セイタイ ノ テイサンソ オウトウ ト ビョウタイ : ケッカン リモデリング ニオケル テンシャ インシ HIF ノ カンヨ「

Recent studies have shown that the cellular immune response to the hypoxic microenvironment constructed by vascular remodeling development modulates the resulting pathologic alterations. A major mechanism mediating adaptive responses to reduced oxygen availability is the regulation of transcription by hypoxia-inducible factor１（HIF‐１）. Impairment of HIF‐１‐ dependent inflammatory responses in T cells causes an augmented vascular remodeling induced by arterial injury, which is shown as prominent neointimal hyperplasia and increase in infiltration of inflammatory cells at the adventitia in mice lacking Hif‐１α specifically in T cells. Studies to clarify the mechanism of augmented vascular remodeling in the mutant mice have shown enhanced production of cytokines in activated T cells and augmented antibody production in response to a T-dependent antigen in the mutant mice. This minireview shows that HIF‐１α in T cells plays a crucial role in vascular inflammation and remodeling in response to cuff injury as a negative regulator of the T cell-mediated immune response and suggests potential new therapeutic strategies that target HIF‐１α

Effects of a trauma center on early mortality after trauma in a regional city in Japan: a population-based study

Background: Although the effects of the trauma center(TC) were researched in several studies, there have been few studies on changes in the regional mortality due to the implementation of a TC.An emergency medical center (EMC) and TC were implemented at Nagasaki University Hospital (NUH) for the first time in the Nagasaki medical region of Japan in April 2010 and October 2011, respectively, and they have cooperated with each other in treating trauma patients. The purpose of this study was to investigate the effects on the early mortality at population level of a TC working in cooperation with an EMC. Methods: This is a retrospective study using standardized regional data (ambulance service record) in Nagasaki medical region from April 2007 through March 2017. We included 19,045 trauma patients directly transported from the scene. The outcome measures were prognosis for one week. To examine the association between the implementation of the EMC and TC and mortality at a region, we fit adjusted logistic regression models. Results: The number of patients of each fiscal year increased from 1492 in 2007 to 2101 in 2016.The number of all patients transported to NUH decreased until 2009 to 70, but increased after implementation of the EMC and TC. Overall mortality of all patients in the region improved from 2.3% in 2007 to 1.0% in 2016.In multivariate logistic regression model, odds ratio of death was significantly smaller at 2013 and thereafter if the data from 2007 to 2011 was taken as reference. Conclusions: Implementation of the EMC and TC was associated with early mortality in trauma patients directly transported from the scene by ambulance. Our analysis suggested that the implementation of EMC and TC contributed to the improvement of the early mortality at a regional city with 500000 populations. Level of evidence: Level III

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

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

Evaluation of an Additional Generator on the Economic Effect Based on a Load Sharing Optimization of Medium-Speed/High-Speed Diesel Generators in a Microgrid

This study investigates the additional installation of a high-speed diesel generator to independent microgrids (MG) such as remote islands where relatively efficient medium-speed diesel generators (DGs) are mainly used. While small-sized and lightweight, high-speed DGs are not widely spread for continuous usage because their efficiency is lower than that of the medium-speed DGs. The objective of this study is to evaluate the performance of the new method of load sharing optimization to improve the economy by interconnecting a high-speed DG to an independent MG where the medium-speed DGs are operated. The study investigates the effect of operation cost reduction by installing the new load sharing method of operation following the load sharing pattern derived by the mixed-integer programming. As a result of this study, there was some effect to installing a high-speed DG operated by the conventional method. In addition, by adding the new method of load sharing with optimization, the economic effect became even higher

Evaluation of an Additional Generator on the Economic Effect Based on a Load Sharing Optimization of Medium-Speed/High-Speed Diesel Generators in a Microgrid

This study investigates the additional installation of a high-speed diesel generator to independent microgrids (MG) such as remote islands where relatively efficient medium-speed diesel generators (DGs) are mainly used. While small-sized and lightweight, high-speed DGs are not widely spread for continuous usage because their efficiency is lower than that of the medium-speed DGs. The objective of this study is to evaluate the performance of the new method of load sharing optimization to improve the economy by interconnecting a high-speed DG to an independent MG where the medium-speed DGs are operated. The study investigates the effect of operation cost reduction by installing the new load sharing method of operation following the load sharing pattern derived by the mixed-integer programming. As a result of this study, there was some effect to installing a high-speed DG operated by the conventional method. In addition, by adding the new method of load sharing with optimization, the economic effect became even higher