Convenient modular method for affinity labeling (MoAL method) based on a catalytic amidation

金沢大学医薬保健研究域薬学系A modular methodology for affinity labeling, in which three essential elements generally constituting affinity probes are prepared separately as individual molecules, has been developed based on a catalytic amidation. © 2009 The Royal Society of Chemistry

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

簡便なアフィニティーラベル化法の確立とフラボノイド標的タンパク質同定への展開

金沢大学医薬保健研究域薬学系本研究の目的は2-chloro-4,6-dimethoxy-1,3,5-triazine(CDMT)を用いた新規アフィニティーラベル法を確立し、フラボノイドの一種でアポトーシス抑制作用を有するオウゴニンの標的タンパク質を同定することである。まずは、オウゴニンの構造にジメチルアミノ基を導入したプローブの設計、合成を試みた。幾つかのルートで試みたが残念ながら目的物を合成することはできなかった。今後はより合成しやすいプローブの設計を行う必要がある。研究課題/領域番号:20890081, 研究期間(年度):2008 – 200

Construction of a state-space model with multiple flow rate inputs for an OTEC plant using Rankine cycle

Recently, the importance of sustainable energy using renewable resources has been recognized. As one of the sustainable energy resources, ocean thermal energy conversion (OTEC) is important for the development of a next-generation energy source. This paper proposes a method to construct a state-space model for an OTEC plant using the Rankine cycle. The state-space model is constructed based on a linear approximation of a simple dynamic model. The flow rates of warm seawater, cold seawater, and working fluid are considered as inputs to the model, and the power output is selected as the output of the model. The state-space model, described as a time-invariant system, is derived numerically. The constructed model is evaluated through numerical simulations of the step response; the power generation control is verified using proportional integral controllers, and the advantage as a state-space model is verified using a linear quadratic regulator. The simulation results demonstrate the effectiveness and limitation of the proposed model. Because the simple dynamic model to be approximated is constructed based on the physical laws, various kinds of state-space models corresponding to the physical parameters can be obtained easily

Mitochondrial p32/C1qbp Is a Critical Regulator of Dendritic Cell Metabolism and Maturation

Summary: Dendritic cell (DC) maturation induced by Toll-like receptor agonists requires activation of downstream signal transduction and metabolic changes. The endogenous metabolite citrate has recently emerged as a modulator of DC activation. However, the metabolic requirements that support citrate production remain poorly defined. Here, we demonstrate that p32/C1qbp, which functions as a multifunctional chaperone protein in mitochondria, supports mitochondrial metabolism and DC maturation. Metabolic analysis revealed that the citrate increase induced by lipopolysaccharide (LPS) is impaired in p32-deficient DCs. We also found that p32 interacts with dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase [PDH] complex) and positively regulates PDH activity in DCs. Therefore, we suggest that DC maturation is regulated by citrate production via p32-dependent PDH activity. p32-null mice administered a PDH inhibitor show decreased DC maturation and ovalbumin-specific IgG production in vivo, suggesting that p32 may serve as a therapeutic target for DC-related autoimmune diseases. : Although mitochondrial metabolic pathways are essential for DC activation, the precise molecular mechanism remains poorly understood. Gotoh et al. show that mitochondrial p32/C1qbp supports dendritic cell metabolism and maturation. In addition, mitochondrial p32 and pyruvate dehydrogenase activity are necessary for DC maturation in vitro and in vivo. Keywords: dendritic cell, mitochondria, p32/C1qbp, citrate, pyruvate dehydrogenas