Changes of Histamine Contents and Mast Cell Population in the Gastric Mucosa of Carbon Tetrachloride-Induced Cirrhotic Rats

For the purpose of clarifying the mechanism of gastric mucosal lesion complicated with liver cirrhosis, the authers examined the changes of histamine contents and mast cell population in the gastric mucosa of carbon tetrachloride-induced cirrhotic rats. The histamine contents in the gastric mucosa and the mast cell count in the superficial area of the mucosa were significantly increased spontaneously and reduced with cold restraint stress in cirrhotic rats. However, no reductions in the both factors were observed in normal rats. The incedence of gastric mucosal lesions in cirrhotic rats was 38%, while it was 0% in normal rats, and rose to 100% in the former against 28% in the latter with stress. The hexosamine contents in the gastric mucosa were significantly lower in cirrhotic rats than in normal rats. It is considered that in cirrhotic rats easy release of gastric mucosal histamine with stress, which is associated with degranulation of mast cells in superficial layer, results in development of gastric mucosal lesions, and that the reduction in defensive capacity may be one of the causes for the increase in mast cells

Cluster II che genes of Pseudomonas syringae pv. tabaci 6605, orthologs of cluster I in Pseudomonas aeruginosa, are required for chemotaxis and virulence

Pseudomonas syringae pv. tabaci 6605 (Pta6605) is a causal agent of wildfire disease in host tobacco plants and is highly motile. Pta6605 has multiple clusters of chemotaxis genes including cheA, a gene encoding a histidine kinase, cheY, a gene encoding a response regulator, mcp, a gene for a methyl-accepting chemotaxis protein, as well as flagellar and pili biogenesis genes. However, only two major chemotaxis gene clusters, cluster I and cluster II, possess cheA and cheY. Deletion mutants of cheA or cheY were constructed to evaluate their possible role in Pta6605 chemotaxis and virulence. Motility tests and a chemotaxis assay to known attractant demonstrated that cheA2 and cheY2 mutants were unable to swarm and to perform chemotaxis, whereas cheA1 and cheY1 mutants retained chemotaxis ability almost equal to that of the wild-type (WT) strain. Although WT and cheY1 mutants of Pta6605 caused severe disease symptoms on host tobacco leaves, the cheA2 and cheY2 mutants did not, and symptom development with cheA1 depended on the inoculation method. These results indicate that chemotaxis genes located in cluster II are required for optimal chemotaxis and host plant infection by Pta6605 and that cluster I may partially contribute to these phenotypes

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

急性出血性胃潰瘍の発生機序に関する実験的研究 : Histamine の作用機序を中心に

Studies to elucidate the mechanism responsible for histamine effects on the development of acute hemorrhagic ulcers were undertaken using laboratory animals, i. e. a control group consisting of rats with chronic gastric fistula, V. B6 deficient diet group, cimetidine administered group and vagotomized group. The respective groups were subjected to cold restraint and the degree of hemorrhage, erosion, gastric acid secretion, gastric mucosal histamine content and state of microvasculature of gastric mucosa were observed over time, and the following results were obtained. 1. There was a decrease in the degree of hemorrhage and erosion in the V. B6 deficient diet and cimetidine administered groups and the vagotomized group. 2. Gastric acid secretion was significantly decreased in all groups subjected to cold restraint for up to 60 minutes. 3. The gastric mucosal histamine content was significantly decreased in the control and cimetidine administered groups after cold restraint for 30 minutes. In the V. B6 deficient diet group, the content decreased to about 1/3, but failed to demonstrate a significant difference. The vagotomized group showed a two-fold increase, which after cold restraint for 120 minutes decreased significantly. 4. The microvasculature of the gastric mucosa in the control group was. poorly visualized by FITC-dextran method and presented a static appearance. In the other three groups, the capillaries of the gastric mucosa were well visualized and no static pattern was observed. The above findings suggest that histamine in the gastric mucosa is released by cold restraint and acts upon microcirculation within the gastric mucosa rather than upon gastric acid secretion, causing stasis and mucosal devitalization, and thus assumes a role in the development of ulcer.This study was supported in part by a research grant from the Japanese Ministry of Education (General Research C 257329)

ストレス潰瘍発生におよぼす活性アミンの影響 : 寒冷拘束ラットにおける脳内および胃壁内ノルアドレナリン，5-ハイドロキシトリプタミン，ヒスタミンの検討

Acute hemorrhagic gastroduodenal ulcers are frequently induced by various types of stress. With the purpose of studying the central nervous system factors and gastric mucosal local factors involved in the development of such ulcers, Wistar strain rats were subjected to restraint and cold exposure for 120 minutes, and the intragastric pH, and the noradrenalin, 5-hydroxytryptamine and histamine contents in the brain and gastric wall were measured over time, and the following results were obtained. 1. The intragastric pH decreased with time up to 120 minutes, but the difference with the pre-restraint value was not significant. 2. At 60 minutes after restraint when the ulcerogenic rate became markedly increased, of the amines in the brain, the noradrenalin content showed a significant decrease, while 5-hydroxytryptamine increased significantly, but the histamine value failed to show any significant change. 3. Of the amines in the gastric wall, the histamine level decreased significantly after 30 minutes, and the 5-hydroxytryptamine value showed a significant decrease after 60 minutes. On the basis of the above findings, it is assumed that the effects of gastric acid on the development of acute hemorrhagic gastroduodenal ulcers are small. However, it is considered that of the amines in the brain, the changes in values of noradrenalin and 5-hydroxytryptamine, and of these in the gastric wall, the changes in 5-hydroxytryptamine and histamine levels have important implications