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关键词： 面部遗传学   人脸图像   解剖学   结构划分  

摘要： 每天生活在形形色色人脸的海洋中，人与人之间的身份识别、相互交往、情感表达等方面都依赖于从面部解析信息。相关研究表明人脸具有很高的遗传性，高达80％以上，但是目前识别出的面部形态相关的遗传因子寥寥无几。仅有的关于人脸遗传学结构的研究主要集中在欧裔、非洲人群，对中国汉族人群的研究相对较少。在第一个研究课题中，采集了～3000人的泰州汉族人群，从传统的距离和角度以及以解剖学结构划分的不同面部区域两个角度定义表型，采用多重线性回归分析(MLR)和偏最小二乘回归分析(PLSR)的方法进行全基因组关联分析。共鉴别出6个基因区域(SOX9、PISRT1、DCHS2/SFRP2、HOXD1/MTX2、STK3、VPS13B)，其中是SOX9、DCHS2/SFRP2、HOXD1/MTX2、VPS13B基因区域在之前文章中被报导过。PISRT1与眼睛部位相关（最显著的P值为1.73×10-10），其余基因区域均与鼻子部位相关（最显著的P值为2.15×10-12）。第二个研究课题在～600人的维族男性样本中重构DNA预测面部形态模型，并对该模型从不同层次上进行评估。其结果显示:(1)在独立样本中的真实人脸与预测人脸之间的相似性显著高于真实人脸与随机人脸的相似性（RGF:p=3.90×10-4;RAF:p=1.11×10-8）。(2)在“n选1”的法医场景模拟实验中，基于预测模型的识别准确率显著高于随机状态下的识别准确率;以n=5为例，识别准确率相较于随机状态下的20％，提升至30％(p=9.8×10-5)。(3)在人眼评估实验中，基于人眼识别的平均准确率为23.72％，显著高于随机情况下的20％(p=1.70×10-23)。以上综合论证了目前所构造的预测模型具有一定的预测效力。这是目前已知的基于DNA预测人脸最为精准的模型，也是首次采用人眼识别的手段评估模型。不同于眼色、肤色等单变量表型的预测，对于人的面部形态这一表型面临着基因复杂性和表型复杂性的双重考验，构建其预测模型极其困难。而一旦成功，将会对法医刑侦、溯祖研究、医学等方面产生广泛而深刻的影响。

关键词： 颅内动脉瘤   形成   遗传学   研究  

摘要： 颅内动脉瘤是导致自发性蛛网膜下腔出血的主要原因,该病致残率和致死率高。目前颅内动脉瘤的发病机制仍不能完全清楚,它的形成是由遗传学、多种后天因素综合作用的结果。遗传因素可导致部分动脉瘤的形成已获得共识,现主要从遗传学方面就有关颅内动脉瘤的研究进展

关键词： Bioengineering   Bioinformatics  

摘要： Gathering information on DNA activity during development remains problematic as DNA regulation continues to periodically change, creating unknown downstream variations in final cell heterogeneity. The fluidity and complexity create extreme difficulty and impedes understanding of the process of epigenetics. Enormous amounts of modifications happen within DNA replication; current research only begins to realize the significance of histone modifications, the role they play in mRNA expression and epigenetics of cell fate. With approximately 3 billion base pairs, histone modifications are nearly endless, each one can change the regulation of DNA in diverse ways, silencing or enhancing the expression of the DNA. With current analyses, such as Chromatin immunoprecipitation sequencing (ChIP-Seq), the ability to utilize high-powered computing and differing downstream analysis techniques, insightful observations can help realize the complexities of epigenetics and reprogramming. We converted raw ChIP-seq data from Cacchiarelli, et al. into heatmaps and developed computing techniques to analyze six histone modifications through reprogramming with different sets of transcription factors. Heatmaps were generated and sorted two dissimilar ways for visualization. Some histone modifications depicted their typical roles while we saw some interesting clusters that developed over time. We were also able to discover which genes had the biggest peak enrichment differential. With insight into how each histone modification acts on the DNA over time and how certain promoters change expression, methods for mechanisms and stimulus affecting the expression and speed of reprogramming can be determined. This can then lessen reprogramming time and further enhance the importance of epigenetics in cell fate.

关键词： Molecular biology   Medicine   Pathology  

摘要： Homogeneous populations of mature differentiated primary cell types can display variable responsiveness to extracellular stimuli, though little is known about the underlying mechanisms that govern such heterogeneity at the level of gene expression. Here we show that morphologically homogenous human endothelial cells exhibit heterogeneous expression of VCAM1 after TNFα stimulation. Variability in VCAM1 expression was not due to heterogeneity of intracellular signal transduction, but rather to preexisting established heterogeneous states of promoter DNA methylation that were generationally conserved through mitosis. Variability in DNA methylation of the VCAM1 promoter resulted in graded RelA and RNA polymerase II binding that gave rise to a distribution of VCAM1 transcription in the population after TNFα stimulation. Microarray analysis and single cell RNA sequencing revealed that a number of cytokine-inducible genes shared this heterogeneous response pattern. These results show that heritable epigenetic heterogeneity is fundamental in inflammatory signalling and highlight VCAM1 as a metastable epiallele.

摘要： The multi-subunit BAF (SWI/SNF) complex is capable of using energy generated from ATP hydrolysis to reorder chromatin structure. Such chromatin changes are known to affect cell biological processes through gene expression regulation. Thus, BAF complex plays pivotal roles in many developmental event. As a focus of the studies present, we identified the BAF complex as a powerful regulator of coticogenesis and embryogenesis. In this study, we employed a novel mouse model system in which deletion of the BAF complex subunits BAF155 and BAF170 results in proteomic degradations of the entire BAF complex and resultant loss of its epigenetic function. The first part of the thesis, highlights how the BAF complex stability is dependent on the dual presence of the scaffolding subunits BAF155 and BAF170, and the disturbance in the H3K27me2/3 epigenetic landscape when they are ablated specifically in the forebrain under the control Foxg1-Cre activity or in the entire embryo using the ubiquitous-inducible CAG-Cre. Preliminary evidence of the involvement of BAF complex in cortical development was thus obtained in the first part of the studies. In the second part, we gathered conclusive evidence on how the BAF complex regulates cortical and hippocampal development. Our investigation in the dcKO_hGFAP_Cre developing cortex revealed the BAF complexes induces heterochromatin state at gene loci involved in neural progenitor proliferation and Wnt signaling; leading to their suppression. On the other hand, the BAF complex enhances the transcription of neuronal differentiation-related genes by promoting euchromatin formation at associated genomic regions. Together, we reported that the activity of the BAF complex ensures the appropriate proliferative capacity of neural progenitors and their neuronal output in late cortical development.

关键词： Neurosciences   Bioinformatics  

摘要： Decline in cognitive function is a characteristic of brain aging and may lead to the development of more severe neurodegenerative diseases. While aging has been implicated as the main risk factor for the development of these diseases, a gap remains in the understanding of the exact molecular and cellular mechanisms promoting the development of cognitive aging. DNA modifications are malleable epigenetic marks required for central nervous system development and remain dynamically regulated in the adult brain. The most well-studied DNA modification is DNA methylation, which often occurs in CpG context, but in the neurons is present at relatively high levels in non-CpG context as well. Loss of epigenetic homeostasis is proposed as a hallmark of aging. Specifically, changes in DNA methylation are associated with aging and a subset of those can be used to predict chronological age. In addition, aberrant regulation of DNA methylation is also observed in neurodegenerative disease. Nevertheless, the relationship between DNA methylation and brain aging remains associative with very little knowledge on non-CpG methylation. Furthermore, the functional role of DNA methylation changes with aging is unknown and is constrained by the complexity of gene transcription regulation by DNA methylation. By utilizing different bisulfite sequencing approaches and applying them to both male and female mice we demonstrate that age-related alteration in DNA methylation occur at specific loci across the genome, rather than globally decrease has been previously proposed. These changes to methylation are sex-specific and are abundant in non-CpG context. Additionally, by perturbing the aging process using calorie-restriction, an established anti-aging intervention, we show that age-related alteration to DNA methylation in the brain can be prevented and that calorie-restricted specific changes may contribute to maintaining epigenetic homeostasis by regulating the DNA methylation machinery. Lastly,

关键词： G9a   G9a抑制剂   吲哚衍生物   虚拟筛选  

摘要： 目的:面对日益恶化的环境和越来越大的生活压力,癌症的发病率在逐年攀升,寻找疗效确切的抗肿瘤药物刻不容缓。研究表明,蛋白甲基转移酶异常表达会导致组蛋白甲基化模式失衡并广泛促进人类癌症的发生发展。其中以组蛋白甲基转移酶(HMTs),特别是G9a(常染色质组蛋白赖氨酸N-甲基转移酶,EHMT2)为靶点的抗肿瘤药物研究为当前的研究热点。然而,目前G9a抑制剂的研究仍处于基础研究阶段,尚未有G9a抑制剂进入临床研究的报道。本课题研究目的是利用虚拟筛选的工作基础,寻找新型的G9a活性先导化合物,并进一步通过计算机辅助药物设计方法设计并合成相应的系列结构衍生物,通过抗肿瘤活性评价及构效关系分析,设计合成具有更高活性和选择性的G9a抑制剂,进而拓展G9a抑制剂的结构类型,为下一代抑制剂的研发提供了借鉴意义。目前,目标化合物的合成及抗肿瘤活性初步筛选工作已完成,目标化合物对G9a靶向性及机制研究正在进行中。方法:1、计算机虚拟筛选及先导化合物的确定利用虚拟筛选相关专业软件,根据G9a晶体结构(PDB:4NVQ)及其配体初步建立G9a药效团模型,并从Chembridge数据库中筛选出一定数量的小分子化合物,并将其对接到G9a蛋白受体上,最后选择结构差异较大且打分函数在一定的范围内的候选分子共50个作为研究对象。并对其抗H1299细胞株增殖活性进行评价及验证;选择药效团评价指数较高且初筛活性评价较突出的化合物作为先导化合物。2、基于先导化合物的结构优化设计及合成综合分析对接模型,对先导化合物的结构优化设计并设计合成路线。本文吲哚或3-氯甲氧基茴香醛为原料,经维尔斯迈尔—哈克反应、亨利反应等步骤,合成关键中间体,最后经皮克特—施彭格勒反应合成两个系列目标化合物共30个吲哚类生物碱。目标化合物的结构经高分辨质谱(MS)、核磁共振氢谱(1H-NMR)、核磁共振碳谱(13C-NMR)确证。3、目标化合物活性评价通过SRB法检测30个目标化合物的抗肿瘤活性。该方法以人非小细胞肺癌细胞H1299为测试细胞株,以G9a抑制剂BIX01294、UNC0642为阳性药,以化合物对细胞增殖的抑制率,评价化合物抗肿瘤活性。结果:1、通过虚拟筛选得到具有G9a抑制潜力的50个化合物,在10μM初筛浓度下,阳性药BIX01294和UNC0642的H1299抑制率分别为92.8%、76.7%;而候选化合物11687、27368和46490抑制率分别为95.5%、72.9%、68.8%,与阳性药抑制活性相当。进一步测定化合物11687、27368、46490半数抑制浓度IC50分别为2.99±0.26μM,7.81±1μM、小于0.78μM。综合药效团评价指数和抗增殖活性初筛结果,以化合物27368作为先导化合物。2、本文共合成30个吲哚类小分子化合物,本课题共设计合成了 42个中间体及30个目标化合物,经scifinder检索其中42个化合物未见报道。其中化合物1、2、3、4、13、14、15、16、17、19、22、23、24、25、26 对非小细胞肺癌 H1299 具有明显的抑制作用。结论:利用虚拟筛选确定G9a抑制剂的先导化合物,并进一步通过计算机辅助药物设计方法,优化设计并合成相应的系列结构衍生物30个,并对它们进行了结构表征;通体外抗肿瘤活性筛选实验发现化合物1、2、3、4、13、14、15、16、17、19、22、23、24、25、26对非小细胞肺癌H1299具有明显的抑制作用。以上结果为进一步G9a抑制剂的研究提供参考价值。

关键词： kappa opioid receptor   addiction   biased agonist  

摘要： Endogenous opioids mediate both analgesic and affective responses to stress. While the mu opioid receptor (MOR) produces the reinforcing euphoric effects responsible for the high abuse potential of traditional opioid analgesics, the kappa opioid receptor (KOR) is hypothesized to mediate the dysphoric component of stress. With increasing rates of opioid addiction, extensive research efforts are focused on better understanding each of these systems and how they interact, with the goal of developing less addictive pain management strategies and better approaches to addiction treatment. With this in mind, we conducted both clinical and pre-clinical studies aimed at developing better treatment strategies for opioid use and the management of patients with opioid use disorder (OUD). First, we assessed a local cohort of patients with (OUD) for a collection of single nucleotide polymorphisms (SNPs) related to reward processing, with the goal of furthering efforts to develop a gene-based screening mechanism for OUD risk assessment. Second, we conducted preclinical assessments of the G protein-biased KOR agonist nalfurafine as a potential adjuvant medication for increasing the therapeutic efficacy of opioid-based analgesia. Genetic analysis of OUD patients identified two SNPs within the gene encoding the mu opioid receptor, one SNP within the gene encoding the serotonin 2B (5-HT2B) receptor, and one SNP within the gene encoding Regulator of G protein Signaling 2 (RGS2), with the frequency of each SNP varying significantly from that observed in reference populations of European descent. Preclinical investigations with nalfurafine use in mice demonstrated a greater analgesic synergy when co-administered with morphine than morphine co-administered with the unbiased KOR agonist U50,488. As G protein-biased KOR agonists are hypothesized to produce less dysphoria (a therapeutically limiting side effect of KOR agonists), they may present a viable method for reducing the dose of MOR-t

关键词： 辽东栎   蒙古栎   转录组   EST-SSR   槲栎组   群体遗传  

摘要： 栎属隶属于壳斗科,该属物种种类繁多,广泛地分布于北半球,且大部分物种都是森林中较常见的优势种和建群种,有着重要的经济和社会价值。栎属物种之间的形态特征错综复杂,分布区重叠,物种之间的杂交普遍发生,种间界限很难划定,系统发育关系存在诸多的问题。中国作为栎属植物的起源地之一,且属内的多个物种都是中国特有种,相比较欧洲与美洲对于栎属植物的大量研究,我国对于栎属物种的研究相对较少,所以对于中国栎属的研究有着极其重要的意义。本研究首先对中国栎属植物中分布最北缘的蒙古栎和辽东栎进行比较转录组分析,并开发出适合于栎属研究的通用EST-SSR引物,在此基础上开展中国栎属槲栎组11个物种的群体遗传学研究,以期探讨槲栎组的遗传结构和种间关系。现将主要研究结果总结如下:(1)辽东栎和蒙古栎的比较转录组分析及相关的EST-SSR引物开发本研究通过比较转录组的方法对栎属槲栎组的辽东栎和蒙古栎两个近缘物种进行比对分析,基于Illumina双末端测序技术获得了辽东栎和蒙古栎的转录组数据,总计产生约2400万个Reads,两物种组装后共获得103,618个Unigenes。通过对两个物种的比较转录组分析共鉴定出12,981个直系同源基因。根据对Ka/Ks值的估计和富集分析,有1179个(9.08%)的同源基因受到了强烈的正选择作用,其中大部分的同源基因是与“DNA修复”、“响应寒冷”和“响应干旱”等功能相关。这一发现可能为这两个关系密切的栎属物种在适应干旱和寒冷等极端环境时的差异提供了一些解释。根据Ks值的分布估算出两种栎属植物的分歧时间,大约是4.27-5.93 Mya。通过转录组数据检测到16,608个SSR位点,成功设计12,363对引物。随后,随机选取158对引物进行多态性的检测,有77对引物至少在槲栎组11个种的其中一个种中是多态的。(2)栎属槲栎组的群体遗传学初步研究基于槲栎组11个种92居群1672个体,2个外类群28个体,总计1700栎属植物个体,通过从转录组研究中开发的77对引物中筛选出的19对高多态性引物,对槲栎组的群体遗传学进行初步研究。基于EST-SSR引物的研究结果显示槲栎组11个种的遗传多样性水平较低(Hs=0.401,Ht=0.501)。AMOVA分析的结果表明遗传变异主要是发生在居群内(88.55%)。整个槲栎组物种水平上的遗传分化不显著(Fst=0.11),说明基因流是槲栎组居群遗传结构的主要影响因素。STRUCTURE聚类分析的结果表明槲栎组11个种的杂交现象非常严重,几乎没有完整一个种可以分化出来。对于云南波罗栎和槲树总是聚到同一分组的现象,支持前人将两者合并为同一物种的观点。

关键词： 高中   生物学   遗传学   解题方法研究  

摘要： 高中生物学属于生命科学的范畴,也是与日常生活联系最紧密、实用性最强的学科之一.高中生物学是理科高考的必考科目之一,而遗传学在高中生物学中占据着最重要的地位,也是高考必考知识点.但是由于高中生物遗传学需要的逻辑性与理解能力比较强,并且遗传学涉及到许多遗传学实验与高端前沿科学,因此许多学生似乎理解了生物知识,但其解题能力却不够,导致生物学考试成绩不够理想.本文将针对高中生物遗传学的解题方法进行分析.