The Genomic Signature of Crop-Wild Introgression in Maize

The evolutionary significance of hybridization and subsequent introgression has long been appreciated, but evaluation of the genome-wide effects of these phenomena has only recently become possible. Crop-wild study systems represent ideal opportunities to examine evolution through hybridization. For example, maize and the conspecific wild teosinte Zea mays ssp. mexicana, (hereafter, mexicana) are known to hybridize in the fields of highland Mexico. Despite widespread evidence of gene flow, maize and mexicana maintain distinct morphologies and have done so in sympatry for thousands of years. Neither the genomic extent nor the evolutionary importance of introgression between these taxa is understood. In this study we assessed patterns of genome-wide introgression based on 39,029 single nucleotide polymorphisms genotyped in 189 individuals from nine sympatric maize-mexicana populations and reference allopatric populations. While portions of the maize and mexicana genomes were particularly resistant to introgression (notably near known cross-incompatibility and domestication loci), we detected widespread evidence for introgression in both directions of gene flow. Through further characterization of these regions and preliminary growth chamber experiments, we found evidence suggestive of the incorporation of adaptive mexicana alleles into maize during its expansion to the highlands of central Mexico. In contrast, very little evidence was found for adaptive introgression from maize to mexicana. The methods we have applied here can be replicated widely, and such analyses have the potential to greatly informing our understanding of evolution through introgressive hybridization. Crop species, due to their exceptional genomic resources and frequent histories of spread into sympatry with relatives, should be particularly influential in these studies

Nonsteroidal anti-inflammatory drugs (NSAIDs), cyxlooxygenase-2 selective inhibitors (coxibs) and gastrointestinal harm: review of clinical trials and clinical practice

BACKGROUND: Gastrointestinal harm, known to occur with NSAIDs, is thought to be lower with NSAID and gastroprotective agent, and with inhibitors selective to cyclooxygenase-2 (coxibs) at usual plasma concentrations. We examine competing strategies for available evidence of reduced gastrointestinal bleeding in clinical trials and combine this evidence with evidence from clinical practice on whether the strategies work in the real world, whether guidance on appropriate prescribing is followed, and whether patients adhere to the strategies. METHODS: We used a series of systematic literature searches to find full publications of relevant studies for evidence about the efficacy of these different gastroprotection strategies in clinical trials, and for evidence that they worked and were adhered to in clinical practice – whether they were effective. We chose to use good quality systematic reviews and meta-analyses when they were available. RESULTS: Evidence of efficacy of coxibs compared to NSAIDs for upper gastrointestinal bleeding was strong, with consistent reductions in events of about 50% in large randomised trials (34,460 patients), meta-analyses of randomised trials (52,474 patients), and large observational studies in clinical practice (3,093 bleeding events). Evidence on the efficacy of NSAID plus gastroprotection with acid suppressants (proton pump inhibitors, PPIs, and histamine antagonists, H2As) was based mainly on the surrogate measure of endoscopic ulcers. The limited information on damage to the bowel suggested that NSAID plus PPI was more damaging than coxibs. Eleven observational studies studied 1.6 million patients, of whom 911,000 were NSAID users, and showed that 76% (range 65% to 90%) of patients with at least one gastrointestinal risk factor received no prescription for gastroprotective agent with an NSAID. The exception was a cohort of US veterans with previous gastrointestinal bleeding, where 75% had gastroprotection with an NSAID. When gastroprotection was prescribed, it was often described as inadequate. A single study suggested that patient adherence to prescribed gastroprotection was low. CONCLUSION: Evidence for efficacy of gastroprotection strategies with NSAIDs is limited. In clinical practice few patients who need gastroprotection get it, and those who get it may not take it. For coxibs, gastroprotection is inherent, although probably not complete

Cyclo-oxygenase-2 selective inhibitors and nonsteroidal anti-inflammatory drugs: balancing gastrointestinal and cardiovascular risk

<p>Abstract</p> <p>Background</p> <p>Differences between gastrointestinal and cardiovascular effects of traditional NSAID or cyclooxygenase-2 selective inhibitor (coxib) are affected by drug, dose, duration, outcome definition, and patient gastrointestinal and cardiovascular risk factors. We calculated the absolute risk for each effect.</p> <p>Methods</p> <p>We sought studies with large amounts of information to calculate annualised rates for clearly defined gastrointestinal (complicated upper gastrointestinal perforations, ulcers, or bleeds, but not symptomatic or endoscopic ulcers) and serious cardiovascular outcomes (antiplatelet trial collaborators – APTC – outcome of fatal or nonfatal myocardial infarction or stroke, or vascular death).</p> <p>Results</p> <p>Meta-analyses and large randomised trials specifically analysing serious gastrointestinal bleeding or cardiovascular events occurring with five different coxibs had appropriate data. In total there were 439 complicated upper gastrointestinal events in 49,006 patient years of exposure and 948 serious cardiovascular events in 99,400 patient years of exposure. Complicated gastrointestinal events occurred less frequently with coxibs than NSAIDs; serious cardiovascular events occurred at approximately equal rates. For each coxib, the reduction in complicated upper gastrointestinal events was numerically greater than any increase in APTC events. In the overall comparison, for every 1000 patients treated for a year with coxib rather than NSAID, there would be eight fewer complicated upper gastrointestinal events, but one more fatal or nonfatal heart attack or stroke. Three coxib-NSAID comparisons had sufficient numbers of events for individual comparisons. For every 1000 patients treated for a year with celecoxib rather than an NSAID there would be 12 fewer upper gastrointestinal complications, and two fewer fatal or nonfatal heart attacks or strokes. For rofecoxib there would be six fewer upper gastrointestinal complications, but three more fatal or nonfatal heart attacks or strokes. For lumiracoxib there would be eight fewer upper gastrointestinal complications, but one more fatal or nonfatal heart attack or stroke.</p> <p>Conclusion</p> <p>Calculating annualised event rates for gastrointestinal and cardiovascular harm shows that while complicated gastrointestinal events occur more frequently with NSAIDs than coxibs, serious cardiovascular events occur at approximately equal rates. For each coxib, the reduction in complicated upper gastrointestinal events was numerically greater than any increase in APTC events.</p

Krüppel-Like Factor 6 Expression Changes during Trophoblast Syncytialization and Transactivates ßhCG and PSG Placental Genes

BACKGROUND: Krüppel-like factor-6 (KLF6) is a widely expressed member of the Sp1/KLF family of transcriptional regulators involved in differentiation, cell cycle control and proliferation in several cell systems. Even though the highest expression level of KLF6 has been detected in human and mice placenta, its function in trophoblast physiology is still unknown. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we explored KLF6 expression and sub-cellular distribution in human trophoblast cells differentiating into the syncytial pathway, and its role in the regulation of genes associated with placental development and pregnancy maintenance. Confocal immunofluorescence microscopy demonstrated that KLF6 is expressed throughout human cytotrophoblast differentiation showing no evident modifications in its nuclear and cytoplasmic localization pattern. KLF6 transcript and protein peaked early during the syncytialization process as determined by qRT-PCR and western blot assays. Overexpression of KLF6 in trophoblast-derived JEG-3 cells showed a preferential nuclear signal correlating with enhanced expression of human β-chorionic gonadotropin (βhCG) and pregnancy-specific glycoprotein (PSG) genes. Moreover, KLF6 transactivated βhCG5, PSG5 and PSG3 gene promoters. Deletion of KLF6 Zn-finger DNA binding domain or mutation of the consensus KLF6 binding site abolished transactivation of the PSG5 promoter. CONCLUSIONS/SIGNIFICANCE: Results are consistent with KLF6 playing a role as transcriptional regulator of relevant genes for placental differentiation and physiology such as βhCG and PSG, in agreement with an early and transient increase of KLF6 expression during trophoblast syncytialization

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

The progressive elevation of alpha fetoprotein for the diagnosis of hepatocellular carcinoma in patients with liver cirrhosis

BACKGROUND: Hepatocellular carcinoma is the most common cause of primary liver neoplasms and is one of the main causes of death in patients with liver cirrhosis. High Alpha fetoprotein serum levels have been found in 60–70% of patients with Hepatocellular carcinoma; nevertheless, there are other causes that increase this protein. Alpha fetoprotein levels ≥200 and 400 ng/mL in patients with an identifiable liver mass by imaging techniques are diagnostic of hepatocellular carcinoma with high specificity. METHODS: We analysed the sensitivity and specificity of the progressive increase of the levels of alpha fetoprotein for the detection of hepatocellular carcinoma in patients with liver cirrhosis. Seventy-four patients with cirrhosis without hepatocellular carcinoma and 193 with hepatic lesions diagnosed by biopsy and shown by image scans were included. Sensitivity and specificity of transversal determination of alpha fetoprotein ≥ 200 and 400 ng/mL and monthly progressive elevation of alpha fetoprotein were analysed. Areas under the ROC curves were compared. Positive and negative predictive values adjusted to a 5 and 10% prevalence were calculated. RESULTS: For an elevation of alpha fetoprotein ≥ 200 and 400 ng/mL the specificity is of 100% in both cases, with a sensitivity of 36.3 and 20.2%, respectively. For an alpha fetoprotein elevation rate ≥7 ng/mL/month, sensitivity was of 71.4% and specificity of 100%. The area under the ROC curve of the progressive elevation was significantly greater than that of the transversal determination of alpha fetoprotein. The positive and negative predictive values modified to a 10% prevalence are of: 98.8% and 96.92%, respectively; while for a prevalence of 5% they were of 97.4% and 98.52%, respectively. CONCLUSION: The progressive elevation of alpha fetoprotein ≥7 ng/mL/month in patients with liver cirrhosis is useful for the diagnosis of hepatocellular carcinoma in patients that do not reach αFP levels ≥200 ng/mL. Prospective studies are required to confirm this observation

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal