Transcriptional Regulation of Secretase Genes in Alzheimer’s Disease

老年性痴呆(Alzheimer’sDisease,AD)是严重危害人民健康的一类神经退行性疾病。导致AD的一个关键致病原因是大脑中淀粉样蛋白（Aβ）的过度产生和堆积。Aβ是由其前体蛋白APP经β-分泌酶（BACE1）和γ-分泌酶依次水解而生成的，因此对于这些参与Aβ产生的分泌酶的研究，包括对于它们在基因表达水平上的调控研究，具有重要意义。脑缺血和中风造成大脑相关区域缺氧会使AD的发生率大大增加，但是缺氧损伤导致AD的内在机制还不清楚。在本研究中，我们发现急性缺氧可以提高BACE1的mRNA水平和蛋白水平，并使得酶活性升高，导致APPC端片段β-CTF和Aβ的产量增加。我们通过序列分析、点突变和...Deposition of beta-amyloid peptide (Aβ) in the brain is the one of the most critical pathological hallmarks in Alzheimer’s disease (AD). Aβ is generated by sequential proteolytic cleavages of beta-amyloid precursor protein (APP) by two secretases, β-secretase (BACE1) and γ-secretase. However, knowledge on transcriptional regulation of these secretase genes is limited. The incidence of AD is greatl...学位：理学博士院系专业：生命科学学院生物学系_细胞生物学学号：2162006015331

Training System Building of the Executives in A Company Based on ompetency Model

作为人力资本开发和获取的重要手段，培训被越来越多的企业用来为公司创造价值、应对竞争挑战，以及保持企业的核心竞争力。如何通过培训增加其竞争力，同时实现企业和员工的共同发展，已经成为很多企业必须面对的重大问题。 本文将A公司的164名高级管理人员作为主要研究对象，深入分析这一群体的特点以及现有培训体系的问题，提出在胜任力素质模型的基础上进行高级管理人员培训体系的构建。本文的思路是：首先建立A公司高级管理人员的胜任力素质模型，对高级管理人员的胜任力水平进行评估；其次，基于胜任力素质模型和胜任力评估确定高级管理人员的培训需求；依据培训需求，基于胜任力素质模型设计有系统性的高级管理人员培训体系；最后，...As an important means of human capital development and achieving, training has been adopted by more and more enterprises to create value ,to cope with competitive challenges and to maintain the core competitiveness of the enterprises. How to increase their core competitiveness by training ,as while as to realize the common development of enterprises and employees ,has become a major issue that man...学位：工商管理硕士院系专业：管理学院工商管理教育中心（MBA中心）_工商管理硕士(MBA)学号：1792009115088

Advances in understanding the β-amyloid precursor protein intracellular domain

老年性痴呆症(Alzheimer's disease,AD)一个重要的病理学特征,是在神经细胞外形成由β-淀粉样蛋白(β-amyloid,Aβ)组成的淀粉样斑(amyloid plaques)。β-淀粉样蛋白前体蛋白(β-amyloid procursor protein,APP)经β-分泌酶和γ-分泌酶依次水解后产生Aβ和APP胞内结构域(APP intracellular domain,AICD)。现在已经知道Aβ在AD的发病机制中起着关键作用,但是关于AICD的生理及病理功能还不清楚。近年来研究发现AICD可以与细胞内多种蛋白相互作用,而且AICD在基因转录、细胞凋亡以及APP的加工和运输过程中均有调节功能。本文针对这一领域的研究进展,对AICD的生理及病理功能进行探讨。One of the neuropathologic hallmarks of Alzheimer’s disease (AD) is the presence of senile plaques which consist of β-amyloid peptide (Aβ) in the brain. Aβ is derived from β-amyloid precursor protein (APP) through sequential cleavages by the β-secretase and the γ-secretase. In addition to Aβ, γ-cleavage releases the intracellular domain of APP (AICD). However, although it is well-established that Aβ is the prime culprit for AD pathogenesis, the physio/pathological functions of AICD remain largely elusive. Here we review recent progress toward elucidating the functional roles of AICD, which include modulating intracellular trafficking/processing of APP, inducing apoptosis, and regulating gene expression at transcriptional level.国家自然科学基金(30672198);; 福建省高等学校新世纪优秀人才支持计

基于慕课的医学生物化学实验教学方法探索

慕课是大规模网络开放课程的简称,在慕课平台上,大学名师的精彩讲授、学生的自主学习体验、师生形式多样的互动过程等被完整系统地实现。针对生物化学课程及现代化教学的特点,将慕课资源应用到教学的各个环节中,这就要求教师在生物化学课程慕课的录制过程中充分利用视频教学的特点,有针对性地开展教学。文章重点探讨了慕课在生物化学课程教学中的应用及录制时的特点,以便教师合理设置课程内容。实践证明,这种线上与线下教学模式的探索提高了学生的学习兴趣,为生物化学课程改革提供了思路。福建省教育厅中青年教师教育科研基金资助项目（JZ160069

巴茱合剂治疗老年性痴呆肾虚髓减证36例

目的观察巴茱合剂治疗老年性痴呆肾虚髓减证的临床疗效。方法选取老年性痴呆肾虚髓减证患者74例随机分为治疗组36例和对照组38例。治疗组给予巴茱合剂口服,对照组给予金匮肾气丸配合银杏叶提取物片(金纳多)口服,疗程3个月。运用阿尔茨海默病评价量表-认知部分(ADAS-cog)、简易精神状态量表(MMSE)评价患者的智能,日常生活能力量表(ADL)评价患者的日常生活能力,中医证候疗效积分评价疗效。结果治疗组总有效率为88.9%,优于对照组71.1%,2组ADAS-cog评分、MMSE评分、ADL评分、中医证候疗效积分较治疗前均有所改善(P<0.05),且治疗组ADAS-cog评分、MMSE评分、中医证候疗效积分改善优于对照组(P<0.05)。2组治疗过程中未见不良反应发生。结论巴茱合剂能够改善老年性痴呆肾虚髓减证患者中医证候、智能及日常生活能力,未见不良反应发生。福建省科技重点项目(2012D064);; 厦门市中医药科研项目(wst201208);; 福建省中医科研课题(wzln201312

Explaining public-private partnerships in China: case study of primary land development in Beijing

Public-private partnership (PPP) has been an important issue in recent decades. PPP is seen by some as a cure for inefficient and over-burdensome modern government. Yet, by observing practices in China, this research aims to answer the simple questions: why has there been a decline in PPPs? How does government decide whether or not to establish partnership with private enterprises? By investigating the case of Primary Land Development (PLD) in China especially in Beijing, this research has attempted to provide explanations mainly in relation to coordination effectiveness involving a resource interdependence theory. Logic of institutionalism is followed. External environment, key institutions and attributes of PLD field are also carefully examined to further explain the change of resources and coordination effectiveness. This research conducts longitudinal comparison of cases within one case city: Beijing. The focal level is Beijing municipal level. Three time horizons are examined, which are 2002—2004, 2005—2008, and 2009-2010. The First-hand data in this study have two main sources: in-depth interviews with key policy participants and archives acquired through fieldwork. Secondary data including statistical yearbooks, laws and policies, news, and research carried out by previous students are also employed by the research. This research examines the changes of external political and economic environment in each time horizon. It compares the coordination effectiveness between PLD policy-makers and PLD implementers and between PLD implementers and other stakeholders in PLD process within each time period. Through examining the three stages of PLD in Beijing, this research develops the following findings. First, fiscal decentralization and cadre management are two important elements shaping the incentives of policy-makers in China. Second, coordination effectiveness in two dimensions influence policy-makers in decisions related to PPP. Third, the degree and the extent of resource interdependence influences whether coordinator can employ the most suitable and effective mechanisms to coordinate. Fourth, changes to the external economic and political environment will change the incentives and policy choices of policy-makers, and also change the resources held by different actors. Fifth, coordination matters. When traditional mechanisms such as hierarchy and the market do not work well in many cases, the ability to employ new coordination mechanisms such as networks is particularly important in achieving the desired goals of coordinators. Finally, in countries like China which is dominated by political logic, the more politically significant a field is, the less likely it is that PPPs will exist.published_or_final_versionPolitics and Public AdministrationDoctoralDoctor of Philosoph

借助相变材料的能量转换系统和方法

本公开提供了一种能量转换系统和方法，用于在没有任何外部电源的情况下，通过铁电材料的相变直接从热能产生电能。能量转换系统包括电路，该电路包括相变电容器和电荷储存器。相变电容器具有包含相变铁电材料的介电层。当相变电容器初始化并且受到跨过相变铁电材料的相变温度的热循环时，介电层的极化强度在铁电相和顺电相之间产生突变，从而使得电流在相变电容器和电荷储存器之间通过负载流动，进而将热能转换为电能。本能量转换方法在能量转换过程中不需要任何外部偏置电场

润滑油水污染对齿轮热弹流润滑特性的影响研究

以渐开线直齿圆柱齿轮为研究对象，考虑热效应和时变效应，建立油水两相流模型和齿轮的热弹流润滑模型，探究了润滑油中含水率对油水两相流体的黏度及齿面润滑特性的影响。研究结果表明，润滑油中混入冷却水后，当含水率不超过5%时，随着含水率的增加，油水两相流体的黏度不断增大；含水率为5%时，油水两相流体的黏度达到其峰值，之后随着含水率的增加，油水两相流体的黏度不断减小。适当增加含水率可改善齿面的润滑特性，但考虑油膜温升及对设备的腐蚀磨损，应将含水率控制在5%以内

慕课对医学生物化学实验教学改革的启示

慕课是大规模开放式在线课程,是信息时代的新型教学模式。与传统实验教学相比,慕课具有教学理念先进、教学内容合理、教学设计科学、评价方式灵活等优势。医学生物化学实验教学需吸收和借鉴慕课的优点,转变教学理念,优化教学内容,改进教学设计,创新评价方法,提高实验教学质量。福建省教育厅中青年教师教育科研项目(JZ160069

Transcriptional Regulation of Mouse bace1 Gene by HIF-1

阿尔茨海默症的一个关键致病原因是大脑中淀粉样蛋白(Aβ)的过度产生或堆积.Aβ是由其前体蛋白APP经β-和γ-分泌酶依次水解而生成的,但对于这些分泌酶基因表达的转录调控的了解还很少.由于大脑发生缺氧/缺血会造成Aβ的产量增加,而缺氧时所激活的转录因子HIF-1(Hypoxia-Inducible Factor 1)会调控下游多种基因的表达,我们对HIF-1是否参与调控β-分泌酶的表达进行了研究.对小鼠β-分泌酶基因bace1的调控序列进行分析,发现其中含有一个缺氧应答元件(Hypoxia-Responsive Element,HRE).我们的数据显示,HRE突变片段启动报告基因荧光素酶表达的活性比正常序列片段的启动活性明显降低.电泳迁移率的变动分析(EMSA)实验进一步证实,HIF-1可以与小鼠bace1中HRE元件相互作用.当在哺乳动物细胞中过度表达HIF-1时,BACE1的mRNA水平和蛋白质水平均有明显的增高.这些结果表明小鼠bace1基因的表达受转录因子HIF-1的调控.鉴于目前阿尔茨海默症研究领域都把抑制BACE1作为首选治疗靶位,HIF-1因而有可能成为治疗AD的一种药物靶点.Deposition of beta-amyloid protein(Aβ) in the brain is one of the most critical pathological hallmarks in Alzheimer's disease(AD).Aβ is generated by sequential proteolytic cleavages of beta-amyloid precursor protein(APP) by two secretases,β-and γ-secretase.However,knowledge on transcriptional regulation of these secretase genes is limited.Since hypoxia/ischemia has been found to increase Aβ production in the brain and hypoxia is known to stimulate expression and activity of transcription factor HIF-1(hypoxia-inducible factor 1).Here,we study whether HIF-1 regulates the expression of the β-secretase gene.Sequence analysis revealed a hypoxia-responsive element(HRE) in the putative promoter region of the mouse β-secretase gene,bace1.Mutation of the HRE dramatically impaired the activity of the mouse bace1 promoter,as measured by in vitro luciferase activity assay.In addition,the electrophoretic mobility shift assay(EMSA) demonstrated a clear binding of HIF-1 to the HRE.Moreover,overexpression of HIF-1α significantly increased the level of bace1 mRNA and protein.Taken together,our results demonstrate,for the first time,that the expression of mouse bace1 is transcriptionally regulated by HIF-1,suggesting that HIF-1 may be a therapeutic target for treating AD and providing a molecular mechanism for increased incidence of AD following cerebral ischemic and stroke injuries.国家自然科学基金(30672198);; 美国国立卫生研究院研究基金(AG030197)资