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Inscuteable maintains type I neuroblast lineage identity via Numb/Notch signaling in the Drosophila larval brain

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Journal of genetics and genomics 2017年第3期44卷 151-162页

作者： Huanping An Wanzhong Ge Yongmei Xi Xiaohang Yang Division of human Reproduction and Developmental Cenetics. The Women's Hospital School of Medicine Zhejiang University Hangzhou 310000 China Institute of genetics Zhejiang University Hangzhou 310012 China Department of genetics School of Medicine Zhejiang University Hangzhou 310012 China College of Life Sciences Zhejiang University Hangzhou 310012 China Joint Institute of genetics and genomic medicine Between Zhejiang University and University of Toronto Zhejiang University Hangzhou 310012 China

In the Drosophila larval brain, type I and type Ⅱ neuroblasts（NBs） undergo a series of asymmetric divisions which give rise to distinct progeny lineages. The intermediate neural progenitors（INPs） exist only in type Ⅱ NB lineages. In this study, we reveal a novel function of Inscuteable（Insc） that acts to maintain type I NB lineage identity. In insc type I NB clones of mosaic analyses with a repressible cell marker（MARCM）, the formation of extra Deadpan（Dpn）tNB-like and GMC-like cells is observed. The lack of Insc leads to the defective localization and segregation of Numb during asymmetric cell division. By the end of cytokinesis, this results in insufficient Numb in ganglion mother cells（GMCs）. The formation of extra Deadpan（Dpn）tcells in insc clones is prevented by the attenuation of Notch activity. This suggests that Insc functions through the Numb/Notch signaling pathway. We also show that in the absence of Insc in type I NB lineages, the cellular identity of GMCs is altered where they adopt an INP-like cell fate as indicated by the initiation of Dpn expression accompanied by a transient presence of Earmuff（Erm）.These INP-like cells have the capacity to divide multiple times. We conclude that Insc is necessary for the maintenance of type I NB lineage identity. Genetic manipulations to eliminate most type I NBs with overproliferating type Ⅱ NBs in the larval brain lead to altered circadian rhythms and defective phototaxis in adult flies. This indicates that the homeogenesis of NB lineages is important for the adult＇s brain function.

关键词： Drosophila larval brain neuroblasts(NBs) Inscuteable(Insc) NB lineage maintenance Type I and type Ⅱ NBs Numb/Notch signaling

Understanding genetics, sex and signaling: Implications of sex-dependent APOE4-neutrophil-microglia interactions for Alzheimer’s and tauopathies

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Signal Transduction and Targeted Therapy 2024年第10期9卷 4167-4169页

作者： Natja Haag Juliane Bremer Hans Zempel Institute for human genetics and genomic medicine University Hospital RWTH AachenAachenGermany Institute of Neuropathology University Hospital RWTH AachenAachenGermany Institute of human genetics Faculty of Medicine and University Hospital CologneUniversity of CologneCologneGermany Center for Molecular medicine Cologne(CMMC) University of CologneCologneGermany Department of Nuclear medicine Faculty of Medicine and University Hospital CologneUniversity of CologneCologneGermany

A recent study published in Nature medicine uncovers a novel sex-dependent mechanism involving the apolipoprotein E ε4 (APOE4) and in particular neutrophils and their signaling to microglia, which then would mediate cognitive decline in late-onset Alzheimer’s disease (AD).1 We here put the main findings into perspective with current knowledge about APOE4 genotype and neutrophils in the pathogenesis of AD and related tauopathies, and discuss future research directions and therapeutic implications.

关键词： Alzheimer tau medicine

Characterizing functional consequences of DNA copy number alterations in breast and ovarian tumors by spaceMap

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Journal of genetics and genomics 2018年第7期45卷 361-371页

作者： Christopher J.Conley Umut Ozbek Pei Wang Jie Peng Department of Statistics University of California Davis Department of Population Health Science and Policy Icahn School of Medicine at Mount Sinai Department of genetics and genomic Sciences Icahn School of Medicine at Mount Sinai

We propose a novel conditional graphical model -- spaceMap -- to construct gene regulatory networks from multiple types of high dimensional omic profiles. A motivating application is to characterize the perturbation of DNA copy number alterations （CNAs） on downstream protein levels in tumors. Through a penalized multivariate regression framework, spaceMap jointly models high dimensional protein levels as responses and high dimensional CNAs as predictors. In this setup, spaceMap infers an undirected network among proteins together with a directed network encoding how CNAs perturb the protein network, spaceMap can be applied to learn other types of regulatory relationships from high dimensional molecular profiles, especially those exhibiting hub structures. Simulation studies show spaceMap has greater power in detecting regulatory relationships over competing methods. Additionally, spaceMap includes a network analysis toolkit for biological interpretation of inferred networks. We applies spaceMap to the CNAs, gene expression and proteomics data sets from CPTAC-TCGA breast （n = 77） and ovarian （n = 174） cancer studies. Each cancer exhibits disruption of＇ion transmembrane transport＇ and ＇regulation from RNA polymerase lI promoter＇ by CNA events unique to each cancer. Moreover, using protein levels as a response yields a more functionally-enriched network than using RNA expressions in both cancer types. The network results also help to pinpoint crucial cancer genes and provide insights on the functional consequences of important CNA in breast and ovarian cancers.

关键词： Integrative genomics Proteogenomics Conditional graphical models Network analysis

Endothelial Cell Senescence and Age-Related Vascular Diseases

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Journal of genetics and genomics 2014年第9期41卷 485-495页

作者： Xiao-Li Tian Yang Li Department of human Population genetics and Beijing Key Laboratory of Cardiometabolic Molecular medicine Institute of Molecular Medicine(IMM)Peking University

Advanced age is an independent risk factor for ageing-related complex diseases, such as coronary artery disease, stroke, and hypertension, which are common but life threatening and related to the ageing-associated vascular dysfunction. On the other hand, patients with progeria syndromes suffer from serious atherosclerosis, suggesting that the impaired vascular functions may be critical to organismal ageing, or vice versa. However, it remains largely unknown how vascular cells, particularly endothelial cell, become senescent and how the senescence impairs the vascular functions and contributes to the age-related vascular diseases over time. Here, we review the recent progress on the characteristics of vascular ageing and endothelial cell senescence in vitro and in vivo, evaluate how genetic and envi- ronmental factors as well as autophagy and stem cell influence endothelial cell senescence and how the senescence contributes to the age- related vascular phenotypes, such as atherosclerosis and increased vascular stiffness, and explore the possibility whether we can delay the age-related vascular diseases through the control of vascular ageing.

关键词： Endothelial cell senescence Genetic Vascular ageing Age-related diseases Stem cell

Johanson-Blizzard syndrome with mild phenotypic features confirmed by UBR1 gene testing

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World Journal of Gastroenterology 2008年第44期14卷 6863-6866页

作者： Naim Alkhouri Barbara Kaplan Marsha Kay Amy Shealy Carol Crowe Susanne Bauhuber Martin Zenker Department of Pediatric Gastroenterology and Nutrition Cleveland ClinicClevelandOH 44195United States genomic medicine Institute Cleveland ClinicClevelandOH 44195United States Department of genetics MetroHealth Medical CenterClevelandOH 44195United States Institute of human genetics 91054 ErlangenGermany

Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive condition associated with exocrine pancreatic insufficiency,and is characterized by hypoplastic nasal alae,mental retardation,sensorineural hearing loss,short stature,scalp defects,dental abnormalities and abnormal hair patterns. Growth hormone deficiency,hypopituitarism,and impaired glucagon secretion response to insulin-induced hypoglycemia have been reported. Congenital heart defects have also been described in this condition. Mental retardation is typically moderate to severe in patients with JBS; however,normal intelligence can occur. In the pancreas,there is a selective defect of acinar tissue,whereas the islets of Langerhans and ducts are preserved. Diabetes has been reported in older children,suggesting the progressive nature of pancreatic disease. The molecular basis of JBS has recently been mapped to chromosome 15q15-q21 with identified mutations in the UBR1 gene. We report the case of a 7-year-old female with pancreatic insufficiency and mild phenotypic features,in whom the diagnosis of JBS was established using recently described molecular testing for the UBR1 gene.

关键词： Johanson-Blizzard syndrome Pancreatic insufficiency Sensorineural hearing loss UBR1 gene

Battle of the sexes: contrasting roles of testis-specific protein Y-encoded (TSPY) and TSPX in human oncogenesis

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Asian Journal of Andrology 2019年第3期21卷 260-269页

作者： Yun-Fai Chris Lau Yunmin Li Tatsuo Kido Division of Cell and Developmental genetics Department of Medicine VA Medical Center and Institute for Human Genetics University of California San Francisco CA 94121 USA

The Y-located testis-specific protein Y-encoded (TSPY) and its X-homologue TSPX originated from the same ancestral gene, but act as a proto-oncogene and a tumor suppressor gene, respectively. TSPY has specialized in male-specific functions, while TSPX has assumed the functions of the ancestral gene. Both TSPY and TSPX harbor a conserved SET/NAP domain, but are divergent at flanking structures. Specifically, TSPX contains a C-terminal acidic domain, absent in TSPY. They possess contrasting properties, in which TSPY and TSPX, respectively, accelerate and arrest cell proliferation, stimulate and inhibit cyclin B-CDK1 phosphorylation activities, have no effect and promote proteosomal degradation of the viral HBx oncoprotein, and exacerbate and repress androgen receptor (AR) and constitutively active AR variant, such as AR-V7, gene transactivation. The inhibitory domain has been mapped to the carboxyl acidic domain in TSPX, truncation of which results in an abbreviated TSPX exerting positive actions as TSPY. Transposition of the acidic domain to the C-terminus of TSPY results in an inhibitory protein as intact TSPX. Hence, genomic mutations/aberrant splicing events could generate TSPX proteins with truncated acidic domain and oncogenic properties as those for TSPY. Further, TSPY is upregulated by AR and AR-V7 in ligand-dependent and ligand-independent manners, respectively, suggesting the existence of a positive feedback loop between a Y-located proto-oncogene and male sex hormone/receptors, thereby amplifying the respective male oncogenic actions in human cancers and diseases. TSPX counteracts such positive feedback loop. Hence, TSPY and TSPX are homologues on the sex chromosomes that function at the two extremes of the human oncogenic spectrum.

关键词： androgen receptor AR-V7 cell cycle regulation cyclin B-CDK1 oncogene sex chromosomes sex differences TSPX TSPY tumor suppressor

Dietary carbohydrate intake and risk of type 2 diabetes:a 16-year prospective cohort study

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Science China Life Sciences 2025年

作者： Lu Gan Yi Yang Bin Zhao Kai Yu Kehua Guo Fang Fang Zhiguang Zhou Demetrius Albanes Jiaqi Huang Key Laboratory of Diabetes Immunology Ministry of Education and Department of Metabolism and Endocrinology The Second Xiangya Hospital of Central South University CSU-Sinocare Research Center for Nutrition and Metabolic Health Xiangya School of Public Health Central South UniversityFurong Laboratory Division of Cancer Epidemiology and genetics National Cancer Institute NIH Department of Health and Human Services School of Computer Science and Engineering Central South University Institute of Environmental medicine Karolinska Institute National Clinical Research Center for Metabolic Diseases Key Laboratory of Diabetes Immunology Ministry of Education and Department of Metabolism and Endocrinology The Second Xiangya Hospital of Central South University

Despite considerable research underscoring the importance of carbohydrate intake in relation to the risk of type 2 diabetes(T2D), a comprehensive assessment of this relationship is currently lacking. We aimed to examine the associations of various types and food sources of dietary carbohydrate intake with the risk of T2D, to evaluate potential effect modification by other factors, including genetic susceptibility,and to explore the potential mediators for such associations. The present study included 161,872 participants of the UK Biobank who were free of prevalent cancer, cardiovascular disease, or diabetes, and had at least one validated 24-h dietary recall assessment. Multivariableadjusted age-stratified Cox proportional hazard regression models were applied to estimate hazard ratios(HRs) and 95% confidence intervals(CI) for the associations of various types and food sources of dietary carbohydrate intake with risk of T2D. During a median follow-up of13.6 years, 4,176 incident cases of T2D were identified. In the multivariable-adjusted models, a greater intake of fiber, carbohydrates from whole grains, and carbohydrates from non-starchy vegetables was significantly associated with a lower risk of T2D(highest vs. lowest quantile, HR [95% CI]=0.70 [0.62–0.79], 0.74 [0.67–0.82], and 0.83 [0.75–0.92], respectively, all P for trend <0.005). In contrast, a higher intake of starch and carbohydrate from starchy vegetables was associated with an increased risk of T2D(highest vs. lowest quantile, HR [95%CI]=1.31 [1.16–1.48] and 1.19 [1.09–1.31], respectively, both P for trend <0.005). Replacing one serving of refined grains or starchy vegetables with an equal amount of whole grains or non-starchy vegetables was associated with 4% to 10% lower risk of T2D(all P values <0.001).The observed associations were generally similar across population subgroups, including individuals with different genetic susceptibility to T2D. Mediation analyses of the inverse association between T

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HLA polymorphism of the Zhuang population reflects the common HLA characteristics among Zhuang-Dong language-speaking populations

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2011年第6期12卷 428-435页

作者： Li SHI Xiao-qin HUANG Lei SHI Yu-fen TAO Yu-feng YAO Liang YU Ke-qin LIN Wen YI Hao SUN Katsushi TOKUNAGA Jia-you CHU Institute of Medical Biology Chinese Academy of Medical Sciences & Peking Union Medical College Kunming 650118 China Department of human genetics Graduate School of Medicine University of Tokyo Tokyo 113-0033 Japan Department of human genetics Graduate School of Medicine University of Tokyo Tokyo 113-0033 Japan Department of human genetics Graduate School of Medicine University of Tokyo Tokyo 113-0033 Japan

A study of the human leukocyte antigen （HLA） genetic characteristics in the Zhuang, the largest ethnic population in China, would provide insight into Zhuang history and give a useful tool for disease associations, transplantation, and anthropology. In the present study, we report the comprehensive HLA-A, HLA-B, HLA-C, and HLA-DRB1 alleles and haplotypes in the Zhuang population of southern China for the first time. A total of 13 HLA-A, 24 HLA-B, 22 HLA-C, and 18 HLA-DRB1 were identified in 104 Zhuang individuals. The frequencies of HLA-A＊11：01, A^＊02：07, A^＊24：02, A^＊02：03, and A^＊33：03 on A loci, B^＊15：02, B^＊58：01, B^＊46：01, and B^＊13：01 on B loci, C^＊03：04, C^＊08：01, C^＊01：02, C^＊03：02, and C^＊07：02 on C loci, and DRBl＊15：01, DRBl^＊16：02, DRB1^＊14：01, DRBl^＊15：02, and DRBI^＊03：01 on the DRB1 loci were 〉10%. The A^＊33：03-C^＊03：02-B^＊58：01-DRBl^＊03：01 and A^＊02：07-C^＊01：02- B^＊46：01-DRB1^＊14：01 haplotypes were predominant in the Zhuang. The phylogenetic tree, as well as the analysis of haplotypes, suggested that the Zhuang are genetically similar to southern Chinese populations, especially the Zhuang-Dong language-speaking populations, such as the Bouyei, Dai, and Maonan. Even though the Zhuang and southern Chinese populations shared common alleles and haplotypes, the Zhuang has maintained its unique genetic characteristics.

关键词： human leukocyte antigen (HLA) alleles Haplotypes Zhuang population

Roles of the Y chromosome genes in human cancers

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Asian Journal of Andrology 2015年第3期17卷 373-380页

作者： Tatsuo Kido Yun-Fai Chris Lau Division of Cell and Developmental genetics Department of Medicine Veterans Affairs Medical Center Institute for Human Genetics University of California San Francisco California 94121 USA

Male and female differ genetically by their respective sex chromosome composition, that is, XY as male and XX as female. Although both X and Y chromosomes evolved from the same ancestor pair of autosomes, the Y chromosome harbors male-specific genes, which play pivotal roles in male sex determination, germ cell differentiation, and masculinization of various tissues. Deletions or translocation of the sex-determining gene, SRY, from the Y chromosome causes disorders of sex development （previously termed as an intersex condition） with dysgenic gonads. Failure of gonadal development results not only in infertility, but also in increased risks of germ cell tumor （GCT）, such as gonadoblastoma and various types of testicular GCT. Recent studies demonstrate that either loss of Y chromosome or ectopic expression of Y chromosome genes is closely associated with various male-biased diseases, including selected somatic cancers. These observations suggest that the Y-linked genes are involved in male health and diseases in more frequently than expected. Although only a small number of protein-coding genes are present in the male-specific region of Y chromosome, the impacts of Y chromosome genes on human diseases are still largely unknown, due to lack of in vivo models and differences between the Y chromosomes of human and rodents. In this review, we highlight the involvement of selected Y chromosome genes in cancer development in men.

关键词： germ cell tumors RBMY, Y-linked somatic cancers TSPY Y chromosome