The Expression Level of HIV-1 Vif Is Optimized by Nucleotide Changes in the Genomic SA1D2prox Region during the Viral Adaptation Process

HIV-1 Vif plays an essential role in viral replication by antagonizing anti-viral cellular restriction factors, a family of APOBEC3 proteins. We have previously shown that naturally-occurring single-nucleotide mutations in the SA1D2prox region, which surrounds the splicing acceptor 1 and splicing donor 2 sites of the HIV-1 genome, dramatically alter the Vif expression level, resulting in variants with low or excessive Vif expression. In this study, we investigated how these HIV-1 variants with poor replication ability adapt and evolve under the pressure of APOBEC3 proteins. Adapted clones obtained through adaptation experiments exhibited an altered replication ability and Vif expression level compared to each parental clone. While various mutations were present throughout the viral genome, all replication-competent adapted clones with altered Vif expression levels were found to bear them within SA1D2prox, without exception. Indeed, the mutations identified within SA1D2prox were responsible for changes in the Vif expression levels and altered the splicing pattern. Moreover, for samples collected from HIV-1-infected patients, we showed that the nucleotide sequences of SA1D2prox can be chronologically changed and concomitantly affect the Vif expression levels. Taken together, these results demonstrated the importance of the SA1D2prox nucleotide sequence for modulating the Vif expression level during HIV-1 replication and adaptation

The impact of sleep–wake problems on health-related quality of life among Japanese nursing college students: a cross sectional survey

Aim: This study was conducted to examine the impact of sleep–wake problems on health-related quality of life of Japanese nursing college students.Methods: This cross-sectional study was conducted in 2019 on 150 third and fourth-year nursing college students from two locations in Japan. Insomnia severity was assessed using the Insomnia Severity Index (ISI) and health-related quality of life using the SF-8 questionnaire. The total sleep time (TST) was divided into 3 groups: < 6 h, 6–7 h (reference), and ≥ 7 h. The total ISI score was divided into 2 groups: ≥ 8 points and < 8 points (reference). Logistic regression analysis was performed to evaluate sleep–wake problems related to decline in mental health.Results: The median mental health indicated in the SF-8 questionnaire was divided into two groups, and the factors causing decline in mental health were investigated. The odds ratios (95% confidence interval) for adjusted ISI ≥ 8 and TST on weekdays < 6 h was 6.51 (2.96–14.30) and 3.38 (1.40–8.17), respectively. Mental health status was significantly lower when ISI ≥ 8 and even lower when TST < 6 h.Conclusion: Insomnia and short sleep duration are associated with decreased mental health status in nursing college students. Many tended to lack sleep on weekdays. Sleep–wake problems identified while in university should be comprehensively dealt with

Unc-51/ATG1 Controls Axonal and Dendritic Development via Kinesin-Mediated Vesicle Transport in the Drosophila Brain

Background:Members of the evolutionary conserved Ser/Thr kinase Unc-51 family are key regulatory proteins that control neural development in both vertebrates and invertebrates. Previous studies have suggested diverse functions for the Unc-51 protein, including axonal elongation, growth cone guidance, and synaptic vesicle transport.Methodology/Principal Findings:In this work, we have investigated the functional significance of Unc-51-mediated vesicle transport in the development of complex brain structures in Drosophila. We show that Unc-51 preferentially accumulates in newly elongating axons of the mushroom body, a center of olfactory learning in flies. Mutations in unc-51 cause disintegration of the core of the developing mushroom body, with mislocalization of Fasciclin II (Fas II), an IgG-family cell adhesion molecule important for axonal guidance and fasciculation. In unc-51 mutants, Fas II accumulates in the cell bodies, calyx, and the proximal peduncle. Furthermore, we show that mutations in unc-51 cause aberrant overshooting of dendrites in the mushroom body and the antennal lobe. Loss of unc-51 function leads to marked accumulation of Rab5 and Golgi components, whereas the localization of dendrite-specific proteins, such as Down syndrome cell adhesion molecule (DSCAM) and No distributive disjunction (Nod), remains unaltered. Genetic analyses of kinesin light chain (Klc) and unc-51 double heterozygotes suggest the importance of kinesin-mediated membrane transport for axonal and dendritic development. Moreover, our data demonstrate that loss of Klc activity causes similar axonal and dendritic defects in mushroom body neurons, recapitulating the salient feature of the developmental abnormalities caused by unc-51 mutations.Conclusions/Significance:Unc-51 plays pivotal roles in the axonal and dendritic development of the Drosophila brain. Unc-51-mediated membrane vesicle transport is important in targeted localization of guidance molecules and organelles that regulate elongation and compartmentalization of developing neurons

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

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

遠隔地小規模校での学習支援連携の定着への課題 : 藤女子大学と厚田中学校による2年間の取り組みを振り返って

本論では、今年度で二年目を終えた藤女子大学の学生による石狩市立厚田中学校での学習支援(スクール・アシスタント・ティチャー:SAT)事業の現状と課題、そして将来的な展望を報告する。厚田中学校は、藤女子大学花川校舎から車で50分ほどの海岸部に位置する全校生徒22名の小規模校である。そこで主に教職課程を履修している大学生が、中学校教員や保護者と協力しつつ、数学や家庭科などの授業、学校行事の面で、生徒と触れ合い、多様な学習支援を行なっている。本論は、大学・中学校側のSAT担当教員だけではなく、実際に学習支援に参加した学生の視点から、今年度を振り返り、来年への展望を述べている。現状分析としては、1. 学校行事(学校祭・餅つき大会・卒業式)への参加、2. 地域との関わり(ピザ教室)、3. 学生主体の連絡調整が促進されたことが、今年度の成果といえる。その一方で、依然として、遠隔地域での学習支援という特色上、1. 厚田への交通手段、それに伴う2. 学生の時間の確保が課題として残った。しかし、来年度(2013年)は、厚田中学校での学習支援を経験し三年目の学生も4年生として在籍するため、SAT事業の継続性・発展性を視野に入れた、彼女たちの集大成に期待したい。なお、今年度のSAT事業は、石狩市教育委員会の予算と共に、藤女子大学QOL研究所からの補助金を通して、運営された。This paper aims to report the current conditions and future prospects of learning support partnerships (School Assistant Teacher: SAT) between Atsuta Junior High School and Fuji Women\u27s University. This program has been implemented by Ishikari City board of education with the university students. In this program almost ten students who want to become a teacher has involved in learning support for junior high school students especially in the subject of mathematics. This year is the second year of implementation of this program. Comparing to last year,our project promote university students the involvement in school events, relation with community and guardian of students,and university student\u27s autonomy in terms of coordination of this program. On the other hand we should challenge some problems such as transportation to Atsuta and obtaining the number of students to maintain the learning support in junior high school