転写因子NFIAの褐色脂肪分化と筋細胞分化の制御作用ドメインの解析

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 南學 正臣, 東京大学教授 秋下 雅弘, 東京大学講師 廣田 泰, 東京大学講師 伊地知 秀明, 東京大学講師 森田 啓行University of Tokyo(東京大学

Genetic Deletion of Vasohibin-2 Exacerbates Ischemia-Reperfusion-Induced Acute Kidney Injury

Acute kidney injury (AKI) has been increasingly recognized as a risk factor for transition to chronic kidney disease. Recent evidence suggests that endothelial damage in peritubular capillaries can accelerate the progression of renal injury. Vasohibin-2 (VASH2) is a novel proangiogenic factor that promotes tumor angiogenesis. However, the pathophysiological roles of VASH2 in kidney diseases remain unknown. In the present study, we examined the effects of VASH2 deficiency on the progression of ischemia-reperfusion (I/R) injury-induced AKI. I/R injury was induced by bilaterally clamping renal pedicles for 25 min in male wild-type (WT) andVash2homozygous knockout mice. Twenty-four hours later, I/R injury-induced renal dysfunction and tubular damage were more severe in VASH2-deficient mice than in WT mice, with more prominent neutrophil infiltration and peritubular capillary loss. After induction of I/R injury, VASH2 expression was markedly increased in injured renal tubules. These results suggest that VASH2 expression in renal tubular epithelial cells might be essential for alleviating I/R injury-induced AKI, probably through protecting peritubular capillaries and preventing inflammatory infiltration

Impact of Gestational Age at Delivery on Fetal Heart Rate Monitoring During the Second Stage of Labor

Objective: To clarify whether gestational age at delivery affects the interpretation level of fetal heart rate (FHR) tracings in the second stage of labor in primiparous and singleton pregnancies.Methods: The database at one tertiary hospital in Japan was retrospectively reviewed for women with singleton fetuses in cephalic presentation and vaginal labor at ≥37+0 gestational weeks between June 1, 2011, and March 31, 2013. Continuous FHR tracings in the second stage of labor were subdivided into 10-minute intervals, each of which we called a window, from the beginning through delivery, and were assessed according to the five-tier classification proposed by the Japan Society of Obstetrics and Gynecology, in which level 1 is normal, level 2 is subnormal, and levels 3-5 are abnormal patterns. Subjects were divided into two groups, including early term (37 0/7 to 38 6/7 weeks) and full term (39 0/7 to 41 6/7 weeks), according to the delivery age.Results: In total, 914 parturient women were eligible for the study protocol, including 228 and 686 women in early and full term, respectively. Vacuum extraction was more often observed in full term than in early term (P=0.007). Although the maximal level, number of level-5 windows, number of level-4 windows, and number of level-3 and level-4 windows were similar between the groups, the summation of level-4 windows ≥3 was significantly higher in full term than in early term (P=0.004).Conclusion: Full term delivery has a higher risk than does early term delivery from the standpoint of FHR monitoring

Cytology Reporting System for Lung Cancer from the Japan Lung Cancer Society and the Japanese Society of Clinical Cytology: An Extensive Study Containing More Benign Lesions

Introduction: The Japan Lung Cancer Society (JLCS) and the Japanese Society of Clinical Cytology (JSCC) have proposed a new four-tiered cytology reporting system for lung carcinoma (JLCS-JSCC system). Prior to the proposal, the Papanicolaou Society of Cytopathology (PSC) had proposed a revised reporting system (PSC system), which comprises the “neoplastic, benign neoplasm, and low-grade carcinoma” category (N-B-LG category), in addition to the 4 categories of the JLCS-JSCC system. This study aimed to evaluate the interobserver agreement of the JLCS-JSCC system with an additional dataset with more benign lesions in comparison with the PSC system. Methods: We analyzed 167 cytological samples, which included 17 benign lesions, obtained from the respiratory system. Seven observers classified these cases into each category by reviewing one Papanicolaou-stained slide per case according to the JLCS-JSCC system and PSC system. Results: The interobserver agreement was moderate in the JLCS-JSCC (k = 0.499) and PSC (k = 0.485) systems. Of the 167 samples, 17 samples were benign lesions: 7 pulmonary hamartomas, 5 sclerosing pneumocytomas, 2 squamous papillomas, one solitary fibrous tumor, one meningioma, and one lymphocytic proliferation. There were diverse sample types as follows: 11 touch smears, 3 brushing smears, 2 aspirations, and one sputum sample. Fourteen samples (82.3%) were categorized into “negative” or “atypical” by more than half of the observers in the JLCS-JSCC system. Conversely, 3 samples were categorized as “suspicious” or “malignant” by more than half of the observers in the JLCS-JSCC system. On the other hand, 11 samples (64.7%) were categorized into the N-B-LG category by more than half of the observers in the PSC system. Conclusions: The concordance rate in the JLCS-JSCC system was slightly higher than that in the PSC system; however, the interobserver agreement was moderate in both the JLCS-JSCC and PSC systems. These results indicate that both the JLCS-JSCC and PSC systems are clinically useful. Therefore, both systems are expected to have clinical applications. It may be important to integrate the 2 systems and construct a universal system that can be used more widely in clinical practice

陰膳方式食物収集による日本人の栄養調査 : 血清脂質と栄養摂取量

Nutrient intake was surveyed by total food duplicate method in combination with serum biochemistry among adult Japanese women. The survey was conducted twice in the same 19 sites all over Japan, once in the years around 1980 (the first survey on 199 women) and then in 1991-6 (the second survey on 379 women). The participants 19 sites were classified into four groups of those in Hokkaido, urban areas, rural areas and Okinawa by the location of residence, and relation of findings serum lipid analyses with nutrient intakes was examined. In the Hokkaido group, cholesterol and triglyceride in serum, and intake of animal fat and saturated fatty acids (SFAs) were lower in the second survey than in the first survey. In the urban group, serum cholesterol, and intakes of animal fats and SFAs were the highest among the four groups both in the first and second surveys. In contrast, serum cholesterol, and intakes of animal fats and SFAs in the rural group were lower than the levels in other groups in the first survey, but the three groups in the second survey. In Okinawa, serum cholesterol was lower than others in the second survey. Intake of fat-based energy was high, but intakes of monounsaturated fatty acids and n-6 polyunsaturated fatty acids were also high. When all subjects were combined, the serum cholesterol level was 193mg/100ml (as an arithmetic mean) in the first survey and it was 202 mg/100 ml in the second survey, and this increase was paralleled by the increase in the number of aged survey subjects. Serum triglyceride level was 111mg/100ml in the first survey, and 99 mg/dl in the second survey. The reduction may be attributable to the reduced nutrient intake among young people. Serum cholesterol correlated significantly with intake of animal fats and SFAs, but the correlation with total energy intake was significant only in the second survey. BMI correlated significantly with serum triglyceride levels in both surveys, but the correlation coefficient was smaller in the second survey than in the first survey. There was no correlation between BMI and serum cholesterol in both surveys

Prepotent Response Inhibition and Interference Control in Autism Spectrum Disorders: Two Meta-Analyses

Search String Advanced > Saved Searches > ARTICLE TOOLS Get PDF (432K) Save to My Profile E-mail Link to this Article Export Citation for this Article Get Citation Alerts Request Permissions More Sharing ServicesShare|Share on citeulikeShare on facebookShare on deliciousShare on www.mendeley.comShare on twitter Abstract Article References Cited By View Full Article (HTML) Enhanced Article (HTML) Get PDF (432K) UvA-linker Full Text Keywords: ASD; autism; inhibition; interference; cognitive control; meta-analysis There is a substantial amount of data providing evidence for, but also against the hypothesis that individuals with autism spectrum disorders (ASD) encounter inhibitory control deficits. ASD is often associated with interference control deficits rather than prepotent response inhibition. Moreover, the developmental trajectory for these inhibitory control processes is hypothesized to differ in ASD as compared to typical development. In efforts to gain a more comprehensive perspective of inhibition in ASD, separate quantitative analysis for prepotent response inhibition studies and interference control studies were conducted. Together, these two meta-analyses included 41 studies with a combined sample size of 1,091 people with ASD (M age 14.8 years), and 1,306 typically developing (TD) controls (M age 13.8 years).The meta-analyses indicated that individuals with ASD show increased difficulties in prepotent response inhibition (effect size 0.55) and in interference control (effect size 0.31). In addition, age was a relevant moderator for prepotent response inhibition but not for interference control. Exploratory analyses revealed that when IQ was taken into account, heterogeneity considerably decreased among interference control studies but not among prepotent response inhibition. In contrast to the general belief, both prepotent response inhibition and interference control problems were observed in individuals with ASD. However, a large variation between studies was also found. Therefore, there remain factors beyond inhibition type, age, or IQ that significantly influence inhibitory control performance among individuals with ASD

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

TRPV4 is functionally expressed in oligodendrocyte precursor cells and increases their proliferation

This article is part of the special issue on Thermal biology in Pflügers Archiv – European Journal of Physiology.Oligodendrocytes, which differentiate from oligodendrocyte precursor cells (OPCs), ensheath axons with myelin, play an essential role in rapid conduction of action potentials and metabolically support neurons. Elucidation of the mechanisms underlying the proliferation, migration, differentiation, and survival of OPCs is considered indispensable for determining the causes of central nervous system diseases. However, the relationship between these functions of OPCs and their intracellular Ca²⁺ signaling has not been fully elucidated. Here, we investigated the function of transient receptor potential vanilloid 4 (TRPV4), a Ca²⁺-permeable channel that responds to hypo-osmolarity, mild temperature, mechanical stimulation, and endogenous arachidonic acid metabolites, in OPCs. Trpv4 mRNA was detected in OPCs in vivo and in primary cultured rat OPCs. In Ca²⁺ imaging experiments, treatment with the selective TRPV4 agonist GSK1016790A induced sustained elevation of the intracellular Ca²⁺ concentration in OPCs in a concentration-dependent manner, which was almost completely suppressed by co-treatment with the selective TRPV4 antagonist HC067047. Stimulation of TRPV4 by GSK1016790A augmented OPC proliferation, which was abolished by co-treatment with HC067047, the intracellular Ca²⁺ chelator BAPTA-AM, and the protein kinase C inhibitor bisindolylmaleimide II. By contrast, GSK1016790A did not significantly affect the migration or differentiation of OPCs. Taken together, these results suggest that TRPV4 is functionally expressed in OPCs and increases the proliferation of these cells without affecting their ability to differentiate into oligodendrocytes

Changes in oral microflora following 0.3% cetylpyridinium chloride‐containing mouth spray intervention in adult volunteers after professional oral care: Randomized clinical study

Abstract Objectives This study explored the changes in bacterial flora composition and total bacterial count in the saliva and tongue coating, along with the change in the tongue coating index (TCI) following an intervention with 0.3% cetylpyridinium chloride (CPC) mouth spray after professional oral care. Materials and Methods Fifty‐two adult volunteers aged 30–60 years were equally divided into CPC spray (n = 26) and control (n = 26) groups. All subjects underwent scaling and polishing. The CPC spray group was administered four puffs of CPC spray to the tongue dorsum four times a day for 3 weeks. The control group performed only routine daily oral care (brushing) and did not use any other spray. Bacteriological evaluation of saliva and tongue coating was performed using 16S ribosomal RNA gene sequencing and quantitative polymerase chain reaction. The tongue coating was evaluated to calculate the TCI. A per‐protocol analysis was conducted for 44 subjects (CPC spray group, n = 23; control group, n = 21). Results At 1 and 3 weeks after CPC spray use, the flora of the saliva and tongue coating changed; the genus Haemophilus was dominant in the CPC spray group, whereas the genus Saccharibacteria was dominant in the control group. The sampling time differed among individual participants, which may have affected the bacterial counts. There was no significant intragroup change in TCI in either group. Conclusions CPC spray affected the bacterial flora in the saliva and tongue coating, particularly with respect to an increase in the abundance of Haemophilus. However, CPC spray did not change the TCI. These results suggest that it may be optimal to combine CPC spray with a physical cleaning method such as using a tongue brush or scraper. Clinical Trial Registration: University Hospital Medical Information Network UMIN000041140