Genetic variation in PPARG encoding peroxisome proliferator-activated receptor γ associated with carotid atherosclerosis

Background and Purpose-Peroxisome proliferator-activated receptor γ is a crucial molecule in atherogenesis because it is associated with metabolic risk factors such as obesity and diabetes and also plays a key role in subcellular metabolism of arterial wall macrophage foam cells. Genetic variation in PPARG has been associated with metabolic and cardiovascular end points. Methods-We investigated the relationship between 2 common PPARG polymorphisms, namely P12A and c.1431C\u3eT, and carotid atherosclerosis in a sample of 161 Canadian aboriginal people. Dependent variables were carotid intima media thickness (IMT), assessed using B-mode ultrasonography, and total carotid plaque volume (TPV), assessed using 3D ultrasound. Results-Using multivariate analysis, we found that subjects with ≥ 1 PPARG A12 allele had less carotid IMT than others (0.72±0.03 versus 0.80±0.02 mm; P=0.0045), with no between-genotype difference in TPV. In contrast, subjects with the PPARG c.1431T allele had greater TPV than others (124±18.4 versus 65.1±23.7 mm3; P=0.0079), with no between-genotype difference in IMT. Conclusions-The findings show an association between PPARG genotypes and carotid arterial phenotypes, and further reflect the prevailing view that the PPARG A12 allele protects against deleterious phenotypes. Also, whereas IMT and TPV are somewhat correlated with each other, they might also represent distinct traits with discrete determinants representing different stages of atherogenesis

Transport properties of dense fluid argon

We calculate using molecular dynamics simulations the transport properties of realistically modeled fluid argon at pressures up to $\simeq 50GPa$ and temperatures up to $3000K$. In this context we provide a critique of some newer theoretical predictions for the diffusion coefficients of liquids and a discussion of the Enskog theory relevance under two different adaptations: modified Enskog theory (MET) and effective diameter Enskog theory. We also analyze a number of experimental data for the thermal conductivity of monoatomic and small diatomic dense fluids.Comment: 8 pages, 6 figure

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