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

Solid-phase synthesis of an A-B loop mimetic of the C epsilon 3 domain of human IgE: macrocyclization by Sonogashira coupling

The solid-phase synthesis of a cyclic peptide containing the 21-residue epitope found in the A-B loop of the Cepsilon3 domain of human immunoglobulin E has been carried out. The key macrocyclization step to form the 65-membered ring is achieved in similar to15% yield via an "on-resin" Sonogashira coupling reaction which concomitantly installs a diphenylacetylene amino acid conformational constraint within the loop

Conformance Checking of Dynamic Access Control Policies

The capture, deployment and enforcement of appropriate access control policies are crucial aspects of many modern software-based systems. Previously, there has been a significant amount of research undertaken with respect to the formal modelling and analysis of access control policies; however, only a limited proportion of this work has been concerned with dynamic policies. In this paper we explore techniques for the modelling, analysis and subsequent deployment of such policies - which may rely on external data. We use the Alloy modelling language to describe constraints on policies and external data; utilising these constraints, we test static instances constructed from the current state of the external data. We present Gauge, a constraint checker for static instances that has been developed to be complementary to Alloy, and show how it is possible to test systems of much greater complexity via Gauge than can typically be handled by a model finder. © 2011 Springer-Verlag

Avaliação da atividade antimicrobiana de Maytenus rigida Mart. (Celastraceae) Evaluation of the antimicrobial activity of Maytenus rigida Mart. (Celastraceae)

A realização de estudos farmacológicos é fundamental para comprovar a eficácia do uso de plantas medicinais pela população para o tratamento de doenças e descobrir novos fitoterápicos. Esse estudo teve como objetivo avaliar o potencial antimicrobiano do extrato etanólico e fase acetato de etila do bom nome (Maytenus rigida Mart.) sobre Staphylococcus aureus ATCC 25923, 3 amostras de Staphylococcus aureus multirresistentes isoladas de pacientes com infecções nosocomiais, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 e Salmonella sp. (228-R-Tet, 118-R-Sut e 01-S) isoladas de ambiente aquático, utilizando o método de difusão em agar. Os testes revelaram que o extrato e fase de M. rigida apresentaram atividade antimicrobiana in vitro frente a todas as cepas de S. aureus testadas, apresentando concentração inibitória mínima (MIC) de 400 mg mL-1. Entretanto, estes produtos não apresentaram atividade frente às linhagens de bactérias Gram-negativas testadas, Escherichia coli, Pseudomonas aeruginosa e Salmonella sp.<br>Ppharmacological studies are essential to prove the effectiveness of using medicinal plants to treat diseases and discover new phytotherapics. This study aimed to evaluate the antimicrobial potential of ethanol and ethyl acetate extracts of "bom-nome" (Maytenus rigida Mart.) against Staphylococcus aureus ATCC 25923, three samples of multiresistant Staphylococcus aureus isolated from patients with nosocomial infections, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Salmonella sp. (228-R-Tet, 118-R-Sut and 01-S) isolated from water environment, using the agar diffusion test. Both extracts showed in vitro antimicrobial activity against all S. aureus strains, presenting 400 mg mL-1 minimum inhibitory concentration (MIC). However, these products did not show activity against strains of the Gram-negative bacteria Escherichia coli, Pseudomonas aeruginosa and Salmonella sp