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Targeting stem cell signaling pathways for drug discovery:advances in the Notch and Wnt pathways

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Science China(life Sciences) 2014年第6期57卷 575-580页

作者： AN Songzhu Michael DING Qiang ZHANG Jie XIE JingYi li lingsong Curegenix Inc. Center for Stem Cell and NanoMedicine Shanghai Advanced Research InstituteChinese Academy of Sciences

Signaling pathways transduce extracellular stimuli into cells through molecular cascades to regulate cellular *** stem cells,a small number of pathways,notably those of TGF-?/BMP,Hedgehog,Notch,and Wnt,are responsible for the regulation of pluripotency and *** embryonic development,these pathways govern cell fate specifications as well as the formation of tissues and *** adulthood,their normal functions are important for tissue homeostasis and regeneration,whereas aberrations result in diseases,such as cancer and degenerative *** complex biological systems,stem cell signaling pathways work in concert as a network and exhibit crosstalk,such as the negative crosstalk between Wnt and *** the past decade,genetic and genomic studies have identified a number of potential drug targets that are involved in stem cell signaling ***,discovery of new targets and drugs for these pathways has become one of the most active areas in both the research community and pharmaceutical *** progress has been made and several promising drug candidates have entered into clinical *** review focuses on recent advances in the discovery of novel drugs which target the Notch and Wnt pathways.

关键词： Wnt信号通路 Notch 药物发现干细胞信号传导途径转化生长因子细胞功能信号途径

Maintenance of human embryonic stem cells on gelatin

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Chinese Science Bulletin 2009年第22期54卷 4214-4220页

作者： li Yang liN ChangSheng WANG li liU Ying MU XiaoNing MAYue li lingsong Peking University Stem Cell Research Center and China National Center for International Research Beijing 100191 China Department of Reproduction Beijing Obstetrics and Genecology Hospital Beijing 100026 China The Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China

Matrigel is routinely used as a coating material in the feeder-free culture system of human embryonic stem cells (hESCs). However, matrigel is costive and inconvenient to use. In this study, the possibility of using gelatin as an alternative coating material was investigated. The results showed that, after trypsinization, hESCs were maintained undifferentiated on gelatin. These hESCs expressed pluripotent markers, formed teratoma and maintained a normal karyotype. As measured at passage 10, the hESCs expressed a high level of Oct4 on both gelatin and Matrigel. hESCs growing on gelatin formed AP-positive colonies in similar size and number to those growing on Matrigel (P > 0.05). Moreover, hESCs growing on gelatin contained a comparable percentage of SSEA-4-positive cells to those growing on Matrigel (95.1% vs.94.3%, P > 0.05). H-1 hESCs were maintained undifferentiated on gelatin for 20 passages and remained the stable normal karyotype. This gelatin-based culture protocol may allow us to propagate hESCs in large scale, with less cost.

关键词：人类胚胎干细胞明胶维护涂层材料培养体系胰蛋白酶阳性克隆阳性细胞

Genome editing and animal models

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Chinese Science Bulletin 2014年第1期59卷 1-6页

作者： Ruby Yanru Chen-Tsai Ruhong Jiang Luping Zhuang Junfeng Wu lingsong li Jiarui Wu Department of Animal Disease Modeling Center for Stem Cell and NanoMedicine Shanghai Advanced Research InstituteChinese Academy of Sciences

Transgenic technology allows a gene of interest to be introduced into the genome of a laboratory animal,and provides an extremely powerful tool to dissect the molecular mechanisms of *** mouse models made by microinjection of DNA into zygotic pronuclei in particular have been widely used by the genetics community for 30 ***,it remains a rather crude approach:injected sequences randomly insert in multiple copies as concatamers,they can be mutagenic,and they have variable or silenced expression depending on the site of integration,a phenomenon called position *** a result,multiple lines are required in order to confirm appropriate transgene *** can be partially overcome by flanking transgenes with insulator sequences to protect the transgene from the influence of the surrounding regulatory ***(\300 kb)BACbased transgenic vectors have also been shown to be more resistant to position ***,animals carrying extra copies of fairly large regions of the genome could have unpredictable *** most effective method used to control for position effects is to target transgene insertion to specific genomic loci,the so-called targeted transgenesis;for instance,the fast,site-specific transgenic technology Targatt *** purpose of this review is to provide an overview on the current existing methods for making targeted transgenic mouse models.

关键词：动物模型基因组转基因小鼠模型转基因技术编辑位置效应显微注射 DNA导入

Association between vascular endothelial growth factor gene promoter polymorphisms and sporadic amyotrophic lateral sclerosis in a Han Chinese population Case-control study

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Neural Regeneration Research 2009年第12期4卷 1110-1115页

作者： Na liu Nan Zhang Jun Zhang liping Wang Xiaoyan Zhang Wei Sui Huagang Zhang lingsong li Dafang Chen Dongsheng Fan Department of Neurology Peking University Third Hospital Beijing 100191 China Peking University Stem Cell Research Center Beijing 100191 China Department of Epidemiology and Statistics School of Public Health Peking University Beijing 100191 China

BACKGROUND： Studies have shown that vascular endothelial growth factor （VEGF） gene polymorphisms highly correlate with sporadic amyotrophic lateral sclerosis （ALS）, although this remains controversial. To date, the relationship between VEGF gene polymorphism and sporadic ALS in a Han Chinese population remains unclear. OBJECTIVE： To explore the relationship between sporadic ALS and VEGF gene promoter 7 locus polymorphisms in a Hart Chinese population, and to investigate whether this relationship exhibits gender differences. DESIGN, TIME AND SETTING： A case-control study regarding genetic association was performed at the Central Laboratory of Peking University Third Hospital from 2002 to 2006. PARTICIPANTS： A total of 93 patients, who were diagnosed with definite or probable ALS according to E1 Escorial-revised diagnostic criteria, were selected from the Outpatient Department of Neurology, Peking University Third Hospital from 2002 to 2006. All patients were from Hart populations, with no family history of ALS. In addition, 103 gender- and age-matched healthy volunteers were selected as controls. METHODS： Peripheral venous blood was collected, and whole blood genomic DNA was extracted. VEGF gene promoter 7 locus polymorphisms were analyzed by PCR using the fluorescent Taqman system. The relationship between VEGF gene promoter single nucleotide polymorphisms and ALS was analyzed using Logistic regression model analysis and was stratified according to gender. MAIN OUTCOME MEASURES： 7 VEGF gene promoter polymorphisms genotype distribution and allele frequencies. RESULTS： There were no significant differences in VEGF gene promoter 7 locus genotype distribution and allele frequency between case and control groups （P 〉 0.05）. Stratified analysis based on gender demonstrated that female Han subjects carrying the VEGF genotype -1154AA, -2549TT, -634CC genotype were more susceptible to ALS than those carrying -1154GG, -2549CC, -634GG （VEGF-1154AA： OR= 8.9, 95%CI= 1 .0-77.3, P

关键词： amyotrophic lateral sclerosis genetic polymorphisms vascular endothelial growth factor

高迁移率族蛋白1在继发性输尿管狭窄中的作用机制与意义

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泌尿外科杂志(电子版) 2024年第3期16卷 64-67页

作者：程立郑杰陶凌松刘应清华东师范大学附属芜湖医院泌尿外科

输尿管狭窄是一种常见的泌尿系统疾病,其多为继发性病变并对患者的生活质量造成严重影响。高迁移率族蛋白1 (high mobility group box 1,HMGB1)是一种高度保守和广泛表达的核蛋白,被认为参与细胞增殖、分化等一系列生物学过程。近年有... 详细信息

输尿管狭窄是一种常见的泌尿系统疾病,其多为继发性病变并对患者的生活质量造成严重影响。高迁移率族蛋白1 (high mobility group box 1,HMGB1)是一种高度保守和广泛表达的核蛋白,被认为参与细胞增殖、分化等一系列生物学过程。近年有研究发现HMGB1在输尿管狭窄的发生与发展中起到重要作用。本文对HMGB1在继发性输尿管狭窄中的作用机制、相关HMGB1抑制剂对术后输尿管狭窄防治研究的进展作一综述,旨在为治疗继发性输尿管狭窄提供新思路。

关键词：输尿管狭窄高迁移率族蛋白1 蛋白质抑制剂

海陆过渡相三角洲沉积体系陆源有机质沉积特征及其影响因素的模拟实验研究

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沉积学报 2024年第1期42卷 251-265页

作者：刘海徐耀辉李阳黄凌松吕奇奇刘忠保油气地球化学与环境湖北省重点实验室长江大学资源与环境学院武汉430100 油气资源与勘探技术教育部重点实验室长江大学武汉430100 长江大学地球科学学院武汉430100

【目的】海陆过渡相三角洲沉积体系由于油气成藏条件优越,广泛发育陆源海相烃源岩,陆源有机质是其主要的母质来源。为了探究海陆过渡相三角洲沉积体系中陆源有机质的沉积特征及其影响因素,开展了陆源有机质沉积模拟实验。【方法】通过... 详细信息

【目的】海陆过渡相三角洲沉积体系由于油气成藏条件优越,广泛发育陆源海相烃源岩,陆源有机质是其主要的母质来源。为了探究海陆过渡相三角洲沉积体系中陆源有机质的沉积特征及其影响因素,开展了陆源有机质沉积模拟实验。【方法】通过碳硫分析仪检测总有机碳含量,结合3D激光扫描技术,实现了实验条件下陆源有机质搬运沉积过程的动态定量表征。【结果】(1)在三角洲平原,陆源有机质主要在河道漫溢处、废弃河道、砂坝背流面等部位局部富集,剖面上主要以透镜型、断续型、互层型分布;在三角洲前缘和前三角洲,有机质平面上呈席状展布,剖面上以厚度较大的条带型分布;(2)陆源有机质在缓坡三角洲体系搬运距离较远,随着三角洲沉积厚度逐渐增大,三角洲初始坡度对陆源有机质搬运距离的影响减小;(3)水动力强度和波浪是影响有机质搬运距离的重要因素,水动力越弱越有利于有机质的沉积,在三角洲平原低能环境中存在有机质局部富集区。波浪会阻止有机质向前搬运并在三角洲前缘形成多个砂坝,有机质沉积于坝间凹槽呈环带状;(4)在海陆过渡相三角洲沉积体系内,从三角洲平原到三角洲前缘—前三角洲区域的有机碳含量逐步升高,进入陆架区,随着搬运距离的继续增大,有机碳含量减少。【结论】通过深入研究陆源有机质的富集部位和影响因素,建立了水槽实验模式下陆源有机质沉积模式,这对海陆过渡相三角洲沉积体系的油气探勘开发提供了重要的依据。

关键词：陆源有机质 3D激光扫描沉积模拟沉积特征影响因素

Upregulation of FIk-1 by bFGF via the ERK pathway is essential for VEGF-mediated promotion of neural stem cell proliferation

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Cell Research 2007年第1期 73-79页

作者： Zhifeng Xiao~1 Yaxian Kong~1 Shufa Yang~1 Meiyu li~1 Jinhua Wen~1 lingsong li~1 ~1Peking University Stem Cell Research Center and Cell Biology.Department,Peking University Health Science Center,Beijing,China

Neural stem cells (NSCs) constitute the cellular basis for embryonic brain development and *** processis regulated by NSC niche including neighbor cells such as vascular and glial *** both vascular and glial cellssecrete vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF),we assessed the effect ofVEGF and bFGF on NSC proliferation using nearly homogeneous NSCs that were differentiated from mouse embryonicstem *** alone did not have any significant *** bFGF was added,however,VEGF stimulated NSCproliferation in a dose-dependent manner,and this stimulation was inhibited by ZM323881,a VEGF receptor (Flk-1)-specific ***,ZM323881 also inhibited cell proliferation in the absence of exogenous VEGF,suggestingthat VEGF autocrine plays a role in the proliferation of *** stimulatory effect of VEGF on NSC proliferationdepends on bFGF,which is likely due to the fact that expression of Flk-1 was upregulated by bFGF via phosphoryla-tion of ERK1/***,this study may provide insight into the mechanisms by which mieroenvironmental nichesignals regulate NSCs.

关键词： neural stem cells vascular endothelial growth factor fibroblast growth factor embryonic stem cells

PLC在蒸汽锅炉汽包液位PID控制系统的应用分析

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可编程控制器与工厂自动化 2006年第8期 130-133页

作者：李凌松永宏电机股份有限公司

工业蒸汽锅炉是发电、炼油、化工等工业部门的动力和热源设备。锅炉汽包液位控制的稳定与否是关系到生产安全的重要因素之一。本文通过对带PID控制功能的台湾永宏PLC在锅炉汽包液位控制系统的应用原理和可靠性作了较为详尽的分析,指出... 详细信息

工业蒸汽锅炉是发电、炼油、化工等工业部门的动力和热源设备。锅炉汽包液位控制的稳定与否是关系到生产安全的重要因素之一。本文通过对带PID控制功能的台湾永宏PLC在锅炉汽包液位控制系统的应用原理和可靠性作了较为详尽的分析,指出了选用恰当PID控制方案对锅炉安全运行的重要性,提出了锅炉PLC控制系统的基本设计思路和各个环节控制实现方法。

关键词：锅炉液位控制可编程控制器控制系统

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可编程序控制器在机床数控系统中应用探讨

可编程控制器与工厂自动化 2006年第12期 95-99页

作者：李凌松湖北润发集团

可编程序控制器(简称PLC)是专为在工业环境中应用而设计的一种工业控制用计算机,具有抗干扰能力强、可靠性高、体积小等优点,是实现机电一体化的理想装置,目前在机械加工行业中的应用日益广泛。本文介绍的是永宏PLC在机床数控系统中应... 详细信息

可编程序控制器(简称PLC)是专为在工业环境中应用而设计的一种工业控制用计算机,具有抗干扰能力强、可靠性高、体积小等优点,是实现机电一体化的理想装置,目前在机械加工行业中的应用日益广泛。本文介绍的是永宏PLC在机床数控系统中应用的有关控制原理与方法,分析了控制系统在设计和使用中需要认识与解决的问题,给出了控制系统方案及软硬件结构的设计思路。

关键词：可编程控制器定位控制机床数控系统