms. Waters’ strong suit. ", "What’s important here is that Maxine Waters - a top Democrat and ardent supporter of big government in all its myriad forms - just accidentally admitted that people across the nation struggle under an onerous tax burden. ", "Yes, Maxine Waters, perhaps the ultimate example of the left-wing mindset tried to attack Trump by destroying the Democrats pro-taxation narrative. ", "It’s glorious to behold: .@MaxineWaters: \"This president is basically laughing at us\" #inners https://t.co/VeXSdH9LPQ — All In w/Chris Hayes (@allinwithchris) April 18, 2017\n\nMaxine Waters foamy-mouthed Trump hate Look, if we ignore her foamy-mouthed Trump hate, we basically agree with her here. ", "Americans ARE over-taxed, they DO struggle to pay the IRS, and many (we’d say most) are forced to pay taxes that they can’t (and shouldn’t have to) afford. ", "This, of course, is because Democrats refuse to embrace any sort of tax reform. ", "It’s one of the reasons Trump got elected. ", "That she’s making this point in an effort to somehow damage President Trump? ", "Hilarious.", "\n\nRobert Laurie -- Bio and Archives Robert Laurie’s column is distributed by HermanCain.com, which can be found at HermanCain.com Be sure to “like” Robert Laurie over on Facebook and follow him on Twitter. ", "You’ll be glad you did.", "\n\n{/exp:ce_cache:it}" ]

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[ "Street Fighter V: Arcade Edition had its first location test over the past weekend. ", "For those who may be wondering how the location test actually works, NihongoGamer took some footage of the location test at the Taito Station arcade in Shinjuku for an insider’s look.", "\n\nThe video below goes over some of the actual quirks of the location test, as well as the build of the game that was used. ", "Taito Station’s cabinets were side by side, instead of head to head as is usually the case. ", "As previously reported, the arcade itself DualShock 4 pads for any players who preferred using one.", "\n\nAs for the game itself, the build at the location tests had a training mode on top of the arcade mode. ", "In versus matches, players adhered to the “winners stay” rule, though players themselves were limited to 5 wins before they had to stand up and let someone else play.", "\n\nSource: NihongoGamer" ]

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