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

Correlation of surface chemical states with hydrogen isotope retention in divertor tiles of JET with ITER-Like Wall

To understand the fuel retention mechanism correlation of surface chemical states and hydrogen isotope retention behavior determined by XPS (X-ray photoelectron spectroscopy) and TDS (Thermal desorption spectroscopy), respectively, for JET ITER-Like Wall samples from operational period 2011–2012 were investigated. It was found that the deposition layer was formed on the upper part of the inner vertical divertor area. At the inner plasma strike point region, the original surface materials, W or Mo, were found, indicating to an erosion-dominated region, but deposition of impurities was also found. Higher heat load would induce the formation of metal carbide. At the outer horizontal divertor tile, mixed material layer was formed with iron as an impurity. TDS showed the H and D desorption behavior and the major D desorption temperature for the upper part of the inner vertical tile was located at 370 °C and 530 °C. At the strike point region, the D desorption temperature was clearly shifted toward higher release temperatures, indicating the stabilization of D trapping by higher heat loadPeer reviewe

Deuterium retention behavior in simultaneously He+–D2+ implanted tungsten

Poly-crystalline tungsten (W) samples were simultaneously irradiated with Helium (He) and Deuterium (D) ions using the triple-ion implantation device. He effect on D retention and transportation was studied using different combination of ion energies and He/D flux ratios in the simultaneous implantation. The experimental results show that D trapping at dislocation loops is significantly reduced in the case of 3 keV He+–3 keV D2+at He/D flux ratios over 0.6. D trapping by stronger trapping sites such as vacancies and vacancy clusters showed less dependence on the flux ratio. On the contrary, the D retention increases at each He/D flux ratio in the case of 3 keV He+–1 keV D2+compared to only D2+ implantation even the He/D flux ratio reaches a value of 1.0. TEM observations confirmed that dense dislocation loops are formed rather than He bubbles, which is responsible for the enhanced D retention in W. Keywords: Simultaneous implantation, D retention, Helium, Flux ratio, Transportation, Thermal desorption spectroscop

Correlation of surface chemical states with hydrogen isotope retention in divertor tiles of JET with ITER-Like Wall

To understand the fuel retention mechanism, correlation of surface chemical states and hydrogen isotope retention behavior determined by XPS (X-ray photoelectron spectroscopy) and TDS (Thermal desorption spectroscopy), respectively, for JET ITER-Like Wall samples from operational period 2011-2012 were investigated. It was found that the deposition layer was formed on the upper part of the inner vertical divertor area. At the inner plasma strike point region, the original surface materials, W or Mo, were found, indicating to an erosion-dominated region, but deposition of impurities was also found. Higher heat load would induce the formation of metal carbide. At the outer horizontal divertor tile, mixed material layer was formed with iron as an impurity. TDS showed the H and D desorption behavior and the major D desorption temperature for the upper part of the inner vertical tile was located at 370 °C and 530 °C. At the strike point region, the D desorption temperature was clearly shifted toward higher release temperatures, indicating the stabilization of D trapping by higher heat load.2nd Asia-Pacific Symposium on Tritium scienc