课程文献中心 更多>>

关键词： 妊娠   甲状腺功能减低   表观遗传学   DNA甲基化   妊娠结局   出生体重  

摘要： 目的:甲状腺激素参与调节蛋白质、脂类和碳水化合物的代谢活动,是新陈代谢、发育和生长的关键调节因子,促进胎儿的大脑和生长发育,并可影响孕妇血脂代谢水平。妊娠早期或中期母体轻微的甲状腺功能变化包括亚临床甲状腺功能减低和低甲状腺素血症都会对子代的生长发育受到不同程度影响,胎儿和新生儿具有巨大的可塑性和通过表观遗传修饰改变基因表达水平来对环境因素(营养、氧气、激素)作出反应的能力。本研究目的通过大样本流行病学研究甲状腺激素与血脂水平对妊娠结局的影响;并从表观遗传学的角度,以DNA甲基化为切入点,探索孕妇外周血和脐带血中全基因组总甲基化的改变对子代的影响,揭示表观遗传受激素影响的变化模式。方法:1.选取2018年01月至2018年12月上海交通大学医学院附属国际和平妇幼保健院和上海松江区妇幼保健院正规产检并建立围产保健档案的妊娠妇女共10574例,分析孕12-16周甲状腺激素和血脂水平的相关性,以及对妊娠结局的影响。2.收集亚临床甲状腺功能减退和甲状腺功能正常孕妇各50例,留取分娩时孕妇外周血和脐带血,ELISA法检测与孕妇外周血和脐带血DNA整体甲基化水平。采用线性回归模型研究TSH、FT4、FT3或TG与TC的关系。通过残差图评估潜在的非线性,对模型假设进行检验。采用t检验对母体及脐带血甲基化检验,比较差异性。结果:1.孕妇血清FT4水平与TG、TC水平均呈负相关(P均<0.05),较高水平FT3与TG呈正相关,与TC呈负相关(P均<0.05)。母体TSH水平与TG水平呈负相关,与TC相关性无统计学差异(P=0.79)。2.在妊娠结局上,妊娠期糖尿病组孕妇血清TSH、FT4水平降低,T3、FT3、TG、TC水平升高(P<0.05),妊娠期高血压疾病中孕妇血清FT3、TG水平升高,胎盘早剥孕妇TSH水平升高,胎膜早破的孕妇血清TC水平升高,早产的孕妇血清TG水平升高(P均<0.05)。3.在新生儿出生体重上,孕妇血清FT4水平与新生儿出生体重呈负相关,孕妇血清TG、TC均与新生儿出生体重呈正相关(P均<0.05);FT4水平降低,TG水平升高增加大于胎龄儿(LGA)风险;FT4水平升高,TG水平降低增加女婴小于胎龄儿(SGA)风险;孕妇血清FT4水平降低联合TG水平升高对新生儿出生体重呈交互作用,出生男婴的LGA风险增加(OR=1.79,95%CI(1.38,2.33))。4.孕妇亚临床甲状腺功能减低与甲状腺功能正常组之间母体外周血全基因组甲基化水平有差异,P>0.05,在脐带血中差异无统计学意义,P<0.05。结论:合理的甲状腺激素和血脂水平的控制,改善母胎结局的影响,降低后代出生SGA,LGA和巨大儿的风险;表观遗传学改变可能是妊娠期甲状功能减低孕妇发生妊娠不良结局的病理机制之一。

关键词： 糖尿病肾病   西格列汀   p38丝裂原活化蛋白激酶  

摘要： 非酒精性脂肪性肝病(non alcoholic fatty liver disease,NAFLD)业已成为全球最常见的慢性肝脏疾病,其发生发展与不良饮食、生活习惯等环境外界因素相关,但具体发病机制至今未完全阐明。表观遗传学可以解释环境因子对表型的影响,其研究主要集中于DNA甲基化、组蛋白修饰以及非编码RNA调控三个方面。越来越多的研究表明,表观遗传修饰在NAFLD的发生发展中起重要作用。

关键词： 癫痫   儿童   分子遗传学分析   全基因组测序   单核苷酸变异   拷贝数变异  

摘要： 目的:研究与遗传相关的癫痫患儿的临床特点和预后随访,对其进行全基因组测序(whole genome sequencing,WGS),分析变异基因与癫痫之间的联系,探讨临床表型与基因型的关系,探寻癫痫在分子遗传学水平的病因学机制,为明确诊断、精准治疗、遗传咨询提供理论依据。方法:2016年10月至2017年12月在深圳市儿童医院神经内科收集与遗传相关的癫痫病例333个家系样本,建立完整的家系及临床资料并进行随访,采用WGS及Sanger验证进行基因检测,分析333例癫痫患儿的临床表型、治疗、预后及基因型。结果:1、多数难治性癫痫及具有遗传背景的癫痫患儿起病年龄较小,65%于1岁以内起病,男女比例为1.45:1,30%有两种以上临床发作形式。癫痫综合征分类有West综合征71例,大田原综合征21例,Dravet综合征11例,Lennox-Gastaut综合征10例,癫痫伴慢波睡眠期持续棘慢波7例,DOOSE综合征1例,婴儿癫痫伴游走性局灶性发作1例,及未分类不明原因癫痫性脑病48例等。2、25%患儿合并有心血管系统、泌尿生殖系统、消化系统等畸形,其中5%存在多发畸形;头颅影像学结果提示56%患儿存在脑发育畸形、脑发育不良、脑萎缩等表现;81%患儿需要两种及以上抗癫痫药物治疗,20%以上患儿使用了生酮饮食;参照Engel分级,治疗疗效评价Ⅰ级为49%,有效率为67%。3、基因检测结果:158例检出候选致病单核苷酸变异(single nucleotide variants,SNV)186个,15例检出外显子拷贝数变异(copy number variants,CNV)15个,20例检出大片段CNV20个,候选致病变异检出率为54%,SNV检出率为47%,CNV检出率为10%。71例检出致病/疑似致病SNV 84个,检出率21%,其中未见文献报道的新变异45个(54%,45/84)。家系验证:de novo变异46个(55%),遗传变异18个(21%),变异来源不明20个(24%)。变异类型:错义变异104个(56%),无义变异23个(12%),移码变异35个(19%),剪接变异17(9%),其余少量为框内删除或插入、起始密码子变异、终止密码子缺失、内含子变异等共7个(4%)。4、致病/疑似致病变异检出次数在两次以上的基因分别为SCN1A、TSC2、TSC1、GNAO1、WWOX、ZEB2、BCKDK、CDKL5、PAFAH1B1、PCDH19、STXBP1、SUOX,其中变异检出率最高的前三位基因为SCN1A、TSC2及TSC1。5、推测TARS2与癫痫相关,参与了癫痫的发生发展,扩充了该基因的临床表型谱。6、9%患儿有多种基因发现,在两个基因上检出候选致病变异,或者同时检出SNV和CNV。7、本研究多次检出的复发性CNV有17p13.3、16p11.2、15q11.2、7q11.23缺失等。8、发现7q31缺失有癫痫表型,推测该CNV中FOXP2、IMMP2L、KCND2与癫痫相关,可能为该患儿癫痫的参与因素。9、发现无脑回畸形伴癫痫17例,PAFAH1B1基因点变异或缺失占比41%,是引起无脑回畸形伴癫痫的主要遗传因素。10、Mowat-Wilson综合征3例均为无义变异,推测在ZEB2蛋白上截断变异越靠前,蛋白丧失的功能域越多,临床表型越重。11、发现KCNH1、PRKCG、CHRNA2、CTSD等基因与West综合征表型相关。12、结节性硬化症患者临床异质性明显,TSC2比TSC1变异引起的临床表型更严重,预后差,基因检测为阴性的患者需注意变异嵌合体可能。13、Dravet综合征临床表型轻重与SCN1A基因变异类型及位置有关,截断变异,或错义变异位于Nav1.1通道孔区及电压敏感区对临床表型的影响较大。14、WGS确诊葡萄糖转运子Ⅰ缺乏综合征1例,吡哆醇依赖性癫痫1例,采用相应治疗后显著改善患儿预后。15、两个病例分别发现WWOX基因纯合变异及SUOX基因复合杂合变异,为家长提供遗传咨询及再生育指导。16、79例患儿曾行全外显子/基因检测包检测阴性,WGS检出致病/疑似致病SNV6个,CNV6个,致病变异检出率增加15%。结论:1、本研究候选致病变异(SNV/CNV)检出率为54%,发现了既往未见文献报道的SNV新变异45个,丰富了相关疾病的基因型谱数据库。2、本研究中CNV检出率为10%,提示CNV是癫痫重要的遗传机制之一。3、推测TARS2、FOXP2、IMMP2L、KCND2与癫痫相关,参与了患儿癫痫的发生发展,为疾病的遗传病因研究提供了方向。4、扩充了相关基因的临床表型谱,为疾病的异质性和复杂性解读提供了临床支持。5、丰富了无脑回畸形、Mowat-Wilson综合征、West综合征、结节性硬化症、Dravet综合征等疾

关键词： Medical and Health Sciences not elsewhere classified   Self Determination Theory   motivation   Self-Regulation   health behaviors   epigenetics   cortisol   TNF-alpha   endocrinology  

摘要： This thesis explored the role of motivational processes in improved human functioning. There is a large body of evidence supporting the idea that higher quality motivation can have important implications for health and well-being via improved behavioural engagement. However, what is less well understood is whether there is a direct effect of motivation on physiological health beyond that which is explained by engagement with the activity itself. The aim of this thesis was to explore associations between motivational processes and biological markers implicated with improved physical health and human functioning. The programme of research began by systematically reviewing multidimensional theories of motivation and physiological responses associated with activation of the endocrine system. Across several conceptually similar theories of motivation, it was evidenced that higher quality motivation was associated with an attenuated cortisol response in a variety of environments eliciting social-evaluative threat. Furthermore, the needs for power and affiliation were associated with lower and higher levels of salivary secretory immunoglobulin A, respectively. Based on the limitations identified in the systematic review, two subsequent chapters further explored the role of high quality motivation in reducing the cortisol response. Using an experimental design grounded in self-determination theory, Chapter Three explored the effect that manipulating autonomous and controlled motivation had on participants' cortisol responses, while concurrently measuring self-control exertion. A repeated measures ANCOVA revealed a significant quadratic interaction (F (1, 32) = 5.40, p =.027, ηp2 = .14). Participants in the controlled regulation condition experienced an increased, with autonomy supportive experiencing a decreased, cortisol response. There was also evidence of motivational effects on self-control performance, although the results contradicted the hypothesis. A mixed ANCOVA r

关键词： Biology   Genetics   Conservation biology  

摘要： The southeastern United States harbors one of the most diverse temperate fresh water fish regions of the world. Unfortunately, due to improper land use practices and habitat degradation, owed primarily to humans, many of the species in this region are imperiled and may become extinct without appropriate conservation efforts. This study looks to provide a robust analysis of the population dynamics of an endangered endemic of southwest Kentucky, the Relict Darter (Etheostoma chienense) and its sister taxa, the undescribed but recognized Clarks Darter (Etheostoma cf. oophylax). Mitochondrial sequence data coupled with SNP data were used to infer population structure, gene flow, genetic variation, and effective population sizes of both species. This study suggests that the endangered Relict Darter has low levels of genetic variation throughout its range as well as a dangerously low effective population size, likely the result of a population bottleneck and subsequent genetic drift. It is suggested that conservation efforts be taken to supply more genetic variation to the Relict Darter before it is too late. The Clarks Darter showed some genetic variation among distant sites, but more samples are needed throughout the range in order to fully understand the population dynamics of this species.

ISBN: (数字)9780128167335 ISBN: (纸本)9780128163634

摘要： Transgenerational Epigenetics, Second Edition, offers the only up-to-date, comprehensive analysis of the inheritance of epigenetic phenomena between generations with an emphasis on human disease relevance, drug discovery, and next steps in clinical translation. International experts discuss mechanisms of epigenetic inheritance, its expression in animal and plant models, and how human ailments, such as metabolic disorders and cardiovascular disease are influenced by transgenerational epigenetic inheritance. Where evidence is sufficient, epigenetic clinical interventions are proposed that may help prevent or reduce the severity of disease before offspring are born. This edition has been thoroughly revised in each disease area, featuring newly researched actors in epigenetic regulation, including long noncoding RNA in addition to histone modifications and DNA methylation. Therapeutic pathways in treating cancer and extending human longevity are also considered, as are current debates and future directions for research.

关键词： 子痫前期   Wnt2基因   发病机制   滋养细胞   细胞增殖   细胞凋亡   生物学行为   表观遗传学   甲基化  

摘要： 研究背景子痫前期(PE)是妊娠期特有的疾病,临床上以妊娠20周以后出现高血压、蛋白尿为特征,在全球范围内妊娠妇女的发病率约为2%～8%。子痫前期对母儿的危害均较大,是孕产妇及围产儿死亡率增高的主要原因之一,因此能够尽早诊断和有效治疗非常重要。子痫前期的发病机制颇为复杂,至今尚未完全阐明,目前以“子宫螺旋小动脉重铸不良、胎盘浅着床学说”最为学界所认可。该学说认为,子痫前期患者胎盘形成的早期,滋养细胞增殖及分化异常,伴凋亡过多,引起滋养细胞浸润能力下降、侵入子宫壁受限,进而引起子宫螺旋小动脉重铸不良及胎盘着床过浅,出现胎盘低血流量从而导致子痫前期的发病。妊娠的成功维持有赖于多个基因及信号转导通路的参与,越来越多的研究发现,在胎盘形成及发育过程中Wnt信号通路扮演着重要角色。Wnt2基因是Wnt基因家族的重要成员,是被识别的第二个Wnt基因。动物实验研究发现,将小鼠的Wnt2基因靶向破坏,其子代的出生体重下降,且半数于围产期死亡。另外,Wnt2基因突变导致胎儿毛细血管减少、纤维质沉积增加,并导致胎盘血管生成缺陷相关的胎盘异常。表观遗传学修饰通过改变基因组DNA对转录因子的可访问性,从而影响基因的活动。胎盘的表观遗传学调控指的是,在不改变DNA核苷酸序列的前提下,通过DNA甲基化、组蛋白修饰、RNA调控等方式来调控基因的表达,从而影响胎盘中相应蛋白的合成,以调节胎盘的发育。DNA甲基化是研究最广泛、特征最明显的表观遗传学修饰模式,人类胎盘中异常的表观遗传模式,尤其是易感基因启动子区的DNA甲基化状态的改变,与多种妊娠相关并发症的病理生理学有关。动物实验研究结果显示,双酚A导致小鼠胎盘Wnt2基因启动子区的DNA甲基化程度增加,引起Wnt2表达下调,引发小鼠出现子痫前期样综合征。我们推测在人类子痫前期的发病过程中,Wnt2基因的表观遗传学调控异常导致基因表达的变化,进而影响滋养细胞的生物学行为,可能参与了子痫前期的发病机制。本研究旨在通过对胎盘组织中Wnt2基因的表达及调控机制的研究,探讨Wnt2基因在子痫前期发病的分子机制中的发挥的可能作用,为子痫前期的临床诊断和治疗提供新的理论依据。第一部分 Wnt2基因在子痫前期患者胎盘组织中的表达的研究研究目的:研究早发型重度子痫前期患者、晚发型重度子痫前期患者及正常晚期妊娠妇女胎盘组织中Wnt2基因mRNA及蛋白的表达,探讨Wnt2基因在子痫前期发病中的作用。研究方法:1.研究对象:选取2018年1月至2018年12月在滨州医学院附属医院产科病房经剖宫产分娩的早发型重度子痫前期患者30例作为早发型重度子痫前期组(ZPE),晚发型重度子痫前期患者30例作为晚发型重度子痫前期组(WPE),随机选取同期住院经剖宫产分娩的正常晚期妊娠妇女30例作为对照组(NC)。2.实验方法:采用qRT-PCR技术检测早发型重度子痫前期患者、晚发型重度子痫前期患者及正常晚期妊娠妇女胎盘组织中Wnt2 mRNA的表达,并采用Western blot技术及免疫组织化学技术检测Wnt2蛋白的表达。研究结果:1.早发型重度子痫前期组、晚发型重度子痫前期组和对照组三组之间比较,在山东大学博士学位论文平均年龄、体重指数、胎次方面差异均无统计学意义(P>0.05)。对照组与早发型重度子痫前期二组之间比较,在分娩孕周、收缩压、舒张压、尿蛋白量、新生儿出生体重及新生儿1min Apgar评分方面,差异均有统计学意义(P<0.05)。对照组与晚发型重度子痫前期组二组之间比较,在分娩孕周、收缩压、舒张压、尿蛋白量、新生儿出生体重及新生儿1min Apgar评分方面,差异均有统计学意义(P<0.05)。早发型重度子痫前期组与晚发型重度子痫前期组二组之间比较,在收缩压、舒张压、尿蛋白量方面,差异均无统计学意义(P>0.05);在分娩孕周、新生儿出生体重及新生儿1min Apgar评分方面,差异均有统计学意义(P<0.05)。***-PCR检测结果显示早发型重度子痫前期组患者胎盘组织中Wnt2 mRNA的相对表达量低于对照组,差异有统计学意义(P<0.05);晚发型重度子痫前期组患者胎盘组织中Wnt2 mRNA的相对表达量低于对照组,差异有统计学意义(P<0.05);早发型重度子痫前期组患者胎盘组织中Wnt2 mRNA的相对表达量较晚发型重度子痫前期组低,差异具有统计学意义(P<0.05)。*** blot检测结果显示,早发型重度子痫前期组患者胎盘组织中Wnt2蛋白的表达量低于对照组,差异有统计学意义(P<0.05);晚发型重度子痫前期组患者胎盘组织中Wnt2蛋白的表达量低于对照组,差异有统计学意义(P<0.05);早发型重度子痫前期组患者胎盘组织中Wnt2蛋白的表达量较晚发型重度子痫前期组低,差异具有统计学意义(P<0.05)

关键词： Botany   Systematic biology  

摘要： Grammitids are a large monophyletic group of primarily epiphytic ferns in Polypodiaceae. Genera Oreogrammitis, Radiogrammitis and Themelium (ORT) formed a clade in grammitid phylogeny where three genera are polyphyletic in the ORT clade. A study was conducted to delineate the phylogenetic relationships of the ORT group by using intensive taxon sampling and with nine genetic markers from both nuclear and chloroplast genomes. Gene sequences were analyzed in maximum likelihood and Bayesian algorithms. Nuclear gene trees and nuclear and plastid gene trees were summarized to construct species trees under multi-species coalescent method in ASTRAL program. All the analyses with higher number of species and data revealed that the three genera are polyphyletic. Thus, taxonomic revisions are suggested. Oreogrammitis must be redefined to include Radiogrammitis and Themelium. Oreogrammitis hookeri is an endemic Hawaiian grammitid fern. It is one of the three Hawai‘i endemic Oreogrammitis species. Oreogrammitis hookeri can be found in all the major islands in Hawaiian archipelago whereas the other two species have limited distribution. Some populations of O. hookeri contain unique alleles and the species may have been undergoing incipient speciation or represent cryptic species complex. Current study was conducted to investigate the population structure of O. hookeri with populations sampled from all the major islands except Lanai. Double Digest Restriction Site Associated DNA sequencing (ddRADseq) technique was used to generate genomic data. Analysis of 176 loci in STRUCTURE program showed that there are two genotypes in O. hookeri. Populations collected from Kauaʻi and Mauna Loa, Hawai‘i is one genotype and Oʻahu and Kilauea, Hawai‘i is another genotype. Maui and Molokaʻi contain both genotypes. Incipient speciation or existence of cryptic species of O. hookeri can be ruled out because Maui-Molokaʻi genetic cluster contain both genotypes thus it supports the idea that individu

ISBN: (数字)9780128148808 ISBN: (纸本)9780128148792

摘要： Epigenetics and Regeneration compiles the first foundational reference on epigenetic mechanisms governing tissue development, repair, homeostasis, and regeneration, as well as pathways to employ these mechanisms in clinical practice and translational science. In this book, life science researchers, clinicians, and students will discover an interdisciplinary resource bringing together common themes in the field, background overviews, research methods, recent advances, and opportunities for drug discovery. Throughout this volume, special attention is paid to pre-clinical and first clinical studies aimed at increasing the regenerative potential of damaged tissues by epigenetic drugs, as well as innovative, discipline spanning strategies to enhance cell reprogramming. As an all-inclusive, evidence-based volume, Epigenetics and Regeneration will stimulate discussion and boost new research in this fascinating and impactful area of translational epigenetics.