Objective:Alcohol use disorders are common conditions that have enormous social and economic consequences. Genome-wide association analyses were performed to identify genetic variants associated with ...a proxy measure of alcohol consumption and alcohol misuse and to explore the shared genetic basis between these measures and other substance use, psychiatric, and behavioral traits.Method:This study used quantitative measures from the Alcohol Use Disorders Identification Test (AUDIT) from two population-based cohorts of European ancestry (UK Biobank N=121,604 and 23andMe N=20,328) and performed a genome-wide association study (GWAS) meta-analysis. Two additional GWAS analyses were performed, a GWAS for AUDIT scores on items 1–3, which focus on consumption (AUDIT-C), and for scores on items 4–10, which focus on the problematic consequences of drinking (AUDIT-P).Results:The GWAS meta-analysis of AUDIT total score identified 10 associated risk loci. Novel associations localized to genes including JCAD and SLC39A13; this study also replicated previously identified signals in the genes ADH1B, ADH1C, KLB, and GCKR. The dimensions of AUDIT showed positive genetic correlations with alcohol consumption (rg=0.76–0.92) and DSM-IV alcohol dependence (rg=0.33–0.63). AUDIT-P and AUDIT-C scores showed significantly different patterns of association across a number of traits, including psychiatric disorders. AUDIT-P score was significantly positively genetically correlated with schizophrenia (rg=0.22), major depressive disorder (rg=0.26), and attention deficit hyperactivity disorder (rg=0.23), whereas AUDIT-C score was significantly negatively genetically correlated with major depressive disorder (rg=−0.24) and ADHD (rg=−0.10). This study also used the AUDIT data in the UK Biobank to identify thresholds for dichotomizing AUDIT total score that optimize genetic correlations with DSM-IV alcohol dependence. Coding individuals with AUDIT total scores ≤4 as control subjects and those with scores ≥12 as case subjects produced a significant high genetic correlation with DSM-IV alcohol dependence (rg=0.82) while retaining most subjects.Conclusions:AUDIT scores ascertained in population-based cohorts can be used to explore the genetic basis of both alcohol consumption and alcohol use disorders.
We introduce a new capability of the Neil Gehrels Swift Observatory to provide event-level data from the Burst Alert Telescope (BAT) on demand in response to transients detected by other instruments. ...We show that the availability of these data can effectively increase the rate of detections and arcminute localizations of gamma-ray bursts (GRB) like GRB 170817 by >400%. We describe an autonomous spacecraft-commanding pipeline purpose built to enable this science; to our knowledge, this is the first fully autonomous extremely low-latency commanding of a space telescope for scientific purposes. This pipeline has been successfully run in its complete form since 2020 January, and has resulted in the recovery of BAT event data for >800 externally triggered events to date (gravitational waves, GWs; neutrinos; GRBs triggered by other facilities; fast radio bursts; and very high-energy detections), now running with a success rate of ∼90%. We exemplify the utility of this new capability by using the resultant data to (1) set the most sensitive upper limits on prompt 1 s duration short GRB-like emission within 15 s around the unmodeled GW burst candidate S200114f, and (2) provide an arcminute localization for short GRB 200325A and other bursts. We also show that using data from GUANO to localize GRBs discovered by other instruments, we can increase the net rate of arcminute-localized GRBs by 10%-20% per year. Along with the scientific yield of more sensitive searches for subthreshold GRBs, the new capabilities designed for this project will serve as the foundation for further automation and rapid target of opportunity capabilities for the Swift mission, and have implications for the design of future rapid-response space telescopes.
The exome sequences of approximately 8,000 children with autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD) and 5,000 controls were analyzed, finding that ...individuals with ASD and individuals with ADHD had a similar burden of rare protein-truncating variants in evolutionarily constrained genes, both significantly higher than controls. This motivated a combined analysis across ASD and ADHD, identifying microtubule-associated protein 1A (MAP1A) as a new exome-wide significant gene conferring risk for childhood psychiatric disorders.
Coronaviruses are adept at evading host antiviral pathways induced by viral double-stranded RNA, including interferon (IFN) signaling, oligoadenylate synthetase-ribonuclease L (OAS-RNase L), and ...protein kinase R (PKR). While dysregulated or inadequate IFN responses have been associated with severe coronavirus infection, the extent to which the recently emerged SARS-CoV-2 activates or antagonizes these pathways is relatively unknown. We found that SARS-CoV-2 infects patient-derived nasal epithelial cells, present at the initial site of infection; induced pluripotent stem cell-derived alveolar type 2 cells (iAT2), the major cell type infected in the lung; and cardiomyocytes (iCM), consistent with cardiovascular consequences of COVID-19 disease. Robust activation of IFN or OAS-RNase L is not observed in these cell types, whereas PKR activation is evident in iAT2 and iCM. In SARS-CoV-2-infected Calu-3 and A549
lung-derived cell lines, IFN induction remains relatively weak; however, activation of OAS-RNase L and PKR is observed. This is in contrast to Middle East respiratory syndrome (MERS)-CoV, which effectively inhibits IFN signaling and OAS-RNase L and PKR pathways, but is similar to mutant MERS-CoV lacking innate immune antagonists. Remarkably, OAS-RNase L and PKR are activated in
knockout A549
cells, demonstrating that SARS-CoV-2 can induce these host antiviral pathways despite minimal IFN production. Moreover, increased replication and cytopathic effect in
knockout A549
cells implicates OAS-RNase L in restricting SARS-CoV-2. Finally, while SARS-CoV-2 fails to antagonize these host defense pathways, which contrasts with other coronaviruses, the IFN signaling response is generally weak. These host-virus interactions may contribute to the unique pathogenesis of SARS-CoV-2.
ABSTRACT To date, the Burst Alert Telescope (BAT) onboard Swift has detected ∼1000 gamma-ray bursts (GRBs), of which ∼360 GRBs have redshift measurements, ranging from z = 0.03 to z = 9.38. We ...present the analyses of the BAT-detected GRBs for the past ∼11 years up through GRB 151027B. We report summaries of both the temporal and spectral analyses of the GRB characteristics using event data (i.e., data for each photon within approximately 250 s before and 950 s after the BAT trigger time), and discuss the instrumental sensitivity and selection effects of GRB detections. We also explore the GRB properties with redshift when possible. The result summaries and data products are available at http://swift.gsfc.nasa.gov/results/batgrbcat/index.html. In addition, we perform searches for GRB emissions before or after the event data using the BAT survey data. We estimate the false detection rate to be only one false detection in this sample. There are 15 ultra-long GRBs (∼2% of the BAT GRBs) in this search with confirmed emission beyond ∼1000 s of event data, and only two GRBs (GRB 100316D and GRB 101024A) with detections in the survey data prior to the starting of event data.
Chronic myeloid leukaemia (CML) is driven by the activity of the BCR-ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of ...patients treated with imatinib surviving for more than 10 years. Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML. Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR-ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment. Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph
) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib. Consistent with this profile, acquired resistance was observed with single-agent therapy in mice; however, the combination of ABL001 and nilotinib led to complete disease control and eradicated CML xenograft tumours without recurrence after the cessation of treatment.
Rationale
Allergic diseases are an increasing public health concern, and early life environment is critical to immune development. Maternal diet during pregnancy has been linked to offspring allergy ...risk. In turn, maternal diet is a potentially modifiable factor, which could be targeted as an allergy prevention strategy. In this systematic review, we focused on non‐allergen‐specific modifying factors of the maternal diet in pregnancy on allergy outcomes in their offspring.
Methods
We undertook a systematic review of studies investigating the association between maternal diet during pregnancy and allergic outcomes (asthma/wheeze, hay fever/allergic rhinitis/seasonal allergies, eczema/atopic dermatitis (AD), food allergies, and allergic sensitization) in offspring. Studies evaluating the effect of food allergen intake were excluded. We searched three bibliographic databases (MEDLINE, EMBASE, and Web of Science) through February 26, 2019. Evidence was critically appraised using modified versions of the Cochrane Collaboration Risk of Bias tool for intervention trials and the National Institute for Clinical Excellence methodological checklist for cohort and case‐control studies and meta‐analysis performed from RCTs.
Results
We identified 95 papers: 17 RCTs and 78 observational (case‐control, cross‐sectional, and cohort) studies. Observational studies varied in design and dietary intakes and often had contradictory findings. Based on our meta‐analysis, RCTs showed that vitamin D supplementation (OR: 0.72; 95% CI: 0.56‐0.92) is associated with a reduced risk of wheeze/asthma. A positive trend for omega‐3 fatty acids was observed for asthma/wheeze, but this did not reach statistical significance (OR: 0.70; 95% CI: 0.45‐1.08). Omega‐3 supplementation was also associated with a non‐significant decreased risk of allergic rhinitis (OR: 0.76; 95% CI: 0.56‐1.04). Neither vitamin D nor omega‐3 fatty acids were associated with an altered risk of AD or food allergy.
Conclusions
Prenatal supplementation with vitamin D may have beneficial effects for prevention of asthma. Additional nutritional factors seem to be required for modulating the risk of skin and gastrointestinal outcomes. We found no consistent evidence regarding other dietary factors, perhaps due to differences in study design and host features that were not considered. While confirmatory studies are required, there is also a need for performing RCTs beyond single nutrients/foods.
Our systematic review focused on the maternal diet in pregnancy and allergy outcomes in the offspring. Results from the observational studies provided no conclusive evidence on whether the mother’s diet when pregnant affects the development of offspring allergic disease. Data from the randomized controlled trials indicated that vitamin D supplementation in doses higher than recommended by most countries, lead to a 30% reduction in offspring asthma. As a result, no recommendations about what pregnant women should eat or which supplements to take, to prevent their offspring from developing allergic disease can be made at this stage. Further studies should be performed, using standardised methods focusing on the total diet rather than one nutrient, using validated instruments to measure dietary intake and clearly defining the phenotype ad genetic characteristics of each woman.
Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive ...methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients.
Patients receiving ART who had plasma HIV-1 RNA levels below 50 copies/mL but detectable viremia by single copy assay (SCA) were randomized to add either raltegravir or placebo to their ART regimen for 12 weeks; patients then crossed-over to the other therapy for an additional 12 weeks while continuing pre-study ART. The primary endpoint was the plasma HIV-1 RNA by SCA averaged between weeks 10 and 12 (10/12) compared between treatment groups. Fifty-three patients were enrolled. The median screening HIV-1 RNA was 1.7 copies/mL. The HIV-1 RNA level at weeks 10/12 did not differ significantly between the raltegravir-intensified (n = 25) and the placebo (n = 24) groups (median 1.2 versus 1.7 copies/mL, p = 0.55, Wilcoxon rank sum test), nor did the change in HIV-1 RNA level from baseline to week 10/12 (median -0.2 and -0.1 copies/mL, p = 0.71, Wilcoxon rank sum test). There was also no significant change in HIV-1 RNA level from weeks 10/12 to weeks 22/24 after patients crossed-over. There was a greater CD4 cell count increase from baseline to week 12 in the raltegravir-intensified group compared with the placebo group (+42 versus -44 cells/mm(3), p = 0.082, Wilcoxon rank sum test), which reversed after the cross-over. This CD4 cell count change was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood.
In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells. New therapeutic strategies to eliminate reservoirs that produce residual viremia will be required to eradicate HIV-1 infection.
ClinicalTrials.gov NCT00515827
The Swift Burst Alert Telescope (BAT) is a coded aperture gamma-ray instrument with a large field of view that primarily operates in survey mode when it is not triggering on transient events. The ...survey data consists of eighty-channel detector plane histograms that accumulate photon counts over time periods of at least 5 minutes. These histograms are processed on the ground and are used to produce the survey dataset between 14 and 195 keV. Survey data comprises >90% of all BAT data by volume and allows for the tracking of long term light curves and spectral properties of cataloged and uncataloged hard X-ray sources. Until now, the survey dataset has not been used to its full potential due to the complexity associated with its analysis and the lack of easily usable pipelines. Here, we introduce the BatAnalysis python package , a wrapper for HEASoftpy, which provides a modern, open-source pipeline to process and analyze BAT survey data. BatAnalysis allows members of the community to use BAT survey data in more advanced analyses of astrophysical sources including pulsars, pulsar wind nebula, active galactic nuclei, and other known/unknown transient events that may be detected in the hard X-ray band. We outline the steps taken by the python code and exemplify its usefulness and accuracy by analyzing survey data from the Crab Pulsar, NGC 2992, and a previously uncataloged MAXI Transient. The BatAnalysis package allows for ∼ 18 years of BAT survey to be used in a systematic way to study a large variety of astrophysical sources.
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