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

Cutaneous Myxoma of Multiple Lesions

Summary:. Cutaneous myxoma is a rare neoplasm typically occurring as an asymptomatic nodule on the head, neck, and chest regions of adults. However, multiple cutaneous myxoma of the subungual space is even rarer. Here, we report a case of multiple cutaneous myxoma of the subungual space in which the tumor was removed by creating a mid-radial incision while preserving the nail matrix. The excisional biopsy samples were dispatched for histopathological examination and confirmed to be cutaneous myxoma. To the best of our knowledge, this is the first report on multiple cutaneous myxoma of the subungual space

1 mA Stable Energy Recovery Beam Operation with Small Beam Emittance

A compact energy-recovery linac (cERL) have been operating since 2013 at KEK to develop critical components for ERL facility. Details of design, construction and the result of initial commissioning are already reported*. This paper will describe the details of further improvements and researches to achieve higher averaged beam current of 1 mA with continuous-wave (CW) beam pattern. At first, to keep the small beam emittance produced by 500 kV DC-photocathode gun, tuning of low-energy beam transport is essential. Also, we found some components degrades the beam quality, i.e., a non-metallic mirror which disturbed the beam orbit. Other important aspects are the measurement and mitigation of the beam losses. Combination of beam collimator and tuning of the beam optics can improve the beam halo enough to operate with 1 mA stably. The cERL has been operated with beam energy at 20 MeV or 17.5 MeV and with beam rep-rate of 1300 MHz or 162.5 MHz depending on the purpose of experiments. In each operation, the efficiency of the energy recovery was confirmed to be better than 99.9 %.10th International Particle Accelerator Conferenc

Construction and commissioning of the compact energy-recovery linac at KEK

Energy-recovery linacs (ERLs) are promising for advanced synchrotron light sources, high-power free electron lasers (FELs), high-brightness gamma-ray sources, and electron–ion colliders. To demonstrate the critical technology of ERL-based light sources, we have designed and constructed a test accelerator, the compact ERL (cERL). Using advanced technology that includes a photocathode direct current (DC) electron gun and two types of 1.3-GHz-frequency superconducting cavities, the cERL was designed to be capable of recirculating low emittance (1 mm mrad) and high average-current (10 mA) electron beams while recovering the beam energy. During initial commissioning, the cERL demonstrated successful recirculation of high-quality beams with normalized transverse emittance of 0.14 mm mrad and momentum spread of 1.2 10−4 (rms) at a beam energy of 20 MeV and bunch charge below 100 fC. Energy recovery in the superconducting main linac was also demonstrated for high-average-current continuous-wave beams. These results constitute an important milestone toward realizing ERL-based light sources