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

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Acetonitrile-Induced Destabilization in Liposomes

To understand the behavior of cellular interfaces, it is important to clarify the effect of chemical compounds on artificial cell membranes. In this study, an aqueous acetonitrile solution was mixed with a suspension of lipid vesicles, and the changes in vesicle behavior arising as a result of acetonitrile application were observed. The fast Fourier transformations (FFTs) of the membrane waviness/crinkliness of the vesicles were carried out, and the membrane thermal fluctuations were analyzed. The experimental results show that the addition of acetonitrile molecules enhances the fluctuation of lipid membranes. In particular, the k = 2 mode fluctuation was significantly enhanced. This finding is expected to lead us to a further understanding of the fundamental properties of living cells

Confinement Effects on Polymer Dynamics: Thermo-Responsive Behaviours of Hydroxypropyl Cellulose Polymers in Phospholipid-Coated Droplets (Water-in-Oil Emulsion)

In order to construct the artificial cells and to understand the physicochemical properties of living cells, it is important to clarify the cell-sized confinement effect on the behaviours of bio-inspired polymers. We report the dynamic behaviours of aqueous hydroxypropyl cellulose (HPC) solution coated with phospholipids in oil (water-in-oil droplets, W/O droplets), accompanied by an increase in the temperature. We directly observed the beginning of phase separation of HPC solution using a fluorescence microscope and confirmed the dependence of such phenomena on droplet size. The results indicate that the start time of phase separation is decreased with an increase in droplet size. The experimental results suggest that the confinement situation accelerates the phase separation of aqueous HPC solutions

Deformation of Lipid Membranes Containing Photoresponsive Molecules in Response to Ultraviolet Light

Recently, membrane deformation using photoresponsive molecules has been extensively studied toward controlling their shapes because light can supply energy without contacting the vesicles. In this study, photoresponsive <i>pseudogem</i>-bis­(diphenylimidazole) [2.2]­paracyclophane (<i>pseudogem</i>-bisDPI­[2.2]­PC) molecules were doped into dioleoylphosphatidylcholine (DOPC) membranes, and the deformation of the DOPC/<i>pseudogem</i>-bisDPI­[2.2]­PC vesicles was observed under ultraviolet (UV)-light irradiation. It was also found that the volume-to-surface area ratio of spherical vesicles was changed by UV irradiation. Further, we performed high performance liquid chromatography (HPLC) analysis of membrane components in order to clarify the absence of irreversible chemical reactions and UV-irradiation experiments under an osmotic pressure in order to investigate the volume change of the vesicles. Then, we calculated the time-correlation function of membrane fluctuation. Change in the relaxation time of the time-correlation function indicated that the photoisomerization of <i>pseudogem</i>-bisDPI­[2.2]­PC might decrease the membrane fluidity. We consider that decreasing fluidity is induced by physical entanglement between photochromic compounds and lipids. This technique of membrane deformation may be expected to be applied to various situations such as drug delivery systems (DDS)