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

The Hyper Suprime-Cam SSP survey: Overview and survey design

Hyper Suprime-Cam (HSC) is a wide-field imaging camera on the prime focus of the 8.2-m Subaru telescope on the summit of Mauna Kea in Hawaii. A team of scientists from Japan, Taiwan, and Princeton University is using HSC to carry out a 300-night multi-band imaging survey of the high-latitude sky. The survey includes three layers: the Wide layer will cover 1400 deg2 in five broad bands (grizy), with a 5 σ point-source depth of r ≈ 26. The Deep layer covers a total of 26 deg2 in four fields, going roughly a magnitude fainter, while the UltraDeep layer goes almost a magnitude fainter still in two pointings of HSC (a total of 3.5 deg2). Here we describe the instrument, the science goals of the survey, and the survey strategy and data processing. This paper serves as an introduction to a special issue of the Publications of the Astronomical Society of Japan, which includes a large number of technical and scientific papers describing results from the early phases of this survey

Recherches sur les précurseurs cystéinylés de l'arôme variétal des vins de Sauvignon blanc (Approche analytique et étude de leur biotransformation par Saccharomyces cerevisiae)

La combinaison de méthodes analytiques (RMN, IR, SM, CPG-SM) a permis l'élucidation des changements structuraux associés au pH, du S-4 (4-méthylpentan-2-one)-L-cystéine, (P-4MMP). A un pH compris entre 5,5 et 8, le P-4MMP présente une tautométrie céto-énolique induisant une cyclisation intramoléculaire. Une méthode de dosage rapide par CPG-SM du potentiel aromatique (P-4MMP et S-3-(hexan-1-ol)-L-cystéine, P-3MH), sous forme de dérivés, a pu être entreprise. Par ailleurs, la mise en place d'une méthode stéréo-sélective de dosage du P-3MMH a permis de dévoiler une distribution des diastéréoisomères en faveur de la forme S, dans les raisins touchés par la pourriture noble. Ce travail a contribué à la compréhension des mécanismes impliqués dans la biotransformation des S-conjugués à la cystéine par S. cerevisiae. La teneur en azote peut moduler la libération des thiols. Par une approche génétique, le gène URE 2, impliqué dans la NCR, modulateur de la libération des thiols a été identifié.The combination of analytical methods (NMR, IR, MS, GC/MS) allowed the elucidation of structural changes at different pH of S-4 (4-methylpentan-2-one)-L-cysteine, (P-4MMP). From pH 5,5 to 8, the P-4MMP is present as keto-enol tautomeric mixture and leads to intermolecular cyclisation. A GCMS method measurement of the aroma potential (P-4MMP and S-3-(hexan 1-ol)-L-cysteine, P-3MH), under derivative form began. The development of a stereo-selective method of P-3MH assay revealed a distribution in favour of S confifuration for the P-3MH diastereoisomers, in the Bordeaux white must infected by B. cinerea. This study has also permitted the understanding of biotransformation mechanisms of S-conjugates in volatile thiols by S. cerevisiae. The nitrogen concentration can modulate the thiols release. By genetic study, the URE2 gene (NCR) of release regulation was identified.BORDEAUX2-BU Santé (330632101) / SudocVILLENAVE D'ORNON-Bib. ISVV (335502201) / SudocSudocFranceF

Impact of some components on Bordeaux roses and clairets aroma

Twenty rose and ten claret A.O.C. Bordeaux wines made from Cabernet Sauvignon, Cabernet franc and Merlot grapes were separately tasted by the same jury of ten professionals. They were asked to classify the wines according to the intensity of the fruity character. The fruitiest sample was given first rank. The wines’ bdamascenone, b-ionone, phenyl-2-ethanol, isoamyl acetate, phenyl-ethyl acetate (APE), 3-mercaptohexan-1-ol (3MH) and 3-mercaptohexyl acetate (A3MH) contents were also measured. The higher the latter three compounds' values, the higher the wines’ fruity character. Highly significant correlation were found between the sensorial analysis results and these compounds contents. In order to confirm the 3MH, A3MH and APE contribution to the fruity aroma of rose wines, a tasting has been carried out. For this, these three compounds were added to a rose wine up to the concentrations found in the wine judged the fruitiest by the tasters. 100 % of the tasters identified the supplemented glasses, and 90 % prefered the supplemented wine. This second experiment clearly demonstrate that 3MH, A3MH and APE can be considered key components of Bordeaux rose wines’ fruity aroma. The production of APE by yeast has been known for a long time. The 3MH is present in must under cysteinylated precursor form. The transformation of the precursor into aroma is made by the Saccharomyces cerevisiae yeasts during alcoholic fermentation. Thus the choice of yeast strains has a decisive impact on the fruity aroma of Bordeaux rose and claret wines

A S-cysteine conjugate, precursor of aroma of White Sauvignon

4-mercapto-4-methylpentan-2-one (4-MMP), a strongly odorant compound responsible for the « boxtree » or « broom plant » odour of the Sauvignon wines, can be enzymaticaly released in vitro from an odourless must extract. The enzyme source used is a cell-free extract of the gastrointestinal bacterium Eubacterium limosum. This crude preparation exhibits a cysteine β-lyase activity which requires the presence of pyridoxal phosphate. The release of 4-MMP is inhibited when the substrate is previously treated with N-hydroxysuccimide acetate which reacts with a primary amine. The same bacterial extract is also able to release 4-MMP, pyruvic acid and ammonium, from S-(4-méthylpentan-2-one)-L-cysteine. On the other hand, the cleavage of S-(4-méthylpentan-2-one)D,L-homocysteine and S-(4-méthylpentan-2-one)- glutathione is very limited. These results suggest that the precursor of 4-MMP in Sauvignon must is a S-cysteine conjugate. Such an aroma precursor in grapes or in other fruits has never been round berore

Identification of new volatile thiols in the aroma of Vitis vinifera L. var. Sauvignon blanc wines

Three new flavour-active mercapto-alcohols have been identified in Sauvignon blanc wines: 4-mercapto-4-methylpentan-2-ol, 3-mercaptohexan-1-ol and 3-mercapto-3-methylbutan-1-ol. The first two have a perception threshold of the order of 60 ng/l in an aqueous alcohol solution and their respective odours are reminiscent of citrus zest and grapefruit. The perception threshold of 3-mercapto-3-methylbutan-1-ol, with its odour of cooked leeks, is higher (1500 ng/l in the same solution). These three compounds may contribute towards the typical aroma of Sauvignon blanc wines