Track A Basic Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138319/1/jia218438.pd

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

Evaluating sensory conflict and postural instability theories of motion sickness

Two experiments were carried out to evaluate the sensory conflict and the postural instability theories of motion sickness. The central hypothesis of sensory conflict theory is that motion sickness is caused by conflict between the current pattern of sensory inputs about self-movement and the pattern that is expected on the basis of previous experience. A subsidiary hypothesis is that the degree of motion sickness is proportional to the magnitude of sensory conflict. The central hypothesis of postural instability theory is that motion sickness is caused by loss of postural control. A subsidiary hypothesis is that the degree of motion sickness is proportional to amount of postural instability, which can be manipulated by physical restraint. In both experiments there were two levels of sensory conflict and two levels of postural restraint. Dependent variables were latency of onset and severity of motion sickness. The widespread occurrence of motion sickness in both experiments clearly confirmed the main hypothesis of sensory conflict theory. The results from Experiment 1, that there was significantly more motion sickness in the restrained condition, and from Experiment 2, that there was no significant difference in symptoms between the two restraint conditions, provide no support for the subsidiary hypothesis of postural instability theory. Evidence relating to the subsidiary proposition of sensory conflict theory was inconsistent

Discussion on 'conventional retaining walls: pilot and full scale studies' by Symons and Murray

Conventional retaining walls: pilot and full-scale studies A main objective of the most recent pilot-scale investigation was to examine the pressures developed during swelling of London clayfill. This phase of the study which extended over 20 months was incomplete at the time of preparation of the Paper. ...& mor