The relation between subjective symptom and circulation during orthostatic stress using a tilt table

起立負荷時における気分不良の有無と体循環,脳循環との関係について検討することを目的とし,電動チルト台を用いて起立負荷を行った.対象者は20代の自律神経疾患を有さない健常女性12名とし,起立負荷によって気分不良を示さなかった群を正常群とし,示した群を気分不良群とした.電動tilt tableを0°→ 30°→ 45°→ 60°→ 0°と変化させ,各段階を約3分ずつ保持した.その際,平均動脈血圧(MBP),心拍出量,心拍数,1回拍出量,総末梢血管抵抗,腓腹筋内側頭部のTotal Hb,中大脳動脈の平均血流速度(FV)と末梢血管抵抗(PI)を測定し,気分不良尺度を10段階評価でもって記録した.その結果,正常群は起立負荷に伴いFVは低下を示したが,MBP,PIに著変はなく,気分不良群はMBPの上昇に対してPIは減少し,FVはほぼ変化はみられなかった.一般的にめまいなどの気分不良症状は脳血流量の減少により生じるとされていたが,今回の結果では気分不良には脳血流量の増加による脳細動脈へのストレスなどが考えられた.This study aimed at considering the relation between subjective symptoms and the circulation of healthy women during orthostatic stress using a tilt table. From 12 healthy women in there twenties who don't have autonomic nervous disorders, two groups were formed: 1) a normal group which didn't feel ill during orthostatic stress, and 2) a FI group which feel ill during orthostatic stress. An electric tilt table was changed from 0°→30°→45°→60°→0°, and each stage was held for about 3 minutes. Mean artery blood pressure (MBP), cardiac output, heart rate, stroke volume, total peripheral resistance and total hemoglobin at the part of interior gastrocnemius (Total Hb), flow velocity (FV) and peripheral resistance (PI) of the middle cerebral artery (MCA) were measured. The scale of poor feeling was also recorded by10 stage evaluations. Consequently, although the normal group showed an FV fall with orthostatic stress,there were no significant changes in MBP and PI. In the FI group, PI decreased but FV didn't show muchchange with the rise of MBP. According to this result, the stress to the arteriola caused not by a fall but anincrease in the cerebral blood flows etc. seems thus to have been the source of the feeling

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target