Heat Shock Factor 1 Contributes to Ischemia-Induced Angiogenesis by Regulating the Mobilization and Recruitment of Bone Marrow Stem/Progenitor Cells

Bone marrow (BM)-derived stem/progenitor cells play an important role in ischemia-induced angiogenesis in cardiovascular diseases. Heat shock factor 1 (HSF1) is known to be induced in response to hypoxia and ischemia. We examined whether HSF1 contributes to ischemia-induced angiogenesis through the mobilization and recruitment of BM-derived stem/progenitor cells using HSF1-knockout (KO) mice. After the induction of ischemia, blood flow and microvessel density in the ischemic hindlimb were significantly lower in the HSF1-KO mice than in the wild-type (WT) mice. The mobilization of BM-derived Sca-1- and c-kit-positive cells in peripheral blood after ischemia was significantly lower in the HSF1-KO mice than in the WT mice. BM stem/progenitor cells from HSF1-KO mice showed a significant decrease in their recruitment to ischemic tissue and in migration, adhesion, and survival when compared with WT mice. Blood flow recovery in the ischemic hindlimb significantly decreased in WT mice receiving BM reconstitution with donor cells from HSF1-KO mice. Conversely, blood flow recovery in the ischemic hindlimb significantly increased in HSF1-KO mice receiving BM reconstitution with donor cells from WT mice. These findings suggest that HSF1 contributes to ischemia-induced angiogenesis by regulating the mobilization and recruitment of BM-derived stem/progenitor cells

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

Research and Design of a Routing Protocol in Large-Scale Wireless Sensor Networks

无线传感器网络，作为全球未来十大技术之一，集成了传感器技术、嵌入式计算技术、分布式信息处理和自组织网技术，可实时感知、采集、处理、传输网络分布区域内的各种信息数据，在军事国防、生物医疗、环境监测、抢险救灾、防恐反恐、危险区域远程控制等领域具有十分广阔的应用前景。 本文研究分析了无线传感器网络的已有路由协议，并针对大规模的无线传感器网络设计了一种树状路由协议，它根据节点地址信息来形成路由，从而简化了复杂繁冗的路由表查找和维护，节省了不必要的开销，提高了路由效率，实现了快速有效的数据传输。 为支持此路由协议本文提出了一种自适应动态地址分配算——ADAR（AdaptiveDynamicAddre...As one of the ten high technologies in the future, wireless sensor network, which is the integration of micro-sensors, embedded computing, modern network and Ad Hoc technologies, can apperceive, collect, process and transmit various information data within the region. It can be used in military defense, biomedical, environmental monitoring, disaster relief, counter-terrorism, remote control of haz...学位：工学硕士院系专业：信息科学与技术学院通信工程系_通信与信息系统学号：2332007115216

Star Formation in the Large Magellanic Cloud(Proceedings of Japan-France Seminar on Chemical Evolution of Galaxies with Active Star Formation)

The Large and the Small Magellanic Clouds (LMC and SMC) made close encounters some 10^8 years ago on their binary orbits around the Galaxy. The LMC and SMC perturbed each other seriously to enhance their star formation. The present paper applies a cloud model for interstellar gas and numerically estimate the past star formation rate at the galaxy collision

Cloning and characterization of the genomic DNA of the human MSSP genes.

MSSP proteins have been identified by their binding to an upstream element of c-myc. Independently, two different approaches yielded two cDNA clones highly homologous to the MSSP cDNAs, suggesting an involvement of MSSP in the regulation of the cell cycle (scr2) and in the repression of HIV-1 and ILR2 alpha-promoter transcription (human YC1). Screening human genomic libraries, we have isolated clones belonging to two different gene loci. Whereas the human MSSP gene 1 turned out to be intronless, the organization of the coding sequence within gene 2 is more complex. It spans more than 60 kb and contains 16 exons (including two alternative first exons), ranging from 48 to 287 bp, respectively. The intron sizes vary from 0.1 to more than 13 kb. Gene 1 has been completely sequenced. A deletion series of its upstream region was conjugated to the luciferase gene, but the transfection of the constructs did not display any promoter activity. Moreover, compared with gene 2 and the cDNA sequences known so far, about 20 point mutations as well as flanking direct repeats have been detected in the MSSP gene 1, showing that it possesses all the characteristics of processed retropseudogenes. Sequence analysis of a 1.7 kb fragment of the 5' flanking region of the MSSP gene 2 revealed that the promoter of gene 2 lacks consensus sequences for TATA and CCAAT boxes, is GC-rich, and contains numerous potential transcription factor binding elements including an Sp1 binding site. DNase I footprinting experiments showed that the putative Sp1 site was bound by proteins. The results of primer extension and S1 mapping analyses suggested the transcription of the gene starts at multiple positions upstream from the initiator methionine codon. Luciferase assays employing progressive deletions of the 1.7 kb promoter region allowed us to define the minimal promoter region of 428 bp (-488/+) and revealed a complex pattern of the transcriptional regulation the human MSSP gene 2. Furthermore, it can be concluded that the MSSP gene 2 encodes both MSSP-1 and MSSP-2, and moreover scr2 and human YC1

Transcription factor cooperativity with heat shock factor 1

The heat shock response has been characterized by the induction of major heat shock proteins that suppress protein aggregation by facilitating protein folding. Recently, we found that mammalian heat shock factor 1, a master regulator of HSP genes, regulates non-HSP genes that suppress protein aggregation by controlling protein degradation in cooperation with the transcription factor NFAT