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

Soil erosion fragility assessment using an impact model and geographic information system Avaliação da fragilidade à erosão do solo por meio de um modelo de impacto e sistema de informações geográficas

A study was taken in a 1566 ha watershed situated in the Capivara River basin, municipality of Botucatu, São Paulo State, Brazil. This environment is fragile and can be subjected to different forms of negative impacts, among them soil erosion by water. The main objective of the research was to develop a methodology for the assessment of soil erosion fragility at the various different watershed positions, using the geographic information system ILWIS version 3.3 for Windows. An impact model was created to generate the soil's erosion fragility plan, based on four indicators of fragility to water erosion: land use and cover, slope, percentage of soil fine sand and accumulated water flow. Thematic plans were generated in a geographic information system (GIS) environment. First, all the variables, except land use and cover, were described by continuous numerical plans in a raster structure.The land use and cover plan was also represented by numerical values associated with the weights attributed to each class, starting from a pairwise comparison matrix and using the analytical hierarchy process. A final field check was done to record evidence of erosive processes in the areas indicated as presenting the highest levels of fragility, i.e., sites with steep slopes, high percentage of soil fine sand, tendency to accumulate surface water flow, and sites of pastureland. The methodology used in the environmental problems diagnosis of the study area can be employed at places with similar relief, soil and climatic conditions.<br>A área de estudo, com 1566 ha, abrange uma microbacia hidrográfica, posicionada em local de relevo em contato reverso-frente de cuesta-depressão periférica paulista, inclusa na Bacia do Rio Capivara, no município de Botucatu, Estado de São Paulo. Esse ambiente é frágil, podendo sofrer diferentes formas de impactos negativos, dentre as quais a erosão hídrica do solo. O objetivo principal foi desenvolver uma metodologia, com auxílio do sistema de informações geográficas ILWIS v. 3.3 para Windows, para avaliar a fragilidade à erosão do solo em diferentes posições na microbacia. Um modelo de impacto foi criado para gerar o plano de fragilidade à erosão do solo, com base em quatro planos temáticos relacionados com indicadores de fragilidade a erosão hídrica: uso e cobertura do solo, declividade, percentagem de areia fina e acúmulo de fluxo de água. Em um primeiro passo, excetuando-se o uso e cobertura do solo, as outras três variáveis foram descritas por planos numéricos contínuos em estrutura raster. O plano de uso e cobertura do solo pôde ser representado também por valores numéricos, associados a pesos atribuídos a cada classe, a partir de uma matriz de comparação por pares, considerando-se o método de hierarquia analítica. Realizou-se uma checagem de campo final, em que foram registradas evidências de processos erosivos, naquelas áreas apontadas como apresentando maiores níveis de fragilidade, ou seja, locais com declividade acentuada, solo com alta percentagem de areia fina, tendência de acúmulo de fluxo superficial de água e ocupadas por pastagem. A metodologia desenvolvida pode ser usada no diagnóstico de problemas ambientais em locais com condições similares às da área de estudo

High Throughput Screening Identifies Novel Lead Compounds with Activity against Larval, Juvenile and Adult Schistosoma mansoni

An estimated 600 million people are affected by the helminth disease schistosomiasis caused by parasites of the genus Schistosoma. There is currently only one drug recommended for treating schistosomiasis, praziquantel (PZQ), which is effective against adult worms but not against the juvenile stage. In an attempt to identify improved drugs for treating the disease, we have carried out high throughput screening of a number of small molecule libraries with the aim of identifying lead compounds with balanced activity against all life stages of Schistosoma. A total of almost 300,000 compounds were screened using a high throughput assay based on motility of worm larvae and image analysis of assay plates. Hits were screened against juvenile and adult worms to identify broadly active compounds and against a mammalian cell line to assess cytotoxicity. A number of compounds were identified as promising leads for further chemical optimization