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Single Mutations in Tau Modulate the Populations of Fibril Conformers through Seed Selection†

Angewandte Chemie 2014年第6期126卷

作者： Virginia Meyer Paul D. Dinkel Yin Luo Xiang Yu Guanghong Wei Jie Zheng Gareth R. Eaton Buyong Ma Ruth Nussinov Sandra S. Eaton Martin Margittai Department of Chemistry and Biochemistry University of Denver Denver CO 80208 (USA) State Key Laboratory of Surface Physics Key Laboratory for Computational Physical Sciences (MOE) and Department of Physics Fudan University Shanghai (P. R. China) Department of Chemical & Biomolecular Engineering The University of Akron Akron OH 44325 (USA) Leidos Biomedical Research Inc. Cancer and Inflammation Program National Cancer Institute Frederick National Laboratory Frederick MD 21702 (USA) Sackler Institute of Molecular Medicine Department of Human Genetics and Molecular Medicine Sackler School of Medicine Tel Aviv University Tel Aviv 69978 (Israel)

Seeded conversion of tau monomers into fibrils is a central step in the progression of tau pathology in Alzheimer’s disease and other neurodegenerative disorders. Self‐assembly is mediated by the microtubule binding repeats in tau. There are either three or four repeats present depending on the protein isoform. Here, double electron‐electron resonance spectroscopy was used to investigate the conformational ensemble of four‐repeat tau fibrils. Single point mutations at key positions in the protein (ΔK280, P301S, P312I, D314I) markedly change the distribution of fibril conformers after template‐assisted growth, whereas other mutations in the protein (I308M, S320F, G323I, G326I, Q336R) do not. These findings provide unprecedented insights into the seed selection of tau disease mutants and establish conformational compatibility as an important driving force in tau fibril propagation.

关键词： Alzheimer‐Krankheit ESR‐Spektroskopie Konformationsanalyse Proteine Tau‐Fibrillen

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A Full Eulerian Fluid-Membrane Coupling Method with a Smoothed Volume-of-Fluid Approach

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Communications in computational Physics 2012年第7期12卷 544-576页

作者： Satoshi Ii Xiaobo Gong Kazuyasu Sugiyama Jinbiao Wu Huaxiong Huang Shu Takagi Department of Mechanical Engineering The University of Tokyo7-3-1 Hongo Bunkyo-kuTokyo113-8656Japan Department of Engineering Mechanics NAOCEShanghai Jiaotong UniversityShanghai 200240China LMAM&School of Mathematical Sciences Peking UniversityBeijing 100871China Department of Mathematics and Statistics York University4700 Keele StreetTorontoOntarioCanada Computational Science Research Program RIKEN2-1 Hirosawa WakoSaitama351-0198Japan.

A novel full Eulerian fluid-elastic membrane coupling method on the fixed Cartesian coordinate mesh is proposed within the framework of the volume-of-fluid *** present method is based on a full Eulerian fluid-(bulk)structure coupling solver(Sugiyama et al.,***.,230(2011)596–627),with the bulk structure replaced by elastic *** this study,a closed membrane is considered,and it is described by a volume-of-fluid or volume-fraction information generally called VOF function.A smoothed indicator(or characteristic)function is introduced as a phase indicator which results in a smoothed VOF *** smoothed VOF function uses a smoothed delta function,and it enables a membrane singular force to be incorporated into a mixture momentum *** order to deal with a membrane deformation on the Eulerian mesh,a deformation tensor is introduced and updated within a compactly supported region near the *** the neo-Hookean and the Skalak models are employed in the numerical simulations.A smoothed(and less dissipative)interface capturing method is employed for the advection of the VOF function and the quantities defined on the *** stability restriction due to membrane stiffness is relaxed by using a quasi-implicit *** present method is validated by using the spherical membrane deformation problems,and is applied to a pressure-driven flow with the biconcave membrane capsules(red blood cells).

关键词： Fluid-membrane interaction Eulerian formulation Cartesian mesh volume-of-fluid quasi-implicit approach red blood cell

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103 Probing DNA shape and methylation state on a genomic scale with DNase I

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Journal of Biomolecular Structure and Dynamics 2013年第SUPP 1期31卷 65页

作者： Allan Lazarovici[a][b] Tianyin Zhou[c] Anthony Shafer[d] Ana Carolina Dantas Machado[c] Richard Sandstrom[d] Peter J. Sabo[d] Yan Lu[c] Remo Rohs[c] John A. Stamatoyannopoulos[d] & Harmen J. Bussemaker[b][e][*] [a] Department of Electrical Engineering Columbia University New York NY 10027 USA [b] Department of Biological Sciences Columbia University New York NY 10027 USA [c] Molecular and Computational Biology Program Departments of Biological Sciences Chemistry and Physics and Astronomy University of Southern California Los Angeles CA 90089 USA [d] Departments of Genome Sciences and Medicine University of Washington Seattle WA 98195 USA [e] Center for Computational Biology and Bioinformatics Columbia University New York NY 10032 USA Phone: Phone: (212) 854-9932 Fax: Phone: (212) 854-9932

DNA binding proteins find their cognate sequences within genomic DNA through recognition of specific chemical and structural features. Here, we demonstrate that high-resolution DNase I cleavage profiles can provide detailed information about the shape and chemical modification status of genomic DNA. Analyzing millions of DNA-backbone hydrolysis events on naked genomic DNA, we show that the intrinsic rate of cleavage by DNase I closely tracks the width of the minor groove. Integration of these DNase I cleavage data with bisulfite sequencing data for the same cell type genome reveals that the cleavage directly adjacent to CpG dinucleotides is enhanced at least eight-fold by cytosine methylation. This phenomenon we show is attributable to methylation-induced narrowing of the minor groove. Furthermore, we demonstrate that it enables simultaneous mapping of DNase I hypersensitivity and regional DNA methylation levels using densein vivocleavage data. Taken together, our results suggest a general mechanism through which CpG methylation can modulate protein–DNA interaction strength via the remodeling of DNA shape.

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Distinct mechanisms of FAK mechanoactivation by different extracellular matrix proteins

Distinct mechanisms of FAK mechanoactivation by different ex...

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第五届中美生物医学工程暨海内外生物力学学术研讨会

作者： Jihye Seong Arash Tajik Jie Sun Jun-Lin Guan Martin J.Humphries Susan E.Craig Asha Shekaran Andres J.Garcia Ning Wang Yingxiao Wang Neuroscience Program University of IllinoisUrbana-ChampaignUrbanaIL61801USA Department of Mechanical Science and Engineering University of IllinoisUrbana-ChampaignUrbanaIL61801USA Department of Bioengineering & Beckman Institute for Advanced Science and Technology University of IllinoisUrbana-ChampaignUrbanaIL61801USA Division of Molecular Medicine and Genetics Departments of Internal Medicine and Cell & Developmental BiologyUniversity of Michigan Medical SchoolAnn ArborMI48109USA Wellcome Trust Centre for Cell-Matrix Research Faculty of Life SciencesUniversity of ManchesterManchesterUK Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience Georgia Institute of TechnologyAtlantaGA30332USA Department of Biomedical Engineering School of Life Science and TechnologyHuazhong University of Science and Technology Department of Integrative and Molecular Physiology Center for Biophysics and Computational BiologyInstitute for Genomic BiologyUniversity of IllinoisUrbana-ChampaignUrbanaIL61801USA Department of Bioengineering University of CaliforniaSan DiegoCA92093USA

Introduction Cells can sense and respond to the mechanical microenvironment by converting forces into biochemical signals inside the cells,*** adhesions are the major sites of interaction between a cell and its extracellular matrix(ECM) microenvironment, thus outside mechanical signals can be sensed at focal adhesions through transmembrane receptor *** particular,it has been shown that matrix elasticity can control the cell fate

关键词： FAK Distinct mechanisms of FAK mechanoactivation by different extracellular matrix proteins ECM

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Radiological characteristics of charged particle interactions in the first clay-nanoparticle dichromate gel dosimeter

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Journal of Physics: Conference Series 2013年第1期444卷

作者： M L Taylor T Maeyama N Fukunishi K L Ishikawa K Fukasaku T Furuta S Takagi S Noda R Himeno S Fukuda RMIT University/School of Applied Sciences Melbourne Australia Peter MacCallum Cancer Centre/Physical Sciences Melbourne Australia RIKEN/Nishina Centre for Accelerator-Based Science Wako Japan RIKEN/Computational Science Research Program Wako Japan The University of Tokyo/Department of Nuclear Engineering and Management Graduate School of Engineering Tokyo Japan The University of Tokyo/Photon Science Centre Graduate School of Engineering Tokyo Japan Himon'ya Hospital Department of Neurosurgery Tokyo Japan RIKEN/Advanced Centre for Computing and Communication Wako Japan The University of Tokyo/Department of Mechanical Engineering Graduate School of Engineering Tokyo Japan National Institute of Radiological Sciences / Research Centre for Charged Particle Therapy Chiba Japan

The incorporation of clay nanoparticles into gel dosimeters shows promise for significant diffusion reduction – but to what extent does the presence of the nano-clay influence charged particle interactions and, in particular, what is the impact on water equivalence? In this work, we quantify the radiological characteristics of electron, proton and carbon ion interactions in the RIKEN dichromate nanoclay gel and specifically evaluate the water equivalence over a broad energy range. Results indicate that the radiological properties are sufficiently representative of tissues that this low-diffusion gel could readily be used for validation of complex dose distributions. Electron and proton ranges are within 1 % of those in water. Mean effective atomic numbers for electron interactions in the range 10 keV – 10 GeV are within 1 % of those of water which, coupled with the similar mass density, ultimately means the overall impact on dose distributions is not great. The range of C6+ ions in the nanoclay gel is closer to that of water (< 4 %) than a common polymer gel dosimeter (< 7 %), though experimentally measured R1 values indicate an over-response at low doses.

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Response of aqueous dichromate and nanoclay dichromate gel dosimeters to carbon ion irradiation

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Journal of Physics: Conference Series 2013年第1期444卷

作者： T Maeyama N Fukunishi K L Ishikawa K Fukasaku T Furuta S Takagi S Noda R Himeno S Fukuda RIKEN/Nishina Center for Accelerator-Based Science Wako Japan RIKEN/Computational Science Research Program Wako Japan The University of Tokyo/Department of Nuclear Engineering and Management Graduate School of Engineering Tokyo Japan The University of Tokyo/Photon Science Center Graduate School of Engineering Tokyo Japan Himon'ya Hospital/ Department of Neurosurgery Tokyo Japan RIKEN/Advanced Center for Computing and Communication Wako Japan The University of Tokyo/Department of Mechanical Engineering Graduate School of Engineering Tokyo Japan National Institute of Radiological Sciences/ Research Center for Charged Particle Therapy Chiba Japan

We have recently reported the significant reduction of radiation product diffusion by the incorporation of clay nanoparticles into dichromate gel (DCG) dosimeters. In this work, we investigate the influence of the nanoclay addition and gelation on the MRI R1 (1/T1) image response of the dichromate dosimeter to the therapeutic carbon ion beam (12C6+ 290 MeV/u). The MRI R1 distribution in the aqueous dichromate solution well reproduces physical dose-depth distribution with a high linear-energy-transfer (LET) efficiency. The nanoclay DCG dosimeters, on the other hand, exhibit composition-dependent LET efficiency degradation, while a sharp Bragg peak can still be detected. These results indicate that the nanocomposite gel addition may induce change in the radiation-induced reaction mechanism.

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Efactagent: Agent architecture for management, search and retrievel of e-learning artifacts

Efactagent: Agent architecture for management, search and re...

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IADIS International Conference WWW/Internet 2011, ICWI 2011

作者： Braga, Regina Campos, Fernanda Santos, Neide Souza, Ana Cláudia Knowledge Engineering Research Center Computer Science Program Federal University of Juiz de Fora Juiz De Fora - Minas Gerais Brazil Computational Sciences Program State University of Rio de Janeiro Rio De Janeiro - RJ Brazil

ISBN: (纸本)9789898533012

E-Learning activities are growing around the world, accompanied by a proliferation of data, learning objects (LO) and tools. This imposes new challenges as, for example, how to find available artifacts. This work aims to propose an architecture based on intelligent agents to search, retrieve and execute LO, generated within research projects related to educational domains. It allows the search, retrieval and use of LO, through the use of ontological annotations and using intelligent mechanisms that will act on those annotations. To reach this goal, the paper presents BROAD ontology and proposes the EFACTAgent architecture. © 2011 IADIS.

关键词： Ontology

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The ABCs of Experimental Evolution

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International Scholarly Research Notices 2013年第1期2013卷

作者： Zaid Abdo Mathew Stein Andrzej Wojtowicz Kim M. Pepin Departments of Statistics University of Idaho Moscow ID 83844 USAuidaho.edu Department of Mathematics University of Idaho Moscow ID 83844 USAuidaho.edu Program of Bioinformatics and Computational Biology (BCB) University of Idaho Moscow ID 83844 USAuidaho.edu USDA-ARS South Atlantic Area 950 College Station Road Athens GA 30605-2720 USA Department of Computer Engineering University of Idaho Moscow ID 83844 USAuidaho.edu Micron Technology Inc. Boise ID 83716 *** Department of Animal Sciences Washington State University Pullman WA 99164 USAwsu.edu Fogarty International Center National Institutes of Health 31 Center Drive MSC 2220 Bethesda MD 20892-2220 USAfic.nih.gov Department of Biology Colorado State University Campus Delivery 1878 Fort Collins CO 80523 USAcolostate.edu

Microbial evolution is complex and is influenced by many sources of variation. Experimental evolution is no exception, although it is more controlled, easily replicated, and typically devoid of interactions between species. Mathematical modeling of the evolutionary process can help in understanding the underlying mechanisms that drive outcome of such experiments. These models can be complex and parameter rich, limiting their feasibility for statistical inference. In this paper, we introduce the use of Approximate Bayesian Computation (ABC) as a tool for statistical inference in the study of experimental evolution. ABC is a fast and simple method for fitting complex models to data. We utilize this method, coupled with a mechanistic model of experimental evolution, to study the evolution process of bacteriophage ϕ X174 under benign selection pressure. Our results highlight three mutation-selection scenarios that could explain this process: high mutation/low selection pressure, low mutation/high selection pressure, and low mutation/low selection pressure, with posterior support of 19%, 9.5%, and 71.5% for each of these scenarios, respectively. Sequence data support the first candidate. Though surprising, this scenario was not improbable based on our analysis.

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Compaction and Tensile Forces Determine the Accuracy of Folding Landscape Parameters from Single Molecule Pulling Experiments

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Physical Review Letters 2011年第13期106卷 138102-138102页

作者： Greg Morrison Changbong Hyeon Michael Hinczewski D. Thirumalai School of Engineering and Applied Science Harvard University Cambridge Massachusetts 02138 USA Biophysics Program Institute For Physical Science and Technology University of Maryland College Park Maryland 20742 USA School of Computational Sciences Korea Institute for Advanced Study Seoul 130-722 Republic of Korea

We establish a framework for assessing whether the transition state location of a biopolymer, which can be inferred from single molecule pulling experiments, corresponds to the ensemble of structures that have equal probability of reaching either the folded or unfolded states (Pfold=0.5). Using results for the forced unfolding of a RNA hairpin, an exactly soluble model, and an analytic theory, we show that Pfold is solely determined by s, an experimentally measurable molecular tensegrity parameter, which is a ratio of the tensile force and a compaction force that stabilizes the folded state. Applications to folding landscapes of DNA hairpins and a leucine zipper with two barriers provide a structural interpretation of single molecule experimental data. Our theory can be used to assess whether molecular extension is a good reaction coordinate using measured free energy profiles.

关键词： Free energy

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Agile parallel bioinformatics workflow management using Pwrake

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BMC Research Notes 2011年第1期4卷 1-8页

作者： Mishima, Hiroyuki Sasaki, Kensaku Tanaka, Masahiro Tatebe, Osamu Yoshiura, Koh-Ichiro Department of Human Genetics Nagasaki University Graduate School of Biomedical Sciences Nagasaki Nagasaki 1-12-4 Sakamoto Japan Nagasaki University Global Center of Excellence Program Nagasaki Nagasaki 1-12-4 Sakamoto Japan Center for Computational Sciences University of Tsukuba Tsukuba Ibaraki 1-1-1 Tennodai Japan Core Research for Evolutional Science and Technology Japan Science and Technology Agency Kawaguchi Saitama 4-1-8 Honcho Japan Departmentent of Computer Science Graduate School of Systems and Information Engineering University of Tsukuba Tsukuba Ibaraki 1-1-1 Tennodai Japan

Background: In bioinformatics projects, scientific workflow systems are widely used to manage computational procedures. Full-featured workflow systems have been proposed to fulfil the demand for workflow management. However, such systems tend to be over-weighted for actual bioinformatics practices. We realize that quick deployment of cutting-edge software implementing advanced algorithms and data formats, and continuous adaptation to changes in computational resources and the environment are often prioritized in scientific workflow management. These features have a greater affinity with the agile software development method through iterative development phases after trial and error. Here, we show the application of a scientific workflow system Pwrake to bioinformatics workflows. Pwrake is a parallel workflow extension of Ruby's standard build tool Rake, the flexibility of which has been demonstrated in the astronomy domain. Therefore, we hypothesize that Pwrake also has advantages in actual bioinformatics workflows. Findings. We implemented the Pwrake workflows to process next generation sequencing data using the Genomic Analysis Toolkit (GATK) and Dindel. GATK and Dindel workflows are typical examples of sequential and parallel workflows, respectively. We found that in practice, actual scientific workflow development iterates over two phases, the workflow definition phase and the parameter adjustment phase. We introduced separate workflow definitions to help focus on each of the two developmental phases, as well as helper methods to simplify the descriptions. This approach increased iterative development efficiency. Moreover, we implemented combined workflows to demonstrate modularity of the GATK and Dindel workflows. Conclusions: Pwrake enables agile management of scientific workflows in the bioinformatics domain. The internal domain specific language design built on Ruby gives the flexibility of rakefiles for writing scientific workflows. Furthermore, readability

关键词： Ruby Iterative Development Agile Software Development Host Language Bioinformatics Domain

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