Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Antixenosis of bean genotypes to Chrysodeixis includens (Lepidoptera: Noctuidae)

The objective of this work was to evaluate bean genotypes for resistance to soybean looper (Chrysodeixis includens). Initially, free-choice tests were carried out with 59 genotypes, divided into three groups according to leaf color intensity (dark green, light green, and medium green), in order to evaluate oviposition preference. Subsequently, 12 genotypes with high potential for resistance were selected, as well as two susceptible commercial standards. With these genotypes, new tests were performed for oviposition in a greenhouse, besides tests for attractiveness and consumption under laboratory conditions (26 +/- 2 degrees C, 65 +/- 10% RH, and 14 h light: 10 h dark photophase). In the no-choice test with adults, in the greenhouse, the 'IAC Jabola', Arcelina 1, 'IAC Boreal', 'Flor de Mayo', and 'IAC Formoso'genotypes were the least oviposited, showing antixenosis-type resistance for oviposition. In the free-choice test with larvae, Arcelina 4, 'BRS Horizonte', 'Perola', H96A102-1-1-1-52, 'IAC Boreal', 'IAC Harmonia', and 'IAC Formoso'were the less consumed genotypes, which indicates antixenosis to feeding. In the no-choice test, all genotypes (except for 'IAPAR 57') expressed moderate levels of antixenosis to feeding against C. includens larvae.O objetivo deste trabalho foi avaliar genótipos de feijoeiro quanto à resistência a lagarta-falsa-medideira (Chrysodeixis includens). Inicialmente, foram realizados testes com chance de escolha com 59 genótipos, divididos em três grupos, de acordo com a intensidade de coloração das folhas (verde-escura, verde-clara e verde-médio), para avaliar a preferência quanto à oviposição. Em seguida, selecionaram-se 12 genótipos com grande potencial de resistência, assim como dois padrões comerciais suscetíveis. Com estes genótipos, realizaram-se novos ensaios de oviposição, em casa de vegetação, além de testes de atratividade e consumo, em condições de laboratório (26±2ºC, 65±10% UR e fotófase de 14 h luz: 10 h escuro). No teste sem chance de escolha, com adultos, em casa de vegetação, os genótipos 'IAC Jabola', Arcelina 1, 'IAC Boreal', 'Flor de Mayo' e 'IAC Formoso' foram os menos ovipositados, tendo apresentado resistência do tipo antixenose à oviposição. No teste com chance de escolha, com larvas, Arcelina 4, 'BRS Horizonte', 'Pérola', H96A102-1-1-1-52, 'IAC Boreal', 'IAC Harmonia' e 'IAC Formoso' foram os genótipos menos consumidos, o que indica antixenose à alimentação. No teste sem chance de escolha, todos os genótipos (exceto 'IAPAR 57') expressaram níveis moderados de antixenose à alimentação de larvas de C. includens.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Active polar fluid flow in finite droplets.

We present a continuum level analytical model of a droplet of active contractile fluid consisting of filaments and motors. We calculate the steady state flows that result from a splayed polarisation of the filaments. We account for interaction with the external medium by imposing a viscous friction at the fixed droplet boundary. We then show that the droplet has non-zero force dipole and quadrupole moments, the latter of which is essential for self-propelled motion of the droplet at low Reynolds' number. Therefore, this calculation describes a simple mechanism for the motility of a droplet of active contractile fluid embedded in a three-dimensional environment, which is relevant to cell migration in confinement (for example, embedded within a gel or tissue). Our analytical results predict how the system depends on various parameters such as the effective friction coefficient, the phenomenological activity parameter and the splay of the imposed polarisation

A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology. © 2022 American Society of Human Genetic