Statistical And Computational Methods For Molecular Biology And Biomedicine

分子生物学和生物医学的统计和计算方法

• 批准号: 7966721
• 负责人: peter j munson
• 金额: $ 26.29万
• 依托单位: CENTER FOR INFORMATION TECHNOLOGY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7966721
• 关键词: Address; Affect; Agreement; Algorithms; Area; Biological; Biological Neural Networks; Biomedical Research; Biophysics; Book Chapters; Caliber; Cell Count; Cell Nucleolus; Cell Nucleus; Classification; Collaborations; Complex; Computer Architectures; Computing Methodologies; Core Facility; DNA Sequence; Development; Devices; Diffusion Magnetic Resonance Imaging; Electrodes; Engineering; Epidemiology; Erythrocytes; Excision; France; Genes; Genetic Transcription; Goals; Human; Imaging Techniques; Immune; Immune response; In Vitro; Information Technology; International; Investigation; Joints; Laboratories; Link; Liquid substance; Malaria; Manuscripts; Measures; Medical; Messenger RNA; Methods; Microdissection; Modeling; Molecular Biology; National Cancer Institute; National Institute of Allergy and Infectious Disease; National Institute of Child Health and Human Development; National Institute of Mental Health; Neurons; Operative Surgical Procedures; Paper; Parasites; Photons; Plasmodium; Population; Population Biology; Population Study; Preparation; Property; Proteins; Publishing; Pythons; Recurrence; Regulation; Relative (related person); Research; Research Personnel; Science; Societies; Software Tools; Spain; Spatial Distribution; Staging; Statistical Computing; Statistical Models; Structure; System; Tail; Techniques; Tertiary Protein Structure; Testing; Theoretical Studies; Time; Tissue Sample; Transport Process; United States National Institutes of Health; Validation; Weight; Work; Writing; base; computerized data processing; fluorophore; human disease; improved; instrumentation; international center; meetings; novel; optical imaging; protein folding; protein function; protein structure; reconstruction; response; simulation; symposium; theories; three dimensional structure; transmission process; vector; vector mosquito

In a joint study with investigators in Laboratory of Molecular Biology, NCI and Institut National de la Recherche Agronomique (INRA), France, we are attacking the problem of protein structure classification, with the goal of improving automated methods for recognizing and classifying protein domains in three dimensional structures. Domains are thought to be the building blocks of complex structures, and often determine protein function. We have recently shown that two distinct structure similarity measures (VAST and SHEBA) can obtain at best about 75-80% agreement with a standard manually curated protein classification (SCOP), calling into question the existence of sharp boundaries between protein "folds". We have published a further analysis of "C-class" or alpha/beta protein domains, by hierarchically clustering domains based on measured structural similarity by three different methods (VAST, SHEBA and DALI). We found that automatic classifications differ little from each other, relative to their overall differences from SCOP. One implication is that identification of conserved motifs or cores may be necessary before identifying domain classes. We have developed three related algorithms for defining domains based on recurrence of similar domains in other structural contexts in other proteins in the PDB. Starting with a list of similar fragments to the query structure, the algorithms determine whether to divide the query into one or multiple domains, and the domain boundaries. Some domains appear to be discontinuous within the structure, indicating a possible evolutionary insertion of the underlying DNA sequence corresponding to the inserted domain. Testing and validation of these algorithms is currently underway. With an investigator in the Division of International Epidemiology and Population Studies, Fogarty International Center, we have developed a phenomenological model of Plasmodium/red blood cell dynamics moderated by host immune and erythropoietic responses. All stages of the parasite's intra-host lifecycle are incorporated in the model, along with plausible human immune responses. An invited talk describing previous results of this work was presented the 2009 SIAM Conference on Dynamical Systems. We are studying how regulation of parasitmia by both host and parasite factors affects transmissibility of the parasite to its mosquito vector; in particular, we are studying the difference in transmission strategies between the different Plasmodium species which cause human disease. Working with experimental investigators in the Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, we are studying the population biology of Plasmodium parasites within their mosquito vectors, particularly, the spread of genes in the parasite population which might affect the adaptability of the parasite to new carriers. With investigators in the Section on Medical Biophysics, Laboratory of Integrative Biophysics, National Institute of Child Health and Human Development, and with the Signal Processing and Instrumentation Section, Computational Bioscience and Engineering Laboratory, Division of Computational Bioscience, Center for Information Technology, we are working on model of the thermal and fluid transport processes that occur in the operation of expression microdissection (xMD), a method of extracting large number of cells of specific types from a tissue sample. Because of a new NIH-wide initiative to expand applications of the xMD, the current modeling focuses on new configurations of the xMD device. In 2008 results of some of this work were presented at the 2008 Meeting of the Biomedical Society. With investigators with the National Cancer Institute and CIC BioGune (a non-profit laboratory in Bilbao, Spain), investigated the physical topology of gene transcription. This work is a continuation of a project that started when the Spanish investigator was a post-doctorial fellow here at NIH. During 2009 a paper discussing the result that the mRNA from the gene which expresses Zac1 protein was preferentially close to the nucleolus, even though mRNA form other transcribing genes of similar spatial distribution in nuclei were not, was published in Chromosoma. With investigators in the Section on Medical Biophysics, Laboratory of Integrative Biophysics, NICHD, and with the Signal Processing and Instrumentation Section, Computational Bioscience and Engineering Laboratory, Division of Computational Bioscience, Center for Information Technology, we are working of a model of the thermal and fluid transport processes that occur in the operation of expression microdissection (xMD), a newly developed method of extraction large number of cells from a tissue sample. xMD shows great promise, but a better theoretical understanding of its operations is needed before it can commercially developed or be fully exploited in an NIH core facility. In a project with investigators of NIMH, we analyzed multiple-electrode recordings from in-vitro neural network preparations in order to deduce the underlying cortical network topology. We developed a new algorithm for network reconstruction from the observed avalanche dynamics in multiple electrode neuronal recordings. Applying this algorithm to the multiple-electrode recordings from in-vitro neural network preparations we revealed a novel property of these networks which show robust clustering properties upon removal of the weak links. Simulations indicate that such network architecture results when the link weights are correlated with the clustering coefficients of the respective end nodes. A manuscript describing this work is in preparation. In a continuing project with investigators in the Laboratory of Integrative and Medical Biophysics (LIMB), NICHD we conduct a theoretical study of the observed skewed and heavy-tailed distribution of the axonal diameters. We show that the observed distribution can arise when optimizing the information transfer through axonal bundles. A book chapter titled "Statistical Issues in DT-MRI" describing the work done in collaboration with this group will appear in "Diffusion MRI: Theory, Methods and Applications" late in 2009. In another project with LIMB, NICHD, related to the development of the optical imaging techniques we derived theoretical predictions for the effects of the photon-fluorophore interactions in the time-gated optical imaging techniques. A software tool written in Python (Fluorofit) implements this model and enables efficient estimation of the relevant biological parameters. This software tool has been made available to our collaborators.

在与美国国家癌症研究所分子生物学实验室和法国国家农业研究所 (INRA) 的研究人员进行的一项联合研究中，我们正在解决蛋白质结构分类问题，目标是改进在三维结构中识别和分类蛋白质结构域的自动化方法。结构域被认为是复杂结构的组成部分，并且通常决定蛋白质功能。我们最近表明，两种不同的结构相似性度量（VAST 和 SHEBA）最多可以与标准手动策划的蛋白质分类 (SCOP) 获得约 75-80% 的一致性，这对蛋白质“折叠”之间是否存在清晰的边界提出了质疑。 我们发表了对“C 类”或 α/β 蛋白结构域的进一步分析，通过基于三种不同方法（VAST、SHEBA 和 DALI）测量的结构相似性对结构域进行分层聚类。 我们发现，相对于 SCOP 的整体差异，自动分类彼此之间差异不大。 一个暗示是，在识别结构域类别之前，可能需要识别保守基序或核心。我们开发了三种相关算法，用于根据 PDB 中其他蛋白质的其他结构上下文中相似域的重复来定义域。 从与查询结构相似的片段列表开始，算法确定是否将查询划分为一个或多个域以及域边界。 一些结构域在结构内似乎是不连续的，表明与插入结构域相对应的基础 DNA 序列可能是进化插入的。 这些算法的测试和验证目前正在进行中。 我们与福格蒂国际中心国际流行病学和人口研究部门的一名研究人员合作，开发了一种由宿主免疫和红细胞生成反应调节的疟原虫/红细胞动力学现象学模型。寄生虫在宿主内生命周期的所有阶段以及合理的人类免疫反应都纳入模型中。 2009 年 SIAM 动力系统会议上进行了一场受邀演讲，描述了这项工作的先前成果。我们正在研究宿主和寄生虫因素对寄生虫的调节如何影响寄生虫向其蚊媒的传播能力；特别是，我们正在研究引起人类疾病的不同疟原虫物种之间传播策略的差异。 我们与国家过敏和传染病研究所疟疾和媒介研究实验室的实验研究人员合作，正在研究蚊子媒介中疟原虫寄生虫的种群生物学，特别是寄生虫种群中基因的传播，这可能会影响寄生虫对新载体的适应性。 我们与国家儿童健康和人类发展研究所综合生物物理实验室医学生物物理学科的研究人员以及信息技术中心计算生物科学部计算生物科学和工程实验室信号处理和仪器科的研究人员一起，研究表达显微切割（xMD）操作中发生的热和流体传输过程的模型，表达显微切割是一种从组织样本中提取大量特定类型细胞的方法。由于 NIH 范围内的一项新举措旨在扩展 xMD 的应用，当前的建模重点是 xMD 设备的新配置。 2008 年，部分研究成果在生物医学会 2008 年会议上公布。 与国家癌症研究所和 CIC BioGune（西班牙毕尔巴鄂的非营利实验室）的研究人员一起，研究了基因转录的物理拓扑。这项工作是西班牙研究者在 NIH 担任博士后研究员时启动的一个项目的延续。 2009 年，《Chromosoma》发表了一篇论文，讨论了表达 Zac1 蛋白的基因的 mRNA 优先靠近核仁的结果，尽管细胞核中具有相似空间分布的其他转录基因的 mRNA 并非如此。 我们与 NICHD 综合生物物理实验室医学生物物理学科的研究人员以及信息技术中心计算生物科学部计算生物科学和工程实验室信号处理和仪器科的研究人员一起，研究表达显微切割 (xMD) 操作中发生的热和流体传输过程的模型，这是一种新开发的从组织样本中提取大量细胞的方法。 xMD 显示出巨大的前景，但在进行商业开发或在 NIH 核心设施中充分利用之前，需要对其操作有更好的理论理解。 在与 NIMH 研究人员合作的一个项目中，我们分析了体外神经网络制剂的多电极记录，以推断潜在的皮层网络拓扑。我们根据多电极神经元记录中观察到的雪崩动力学开发了一种新的网络重建算法。将该算法应用于体外神经网络制剂的多电极记录，我们揭示了这些网络的一个新特性，该特性在去除弱链接后显示出强大的聚类特性。模拟表明，当链路权重与相应端节点的聚类系数相关时，就会产生这种网络架构。描述这项工作的手稿正在准备中。 在与 NICHD 综合与医学生物物理实验室 (LIMB) 的研究人员一起进行的一个持续项目中，我们对观察到的轴突直径的倾斜和重尾分布进行了理论研究。我们表明，当通过轴突束优化信息传输时，可能会出现观察到的分布。题为“DT-MRI 中的统计问题”的书籍章节描述了与该小组合作完成的工作，该章节将出现在 2009 年底的“扩散 MRI：理论、方法和应用”中。 在与 LIMB、NICHD 合作的另一个与光学成像技术开发相关的项目中，我们对时间选通光学成像技术中光子-荧光团相互作用的影响进行了理论预测。用 Python 编写的软件工具（Fluorofit）实现了该模型，并能够有效估计相关生物参数。该软件工具已提供给我们的合作者。