Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Tracing isotopic signatures (δD and δ18O) in precipitation and glacier melt over Chorabari Glacier–Hydroclimatic inferences for the Upper Ganga Basin (UGB), Garhwal Himalaya

Study region: Chorabari Glacier in Upper Ganga Basin, Garhwal Himalaya. Study focus: Authors attempt to characterize the isotopic signatures in different components of the hydrological cycle and decipher the role of summer and winter precipitation on glacier melt using stable isotopes (δD, δ18O) coupled with existing hydrometeorological observations during the glacier ablation season (June–September) for the years 2011–2012. New hydrological insights: The isotopic composition of various components of hydrological cycle i.e., precipitation (rainfall and snowfall), glacier surface ice and glacier melt have partly overlapping isotopic ranges. δ18O, δD and d–excess compositon indicates that precipitation during pre-monsoon (May/June) and post-monsoon (September/October) season have mixing of local moisture with that from westerlies. While during monsoon (June–September) rainfall-runoff contributes to the streamflow with snow and glacier melt. The depletion pattern of snow covered area (SCA) reflected by snow depletion curves (SDC) imply that most of the solid precipitation in the region results from westerlies, while during summers the precipitation from the Indian Summer Monsoon (ISM) is in the form of rainfall over higher altitudes. The isotopic depletion curve (IDC) of meltwater follows the trend of SDC’s. The backward wind trajectories for the precipitation events also indicate that the source of winter precipitation is from westerlies while summer precipitation is from ISM. Present day δ18O, δD and d–excess composition and their climatic interpretation are site and time specific

Behavior of water dimer under the influence of external electric fields

1056-1060A detailed quantum chemical study has been carried out at the CCSD(T) level of theory to understand the behavior of water dimer under the influence of external electric fields. The energy values obtained at this level of theory follow the same trend as observed with the DFT and MP2 levels of theory. Our calculations show that water dimer gets stabilized with increase in the strength of electric field. A slight increase in the hydrogen bond distance and relatively larger decrease in the hydrogen bond angle is found with the increase in the strength of electric field. The dipole moment and HOMO-LUMO energy gap increase with the increase in the strength of electric field

Relative abundances of foraminifera and age models of DSDP Site 22-214 (eastern Indian Ocean) and ODP Hole 130-807A (western Pacific)

This study investigates the timing of development of oligotrophic conditions and thickening of the West Pacific Warm Pool (WPWP) during the Pliocene. It has been hypothesized that the evolution of the WPWP and the establishment of strong equatorial Pacific zonal gradients are closely related to the narrowing of the Indonesian Gateway (IG) as well as the closure of the Central American Seaway (CAS). However, the timing of these events remains unclear. Here we report Pliocene-to-recent relative abundances of planktic foraminifera at DSDP Site 214, in the eastern Indian Ocean, and at ODP Site 807, in the western Pacific, along with stable isotope values at the latter site. A comparison of the abundance of mixed-layer species (MLS) from both sites indicates a pronounced increase in their population between ~3.15 and 1.6 Ma. On the contrary, there is a contemporaneous decrease in the Globigerinita glutinata population during this time, which together suggest the development of oligotrophic conditions in the western tropical Pacific. Our data suggest that the oligotrophic WPWP resembling present-day conditions developed around ~3.15 Ma, and was closely linked to the gradual constriction of the IG