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.

在与分子生物学实验室，NCI和法国国家de la Recherche Agronomique（INRA）研究人员的联合研究中，我们正在攻击蛋白质结构分类的问题，目的是改善自动化方法以识别和分类三维结构中的蛋白质域。域被认为是复杂结构的基础，通常决定蛋白质功能。我们最近表明，与标准的手动策划蛋白质分类（SCOP）的两种不同的结构相似性度量（广大和Sheba）最多可以获得约75-80％的一致性，据说质疑蛋白质“折叠”之间存在急剧边界。 我们通过通过三种不同的方法（vast，sheba和dali）基于测量的结构相似性，通过层次聚类域（vast，sheba和dali），通过层次聚类域进行了对“ C级”或α/β蛋白领域的进一步分析。 我们发现，相对于SCOP的整体差异，自动分类彼此之间的不同几乎没有差异。 一个含义是，在识别域类别之前，可能需要识别保守的基序或核心。我们已经开发了三种相关算法，用于根据PDB中其他蛋白质中其他结构环境中相似域的复发来定义域。 从与查询结构相似的片段列表开始，算法确定是否将查询分为一个或多个域和域边界。 某些域在结构中似乎是不连续的，表明可能对与插入域相对应的基础DNA序列进行进化插入。 这些算法的测试和验证目前正在进行中。 在Fogarty International Center的国际流行病学和人口研究划分的研究人员中，我们开发了一种由宿主免疫和促红细胞生成反应缓解的疟原虫/红细胞动力学的现象学模型。寄生虫内宿主生命周期的所有阶段都纳入模型中，以及合理的人类免疫反应。介绍了一场描述这项工作先前结果的邀请演讲，并介绍了2009年暹罗动态系统会议。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对其蚊子载体的传播。特别是，我们正在研究引起人类疾病的不同疟原虫之间的传播策略差异。 与国家过敏和感染性疾病研究所的实验研究者合作，我们正在研究其蚊子向量中疟原虫寄生虫的种群生物学，尤其是基因在寄生虫种群中的传播，这可能影响寄生虫对新载体的适应性。 在有关医学生物物理学，综合生物物理学实验室，国家儿童健康与人类发展研究所以及信号处理和仪器部分，计算生物科学和工程实验室，计算生物科学中心，信息技术中心的划分的情况下，我们正在研究较大的热和流动过程中的热模型中的热量（XMD）extraction（XMD）的方法。由于NIH范围内的新计划扩展了XMD的应用程序，因此当前的建模集中于XMD设备的新配置。 2008年，其中一些工作的结果在2008年生物医学社会会议上提出。 与国家癌症研究所和CIC Biogune（西班牙毕尔巴鄂的非营利性实验室）的研究人员一起研究了基因转录的物理拓扑。这项工作是一个项目的延续，该项目始于西班牙调查员是美国国立卫生研究院（NIH）的作品后研究员。在2009年期间，一篇论文讨论了表达ZAC1蛋白的基因的mRNA优先接近核仁，即使mRNA形成了核中类似空间分布的其他转录基因，但也发表在染色体中。 研究人员在有关医学生物物理学的部分，综合生物物理学的实验室，NICHD以及信号处理和仪器部分，计算生物科学和工程实验室，计算生物科学中心，信息技术中心的划分，我们正在工作，我们正在工作，在表达微置换型（XMD）中，在表达微置换过程中发生的热和流体运输过程的模型（XMD）是一种大量的分数。 XMD表现出巨大的希望，但是需要对其运营进行更好的理论理解，然后才能在NIH核心设施中进行商业开发或充分利用。 在与NIMH的研究人员的项目中，我们分析了体外神经网络制剂的多电极记录，以推断基础的皮质网络拓扑。我们从多个电极神经元记录中观察到的雪崩动力学开发了一种用于网络重建的新算法。将此算法应用于Vitro神经网络制剂中的多电极记录，我们揭示了这些网络的新型属性，该属性在删除弱环节后显示出强大的聚类属性。仿真表明，当链路权重与相应末端节点的聚类系数相关时，这种网络体系结构会产生。描述这项工作的手稿正在准备。 在综合和医学生物物理学实验室（Limb）实验室的一个持续项目中，NICHD对观察到的轴突直径的偏斜和重尾分布进行了理论研究。我们表明，在优化通过轴突束的信息传输时，观察到的分布可能会出现。题为“ DT-MRI中的统计问题”的一章描述与该组合作完成的工作的书将出现在2009年底中的“扩散MRI：理论，方法和应用”中。 在另一个具有肢体NICHD的项目中，与光学成像技术的开发有关，我们得出了对时间门控光学成像技术中光子氟化体相互作用的影响的理论预测。用Python（Fluorofit）编写的软件工具实现了该模型，并可以有效地估算相关的生物学参数。该软件工具已提供给我们的合作者。