MALDI-TOF mass spectrometric determination of 11 phenothiazines with heavy side chains in urine

A rapid screening method was developed for the determination of phenothiazines by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). In this method, α-cyano-4-hydroxy cinnamic acid (CHCA) was used as the matrix to assist the ionization of phenothiazines. The identification of 11 phenothiazines with heavy side chains was performed by their protonated molecular ions [M + H]+ at m/z = 340 – 447, and the quantification was achieved using triflupromazine at m/z = 353 as the internal standard (IS). The relative ionization efficiencies of 11 phenothiazines and IS on MALDI-TOF-MS were different from those on ESI-TSQ-MS, but the product ion spectra on MALDI-MS-MS were quite similar to those on ESI-MS-MS except in the case of flupentixol. The limit of detection was 0.3 ng/ml with its quantification range of 1 – 50 ng/ml urine in the best case, and limit of detection was 5 ng/ml with its quantification range of 10 – 100 ng/ml urine in the worst case for 10 phenothiazines except thiethylperazine. Present method provides a simple and high throughput method for the screening of these phenothiazines using only 20 μl of urine. To our knowledge, this study is the first trial to analyze phenothiazines by MALDI-TOF MS (-MS)

【調査報告】 半田市におけるブレジャーの現状と可能性

departmental bulletin pape

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 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

Thermogenic methane and hydrogen generation in subducted sediments of the Nankai Trough

Abstract Active and widespread CH4 accumulations and emissions in the Nankai Trough subduction zone are attested by numerous mud volcanoes, gas plumes, and gas hydrates containing biogenic and thermogenic CH4. However, the source rocks of the thermogenic CH4 and the geological source of H2 for microbial CH4 production by methanogens remain uncertain. Here, we reveal the timing and rate of thermogenic CH4 and H2 generation from shales and metapelites associated with oceanic plate subduction in the Nankai Trough by gas and geochemical analyses. The results show that the thermogenic CH4 and H2 are generated mainly in the underthrust sediments below the décollement. The sustainable H2 supply from the underthrust sediments can potentially contribute to microbial CH4 production. The findings enhance our understanding of the active CH4 emission, large-scale gas hydrate formation, and subseafloor biosphere in the oceanic plate subduction zone