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

ARE THERE BENEFITS OF SPORTS PARTICIPATION IN THE PREVENTION OF PRESSURE SORES IN SPINAL CORD INJURED PERSONS?

The purpose of this study was to investigate the benefits of sports participation in the prevention of pressure sores. A questionnaire was mailed to 668 men and woman with spinal cord injury. The questionnaire was designed to clarify the effects of physical activity and lifestyle on the development of pressure sores.Usable questionnaires were recelived from 466 persons, representing a response rate of 70%. Thirty-eight percent were quadriplegic and 62% paraplegic, with incomplete injuries accounting for 26% of the combined group. About half of the 466 subjects reported the development of pressure sores in their wheelchair life. Only 34% of the active subjects, participated in sports regularly, reported the development of pressure sores in their wheelchair life. On the other hand, 49% of the inactive subjects who did not participate in wheelchair sports reported the development of pressure sores. When the development of pressure sores before sports participation was compared with that after commencement of sports participation, there was no significant difference in the development of pressure sores between these periods. It was concluded that although quadriplegics and paraplegics without pressure sores had a greater tendency to participate in sports activity, there were no clear positive benefits of sports involvement on the prevention of pressure sores

Comparison of Proanthocyanidin Content in Rabbiteye Blueberry (<i>Vaccinium virgatum</i> Aiton) Leaves and the Promotion of Apoptosis against HL-60 Promyelocytic Leukemia Cells Using ‘Kunisato 35 Gou’ Leaf Extract

Polyphenol-rich rabbiteye blueberry (Vaccinium virgatum Aiton) leaves have attracted attention as a food material. In this study, we compared the total polyphenols, total proanthocyanidin content, and antioxidant activity of the leaves of 18 blueberry varieties and investigated the seasonal variation in polyphenols. We also evaluated the anti-cancer cell proliferation properties of the rabbiteye blueberry leaf specific cultivar ‘Kunisato 35 Gou’. Rabbiteye blueberry leaves had significantly higher total polyphenol and total proanthocyanidin values than northern highbush blueberry and southern highbush blueberry leaves. The antioxidant activity of blueberry leaves was highly positively correlated with both the total polyphenol and total proanthocyanidin content. Variations were observed in the total polyphenol and total proanthocyanidin content of rabbiteye blueberry leaves harvested at different points in the growing season; leaves collected in fall to winter contained more epicatechin in addition to proanthocyanidins. In the evaluation of anti-cancer cell proliferation properties against HL-60 promyelocytic leukemia cells, the September-harvested extracts of rabbiteye blueberry ‘Kunisato 35 Gou’ showed strong properties, and the use of an FITC Annexin V apoptosis detection kit with propidium iodide confirmed that this HL-60 cell death occurred via apoptosis. Limiting the harvest time would make rabbiteye blueberry leaves a more functional food ingredient

Diagnosis and management of pancreatic neuroendocrine tumor in von Hippel-Lindau disease

The pancreatic manifestations seen in patients with von Hippel-Lindau (VHL) disease are subdivided into 2 categories: pancreatic neuroendocrine tumors (NET), and cystic lesions, including simple cyst and serous cystadenoma. The VHL-associated cystic lesions are generally asymptomatic and do not require any treatment, unless they are indistinguishable from other cystic tumor types with malignant potential. Because pancreatic NET in VHL disease are non-functioning and have malignant potential, it is of clinical importance to find and diagnose these as early as possible. It will be recommended that comprehensive surveillance using dynamic computed tomography for abdominal manifestations, including pancreatic NET, should start from the age of 15 years in VHL patients. Unlike sporadic non-functioning NET without VHL disease, in which surgical resection is generally recommended, VHL patients at lower metastatic risk of pancreatic NET should be spared the risks of operative resection

Vaccinium virgatum Aiton Leaves Extract Suppressed Lipid Accumulation and Uric Acid Production in 3T3-L1 Adipocytes

Blueberry (Vaccinium virgatum Aiton; Kinisato 35 Gou) leaves have recently attracted increasing attention as a useful material for the prevention of lifestyle diseases. Here, we examined the effects of the hot water extract of blueberry leaves (BLEx) on lipogenesis and uric acid production in 3T3-L1 adipocytes. The results showed that BLEx suppressed lipid accumulation and the mRNA expression of differentiation markers in 3T3-L1 adipocytes. A fractionation study showed that the highly polymerized proanthocyanidin-rich fraction was responsible for this effect. Upon maturation to adipocytes, 3T3-L1 cells produced uric acid and tumor necrosis factor-&alpha;, and hypoxia stimulated the production of uric acid and xanthine oxidoreductase activity. BLEx suppressed the production of uric acid under these conditions. Although BLEx inhibited the enzymatic activity of xanthine oxidase, this activity was observed in several fractions containing catechin, epicatechin, chlorogenic acid, rutin, and low molecular weight proanthocyanidins. Taken together, these results indicate that BLEx contains various compounds with the ability to suppress lipid accumulation and uric acid production in adipocytes